Reduced levels of serum albumin concentration, a routine blood test, within the "normal" range have been reported to be associated with mortality risk. The literature is reviewed, with a focus on cohort studies meeting specified criteria, and findings are summarized. In studies of many populations, comprising healthy subjects and patients with acute or chronic illness, serum albumin concentration is inversely related to mortality risk in a graded manner over its entire range; the estimated increase in the odds of death ranges from 24% to 56% for each 2.5 g/l decrement in serum albumin concentration. The association predicts overall and cause-specific mortality including cardiovascular mortality. It is likely that albumin concentration is a highly sensitive indicator of preclinical disease and disease severity. A direct protective effect of the albumin molecule is suggested by the persistence of the association after adjustment for other known risk factors and preexisting illness, and after exclusion of early mortality. Although biologically plausible, there is no direct evidence for this hypothesis. Serum albumin concentration is an independent predictor of mortality risk and could be useful in the quantification of risk in a broad range of clinical and research settings.

The surface chemistry of biomaterials can have a significant impact on their performance in biological applications. Our recent work suggests that cerium oxide nanoparticles are potent antioxidants in cell culture models and we have evaluated several therapeutic applications of these nanoparticles in different biological systems. Knowledge of protein adsorption and cellular uptake will be very useful in improving the beneficial effects of cerium oxide nanoparticles in biology. In the present study, we determined the effect of zeta potential of cerium oxide nanoparticles on adsorption of bovine serum albumin (BSA) and cellular uptake in adenocarcinoma lung cells (A549). The zeta potential of the nanoparticles was varied by dispersing them in various acidic and basic pH solutions. UV-visible spectroscopy and inductively coupled plasma mass spectrometry (ICP-MS) were used for the protein adsorption and cellular uptake studies, respectively. Nanoceria samples having positive zeta potential were found to adsorb more BSA while the samples with negative zeta potential showed little or no protein adsorption. The cellular uptake studies showed preferential uptake for the negatively charged nanoparticles. These results demonstrate that electrostatic interactions can play an important factor in protein adsorption and cellular uptake of nanoparticles.

A simple, one-pot, "green" synthetic route, based on the "biomineralization" capability of a common commercially available protein, bovine serum albumin (BSA), has been developed for the preparation of highly stable Au nanocrystals (NCs) with red emission and high quantum yield.

Quantum dots (QDs) are emerging as alternative or complementary tools to the organic fluorescent dyes currently used in bioimaging. QDs hold several advantages over conventional fluorescent dyes including greater photostability and a wider range of excitation/emission wavelengths. However, recent work suggests that QDs exert deleterious effects on cellular processes. This study examined the subcellular localization and toxicity of cadmium telluride (CdTe) QDs and pharmacological means of preventing QD-induced cell death. The localization of CdTe QDs was found to depend upon QD size. CdTe QDs exhibited marked cytotoxicity in PC12 and N9 cells at concentrations as low as 10 microg/ml in chronic treatment paradigms. QD-induced cell death was characterized by chromatin condensation and membrane blebbing and was more pronounced with small (2r=2.2+/-0.1 nm), green emitting positively charged QDs than large (2r=5.2+/-0.1 nm), equally charged red emitting QDs. Pretreatment of cells with the antioxidant N-acetylcysteine and with bovine serum albumin, but not Trolox, significantly reduced the QD-induced cell death. These findings suggest that the size of QDs contributes to their subcellular distribution and that drugs can alter QD-induced cytotoxicity.

The ideal mathematical model for predicting survival for individual patients with primary biliary cirrhosis should be based on a small number of inexpensive, noninvasive measurements that are universally available. Such a model would be useful in medical management by aiding in the selection of patients for and timing of orthotopic liver transplantation. This paper describes the development, testing and use of a mathematical model for predicting survival. The Cox regression method and comprehensive data from 312 Mayo Clinic patients with primary biliary cirrhosis were used to derive a model based on patient's age, total serum bilirubin and serum albumin concentrations, prothrombin time and severity of edema. When cross-validated on an independent set of 106 Mayo Clinic primary biliary cirrhosis patients, the model predicted survival accurately. Our model was found to be comparable in quality to two other primary biliary cirrhosis survival models reported in the literature and to have the advantage of not requiring liver biopsy.

