BACKGROUND

Patients undergoing either Roux-en-Y gastric bypass (RYGBP) or biliopancreatic diversion (BPD) with RYGBP are at risk of developing metabolic sequelae secondary to malabsorption. We compared the differences in nutritional complications between these two bariatric operations.

METHODS

A retrospective analysis of a prospective database was done. From June 1994 to December 2001, 243 morbidly obese patients underwent various bariatric procedures at our institution. Of these patients, 79 (BMI 45.6 +/- SD = 4.9) who underwent RYGBP (gastric pouch 15 +/- 5 ml, biliopancreatic limb 60-80 cm, alimentary limb 80-100 cm and common limb the remainder of the small intestine), and 95 super obese (BMI 57.2 +/- 6.1) who underwent a BPD (gastric pouch 15 +/- 5 ml, biliopancreatic limb 150-200 cm, common limb 100 cm and alimentary limb the remainder of the small intestine), were selected and studied for the incidence of micronutrient deficiencies and level of serum albumin at yearly intervals postoperatively. A variety of nutritional parameters including Hb, Fe, ferritin, folic acid, vitamin B12 and serum albumin were measured preoperatively and compared postoperatively at 1, 3, 6, 12, 18 and 24 months, and yearly thereafter.

RESULTS

Nutritional parameters were compared preoperatively and at similar periods postoperatively. No statistically significant (P < 0.05) difference in the occurrence of deficiency was observed between the groups for any of the nutritional parameters studied, except for ferritin, which showed a significant difference at the 2-year follow-up (37.7% low ferritin levels after RYGBP vs. 15.2% after BPD, P = 0.0294). All of these deficiencies were mild, without clinical symptomatology and were easily corrected with additional supplementation of the deficient micronutrient, with no need for hospitalization. Regarding serum albumin, there was only one patient with a level below 3 g/dl in the RYGBP group and two in the BPD group. These three patients were hospitalized and received total parenteral nutrition for 3 weeks, without further complications.

CONCLUSIONS

There was no significant difference in the incidence of deficiency of the nutritional parameters studied, except for ferritin, following RYGBP vs. BPD with RYGBP. The most common deficiencies encountered were of iron and vitamin B12. The incidence of hypoalbuminemia was negligible in both groups, with mean values above 4 g/dl.

HeLa cells have been previously used to demonstrate that virulent strains of Legionella pneumophila (but not salt-tolerant avirulent strains) efficiently invade nonphagocytic cells. Hsp60, a member of the GroEL family of chaperonins, is displayed on the surface of virulent L. pneumophila (R. A. Garduño et al., J. Bacteriol. 180:505-513, 1988). Because Hsp60 is largely involved in protein-protein interactions, we investigated its role in adherence-invasion in the HeLa cell model. Hsp60-specific antibodies inhibited the adherence and invasiveness of two virulent L. pneumophila strains in a dose-dependent manner but had no effect on the association of their salt-tolerant avirulent derivatives with HeLa cells. A monospecific anti-OmpS (major outer membrane protein) serum inhibited the association of both virulent and avirulent strains of L. pneumophila to HeLa cells, suggesting that while both Hsp60 and OmpS may mediate bacterial association to HeLa cells, only virulent strains selectively displayed Hsp60 on their surfaces. Furthermore, the surface-associated Hsp60 of virulent bacterial cells was susceptible to the action of trypsin, which rendered the bacteria noninvasive. Additionally, pretreatment of HeLa cells with purified Hsp60 or precoating of the plastic surface where HeLa cells attached with Hsp60 reduced the adherence and invasiveness of the two virulent strains. Finally, recombinant Hsp60 covalently bound to latex beads promoted the early association of beads with HeLa cells by a factor of 20 over bovine serum albumin (BSA)-coated beads and competed with virulent strains for association with HeLa cells. Hsp60-coated beads were internalized in large numbers by HeLa cells and remained in tight endosomes that did not fuse with other vesicles, whereas internalized BSA-coated beads, for which endocytic trafficking is well established, resided in more loose or elongated endosomes. Mature intracellular forms of L. pneumophila, which were up to 100-fold more efficient than agar-grown bacteria at associating with HeLa cells, were enriched for Hsp60 on the bacterial surface, as determined by immunolocalization techniques. Collectively, these results establish a role for surface-exposed Hsp60 in invasion of HeLa cells by L. pneumophila.

