Статті в журналах: "Glucose irreversible loss (GIL)"

1

Barry, T. N., and T. R. Manley. "Glucose and protein metabolism during late pregnancy in triplet-bearing ewes given fresh forages ad lib." British Journal of Nutrition 54, no. 2 (September 1985): 521–33. http://dx.doi.org/10.1079/bjn19850137.

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1. Ewes of the Booroola x Romney genotype carrying triplet lambs were given fresh forages ad lib. in late pregnancy. In Expt 1, groups of three ewes were given kale (Brassica oleracea), perennial ryegrass (Loliumperenne) or perennial ryegrass (0.75)–barley (0.25). In Expt 2, groups of two or three ewes were given fresh perennial ryegrass and infused into the abomasum with iso-energetic quantities of casein and glucose in a 2 x 2 factorial arrangement. Post-lambing ewe live weights were 40–50 kg. Glucose irreversible loss (GIL) was determined from dilution of D-[U-14C]glucose.2. For ewes given kale, perennial ryegrass and perennial ryegrass—barley in Expt 1, mean metabolizable energy (ME) intakes were 0.50, 0.82 and 0.83 MJ/kg live Weight0.75 per d, GIL was 112, 142 and 157 g/d, and mean birth weight 2.22, 3.05 and 2.95 kg/lamb.3. In Expt 2, infusion of glucose, casein, and glucose+casein depressed herbage ME intake respectively by 1.6, 0.9 and 0.3 times the amount of ME infused. GIL (185–325 g/d) was increased by 800 and 350 g respectively for each kg of glucose or casein infused. Casein infusion increased calculated amino acid absorption from 0.18 to 0.36 of ME, increased wool growth and increased calculated maternal N balance. Birth weight was unaffected by nutritional treatment and averaged 3.29 kg/lamb.4. When values from both experiments were combined, birth weight was related to GIL by a hyperbolic relation, with maximum predicted birth weight being 4.1 kg/lamb. It was postulated that this value was never attained in practice, due to uterine expansion being restricted by the low maternal body size. Marked decreases in birth weight occurred when GIL decreased below 173 g/d.5. It was calculated that ewes in all treatment groups were in negative energy balance, and that glucose supplied by the kale and unsupplemented ryegrass diets were respectively below and equal to calculated conceptus uptakes of glucose necessary to maintain growth of triplet fetuses. It was further calculated that amino acid requirements of triplet-bearing ewes in late pregnancy were likely to exceed substantially net absorption from digestion of fresh forage diets, and that maternal tissues go into negative N balance to ensure fetal growth, thus explaining the lack of response to abomasal casein infusion.

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2

Barry, T. N., T. R. Manley, Carolyn Redekopp, and T. F. Allsop. "Endocrine regulation of metabolism in sheep given kale (Brassica oleracea) and ryegrass (Lolium perenne) – clover (Trifolium repens) fresh-forage diets." British Journal of Nutrition 54, no. 1 (July 1985): 165–73. http://dx.doi.org/10.1079/bjn19850102.

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1. Diets of fresh kale (Brassica oleracea) and ryegrass (Loliumperenne) – elover (Trifolium repens) herbage were fed to growing sheep in three experiments. In Expts 1 and 3 the sheep were confined indoors and fed at hourly intervals, and all were given supplementary iodine to counteract kale goitrogens. Lambs grazed the two forages for 24 weeks in Expt 2, with and without intramuscular injections of iodized oil. The kale and herbage contained respectively 11 and <0.1 g S-methyl-L-cysteine sulphoxide (SMCO)/kg dry matter (DM) and values for readily fermentable: structural carbohydrate (CHO) were 3.1 and 0.8, respectively.2. Blood samples were withdrawn from indwelling catheters (Expts 1 and 3) or venipuncture (Expt 2) and the plasma analysed for a range of hormones using radioimmunoassay procedures. Glucose irreversible loss (GIL) was measured in Expt 1 using primed continuous infusions of D-[U-14C]glucose. Samples of adipose tissue were removed from the shoulder area in Expt 3, and rates of D-[U-14C]glucose and [U-14C]acetate incoporation and oxidation were measured in vitro, together with the rate of glycerol release.3. In the presence of supplementary I2, kale feeding was associated with an elevation in plasma concentration of free thyroxine (T4) Regardless of I2 supplementation, sheep fed on kale had much higher plasma growth hormone concentrations than sheep fed on ryegrass-clover herbage, and this was accompanied by reduced plasma somatostatin concentrations.4. Plasma insulin and glucagon concentrations were similar for sheep fed on the two diets; GIL tended to be slightly but not significantly greater (9.4%) for sheep fed on kale than for those fed on ryegrass-clover herbage.5. Kale feeding was associated with increased uptakes of acetate and glucose into adipose tissue, reduced rates of oxidation of both substrates and no difference in rate of glycerol release. Each 1 nmol increase in glucose uptake was associated with 8.7 nmol acetate uptake ( P < 0.001).6. It is proposed that ruminants counteract protein inactivation, caused by production of dimethyl disulphide from SMCO in the rumen, through increasing circulating concentrations of growth hormone and T4, which then stimulate synthesis of replacement body proteins.

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3

Ford, E. J. H., and Joan Evans. "The effect of triamcinolone on glucose metabolism in ketotic sheep." Journal of Agricultural Science 106, no. 2 (April 1986): 337–40. http://dx.doi.org/10.1017/s0021859600063930.

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SUMMARYThe withdrawal of food from Clun Forest ewes pregnant with twins produced signs of pregnancy toxaemia accompanied by a significant decrease in the concentration of glucose, a significant increase in the concentration of ketones, non-esterified fatty acids (NEFA) and 3-hydroxybutyrate in plasma and a significant decrease in total entry rate and irreversible loss of glucose. A single intramuscular injection of 0·05 or 0·2 mg/kg of triamcinolone acetonide had no significant effect on the concentration of glucose, ketones or 3-hydroxybutyrate in plasma or on the total entry, irreversible loss or recycling of glucose in ketotic or in normal pregnant sheep. The low dose had a significant effect on the concentration of NEFA in plasma. Recovery from the clinical signs was slow after either dose of steroid but appeared to be hastened by the onset of parturition which was more rapid after the higher dose.

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4

Eizirik, D. L., V. Grill, K. Inoue, and M. Cetkovic-Cvrlje. "Irreversible loss of normal beta-cell regulation by glucose in neonatally streptozotocin diabetic rats." Diabetologia 37, no. 4 (April 1, 1994): 351–57. http://dx.doi.org/10.1007/s001250050116.

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5

Inoue, K., M. Cetkovic-Cvrlje, D. L. Eizirik, and V. Grill. "Irreversible loss of normal beta-cell regulation by glucose in neonatally streptozotocin diabetic rats." Diabetologia 37, no. 4 (April 1994): 351–57. http://dx.doi.org/10.1007/bf00408470.

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6

Garegrat, Reema, Suprabha Patnaik, Pradeep Suryawanshi, and Chaitanya Datar. "Focal congenital hyperinsulinism resulting from biallelic loss of function of KCNJ11 gene." BMJ Case Reports 14, no. 3 (March 2021): e240218. http://dx.doi.org/10.1136/bcr-2020-240218.

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Congenital hyperinsulinism (CHI) characterised by inappropriate secretion of insulin despite low blood glucose can result in irreversible brain damage if not promptly treated. The most common genetic cause of hyperinsulinism is the pathogenic variants in ABCC8 and KCNJ11, causing dysregulated insulin secretion. Rapid testing is crucial for all patients because finding a mutation significantly impacts this condition’s clinical management. We report a rare case of focal CHI after a homozygous KCNJ11 mutation who underwent a selective lesionectomy and required octreotide for euglycaemia.

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7

Meier, S., P. J. S. Gore, C. M. E. Barnett, R. T. Cursons, D. E. Phipps, K. A. Watkins, and G. A. Verkerk. "Metabolic adaptations associated with irreversible glucose loss are different to those observed during under-nutrition." Domestic Animal Endocrinology 34, no. 3 (April 2008): 269–77. http://dx.doi.org/10.1016/j.domaniend.2007.08.002.

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8

H Oddy, V., JM Gooden, GM Hough, BE Teleni, and EF Annison. "Partitioning of Nutrients in Merino Ewes. 11 Glucose Utilization by Skeletal Muscle, the Pregnant Uterus and the Lactating Mammary Gland in Relation to Whole Body Glucose Utilization." Australian Journal of Biological Sciences 38, no. 1 (1985): 95. http://dx.doi.org/10.1071/bi9850095.

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The net uptake and oxidation of glucose by leg muscle, pregnant uterus, and lactating mammary gland, together with the rate of irreversible loss and oxidation of glucose in the whole body of Merino ewes are reported. The ewes were fed on either chaffed oaten hay (OR), chaffed lucerne hay (L), or a mixture of chaffed oaten and lucerne hays (OHL). Measurements were made during five different physiological states: dry (nonpregnant), at 94 and 125 days of pregnancy, and at 20 and 50 days after lambing.

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9

Obara, Y., and D. W. Dellow. "Effects of intraruminal infusions of urea, sucrose or urea plus sucrose on plasma urea and glucose kinetics in sheep fed chopped lucerne hay." Journal of Agricultural Science 121, no. 1 (August 1993): 125–30. http://dx.doi.org/10.1017/s0021859600076875.

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SUMMARYThe effect of rumen fermentation on the relationship between urea and glucose kinetics was examined in sheep fed chopped lucerne hay with intraruminal infusions of water, urea, sucrose, or urea plus sucrose at Palmerston North, New Zealand in 1986. Sheep were fed hourly and infused intraruminally with water (1200 m1/day), or a similar volume containing either urea alone (13·7g/day), sucrose alone (178·2 g/day) or urea (14·6 g/day) plus sucrose (175·0 g/day). The added sucrose resulted in a lower rumen ammonia concentration (P< 0·05), lower plasma urea concentration (P< 0·05) and reduced urinary urea excretion (P< 0·05). Urea recycled to the gut tended to increase with the sucrose, urea or sucrose plus urea treatments compared with the water treatment. The fermentation of sucrose in the rumen resulted in decreases in ruminal pH (P< 0·05) and in the ratio of acetate to propionate (A:P) (P< 0·05). The infusion of sucrose also increased the concentration of propionate in rumen fluid (P< 0·05), tended to increase the plasma glucose level and increased plasma glucose irreversible loss (P< 0·05). The infusion of urea resulted in an increase in the plasma urea level (P< 0·05), urea pool size (P< 0·05) and urea irreversible loss (P< 0·01). However, urea infusion did not affect glucose metabolism or volatile fatty acid (VFA) fermentation. The effects of sucrose infusion on glucose and urea kinetics were broadly similar when given alone or with urea, apart from changes in the urea degradation rate. It was concluded that the additional fermentative activity resulting from sucrose increased propionate production which, in turn, was available for glucose production, thus ‘sparing’ amino acids for tissue protein utilization and reducing urea excretion.

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10

Sutoh, M., Y. Obara, and S. Miyamoto. "The effect of sucrose supplementation on kinetics of nitrogen, ruminal propionate and plasma glucose in sheep." Journal of Agricultural Science 126, no. 1 (February 1996): 99–105. http://dx.doi.org/10.1017/s0021859600088845.

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SUMMARYThe effects of dietary sucrose on the metabolic rate of plasma glucose and ruminal propionate as well as the change in nitrogen kinetics were examined in four mature wethers fitted with rumen fistulas in Tsukuba, Japan in 1990. Wethers were fed at 12 equal intervals daily on crushed lucerne hay cubes (1233 g DM/day), with or without 204 g/day of sucrose. Plasma urea and glucose kinetics were determined following a single intravenous injection of [I5N]urea and [U-13C]glucose respectively; and the kinetics of ruminal ammonia and propionate were determined following a single intraruminal injection of [15N]ammonium chloride and [2–13c]sodium propionate respectively. Following supplementation of sucrose to the diet, nitrogen retention was increased (P< 0·05) with a decrease in plasma urea concentration (P< 0·05) and urinary urea excretion (P< 0·05). Sucrose supplementation decreased (P< 005) the concentration and irreversible loss rate of ruminal ammonia. Urinary allantoin excretion did not change with sucrose treatment, but the flow rate of non-ammonia-nitrogen from the rumen was increasedP< 0·05). The transfer rate of ruminal ammonia to plasma urea was also decreased (P< 0·01), whilst the transfer rate of plasma urea to ruminal ammonia was increased (P< 0·05) by dietary sucrose. Sucrose supplementation resulted in a higher concentration of propionate and butyrate (P< 0·05) in the rumen with no significant change in acetate or pH. The concentration of plasma glucose did not change with sucrose treatment, but the concentration of insulin, pool size (P< 0·05) and the irreversible loss rate of glucose (P< 0·01) were increased, reflecting the increase in the production rate of ruminal propionate (P< 0·05). It was concluded that the supplementation of sucrose affected the metabolism of urea and glucose in plasma via a change in ruminal production rate of ammonia and propionate, respectively.

