Derangement Of Cellular Metabolism Research Articles

Brain Protection after Anoxic Brain Injury: Is Lactate Supplementation Helpful?

While sudden loss of perfusion is responsible for ischemia, failure to supply the required amount of oxygen to the tissues is defined as hypoxia. Among several pathological conditions that can impair brain perfusion and oxygenation, cardiocirculatory arrest is characterized by a complete loss of perfusion to the brain, determining a whole brain ischemic-anoxic injury. Differently from other threatening situations of reduced cerebral perfusion, i.e., caused by increased intracranial pressure or circulatory shock, resuscitated patients after a cardiac arrest experience a sudden restoration of cerebral blood flow and are exposed to a massive reperfusion injury, which could significantly alter cellular metabolism. Current evidence suggests that cell populations in the central nervous system might use alternative metabolic pathways to glucose and that neurons may rely on a lactate-centered metabolism. Indeed, lactate does not require adenosine triphosphate (ATP) to be oxidated and it could therefore serve as an alternative substrate in condition of depleted energy reserves, i.e., reperfusion injury, even in presence of adequate tissue oxygen delivery. Lactate enriched solutions were studied in recent years in healthy subjects, acute heart failure, and severe traumatic brain injured patients, showing possible benefits that extend beyond the role as alternative energetic substrates. In this manuscript, we addressed some key aspects of the cellular metabolic derangements occurring after cerebral ischemia-reperfusion injury and examined the possible rationale for the administration of lactate enriched solutions in resuscitated patients after cardiac arrest.

Traumatic Brain Injury in Children: Sport-related Concussions in Children

ABSTRACT Concussion is a worldwide health concern among children and adolescents. Over the decades concussion has been gradually better recognized as an entity that accounts for a significant disability post head trauma in patients. Patients present with cognitive, somatic and oculo-vestibular symptoms that can be incapacitating. Most concussion symptoms are transient and resolve within 1–2 weeks but can persist for years. Concussion pathophysiology is complex and may not be fully understood but it involves numerous mechanisms including cellular metabolic derangements, cerebral blood inflow, and axonal disruption. With no associated objective biomarkers or visible pathologic brain changes, diagnosis of concussion can be challenging. Many organizations and collaborative groups have suggested numerous definitions and diagnostic criteria for concussion in an attempt to improve the evidence-based clinical assessments and therapies for concussion. Proper assessment and evaluation is crucial starting from counseling of the patient, gradual return to cognitive and physical activity in an individualized treatment plan to ensure a timely return to daily activities and full sport participation. This report provides a grasp over the current state of sport-related concussion knowledge, diagnosis, and clinical evaluation in children and adolescent, with a focus on the ocular symptoms and signs.

Validation of an artificial intelligence algorithm applied to a metabolic substrate analysis of urine for detection of urothelial cancer.

e16008 Background: Urine tests such as urine cytology are commonly used for the diagnosis and monitoring of urothelial cancer. These tests are often limited by issues related to sensitivity or specificity. It is well known that derangement of cellular metabolism is one of the hallmarks of carcinogenesis. As urothelial cancer is in constant contact with urine, we hypothesize that metabolite composition in the urine may provide insight into possible urothelial cancer presence in the urinary tract. In this study, we evaluated a metabolomics based urine test for the detection of urothelial cancer. Methods: In this prospective, multi-institutional IRB approved study, urine samples were collected from a total of 57 urothelial cancer patients and non-urothelial cancer controls. Gas chromatography profiles of urine small molecule metabolites were generated to yield over 2400 data points of metabolite peaks and troughs for every urine sample. A machine-learning based algorithm (Abilis Life Sciences) was constructed to predict urothelial cancer versus non-cancer controls through analysis of peaks and trough patterns of urine metabolomics profiles. Predictions were made in a blinded fashion and descriptive statistics of test sensitivity and specificity were generated. Results: The urine metabolite composition of 57 patients were analyzed and urothelial cancer predictions were generated. The test demonstrated an overall accuracy of 89.5% (51 out of 57 cases correctly predicted). The sensitivity of the test was 97.1% (34 out of 35) and specificity was 77.3% (17 out of 22). The Positive Predictive Value is 87.2%, while the Negative Predictive Value is 94.4%. The area under the curve for the receiver operating characteristic curve was 0.87. Conclusions: Urine based metabolic profile analysis using artificial intelligence algorithms is a promising potential diagnostic test for detection of urothelial cancer. Further testing is ongoing to increase robustness of the validation.