The plaque-derived gram-negative microorganism Y4 identified as a member of the genus Actinobacillus, was tested for a soluble cytotoxic factor(s). Sonication or incubation of viable Y4 microorganisms in distilled water or normal human serum resulted in liberation of a soluble material which was cytotoxic in vitro for human polymorphonuclear leukocytes (PMNs). The Y4 soluble sonic extract was also cytotoxic to human peripheral blood monocytes. However, human lymphocytes, platelets, and fibroblasts, as well as rabbit, rat, and mouse leukocytes and chicken embryo fibroblasts, were not killed by exposure to the Y4 sonic extract. No hemolytic activity was detected in the Y4 sonic extract. No hemolytic activity was detected in the Y4 sonic extract. Consequently, the factor(s) in the Y4 sonic extract was referred to as Y4 leukotoxin. The Y4 leukotoxin was inactive at 4 degrees C, heat sensitive (56 degrees C, 30 min), and inactivated by proteases. The cytotoxic effect of Y4 leukotoxin on PMNs was dose, time, and temperature dependent. The leukotoxin did not bind to viable PMNs at 4 degrees C but did bind to dead PMN membrane components at both 4 and 37 degrees C. The addition of bovine serum albumin (51 mg/ml) to PMN-Y4 leukotoxin cultures inhibited the release of lactate dehydrogenase from the PMNs, but did not prevent the death of the cells as indicated by electron microscopy. Lysosomal markers were released in parallel to the cytoplasmic enzyme lactate dehydrogenase from Y4 leukotoxin-treated PMNs. The addition of 0.02 M ethylenedinitrilotetraacetic acid to these cultures inhibited release of lysosomal markers but enhanced the release of lactate dehydrogenase. These results suggested that a soluble leukotoxin with specificity for only human PMNs and monocytes can be liberated from viable Y4. What role this leukotoxin plays in the pathogenicity of the Y4 microorganism is not yet known. However, this leukotoxin is one of the first materials from a plaque-derived microorganism with a potential role in the pathogenesis of juvenile periodontitis.

Norepinephrine stimulates the growth of a range of bacterial species in nutritionally poor SAPI minimal salts medium containing 30% serum. Addition of size-fractionated serum components to SAPI medium indicated that transferrin was required for norepinephrine stimulation of growth of Escherichia coli. Since bacteriostasis by serum is primarily due to the iron-withholding capacity of transferrin, we considered the possibility that norepinephrine can overcome this effect by supplying transferrin-bound iron for growth. Incubation with concentrations of norepinephrine that stimulated bacterial growth in serum-SAPI medium resulted in loss of bound iron from iron-saturated transferrin, as indicated by the appearance of monoferric and apo- isoforms upon electrophoresis in denaturing gels. Norepinephrine also caused the loss of iron from lactoferrin. The pharmacologically inactive metabolite norepinephrine 3-O-sulfate, by contrast, did not result in iron loss from transferrin or lactoferrin and did not stimulate bacterial growth in serum-SAPI medium. Norepinephrine formed stable complexes with transferrin, lactoferrin, and serum albumin. Norepinephrine-transferrin and norepinephrine-lactoferrin complexes, but not norepinephrine-apotransferrin or norepinephrine-albumin complexes, stimulated bacterial growth in serum-SAPI medium in the absence of additional norepinephrine. Norepinephrine-stimulated growth in medium containing (55)Fe complexed with transferrin or lactoferrin resulted in uptake of radioactivity by bacterial cells. Moreover, norepinephrine-stimulated growth in medium containing [(3)H]norepinephrine indicated concomitant uptake of norepinephrine. In each case, addition of excess iron did not affect growth but significantly reduced levels of radioactivity ((55)Fe or (3)H) associated with bacterial cells. A role for catecholamine-mediated iron supply in the pathophysiology of infectious diseases is proposed.

