Mark Peyrot, PhD

• Department of Sociology
• Loyola College
• Department of Medicine
• The Johns Hopkins University
• School of Medicine
• Baltimore, MD

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Appropriate 162 hematology and Oncology personalized immobilization should be made for every baby. A detailed research of all preoperative and postoperative imaging, ideally with the assistance of a radiologist and operating neurosurgeon ought to be undertaken for figuring out accurate extent of illness for quantity generation. Volumes ought to encompass the presenting enhancing radiological abnormality with acceptable margins as per the histologic subtype of the tumor. All efforts should be made to consider high precision conformal techniques so as to reduce doses of radiation to regular healthy tissues as much as potential. In very younger youngsters, radiation might should be given beneath quick anesthesia and necessitates some adjustments in the strategies. The time from surgery to start of radiotherapy should be stored to a minimal ideally, four weeks. Children may expertise gentle nausea about 30 minutes to one hour after therapy, especially within the first few fractions. Chemotherapy the function of chemotherapy in managing mind tumors is rising every single day. If the pediatric oncologist determines that chemotherapy must be administered the suitable therapy is varied for varied brain tumors. Pilocytic astrocytoma: Characterized by a fibrillary background and Rosenthal fibers. Chemotherapy: is reserved for very young youngsters and infants and most commonly include carboplatin and vincristine. Radiotherapy: Local or wide-field irradiation to 5000 cGy to 6000 cGy is the mainstay of remedy. Chemotherapy: Most lately, temozolomide and concurrent radiation adopted by upkeep temozolomide remedy is being increasingly utilized following important survival advantage demonstrated in adult glioblastomas. In distinction, those arising from midbrain or medulla are prone to be low-grade lesions which have a more indolent course and better end result. For focal tumors (nontectal), full resection may be secure and should not require any additional therapy. Neither hyperfractionated radiotherapy nor chemotherapy has been shown to add profit. Following the success of temozolomide in grownup high-grade Childhood Brain tumors gliomas, comparable schedule has been attempted in these patients but without any vital achieve in consequence. Low-grade lesions are handled with related irradiation doses however total reply much less favorably than their counterparts in different places. Management the preliminary step in treatment is surgical resection in many of the sufferers. Total or near-total resection of the primary tumor site is associated with better survival, predominantly in non-disseminated patients. Following surgical procedure, sufferers usually are stratified into considered one of two danger groups, based mostly on extent of surgical resection and illness extent on the time of analysis. Patients higher than three years of age with average-risk disease are to be treated with cranio spinal (2340 cGy) and local enhance radiotherapy (5580 cGy), supplemented with adjuvant chemotherapy. Recent trials have included using carboplatin as a radiosensitizer during radiation remedy and the delivery of higher-dose chemotherapy, basically an intensified cisplatin, cyclophosphamide, vincristine, and etoposide routine, supported by peripheral stem cell rescue, following radiotherapy, with probably better results. Treatment of Patients youthful than 3 years is problematic, because of the immaturity of the brain and the resultant deleterious results of entire brain irradiation, elevated chance of dissemination at the time of prognosis in younger patients. More intensive chemotherapeutic regimens utilizing peripheral stem cell help or regimens which have been supplemented with high-dose, intravenous, and intrathecal methotrexate have shown possible increased efficacy. Supratentorial Primitive Neuroectodermal Tumors They are comparatively uncommon, comprising 2. These are morphologically similar to "medulloblastoma" however positioned supratentorially. Management Surgical: Forms the mainstay of the therapy, but the diploma of surgical resection has been related variably to outcome Radiotherapy and chemotherapy: Postsurgical management has been just like that employed for high-risk medulloblastoma sufferers. Pineoblastomas They are a subvariant of embryonal tumors and are managed equally to highrisk medulloblastomas. Survival appears more favorable in patients older than three years at analysis treated with in depth resections, craniospinal and local enhance radiotherapy, and chemotherapy. Most arise in the posterior fossa (most generally from fourth ventricle) but also can come up within the supratentorial compartment.

Syndromes

• Emotional distress
• Jaw that may protrude forward
• Agitation
• Difficulty closing the eyes while sleeping (rarely permanent)
• Interleukin-2
• Reducing or avoiding caffeine, certain cold medicines, and stimulants
• Cause of a fever

