Metabolic Insufficiency Research Articles

Inhibition of Autophagy Promotes Bortezomib-Mediated Cell Death in Myeloma Cells

The 26S proteasome is a key regulator of proteins controlling many important cellular functions, including cell cycle progression, differentiation, gene transcription and apoptosis. Proteasome inhibition is a new therapeutic strategy that has shown promise in the treatment of B cell malignancies, primarily multiple myeloma. We and others have demonstrated that proteasome inhibitors induce endoplasmic reticulum (ER) stress and activate an unfolded protein response (UPR) in transformed cells. Our previous work demonstrated that bortezomib induces an endoplasmic reticulum (ER) stress response ultimately leading to calcium-dependent apoptotic cell death. Co-treatment of myeloma cells with the mitochondrial uniporter inhibitor ruthenium red (RuR) abrogated bortezomib mediated cell death, indicating that the cytotoxic effects of proteasomal inhibition requires dysregulation of intracellular Ca2+. Intracellular Ca2+ has also been implicated in the cellular stress response known as autophagy or “self-eating”. Macroautophagy (hereafter referred to as autophagy) is induced by various cellular stresses including nutrient deprivation, metabolic insufficiency, interruption of growth factor signaling, elevated ROS, accumulation of intracellular Ca2+, and the UPR. The biochemical events linking the cellular stress response with the induction of autophagy, and the relationship between autophagy and apoptosis is not well understood.In this study, we investigate the role of the Ca2+ dependent serine protease, calpain, as a mediator of the conversion from autophagic cell survival to accelerated cell death in the ER stress response. We demonstrate that the proteasome inhibitor, bortezomib, initiates autophagy in myeloma cells, and protection from bortezomib-mediated cell death by mitochondrial Ca2+ inhibitors is associated with a promotion and stabilization of the autophagosome. This response can be reversed, and indeed, accelerated, leading to enhanced cell death, by blockade of calpain activity. Inhibition of calpain activity with the tri-peptide zLLY-FMK (Calpain Inhibitor IV, (CiIV) or the non-peptide inhibitor, PD150606, demonstrated a significant increase in the cytotoxic activity of bortezomib. Similarly, elimination of the small catalytic subunit, CAPNS1, using siRNA, enhanced bortezomib-mediated cell death, and prevented autophagosome-lysosomal progression. Furthermore, inhibition of calpain by clinically approved HIV protease inhibitors including Nelfinavir, Ritonavir, Saquinavir, and Indinavir sulfate, significantly increased the cytotoxic activity of bortezomib in vitro. We suggest that disregulation of Ca2+ by bortezomib-mediated ER stress activates the autophagic survival response. Inhibition of mitochondrial Ca2+ uptake by the uniporter inhibitor RuR promotes autophagy, and confers resistance to bortezomib. Conversely, inhibition of the Ca2+-dependent serine protease, calpain, prevents autophagolysosome maturation, and subverts the survival response to cell death. These data are likely to have important clinical implications for the treatment of refractory myeloma and other B cell malignancies.

Introduction: Uveal melanoma

Introduction: Uveal melanoma

SuPAR associates to glucose metabolic aberration during glucose stimulation in HIV-infected patients on HAART