Degradable hydrogels have been extensively used in biomedical applications such as drug delivery, and recent interest has grown in hydrogels that degrade in recognition of a cellular response. This contribution describes a poly(ethylene glycol) (PEG) hydrogel platform with human neutrophil elastase (HNE) sensitive peptide cross-links formed using thiol-ene photopolymerization rendering the gel degradable at sites of inflammation. Further, protein therapeutics can be physically entrapped within the network and selectively released upon exposure to HNE. HNE-responsive hydrogels exhibited surface erosion where the degradation kinetics was influenced by changes in peptide k(cat), concentration of HNE, and concentration of peptide within the gel. Using this platform, we were able to achieve controlled, zero-order release of bovine serum albumin (BSA) in the presence of HNE, and release was arrested in the absence of HNE. To further exploit the advantages of surface eroding delivery systems, a smaller protein (carbonic anhydrase) was delivered at the same rate as BSA and only dependent on gel formulation and environmental conditions. Also, protein release was predicted from a 3-layered hydrogel device using mass loss data. Lastly, the bioactivity of lysozyme was maintained above 90% following the exposure to thiol-ene photopolymerization conditions.

OBJECTIVE

Dysbiosis is thought to be relevant to the etiology and pathogenesis of Crohn's disease (CD). In this study, we investigated the abundance of Faecalibacterium prausnitzii, as well as Bilophila wadsworthia, in the gut microbiota of Japanese CD patients.

METHODS

Forty-seven CD patients and 20 healthy controls were enrolled. Abundance of F. prausnitzii in fecal samples was quantified by real-time polymerase chain reaction. The gut microbiota profile was evaluated by terminal restriction fragment length polymorphisms.

RESULTS

The abundance of F. prausnitzii significantly decreased in CD patients compared with healthy subjects. B. wadsworthia was scarcely detected in the same samples. Among CD patients, the Crohn's Disease Activity Index, C-reactive protein levels, and erythrocyte sedimentation rate were significantly lower, and serum albumin levels were significantly higher in the high F. prausnitzii group compared with the low group. Terminal restriction fragment length polymorphisms analysis showed that fecal bacterial communities of CD patients differed from those of healthy individuals. The changes in simulated bacterial composition indicated that class Clostridia, including genus Faecalibacterium, was significantly less abundant in CD patients as compared with healthy individuals. The bacterial diversity measured by the Shannon Diversity Index was significantly reduced in CD patients compared with healthy individuals.

CONCLUSIONS

The decreased abundance of class Clostridia, including F. prausnitzii, may translate into a reduction of commensal bacteria-mediated, anti-inflammatory activities in the mucosa, which are relevant to the pathophysiology of CD. In contrast, the role of B. wadsworthia was suspected to be minimal.

BACKGROUND

Hypoalbuminemia is associated with poor prognosis in patients with certain chronic diseases, such as end-stage renal disease and cancer. Although low serum albumin is common in patients with heart failure (HF), the relationship between albumin and HF prognosis has not been well characterized. This study investigated the effect of serum albumin level on survival in patients with advanced HF.

METHODS

We analyzed 1726 systolic HF patients (age 52 +/- 13 years, ejection fraction [EF] 23% +/- 7%) followed at a university HF center. Albumin level was determined at initial referral. Patients were divided by into groups based on presence of hypoalbuminemia (< or = 3.4 g/dL). Mean albumin was 3.8 +/- 0.6 g/dL, and 25% of patients had hypoalbuminemia.

RESULTS

Patients with and without low albumin levels were similar in age, HF etiology, and EF. Hypoalbuminemia was associated with higher New York Heart Association (NYHA) class, higher serum urea nitrogen, creatinine level, C-reactive protein, and B-type natriuretic peptide but lower levels of sodium, hemoglobin, and cholesterol. In patients with BMI < 25 kg/m(2), 27% had albumin < or = 3.4 g/dL, compared to 22% of those with BMI>> or = 25 kg/m(2) (P < .01). One-year survival was 66% in patients with and 83% in those without hypoalbuminemia (P < .0001). Risk-adjusted hazard ratios for 1- and 5-year mortality were 2.2 (1.4-3.3) and 2.2 (1.4-3.2), respectively.

CONCLUSIONS

Hypoalbuminemia is common in HF and is independently associated with increased risk of death in HF. Further investigation of pathophysiologic mechanisms underlying hypoalbuminemia in HF is warranted.

BACKGROUND

Fetal exposure to environmental estrogens may contribute to hypofertility and/or to testicular germ cell cancer. However, many of these xenoestrogens have only a weak affinity for the classical estrogen receptors (ERs,) which is 1,000-fold less potent than the affinity of 17beta-estradiol (E(2)). Thus, several mechanisms have been suggested to explain how they could affect male germ cell proliferation at low environmental relevant concentrations.