Neuroimaging in mitochondrial disorders

MRI and 1H magnetic resonance spectroscopy (1HMRS) are the main neuroimaging methods to study mitochondrial diseases. MRI can demonstrate seven 'elementary' central nervous system (CNS) abnormalities in these disorders, including diffuse cerebellar atrophy, cerebral atrophy, symmetric signal changes in subcortical structures (basal ganglia, brainstem, cerebellum), asymmetric signal changes in the cerebral cortex and subcortical white matter, leukoencephalopathy, and symmetric signal changes in the optic nerve and the spinal cord. These elementary MRI abnormalities can be variably combined in the single patient, often beyond what can be expected based on the classically known clinical-pathological patterns. However, a normal brain MRI is also possible. 1HMRS has a diagnostic role in patients with suspected mitochondrial encephalopathy, especially in the acute phase, as it can detect within the lesions, but also in normal appearing nervous tissue or in the ventricular cerebrospinal fluid (CSF), an abnormally prominent lactate peak, reflecting failure of the respiratory chain with a shift from the Krebs cycle to anaerobic glycolysis. So far, studies correlating MRI findings with genotype in mitochondrial disease have been possible only in small samples and would greatly benefit from data pooling. MRI and 1HMRS have provided important information on the pathophysiology of CNS damage in mitochondrial diseases by enabling in vivo non-invasive assessment of tissue abnormalities, the associated changes of blood perfusion and cellular metabolic derangement. MRI and 1HMRS are expected to serve as surrogate biomarkers in trials investigating therapeutic options in mitochondrial disease.

Across Sectional Study on Thyroid Profile in Type Ii Diabetes Mellitus

Background & Objectives: Diabetes Mellitus (DM) is a common endocrine disorder which involves multiple organ systems and leads to significant morbidity and mortality due to accompanying complications. DM has been defined as A METABOLIC SYNDROME characterized by chronic hyperglycemia & disturbance in carbohydrate, fat, protein metabolism with absolute or relative deficiency in insulin secretion or insulin action. There are macro and micro vascular complications of diabetes involving kidneys, eyes, blood vessels, nerves and heart. Thyroid diseases are also a common endocrinopathy seen in adult population. Thyroid hormones are intimately involved in cellular metabolism. Thus excess or deficit of either insulin or thyroid hormones could result in functional derangement of cellular metabolism. This study would be an attempt to study the prevalence of thyroid disorders in patients with type II diabetes. Materials & Methods: This cross sectional study included 100 patients with type II diabetes without previous thyroid abnormalities after meeting inclusion criteria during Jan 2015 to June 2015 held at Mamata Medical College & General Hospital- Khammam, TS state. Results: Out of 100 patients with type II DM, 14 had abnormal thyroid profile of which 13 had subclinical hypothyroidism, 1 patient had overt hypothyroidism, 61% were females, more among those with duration up to 5 years (68%). Conclusion: The prevalence of thyroid dysfunction is more common among type II DM patients than in general population. The prevalence is higher in females than in males.

The relationship between hyperhomocysteinemia and neurodegeneration.

Homocysteine (Hcy) is a key junction in methionine metabolism. In inherited forms of hyperhomocysteinemia patients develop early vascular damage and cognitive decline. Hyperhomocysteinemia is a common consequence of dietary, behavioral and pathological conditions and is epidemiologically related to different diseases, among them neurodegenerative ones are receiving progressively more attention in the last years. Several detrimental mechanisms that see in Hcy a possible promoter seem to be implicated in neurodegeneration (protein structural and functional modifications, oxidative stress, cellular metabolic derangements, epigenetic modifications, pathological aggregates deposition, endothelial damage and atherothrombosis). Interventional studies exploring B group vitamins administration in terms of prevention of Hcy-related cognitive decline and cerebrovascular involvement have shown scant results. In this review, current and possible alternative/complementary approaches are discussed.