We have recently shown that the level of soluble urokinase plasminogen activator receptor (suPAR), which is associated with the immune status of HIV-infected patients undergoing highly active antiretroviral therapy (HAART), correlates with the insulin action of such patients. Here we extend these findings by investigating the association of suPAR to glucose metabolic insufficiency during an oral glucose challenge (OGTT). In 16 HIV-infected patients with lipodystrophy and 15 HIV-infected patients without lipodystrophy, glucose tolerance, insulin sensitivity (ISI(composite)), prehepatic insulin secretion, proinsulin level and suppression of free fatty acids (FFA) were determined during an OGTT. Stability of suPAR was tested in 6 HIV-infected patients during a 3h OGTT. Lipodystrophy was associated with a 70% increase in plasma suPAR (P<0.05). During the OGTT, plasma suPAR correlated inversely with ISI(composite) and positively with 2h plasma glucose, fasting insulin secretion, fasting intact proinsulin and FFA level during the OGTT (all P<0.05). In multiple regression analyses, in which anthropometric measures (BMI, limbadiposity and fat mass), immune markers (CD4, HIV-RNA, duration of HIV infection), and dyslipidemia (plasma total cholesterol, triglyceride and free fatty acid level during the OGTT) were included, suPAR remained a significant marker of glucose tolerance and insulin sensitivity. Plasma suPAR exhibited a small CV (11%) during the 3h OGTT. suPAR associated to important glucose metabolic aberrations in HIV-infected patients on HAART. Moreover, suPAR was stable after a glucose challenge. Future research is required to confirm these findings and explore the potential of suPAR as marker of dysmetabolism in HIV-infected patients.

Gene expression profiles of metabolic enzyme transcripts in Alzheimer's disease

The successfully functioning brain is a heavy user of metabolic energy. Alzheimer's disease, in which cognitive faculties decline, may be due, at least in part, to metabolic insufficiency. Using microarray analysis and quantitative RT-PCR, the expression of mRNA transcripts involved in glucose metabolism was investigated in Alzheimer's diseased post-mortem human hippocampal samples. Of the 51 members of the glycolytic, tricarboxylic acid cycle, oxidative phosphorylation, and associated pathways investigated by qPCR, 15 were confirmed to be statistically significantly ( p < 0.05) down-regulated in Alzheimer's disease. This finding suggests that reductions in the levels of transcripts encoded by genes that participate in energy metabolism may be involved in Alzheimer's disease.

Omega-3 fatty acid status in attention-deficit/hyperactivity disorder

Lower levels of long-chain polyunsaturated fatty acids, particularly omega-3 fatty acids, in blood have repeatedly been associated with a variety of behavioral disorders including attention-deficit/hyperactivity disorder (ADHD). The exact nature of this relationship is not yet clear. We have studied children with ADHD who exhibited skin and thirst symptoms classically associated with essential fatty acid (EFA) deficiency, altered plasma and red blood cell fatty acid profiles, and dietary intake patterns that do not differ significantly from controls. This led us to focus on a potential metabolic insufficiency as the cause for the altered fatty acid phenotype. Here we review previous work and present new data expanding our observations into the young adult population. The frequency of thirst and skin symptoms was greater in newly diagnosed individuals with ADHD ( n = 35 ) versus control individuals without behavioral problems ( n = 112 ) drawn from the Purdue student population. A follow up case-control study with participants willing to provide a blood sample, a urine sample, a questionnaire about their general health, and dietary intake records was conducted with balancing based on gender, age, body mass index, smoking and ethnicity. A number of biochemical measures were analyzed including status markers for several nutrients and antioxidants, markers of oxidative stress, inflammation markers, and fatty acid profiles in the blood. The proportion of omega-3 fatty acids was found to be significantly lower in plasma phospholipids and erythrocytes in the ADHD group versus controls whereas saturated fatty acid proportions were higher. Intake of saturated fat was 30% higher in the ADHD group, but intake of all other nutrients was not different. Surprisingly, no evidence of elevated oxidative stress was found based on analysis of blood and urine samples. Indeed, serum ferritin, magnesium, and ascorbate concentrations were higher in the ADHD group, but iron, zinc, and vitamin B6 were not different. Our brief survey of biochemical and nutritional parameters did not give us any insight into the etiology of lower omega-3 fatty acids, but considering the consistency of the observation in multiple ADHD populations continued research in this field is encouraged.