OBJECTIVE

In this study we aimed to explore the possible promoting effect of bisphenol A (BPA) on human testicular seminoma cells. BPA is a well-recognized estrogenic endocrine disruptor used as a monomer to manufacture poly carbonate plastic and released from resin-lined food or beverage cans or from dental sealants.

RESULTS

BPA at very low concentrations (10(-9) to 10(-12) M) similar to those found in human fluids stimulated JKT-1 cell proliferation in vitro. BPA activated both cAMP-dependent protein kinase and cGMP-dependent protein kinase pathways and triggered a rapid (15 min) phosphorylation of the transcription factor cAMP response-element-binding protein (CREB) and the cell cycle regulator retinoblastoma protein (Rb). This nongenomic activation did not involve classical ERs because it could not be reversed by ICI 182780 (an ER antagonist) or reproduced either by E(2) or by diethylstilbestrol (a potent synthetic estrogen), which instead triggered a suppressive effect. This activation was reproduced only by E(2) coupled to bovine serum albumin (BSA), which is unable to enter the cell. As with E(2)-BSA, BPA promoted JKT-1 cell proliferation through a G-protein-coupled nonclassical membrane ER (GPCR) involving a Galpha(s) and a Galpha(i)/Galpha(q) subunit, as shown by the reversible effect observed by the corresponding inhibitors NF449 and pertussis toxin.

CONCLUSIONS

This GPCR-mediated nongenomic action represents--in addition to the classical ER-mediated effect--a new basis for evaluating xenoestrogens such as BPA that, at low doses and with a high affinity for this GPCR, could interfere with the developmental programming of fetal germ cell proliferation and/or differentiation when they cross the placenta.

BACKGROUND

Serum albumin level predicts mortality in dialysis patients and is used to assess their health status and the quality of delivered care. Whether the threshold level of serum albumin at which mortality risk increases in peritoneal dialysis (PD) patients is the same as for hemodialysis (HD) patients has not been studied.

METHODS

Observational cohort study of dialysis patients undertaken to determine the survival-predictability of serum albumin level in PD patients and compare it with that in HD patients.

METHODS

130,052 dialysis patients (PD, 12,171; HD, 117,851) who received treatment in any of the 580 dialysis units owned by DaVita Inc between July 1, 2001, through June 30, 2006, followed up through June 30, 2007.

METHODS

Baseline and time-averaged serum albumin level (assayed using bromcresol green) and change in serum albumin level over 6 months.

METHODS

All-cause, cardiovascular, and infection-related mortality.

RESULTS

PD patients with baseline serum albumin level <3.0 g/dL had a more than 3-fold higher adjusted risk of all-cause and cardiovascular mortality and 3.4-fold higher risk of infection-related mortality (reference group: serum albumin, 4.00-4.19 g/dL). Adjusted all-cause mortality was significantly lower in PD patients with a ≥0.3-g/dL increase in serum albumin level over 6 months and significantly higher in those for whom it decreased by ≥0.2 g/dL (reference group: serum albumin change, +0.1 to -0.1 g/dL). A significant increase in death risk was evident for HD patients with serum albumin level <4.0 g/dL, but at <3.8 g/dL for PD patients. For each albumin category, overall death risk for PD patients was lower than for HD patients (reference group: HD patients with serum albumin of 4.00-4.19 g/dL).

CONCLUSIONS

Study can identify associations only without attribution of causality and residual confounding cannot be excluded.

CONCLUSIONS

Serum albumin predicts all-cause, cardiovascular, and infection-related mortality in both PD and HD patients. However, the threshold at which risk of death increases varies by dialysis modality, and this difference should be considered by agencies or organizations that set quality standards.

BACKGROUND

Albumin is the most abundant plasma protein, is highly soluble, very stable and has an extraordinarily long circulatory half-life as a direct result of its size and interaction with the FcRn mediated recycling pathway. In contrast, many therapeutic molecules are smaller than the renal filtration threshold and are rapidly lost from the circulation thereby limiting their therapeutic potential. Albumin can be used in a variety of ways to increase the circulatory half-life of such molecules.

METHODS

This article will review the mechanisms which underpin albumin's extraordinarily long circulatory half-life and how the understanding of these processes are currently being employed to extend the circulatory half-life of drugs which can be engineered to bind to albumin, or are conjugated to, or genetically fused to, albumin.