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11

Thordarson, G., G. H. McDowell, S. V. Smith, S. Iley, and I. A. Forsyth. "Effects of continuous intravenous infusion of an ovine placental extract enriched in placental lactogen on plasma hormones, metabolites and metabolite biokinetics in non-pregnant sheep." Journal of Endocrinology 113, no. 2 (May 1987): 277–83. http://dx.doi.org/10.1677/joe.0.1130277.

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ABSTRACT Continuous intravenous infusions of saline or of a placental extract containing ovine placental lactogen were given to three non-pregnant, non-lactating ewes over periods of 36 h, 1 week apart. During saline infusion no placental lactogen was detected in jugular vein plasma, but infusion of the placental extract raised the placental lactogen concentration from undetectable to 40-50 μg/l, similar to concentrations in ewes with one fetus on day 90 of pregnancy. By comparison with the saline control period, infusion of the placental extract consistently increased both plasma concentrations and irreversible loss of non-esterified fatty acids. Plasma concentrations of glucose and urea, but not irreversible loss of these metabolites, were consistently increased. Although the placental extract was not subjected to extensive purification, it was enriched in placental lactogen and contained no detectable contamination with insulin, prolactin or growth hormone. The results are suggestive of a role for placental lactogen in modifying metabolism and acting during pregnancy to provide nutrients for fetal metabolism. J. Endocr. (1987) 113, 277–283

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12

Caumo, A., and C. Cobelli. "Hepatic glucose production during the labeled IVGTT: estimation by deconvolution with a new minimal model." American Journal of Physiology-Endocrinology and Metabolism 264, no. 5 (May 1, 1993): E829—E841. http://dx.doi.org/10.1152/ajpendo.1993.264.5.e829.

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A method for the estimation of hepatic glucose production during a labeled intravenous glucose tolerance test (IVGTT) is proposed. Stable-label IVGTT data in normal subjects have been considered. The method is based on deconvolution and uses a new two-compartment minimal model of glucose kinetics to describe the time-varying impulse response of the glucose system. A new model of glucose kinetics was needed because the available single-compartment minimal model, specifically developed to interpret labeled IVGTT data, provided a nonphysiological pattern of hepatic glucose production. The new minimal model has two novel features: glucose kinetics are described by a two-compartment structure, and insulin exerts its action on the irreversible loss of the slowly exchanging glucose pool. The deconvolution scheme used to reconstruct hepatic glucose production is described in detail both in terms of computational aspects and reliability. Confidence limits of the reconstructed hepatic glucose production in each individual are derived by taking into account both the measurement error of the data and the uncertainty associated with the description of the impulse response. Physiological plausibility of the time course of hepatic glucose production provided by this new method is discussed. The ability of the new model to reconstruct hepatic glucose production considerably enriches the kinetic portrait of glucose metabolism that can be obtained from the minimal-model analysis of labeled IVGTT data.

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13

Crooks, Daniel R., Nunziata Maio, Martin Lang, Christopher J. Ricketts, Cathy D. Vocke, Sandeep Gurram, Sevilay Turan, et al. "Mitochondrial DNA alterations underlie an irreversible shift to aerobic glycolysis in fumarate hydratase–deficient renal cancer." Science Signaling 14, no. 664 (January 5, 2021): eabc4436. http://dx.doi.org/10.1126/scisignal.abc4436.

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Understanding the mechanisms of the Warburg shift to aerobic glycolysis is critical to defining the metabolic basis of cancer. Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is an aggressive cancer characterized by biallelic inactivation of the gene encoding the Krebs cycle enzyme fumarate hydratase, an early shift to aerobic glycolysis, and rapid metastasis. We observed impairment of the mitochondrial respiratory chain in tumors from patients with HLRCC. Biochemical and transcriptomic analyses revealed that respiratory chain dysfunction in the tumors was due to loss of expression of mitochondrial DNA (mtDNA)–encoded subunits of respiratory chain complexes, caused by a marked decrease in mtDNA content and increased mtDNA mutations. We demonstrated that accumulation of fumarate in HLRCC tumors inactivated the core factors responsible for replication and proofreading of mtDNA, leading to loss of respiratory chain components, thereby promoting the shift to aerobic glycolysis and disease progression in this prototypic model of glucose-dependent human cancer.

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14

Fern, Robert, Peter Davis, Stephen G. Waxman, and Bruce R. Ransom. "Axon Conduction and Survival in CNS White Matter During Energy Deprivation: A Developmental Study." Journal of Neurophysiology 79, no. 1 (January 1, 1998): 95–105. http://dx.doi.org/10.1152/jn.1998.79.1.95.

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Fern, Robert, Peter Davis, Stephen G. Waxman, and Bruce R. Ransom. Axon conduction and survival in CNS white matter during energy deprivation: a developmental study. J. Neurophysiol. 79: 95–105, 1998. We investigated the postnatal development of axon sensitivity to the withdrawal of oxygen, glucose, or the combined withdrawal of oxygen + glucose in the isolated rat optic nerve (a CNS white matter tract). Removal of either oxygen or glucose for 60 min resulted in irreversible injury in optic nerves from adult rats, assessed by loss of the evoked compound action potential (CAP). Optic nerves at ages <P10 showed no permanent loss of function. CAP sensitivity to the withdrawal of oxygen or glucose emerged during a critical period in development between postnatal days 10–20 (P10–P20). The CAP was unchanged in adult optic nerve for 45 min after the withdrawal of glucose, demonstrating the presence of a significant energy reserve. Periods of glucose withdrawal >45 min caused the selective loss of late CAP components; this was not seen with oxygen deprivation. The amplitude of the early component recovered to 94.8% of control after 60 min of glucose withdrawal, although total CAP area recovered to only 42.3%. Combined oxygen + glucose withdrawal for 60 min produced a greater degree of permanent CAP loss than 60 min of glucose or oxygen withdrawal individually in optic nerves from rats older than P4. Younger than P4 optic nerves showed no permanent loss of function from 60 min of combined oxygen + glucose withdrawal. Unexpectedly, optic nerves from P21–P49 rats recovered significantly less after all three conditions than adult opticnerves (>P50). It is probable that this period of final myelination corresponds to a time of heightened metabolic activity in white matter. The tolerance of CNS white matter to energy deprivation can be categorized into four stages that are correlated with specific developmental features: premyelination (P0–P4), highly tolerant to anoxia, aglycemia and combined anoxia/aglycemia; early myelination (P5–P20), partially tolerant of anoxia and aglycemia but not to combined anoxia/aglycemia; late myelination (P21–P49), very low tolerance of anoxia, aglycemia and combined anoxia/aglycemia; and mature (>P50), low tolerance of anoxia, aglycemia and combined anoxia/aglycemia. The relative resistance of optic nerve function to glucose withdrawal in the presence of oxygen, compared with glucose withdrawal in the absence of oxygen, is presumably due to the presence of oxygen-dependent energy reserves such as astrocytic glycogen, amino acids. and phospholipids.

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15

Cappelli, F. Piccioli, C. J. Seal, and D. S. Parker. "Glucose and ]13C[leucine metabolism by the portal-drained viscera of sheep fed on dried grass with acute intravenous and intraduodenal infusions of glucose." British Journal of Nutrition 78, no. 6 (December 1997): 931–46. http://dx.doi.org/10.1079/bjn19970210.

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The effect of exogenous glucose supply by either intrajugular (IJG) or intraduodenal (IDG) infusion at 2.0 mg glucose/kg body weight per min was investigated in four wether sheep (average weight 44 (sd 4) kg) chronically catheterized in the carotid artery and portal veins. Sheep were fed on a dried grass pellet diet hourly using continuous belt feeders. Whole-body glucose irreversible loss (IL) rate, measured with [6-3H[glucose, was increased by 0.5 and 0.8 of exogenous supply for IJG and IDG infusions respectively. Portal glucose utilization, measured by isotope dilution across the portal-drained viscera, was unaffected by additional glucose regardless of the route of glucose supply (P = 0.76 for control ν. glucose infusions) and was a constant proportion of glucose IL (0.28) for all treatments. Portal plasma flow was higher during IDG infusions compared with IJG infusions (1.65 ν. 1.44 litres/min, P=0.055). Circulating total free amino acid concentrations fell during glucose infusions (2146, 1808 and 1683 μmol/l for control, IJG and IDG treatments respectively, P=0.067 for treatment effect) but net portal absorption was not affected by increased glucose supply. Recovery in the portal vein of [1-13C[leucine infused into the duodenum averaged 0.65 and was not affected by increasing glucose supply to the gut tissues. The results show that glucose utilization by gut tissues is responsive to changes in both vascular and luminal glucose supply. The effects of changing gut tissue use of glucose and increased whole body glucose IL on metabolism of nutrients is discussed.

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16

Zhang, Wenzhuo, Jason Widjaja, Libin Yao, Yong Shao, Xiaocheng Zhu, and Chao Li. "Short-Term Results Suggest That Sleeved Stomach without Resection Is as Effective as Sleeve Gastrectomy in Improving Glucose Control in Type 2 Diabetes Mellitus Sprague-Dawley Rat Model." BioMed Research International 2020 (May 2, 2020): 1–6. http://dx.doi.org/10.1155/2020/9024923.

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Background. Although sleeve gastrectomy results in good weight loss and metabolic improvements, it is an irreversible procedure. Therefore, we attempted to assess the possibility of creating a sleeved stomach without resection. Material and Methods. A total of 22 male Sprague-Dawley rats with type 2 diabetes were randomly assigned into 3 different groups: (1) sleeve gastroplasty with gastric remnant-jejunal anastomosis (SGP, n=8); (2) sleeve gastrectomy (SG, n=8); and (3) SHAM (n=6). Body weight, food intake, fasting blood glucose (FBG), hormonal analysis, and oral glucose tolerance test (OGTT) were performed and measured preoperatively and postoperatively. Results. During the postoperative period, SGP and SG showed significantly lower food intake and body weight when compared with the preoperative levels, respectively (p value < 0.05). Postoperatively, SGP and SG showed improvements in FBG and glucose tolerance levels compared to their respective preoperative levels (p<0.05). FBG and glucose tolerance levels did not differ between SGP and SG postoperatively. SG resulted in a reduction in fasting ghrelin levels when compared with the preoperative level (p<0.05). Fasting insulin levels did not differ preoperatively and postoperatively among all groups. Postoperatively, fasting GLP-1 levels were higher in SGP and SG when compared with the preoperative levels, but no statistical significance was observed. Compared preoperatively, the SGP and SG procedures resulted in a decline in HOMA-IR at postoperative 6th week (p<0.05). Conclusion. Our animal experiment suggested that at least in the short term, sleeved stomach without resection resulted in similar weight loss and improved glucose control effects compared to sleeve gastrectomy.

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17

Yi, Junyeong, Tae Su Kim, Jhang Ho Pak, and Jong Woo Chung. "Protective Effects of Glucose-Related Protein 78 and 94 on Cisplatin-Mediated Ototoxicity." Antioxidants 9, no. 8 (August 2, 2020): 686. http://dx.doi.org/10.3390/antiox9080686.