Bone Mineral Density in patients with Myelomeningocele

Patients and methods Eighty patients with myelomeningocele were randomly chosen from a roster of > 500 patients with (MMC) followed at a multidisciplinary spina bifida unit in a thirdlevel public university hospital, which serves as the referral centre for these patients in our country. Patients with known metabolic acidosis, renal insufficiency, or other metabolic bone disease (i.e., hyperparathyroidism) were excluded from this study. We measured Bone Mineral Density (BMD) with total-body DXA scan with subregional areas values and the biochemical markers of bone mineral metabolism in blood and urine. To study relationships among the variables, the Chi-squared, ANOVA and lineal regression tests were applied

The potential dangers of treating head injury patients with corticosteroids

In the past, corticosteroids were given to head-injured patients in order to prevent secondary brain damage, even if clinical trials had been inconclusive and potential risks of complications were of concern. Recently, CRASH, a large, multi-centre study on short-term, high-dose corticosteroid treatment in head trauma, was interrupted after enrolling > 10,000 patients because corticosteroid treatment was associated with significantly higher mortality within two weeks. Participating clinicians were not requested to judge the causes of death, but rates of infections and gastrointestinal haemorrhages did not differ between treated patients and controls. Other potential corticosteroid complications include metabolic derangements (particularly hyperglycaemia), adrenal insufficiency and critical illness myopathy. Furthermore, experimental data suggest that corticosteroids may have some harmful effects on neural tissue. In this review, the potential risks of treating head-injured patients with corticosteroids are examined.

Lactate is a critical “sensed” variable in caudal hindbrain monitoring of CNS metabolic stasis

Caudal hindbrain "sensing" of glucoprivation activates central neural mechanisms that enhance systemic glucose availability, but the critical molecular variable(s) linked to detection of local metabolic insufficiency remains unclear. Central neurons and glia are metabolically coupled via intercellular trafficking of the glycolytic product lactate as a substrate for neuronal oxidative respiration. Using complementary in vivo models for experimental manipulation of lactate availability within the caudal hindbrain, we investigated the hypothesis that lactate insufficiency may be monitored by local metabolically "sensitive" neurons as an indicator of central nervous system energy imbalance. The data show that caudal fourth ventricular (CV4) administration of the monocarboxylate transporter inhibitor alpha-cyano-4-hydroxycinnamate (4CIN) resulted in dose-dependent increases in blood glucose in euglycemic animals, whereas the degree and duration of hypoglycemia elicited by insulin administration were exacerbated by exogenous L-lactate delivery to the CV4. Immunocytochemical processing of the hindbrain for the inducible c-fos gene product Fos revealed that 4CIN enhanced Fos immunoreactivity in the dorsal vagal complex (DVC), e.g., the nucleus of the solitary tract and dorsal vagal motor nucleus, and adjacent area postrema, sites where cells characterized by unique sensitivity to diminished glucose and/or glycolytic intermediate/end product levels reside, and in the medial vestibular nucleus (MV), and that CV4 L-lactate infusion increased Fos labeling within the DVC and MV after insulin-induced hypoglycemia. Together, these results support the view that lactate is a critical monitored metabolic variable in caudal hindbrain detection of energy imbalance resulting from glucoprivation and that diminished uptake and/or oxidative catabolism of this fuel activates neural mechanisms that increase systemic glucose availability.

The Favorable Outcome of Human Islet Transplantation in Korea: Experiences of 10 Autologous Transplantations

Cystic neoplasms of the pancreas are an increasingly diagnosed entity, and surgical resection of the pancreas is advocated. Islet autotransplantation is a therapeutic approach used to prevent diabetes in cases of pathologically benign neoplasm after major pancreatectomy. A total of 10 patients underwent pancreatectomy with islet autotransplantation. To evaluate islet transplantation efficiency, the authors compared 23 subjects who did not undergo islet transplantation after partial pancreatectomy with 87 subjects with normal glucose tolerance and with 77 diabetic subjects that did not undergo pancreatectomy. Ten female patients with nine cystic neoplasms and one patient with pancreatic injury underwent transplantation. Their mean islet equivalents (IEQ) was 3,159 IEQ/kg. During follow-up, two recipients required insulin or oral agents. At the 12-month follow-up, homeostasis model assessment (HOMA)-beta was 77.36+/-17.68, the insulinogenic index (INSindex) was 0.49+/-0.11, and fasting C-peptide and hemoglobin A1c were 1.28+/-0.18 ng/mL and 5.73+/-0.26%, respectively. Islet replacement was found to increase HOMA-beta by approximately 17% compared with distal pancreatectomy in normal glucose tolerance subjects without islet autotransplantation and by 46% compared with distal pancreatectomy diabetes subjects without islet autotransplantation. Factors different in the two insulin and oral hypoglycemic agent (OHA)-requiring recipients and the eight insulin- and OHA-free recipients were pancreatectomy extent, preoperative glucose metabolism insufficiency, age, and underlying cystic neoplasm disease. Even partial islet graft function can have a beneficial metabolic effect on the recipient in terms of metabolic parameters such as HOMA-beta and INSindex. This study suggests that islet replacement should be considered for experimental procedures in benign pancreatic conditions.