81: Maternal glucose supplementation alleviates intrauterine inflammation-induced inhibition of autophagy in fetal brain

We have previously shown that fetal brain ceramide, a major component of myelin and an important inducer of autophagy, was decreased in the chorioamnionitis mouse model. Maternal glucose treatment increased ceramide levels and alleviated fetal brain injury. The objectives of this study were to determine whether autophagy is altered by lipopolysaccharide (LPS) - induced intrauterine (IU) inflammation and how maternal glucose supplementation ameliorates fetal brain injury. A mouse model of chorioamnionitis at term was utilized (n=36). Dams were randomly assigned to 4 groups: saline+saline, saline+glucose, LPS+saline and LPS+glucose. Pregnant CD-1 mice at E18 received either saline or LPS via IU injection. After surgery, dams received either 10% glucose (0.2ml at 2, 3, 4 and 5 h) or same amount of saline intraperitoneally. Fetal brains were collected at 6 h after LPS injection. Immunohistochemistry, western blot, electron microscopy (EM) and free fatty acid assay were performed on fetal brains. LPS injection significantly decreased autophagic markers, LC3 and beclin-1 protein levels in fetal brain compared to control by western blot; glucose treatment increased LC3 and beclin-1 expression following LPS exposure (p<0.05, One-way ANOVA). These results were confirmed by immunohistochemistry. EM demonstrated that immature autophagosome (incomplete closure of double membrane) appeared in LPS+saline group, accompanied by damaged cell morphology (endoplasmic reticulum stress). Glucose treatment decreased the immature autophagosome and improved cellular morphology. Free fatty acid analysis did not demonstrate changes between groups, indicating direct influence of glucose on ceramide levels. Maternal glucose administration after LPS-induced IU inflammation ameliorates a decrease in autophagy in fetal brain, suggesting a neuroprotective mechanism by which glucose prevents derangements of cellular metabolism. Clinically, these data suggest that once chorioamnionitis is diagnosed, maternal glucose supplementation may be of benefit in optimizing neurological outcomes in the offspring.

Concurrent acute spontaneous tumor lysis syndrome complicated with multiple organ failure in a patient with pre-existing undiagnosed lung cancer.

Acute kidney injury, a common complication associated with malignancy, occurs in various clinical situations for numerous reasons. Acute tumor lysis syndrome (TLS) is possibly the most significant cause of acute kidney injury in cancer patients, because it is fulminant at onset and associated with severe metabolic derangements. Acute spontaneous tumor lysis syndrome is rare and most of the related malignancies belong to hematologic malignancies but it has seldom been investigated as bulky or advanced metastatic non-hematologic malignancies. TLS comprises a clinical laboratory derangement of cellular metabolism which can lead to acute renal impairments, cardiac arrhythmia, seizures and patient demise. Prevention and treatment of tumor lysis syndrome depends on early recognition of at-risk patients, volume repletion and xanthin oxidase inhibitors. In addition, in patients with high risk tumor types, prophylactic use of rasburicase before chemotherapy is required. If dialysis is required, continuous modalities may be favored, particularly in patients with more severe TLS. This case report discusses a 79-year-old man with controlled Alzheimer's disease presented with picture of septic shock and multiorgan dysfunction (acute kidney injury, acute lung injury, acute brain injury) pulmonary suppuration in the right lung field due to aspiration pneumonia with infection-induced systemic inflammatory response (SIRS) was diagnosed. Further work-up revealed lung cancer on chest CT scan. Antibiotic, respirator and hemodialysis treatment improved his condition but died several days later. Acute spontaneous TLS may present in association with infectious SIRS and multiple organ failure, the combination of which results in significant mortality.