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Cisplatin is a widely used chemotherapeutic drug for treating various solid tumors. Ototoxicity is a major dose-limiting side effect of cisplatin, which causes progressive and irreversible sensorineural hearing loss. Here, we examined the protective effects of glucose-related protein (GRP) 78 and 94, also identified as endoplasmic reticulum (ER) chaperone proteins, on cisplatin-induced ototoxicity. Treating murine auditory cells (HEI-OC1) with 25 μM cisplatin for 24 h increased cell death resulting from excessive intracellular reactive oxygen species (ROS) accumulation and caspase-involved apoptotic signaling pathway activation with subsequent DNA fragmentation. GRP78 and GRP94 expression was increased in cells treated with 3 nM thapsigargin or 0.1 μg/mL tunicamycin for 24 h, referred to as mild ER stress condition. This condition, prior to cisplatin exposure, attenuated cisplatin-induced ototoxicity. The involvement of GRP78 and GRP94 induction was demonstrated by the knockdown of GRP78 or GRP94 expression using small interfering RNAs, which abolished the protective effect of mild ER stress condition on cisplatin-induced cytotoxicity. These results indicated that GRP78 and GRP94 induction plays a protective role in remediating cisplatin-ototoxicity.

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18

Cronjé, P. B., J. V. Nolan, and R. A. Leng. "Acetate clearance rate as a potential index of the availability of glucogenic precursors in ruminants fed on roughage-based diets." British Journal of Nutrition 66, no. 2 (September 1991): 301–12. http://dx.doi.org/10.1079/bjn19910033.

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Three experiments were conducted to investigate interactions between acetate and glucose metabolism in sheep fed on roughage-based diets, and to establish whether the clearance rate of an intravenous acetate load would provide a valid index of the dietary acetate:glucogenic precursors ratio. In Expt 1 lambs were fed on a basal diet of wheat straw and supplemented with propionate and protein. Both supplements increased glucose irreversible loss rate (ILR) although not to the same degree. Acetate clearance rates were increased by protein and propionate supplementation and were positively related to glucose ILR irrespective of precursor. In Expt 2 the effects of an increased dietary load of acetate given with or without propionate were investigated. Glucose ILR did not respond to acetate supplementation, but was increased when propionate was fed in addition to acetate. This was reflected in an unchanged ability to clear an intravenous acetate load from the blood when acetate alone was added, but an increased acetate clearance rate when propionate was fed in addition to acetate. In Expt 3 the effects of supplementation with various propionate: acetate ratios were investigated. Acetate clearance was consistently increased by an increased propionate: acetate ratio. These results show that the metabolism of excess acetate is responsive to the dietary supply of glucose precursors, and provide support for the concept that additional glucose precursors are necessary for the efficient utilization of acetate when roughage diets low in protein are fed

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19

Zivkovic, Marijana, Vanja Misic, Mirjana Lausevic, Miodrag Milenovic, and Branislava Stefanovic. "Anaesthetic management of ASA 6 patients." Acta chirurgica Iugoslavica 63, no. 2 (2016): 75–77. http://dx.doi.org/10.2298/aci1602075z.

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The criteria to determine brain death include circulatory-respiratory criteria-loss of circulation and respiration and neurological criteria - irreversible cessation of all brain functions. After brain death is proven, intensive care is directed from nonspecific neuroprotection to somatic organs protection. Access to the maintenance of the potential organ donor began achieving rapid hemodynamic stability with the monitoring and correction of serum levels of electrolytes, glucose and lactate, acid-base status, determining and maintaining body temperature-deceased patients with a beating heart are poikilothermic and their temperature depends of the surrounding temperature and analysis accompanying comorbidity and its possible impact, especially on the stability of the cardiovascular system. The result of intensive care and good maintenance of these patients are good quality organs for transplant.

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20

Qader, Saleem S., Javier Jimenez-Feltström, Mats Ekelund, Ingmar Lundquist, and Albert Salehi. "Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27." American Journal of Physiology-Endocrinology and Metabolism 292, no. 5 (May 2007): E1447—E1455. http://dx.doi.org/10.1152/ajpendo.00172.2006.

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Chronic exposure of pancreatic islets to elevated plasma lipids (lipotoxicity) can lead to β-cell dysfunction, with overtime becoming irreversible. We examined, by confocal microscopy and biochemistry, whether the expression of islet inducible nitric oxide synthase (iNOS) and the concomitant inhibition of glucose-stimulated insulin release seen after lipid infusion in rats was modulated by the islet neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP)27. Lipid infusion for 8 days induced a strong expression of islet iNOS, which was mainly confined to β-cells and was still evident after incubating islets at 8.3 mmol/l glucose. This was accompanied by a high iNOS-derived NO generation, a decreased insulin release, and increased cyclic GMP accumulation. No iNOS expression was found in control islets. Addition of PACAP27 to incubated islets from lipid-infused rats resulted in loss of iNOS protein expression, increased cyclic AMP, decreased cyclic GMP, and suppression of the activities of neuronal constitutive (nc)NOS and iNOS and increased glucose-stimulated insulin response. These effects were reversed by the PKA inhibitor H-89. The suppression of islet iNOS expression induced by PACAP27 was not affected by the proteasome inhibitor MG-132, which by itself induced the loss of iNOS protein, making a direct proteasomal involvement less likely. Our results suggest that PACAP27 through its cyclic AMP- and PKA-stimulating capacity strongly suppresses not only ncNOS but, importantly, also the lipid-induced stimulation of iNOS expression, possibly by a nonproteasomal mechanism. Thus PACAP27 restores the impairment of glucose-stimulated insulin release and additionally might induce cytoprotection against deleterious actions of iNOS-derived NO in β-cells.

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21

Tasnim, Saria, Dhara Dave, Yousuf Tawfeeq, Tarek Naguib, and Waqas Rasheed. "A case of ocular neurosyphilis in a patient with HIV." Southwest Respiratory and Critical Care Chronicles 9, no. 41 (October 22, 2021): 44–46. http://dx.doi.org/10.12746/swrccc.v9i41.931.

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In the modern era, neurosyphilis in immunocompetent individuals is very rare compared to pre-antibiotic era. However, the incidence is still a few folds higher in immunodeficient individuals, especially in patients with human immunodeficiency virus (HIV) infection. The cases we found, involved mostly the brain with eye involvement was found in only five other instances. Ocular syphilis is a type of neurosyphilis that can threaten vision leading to blindness if not treated promptly. Its diagnosis can be challenging but it should be considered if the neuro-ophthalmological findings cannot be explained by any other commonly encountered disease and diagnosis by serology should be considered as it is a potentially treatable condition (1). We present a 27 years old male with HIV, not on any therapy who came to the hospital with complete loss of vision in the right eye for 4 months and partial loss of vision in the left eye for 5 weeks. He also had 6-month history of maculopapular rash over his trunk that extended to involve the entire body including the palms prior to presentation. He denied any redness, watering, or itchiness of the eyes, or focal neurological deficits. He also denied a history of diabetes, sexually transmitted infections (STIs), or recent trauma to the eyes. On physical exam, he was cachectic. His visual acuity was less than 20/200 in right eye and 20/100 in left eye. There was desquamative rash in his palms, but not in the trunk or genitals, and had no lymphadenopathy. Figure 1: Desquamative rash on the palms Normal lab included complete blood count, hepatic, renal, thyroid function tests, fasting blood glucose, electrolytes, erythrocyte sedimentation rate, C-reactive protein. Cerebrospinal fluid analysis showed lymphocytic pleocytosis, low glucose and high protein level. A diagnosis of neurosyphilis was confirmed with reactive serum rapid plasma Reagin (RPR) test and positive CSF venereal disease research laboratory (VDRL) test. His CD4 count was 418/mcL and viral load was 289,000/mcL. He tested negative for other STIs including genital herpes, Tuberculosis (TB), Hepatitis and gonorrhea. Intravenous penicillin G was administered for 10 days. HIV treatment was held to avoid immune reconstitution inflammatory syndrome (IRIS). He was discharged with better vision to follow-up with ophthalmology and primary care in order to initiate anti-retroviral therapy. He was advised to observe safe sex practices. Outpatient ophthalmology workup with B-scan, fundoscopy, and optical coherence tomography (OCT) of the macula showed panuveitis, vitritis and disc hyperemia without signs of raised intraocular pressure. In 3 months, he completely regained vision in his left eye and had partial recovery of vision in the right eye. Discussion: Painless vision loss without accompanying symptoms or trauma in a young individual without any obvious cause like diabetes presents a wide differential diagnosis that can be categorized into compressive, mitochondrial, vascular, infectious versus noninfectious optic neuritis, and infiltrative etiologies. Accordingly pituitary lesions, meningioma, slowly-growing aneurysm, leukemia, and lymphoma were considered but were less likely due to absence of raised intraocular pressure. Noninfectious causes including sarcoidosis and infectious causes like TB were considered, but were not likely given absence of constitutional symptoms. Bilateral anterior ischemic optic neuropathy was also considered, but our patient lacked the typical acute onset of vision loss commonly consistent with this disease. Our patients’ HIV history pointed towards an infectious etiology. A reactive serum RPR and CSF VDRL confirmed neurosyphilis while disc hyperemia on ophthalmoscopy and the positive response to IV antibiotic eventually validated the diagnosis. Ocular syphilis commonly causes posterior uveitis and panuveitis though may occasionally cause anterior uveitis, optic neuropathy, retinal vasculitis and interstitial keratitis. It may lead to decreased visual acuity and could eventually cause permanent blindness. It can occur at any stage of syphilis, including primary and secondary syphilis (2). Diagnosis requires a high suspicion as a negative CSF VDRL does not rule out neurosyphilis and only 35% cases of ocular syphilis have neurosyphilis. The recommended adult regimen is IV aqueous crystalline penicillin G 18-24 million units per day (either as continuous infusion or 3-4 million units every 4 hours) for 10-14 days. Alternative regimen for adults is procaine penicillin 2.4 million units IM per day and oral probenecid 500mg four times per day, also for 10-14 days (3). Co-administration of corticosteroids or immunosuppressants along with antibiotics is controversial. Oral steroids, along with supplements, are often required to control ocular inflammation. The use of intravitreal dexamethasone implant for refractory macular edema in syphilitic uveitis has also been reported (4). However, steroids should not be started before starting antibiotics as it could worsen disease to a life and/or sight-threatening degree (5). Patients treated for syphilis should have the VDRL test repeated every three months for a period of 1-year post-treatment as titers should become nonreactive within a year after therapy. Patients should be retreated, if an initially high-titer VDRL test does not decrease fourfold within a year, or if a previously non-reactive VDRL test becomes reactive again (6). Factors associated with poor visual prognosis include the time between onset of uveitis and treatment (>12 weeks), longer duration of ocular symptoms (>28 days) as seen with our patient, presence of macular edema or long-standing optic neuropathy, coinfection with HIV, and poor initial visual acuity. Factors associated with higher success rates included the presence of vasculitis (as detected by fundus fluorescence angiography), anterior uveitis, or neurosyphilis. Common long-term complications of syphilitic uveitis include glaucoma, cataract, epiretinal membrane and macular edema. Choroidal neovascularization and widespread chorioretinal scarring can occur in some patients. The Jarisch-Herxheimer reaction following initiation of antibiotic therapy, may result in fever, malaise and headache, as well as a worsening of ocular manifestations and may be prevented by administration of systemic corticosteroids concurrent with antibiotic treatment (7). Conclusion: Ocular syphilis, although a rare entity, if overlooked in the early stages, can lead to irreversible damage to eyes. Early diagnosis and treatment can prevent permanent blindness. References: 1. Taylor MM, Aynalem G, Olea LM, He P, Smith LV, Kerndt PR. A consequence of the syphilis epidemic among men who have sex with men (MSM): neurosyphilis in Los Angeles, 2001-2004. Sex Transm Dis. 2008;35(5):430. 2. Jon D. W., Dean E., J. Michael J., Emmett T. C. How to Recognize Ocular Syphilis. Review of Ophthalmology. November 2008. 3. Zachary W., Shruthi H.B., Andrew G.L., Nagham A.Z., Nita B. Ophthalmologic Manifestations of Syphilis. American academy of ophthalmology. September 21, 2019 4. Dutta Majumder P, Mayilvakanam L, Palker AH, Sridharan S, Biswas J. Intravitreal sustained-release dexamethasone implant for the treatment of persistent cystoid macular edema in ocular syphilis. Indian J Ophthalmol. 2019 Sep;67(9):1487-1490. 5. Agarwal M, Ranjan R, Paul L, Sharma D. Syphilitic uveitis misdiagnosed as viral retinitis-a misleading history. J Ophthalmic Inflamm Infect. 2018 Dec 04;8(1):22. 6. Jordana G.F., Musa A. Recognizing Ocular Syphilis. Medical Retina, May/June 2018. 7. Vikram V. K., Koushik T. Syphilis Ocular Manifestations. StatPearls; 2021 Jan.