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If, for instance, there ought to be direct oxidation of glycogen in muscle, the plasma glucose specific exercise would miss it (because of the dearth of G6Pase in muscle tissue). However, total carbon dioxide production, measured with oblique calorimetry, would come with the oxidized glycogen along with all the other oxidized substrates. In common, measuring the change of oxygen and carbon dioxide with oblique calorimetry makes it possible to get hold of estimates of net rates of substrate oxidation and in addition offers a detailed estimate of the speed of power expenditure [53]. Simple calculations [54] thus estimate whole-body net carbohydrate oxidation at about 60% of total glucose uptake. Little is left for different tissues, which preferentially derive their metabolic vitality from the oxidation of fatty substrates and return a lot of the glucose to the liver after conversion into lactate (Cori cycle). The role of insulin in maintaining this metabolic setup is permissive somewhat than determinant. The part that counterregulation performs in basal glucose uptake is less properly outlined, but in all probability is centered upon upkeep of lipolysis, since all the anti-insulin hormones are kind of potent lipolytic stimuli. A metabolic futile cycle is one by which a precursor is transformed into a product by a ahead response, which is then reversed to resynthesize the precursor. One example of a futile cycle, G6P to fructose-6-phosphate and back by way of the phosphoglucoisomerase response, has been discussed beforehand and can be measured as the distinction between the turnover price as estimated by 2 H and three H isotopes of glucose. In basic phrases, whenever bidirectional flux through a metabolic pathway is concurrently operative, there exists a cycle, whatever the number of intermediate reactions and regardless of whether or not a quantity of tissues are involved. Another one is protein breakdown in skeletal muscle with reincorporation of amino acids into proteins in the liver. The unfavorable connotation of futility has historically been reserved for these cycles that go on in the same cell. As discussed by Newsholme [56], a metabolic cycle with an inner loop is the best kinetic stratagem to keep the enzymes of a dormant pathway at a minimum of activity, and to ensure a sensitivity gain for ready amplification of incoming signals. Key points · Of fasting glucose uptake, 70% occurs in insulin-independent tissues, and two thirds of the glucose is totally oxidized. Much of this distribution is due to the compulsory use of glucose as gasoline by the brain. Carbohydrates are usually mixed with lipids and protein within the food regimen and make up 40­60% of the caloric content material. Absorption of dietary carbohydrates is influenced by their chemical type (refined sugars or advanced carbohydrates) and by different parts of food. Furthermore, disposition of dietary carbohydrate is indirectly affected by fats and protein to the extent that these latter (i) compete with glucose as substrates, and (ii) interfere with glucoregulatory hormones by altering insulin secretion. To circumvent the difficulties of examine of glucose ingestion, the regulation of glucose homeostasis in the course of the fed state has classically been investigated with the usage of intravenous glucose, which could be administered in formats extra appropriate for formal analysis. Between 10­60 min, glycemia decreases approximately as a single exponential function of time, and a decay constant (k value) could be calculated to estimate tolerance to intravenous glucose. First, the time course of glucose fall in reality is a multi-exponential function of time, so that the decay fixed takes on completely different values based on which segment of the curve is used for evaluation. Second, over the identical time interval, totally different curves can have similar k values; for this reason, the area underneath the glycemic excursion is usually used as an alternative of the k value. However, the world underneath the curve can be influenced by the quantity into which the injected glucose is distributed. Third, and most essential, the shape of the glucose curve is heavily affected by the endogenous insulin response to the acute hyperglycemia brought on by the intravenous bolus. Such response is highly irregular, and after an initial peak proceeds in two or three smaller spikes tightly synchronized with similar glycemic spikes [57]. In basic, in the presence of an intact feedback loop between glucose and insulin, glucose tolerance is the integrated consequence of multiple adjustments within the glucose in addition to within the insulin system: distribution of the exogenous glucose, stimulation of peripheral glucose uptake by insulin and hyperglycemia, suppression of hepatic glucose output, and secretion, distribution and degradation of insulin. The model generates a parameter reflecting the ability of hyperglycemia to stimulate insulin secretion, one other parameter estimating the ability of insulin to stimulate glucose metabolism, and an index of the flexibility of glucose to promote its personal disposal. Labeled (tritiated or deuterated) glucose can be co-injected with cold glucose; acceptable mannequin evaluation of the tracer data makes it possible to dissect out the consequences of insulin on the liver and on peripheral tissues [59]. Because of its complexity of use and interpretation, the latter stays a purely investigative tool. A secondary injection of exogenous insulin or tolbutamide has been used to circumvent the failure of the minimal mannequin in case of insufficient endogenous insulin response [60].

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However, in a post hoc evaluation, a subgroup of subjects-those with higher titers of insulin autoantibodies at the time of enrollment-appeared to show a useful effect of oral insulin with a projected delay of 4. This was not further pursued as a end result of potential cyclosporine toxicity, as mentioned earlier. Conclusions Hundreds of interventions have been proven to stop or reverse immune-mediated diabetes in rodent models. Nonetheless, a number of human research have had transient beneficial results with out main questions of safety. This raises the prospect that mixture therapies could but show helpful [79­81]. Achenbach P, Barker J, Bonifacio E: Modulating the natural historical past of kind 1 diabetes in children at high genetic danger by mucosal insulin immunization. Diabetes Prevention Trial ­ Type 1 Study Group: Effects of insulin in family members of sufferers with kind 1 diabetes mellitus. Various terminologies have been used to indicate the presence of a minimal of one glucose measure on this greater than normal range, together with prediabetes (the most widely used), nondiabetic hyperglycemia and impaired glucose regulation. It has been speculated, through the so-called "thrifty genotype" and "thrifty phenotype" hypotheses [22,23], that phenotypes prone to weight problems and insulin resistance have been bestowed with survival advantages all through the overwhelming majority of human evolution, which was characterised by the harsh environments related to hunter-gatherers and early subsistence agriculturists. However, in fashionable industrialized environments the place the traditional cyclical nature of food availability has flat-lined at the highest attainable stage and the need for purposeful bodily exercise has been all but engineered out of our daily lives, these beforehand advantageous phenotypes have turn out to be highly deleterious. Given these considerations, way of life interventions have traditionally fashioned the primary therapeutic goal in diabetes prevention programs. These outcomes have additionally been replicated across numerous countries and cultures including India [28], Japan [29], and China [30]. Importantly, the advantages of successful way of life change packages have additionally been proven to be lasting over the long term. These results had been achieved despite the actual fact that the active lifestyle intervention discontinued after the initial research period. Therefore it will appear that after individuals are enabled to efficiently change and self-regulate their health habits, benefits could be accrued lengthy after behavioral counseling has ceased. Obesity Weight loss, of between 5 to 10% of initial physique weight and upkeep, was a core element of all successful diabetes prevention applications. Adipose tissue, particularly the tissue surrounding inner organs, is known to be an active endocrine organ that secretes a big selection of pro-inflammatory adipokines, which act at each the local and systemic stage [33]. Increasing adipose tissue mass leads to adverse changes in the profile of secreted adipokines as nicely as increased turnover of free fatty acids, which lead to elevated insulin resistance. Interestingly, useful modifications in glucose metabolism have been shown to appear soon after the initiation of an energy-restricted diet, even before any important discount in physique fats is seen, which suggests that there are a quantity of different mechanisms in play simultaneously [34]. Chapter 6 offers an in depth description of the function of adiposity in glucose regulation. Others have reported that weight reduction seems to be helpful whatever the mechanism of weight reduction. Undertaking inadequate bodily exercise is related to over 20 ailments and conditions and is estimated by the World Health Organization to be the fourth leading explanation for premature mortality globally [38], ahead of both weight problems and dietary components. Observational research has confirmed that bodily activity is a robust determinant of well being in those with prediabetes. For example, in a large international cohort with prediabetes each 2000 steps per day change in strolling activity over a 12-month period, as measured by a pedometer, was associated with an 8% difference within the risk of heart problems [39]. Others have proven that undertaking a hundred and fifty minutes of leisure time strolling activity per week was related to a 60% reduction within the relative threat of diabetes [40]. Mechanistic studies have identified multiple pathways linking bodily exercise to insulin-stimulated glucose uptake [41­43]. Furthermore, muscle is an lively endocrine organ and releases a plethora of myokines which are regulated by muscle fiber activation. Physical exercise acts to favorably alter the distribution and composition of adiposity throughout the body. For instance, increased physical activity is related to lowered ranges of hepatic fats, even without entire physique weight loss, and recent proof points to the position of bodily activity in the promotion of brown adipose tissue [45,46]. This is in keeping with other studies and the results of a meta-analysis which demonstrated that bodily exercise interventions result in round a 50% reduction in the relative danger of type diabetes and are as efficient as other multifactorial interventions that also promoted a nutritious diet and weight reduction [24]. As mentioned earlier, most of the advantages of increased bodily activity are impartial of general physique weight and adiposity.