Hereditary Leiomyomatosis and Renal Cell Carcinoma (HLRCC)

Rapid ("warm") autopsies of patients with advanced metastatic cancer provide invaluable insight into the natural history, pathobiology, and morphology of advanced and treatment-resistant tumors. Here, we report a rapid autopsy case of a hereditary leiomyomatosis and renal cell carcinoma (HLRCC) patient with advanced metastatic renal cell carcinoma (RCC)-the first such case described for either a primary renal tumor or HLRCC-related cancer. Mutations in the fumarate hydratase (FH) gene underlie HLRCC, a rare syndrome involving cutaneous and uterine leiomyomata and aggressive kidney tumors. Loss of heterozygosity at the wild-type FH gene locus results in profound cellular metabolic derangement, "pseudohypoxic" upregulation of hypoxia-inducible factor 1α (HIF-1α)-dependent transcription, and aberrant protein succination; these molecular changes drive oncogenesis of kidney tumors in HLRCC patients. The current index patient had a high-grade RCC with classic morphologic features of HLRCC, including large nuclei with prominent eosinophilic nucleoli and perinucleolar clearing. In addition, this patient's RCC demonstrated extensive sarcomatoid and rhabdoid features-morphologies not previously well described in HLRCC-associated kidney tumors. Here, we report the extent of metastatic dissemination and supplement this unique tumor morphology with mitochondrial enzyme histochemistry and extended immunohistochemical analysis. Tumor cells strongly expressed PAX8, vimentin, CD10, and the HIF target GLUT1 and showed increased nuclear p53 accumulation; the expression of other RCC markers was negative. We also detail microscopic tubular epithelial changes in the grossly uninvolved ipsilateral renal parenchyma and demonstrate sporadic, aberrant upregulation of the HIF targets GLUT1 and CAIX in dysplastic peritumoral tubules.

ROLE OF HYPERGLYCEMIA-MEDIATED ERYTHROCYTE REDOX STATE ALTERATION IN THE DEVELOPMENT OF DIABETIC RETINOPATHY

To evaluate erythrocyte redox state and its surrogates in patients with different stages of diabetic retinopathy and their association with cellular metabolic derangement developed in retinal microvascular cells. Sixty type 2 diabetic patients with nonproliferative diabetic retinopathy (NPDR), 85 patients with proliferative diabetic retinopathy (PDR), and 70 patients with diabetes but without retinopathy were considered as diabetic control (DC) for the study. In addition, 65 normal individuals without diabetes were enrolled as healthy control in this study. Erythrocyte oxidized nicotinamide adenine dinucleotide phosphate / reduced nicotinamide adenine dinucleotide phosphate (NADP / NADPH), oxidized nicotinamide adenine dinucleotide / reduced nicotinamide adenine dinucleotide (NAD / NADH) glutathione, plasma and vitreous lactate, and pyruvate levels were determined by enzymatic reaction-based spectrophotometric assay for the patients and individuals. Erythrocyte NADP+ to NADPH ratio to NADPH ratio was found to be significantly higher among NPDR and PDR patients compared with DC subjects (P < 0.0001). Erythrocyte-reduced glutathione was significantly decreased in patients of NPDR (P = 0.0004) and patients of PDR (P = 0.0157) compared to DC. Erythrocyte NAD to NADH ratio was also significantly decreased in patients of NPDR (P < 0.0001) and PDR (P < 0.0001) compared to DC subjects. Lactate to pyruvate ratio of plasma was elevated significantly in patients with NPDR compared with DC (P < 0.0001) and those having PDR (P = 0.0046). In the vitreous fluid, the lactate to pyruvate ratios were found to be significantly lower in normal individuals without diabetes compared with patients having PDR (P < 0.0001). Hyperglycemia-mediated erythrocyte redox state alterations might be a potential risk factor for the development of NPDR in poorly controlled diabetic subjects.

Conceptual Framework for Cutting the Pancreatic Cancer Fuel Supply

Pancreatic ductal adenocarcinoma (a.k.a. pancreatic cancer) remains one of the most feared and clinically challenging diseases to treat despite continual improvements in therapies. The genetic landscape of pancreatic cancer shows near ubiquitous activating mutations of KRAS, and recurrent inactivating mutations of CDKN2A, SMAD4, and TP53. To date, attempts to develop agents to target KRAS to specifically kill cancer cells have been disappointing. In this regard, an understanding of cellular metabolic derangements in pancreatic cancer could lead to novel therapeutic approaches. Like other cancers, pancreatic cancer cells rely on fuel sources for homeostasis and proliferation; as such, interrupting the use of two major nutrients, glucose and glutamine, may provide new therapeutic avenues. In addition, KRAS-mutant pancreatic cancers have been documented to depend on autophagy, and the inhibition of autophagy in the preclinical setting has shown promise. Herein, the conceptual framework for blocking the pancreatic fuel supply is reviewed.