Ontogeny of Intestinal Glucose Transport in Heavy and Light Body Weight Turkey Poults1

Development of intestinal tissue was measured in newly hatched poults. Both anatomical and physiological measurements were made on poults produced by two half sibling sires with hens that were their full or half siblings. The poults from one sire (HBW) weighed more at hatching than those from the other sire (LBW). Survival of the heavier poults was poor indicating metabolic insufficiencies. A significant positive correlation was noted between hatchling body weights and blood glucose concentration (Christensen et al., 2000a), and this was accompanied by depressed gluconeogenesis in HBW poults. The hypothesis was proposed that the HBW poults with elevated plasma glucose concentrations might have greater glucose absorption from intestinal tissue than did the LBW poults. The data confirmed heavier weights in HBW poults than LBW, and HBW jejunum weight relative to body weight was less than that of LBW. The poults did not differ in intestinal length, glucose transport, maltase activities or plasma triiodothyronine and thyroxine or glucose concentrations. The HBW poults also utilized less yolk during development than did the LBW indicating that the HBW embryos rely more on gluconeogenesis for survival during development than do the LBW. It was concluded that the increased body weight of HBW poults compared to LBW may be due to increased absorption of all nutrients because of a greater intestinal mass relative to body weight rather than to differences in glucose digestion and uptake rates.

White matter lesions in Fabry disease occur in ‘prior’ selectively hypometabolic and hyperperfused brain regions

Fabry disease is an X-linked disorder associated with early onset stroke. We previously found a significantly elevated cerebral blood flow (CBF) in patients with Fabry disease. We set to determine whether elevated resting CBF in Fabry disease is primarily a cerebrovascular abnormality or is secondary to enhanced neuronal metabolism. The relationship of cerebral metabolism and blood flow to Fabry leukoencephalopathy was also investigated. We measured the global and regional cerebral metabolic rate of glucose using 18-fluoro-deoxyglucose (FDG) and PET in 16 patients with Fabry disease (7 patients with leukoaraiotic lesions and 9 without) and in 7 control subjects. MRI fluid attenuated inversion recovery (FLAIR) studies were also performed in the patient and control groups. All control subjects had normal MRI FLAIR studies with no high-signal deep white matter lesions (WML). Patients were partitioned into FLAIR lesion and non-FLAIR lesion groups. We found no evidence of cerebral glucose hypermetabolism in Fabry disease. On the contrary, significantly decreased regional cerebral glucose metabolism (rCMRGlu) was found particularly in the deep white matter in the Fabry non-lesion group and exacerbated in the lesion group. Lesion-susceptible regions were relatively hyperperfused in non-lesion patients compared to the control group. We conclude that the elevated rCBF and decreased white matter rCMRGlu indicates a dissociation between metabolism and blood flow suggesting chronic deep white matter metabolic insufficiency.

Mechanisms of cell survival in hypoxia and hypothermia.