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Large hepatocellular adenomas might trigger signs corresponding to right-upper-quadrant discomfort due to mass effect or might current as a palpable mass. Up to 30% of hepatocellular adenomas may current with intratumoral hemorrhage or rupture and intraperitoneal hemorrhage; these trigger hemodynamic instability and might be life-threatening. Malignant transformation to hepatocellular carcinoma is uncommon however may occur in 5% to 10% of hepatocellular adenomas. Risk factors for rupture embrace pregnancy, tumor diameter greater than 5 cm, subcapsular location, and I-hepatocellular adenoma subtype. About 10% of I-hepatocellular adenomas also have mutations of the -catenin gene; owing to the presence of inflammatory modifications, these are categorized as I-hepatocellular adenomas rather than -hepatocellular adenomas. Historically I-hepatocellular adenomas had been misclassified as telangiectatic focal nodular hyperplasia, a term not in use. Hepatocellular adenomas could regress after cessation of oral contraceptives, androgens, and different offending medication. Pathomolecular Subtypes Specific demographic and clinical options depend upon the pathomolecular subtype. H-Hepatocellular Adenoma Subtype this subtype accounts for 35% to 40% of all hepatocellular adenomas and happens nearly exclusively in women. Overall about 50% of patients with H-hepatocellular adenomas have solitary and 50% have a number of lesions. Most H-hepatocellular adenomas are asymptomatic and found incidentally at imaging. Among the various hepatocellular adenoma subtypes, H-hepatocellular adenomas are the least aggressive biologically. Tumors less than 5 cm in size pose minimal risk of hemorrhage or rupture and nearly no threat of malignant transformation. Among the various hepatocellular adenoma subtypes, -hepatocellular adenomas are the more than likely to endure malignant transformation. These lesions can also hemorrhage, although the exact frequency of bleeding is unknown. I-Hepatocellular Adenoma this subtype accounts for over 50% of all hepatocellular adenoma. Whereas I-hepatocellular adenomas happen most frequently in women with history of oral contraceptive utilization, they might also occur in men. In addition to oral contraceptives, threat components include obesity, hepatic steatosis, and alcohol consumption. Patients with I-hepatocellular adenomas may present with anemia, abnormal serum liver chemistries, and indicators of systemic irritation, including fever, leukocytosis, and elevated serum levels of C-reactive protein. Among the various hepatocellular adenoma subtypes, I-hepatocellular adenomas have the best threat of bleeding, which has been reported to occur in about 30% of those lesions. The subset of I-hepatocellular adenomas with concomitant -cateninactivating mutations could progress to carcinoma. Hepatic Adenomatosis the demographics and threat elements for hepatic adenomatosis are these of the underlying pathomolecular subtype. The risk of bleeding and malignant transformation is dependent upon tumor measurement and pathomolecular subtype; the variety of hepatocellular adenomas is much less necessary. Pathophysiology Hepatocellular adenomas are monoclonal proliferations of hepatocytes. The contribution of oral contraceptive use to the event of those hepatocellular adenomas is incompletely understood. Another hypothesis is that mutations within the gene play the primary role by causing estrogen metabolites to accumulate inside hepatocytes and that the metabolites then stimulate hepatocellular proliferation. Regardless of the trigger, the sustained activation promotes hepatocellular proliferation and the development of hepatocellular adenomas with histologic options on the borderline between benign hepatocellular tumors and hepatocellular carcinomas. The resulting hepatocellular adenomas are characterised by inflammatory mobile infiltrates, overexpression of acute-phase reactants, dilated sinusoids, blood-filled cavities (peliosis), abnormal vessels, and a propensity for hemorrhage.