The significance of glycated albumin (GA), compared with casual plasma glucose (PG) and glycated hemoglobin (HbA(1c)), was evaluated as an indicator of the glycemic control state in hemodialysis (HD) patients with diabetes. The mean PG, GA, and HbA(1c) levels were 164.5 +/- 55.7 mg/dl, 22.5 +/- 7.5%, and 5.85 +/- 1.26%, respectively, in HD patients with diabetes (n = 538), which were increased by 51.5, 31.6, and 17.7%, respectively, compared with HD patients without diabetes (n = 828). HbA(1c) levels were significantly lower than simultaneous PG and GA values in those patients in comparison with the relationship among the three parameters in patients who had diabetes without renal dysfunction (n = 365), as reflected by the significantly more shallow slope of regression line between HbA(1c) and PG or GA. A significant negative correlation was found between GA and serum albumin (r = -0.131, P = 0.002) in HD patients with diabetes, whereas HbA(1c) correlated positively and negatively with hemoglobin (r = 0.090, P = 0.036) and weekly dose of erythropoietin injection (r = -0.159, P < 0.001), respectively. Although PG and GA did not differ significantly between HD patients with diabetes and with and without erythropoietin injection, HbA(1c) levels were significantly higher in patients without erythropoietin. Categorization of glycemic control into arbitrary quartile by HbA(1c) level led to better glycemic control in a significantly higher proportions of HD patients with diabetes than those assessed by GA. Multiple regression analysis demonstrated that the weekly dose of erythropoietin, in addition to PG, emerged as an independent factor associated with HbA(1c) in HD patients with diabetes, although PG but not albumin was an independent factor associated with GA. In summary, it is suggested that GA provides a significantly better measure to estimate glycemic control in HD patients with diabetes and that the assessment of glycemic control by HbA(1c) in these patients might lead to underestimation likely as a result of the increasing proportion of young erythrocyte by the use of erythropoietin.

A relatively simple but sensitive and reliable method of quantitating the oxygen-radical absorbing capacity (ORAC) of antioxidants in serum using a few microliter is described. In this assay system, beta-phycoerythrin (beta-PE) is used as an indicator protein, 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH) as a peroxyl radical generator, and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox, a water-soluble vitamin E analogue) as a control standard. Results are expressed as ORAC units, where 1 ORAC unit equals the net protection produced by 1 microM Trolox. The uniqueness of this assay is that total antioxidant capacity of a sample is estimated by taking the oxidation reaction to completion. At this point all of the nonprotein antioxidants (which include alpha-tocopherol, vitamin C, beta-carotene, uric acid, and bilirubin) and most of the albumin in the sample are oxidized by the peroxyl radical. Results are quantified by measuring the protection produced by antioxidants. This solves many problems associated with kinetics or lag-time measurements. A linear correlation of ORAC value with concentration of serum. Trolox, vitamin C, uric acid, and bovine albumin is demonstrated. The coefficient of variation within a run is found to be about 2% and from run to run about 5%. Trolox, alpha-tocopherol, vitamin C, beta-carotene, uric acid, and bilirubin completely protect beta-PE from oxidation, while bovine albumin protects beta-PE only partially. On a molar basis, the relative peroxyl radical absorbance capacity of Trolox, alpha-tocopherol acid succinate, uric acid, bilirubin, and vitamin C is 1:1:0.92:0.84:0.52. Bovine albumin per unit weight has a lower peroxyl absorbing capacity than these antioxidants.(ABSTRACT TRUNCATED AT 250 WORDS)

OBJECTIVE

To study the uptake of biodegradable microparticles in Caco-2 cells.