Steroid Responsive A3243G Mutation MELAS

Mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) is a multisystem disorder caused by systemic cellular metabolic derangement that is characterized predominantly by rapidly progressive deterioration of the central nervous system. We describe a patient with an abrupt onset of rapidly recurring episodes of aphasia, hemianopsia, and parietal pseudocerebellar ataxia, leading to the diagnosis of A3243G mutation MELAS. These stroke-like episodes appeared to be initiated by metabolic derangement, as evidenced by lactic-acid elevation in the cerebral spinal fluid and lactate peaks observed on magnetic resonance spectroscopy. Magnetic resonance imaging further revealed that neuronal loss during the acute episodes occurred in regions of paradoxically increased cerebral blood flow. Diffusion-tensor and arterial-spin-labeled perfusion imaging showed that the volume of tissue loss after the stroke-like episodes greatly exceeded the limits of the cortical areas affected by the initial metabolic insult. The patient was consented to a trial of compassionate use, high-dose intravenous corticosteroids, resulting in marked and sustained clinical improvement. The majority of neurons lost in an acute episode are injured not by a primary failure to meet metabolic demand, but by a poorly regulated compensatory hyperperfusion response. Regional hyperperfusion leads to apoptotic cell death through a progression from vasogenic to cytotoxic edema. The efficacy of corticosteroids in our study patient demonstrates that inflammatory mediators and blood-brain barrier dysfunction may play a role in the pathophysiological cascade that leads to the regional hyperperfusion in MELAS.

Glutamine attenuates endotoxin-induced lung metabolic dysfunction: Potential role of enhanced heat shock protein 70

Objective Septic shock leads to derangement of cellular metabolism. Enhanced heat shock protein 70 (HSP-70) can preserve cellular metabolism after other forms of cellular stress. Glutamine (GLN) can enhance lung HSP-70 expression after lethal endotoxemia. However, it is unknown whether GLN can enhance HSP-70 expression and attenuate lung metabolic dysfunction after sublethal endotoxemia. Our aim was to determine whether GLN could upregulate HSP-70 and attenuate metabolic dysfunction in lung tissue after sublethal endotoxemia. Methods Sprague-Dawley rats were assigned to one of five groups. The first two groups were treated with Escherichia coli lipopolysaccharide (LPS; 1 mg/kg intravenously). GLN (0.75 g/kg intravenously) or balanced salt solution as a control was administered 5 min after LPS administration. The next two groups of rats were treated with quercetin (HSP-70 inhibitor; 400 mg/kg intraperitoneally) 6 h before LPS administration. The final group received no treatment. Lung tissue was harvested 24-h after LPS and analyzed with immunofluorescence and western blot for HSP-70. Tissue metabolites were quantified by 1H and 31P nuclear magnetic resonance spectroscopy. Results GLN compared with balanced salt solution (BSS) administration in LPS-treated animals led to significant increases in lung HSP-70. Increased HSP-70 expression was observed in lung epithelial cells and macrophages. GLN significantly improved the ratio of adenosine triphosphate to adenosine diphosphate in the lung after LPS. Quercetin inhibited a GLN-mediated increase in lung HSP-70 and blocked a beneficial effect of GLN on the ratio of adenosine triphosphate to adenosine diphosphate after LPS. Conclusions A single dose of GLN can enhance HSP-70 in pulmonary epithelial cells and macrophages after sublethal endotoxemia. Further, GLN can attenuate endotoxin-induced lung metabolic dysfunction. GLN's beneficial effect on lung tissue after metabolic dysfunction caused by sublethal endotoxemia may be mediated in part by enhanced HSP-70.

Effects of proteinosis surfactant proteins on the viability of rat alveolar macrophages.