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Chopabayeva, Nazira N. "Application of Lignin Sorbents for Correction of Carbohydrate-Lipid Profile of Diabetic Patient's Blood Serum." Journal of Composites and Biodegradable Polymers 5, no. 1 (February 27, 2017): 1–9. http://dx.doi.org/10.12974/2311-8717.2017.05.01.1.

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Novel cost-effective sorbents based on hydrolytic lignin of cotton husk have been synthesized by two-step process including condensation of lignin with epichlorhydrin oligomer and subsequent amination of formed chloroderivative with polyamines. The results show the efficiency of lignin sorbents for the removal of water and lipid soluble toxic metabolites from blood serum of diabetic retinopathy patients. Due to high sorption activity of synthesized sorbents in relation to glucose and lipids, including triglycerides, cholesterol and its most atherogenic fractions (LDL-C, VLDL-C) their concentration reduced from pathological levels to physiological norm or the levels of optimum compensated diabetes. Considerable hypolipidemic and hypoglycemic effects of synthesized sorbents in comparison with enterosorbent Polyphepan have potential for prevention and treatment of diabetes. Sorption correction of pathological process decrease risk of diabetic retinopathy progression and can delay irreversible vision loss among working-age adults.

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23

Godfraind, Jean-Marie, Selva Baltan Tekkök, and Krešimir Krnjević. "Hypoxia on Hippocampal Slices from Mice Deficient in Dystrophin (mdx) and Isoforms (mdx3cv)." Journal of Cerebral Blood Flow & Metabolism 20, no. 1 (January 2000): 145–52. http://dx.doi.org/10.1097/00004647-200001000-00019.

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Slices from control C57, mdx, and mdx3cv mice were made hypoxic until both field excitatory postsynaptic potential (fEPSP) and presynaptic afferent volley (AV) disappeared (H1). After reoxygenation and recovery of fEPSP, a second and longer hypoxic test (H2) lasted 3 minutes beyond the time required to block AV. When slices were kept in 10 mmol/L glucose, H1 abolished AV 37 and 19% earlier in slices from mdx and mdx3cv mutants than in control slices (where H1 = 12 ± 4.6 minutes, mean ± SD). During H2 or when slices were kept in 4 mmol/L glucose, AV vanished even more quickly, but the times to block did not differ significantly between slices from controls and mutants. After reoxygenation, AV fully recovered in most slices. Rates of blockade of fEPSPs were comparable in all slices, and most fEPSPs recovered fully after H1. But even in the presence of 10 mmol/L glucose, the second hypoxia suppressed fEPSPs irreversibly in some slices: 2 of 10 from control, 3 of 7 from mdx, and 1 of 6 from mdx3cv mice. Most slices in 4 mmol/L glucose showed no recovery at all: six of seven from control, three of five from mdx, and four of five from mdx3cv mice. Thus, slices from mdx mice were more susceptible than other slices to irreversible hypoxic failure when slices were kept in 10 mmol/L glucose, but they were less susceptible than other slices when kept in 4 mmol/L glucose. In conclusion, the lack of full-length dystrophin (427 kDa) predisposes to quicker loss of nerve conduction in slices from mdx and mdx3cv mutants and improved posthypoxic recovery of fEPSPs in 4 mmol/L glucose in slices from mdx but not mdx3cv mutants, perhaps because the 70-kDa and other C-terminal isoforms are still present in mdx mice.

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Parish, Stanley T., Stanley R. Fauce, and Rita B. Effros. "Manipulaion of TNFalpha delays loss of CD28 expression in human CD8 T cells (96.19)." Journal of Immunology 178, no. 1_Supplement (April 1, 2007): S186. http://dx.doi.org/10.4049/jimmunol.178.supp.96.19.

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Abstract The CD28 costimulatory receptor is essential for T cell activation, glucose metabolism, and optimal telomerase activity. Increased proportions of CD8+CD28 T cells, seen in HIV infection and aging, correlate with decreased vaccine responsiveness and early mortality. CD28 expression is also lost in chronically stimulated cultures of CD8 T cells as they approach replicative senescence, a state of irreversible cell cycle arrest, associated with shortened telomeres and increased levels of TNFα. Based on the link between TNFα and the CD28 gene promoter, we sought to investigate the effects of manipulating TNFα on replicative senescence. Human T cells were repeatedly stimulated with an allogeneic cell line in the presence of either a neutralizing antibody (anti-TNFα) or a TNFα receptor 1 inhibitor (rhuTNFR:Fc). CD28 expression and gene transcription were monitored by flow cytometry and RT-PCR, respectively. Chronic exposure of antigen-stimulated CD8 T cells to rhuTNFR:Fc or anti-TNFα delayed the loss of CD28 expression. Even after completing 17 population doublings, the treated cultures contained >20% more CD28+ cells; CD28 gene transcription was similarly elevated. Finally, telomerase activity was increased by as much as 6-fold in the treated cultures. Manipulation of TNFα, therefore, may be a useful clinical approach to delay accumulation of senescent CD8 T cell in vivo. Supported by NIH AI060362 and AG023720

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Bauman, Dale E., Colin J. Peel, Wayne D. Steinhour, Paul J. Reynolds, Henry F. Tyrrell, A. C. G. Brown, and Gordon L. Haaland. "Effect of Bovine Somatotropin on Metabolism of Lactating Dairy Cows: Influence on Rates of Irreversible Loss and Oxidation of Glucose and Nonesterified Fatty Acids." Journal of Nutrition 118, no. 8 (August 1, 1988): 1031–40. http://dx.doi.org/10.1093/jn/118.8.1031.

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26

Asad, Z., A. Chaudhary, and A. Awab. "ID: 64: REVERSIBLE BLINDNESS ASSOCIATED WITH DIABETIC KETOACIDOSIS: A RARE COMBINATION." Journal of Investigative Medicine 64, no. 4 (March 22, 2016): 975.2–976. http://dx.doi.org/10.1136/jim-2016-000120.134.

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IntroductionA wide spectrum of ocular diseases is associated with diabetes mellitus (DM) and most of them lead to gradual loss of vision that is almost always irreversible. Sudden vision loss in severe diabetic ketoacidosis (DKA) that is reversible with treatment of the metabolic abnormality is a very rare complication that has been reported three times previously.Case PresentationA 59 year-old male with Type 1 DM presented with altered consciousness, epigastric pain, hypothermia and sudden complete bilateral vision loss for three days. He was not complaint with insulin. There was no history or laboratory evidence of ethanol, methanol, ethylene glycol ingestion, head trauma, baseline vision problem, cold or intense bright light exposure.Physical examination revealed rapid shallow breathing at 55/min, blood pressure 90/60 mm Hg, heart rate 102/min and temperature 90.2F. He was oriented only to place,pupils were dilated and non-reactive to light. No light perception in both eyes. Fundoscopy was normal without any evidence of retinal pallor, retinal detachment, retinal hemorrhages, papilledema or cataract.Labs revealed blood glucose 1100 mg/dl, pH 6.95,positive serum and urine ketones, pCO2 11 mm Hg and anion gap 36. He received aggressive warm fluid resuscitation, electrolyte replacements and intravenous insulin infusion with close monitoring. 18 hrs later his blood glucose, pH,anion gap and body temperature normalized and vision spontaneously returned to normal. A repeat fundoscopy exam by ophthalmologist and magnetic resonance image (MRI) brain was completely normal; ruling out posterior ischemic optic neuropathy and occipital stroke. He recovered very well, resumed diet, was ambulatory and had an uneventful rest of hospital course.DiscussionSudden painless vision loss has a wide differential diagnosis and it is usually caused by ischemia at retinal, ocular or cortical level. No history of methanol ingestion or trauma, normal fundoscopy, normal MRI and rapid return of vision after correction of diabetic ketoacidosis strongly suggests that blindness was related to acidosis.Alcoholic ketoacidosis has been reported to cause transient reversible blindness in other case reports and correction of acidosis lead to reversal of blindness. Other rare causes of reversible blindness include posterior reversible encephalopathy syndrome, brain tumors, anterior ischemic optic neuropathy and valsalva retinopathy.The mechanism of acidosis causing blindness is believed to be uncoupling of horizontal cells at pH <7.0 inhibiting photoreceptor transmission as suggested by studies on fish and salamander. Other possible mechanisms include hyperosmolarity causing ischemia or transient lens opacification but in none of the reported cases this was proven. Also lens opacification would have been seen at fundoscopy. Posterior ischemic optic neuropathy is another possibility but it is irreversible. The exact mechanism of blindness remains poorly understood. However irrespective of mechanism of acidosis, its rapid correction to pH >7.0 leads to rapid recovery suggesting a common pathogenesis.

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Kenmochi, Takashi, Masaaki Miyamoto, and Yoko Mullen. "Protection of Mouse Islet Isografts from Nonspecific Inflammatory Damage by Recipient Treatment with Nicotinamide and 15-Deoxyspergualin." Cell Transplantation 5, no. 1 (January 1996): 41–47. http://dx.doi.org/10.1177/096368979600500108.

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The major cause of primary nonfunction of transplanted islets is nonspecific inflammation associated with the transplantation procedures. Using mouse islet isografts, we attempted to prevent graft loss mediated by nonspecific inflammation using recipient treatment with nicotinamide (NA) and 15-deoxyspergualin (DSG). Newborn BALB/c islets, ranging in numbers between 1200 and 1500, were transplanted into syngeneic adult mice made diabetic by intravenous injection of 200 mg/kg streptozotocin. Recipient mice were divided into the following four groups, based on the treatment protocol of NA and DSG: intraperitoneal injection (IP) of normal saline (Group 1), IP injection of 2500 mg/kg NA (Group 2), IP injection of 5 mg/kg DSG (Group 3), and IP injection of NA + DSG (Group 4). Treatment started Day -1 and continued until Day 9 (Day 0 is day of transplantation). Blood and urine glucose, body weight, and intravenous glucose tolerance tests (IV-GTT) were examined after transplantation. Reversal of diabetes, as indicated by normoglycemia and negative urine glucose, was higher in Groups 2 (75%), 3 (50%), and 4 (85.7%), compared to Group 1 (11.1%). Especially in Group 4, the endocrine function and morphology of grafted islets were well preserved as shown by K values of IV-GTT and histological studies. These results suggest the importance of islet protection from irreversible damage by nonspecific inflammation at earlier stages of implantation, and the effectiveness of a short course of treatment with NA and DSG.

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Justesen, Natasja Degn, Michael Stormly Hansen, Mads Radmer Jensen, Oliver Niels Klefter, Jane Maestri Brittain, and Steffen Hamann. "Bilateral Vertebral Artery Vasculitis—A Rare Manifestation of Giant Cell Arteritis and a Difficult Diagnosis Made Possible by 2-[18F]FDG PET/CT." Diagnostics 11, no. 5 (May 14, 2021): 879. http://dx.doi.org/10.3390/diagnostics11050879.

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Giant cell arteritis (GCA) is the most common form of large vessel vasculitis. GCA is a medical and ophthalmological emergency, and rapid diagnosis and treatment with high-dose corticosteroids is critical in order to reduce the risk of stroke and sudden irreversible loss of vision. GCA can be difficult to diagnose due to insidious and unspecific symptoms—especially if typical superficial extracranial arteries are not affected. In these cases, verification of clinical diagnosis using temporal artery biopsy is not possible. This example illustrates the diagnostic value of hybrid imaging with 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography/computed tomography (2-[18F]FDG PET/CT), and the limitations of the temporal artery biopsy in bilateral vertebral GCA, causing transient ischemic attack in the visual cortex. In addition it indicates that inflammation in the artery wall can be visualized on 2-[18F]FDG PET/CT despite long term and ongoing high dose glucocorticoid treatment.