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The preganglionic nerve fibers kind classical nerve terminals and synapses inside the ganglia where they launch acetylcholine to activate nicotinic receptors on the postganglionic neurons. The nerves have small vesicles which comprise acetylcholine and large dense core vesicles which contain neuropeptides. Both acetylcholine and neuropeptides are launched from small varicosities within the nerves, from which they diffuse to the islet endocrine cells and activate specific receptors which trigger stimulation of both insulin and glucagon secretion. A primary physiologic significance of this regulation is the early phase Introduction the normal view is that islet hormone secretion is principally regulated by circulating nutrients (glucose, amino acids, free fatty acids) as properly as the intestine incretin hormones (glucagon-like International Textbook of Diabetes Mellitus, Fourth Edition. Another physiologic importance of the parasympathetic islet nerves may be, along with the sympathetic nerves, the stimulation of glucagon secretion throughout hypoglycemia [4]. The classical mechanism invoked to clarify stimulation of insulin and glucagon secretion throughout vagal nerve activation is the discharge of the neurotransmitter acetylcholine. The launched acetylcholine diffuses to the endocrine cells and prompts muscarinic receptors (mainly the M1 and M3 subtypes of the muscarinic receptor) which outcomes in stimulation of insulin and glucagon secretion [5]. Another mechanism is phosphorylation-/arrestin-dependent coupling of the muscarinic M3 receptor to protein kinase D1 [8]. The critical importance of the cholinergic mediation of islet hormone secretion for glucose homeostasis is evident from studies utilizing mice with both -cell deletion of the M3 receptors or -cell overexpression of M3 receptors [8]. The -cell M3 knockout mice have defective insulin secretion and glucose intolerance, whereas -cell M3 receptor overexpressing mice have elevated insulin secretion and enhanced glucose tolerance. The mice with -cell overexpression of M3 receptors are also immune to diet-induced glucose intolerance and hyperglycemia [8]. The neuropeptides localized to islet parasympathetic nerve terminals and due to this fact potential mediators of the islet noncholinergic effects are gastrin-releasing polypeptide, vasoactive intestinal polypeptide, and pituitary adenylate cyclase-activating polypeptide [9]. It consists of a 27-amino acid residue, which is -amidated in its C-terminal methionine. The peptide is very conserved during evolution, having an identical N-terminal finish to bombesin, and the human and porcine forms of the peptide differ in only two residues. It can be found in nerve terminals and their neuronal cell bodies in pancreatic ganglia, as demonstrated both in mice and rats [26]. These mice are viable, develop normally and have normal baseline glucose and insulin ranges as nicely as regular pancreatic insulin content material. It therefore mimics each the stimulation of insulin and glucagon secretion induced by parasympathetic nerve activation. Parasympathetic results and mediation As reviewed earlier, activation of the parasympathetic nerves stimulates both insulin and glucagon secretion, and this could be of particular relevance for the cephalic and early meal phases of insulin secretion in addition to for the glucagon response to hypoglycemia. In classical neurobiology, a number of standards have to be met earlier than a candidate neurotransmitter, similar to these neuropeptides, may be proven to be a physiologic neurotransmitter [30] (Table 9. These criteria embrace that the potential neurotransmitter is localized to the nerves, is released by activation of the nerves, its effects mimic that of the nerves and that inhibition of its impact alters the responses to nerve activation. Islet sympathetic nerves Islets are densely innervated by sympathetic nerves, as demonstrated by fluorescence microscopy, electron microscopy, and immunocytochemistry [1]. Electrical activation of the sympathetic nerves inhibits insulin secretion and stimulates glucagon secretion [31]. However, hyperpolarization with closure of the voltage-sensitive calcium channels and a direct exocytotic action can also be involved. In addition to noradrenaline, neuropeptides additionally contribute to sympathetically induced inhibition of insulin secretion. Two sympathetic neuropeptides, galanin and neuropeptide Y, might mediate these nonadrenergic effects as a end result of they (a) are localized to each the islet sympathetic nerve terminals and their neuronal cell our bodies in the celiac ganglion, (b) are released from the pancreas in response to electrical activation of the sympathetic nerves, and (c) each inhibit insulin secretion as demonstrated each in vivo and in vitro [1]. Galanin Galanin was isolated from the porcine gastrointestinal tract in 1983 and named because of its glycine C-terminus and alanine N-terminus [32]. Galanin is a extensively distributed neuropeptide both in the central and peripheral nervous techniques. In islets, dense galanin innervation was first demonstrated in dogs, and later in other species, together with people [30,32]. However, species variations exist; for instance, islet galanin innervation is more plentiful in canines and cats than in common laboratory animals like rats and mice [32]. In canines, islet nerves that contain galanin also contain tyrosine hydroxylase as do their neuronal cell our bodies in the celiac ganglion [30].

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For loci identified by whole-genome association only loci reaching genome-wide significance (p < 5 Ч 10-8) are included. Linkage analysis has, nonetheless, been less helpful for identifying genes inflicting complex illnesses. This mannequin has been the idea of a revolution in advanced genetics by stimulating the development of instruments for genetic affiliation research. The advantages of association lie in the larger number of people that can be collected for each examine in addition to the much larger resolution of the mapping. One disadvantage is the large number of markers needed to perform mapping on a genome-wide level and association research had been subsequently originally carried out on small regions known to harbor candidate genes. The transcript expressed in adipose tissue has an extra exon B and a substitution of a proline for alanine at position 12 of this protein, which is seen in about 15% of the European inhabitants. It is well-known that epinephrine excess can suppress insulin secretion and cause diabetes. Three of the studies shared results prior to publication and solely considered constructive outcomes that had been replicated in all research. These very massive research have identified a quantity of new loci and confirmed the impact of many beforehand recognized. Interestingly it looks as if most associations found in one ethnic group also show some evidence of association in populations with different ethnicities. Therefore, further nice mapping of the loci in even larger sample sets is usually needed. To do that cost-efficiently a Cardio-Metabochip has been developed for metabolic/cardiovascular gene mapping. Next-generation sequencing will present even denser protection of genetic variation. The GoT2D consortium aims to map decrease frequency variants by way of low-coverage whole-genome sequencing, deep exome sequencing, and next-generation 2. While loci are generally referred to by the the genetics of type 2 diabetes 405 Table 26. Melatonin works as a chronobiotic issue, adjusting the timing of the biologic clock. Its receptors are present in the pancreas and melatonin is proposed to contribute to the nocturnal reducing of insulin in people. The C allele of rs2943641 has been shown to be associated with insulin resistance and elevated threat of diabetes. The danger allele is related to decreased insulinogenic index and decrease disposition index, suggesting a lowered capability for insulin secretion in relation to insulin sensitivity. Since it was recognized as a diabetes gene it has been shown to be important for several very important features within the pancreatic islet, together with pancreas growth, dedication of -cell mass, and maintenance of the secretory perform of mature -cells. There are many attainable explanations for the missing heritability, together with assumptions made concerning the genetic architecture of the illness and the definitions of heritability. However, there are additionally many other potential explanations for the lacking heritability: yet unmapped widespread variants, distorted parent-of-origin transmission of threat alleles, rare variants, structural polymorphisms. Some argue that disease risk is determined by a lot of very small additive results from comparatively common variants and that disease represents the extremes of a standard distribution [59] whereas others argue that complex illnesses are quite collections of phenocopies brought on by rare, typically latest, mutations [60]. However, one should remember that heritability can solely be estimated from the newest generations for which info on affection standing is out there, whereas most of the variants studied so far are ancestral variants tons of of generations old. We do not know whether these ancestral variants (which have modest results and have escaped purifying selection) can actually explain the diabetes epidemic we see in the newest generations or whether this might be ascribed to uncommon variants with stronger effects. The speedy growth of subsequent generation sequencing instruments has markedly facilitated discovery of rare variants. From being both extremely expensive and effort consuming, sequencing of the whole genome with appropriate protection (approx. Whole-exome sequencing could be performed for less than $400 per sample and these figures are prone to decrease over the approaching years. Applying these strategies in households and huge inhabitants research will hopefully reply the questions concerning the function of uncommon variants in complicated illnesses. Gene­gene and gene­environment interactions Gene­gene interactions, or epistasis, have been instructed as a attainable explanation for difficulties in replicating genetic association in complex ailments [68]. Previous attempts to research epistasis in complicated diseases have targeted on interactions between candidate regions [69,70]. The primary problem when learning epistasis is power, since interplay between loci with modest effects is difficult to detect without extraordinarily giant pattern sizes.