Most animals experience some degree of hypoxia and hypothermia during the course of their natural life history either as a consequence of ambient 'exposure' per se or through metabolic, respiratory and/or circulatory insufficiency. A prevailing experimental approach has been to probe tissues from natural models of hypoxia-tolerant and cold-tolerant vertebrates to look for common mechanisms of defence against O(2) lack and hypothermia. The ability to sustain vital cellular functions in severe cases of either condition varies widely amongst the vertebrates. Like humans, the vast majority of mammals are unable to survive prolonged periods of hypothermia or O(2) deprivation owing to irreversible membrane damage and loss of cellular ion homeostasis in vital organs such as the brain and heart. However, numerous hibernating endotherms, neonatal and diving mammals as well as many ectotherms can tolerate prolonged periods that would, in clinical terms, be called asphyxia or deep hypothermia. The key to their survival under such conditions lies in an inherent ability to downregulate their cellular metabolic rate to new hypometabolic steady states in a way that balances the ATP demand and ATP supply pathways.

Effect of antenatal betamethasone treatment on microtubule-associated proteins MAP1B and MAP2 in fetal sheep.

Betamethasone has been used extensively to accelerate fetal lung maturation, yet little is known of its effects on neuronal morphogenesis in the developing fetus. Microtubule-associated proteins (MAPs) are a diverse family of cytoskeletal proteins that are important for brain development and the maintenance of neuroarchitecture. Vehicle (n = 7) or betamethasone (10 ug h-1, n = 7) was infused I.V. to fetal sheep over 48 h beginning at 0.87 of gestation (128 days of gestation), producing fetal plasma betamethasone concentrations resembling those to which the human fetus is exposed during antenatal glucocorticoid therapy. Paraffin sections of the left hemisphere were stained with monoclonal antibodies against MAP1B and the MAP2 isoforms MAP2a,b,c and MAP2a,b. The level of the juvenile isoform MAP2c was determined by comparison of the two MAP2 immunostainings. We were able to detect MAP1B and MAP2 immunoreactivity (IR) in the fetal sheep brain. MAP2c was the major MAP2, constituting 90.2 % of the total MAPBetamethasone exposure diminished MAP1B IR in the frontal cortex and caudate putamen (P < 0.05) but not in the hippocampus. A decrease of MAP2 IR was found in the frontal cortex, hippocampus and caudate putamen (P < 0.05). Loss of MAP2 IR was mainly due to the loss of MAP2c IR. Haematoxylin-eosin staining did not demonstrate irreversible neuronal damage. Regional cerebral blood flow determined using coloured microspheres was significantly decreased by 28 % in the frontal cortex and by 36 % in the caudate putamen but not in the hippocampus 24 h after the onset of betamethasone exposure (P < 0.05). The loss of MAP1B and MAP2a,b,c IR showed a significant correlation to the cerebral blood flow decrease only in the frontal cortex (P < 0.05). These data suggest that mechanisms other than metabolic insufficiency caused by the decreased cerebral blood flow may contribute to the loss of MAPs. The results suggest that clinical doses of betamethasone may have acute effects on cytoskeletal proteins in the fetal brain.

Longitudinal magnetic resonance imaging study of perfusion and diffusion in stroke: evolution of lesion volume and correlation with clinical outcome.

A prospective longitudinal diffusion-weighted and perfusion-weighted magnetic resonance imaging (DWI/PWI) study of stroke patients (n = 21) at five distinct time points was performed to evaluate lesion evolution and to assess whether DWI and PWI can accurately and objectively demonstrate the degree of ischemia-induced deficits within hours after stroke onset. Patients were scanned first within 7 hours of symptom onset and then subsequently at 3 to 6 hours, 24 to 36 hours, 5 to 7 days, and 30 days after the initial scan. Lesion evolution was dynamic during the first month after stroke. Most patients (18 of 19, 95%) showed increased lesion volume over the first week and then decreased at 1 month relative to 1 week (12 of 14, 86%). Overall, lesion growth appeared to depend on the degree of mismatch between diffusion and perfusion at the initial scan. Abnormal volumes on the acute DWI and PWI (<7 hours) correlated well with initial National Institutes of Health (NIH) stroke scale scores, outcome NIH stroke scale scores, and final lesion volume. DWI and PWI can provide an early measure of metabolic and hemodynamic insufficiency, and thus can improve our understanding of the evolution and outcome after acute ischemic stroke.