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Abdulsahib, Waleed K. "The Effect of Levamlodipine in Glucose-Induced Acute Model of Glaucoma in Rabbits." Open Access Macedonian Journal of Medical Sciences 9, A (July 25, 2021): 505–9. http://dx.doi.org/10.3889/oamjms.2021.6440.

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BACKGROUND: Loss of vision and irreversible blindness are the main consequences of glaucoma. There are two main types of glaucoma: Chronic and acute. AIM: This work aimed to evaluate the intraocular effect of levamlodipine on the acute model of glaucoma in rabbits. METHODS: Eighteen white albino rabbits of both sexes weighing about 2 kg. We divided them into three groups (six animals in each group) used in the experiment. We use the right eye to evaluate the effect of the test drug and used the left eye as a control (vehicle only). We used the first group to evaluate levamlodipine (0.25%), the second group to estimate levamlodipine (0.5%), and the third group to assess pilocarpine 2% (positive control). Drugs were administered 30 min before induction. RESULTS: Glucose (5%) fluid produces a significant intraocular pressure (IOP) elevation after 30 min of administration in the left eye (p ˂ 0.001). Pre-treatment topical administration of levamlodipine (0.25%) prevents the rise in the IOP significantly (p ˂ 0.001) in the right eye when compared to the control group (left eye). Moreover, compared with the eyes of the control group at all stages of the experiment, the topical administration of levamlodipine (0.5%) has a significant preventable effect (p ˂ 0.001), compared with the control group. The IOP of the local pilocarpine (2%) in the third group was significantly decreased (p ˂ 0.001). Finally, compared with levamlodipine (0.5%), pilocarpine has a more significant effect in preventing a rapid increase in intraocular pressure (p ˂ 0.001). CONCLUSION: Levamlodipine is a promising therapeutic agent for patients vulnerable to acute glaucoma.

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Gill, M., R. C. Siddons, D. E. Beever, and J. B. Rowe. "Metabolism of lactic acid isomers in the rumen of silage-fed sheep." British Journal of Nutrition 55, no. 2 (March 1986): 399–407. http://dx.doi.org/10.1079/bjn19860046.

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1. Four mature sheep were offered perennial ryegrass (Lolium perenne, cv. S23) silage (885 g dry matter/d) at hourly intervals. The silage was well fermented with a pH of 4.0, a lactic acid content of 139 g/kg dry matter and an organic matter digestibility of 0.766.2. Continuous intraruminal infusions of14C-labelled sodium salts of [U-14C]acetic acid, [2-14C]propionic acid, [2-14C]butyric acid and D- and L-[U-14C]lactic acid and an intravenous infusion of [U-14C]glucose were made on separate occasions to estimate the fluxes of rumen acetate, propionate, butyrate and lactate as well as plasma glucose. The data were resolved by the use of appropriate four-compartment (rumen) and three-compartment (rumen-plasma) models.3. Irreversible loss rate (g C/h) of rumen acetate (5.32 g C/h) was considerably greater than values obtained for propionate (2.58), butyrate (2.80) and lactate (2.91).4. Total flux of lactate (1.83 mol/d) exceeded the amount of lactate consumed in the diet (1.37 mol/d) indicating a net synthesis of 0.46 mol lactate/d. Approximately 0.90 of total lactate flux was metabolized in the rumen, with 1.00 mol/d converted to acetate, 0.57 to propionate and 0.08 to butyrate. The flux to acetate was significantly (P < 0.05) greater than that to propionate. Both the D- and L-isomers appeared to have similar metabolic fates.5. Lactate appeared to make no direct contribution to glucose flux in the animal, but 0.10 of total lactate was converted to glucose through propionate.6. The results are discussed in relation to overall lactate metabolism, and it is suggested that almost 0.30 of ruminally digested organic matter may be fermented via lactate.

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Lee, GJ, DW Hennessy, PJ Williamson, JV Nolan, TJ Kempton, and RA Leng. "Responses to protein meal supplements by lactating beef cattle given a low-quality pasture hay." Australian Journal of Agricultural Research 36, no. 5 (1985): 729. http://dx.doi.org/10.1071/ar9850729.

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A feeding experiment (47 days) was undertaken to evaluate the role of protein meal supplements for Hereford cows given a low quality subtropical grass hay and suckling calves (mean age 37 � 2.2 days). The rates of supplementation were 0, 5.25, 10.5, 15.75, and 21.0 g pelleted protein meal /kg liveweight W0.75. The consumption of grass hay, and the estimated total metabolizable energy intake (MEI) by cows, were significantly (P < 0.01) increased by supplements of protein meal, and their rate of liveweight loss was reduced (P < 0.01). Unsupplemented cows lost 2.56 kg/day compared with a 0.15 kg gain/day for cows given the highest rate of supplementation. Daily milk production and yields of milk protein, lactose, solids-not-fat and fat increased linearly (P < 0.01) with increasing amounts of protein meal. Throughout lactation, daily milk yield declined most rapidly (P < 0.01) in cows given the lower rates of protein supplementation: on day 33 the milk yield in the cows given 21 g protein meal/kg W0.75 was 83% higher than that of the unsupplemented cows. In a second period the rate of supplementation of cows was altered on day 34 from 0 to 21.0 g/kg W0.75. Milk yield at day 47 increased to the same output as that of cows supplemented at 21.0 g/kg W0.75 from day 1. Growth rates of calves, over both periods, tended to be higher in those calves whose dams received the higher rates of supplementation, but the differences did not become significant (P < 0.05) until day 47. There were no significant differences (P < 0.05) in voluntary intakes of hay by the calves whose dams received the various rates of protein supplementation. The concentration of total volatile fatty acids (VFA) was higher (P = 0.06) in the rumen of supplemented cows, but the molar proportions of VFA did not differ between treatments, viz. acetate, 0.71; propionate, 0.16; butyrate, 0.09; other VFA, 0.04. Rumen ammonia concentration was higher (P < 0.01) in cows supplemented with protein meal at the higher rates. The kinetics of plasma glucose and its products in the cows were studied on day 28 by means of a single intravenous injection of [2-3H] and [U-14C] glucose, and on day 29 by means of an intravenous injection of [2-3H] glucose and [14C] sodium bicarbonate. The rates of irreversible loss of glucose C and of bicarbonate C were higher in all supplemented cows. The results are discussed in relation to the availability of substrates for glucose synthesis, glucose oxidation and utilization for synthesis of lactose in milk.

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Waterman, Richard C., Andrew J. Roberts, Thomas W. Geary, Elaine E. Grings, Leeson J. Alexander, and Michael D. MacNeil. "Effect of reduced heifer nutrition during in utero and post-weaning development on glucose and acetate kinetics." British Journal of Nutrition 106, no. 11 (June 21, 2011): 1702–12. http://dx.doi.org/10.1017/s0007114511002224.

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Energetic efficiency was evaluated in composite bred heifers born from dams receiving 1·8 or 1·2 kg/d winter supplementation for approximately 80 d before parturition. Heifers were then developed post-weaning and randomly assigned to heifer development treatments of either control (100 %; ad libitum; n 8/year) or restricted (80 %; fed 80 % of supplementation fed to controls adjusted to a common body weight: n 8/year) in a 2-year study. A glucose tolerance test (GTT) and acetate irreversible loss test (AILT) were administered to heifers at the termination of a 140 d development period when the heifers were approximately 403 d of age and consumed a silage-based diet, and again at 940 d of age when pregnant with their second calf and grazing dormant forage. No differences were measured (P>0·08) for dam winter nutrition or heifer development treatment for baseline serum metabolites or measures in either the GTT or the AILT. However, changes in baseline serum concentrations (P>0·05) were different between metabolic challenges, which occurred at different stages of development. No difference in acetate disappearance (P = 0·18) and half-life (P = 0·66) was measured between the two metabolic challenges. A trend for glucose half-life to be shorter in heifers born from dams receiving in utero winter treatments that supplied 1·2 kg/d of winter supplementation was observed (P = 0·083). Heifers developed with lower total DM intake during a 140 d development period had similar glucose and acetate incorporation rates as ad libitum-fed heifers when evaluated at two different production stages.

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Ransom, Bruce R., Wolfgang Walz, Peter K. Davis, and Walter G. Carlini. "Anoxia-Induced Changes in Extracellular K+ and pH in Mammalian Central White Matter." Journal of Cerebral Blood Flow & Metabolism 12, no. 4 (July 1992): 593–602. http://dx.doi.org/10.1038/jcbfm.1992.83.

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In gray matter (GM), anoxia induces prominent extracellular ionic changes that are important in understanding the pathophysiology of this insult. White matter (WM) is also injured by anoxia but the accompanying changes in extracellular ions have not been studied. To provide such information, the time course and magnitude of anoxia-induced changes in extracellular K+ concentration ([K+]o) and extracellular pH (pHo) were measured in the isolated rat optic nerve, a representative central WM tract, using ion-selective microelectrodes. Anoxia produced less extreme changes in [K+]o and pHo in WM than are known to occur in GM; in WM during anoxia, the average maximum [K+]o was 14 ± 2.9 m M (bath [K+]o = 3 m M) and the average maximum acid shift was 0.31 ± 0.07 pH unit. The extracellular space volume rapidly decreased by ∼20% during anoxia. Excitability of the rat optic nerve, monitored as the amplitude of the supramaximal compound action potential, was lost in close temporal association with the increase in [K+]o Increasing the bath glucose concentration from 10 to 20 m M resulted in a much larger acid shift during anoxia (0.58 ± 0.08 pH unit) and a smaller average increase in [K+]o (9.2 ± 2.6 m M). The increased extracellular glucose concentration presumably provided more substrate for anaerobic metabolism, resulting in more extracellular lactate accumulation (although not directly measured) and a greater acid shift. Enhanced anaerobic metabolism during anoxia would provide energy for operation of ion pumps, including the sodium pump, that would result in smaller changes in [K+]o. These effects were probably responsible for the observation that the optic nerve showed significantly less damage after 60 min of anoxia in the presence of 20 m M glucose compared to 10 m M glucose. Under normoxic conditions, increasing bath K+ concentration to 30 m M (i.e., well beyond the level shown to occur with anoxia) for 60 min caused abrupt loss of excitability during the period of application but minimal change in the amplitude of the compound action potential following the period of exposure. The anoxia-induced increase in [K+]o, therefore, was not itself directly responsible for irreversible loss of optic nerve function. These observations indicate that major qualitative differences exist between mammalian GM and WM with regard to anoxia-induced extracellular ionic changes.

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Fonseca, Guilherme Wesley Peixoto da, Jerneja Farkas, Eva Dora, Stephan von Haehling, and Mitja Lainscak. "Cancer Cachexia and Related Metabolic Dysfunction." International Journal of Molecular Sciences 21, no. 7 (March 27, 2020): 2321. http://dx.doi.org/10.3390/ijms21072321.

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Cancer cachexia is a complex multifactorial syndrome marked by a continuous depletion of skeletal muscle mass associated, in some cases, with a reduction in fat mass. It is irreversible by nutritional support alone and affects up to 74% of patients with cancer—dependent on the underlying type of cancer—and is associated with physical function impairment, reduced response to cancer-related therapy, and higher mortality. Organs, like muscle, adipose tissue, and liver, play an important role in the progression of cancer cachexia by exacerbating the pro- and anti-inflammatory response initially activated by the tumor and the immune system of the host. Moreover, this metabolic dysfunction is produced by alterations in glucose, lipids, and protein metabolism that, when maintained chronically, may lead to the loss of skeletal muscle and adipose tissue. Although a couple of drugs have yielded positive results in increasing lean body mass with limited impact on physical function, a single therapy has not lead to effective treatment of this condition. Therefore, a multimodal intervention, including pharmacological agents, nutritional support, and physical exercise, may be a reasonable approach for future studies to better understand and prevent the wasting of body compartments in patients with cancer cachexia.