METHODS

Biodegradable microparticles of polylactic polyglycolic acid co-polymer (PLGA 50:50) of mean diameters 0.1 micron, 1 micron, and 10 microns containing bovine serum albumin as a model protein and 6-coumarin as a fluorescent marker were formulated by a multiple emulsion technique. The Caco-2 cell monolayers were incubated with each diameter microparticles (100 micrograms/ml) for two hours. The microparticle uptake in Caco-2 cells was studied by confocal microscopy and also by quantitating the 6-coumarin content of the microparticles taken up by the cells. The effects of microparticle concentration, and incubation time and temperature on microparticle cell uptake were also studied.

RESULTS

The study demonstrated that the Caco-2 cell microparticle uptake significantly depends upon the microparticle diameter. The 0.1 micron diameter microparticles had 2.5 fold greater uptake on the weight basis than the 1 micron and 6 fold greater than the 10 microns diameter microparticles. Similarly in terms of number the uptake of 0.1 micron diameter microparticles was 2.7 x 10(3) fold greater than the 1 micron and 6.7 x 10(6) greater than the 10 microns diameter microparticles. The efficiency of uptake of 0.1 micron diameter microparticles at 100 micrograms/ml concentration was 41% compared to 15% and 6% for the 1 micron and the 10 microns diameter microparticles, respectively. The Caco-2 cell microparticle (0.1 micron) uptake increased with concentration in the range of 100 micrograms/ml to 500 micrograms/ml which then reached a plateau at higher concentration. The uptake of microparticles increased with incubation time, reaching a steady state at two hours. The uptake was greater at an incubation temperature of 37 degrees C compared to at 4 degrees C.

CONCLUSIONS

The Caco-2 cell microparticle uptake was microparticle diameter, concentration, and incubation time and temperature dependent. The small diameter microparticles (0.1 micron) had significantly greater uptake compared to larger diameter microparticles. The results thus suggest that the mechanism of uptake of microparticles in Caco-2 cell is particle diameter dependent. Caco-2 cells are used as an in vitro model for gastrointestinal uptake, and therefore the results obtained in these studies could be of significant importance in optimizing the microparticle-based oral drug delivery systems.

The development of immune deposits on the subepithelial surface of the glomerular capillary wall was studied in isolated rat kidneys perfused at controlled perfusion pressure, pH, temperature, and flow rates with recirculating oxygenated perfusate containing bovine serum albumin (BSA) in buffer and sheep antibody to rat proximal tubular epithelial cell brush border antigen (Fx1A). Control kidney were perfused with equal concentrations of non-antibody immunoglobulin (Ig)G. Renal function was monitored by measuring inulin clearance, sodium reabsorption, and urine flow as well as BSA excretion and fractional clearance. Perfused kidneys were studied by light, immunofluorescence, and electron microscopy. All kidneys perfused with anti-Fx1A developed diffuse, finely granular deposits of IgG along the glomerular capillary wall by immunofluorescence. Electron microscopy revealed these deposits to be localized exclusively in the subepithelial space and slit pores. Similar deposits were produced in a nonrecirculating perfusion system, thereby excluding the formation of immune complexes in the perfusate caused by renal release of tubular antigen. Control kidneys perfused with nonantibody IgG did not develop glomerular immune deposits. Renal function and BSA excretion were the same in experimental and control kidneys. Glomerular deposits in antibody perfused kidneys were indistinguishable from deposits in rats injected with anti-Fx1A or immunized with Fx1A to produce autologous immune complex nephropathy. These studies demonstrate that subepithelial immune deposits can be produced in the isolated rat kidney by perfusion with specific antibody to Fx1A in the absence of circulating immune complexes. In this model deposits result from in situ complex formation rather than circulating immune complex deposition.