CONCLUSIONS

The recent and growing understanding of the pivotal role of FcRn in maintaining the extended circulatory half-life of albumin will necessitate a greater and more thorough investigation of suitable pre-clinical model systems for assessing the pharmacokinetic profiles of drugs associated, conjugated or fused to albumin.

CONCLUSIONS

Association, conjugation or fusion of therapeutic drugs to albumin is a well-accepted and established half-life extension technology. The manipulation of the albumin-FcRn interaction will facilitate the modulation of the circulatory half-life of albumin-enabled drugs, leading to superior pharmacokinetics tailored to the disease state and increased patient compliance. This article is part of a Special Issue entitled Serum Albumin.

Serum albumin is a multi-functional protein that is able to bind and transport numerous endogenous and exogenous compounds. The development of albumin drug carriers is gaining increasing importance in the targeted delivery of cancer therapy, particularly as a result of the market approval of the paclitaxel-loaded albumin nanoparticle, Abraxane®. Considering this, there is renewed interest in isolating and characterizing albumin-binding proteins or receptors on the plasma membrane that are responsible for albumin uptake. Initially, the cellular uptake and intracellular localization of albumin was unknown due to the large confinement of the protein within the vascular and interstitial compartment of the body. Studies have since assessed the intracellular localization of albumin in order to understand the mechanisms and pathways responsible for its uptake, distribution and catabolism in multiple tissues, and this is reviewed herein.

We have examined the role of intrapulmonary TNF in a rat model of acute immune complex-triggered alveolitis. Intratracheal instillation of IgG anti-bovine serum albumin (anti-BSA) followed by intravenous infusion of BSA results in acute alveolitis. Over the 4-h course of evolving lung injury, a 10-fold increase in TNF activity occurred in bronchoalveolar lavage (BAL) fluid. Immunohistochemical analysis of lung sections and BAL cells revealed that alveolar macrophages are the chief source of TNF. Antibodies that specifically neutralize rat TNF activity were raised in rabbits immunized with recombinant mouse TNF alpha. When administered into the lungs with anti-BSA, anti-TNF resulted in a marked reduction (up to 61%) in lung injury. Intratracheal instillation of exogenous TNF alone, or in combination with anti-BSA, resulted in an increase in lung injury compared to controls. Morphometric analysis and measurements of myeloperoxidase activities in whole lung extracts from rats treated with anti-TNF revealed a marked reduction in neutrophils compared to positive controls. The anti-TNF antibody preparation did not inhibit in vitro complement activation or diminish neutrophil chemotactic activity present in activated rat serum. These data indicate that intrapulmonary TNF activity is required for the full development of acute immune complex-triggered alveolitis, that alveolar macrophages are the primary source of this cytokine, and that TNF participates in the pathogenesis of immune complex alveolitis through a mechanism involving neutrophil recruitment.

We previously demonstrated that cyclic ADP-ribose (cADPR) elicits Ca2+ release in airway smooth muscle (ASM) cells through ryanodine receptor channels. CD38 is a cell surface protein that catalyzes the synthesis and degradation of cADPR. In inflammatory diseases such as asthma, augmented Ca2+ responses and Ca2+ sensitivity contribute to increased ASM contractility in response to agonists. In this study, we investigated the regulation of CD38 expression and the role of cADPR-mediated Ca2+ release in airway inflammation. Human ASM cells in culture between the second and fifth passages were exposed to tumor necrosis factor alpha (TNF-alpha), interleukin 1beta, or interferon gamma, or bovine serum albumin (controls). CD38 expression was measured by reverse transcriptase-polymerase chain reaction (RT-PCR), real-time PCR, and Western blot analysis, and ADP-ribosyl cyclase activity was assayed with nicotinamide guanine dinucleotide as the substrate. Ca2+ responses to acetylcholine, bradykinin, and thrombin were measured in fura-2AM-loaded cells by fluorescence microscopy. Cytokines caused significant augmentation of CD38 expression, ADP-ribosyl cyclase activity, and Ca2+ responses to the agonists, compared with the control. TNF-alpha effects were greater than those of the other two cytokines. The cADPR antagonist 8-bromo-cADPR attenuated the Ca2+ responses to the agonists in control and cytokine-treated cells, with the magnitude of inhibition correlating with the level of CD38. This study provides the first demonstration of a role for CD38-cADPR signaling in a model of inflammatory airway disease.