Cognitive performance and biochemical markers in septum, hippocampus and striatum of rats after an i.c.v. injection of streptozotocin: a correlation analysis

In the present study we evaluated the effects of an intracerebroventricular injection of streptozotocin on cognitive behavior and biochemical markers in the brain of middle-aged Wistar rats. Intracerebroventricular injected streptozotocin has previously been reported to decrease the central metabolism of glucose. We found that streptozotocin-treated rats showed an impaired cognitive performance in the delayed non-matching to position task and the Morris water escape task. Glial fibrillary acidic protein, an indicator of reactive astroglial changes, was measured in three different (soluble, Triton X-100 soluble and crude cytoskeletal) protein fractions and its content in the fractions of the septum, hippocampus and striatum of streptozotocin-treated rats was increased. Furthermore, the glial fibrillary acidic protein response of each protein fraction to streptozotocin treatment appeared to be differently regulated. In streptozotocin-treated rats the choline acetyltransferase activity was decreased in the hippocampus only, which was correlated with the hippocampal glial fibrillary acidic protein contents of all three hippocampal protein fractions, thus suggesting that the cholinergic deficit is a consequence of direct damage to the hippocampus. The cognitive deficits in both tasks were related to the increased glial fibrillary acidic protein contents, especially of the soluble and cytoskeletal fraction, and the decreased choline acetyltransferase activity in the hippocampus. Taken together, these findings indicate that it is important to take into account which protein fraction has been used for measuring the glial fibrillary acidic protein response to a stressor. Furthermore, intracerebroventricular injected streptozotocin may provide a relevant model for studying neurodegenerative changes due to a metabolic insufficiency and testing neuroprotective effects of substances.

Effect of adaptive pulse train duration on latissimus dorsi blood flow.

Blood flow, intramuscular pressure, and stroke work of the trained latissimus dorsi muscle (LD) were measured during electrical stimulation at contraction rates between 20 and 160/min using pulse trains of 2 to 6 pulses in length. Epimysial electrodes and intramuscular pressure sensors were implanted in the LD of 5 dogs. The muscle remained in situ. After 12 weeks of a progressive training protocol, LD blood flow (BF) was measured using an ultrasonic flow probe and work (SW) was determined from the measured force and shortening. For pulse trains of 2 or 3 pulses, BF increased with rate, and SW was maintained at all rates. For 4 pulses, BF and SW decreased when the contraction rate exceeded 120/min. SW decreased above 100/min and 80/min for 5 and 6 pulses, respectively. An upper rate limit dependent upon the pulse train duration exists above which BF and SW decline. Exceeding these upper rate limits should be avoided in cardiomyoplasty. Excessive stimulation rates could be detrimental to the muscle by creating a metabolic insufficiency or ischemia. The cardiac assistance benefit is compromised as SW declines during high contraction rates of long pulse train duration.

PLASMA NITRIC OXIDE IN POSTTRAUMA CRITICAL ILLNESS

The time course of nitric oxide (NO) production in posttrauma critical illness was monitored, and its relationship to posttrauma "sepsis/SIRS" and physiologic patterns was described. Eighty multiple trauma patients were studied (514 samples) during their course in the intensive care unit (Injury Severity Score 27.6; 36% deaths). Plasma NO was estimated from NO3 + NO2 by the Griess test and compared with that of 10 healthy controls (HC). At each sample period, the patient was categorized as having bacteremic sepsis (BAC), sepsis syndrome (SS), or systemic inflammatory response syndrome (SIRS), and classified by Physiologic State Severity Classification (PSSC) into normal stress response (A-State), metabolic insufficiency (B-State), or respiratory insufficiency (C2-State), each quantified by their physiologic "distance" from reference state of recovering trauma patients (R-State). A severity index (L2PDEATH), based on a logistic model of state distances from R-State, quantified probability of death. Deaths showed increased NO (p < .05) over survivors or HC by day 3 posttrauma. A fall in vascular tone in deaths was related to the increased NO (p < .0001). The level of NO was higher as sepsis worsened: BAC > SS > SIRS > HC (all simultaneous, p < .05). PSSC and L2PDEATH correlated with incidence > HC and level of NO. In conclusion, the severity of posttrauma critical illness was classified by PSSC and quantified by the L2PDEATH index. These reflect progressively increased NO levels and suggest worsening sepsis status. The reduced total peripheral resistance (TPR)-to-flow relationship (vascular tone) in deaths characteristic of the more severe septic PSSC states appeared related to the increased plasma NO.