We report here preliminary studies of biocidal effects and cellular internalization of ZnO nanoparticles on Escherichia coli bacteria. ZnO nanoparticles were synthesized in di(ethylene glycol) (DEG) medium by forced hydrolysis of ionic Zn2+ salts. Particle size and shape were controlled by addition of small molecules and macromolecules such as tri-n-octylphosphine oxide, sodium dodecyl sulfate, polyoxyethylene stearyl ether, and bovine serum albumin. Transmission electron microscopy (TEM) and X-ray diffraction analyses were used to characterize particle structure, size, and morphology. Bactericidal tests were performed in Luria-Bertani medium on solid agar plates and in liquid systems with different concentrations of small and macromolecules and also with ZnO nanoparticles. TEM analyses of bacteria thin sections were used to study biocidal action of ZnO materials. The results confirmed that E. coli cells after contact with DEG and ZnO were damaged showing a Gram-negative triple membrane disorganization. This behavior causes the increase of membrane permeability leading to accumulation of ZnO nanoparticles in the bacterial membrane and also cellular internalization of these nanoparticles.

BACKGROUND

There is no satisfactory medical therapy for patients with primary sclerosing cholangitis. Ursodiol (ursodeoxycholic acid) benefits patients with primary biliary cirrhosis, another cholestatic liver disease.

METHODS

From May 1989 to July 1995, we enrolled 105 patients with well-documented primary sclerosing cholangitis in a randomized, double-blind study comparing ursodiol (13 to 15 mg per kilogram of body weight per day in divided doses) with placebo. The primary outcome was the time to treatment failure, defined as death; liver transplantation; histologic progression by two stages (of four) or progression to cirrhosis; the development of varices, ascites, or encephalopathy; sustained quadrupling of the serum bilirubin concentration; marked worsening of fatigue or pruritus; inability to tolerate the drug; or voluntary withdrawal from the study.

RESULTS

We analyzed data on the 51 patients in each group with at least 3 months of follow-up; the median follow-up was 2.2 years. There was no significant difference between the groups in time to treatment failure (relative risk of treatment failure in the ursodiol group, 1.01; 95 percent confidence interval, 0.6 to 1.7). During the first two years of follow-up, treatment was unsuccessful in 17 of 32 patients (53 percent) in the placebo group and 16 of 31 (52 percent) in the ursodiol group. There were also no differences in time to treatment failure for patients with early-stage disease or in time to liver transplantation. Ursodiol, but not placebo, was associated with improvement in serum alkaline phosphatase, aspartate aminotransferase, bilirubin, and albumin levels at one and two years.

CONCLUSIONS

In a group of patients with well-defined primary sclerosing cholangitis, ursodiol provided no clinical benefit.

The Committee of the European Concerted Action for Multiple Sclerosis (Charcot Foundation) organised five workshops to discuss CSF analytical standards in the diagnosis of multiple sclerosis. This consensus report from 12 European countries summarises the results of those workshops. It is hoped that neurologists will confer with their colleagues in clinical chemistry to arrange the best possible local practice. The most sensitive method for the detection of oligoclonal immunoglobulin bands is isoelectric focusing. The same amounts of IgG in parallel CSF and serum samples are used and oligoclonal bands are revealed with IgG specific antibody staining. All laboratories performing isoelectric focusing should check their technique at least annually using "blind" standards for the five different CSF and serum patterns. Quantitative measurements of IgG production in the CNS are less sensitive than isoelectric focusing. The preferred method for detection of blood-CSF barrier dysfunction is the albumin quotient. The CSF albumin or total protein concentrations are less satisfactory. These results must be interpreted with reference to the age of the patient and the local method of determination. Cells should be counted. The normal value is no more than 4 cells/microliters. Among evolving optional tests, measurement of the combined local synthesis of antibodies against measles, rubella, and/or varicella zoster could represent a significant advance if it offers higher specificity (not sensitivity) for identifying chronic rather than acute inflammation. Other tests that may have useful correlations with clinical indices include those for oligoclonal free light chains, IgM, IgA, or myelin basic protein concentrations.