Pulmonary alveolar proteinosis (PAP) is a disease of unknown etiology that is characterized by the accumulation of protein- and lipid-rich insoluble material in alveoli and terminal bronchioles of the lung. Alveolar macrophages (AM) in PAP are reportedly extremely large and have low viability. We investigated substances in lavaged lung material from patients with PAP that induced these cellular changes in rat AM. Rat AM were incubated for various periods with liposomes prepared from lipids and isolated hydrophobic surfactant apoproteins, and cell size, viability, and lactate dehydrogenase release were determined. Of the hydrophobic apoproteins, a dimeric form of surfactant-associated protein-C ([SP-C]2) had the most marked effects. In addition, [SP-C]2 induced increased superoxide anion release at an early phase (6 to 12 h) and an increase in glutathione content at 24 h of incubation. At 3 d after incubation, cellular glutathione and adenosine triphosphate (ATP) content were significantly decreased in cells treated with [SP-C]2, [SP-C]2 was presumed to cause early cell death through increased formation of superoxide anion and the subsequent derangement of cellular metabolism. [SP-C]2 was not removed from cells, and SP-B and SP-C were removed at slower rates than lipids. The changes in macrophages induced by [SP-C]2 may contribute to establishing PAP.

Hypoxia-ischaemia model in the 7-day-old rat: possibilities and shortcomings.

The Levene model in 7-day-old rats is the most often used model of hypoxia-ischaemia (HI) in immature animals. The rat central nervous system is immature at birth and corresponds neurodevelopmentally to the term human infant during the second postnatal week. The Levene model of HI differs from clinical asphyxia with respect to the unilateral distribution of brain injury and lack of multi-organ dysfunction. Furthermore, it does not allow cardiovascular monitoring or repeated blood sampling. On the other hand, the progressive nature of HI bears many similarities to birth asphyxia with regard to blood flow changes and cellular metabolic derangements. The model is well characterized, easy to carry out and the low cost allows inclusion of a sufficient number of animals for dose-response evaluation of neuroprotective agents. In addition, it provides the unique opportunity of long-term evaluation of neuropathological and functional outcome.

Intervention in diabetic vascular disease by modulation of growth factors

Several growth factors have been implicated in the derangements of cellular metabolism and proliferation that occur in diabetes, eg, kidney mesangial expansion, retinal neovascular formation, and acceleration of atherosclerosis in large vessels. These phenomena contribute to the development and progression of diabetic microvascular and macrovascular disease. Pharmacological interventions aimed at reducing growth factor alterations, among other actions in diabetic vasculopathy, include a multitude of classes of drugs, such as angiotensin-converting enzyme (ACE) inhibitors, calcium antagonists, lipid-lowering drugs, and somatostatin analogs. New potential interventions, ie, antisense oligonucleotide local delivery, are being applied in growth factor research and may prove beneficial in diabetic macrovascular disease.

The presence of tumour necrosis factor in CSF and plasma after severe head injury

In a cohort of victims of traumatic brain injury, 18 out of 50 patients had a plasma tumour necrosis factor (TNF) concentration above 2 pg/ml within 24 h of injury (mean 12.19, SD 45.96 pg/ml). Twenty-six had CSF samples available of which 17 demonstrated TNF concentrations above 1 pg/ml (mean 3.98, SD 3.61 pg/ml). We conclude that traumatized brain parenchyma is a significant source of TNF activity and implicate the cytokine in cellular metabolic derangements following head injury.

Glycolytic inhibition and calcium overload as consequences of exogenously generated free radicals in rabbit hearts.