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In addition the whole lack of insulin and ablation of glucose catabolism potently prompts hepatic fat catabolism and induces excessive ketone manufacturing and ketoacidosis that may be fatal in untreated kind 1 diabetes. In sort 2 diabetes, insulin levels and motion are partially retained but defects of hepatic glucose manufacturing and uptake persist. Despite impaired insulin signaling to pathways which suppress glucose production, tangential signaling pathways proceed to stimulate the conversion of glucose to lipid and cholesterol-a so-called "insulin paradox. Thus, each forms of diabetes trigger elevated hepatic glucose manufacturing and impaired glucose uptake, but impinge differently on the means in which hepatic glucose and lipid metabolism interact. The essential function of dysregulated hepatic glucose stability in the pathology of diabetes has motivated more than a century of research into the elemental regulatory mechanisms of liver glucose metabolism. Over the previous decade, fashionable tools of molecular biology, genetics, biochemistry, physiology, and metabolomics/flux have offered an enormous amount of perception into regulatory mechanisms of hepatic glucose metabolism. This chapter is an extension of the third edition of the International Textbook of Diabetes Mellitus [1] and devoted to integrating this new info with basic knowledge of regulatory paradigms of glucose metabolism in liver. Hepatic glucose manufacturing Overview Typical lean people spend more than half of their lives within the post-absorptive state, with lower than 5 g of glucose circulating of their blood to support life [6]. Even throughout relaxation the physique makes use of roughly eight g of glucose per hour, and during exercise this fee can enhance greater than twofold. The body would deplete circulating glucose in less than 30 min, resulting in extreme hypoglycemia, loss of neurologic operate and death, if not for a continuing endogenous provide of glucose. Under most conditions, liver offers roughly 90­95% of circulating glucose. This hepatic glucose manufacturing is maintained at exactly the same rate as whole physique glucose utilization, keeping blood glucose between 80­100 mg dL-1 no matter nutritional state or activity degree. Hepatic glucose production is equipped by the breakdown of stored glycogen (glycogenolysis) and the synthesis of new glucose from noncarbohydrate precursors (gluconeogenesis). In people, glycogenolysis and gluconeogenesis contribute about equally to hepatic glucose production following an in a single day quick [7]. After forty eight hours of fasting, glycogen is depleted and glucose is produced almost solely by gluconeogenesis [7]. During fasting, the liver produces glucose at a price that matches peripheral glucose utilization. After an in a single day quick in people (or 6-h quick in mice), glycogenolysis and gluconeogenesis contribute equally to hepatic glucose production. As fasting is prolonged, glycogen shops are depleted and gluconeogenesis becomes a larger contributor to glucose manufacturing. Muscle Am Lac ino tate Ac / ids Regulation of glucose metabolism in liver 195 Inasmuch as most mechanistic research referenced in this chapter have been carried out in rodent fashions, you will need to observe that rats and mice deplete hepatic glycogen much quicker, over approximately 24 and 12 h, respectively. Gluconeogenesis and glycogenolysis are regulated by hormone motion and autonomic mechanisms that alter substrate supply, allostery, posttranslational modification and enzyme transcription. These regulatory mechanisms are disrupted during kind 1 and a pair of diabetes resulting in an incapability to suppress gluconeogenesis and/or glycogenolysis and the event of hyperglycemia. The metabolic mechanism of hyperglycemia throughout diabetes is probably considered one of the most generally studied pathologic options of any disease. Hyperglycemia (>124 mg dL-1 glucose) occurs when the equilibrium between hepatic glucose production and peripheral glucose utilization is disrupted. Many but not all studies find endogenous glucose manufacturing to be increased throughout sort 2 diabetes. Perhaps more pertinent for sort 2 diabetes is the failure of hyperinsulinemia to suppress hepatic glucose production, which is indicative of hepatic insulin resistance, notably with regard to glucose metabolism [8]. Hepatic insulin resistance could be quantified utilizing hyperinsulinemic-euglycemic clamp approaches [8]. Exogenous insulin is administered to obtain hyperinsulinemia whereas glucose is concurrently infused to preserve normoglycemia. The fee of glucose infusion required to preserve normoglycemia reflects each insulin mediated glucose disposal and suppression of hepatic glucose manufacturing. If an isotope tracer of glucose is co-infused, the rate of glucose appearance could be determined from the dilution of the tracer [8]. Type 2 diabetic people have an impaired ability to suppress both hepatic gluconeogenesis and glycogenolysis [9] in response to insulin, and this revelation has led to intensive efforts to understand the metabolic, hormonal, and transcriptional regulation of those pathways utilizing genetically malleable fashions similar to mice.