A panel of members of the 2009 International Myeloma Workshop developed guidelines for risk stratification in multiple myeloma. The purpose of risk stratification is not to decide time of therapy but to prognosticate. There is general consensus that risk stratification is applicable to newly diagnosed patients; however, some genetic abnormalities characteristic of poor outcome at diagnosis may suggest poor outcome if only detected at the time of relapse. Thus, in good-risk patients, it is necessary to evaluate for high-risk features at relapse. Although detection of any cytogenetic abnormality is considered to suggest higher-risk disease, the specific abnormalities considered as poor risk are cytogenetically detected chromosomal 13 or 13q deletion, t(4;14) and del17p, and detection by fluorescence in situ hybridization of t(4;14), t(14;16), and del17p. Detection of 13q deletion by fluorescence in situ hybridization only, in absence of other abnormalities, is not considered a high-risk feature. High serum β(2)-microglobulin level and International Staging System stages II and III, incorporating high β(2)-microglobulin and low albumin, are considered to predict higher risk disease. There was a consensus that the high-risk features will change in the future, with introduction of other new agents or possibly new combinations.

BACKGROUND

The serious problem of hospital undernutrition is still being underestimated, despite its impact on clinical evolution and costs. The screening methods developed so far are not useful for daily clinical practice due to their low effectiveness/cost ratio.

OBJECTIVE

We present an screening tool for CONtrolling NUTritional status (CONUT) that allows an automatic daily assessment of nutritional status of all inpatients that undergo routine analysis.

METHODS

The system is based on a computer application that compiles daily all useful patient information available in hospital databases, through the internal network. It automatically assesses the nutritional status taking into account laboratory information including serum albumin, total cholesterol level and total lymphocyte count. We have studied the association between the results of the Subjective Global Assessment (SGA) and Full Nutritional Assessment (FNA) with those from CONUT, in a sample of 53 individuals.

RESULTS

The agreement degree between CONUT and FNA as measured by kappa index is 0.669 (p = 0.003), and between CONUT and SGA is 0.488 (p = 0.034). Considering FNA as "gold standard" we obtain a sensitivity of 92.3 and a specificity of 85.0.

CONCLUSIONS

CONUT seems to be an efficient tool for early detection and continuous control of hospital undernutrition, with the suitable characteristics for these screening functions.

Controlled release from biodegradable polymers is a novel approach to replace daily painful injections of protein drugs. A major obstacle to development of these polymers is the need to retain the structure and biological activity of encapsulated proteins during months of incubation under physiological conditions. We encapsulated bovine serum albumin (BSA) in injectable poly(DL-lactide- co-glycolide) (PLGA) 50/50 cylindrical implants and determined the mechanism of BSA instability. Simulations of the polymer microclimate revealed that moisture and acidic pH (<3) triggered unfolding of encapsulated BSA, resulting in peptide bond hydrolysis and noncovalent aggregation. To neutralize the acids liberated by the biodegradable lactic/glycolic acid-based polyester, we coincorporated into the polymer an antacid, Mg(OH)2, which increased microclimate pH and prevented BSA structural losses and aggregation for over one month. We successfully applied this stabilization approach in both cylinder- and microsphere-injectable configurations and for delivery of angiogenic basic fibroblast growth factor and bone-regenerating bone morphogenetic protein-2.

BACKGROUND

Kidney disease has been identified as a risk factor for vitamin D deficiency in hospitalized patients, and low levels of 25-hydroxyvitamin D have been suggested to be a risk factor for hyperparathyroidism in patients with chronic kidney disease (CKD). However, little is known about the magnitude of vitamin D deficiency in patients with CKD living in the United States.

METHODS

In this regard, we examined the levels of 25(OH)D in 43 patients with CKD and serum creatinine between 1 and 5 mg/dl (calculated glomerular filtration rate 111-11 ml/min per 1.73 m2) as well as in 103 patients undergoing hemodialysis.