Water oxygen-17 and deuteron spin relaxation rates, measured as a function of resonance frequency, have been used to study the dynamics of protein hydration in aqueous solutions of ribonuclease A, lysozyme, myoglobin, trypsin and serum albumin. The relaxation data conform to the picture of protein hydration dynamics, proposed on the basis of previous studies of smaller proteins, where the long-lived water molecules responsible for the relaxation dispersion are identified with a small number of integrat water molecules seen in the crystal structures. These integral water molecules, with residence times in the range 10(-9)-10(-3) s, are either buried in internal cavities, trapped in narrow clefts or coordinated to metal ions. For the water molecules in the traditional hydration layer at the protein surface, the relaxation data suggest an average residence time in the range 10-50 ps, consistent with high-resolution 1H spectroscopy and computer simulations. The relaxation data also reveal some more specific features of protein hydration, relating to hydration of cavities that appear empty by crystallography, entrapment of water between structural domains of large proteins and subnanosecond 180 degrees flips in buried water clusters.

Residual renal function, defined as the urinary clearance of urea and creatinine, is minimal in many patients treated with hemodialysis (HD) and tends to be ignored in most outcome studies involving HD patients. Recent studies showed that residual renal function, even at a low level, is influential in preventing mortality in the minority of patients with end-stage renal disease treated with peritoneal dialysis. This issue generally has not been examined in patients treated with HD. This prospective observational study of all 114 patients at a single community-based freestanding HD center is designed to examine the impact of residual renal function (defined as renal urea clearance and renal creatinine clearance derived from 24-hour urinary volumes) on mortality over a 2-year period. During that period, 50 deaths occurred in 114 patients. The presence of residual renal function was protective against mortality (odds ratio for death, 0.44; 95% confidence interval, 0.24 to 0.81; P = 0.008), even after adjustment for duration of dialysis treatment, age, smoking, presence of diabetes, presence of cardiovascular disease, serum albumin level, and urea reduction rate. In conclusion, the presence of residual renal function, even at a low level, is associated with a lower mortality risk in HD patients.

Rodent bone marrow cells can contribute to liver. If these findings are applicable to humans, marrow stem cells could theoretically be harvested from a patient and used to repair his/her damaged liver. To explore this potential, CD34(+) or highly purified CD34(+)CD38(-)CD7(-) human hematopoietic stem cells from umbilical cord blood and bone marrow were transplanted into immunodeficient mice. One month after transplantation, carbon tetrachloride (CCl(4)) was administered into the mice to induce liver damage and hepatocyte proliferation. Mice were analyzed in comparison with CCl(4)-injured mice that did not receive transplants and noninjured controls that received transplants with the same stem cell populations, one month after liver damage. Human-specific albumin mRNA and protein were expressed in the mouse liver and human albumin was detected in the serum of mice that had received CCl(4) injury. Human alpha-fetoprotein was never expressed, but in some mice, human cytokeratin 19 was expressed, which may indicate bile duct development in addition to the albumin-secreting hepatocyte-like cells. Human albumin was not expressed in the starting stem cell populations in injured mice that did not receive transplants nor in noninjured mice that had received transplants of human stem cells. Human albumin expression was detected only in CCl(4)-treated mice that received transplants of human stem cells, and recovery was increased by administration of human hepatocyte growth factor 48 hours after the CCl(4)-mediated liver injury. Our studies provide evidence that human "hematopoietic" stem/progenitor cell populations have the capacity to respond to the injured liver microenvironment by inducing albumin expression.

This prospective follow-up study of 422 19-yr-old subjects born very preterm in The Netherlands was performed to determine whether intrauterine growth retardation (IUGR) predisposes to abnormal GFR and microalbuminuria in adolescents. GFR (ml/min per 1.73 m2) was estimated using the Cockcroft-Gault equation, and albumin-creatinine ratio (mg/mmol) was calculated in a cohort of 19-yr-old subjects born very preterm (gestational age <32 wk) in 1983. Birth weights were adjusted for gestational age and expressed as standard deviation scores (sds) as a measure of IUGR. All subjects had normal renal function. Birth weight (sds) was associated negatively with serum creatinine concentration (micromol/L) (beta = -1.0 micromol/L, 95% confidence interval [CI]: -1.9 to -0.2), positively with GFR (beta = 3.0, 95% CI: 1.7 to 4.2), and negatively with the logarithm of albumin-creatinine ratio (beta = -0.05, 95% CI: -0.09 to -0.01) in young adults born very preterm. IUGR is associated with unfavorable renal functions at young adult age in subjects born very premature. These data suggest that intrauterine growth-retarded subjects born very premature have an increased risk to develop progressive renal failure in later life.