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However, when the info was re-analyzed for subjects who had misplaced 7% of physique weight, lobular inflammation and ballooning were considerably improved (as well as steatosis), underscoring the importance of the magnitude of weight reduction to histologic benefit. Weight loss achieved through completely different strategies appears to be crucial issue to improve plasma aminotransferases, liver fat content, and histology. The function of way of life modifications in the absence of weight reduction is less clear and wishes additional assessment in well-designed studies. After remedy there was no difference in weight reduction between the two teams (-8% vs. Surgically induced dietary intervention the use of bariatric surgical procedure instead method to shed pounds has become extra well-liked in latest a long time given the problem of long-term weight loss. Different procedures are currently obtainable and could be divided into three varieties: restrictive (reduction of gastric capacity), malabsortive (bypasses a segment of the small bowel), and hybrid procedures (combination of the above) [63]. There is massive proof on the results of bariatric surgical procedure on glucose management [64], insulin sensitivity [65], and general improvement of associated comorbidities (hypertension, dyslipidemia, and so on) [64] in addition to constructive results on long-term survival [66]. Moreover, many of the current studies are retrospective, uncontrolled or have a small sample measurement [67­78]. Of note, in all of these research there was a very vital physique weight reduction after surgical procedure. The primary drawbacks of these research, nevertheless, have been their pattern dimension (7 to 19 patients, apart from one research [78] that included 70 patients) and the shortage of a control group. In addition, a quantity of research have reported that some sufferers develop new fibrosis after the surgical intervention [68,71,72]. As a consequence of these findings, there have been some issues concerning the effect of bariatric surgery on hepatic fibrosis. However, the examine was somewhat small (n = 16) and of comparatively brief duration (12 months). Their use should be promoted to prevent heart problems, but not as a method for histologic improvement. Fibrates have been reported to improve plasma aminotransferase levels or lower hepatic steatosis, but general results have been inconsistent and histology unchanged [5]. It has been reported to enhance liver enzymes, inflammatory markers, and some histologic parameters [93,94]. Several research reported that statins may lower plasma aminotransferase focus or hepatic steatosis by ultrasound [5,81,82]. In many of these trials results were difficult to separate from weight loss, dietary changes or different way of life modifications through the study. In studies by which a liver biopsy was carried out earlier than and after statin therapy, Kimura et al. Once once more, patients randomized to pentoxifylline had a worse baseline liver histology. Although the results with pentoxifylline are encouraging (especially the results of Zein et al. Although a number of studies have examined the function of these compounds in humans, most of those research have significant study design limitations [98,99], similar to being open-label and lack of proper controls, or use as the first consequence improvement of liver enzymes or liver fats by ultrasound. However, as discussed earlier, the that means from a scientific standpoint of a small discount in liver triglyceride content material (from 10. It decreases hepatic glucose production and improves insulin sensitivity at the degree of the liver, and to a lesser extent, muscle [109]. In animal fashions, exendin-4 has been reported to improve each liver function exams and histology [119,120]. Most of the early studies had been heterogeneous in terms of baseline affected person traits and showed inconsistent scientific efficacy [103,112,130­132]. In this population, pioglitazone (45 mg day-1) significantly decreased insulin resistance at the level of the liver, adipose tissue and skeletal muscle, and improved hepatic steatosis, inflammation and hepatocellular ballooning when in comparability with placebo. They randomized 247 subjects to vitamin E, pioglitazone, or placebo and found histologic improvement in liver steatosis and irritation however not fibrosis after pioglitazone treatment. Moreover, pioglitazone had a modest however significant impact on fibrosis in comparison with placebo (p = zero. Thiazolidinediones have the potential to exacerbate congestive heart failure and promote water retention. Moreover, its use has been associated with a greater threat of osteoporosis and bladder most cancers. However, there was additionally a significant discount in the mixed end result of demise, myocardial infarction, or stroke (p = zero.

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In distinction, polysplenia and asplenia occur at the side of advanced congenital multisystem abnormalities. Embryology the spleen is derived from mesoderm, unlike the adjoining gastrointestinal organs, which are endodermal derivatives. Mesenchymal condensations (splenic anlagen) that finally become the spleen seem near the creating dorsal pancreas in the course of the fourth to fifth weeks of gestation. The mesenchymal condensations are coated by the mesothelium of the growing dorsal mesogastrium, which establishes the connection of the embryonic splenic tissue with the splenorenal and gastrosplenic ligaments. The spleen is positioned within the left higher quadrant during rotation of the stomach. They come up from failure of fusion of the splenic anlagen and should be differentiated from splenosis, which is seeding of splenic tissue throughout the peritoneum from traumatic rupture of the spleen or disruption of the capsule during surgical procedure. In most sufferers, accent spleens are of no medical consequence; they could be found by the way at imaging, surgical procedure, or post-mortem. Occasionally they might turn into concerned in pathologic processes that have an effect on the spleen and have been reported to undergo torsion and infarction, which can produce left-upper-quadrant pain. In hematologic illnesses corresponding to thrombocytopenia purpura, therapeutic splenectomy ought to embrace removal of accessory spleens as a end result of postsplenectomy hypertrophy of an accessory spleen might trigger recurrence of the illness. Splenic Lobulation Splenic lobulations are created by persistence of the normal lobulated fetal spleen. Occasionally a really deep cleft or fissure develops within the spleen, creating a band. Wandering Spleen Wandering spleen is a uncommon situation occurring from congenital or acquired laxity in the supporting splenic ligaments. Prior belly surgical procedure, excessive laxity of ligaments because of the hormonal effects of pregnancy, and "prune stomach" syndrome have been suggested as causes of such acquired laxity. If intermittent torsion and detorsion of the splenic pedicle is going on, patients might describe the sensation or palpation of a movable intra-abdominal mass or complain of intermittent belly pain, discomfort, or fullness. If vascular compromise and infarction occur, patients will complain of extreme pain, which may be accompanied by vomiting and fever. These sufferers have a midline liver, bilateral bilobed lungs, bilateral pulmonary atria, a abdomen in indeterminate place, and a quantity of spleens. Additional anomalies could embrace a wide selection of congenital coronary heart defects, interruption 589 590 Gastrointestinal Imaging of the inferior vena cava with azygos continuation, truncated pancreas, and abdominal heterotaxy. The majority of patients with polysplenia are recognized in early infancy or early childhood with cardiac anomalies. Because the range of cardiac anomalies is wide, some sufferers have minor anomalies and come to medical consideration throughout adulthood. The cardiac defects are so extreme on this syndrome that patients hardly ever reside to adulthood. They are mostly situated on the splenic hilum however may be seen within the supporting splenic ligaments or adjoining to the pancreatic tail. Accessory spleens are provided by a department of the splenic artery and have a venous tributary draining into the splenic vein. Intrapancreatic splenunculi may be more difficult to diagnose as a end result of they could be mistaken for a hypervascular pancreatic tumor. The identical physiologic and pathologic processes that affect the conventional spleen could affect accessory spleens. Localized inflammatory modifications and fluid could also be current in the adjacent ligamentous fats. Splenic Lobulation Splenic lobules are mostly discovered on the medial or hilar border of the spleen. Occasionally they might be seen alongside the margin of the spleen bordering the anterior upper pole of the left kidney. As in contrast with a standard splenic cleft, a splenic laceration is usually irregular and associated with adjoining hemorrhage or hematoma. Round, well-defined mass (arrows) inside the tail of the pancreas is isointense to the adjacent spleen on fat-saturated gradient-echo T1-weighted image (A), fat-saturated inversion recovery T2-weighted picture (B), intravenous gadoliniumenhanced T1-weighted image within the arterial section of enhancement (C), and intravenous gadoliniumenhanced T1-weighted image within the portal venous part of enhancement (D).