RESULTS

In the predialysis patients, we found that 37 of the 43 patients (86%) had suboptimal levels of vitamin D (<30 ng/ml). Regression analysis indicated that there was a negative correlation between 25(OH)D and intact parathyroid hormone (PTH). Alkaline phosphatase showed a similar but less sensitive relationship. Serum albumin levels correlated with 25(OH)D levels. In contrast to findings reported in normal individuals, the levels of calcitriol correlated with those of 25(OH)D in the patients with CKD. In the group undergoing maintenance hemodialyis, we found that 97% of the patients had vitamin D levels in the suboptimal range, and there was no correlation of 25(OH)D levels with either PTH or serum albumin values. These data indicate that vitamin D insufficiency and deficiency are highly prevalent in patients with CKD and may play a role in the development of hyperparathyroidism. The functional significance of low levels of 25(OH)D in patients with stage 5 CKD remains to be determined.

BACKGROUND

Physical activity may lower the risk for coronary heart disease by mitigating inflammation, which plays a key role in the pathophysiology of atherosclerosis. The purpose of this study was to examine the association between physical activity and C-reactive protein concentration in a national sample of the U.S. population.

METHODS

The analytic sample included 13,748 participants>>or=20 years of age in the National Health and Nutrition Examination Survey III (1988-1994) with complete data for the main study variables.

RESULTS

After adjusting for age, sex, ethnicity, education, work status, smoking status, cotinine concentration, hypertension, body mass index, waist-to-hip ratio, high-density lipoprotein cholesterol concentration, and aspirin use, the odds ratios for elevated C-reactive protein concentration (dichotomized at the>>or=85th percentile of the sex-specific distribution) were 0.98 (95% confidence interval = 0.78-1.23), 0.85 (0.70-1.02), and 0.53 (0.40-0.71) for participants who engaged in light, moderate, and vigorous physical activity, respectively, during the previous month compared with participants who did not engage in any leisure-time physical activity. In addition, leisure-time physical activity was positively associated with serum albumin concentration and inversely associated with both log-transformed plasma fibrinogen concentration and log-transformed white blood cell count.

CONCLUSIONS

These results add to mounting evidence that physical activity may reduce inflammation, which is a critical process in the pathogenesis of cardiovascular disease.

Microfabrication technology has been adapted to produce micron-scale needles as a safer and painless alternative to hypodermic needle injection, especially for protein biotherapeutics and vaccines. This study presents a design that encapsulates molecules within microneedles that dissolve within the skin for bolus or sustained delivery and leave behind no biohazardous sharp medical waste. A fabrication process was developed based on casting a viscous aqueous solution during centrifugation to fill a micro-fabricated mold with biocompatible carboxymethylcellulose or amylopectin formulations. This process encapsulated sulforhodamine B, bovine serum albumin, and lysozyme; lysozyme was shown to retain full enzymatic activity after encapsulation and to remain 96% active after storage for 2 months at room temperature. Microneedles were also shown to be strong enough to insert into cadaver skin and then to dissolve within minutes. Bolus delivery was achieved by encapsulating molecules just within microneedle shafts. For the first time, sustained delivery over hours to days was achieved by encapsulating molecules within the microneedle backing, which served as a controlled release reservoir that delivered molecules by a combination of swelling the backing with interstitial fluid drawn out of the skin and molecule diffusion into the skin via channels formed by dissolved microneedles. We conclude that dissolving microneedles can be designed to gently encapsulate molecules, insert into skin, and enable bolus or sustained release delivery.