OBJECTIVE

The neurotoxic effects of cyclosporine therapy are well known but poorly understood. Imaging studies typically show subcortical edema predominantly affecting the posterior regions of the brain. We sought to determine the causes for these findings by comparing radiographic data with various clinical parameters.

METHODS

In a 3-year period, 16 patients with neurologic findings attributed to cyclosporine therapy were examined with CT, MR imaging, or both. In most cases, imaging was performed both at the onset of the neurologic syndrome and after it had resolved. The radiographic findings were evaluated with respect to lesion location and changes over time. Various clinical and laboratory data obtained throughout the patients' hospital course were also reviewed, including cyclosporine levels, blood pressure values, hematologic data, and serum levels of cholesterol, magnesium, creatinine, and albumin.

RESULTS

The only major factor associated with the neurotoxic effects of cyclosporine in all patients was systemic hypertension. Microangiopathic hemolytic anemia, thrombocytopenia, and hypoalbuminemia were also common, and patients usually displayed signs of sympathetic overactivation. The onset of neurologic symptoms was unrelated to serum levels of creatinine, magnesium, cholesterol, or cyclosporine. The clinical and radiographic findings of these patients were identical to those previously reported in patients with hypertensive encephalopathy. Findings resolved in all but one patient after reduction of blood pressure, with or without reduction in cyclosporine dose. In four patients, intracranial hemorrhages occurred during the hypertensive episode, resulting in one fatality.

CONCLUSIONS

The clinical and radiologic findings in patients showing the neurotoxic effects of cyclosporine appear to be identical to those with hypertensive encephalopathy. Other associated factors, such as cyclosporine-induced vasculopathy or hypoalbuminemia may also play a role in the condition, and intracranial hemorrhage may occur owing to associated thrombocytopenia. Symptoms generally resolve after reduction of blood pressure, and follow-up is usually unnecessary in uncomplicated cases.

The second National Health and Nutrition Examination Survey, 1976 to 1980, incorporated medical history, physical examination, anthropometric measurements, dietary information (24-hour recall and food frequency), laboratory tests, and radiographs. In linear regressions of adjusted data from 2,695 children aged 7 years and younger, 91% of the variance in height, 72% of the variance in weight, and 58% of the variance in chest circumference were explained by six variables: age, race, sex, blood lead level, total calories or protein, and hematocrit or transferrin saturation level. Variables that did not significantly improve the models predicting growth included family income, degree of urbanization, serum albumin, copper, iron, and zinc levels, dietary carbohydrate, fat, calcium, potassium, phosphorus, vitamin A, vitamin C, niacin, riboflavin, and thiamine. The highly significant correlation of blood lead level with growth does not contradict the established association of childhood deprivation with increased lead exposure and with nutritional deficiences known to enhance lead absorption. Blood lead level may also represent a composite marker for unidentified genetic, ethnic, environmental, and sociocultural variables, other than race, sex, and nutrition, that affect growth. However, the correlation of stature, particularly height, with blood lead levels in the range of 5 to 35 micrograms/dL is so statistically significant that it merits investigation in other surveys and consideration of the multiple biologic mechanisms by which low-level lead exposure could impair the growth of children.

This work characterizes the thermodynamic processes involved in the binding and separation of (R)- and (S)-warfarin on a high-performance human serum albumin (HSA) column. Frontal analysis was used to determine the strength and degree of binding for each enantiomer. (R)- and (S)-warfarin were found to bind at the same region on HSA; however, (R)-warfarin had a larger number of column binding sites. The number of binding sites for both enantiomers showed a slight increase with temperature. The total changes in free energy for (R)- and (S)-warfarin binding were similar at 37 degrees C, but the contribution due to entropy was greater for the R-enantiomer. These results suggested that (R)-warfarin was interacting mainly with the binding site interior, while (S)-warfarin interacted more with the site's outer surface. This model was confirmed by examining the retention of (R)- and (S)-warfarin on the HSA column under various pH, ionic strength, and organic modifier conditions. The different changes in entropy for these solutes made it possible to vary their separation by changing column temperature. Both thermodynamic properties and column binding capacities were found to be important in determining the degree of separation obtained for these compounds.