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Such recommendation needs to keep in mind the high vitality density of all fats and the potential of fiber-rich carbohydrate meals to promote satiety. There can additionally be inadequate proof to make suggestions about preferred protein kind. In that research a modest improvement in glycemic control occurred in each the high protein and the relatively high carbohydrate control food regimen and was associated with related modest weight reduction which occurred on each diets. This was inevitably associated with an increase in dietary fats, particularly saturated fats. What was regularly not appreciated was that the benefits of a high carbohydrate, excessive fiber food regimen had been demonstrated in research involving very excessive intakes of fiber-rich carbohydrate (40 g dietary fiber or extra per day) usually derived from intact fruit and vegetables, legumes, and flippantly processed wholegrain cereals [19]. This advice concerning the acceptability of high carbohydrate intakes was frequently translated, by sufferers and typically health professionals, into diets high in quickly digested starchy foods such as rice, potato, and "wholemeal" bread. There was no proof that such foods conferred profit by way of glycemic control. They specify that metabolic characteristics counsel probably the most acceptable consumption within this range. For these with marked insulin resistance and appreciably raised triglyceride ranges, intakes in path of the lower end of the range are most popular. Dietary fiber is emphasized in each sets of suggestions with the European set suggesting 20 g/1000 kcal or extra if potential, about half of which should be soluble. Daily consumption of no less than five servings of fiber-rich vegetables or fruit, and at least 4 servings per week of legumes assist to provide minimal necessities and cereal-based foods ought to, every time attainable, be wholegrain and excessive in fiber. However, nature of carbohydrate can also be a determinant of glucose ranges after a meal. This in turn relies upon upon the pace, extent, and site of digestion and absorption. These include the appreciable inter-and intra-individual variation and the fact that the index supplies no indication as to the general impression of the food. For instance, energy-dense meals high in fats and sugar such as ice-cream are inclined to have a low glycemic index. This includes a restriction of fatty meat and meat merchandise in addition to high-fat dairy merchandise, confectionery, muffins, and high-fat manufactured meals, which 582 Chapter 40 Table 40. American Journal of Clinical Nutrition 2002;76:5­56; Minako K: "Glycaemic response and Glycaemic index to five kinds of rice in folks of European and Chinese ethnicity. It is with regard to nature of carbohydrate that there was an apparent discrepancy between North American and European suggestions. European recommendations are far more directional and stated clearly that vegetables, legumes, fruits, and cereal-derived foods had been the preferred carbohydrate choices and that wherever potential, they should have a low glycemic index and be excessive in dietary fiber. A variety of obese sufferers have opted to attempt very low carbohydrate, excessive fats or excessive protein dietary approaches to weight loss. It ought to be clear from this dialogue that the suitable vary of intakes of macronutrients is compatible with the big selection of dietary patterns traditionally consumed by people throughout Europe and North America. The Mediterranean food regimen sometimes eaten in southern Europe is very different from that consumed within the Nordic countries, yet both these dietary patterns, as nicely as the "typical" British diet consisting of meat and three greens at major meals, can all be prepared in order that macronutrient distribution conforms with the really helpful ranges. This applies additionally to the broad range of Asian cuisines which are actually well-liked in Europe and North America. However, it should be noted that whereas using traditional methods Dietary management of diabetes mellitus in Europe and North America 583 of preparation many dishes are certainly suitable for people with diabetes, but when traditional recipes have been tailored for Western consumption they might have elevated amounts of fats, sugars, and rapidly digested starches. Antioxidant vitamins, vitamins, and minerals A entire vary of micronutrients have at one time or one other been the focus of consideration in diabetes. Those with elevated blood stress may be recommended to additional reduce their intake. There is a considerable physique of proof from prospective research in nondiabetic people which means that a variety of antioxidant nutrients and good meals sources of these (fruits, vegetables, nuts, berries) are protecting against heart problems [27,28]. There is a few proof from short-term studies that consumption of meals wealthy in these nutrients and supplementation with a variety of synthetic micronutrients that some markers of oxidative stress could be favorably influenced by substantial intakes [29]. There has additionally been interest in possible roles for chromium, potassium, magnesium and zinc, deficiencies of which can irritate carbohydrate intolerance. Deficiencies, particularly of magnesium, have been detected in poorly controlled sort 1 patients. Sweeteners, supplements and practical meals A range of nonnutritive sweeteners is on the market for use in drinks, cooking, and manufactured foods.

Aidan, 65 years: This hyperglycemia may be offset for a number of years by an increase in pancreatic insulin secretion, and hence hyperinsulinemia accompanies insulin resistance. It is understood that islet parasympathetic nerves are activated in anticipation of meals and early during the ingestive phase of a meal. Demographic and Clinical Features Acute cholecystitis is amongst the most incessantly encountered stomach inflammatory processes.

Rathgar, 44 years: The diploma of splenic enlargement will not be spectacular because these sufferers usually have small, poorly functioning, or nonfunctioning spleens. The latissimus dorsi, quadrates lumborum, and paraspinal muscles are situated within the again. Substance P Substance P was discovered in 1931 and is at present recognized to be inside the tachykinin household of peptides [50].

Sugut, 41 years: This increased activity of the sympathetic nervous system will lead to peripheral vasoconstriction and thereby an increased blood pressure. American Journal of Physiology- Endocrinology and Metabolism 2009;297(4):E889­E897. Small branches of the best bile duct may also insert directly into the gallbladder.

Ateras, 59 years: The most acceptable strategy to reaching weight discount depends upon the necessities of particular person sufferers. Effect on fibrinolysis A current examine on bovine aortic endothelial cells indicated that sure sulfonylureas could enhance fibrinolysis and that the fibrinolytic mechanism is associated with sulfonylurea-enhanced production of plasminogen activator [75]. The impact is due to the direct actions of hormonal adjustments on glucose transport in addition to to the inhibition of glucose uptake secondary to an enhancement of lipolysis and muscle glycogen breakdown [10,35,36].