Over the past decades, albumin has emerged as a versatile carrier for therapeutic and diagnostic agents, primarily for diagnosing and treating diabetes, cancer, rheumatoid arthritis and infectious diseases. Market approved products include fatty acid derivatives of human insulin or the glucagon-like-1 peptide (Levemir(®) and Victoza(®)) for treating diabetes, the taxol albumin nanoparticle Abraxane(®) for treating metastatic breast cancer which is also under clinical investigation in further tumor indications, and (99m)Tc-aggregated albumin (Nanocoll(®) and Albures(®)) for diagnosing cancer and rheumatoid arthritis as well as for lymphoscintigraphy. In addition, an increasing number of albumin-based or albumin-binding drugs are in clinical trials such as antibody fusion proteins (MM-111) for treating HER2/neu positive breast cancer (phase I), a camelid albumin-binding nanobody anti-HSA-anti-TNF-α (ATN-103) in phase II studies for treating rheumatoid arthritis, an antidiabetic Exendin-4 analog bound to recombinant human albumin (phase I/II), a fluorescein-labeled albumin conjugate (AFL)-human serum albumin for visualizing the malignant borders of brain tumors for improved surgical resection, and finally an albumin-binding prodrug of doxorubicin (INNO-206) entering phase II studies against sarcoma and gastric cancer. In the preclinical setting, novel approaches include attaching peptides with high-affinity for albumin to antibody fragments, the exploitation of albumin-binding gadolinium contrast agents for magnetic resonance imaging, and physical or covalent attachment of antiviral, antibacterial, and anticancer drugs to albumin that are permanently or transiently attached to human serum albumin (HSA) or act as albumin-binding prodrugs. This review gives an overview of the expanding field of preclinical and clinical drug applications and developments that use albumin as a protein carrier to improve the pharmacokinetic profile of the drug or to target the drug to the pathogenic site addressing diseases with unmet medical needs.

BACKGROUND

The mechanisms that drive progression from fatty liver to steatohepatitis and cirrhosis are unknown. In animal models, obese mice with fatty livers are vulnerable to liver adenosine triphosphate (ATP) depletion and necrosis, suggesting that altered hepatic energy homeostasis may be involved.

OBJECTIVE

To determine if patients with fatty liver disease exhibit impaired recovery from hepatic ATP depletion.

METHODS

Laboratory analysis of liver ATP stores monitored by nuclear magnetic resonance spectroscopy before and after transient hepatic ATP depletion was induced by fructose injection. The study was conducted between July 15 and August 30, 1998.

METHODS

University hospital.

METHODS

Eight consecutive adults with biopsy-proven nonalcoholic steatohepatitis and 7 healthy age- and sex-matched controls.

METHODS

Level of ATP 1 hour after fructose infusion in patients vs controls.

RESULTS

In patients, serum aminotransferase levels were increased (P = .02 vs controls); albumin and bilirubin values were normal and clinical evidence of portal hypertension was absent in both groups. However, 2 patients had moderate fibrosis and 1 had cirrhosis on liver biopsy. Mean serum glucose, cholesterol, and triglyceride levels were similar between groups but patients weighed significantly more than controls (P = .02). Liver ATP levels were similar in the 2 groups before fructose infusion and decreased similarly in both after fructose infusion (P = .01 vs initial ATP levels). However, controls replenished their hepatic ATP stores during the 1-hour follow-up period (P<.02 vs minimum ATP) but patients did not. Hence, patients' hepatic ATP levels were lower than those of controls at the end of the study (P = .04). Body mass index (BMI) correlated inversely with ATP recovery, even in controls (R = -0.768; P = .07). Although BMI was greater in patients than controls (P = .02) and correlated strongly with fatty liver and serum aminotransferase elevations, neither of the latter 2 parameters nor the histologic severity of fibrosis strongly predicted hepatic ATP recovery.

CONCLUSIONS

These data suggest that recovery from hepatic ATP depletion becomes progressively less efficient as body mass increases in healthy controls and is severely impaired in patients with obesity-related nonalcoholic steatohepatitis.