To identify individual risk factors and to establish an index of risk in biliary tract surgery, data on 16 potential predictive factors were compiled from a series of 186 biliary tract operations excluding simple cholecystectomy. Eight factors had a significant association with postoperative mortality. Linear discriminant analysis showed that serum creatinine, serum albumin and serum bilirubin levels in the week before surgery had independent significance in predicting postoperative mortality. The discriminant function derived identified a high risk group of patients and the predictive value was confirmed in an independent series of 54 biliary tract operations carried out in another surgical unit. The discriminant function derived for patients jaundiced before surgery also defined a high and low risk group and was similarly validated. Identification of high risk patients undergoing surgery for obstructive jaundice may be useful in defining a group of patients to be considered for trials of preliminary biliary drainage.

The present in vitro microperfusion study examined whether insulin affects volume absorption (Jv) in the proximal convoluted tubule (PCT). PCT were perfused with an ultrafiltrate-like solution and were bathed in a serum-like albumin solution. Addition of a physiologic concentration of 10(-10) M insulin to the bathing solution resulted in a stimulation of Jv and a more negative transepithelial potential difference (PD). There was a progressive stimulation of the lumen negative PD and Jv with higher insulin concentrations. Maximal stimulation occurred at 10(-8) M bath insulin. The insulin-induced stimulation of volume reabsorption was also observed when glucose and amino acids were removed from the luminal perfusate. Direct examination of the effect of insulin on glucose, chloride, and bicarbonate absorption demonstrated that the transport of all these solutes was stimulated by insulin. Addition of insulin to the luminal perfusate had no affect on Jv. These data show that insulin has a direct effect to stimulate Jv in the proximal tubule.

BACKGROUND

Although differences between black and white persons in hemoglobin A(1c) (HbA(1c)) values are well established, recent studies suggest that this might not reflect differences in glycemia.

OBJECTIVE

To investigate racial disparities in glycemic markers, including those that reflect biological processes independent of hemoglobin glycation and erythrocyte turnover.

METHODS

Cross-sectional.

METHODS

Community-based.

METHODS

1376 nondiabetic and 343 diabetic adults in a substudy of the Atherosclerosis Risk in Communities Study.

METHODS

Hemoglobin A(1c), fasting glucose, glycated albumin, fructosamine, and 1,5-anhydroglucitol levels.

RESULTS

Among persons with and without diabetes, black persons had significantly higher HbA(1c), glycated albumin, and fructosamine levels than white persons before and after adjustment for covariates and fasting glucose concentration. Serum 1,5-anhydroglucitol levels, which are reduced in the setting of hyperglycemia-induced glycosuria, were lower in black persons than in white persons, although this difference was statistically significant only in nondiabetic adults.

CONCLUSIONS

The design was cross-sectional, a limited number of participants with a history of diabetes was included, and the study did not include integrated measures of circulating nonfasting glycemia.

CONCLUSIONS

Differences between black and white persons in glycated albumin, fructosamine, and 1,5-anhydroglucitol levels parallel differences between these groups in HbA(1c) values. Racial differences in hemoglobin glycation and erythrocyte turnover cannot explain racial disparities in these serum markers. The possibility that black persons have systematically higher levels of nonfasting glycemia warrants further study.

BACKGROUND

National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases.

The diffusion of macromolecules introduced into the cytoplasm of human fibroblasts by erythrocyte-mediated microinjection was measured by the fluorescence recovery after photobleaching technique. The apparent diffusion coefficients for fluorescein-labeled IgG and fluorescein-labeled bovine serum albumin were approximately 10(-8) cm2/sec at 22 degrees C, consistent with the kinetics of spreading of the fluorescent probe following microinjection and approximately 1/70 the values in aqueous buffer. The diffusion of labeled bovine serum albumin was shown to be strongly dependent on temperature and, in fact, similar to that expected in a 61% aqueous sucrose solution. However, the marked reduction in diffusion at 5 degrees C could be fully reversed by incubation with 0.1 mM colchicine. These findings suggest that cytoplasmic diffusion rates are reduced relative to rates in aqueous media as a result of increased aqueous phase viscosity or the impedence provided by structural elements. Several simple models to account for the data are presented.