"Sepsis/SIRS," physiologic classification, severity stratification, relation to cytokine elaboration and outcome prediction in posttrauma critical illness.

To develop a quantitative severity stratification within the framework of a Physiologic State Classification (PSSC) system that can be applied to critically ill post-trauma patients with "sepsis/SIRS" and to relate PSSC to the nature of the plasma cytokine response. At each study time period, a patient was classified into one of seven physiologic States previously derived from clustering 17 cardiopulmonary and metabolic variables from 338 critically ill patients: R = reference, A = normal stress response, B = metabolic insufficiency, C1 (early) and C2 (late) = respiratory insufficiency, D = cardiogenic insufficiency, H = nonshock hypovolemia. The PSSC used State data from a developmental set of 159 trauma patients in a logistic model (L2PDEATH) to provide a quantitative index of severity. This severity index was tested on 80 new trauma patients (mean injury Severity Score (ISS) = 27.6, 64% survivors). Using PSSC State distributions for evaluation of enzyme-linked immunosorbent assay (ELISA) measured cytokines interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor (TNF) showed the multicytokine score to be greatest in those C2- and B-State regions associated with a higher severity as measured by L2PDEATH. Compared with ARDEATH of the Acute Physiology and Chronic Health Evaluation (APACHE) II scoring system, L2PDEATH provided a better indicator of severity of sepsis/systemic inflammatory response syndrome (SIRS) for posttrauma patients. PSSC allows classification of the physiologic and cytokine mediator response to trauma and permits stratification of severity in posttrauma critical illness.

Subtle Cobalamin Deficiency

Subtle Cobalamin Deficiency

10 Malabsorption of food cobalamin

Food-cobalamin malabsorption is marked by the inability to release cobalamin from food, which therefore cannot be taken up by intrinsic factor for absorption. The defect is not detectable by classical clinical tests like the Schilling test which are all based on the absorption of free, crystalline cobalamin. Tests of food-cobalamin absorption have been devised, the most popular ones using cobalamin bound to eggs or to chicken serum. The disparity between the abnormal results of these tests and the normal results with the Schilling test defines the disorder of food-cobalamin malabsorption. Release of cobalamin from food requires acid and pepsin, and most food-cobalamin malabsorptive states can be traced to gastric defects. However, other mechanisms may also play a role. The malabsorption is limited to food cobalamin and any free cobalamin, presumably including recycled biliary cobalamin, will be absorbed normally, which may explain its frequently insidious nature. The effect on cobalamin status covers a broad spectrum. At one extreme, some individuals, perhaps in the earliest stages, have normal cobalamin status, while at the other extreme may be found deficiency every bit as severe as in the most florid case of pernicious anaemia. Most often, however, the deficiency is mild, frequently marked by only a low serum cobalamin level, mild evidence of metabolic insufficiency and, sometimes, minimal clinical sequelae. Moreover, in some cases the gastric defect progresses and intrinsic factor secretion is affected, thus transforming into classical pernicious anaemia; this is not inevitable, however, and probably occurs in only a minority of patients. The course of food-cobalamin malabsorption is therefore a varied one. Nevertheless, it may be the most common cause of subtle or mild cobalamin deficiency and it is also sometimes associated with severe deficiency. Its identification and treatment need to be considered more widely in the clinical setting.