The authors have tested the hypothesis that plasma membrane disruptions are an early form of structural damage to the fibers of eccentrically exercised muscle. Rat serum albumin (RSA) was used as a marker for muscle-fiber wounding in the rat tricep (medial head) exercised eccentrically by downhill running. In all muscles examined, strong staining with a horseradish peroxidase (HRP)-conjugated anti-RSA antibody was observed between fibers (intercellular staining) and also within certain fibers (intracellular staining). This intracellular staining was interpreted as identifying muscle fibers wounded at their plasma membranes and hence rendered transiently or permanently permeable to extracellular RSA. The most striking finding of this study was a 6.9-fold increase relative to unexercised controls in the number of wounded cells in the medial head immediately after eccentric exercise. The authors also reproducibly observed, albeit less frequently, myocytes that stained with anti-RSA in the medial head and several other muscles of the "unexercised," caged laboratory rat. The extreme vulnerability of muscle plasma membranes to mechanically induced stress was revealed in this study by HRP injections into the triceps long head. A single injection of 200 microliters HRP through a 26-gauge needle resulted in extensive labeling of the muscle fibers present in the long head cross-sectioned at the injection site. The authors propose that initially resealable and/or highly localized, unsealable membrane wounds are an early form of exercise-induced damage that could progress along the length of the fiber until, 1 to 4 days after eccentric exercise, it becomes sufficiently severe that it can be readily recognized as the frank fiber necrosis and cellular infiltration described in numerous previous studies. In possessing cells wounded at their plasma membranes, normal, undisturbed rat muscle and eccentrically exercised muscle appears to resemble gut and skin, two additional tissues routinely exposed to mechanical forces in vivo. The authors propose that membrane disruptions provide a route into and out of myofiber cytoplasm distinct from the conventional, membrane-bounded routes of endo- and exocytosis, and therefore may be of importance both technically, as a route for introducing foreign genes into muscle cells, and biologically, as a route for release of the growth factor, basic fibroblast growth factor.

To determine the possible association between anemia and clinical and echocardiographic cardiac disease, a cohort of 432 end-stage renal disease patients (261 on hemodialysis and 171 on peritoneal dialysis) who started dialysis therapy between 1982 and 1991 were followed prospectively for an average of 41 months. Baseline demographic, clinical, and echocardiographic assessments were performed, as well as monthly serial clinical and laboratory tests while the patients were on dialysis therapy. The mean (+/-SD) hemoglobin level during dialysis therapy was 8.8 +/- 1.5 g/dL. After adjusting for age, diabetes, and ischemic heart disease, as well as for blood pressure and serum albumin levels measured serially, each 1 g/dL decrease in mean hemoglobin was independently associated with the presence of left ventricular dilatation on repeat echocardiogram (odds ratio, 1.46; P = 0.018) and the development of de novo (relative risk [RR] = 1.28; P = 0.018) and recurrent (RR = 1.20; P = 0.046) cardiac failure. In addition, each 1 g/dL decrease in the mean hemoglobin level was independently associated with mortality while the patients were on dialysis therapy (RR = 1.14; P = 0.024). Anemia had no independent association with the development of ischemic heart disease while the patients were on dialysis therapy. Anemia, an easily reversible feature of end-stage renal disease, is an independent risk factor for clinical and echocardiographic cardiac disease, as well as mortality in end-stage renal disease patients.

Several workers have observed that there is an extremely close immunological resemblance between the serum albumins of apes and man. Our studies with the quantitative micro-complement fixation method confirm this observation. To explain the closeness of the resemblance, previous workers suggested that there has been a slowing down of albumin evolution since the time of divergence of apes and man. Recent evidence, however, indicates that the albumin molecule has evolved at a steady rate. Hence, we suggest that apes and man have a more recent common ancestry than is usually supposed. Our calculations lead to the suggestion that, if man and Old World monkeys last shared a common ancestor 30 million years ago, then man and African apes shared a common ancestor 5 million years ago, that is, in the Pliocene era.