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Chandankhede, Tejas P. "Case Report On Chronic Pancreatitis In Adult." Journal of Pharmaceutical Research and Innovation 2, no. 1 (July 12, 2022): 17–19. http://dx.doi.org/10.36647/jpri/02.01.a003.

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Introduction: Chronic pancreatitis is an inflammatory disease characterized by progressive destruction of the anatomy and function of the pancreas. The cells are replaced by tissue fibrosis with repeat attacks of pancreatitis. Chronic pancreatitis is an old inflammatory disease that Causes scarring of the pancreas and irreversible changes. Chronic pancreatitis causes abdominal pain and in some cases diabetes and large, bulky fatty stools. Clinical Findings: Abdominal pain, loss of appetite , vomiting , Fever .Diagnostic Evaluation : Bilirubin total : conjugated – 0.14, , blood test : RBS glucose -180, monocyte -0.2% , Granulocytes -00% , HCT -37. Ultrasonography: Pancreatic cholangiopancreatography Therapeutic Intervention : Tab .Pantaprazole 40 mg orally x OD , Tab . Lipcerna 1 tab 1,000 orally with orally TDS, Tab. Antoxipan 1 tab orally x OD , Tab .Omee 20 mg orally x OD , Syr .Aristozyme 200 ml orally x OD , Tab .Paracetamol 650 mg orally x BD . Outcome : After treatment , the patient show improvement My patient was admitted in medicine ward No -28, with AVBRH with a known case of chronic pancreatitis and he has the chief complaint of fever and pain in the abdomen . After appropriate treatment his condition are improved. Keyword : — Calculus; Diabetes; Epidemiology; India; Islets of Langerhans; Manihot; Pancreas, Exocrine; Pancreatitis, Alcoholism; Pancreatitis, Chronic; Frequency.

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Naeini, Seyed, Alireza Khalaj, Ali Abbaszadeh-Kasbi, and Seyed Miri. "Outcomes of Biliointestinal Bypass among Iranian Obese Patients." Surgery Journal 04, no. 04 (October 2018): e197-e200. http://dx.doi.org/10.1055/s-0038-1673662.

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Background There are several surgical approaches to treat obesity not cured with medical approaches. Each method has its advantages and complications. In here, we have conducted a study to evaluate complications of biliointestinal bypass surgery (BIBP). Methods A prospective study was conducted in a private hospital from 2002 to 2016. Those patients, not previously operated for morbid obesity, were eligible. Mean follow-up period was 89 months ( ± 54 months; range: 73–108 months). Main outcome measures were weight, BMI (body mass index), concentrations of blood lipids and glucose, liver transaminases, and obesity-related comorbidities and complications. Results Twenty-three consecutive patients with morbid obesity, including 16 women (69.7%) and seven men (31.3%) with mean age 38.47 ± 10 years (range: 26–57 years) underwent surgery. At the end of follow-up period, a mean BMI reduction of 12.2 kg/m2 kg/m2 (p < 0.001)] was observed. An excess weight loss (EWL) of 63% ( ± 34) was achieved at the end of the study. Additionally, total cholesterol and triglyceride levels decreased postoperative significantly. The main long-term complications were flatulence (60%), borborygmus (47.8%), mal odorous stool (30.4%), and diarrhea (21.7%). Revision rate was 4.34%. There were no cases with irreversible hepatic injury, deaths due to the surgery, or progressive renal failure. Conclusion BIBP seems to be a safe, easily reversible, and one of valid therapeutic approaches in morbidly obese patients. BIBP has the potential to achieve durable weight loss and offers an improved quality of life.

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Tekkök, Selva Baltan, ZuCheng Ye, and Bruce R. Ransom. "Excitotoxic Mechanisms of Ischemic Injury in Myelinated White Matter." Journal of Cerebral Blood Flow & Metabolism 27, no. 9 (February 14, 2007): 1540–52. http://dx.doi.org/10.1038/sj.jcbfm.9600455.

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Axonal injury and dysfunction in white matter (WM) are caused by many neurologic diseases including ischemia. We characterized ischemic injury and the role of glutamate-mediated excitotoxicity in a purely myelinated WM tract, the mouse optic nerve (MON). For the first time, excitotoxic WM injury was directly correlated with glutamate release. Oxygen and glucose deprivation (OGD) caused duration-dependent loss of axon function in optic nerves from young adult mice. Protection of axon function required blockade of both α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) and kainate receptors, or removal of extracellular Ca2+. Blockade of N-methyl-D-aspartate receptors did not preserve axon function. Curiously, even extended periods of direct exposure to glutamate or kainate or AMPA failed to induce axon dysfunction. Brief periods of OGD, however, caused glutamate receptor agonist exposure to become toxic, suggesting that ionic disruption enabled excitotoxic injury. Glutamate release, directly measured using quantitative high-performance liquid chromatography, occurred late during a 60-mins period of OGD and was due to reversal of the glutamate transporter. Brief periods of OGD (i.e., 15 mins) did not cause glutamate release and produced minimal injury. These results suggested that toxic glutamate accumulation during OGD followed the initial ionic changes mediating early loss of excitability. The onset of glutamate release was an important threshold event for irreversible ischemic injury. Regional differences appear to exist in the specific glutamate receptors that mediate WM ischemic injury. Therapy for ischemic WM injury must be designed accordingly.

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Güven, Didem, Ana Dapena, Boran Kartal, Markus C. Schmid, Bart Maas, Katinka van de Pas-Schoonen, Seval Sozen, et al. "Propionate Oxidation by and Methanol Inhibition of Anaerobic Ammonium-Oxidizing Bacteria." Applied and Environmental Microbiology 71, no. 2 (February 2005): 1066–71. http://dx.doi.org/10.1128/aem.71.2.1066-1071.2005.

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ABSTRACT Anaerobic ammonium oxidation (anammox) is a recently discovered microbial pathway and a cost-effective way to remove ammonium from wastewater. Anammox bacteria have been described as obligate chemolithoautotrophs. However, many chemolithoautotrophs (i.e., nitrifiers) can use organic compounds as a supplementary carbon source. In this study, the effect of organic compounds on anammox bacteria was investigated. It was shown that alcohols inhibited anammox bacteria, while organic acids were converted by them. Methanol was the most potent inhibitor, leading to complete and irreversible loss of activity at concentrations as low as 0.5 mM. Of the organic acids acetate and propionate, propionate was consumed at a higher rate (0.8 nmol min−1 mg of protein−1) by Percoll-purified anammox cells. Glucose, formate, and alanine had no effect on the anammox process. It was shown that propionate was oxidized mainly to CO2, with nitrate and/or nitrite as the electron acceptor. The anammox bacteria carried out propionate oxidation simultaneously with anaerobic ammonium oxidation. In an anammox enrichment culture fed with propionate for 150 days, the relative amounts of anammox cells and denitrifiers did not change significantly over time, indicating that anammox bacteria could compete successfully with heterotrophic denitrifiers for propionate. In conclusion, this study shows that anammox bacteria have a more versatile metabolism than previously assumed.

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Milano, G. D., A. Hotston-Moore, and G. E. Lobley. "Influence of hepatic ammonia removal on ureagenesis, amino acid utilization and energy metabolism in the ovine liver." British Journal of Nutrition 83, no. 3 (March 2000): 307–15. http://dx.doi.org/10.1017/s0007114500000386.

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The mass transfers of O2, glucose, NH3, urea and amino acids across the portal-drained viscera (PDV) and the liver were quantified, by arterio–venous techniques, during the last 4 h of a 100 h infusion of 0 (basal), 150 or 400 μmol NH4HCO3/min into the mesenteric vein of three sheep given 800 g grass pellets/d and arranged in a 3 × 3 Latin-square design. Urea irreversible loss rate (ILR) was also determined by continuous infusion of [14C]urea over the last 52 h of each experimental period. PDV and liver movements of glucose, O2and amino acids were unaltered by NH4HCO3administration, although there was an increase in PDV absorption of non-essential amino acids (P= 0·037) and a trend for higher liver O2consumption and portal appearance of total amino acid-N, glucogenic and non-essential amino acids at the highest level of infusion. PDV extraction of urea-N (P= 0·015) and liver removal of NH3(P< 0·001), release of urea-N (P= 0·002) and urea ILR (P= 0·001) were all increased by NH4HCO3infusion. Hepatic urea-N release (y) and NH3extraction(x) were linearly related (R20·89), with the slope of the regression not different from unity, both for estimations based on liver mass transfers (1·16; SE 0·144;PB≠ 1= 0·31) AND [14C]UREA (0·97; se 0·123;Pb≠ 1= 0·84). The study indicates that a sustained 1·5 or 2·4-fold increase in the basal NH3supply to the liver did not impair glucose or amino acid supply to non-splanchnic tissues; nor were additional N inputs to the ornithine cycle necessary to convert excess NH3to urea. Half of the extra NH3removed by the liver was, apparently, utilized by periportal glutamate dehydrogenase and aspartate aminotransferase for sequential glutamate and aspartate synthesis and converted to urea as the 2-amino moiety of aspartate.

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Bozkurt, Devrim, Ender Hur, Burcu Ulkuden, Murat Sezak, Hasim Nar, Ozlem Purclutepe, Sait Sen, and Soner Duman. "Can N-Acetylcysteine Preserve Peritoneal Function and Morphology in Encapsulating Peritoneal Sclerosis?" Peritoneal Dialysis International: Journal of the International Society for Peritoneal Dialysis 29, no. 2_suppl (February 2009): 202–5. http://dx.doi.org/10.1177/089686080902902s41.

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Long-term use of the peritoneum as a dialysis membrane results in progressive irreversible dysfunction, described as peritoneal fibrosis. Oxidative stress during peritoneal dialysis has been established in many studies. Generation of reactive oxygen species (ROS) by conventional peritoneal dialysis solutions, regardless of whether produced by high glucose, angiotensin II, or glucose degradation products may be responsible for progressive membrane dysfunction. The well-known antioxidant molecule N-acetylcysteine (NAC) is capable of direct scavenging of ROS. The aim of the present study was to investigate the effect of NAC therapy on both progression and regression of encapsulating peritoneal sclerosis (EPS). We divided 49 nonuremic Wistar albino rats into four groups: Control group—2 mL isotonic saline intraperitoneally (IP) daily for 3 weeks; CG group—2 mL/200 g 0.1% chlorhexidine gluconate (CG) and 15% ethanol dissolved in saline injected IP daily for a total of 3 weeks; Resting group—CG (weeks 1 – 3), plus peritoneal resting (weeks 4 – 6); NAC-R group—CG (weeks 1 – 3), plus 2 g/L NAC (weeks 4 – 6). At the end of the experiment, all rats underwent a 1-hour peritoneal equilibration test with 25 mL 3.86% PD solution. Dialysate-to-plasma ratio (D/P) urea, dialysate white blood cell count (per cubic milliliter), ultrafiltration (UF) volume, and morphology changes of parietal peritoneum were examined. The CG group progressed to encapsulating peritoneal sclerosis, characterized by loss of UF, increased peritoneal thickness, inflammation, and ultimately, development of fibrosis. Resting produced advantages only in dialysate cell count; with regard to vascularity and dialysate cell count, NAC was more effective than was peritoneal rest. Interestingly, we observed no beneficial effects of NAC on fibrosis. That finding may be a result of our experimental severe peritoneal injury model. However, decreased inflammation and vascularity with NAC therapy were promising results in regard to membrane protection.

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Esumi, K., M. Nishida, D. Shaw, T. W. Smith, and J. D. Marsh. "NADH measurements in adult rat myocytes during simulated ischemia." American Journal of Physiology-Heart and Circulatory Physiology 260, no. 6 (June 1, 1991): H1743—H1752. http://dx.doi.org/10.1152/ajpheart.1991.260.6.h1743.