Cruz, 33 years: Difficult to differentiate from gallbladder carcinoma and could also be related to the latter. In humans, glycogenolysis and gluconeogenesis contribute about equally to hepatic glucose manufacturing following an in a single day fast [7]. Alterations within the auto regulation of blood pressure occur, with aggressive attempts at reducing blood stress resulting in organ hypoperfusion.

Ramirez, 21 years: Neonatal Anemia-Etiology Neonatal anemia may be etiologically categorised into three major groups: 1. Patients might complain of progressive abdominal ache, rising belly girth, and weight reduction. Delayed (more than 5 minutes) contrast-enhanced photographs are helpful for differentiating small, quickly filling hemangiomas from hypervascular metastases.

Rufus, 36 years: As the high-grade dysplastic nodule evolves towards malignancy, irregular neoplastic arterial provide will increase and regular arterial and portal provide decreases. Treatment during infancy or later for surgical procedures, contains platelet transfusions as needed. Endothelial dysfunction is its major driver, as pharmacologic vasodilation with sodium nitroprusside restores the anabolic response of muscle protein synthesis to insulin in wholesome older subjects [10].

Asam, 34 years: Likewise, mice that lack toll-like 5 receptor in the intestine mucosa are much less in a place to defend in opposition to bacterial infection and develop a metabolic syndrome type phenotype that includes elevated physique weight and body fats, insulin resistance, hyperlipidemia, and hypertension [26]. Concept As mentioned, intervening to "open the loop" to perform a glucose clamp requires sources in dollars and labor. Endpoints have been primarily changes in fasting blood glucose levels with values <100 mg dL-1 being outlined as excellent, between 100 and one hundred thirty mg dL-1 as good, and >130 mg dL-1 unsatisfactory [77].

Hassan, 55 years: To compensate for differences in insulin clearance, many investigators divide glucose disposal (Rd) by the increment in insulin under steady-state situations (M/I). It could additionally be seen at the side of fibromatosis in the abdominal wall (abdominal fibromatosis). Further, a recent paper by Eric Lander and coworkers offered compelling evidence that gene­gene interplay can even contribute to lacking heritability by causing "phantom heritability" that inflates the estimated slender sense heritability of the trait [74].

Torn, 46 years: Levy Definition the spleen is essentially the most generally injured intra-abdominal organ in blunt trauma. Indirect inguinal hernias can extend alongside the spermatic wire into the scrotum in men; in girls, indirect inguinal hernias follow the course of the spherical ligament into the labia majus. Thus, roughly 25 times extra glycosyl units are stored in intracellular depots as glycogen than are dissolved in body water as free glucose.

Musan, 60 years: Screening colonoscopy is often initiated at 10 to 12 years of age and happens every 6 to 12 months in order to establish polyps. Multiphasic imaging, together with acquisition of arterial-phase pictures, is important for the detection and characterization of suspected hypervascular metastases. Key points · Glucose concentration is on common 15% larger in the plasma than the whole-blood glucose underneath strange circumstances.

Arokkh, 42 years: Addition of high-dose cystosine arabinoside (AraC) has been used in highly refractory patients. Serology and cultures for infectious agents and lively or chronic infections with viruses. However, such genetic mutations are very uncommon, but hyperproinsulinemia is a standard trait of type 2 diabetes [91].

Brenton, 58 years: In forearm muscle, insulin-stimulated glucose transport (measured with the triple tracer technique) is markedly impaired in lean sort 2 diabetics [36,203,271]. Ischemic cholangiopathy is often caused by hepatic artery thrombosis or stenosis, normally leading to multifocal biliary stricture formation. Recent observations counsel that diabetes ought to be seen as a paracrinopathy of the islets of Langerhans in which intra-islet insulin deficiency ends in extreme glucagon release from the neighboring cells and the ensuing hyperglucagonemia being a critical factor in the pathophysiology of diabetes [3,4].

Garik, 47 years: Although oscillatory insulin secretion may have a job in modulating insulin action, notably at the level of the liver, it has also been proposed lately that this sample may have a significant impact at the level of the cell by stopping desensitization of the insulin signaling pathway that contributes to regulation of -cell mass [128]. One class of lipid rafts accommodates caveolin proteins in invaginated structures referred to as caveolae ("little caves"). The overall contribution of the liver (first move plus recirculation) is due to this fact dominant (approximately 90%).

Hatlod, 53 years: Because weight loss usually is desirable in these sufferers carbohydrate complement is less expedient. The prevalence of each diabetes and its microvascular issues in a Pacific Island inhabitants (20 years or older) of Western Samoa was examined in 1978 and 1991 [31]. As was the case for the time period "glucose toxicity," the use of the words "oxidative stress" could connote a purely deleterious effect corresponding to the buildup of oxidized and dysfunctional lipids, proteins, and nucleic acids due to excess free radicals and other oxidants.

Mezir, 25 years: It is evident that the bodily lively diabetic, like the sedentary one, balances between hyper- and hypoglycemia. Hence, normative data relating to hematologic parameters in the newborn are extremely dependent on gestational age. It is understood that due to common well being and comorbidities, not all elderly hypertensive sufferers might find a way to follow the method to life expenses strictly, however an try must be made to educate them.

Mannig, 31 years: Saito K, Yaginuma N, Takahashi T: Differential volumetry of A, B and D cells in the pancreatic islets of diabetic and nondiabetic subject. In addition, persistent exposure to elevated glucose levels may result in dedifferentiation with lack of genes associated with -cell function and overexpression of genes normally repressed in differentiated cells [66,67]. Site-specific hemorrhages, such as intracranial or intraabdominal bleeds as a outcome of start trauma can lead to rapid exsanguination and demise in neonates.

Gorn, 28 years: Since insulin receptor tyrosine kinase activity assays are carried out in vitro, the results of those assays may present deceptive data with regard to insulin receptor function in vivo. These approaches have supplied new and surprising insight into these regulatory pathways. Change in body weight from screening over 2 years, introduced as observed information Liraglutide 1.

Osmund, 22 years: Therefore, interventions geared toward enhancing insulin sensitivity are of paramount importance. Obese individuals, each diabetic and nondiabetic, have moderate-to-severe insulin resistance with compensatory hyperinsulinemia. After each examine day, the rate of glucose uptake throughout the forearm was measured underneath standardized situations of glycemia and insulinemia to quantitate insulin sensitivity.

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