Free radicals have been implicated in the pathogenesis of reperfusion injury, but it is unclear how they exert their deleterious effects on cellular metabolism. Several lines of indirect evidence suggest that free radicals elevate intracellular Ca2+ concentration ([Ca2+]i) and inhibit glycolysis as part of their mechanism of injury. We tested these ideas directly in hearts subjected to hydroxyl radicals produced by the Fenton and Haber-Weiss reactions. Nuclear magnetic resonance spectra were obtained from Langendorff-perfused rabbit hearts before, during, and after 4 min of perfusion with H2O2 (0.75 mM) and Fe(3+)-chelate (0.1 mM). Isovolumic left ventricular pressure exhibited progressive functional deterioration and contracture after exposure to H2O2 + Fe3+. Phosphorus nuclear magnetic resonance (NMR) spectra revealed partial ATP depletion and sugar phosphate accumulation indicative of glycolytic inhibition. To measure [Ca2+]i, fluorine NMR spectra were acquired in a separate group of hearts loaded with the Ca2+ indicator 5F-BAPTA [5,5'-difluoro derivative of 1,2-bis-(o-aminophenoxy)ethane- N,N,N',N'-tetraacetic acid]. Mean time-averaged [Ca2+]i increased from 347 +/- 14 nM in control to 1,026 +/- 295 nM 4 min after free radical generation (means +/- SEM, n = 7), and remained elevated thereafter. We conclude that free radicals induce clear-cut, specific derangements of cellular metabolism in the form of glycolytic inhibition and calcium overload. The observed increase in [Ca2+]i suggests that the deleterious effects of free radicals are at least partially mediated by secondary changes in cellular calcium homeostasis.

The Compartment Syndrome

In an experimental ischemic compartment syndrome in dogs, phosphorus (31P) nuclear magnetic resonance (NMR) spectroscopy was used to determine the tissue pressure threshold at which resting skeletal muscle begins to use anaerobic energy sources due to insufficient cellular oxygen delivery. The interactive effects of systemic perfusion pressure and moderate muscle trauma on this anaerobic threshold were also evaluated. The severity of cell injury produced by various degrees of compartment pressurization over an eight-hour period was concomitantly studied using muscle biopsy and electron microscopy. Clinical correlation of a preliminary patient series studied using 31P-NMR demonstrated that the threshold for cellular metabolic derangement in skeletal muscle subjected to increased tissue pressure was more closely associated with the difference between mean arterial blood pressure (MABP) and compartment pressure than with the absolute compartment pressure alone. The difference is termed MABP-compartment pressure, or delta P. The lowest delta P at which a normal cellular metabolic state can be maintained is approximately 30 mmHg in normal muscle and 40 mmHg in moderately traumatized muscle. It is imperative to interpret compartment pressure measurements in light of the degree of soft tissue trauma sustained and the patient's blood pressure, as well as the clinical signs and symptoms.

Pathophysiology and treatment of septic shock

Shock is defined as inadequate circulating blood volume producing decreased peripheral vascular perfusion and cellular metabolic derangements, first in the nonvital tissues (the gastrointestinal tract, muscle, connective tissue, and skin) and later in the vital tissues (the brain, heart, lung, liver, and kidneys). This inadequate microcirculatory perfusion is the common denominator of all types of shock. Septic shock is caused by an immunologic reaction characterized by a hyperdynamic state, which produces increased cardiac output and decreased peripheral resistance. This reaction is secondary to endotoxin-antibody-complement complexing and leukocyte lysis that results in the production of histamine, serotonin, super-radicals, lysosomal enzymes, and kinins. These substances induce a marked capillary permeability and a third space loss, leading to hypovolemia. This is the hypodynamic state of spetic shock, which is characterized by decreased cardiac output and increased peripheral resistance. Diagnosis should be established in the hyperdynamic state of septic shock. Monitoring of the patient in septic shock requires continuous evaluation of the status of clinical signs, peripheral perfusion, vital organ function, and volume requirements. There are four principal and equally important objectives in the treatment of septic shock: treatment of sepsis, management of the hypovolemic state, reparation of the metabolic acid-base imbalance, and correction of the nutritional deficit. There are no priorities; all aspects of treatment must be rendered concomitantly and rapidly. It is essential that the septic and hypovolemic processes be treated concomitantly, since preventing the complexing of antigen-antibody and complement will deter vascular permeability and its consequent hypovolemia. Prompt and adequate treatment of hypovolemia prevents the development of attendant cellular metabolic derangements. All patients in septic shock should be admitted to the intensive care unit. Septic shock is one of the most critical medical emergencies. It requires specialized care by medical and paramedical staff trained in intensive care and supported by appropriate monitoring equipment.