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In isolated adult rat myocytes, we tested the hypothesis that metabolic inhibition and simulated ischemia regulate the NADH/NAD+ redox couple with concomitant impairment of energy-dependent process, including contraction and maintenance of high-energy phosphate stores. We developed a method to examine the relationship among the redox couple, ATP content, and contractile performance in single cells under several conditions analogous to myocardial ischemia, with and without reperfusion. Myocytes were paced at 1 Hz while cell contraction and NADH fluorescence were determined simultaneously for single cells at 37 degrees C. Cells were exposed to cyanide and 2-deoxy-D-glucose (metabolic inhibition) or to metabolic inhibition plus 12 mM KCl and 20 mM lactate at pH 6.5 (simulated ischemia). Pyridine nucleotide fluorescence signals from single cells studied in this fashion could be modulated by metabolic inhibitors in a manner similar to that classically described for isolated mitochondria. Metabolic inhibition or simulated ischemia quickly produced maximal reduction of NAD+ to NADH. When cells were exposed to simulated ischemia for 10 min, then superfused with glucose-containing control buffer, 28% of cells exposed to conditions of simulated ischemia developed hypercontracture on reperfusion. Hypercontracture developed despite mitochondrial electron transport being reestablished. When myocyte suspensions in a cuvette were studied spectrofluorimetrically, the pyridine nucleotide fluorescence response to metabolic inhibitors was similar to that for a single cell. This permitted correlation of ATP determinations on cells in suspension with contractile and fluorescence measurements from single myocytes. In the absence of glycolysis there is correspondence among loss of electron transport, decline in high-energy phosphate concentration, and decline in contraction. Irreversible disruption of the electron transport process does not appear to be an early event in ischemic injury.

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Joshi, I., and R. D. Andrew. "Imaging Anoxic Depolarization During Ischemia-Like Conditions in the Mouse Hemi-Brain Slice." Journal of Neurophysiology 85, no. 1 (January 1, 2001): 414–24. http://dx.doi.org/10.1152/jn.2001.85.1.414.

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Focal ischemia evokes a sudden loss of membrane potential in neurons and glia of the ischemic core termed the anoxic depolarization (AD). In metabolically compromised regions with partial blood flow, peri-infarct depolarizations (PIDs) further drain energy reserves, promoting acute and delayed neuronal damage. Visualizing and quantifying the AD and PIDs and their acute deleterious effects are difficult in the intact animal. In the present study, we imaged intrinsic optical signals to measure changes in light transmittance in the mouse coronal hemi-brain slice during AD generation. The AD was induced by oxygen/glucose deprivation (OGD) or by ouabain exposure. Potential neuroprotective strategies using glutamate receptor antagonists or reduced temperature were tested. Eight minutes of OGD ( n = 18 slices) or 4 min of 100 μM ouabain ( n = 14) induced a focal increase of increased light transmittance (LT) in neocortical layers II/III that expanded concentrically to form a wave front coursing through neocortex and independently through striatum. The front was coincident with a negative voltage shift in extracellular potential. Wherever the LT front (denoting cell swelling) propagated, a decrease in LT (denoting dendritic beading) followed in its wake. In addition the evoked field potential was permanently lost, indicating neuronal damage. Glutamate receptor antagonists did not block the onset and propagation of AD or the extent of irreversible damage post-AD. Lowering temperature to 25–30°C protected the tissue from OGD damage by inhibiting AD onset. This study shows that anoxic depolarization evoked by global ischemia-like conditions is a spreading process that is focally initiated at multiple sites in cortical and subcortical gray. The combined energy demands of O2/glucose deprivation and the AD greatly exacerbate neuronal damage. Glutamate receptor antagonists neither block the AD in the ischemic core nor, we propose, block recurrent PID arising close to the core.

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Parish, Stan, Jennifer Wu, and Rita Effros. "Maintaining CD28 expression prevents replicative senescence in human CD 8 T cells (50.23)." Journal of Immunology 184, no. 1_Supplement (April 1, 2010): 50.23. http://dx.doi.org/10.4049/jimmunol.184.supp.50.23.

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Abstract The irreversible loss of expression of the CD28 costimulatory receptor is one of the signature changes in human T cells that are driven to the end stage of replicative senescence by chronic stimulation in cell culture. Besides activation, CD28 is also required for glucose metabolism, stabilization of various cytokine mRNAs, and, importantly, for optimal upregulation of telomerase, the enzyme that stabilizes telomeres. Increased proportions of senescent CD8 T cells are associated with decreased vaccine responsiveness and early mortality in the elderly, and, during HIV disease, with more rapid progression to AIDS. Previous work showed that inhibition of TNFα, which allowed for prolonged CD28 expression, delayed the onset of senescence. In the present study, CD8 T cells were stably transduced with CD28, and compared to empty-vector transduced control cultures. Maintaining continuous CD28 expression led to the significantly increased proliferative potential and sustained telomerase activity. Furthermore, IL-2 and IFNγ message levels were increased, and TNFα and IL-6, cytokines that are significantly increased at replicative senescence, were undetectable by ELISA at 25 population doublings, the time-point at which the control cultures reached senescence. These data underscore the central role of CD28 in memory CD8 T cell biology, and suggest a possible new therapeutic approach for enhancing immune function during aging and AIDS. (Supported by NIH AG023720 & AI060362).

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Winklehner, Michael, Jan Bauer, Verena Endmayr, Carmen Schwaiger, Gerda Ricken, Masakatsu Motomura, Shunsuke Yoshimura, et al. "Paraneoplastic Cerebellar Degeneration With P/Q-VGCC vs Yo Autoantibodies." Neurology - Neuroimmunology Neuroinflammation 9, no. 4 (July 2022): e200006. http://dx.doi.org/10.1212/nxi.0000000000200006.

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Background and ObjectivesParaneoplastic cerebellar degeneration (PCD) is characterized by a widespread loss of Purkinje cells (PCs) and may be associated with autoantibodies against intracellular antigens such as Yo or cell surface neuronal antigens such as the P/Q-type voltage-gated calcium channel (P/Q-VGCC). Although the intracellular location of the target antigen in anti–Yo-PCD supports a T cell–mediated pathology, the immune mechanisms in anti–P/Q-VGCC-PCD remain unclear. In this study, we compare neuropathologic characteristics of PCD with anti–P/Q-VGCC and anti-Yo autoantibodies in an archival autopsy cohort.MethodsWe performed neuropathology, immunohistochemistry, and multiplex immunofluorescence on formalin-fixed and paraffin-embedded brain tissue of 1 anti–P/Q-VGCC, 2 anti–Yo-PCD autopsy cases and controls.ResultsAnti–Yo-PCD revealed a diffuse and widespread PC loss together with microglial nodules with pSTAT1+ and CD8+granzymeB+ T cells and neuronal upregulation of major histocompatibility complex (MHC) Class I molecules. Some neurons showed a cytoplasmic immunoglobulin G (IgG) staining. In contrast, PC loss in anti–P/Q-VGCC-PCD was focal and predominantly affected the upper vermis, whereas caudal regions and lateral hemispheres were spared. Inflammation was characterized by scattered CD8+ T cells, single CD20+/CD79a+ B/plasma cells, and an IgG staining of the neuropil in the molecular layer of the cerebellar cortex and neuronal cytoplasms. No complement deposition or MHC-I upregulation was detected. Moreover, synaptophysin was reduced, and neuronal P/Q-VGCC was downregulated. In affected areas, axonal spheroids and the accumulation of amyloid precursor protein and glucose-regulated protein 78 in PCs indicate endoplasmatic reticulum stress and impairment of axonal transport. In both PCD types, calbindin expression was reduced or lost in the remaining PCs.DiscussionAnti–Yo-PCD showed characteristic features of a T cell–mediated pathology, whereas this was not observed in 1 case of anti–P/Q-VGCC-PCD. Our findings support a pathogenic role of anti–P/Q-VGCC autoantibodies in causing neuronal dysfunction, probably due to altered synaptic transmission resulting in calcium dysregulation and subsequent PC death. Because disease progression may lead to irreversible PC loss, anti–P/Q-VGCC-PCD patients could benefit from early oncologic and immunologic therapies.

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Pollock, C. "Pathogenesis of Peritoneal Sclerosis." International Journal of Artificial Organs 28, no. 2 (February 2005): 90–96. http://dx.doi.org/10.1177/039139880502800203.

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Peritoneal sclerosis is an almost invariable consequence of peritoneal dialysis. In most circumstances it is “simple” sclerosis, manifesting clinically with an increasing peritoneal transport rate and loss of ultrafiltration capacity. In contrast, encapsulating peritoneal sclerosis is a life threatening and usually irreversible condition, associated with bowel obstruction, malnutrition and death. It is unknown whether common etiological factors underlie the development of these 2 clinically and pathologically distinct forms of peritoneal sclerosis. The majority of studies to date have investigated factors that contribute to “simple” sclerosis, although it remains possible that similar mechanisms are amplified in patients who develop encapsulated peritoneal sclerosis. The cellular elements that promote peritoneal sclerosis include the mesothelial cells, peritoneal fibroblasts and inflammatory cells. Factors that stimulate these cells to promote peritoneal fibrosis and neoangiogenesis, both inherent in the development of peritoneal sclerosis, include cytokines that are induced by exposure of the peritoneal membrane to high concentrations of glucose, advanced glycation of the peritoneal membrane and oxidative stress. The cumulative exposure to bioincompatible dialysate is likely to have an etiological role as the duration of dialysis correlates with the likelihood of developing peritoneal sclerosis. Indeed peritoneal dialysis using more biocompatible fluids has been shown to reduce the development of peritoneal sclerosis. The individual contribution of the factors implicated in the development of peritoneal sclerosis will only be determined by large scale peritoneal biopsy registries, which will be able to prospectively incorporate clinical and histological data and support clinical decision making.

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46

ODDY, V. H., S. R. EDWARDS, H. M. WARREN, P. A. SPECK, P. J. NICHOLLS, and S. A. NEUTZE. "Interrelationships between amino acid and glucose metabolism in lambs of different dietary history supplemented with rumen escape protein." Journal of Agricultural Science 128, no. 1 (February 1997): 105–16. http://dx.doi.org/10.1017/s0021859696003917.

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Changes in amino acid and glucose metabolism in response to increments of rumen escape protein (REP) were studied in groups of lambs of three differing dietary histories and consequent weights, but similar ages. Crossbred wether lambs (Merino × (Border Leicester × Merino)) were fed to obtain three distinct growth patterns. The LW group (n = 15) were offered a low quality roughage diet throughout the experiment. The MW group (n = 19) were offered a high quality mixed diet followed by the same low quality diet as LW lambs. The HW group (n = 8) were offered a high quality mixed diet throughout. All diets were offered once daily ad libitum. The LW, MW and HW groups had liveweights of 18, 32 and 41 kg respectively at the commencement of supplementation, and were 33±0·1 weeks of age. REP supplements (formaldehyde-treated casein) were offered at 0, 20, 40, 60 or 80 g/day to MW and LW lambs and at 0 or 40 g/day to HW lambs.REP increased basal digestible organic matter intake (DOMI), liveweight gain (LWG) and urinary N excretion and tended to increase N balance in LW and MW lambs. DOMI, N intake, N balance and LWG were all higher (P < 0·05) in HW compared to MW and LW lambs. REP tended (P < 0·10) to increase LWG in each dietary history group.Blood glucose concentration was higher (P < 0·01) in HW than in other lambs but was not significantly altered by REP supplementation. Irreversible loss of glucose was greater (P < 0·01) in HW lambs and increased (P < 0·001) with REP for LW and MW lambs. REP increased (P < 0·05) phenylalanine (Phe) concentration in blood, Phe flux and oxidation and whole body rates of protein synthesis and degradation. HW lambs had higher (P < 0·05) values for all these parameters than did MW and LW lambs.REP increased (P < 0·05) plasma concentrations of insulin-like growth factor-1, and plasma insulin increased (P < 0·05) in MW but not in LW or HW lambs. REP had no effect on plasma growth hormone (GH) concentration. Plasma concentration of insulin was higher (P < 0·05) in HW than in MW or LW lambs, while GH was not significantly affected by dietary history.The results show that supplementation of ruminant diets with REP increases the rate of flux and oxidation of amino acids, and the rate of glucose utilization. Amino acid supply appears to influence glucose utilization more through oxidation rate than supply, and this relationship is affected by previous dietary history (weight for age) and energy availability, either from the diet or from body stores.

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Sabina, Richard L., Nancy J. Wandersee, and Cheryl A. Hillery. "AMP Deaminase Activation Contributes to Accelerated Adenine Nucleotide Pool Depletion during Periods of Energy Imbalance in Sickle Cell Erythrocytes." Blood 106, no. 11 (November 16, 2005): 1671. http://dx.doi.org/10.1182/blood.v106.11.1671.1671.

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Abstract Mature erythrocytes are unable to synthesize AMP from IMP due to the developmental loss of adenylosuccinate synthetase, which also effectively prevents the synthesis of adenine nucleotides from circulating hypoxanthine, the major salvageable purine compound. Consequently, AMP deaminase (AMPD) activity must be tightly regulated in order to avoid irreversible depletion of the erythrocyte adenine nucleotide pool during periods of energy imbalance. However, increased intracellular calcium promotes activation of erythrocyte AMPD (AMPD3) through a protein-protein interaction with calmodulin (Mahnke and Sabina, Biochemistry44:5551, 2005). Therefore, we hypothesized that Sickle Cell Disease (SCD) erythrocytes would more rapidly accumulate IMP and deplete the adenine nucleotide pool during periods of energy imbalance. In order to test this hypothesis, acid-soluble pools of these metabolites were quantified by anion-exchange HPLC in SCD and control erythrocytes during autoincubation and glucose starvation, both at 37C. Data in the table show that SCD erythrocytes accumulate more IMP during a 6-hour autoincubation compared to control cells, and this is accompanied by a decrease in AMP. Effect of Autoincubation on Erythrocyte AMP and IMP Pools GROUP HOURS AMPa IMP IMP/AMP a, metabolite concentrations reported as μmol/g Hb; †, p<.05 when compared to 0 time in a paired student’s t-test; ‡, p<.05 when compared to control in an unpaired student’s t-test Control (N=4) 0 .29±.08 .15±.06 .58±.28 6 .29±.01 .33±.11† 1.15±.35† SCD (N=5) 0 .22±.04 .08±.03 .36±.10 6 .14±.03† .74±.24†‡ 5.15±1.25†‡ Data in the figure show an accelerated depletion of ATP and increased accumulation of IMP in glucose-starved SCD erythrocytes compared to control cells (*, p<.05 when compared to control in an unpaired student’s t-test). Figure Figure These combined results demonstrate AMPD3 enzyme activation and accelerated adenine nucleotide pool depletion during periods of energy imbalance in SCD erythrocytes. This metabolic imbalance in SCD erythrocytes could contribute to 1) an increased rate of hemolysis, 2) cation channel dysregulation, 3) modulation of adhesive membrane components, and 4) diminished protein phosphorylation. Furthermore, strategies directed against this metabolic imbalance, e.g., diffusible AMPD inhibitors and adenine supplementation, may have a therapeutic benefit in SCD.

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Zhang, Qiu-Yan, Zhi-Jun Wang, Lei Miao, Ying Wang, Ling-Ling Chang, Wei Guo, and Yi-Zhun Zhu. "Neuroprotective Effect of SCM-198 through Stabilizing Endothelial Cell Function." Oxidative Medicine and Cellular Longevity 2019 (November 11, 2019): 1–13. http://dx.doi.org/10.1155/2019/7850154.

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Leonurine, also named SCM-198, which was extracted from Herba leonuri, displayed a protective effect on various cardiovascular and brain diseases, like ischemic stroke. Ischemic stroke which is the leading cause of morbidity and mortality, ultimately caused irreversible neuron damage. This study is aimed at exploring the possible therapeutic potential of SCM-198 in the protection against postischemic neuronal injury and possible underlying mechanisms. A transient middle cerebral artery occlusion (tMCAO) rat model was utilized to measure the protective effect of SCM-198 on neurons. TEM was used to determine neuron ultrastructural changes. The brain slices were stained with Nissl staining solution for Nissl bodies. Fluoro-Jade B (FJB) was used for staining the degenerating neurons. In the oxygen-glucose deprivation and re-oxygenation (OGD/R) model of bEnd.3 cells treated with SCM-198 (0.1, 1, 10 μM). Then, the bEnd.3 cells were cocultured with SH-SY5Y cells. Cell viability, MDA level, CAT activity, and apoptosis were examined to evaluate the cytotoxicity of these treatments. Western blot and immunofluorescent assays were used to examine the expression of protein related to the p-STAT3/NOX4/Bcl-2 signaling pathway. Coimmunoprecipitation was performed to determine the interaction between p-STAT3 and NOX4. In the transient middle cerebral artery occlusion (tMCAO) rat model, we found that treatment with SCM-198 could ameliorate neuron morphology and reduce the degenerating cell and neuron loss. In the in vitro model of bEnd.3 cell oxygen-glucose deprivation and reoxygenation (OGD/R), treatment with SCM-198 restored the activity of catalase (CAT), improved the expression of Cu-Zn superoxide dismutase (SOD1), and decreased the malondialdehyde (MDA) production. SCM-198 treatment prevented OGD/R-induced cell apoptosis as indicated by increased cell viability and decreased the number of TUNEL-positive cells, accompanied with upregulation of Bcl-2 and Bcl-xl protein and downregulation Bax protein. The results were consistent with SH-SY5Y cells which coculture with bEnd.3 cells. The forthcoming study revealed that SCM-198 activated the p-STAT3/NOX4/Bcl-2 signaling pathway. All the data indicated that SCM-198 protected against oxidative stress and neuronal damage in in vivo and in vitro injury models via the p-STAT3/NOX4/Bcl-2 signaling pathway. Our results suggested that SCM-198 could be the potential drug for neuroprotective effect through stabilizing endothelial cell function.

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Webster, Hollie, Gabriel Keeble, Bernard Dell, John Fosu-Nyarko, Y. Mukai, Paula Moolhuijzen, Matthew Bellgard, et al. "Genome-level identification of cell wall invertase genes in wheat for the study of drought tolerance." Functional Plant Biology 39, no. 7 (2012): 569. http://dx.doi.org/10.1071/fp12083.

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In wheat (Triticum aestivum L.) drought-induced pollen sterility is a major contributor to grain yield loss and is caused by the downregulation of the cell wall invertase gene IVR1. The IVR1 gene catalyses the irreversible hydrolysis of sucrose to glucose and fructose, the essential energy substrates which support pollen development. Downregulation of IVR1 in response to drought is isoform specific and shows variation in temporal and tissue-specific expression. IVR1 is now prompting interest as a candidate gene for molecular marker development to screen wheat germplasm for improved drought tolerance. The aim of this study was to define the family of IVR1 genes to enable: (1) individual isoforms to be assayed in gene expression studies; and (2) greater accuracy in IVR1 mapping to the wheat genetic map and drought tolerance QTL analysis. Using a cell wall invertase-specific motif as a probe, wheat genomics platforms were screened for the presence of unidentified IVR1 isoforms. Wheat genomics platforms screened included the IWGSC wheat survey sequence, the wheat D genome donor sequence from Aegilops tauschii Coss, and the CCG wheat chromosome 3B assembly: contig506. Chromosome-specific sequences homologous to the query motif were isolated and characterised. Sequence annotation results showed five previously unidentified IVR1 isoforms exist on multiple chromosome arms and on all three genomes (A, B and D): IVR1–3A, IVR1–4A, IVR1–5B, IVR1.2–3B and IVR1-5D. Including three previously characterised IVR1 isoforms (IVR1.1–1A, IVR1.2–1A and IVR1.1–3B), the total number of isoform gene family members is eight. The IVR1 isoforms contain two motifs common to cell wall invertase (NDPN and WECPDF) and a high degree of conservation in exon 4, suggesting conservation of functionality. Sequence divergence at a primary structure level in other regions of the gene was evident amongst the isoforms, which likely contributes to variation in gene regulation and expression in response to water deficit within this subfamily of IVR1 isoforms in wheat.

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Baran, Natalia, Shraddha Patel, Alessia Lodi, Jose Enriquez Ortiz, Yogesh Dhungana, Meghan Collins, Anna Skwarska, et al. "Accumulation of Intracellular L-Lactate and Irreversible Disruption of Mitochondrial Membrane Potential upon Dual Inhibition of Oxphos and Lactate Transporter MCT-1 Induce Synthetic Lethality in T-ALL Via Mitochondrial Exhaustion." Blood 138, Supplement 1 (November 5, 2021): 680. http://dx.doi.org/10.1182/blood-2021-152845.

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Abstract Metabolic reprogramming is recognized as one of the key hallmarks in acquiring aggressive phenotype and chemoresistance in solid tumors and hematologic malignancies. We have previously demonstrated that T-ALL are characterized by significant dependency on oxidative phosphorylation (OxPhos) with ability to utilize glutamine either in oxidative or reductive directions of TCA cycle, when mitochondria are blocked by Complex I Inhibitor (Baran N, et al. ASH 2020). To survive upon Complex I blockade leukemic cells require functional monocarboxylate transporter MCT1, that enables excretion of lactate and permissive pyruvate flux (Fig.1 a). Here we show that metabolic intervention utilizing OxPhos blockade can be potentiated by targeting MCT1 transporter and propose a novel metabolic synthetic lethality that could be exploited to eradicate T-ALL and other OxPhos-dependent malignancies. We first demonstrated that Complex I inhibition leads to increased MCT1 expression; on the contrary, MCT1 transporter blockade forces cells to increase OxPhos. In turn, the combinatorial therapy with Complex I inhibitor (IACS-010759) and MCT1 inhibitor (AZD3965) causes loss of ATP content (Fig. 1b), significant reduction of cell number and massive induction of apoptosis. Mechanistically, the combination treatment further reduced oxygen consumption rate (OCR) (Fig. 1c) and increased extracellular acidification rate, as measured by Seahorse. In concert with those results, dual inhibition led to TCA blockade, accumulation of intracellular lactate and depletion of glutamine, cystathionine and glutathione, indicating severe disruption of redox balance as measured by mass spectrometry and confirmed by significant accumulation of intracellular and mitochondrial reactive oxygen species (ROS) (Fig. 1d), loss of mitochondrial membrane potential (ΔΨ) (Fig. 1e) and subsequent mitochondria swelling. RNAseq data showed simultaneous upregulation of glycolysis and glutathione-related processes as possible mechanisms of metabolic compensation, yet strong upregulation of genes regulating apoptosis related to mitochondria dysfunction (Fig. 1f). Real-time hyperpolarized MRI based metabolic imaging studies with [1-13C]-pyruvate in patient-derived xenografts in vivo revealed significant decrease of lactate-to-pyruvate ratio in mice treated with AZD3965 or IACS-010759 alone, and in mice treated with drug combination. [13C]-Glucose isotope tracing analysis in patient-derived xenografts in vivo revealed an increased intracellular trapping of lactate as a marker of treatment effectiveness in mice subjected to dual blockade. While MCT1 inhibition induced only moderate reduction of leukemia growth in vitro and tumor burden in vivo, combination with IACS-010759 depleted significantly both, circulating and marrow/spleen/liver resident leukemia cells. Mechanistically, inhibition of MCT1 by AZD3965 therapy in leukemia-bearing mice led to lactate accumulation, OCR increase, moderate ROS production and mitochondrial membrane hyperpolarization, while Complex I blockade resulted in upregulation of MCT-1, reduction of OCR, lactate production and increase of ROS ; consequently, combinatorial therapy caused complete mitochondria shut-down and drastic inhibition of tumor growth both in vitro and in vivo in two xenografts models and led to significant extension of overall survival (p<0.0001) (Fig. 1g). In summary, these results demonstrate a novel synthetic vulnerability of concomitant blockade of OxPhos and MCT-1, uncovering metabolic checkpoints that can ultimately translate into successful therapies in T-ALL and OxPhos-dependent malignancies. Figure 1 Figure 1. Disclosures Skwarska: Halilovich E, Wang Y, Morris E, Konopleva M, Skwarska A.: Patents & Royalties: Combination of a MCL-1 inhibitor and midostaurin, uses and pharmaceutical composition thereof.. Konopleva: Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Rafael Pharmaceuticals: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Ascentage: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; AstraZeneca: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Cellectis: Other: grant support; Sanofi: Other: grant support, Research Funding; KisoJi: Research Funding; Calithera: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Agios: Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support.

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