Subclinical vitamin D insufficiency is characterized by mild secondary hyperparathyroidism and enhanced risk of osteoporotic fracture. However, although low levels of 25-hydroxyvitamin D (25OHD) are common in otherwise normal elderly people, vitamin D status has not generally been taken into account in the previously published reference values for serum PTH. We measured fasting morning serum (obtained from April through June) PTH, total calcium, albumin, phosphate, creatinine, bone markers, and 25OHD in 280 healthy subjects (140 men and 140 women), aged 60-79 yr. Serum PTH was measured by means of 2 immunoradiometric assays, the Allegro intact PTH assay (Nichols Institute Diagnostics) and the new CAP assay (Scantibodies Laboratory, Inc.). We found a high prevalence (167 of 280; 59.6%) of low 25OHD (< or =30 nmol/L) in these otherwise healthy individuals. The PTH concentrations (95% confidence interval) obtained in the whole group of 280 subjects ranged from 13-64 ng/L for the Allegro assay and from 10-44 ng/L for the CAP assay. In the subjects with a serum 25OHD concentration greater than 30 nmol/L, values for both PTH assays were lower, 10-46 and 9-34 ng/L for the Allegro and the CAP assays, respectively. By using these values as a reference range, approximately 25% of the subjects with a serum 25OHD level of 30 nmol/L or less had a high serum PTH level (whatever the assay), reflecting secondary hyperparathyroidism. This might be missed if the reference PTH values are those obtained in the entire group, as is usually done. These results strongly suggest that vitamin D status should be taken into account when establishing reference values for serum PTH in elderly subjects.

BACKGROUND

Perchlorate is commonly found in the environment and known to inhibit thyroid function at high doses. Assessing the potential effect of low-level exposure to perchlorate on thyroid function is an area of ongoing research.

OBJECTIVE

We evaluated the potential relationship between urinary levels of perchlorate and serum levels of thyroid stimulating hormone (TSH) and total thyroxine (T4) in 2,299 men and women,>> or = 12 years of age, participating in the National Health and Nutrition Examination Survey (NHANES) during 2001-2002.

METHODS

We used multiple regression models of T4 and TSH that included perchlorate and covariates known to be or likely to be associated with T4 or TSH levels: age, race/ethnicity, body mass index, estrogen use, menopausal status, pregnancy status, premenarche status, serum C-reactive protein, serum albumin, serum cotinine, hours of fasting, urinary thiocyanate, urinary nitrate, and selected medication groups.

RESULTS

Perchlorate was not a significant predictor of T4 or TSH levels in men. For women overall, perchlorate was a significant predictor of both T4 and TSH. For women with urinary iodine < 100 microg/L, perchlorate was a significant negative predictor of T4 (p < 0.0001) and a positive predictor of TSH (p = 0.001). For women with urinary iodine>> or = 100 microg/L, perchlorate was a significant positive predictor of TSH (p = 0.025) but not T4 (p = 0.550).

CONCLUSIONS

These associations of perchlorate with T4 and TSH are coherent in direction and independent of other variables known to affect thyroid function, but are present at perchlorate exposure levels that were unanticipated based on previous studies.

Albumin is the most abundant protein in serum and contributes to the maintenance of oncotic pressure as well as to transport of hydrophobic molecules. Although albumin is a large anionic protein, it is not completely retained by the glomerular filtration barrier. In order to prevent proteinuria, albumin is reabsorbed along the proximal tubules by receptor-mediated endocytosis, which involves the binding proteins megalin and cubilin. Endocytosis depends on proper vesicle acidification. Disturbance of endosomal acidification or loss of the binding proteins leads to tubular proteinuria. Furthermore, endocytosis is subject to modulation by different signaling systems, such as protein kinase A (PKA), protein kinase C (PKC), phosphatidylinositol 3-kinase (PI3-K) and transforming growth factor beta (TGF-beta). In addition to being reabsorbed in the proximal tubule, albumin can also act as a profibrotic and proinflammatory stimulus, thereby initiating or promoting tubulo-interstitial diseases.

In a historical cohort study, acute renal failure developed in 16.5% of 157 patients with rhabdomyolysis over a two-year study period. Underlying clinical, laboratory, and causative factors associated with the development of acute renal failure were examined. Factors predictive of renal failure in this setting, determined by multiple logistic regression analysis, included the degree of serum creatine kinase, serum potassium, and serum phosphorus level elevation; the degree of depression of serum albumin level; and the presence of dehydration at presentation or sepsis as the underlying cause. The predictive model that was developed correctly classified 93% of subjects and was statistically validated.

Specific albumin binding to the surface of endothelium initiates its transcytosis across continuous endothelium via noncoated plasmalemmal vesicles. Past work has identified several putative albumin-binding proteins (SPARC, gp60, gp30, and gp18). In this study, we examined the specific role of these proteins in the binding of bovine serum albumin (BSA) to endothelium. The 60-kDa albumin-binding protein (gp60, now called albondin) was purified from cultured rat microvascular endothelial cells for antibody production. Anti-albondin antibodies (alpha gp60) specifically recognized albondin expressed by rat, bovine, and human endothelial cells (EC). alpha gp60 and unlabeled native BSA inhibited 125I-BSA binding to confluent EC monolayers and to both albondin and SPARC extracts immobilized on filters. Modification of BSA by maleic anhydride treatment (Mal-BSA) or by surface adsorption to colloidal gold particles (A-Au) renders the ligand specific for gp30 and gp18 while eliminating its ability to inhibit 125I-BSA binding to EC and to both albondin and SPARC extracts. Mal-BSA and A-Au interacted with EC via distinct binding sites not recognizing native BSA. EC internalization of 125I-BSA is inhibited by unlabeled BSA and alpha gp60 IgG but not nonimmune IgG, Mal-BSA, or A-Au. Conversely, internalization of modified BSA is inhibited by unlabeled modified BSA but not BSA or alpha gp60 IgG. Specific 125I-BSA transendothelial transport in rat lungs perfused in situ and for EC monolayers in vitro is inhibited >> or = 90%) by unlabeled BSA and alpha gp60 IgG but not nonimmune IgG and Mal-BSA. No specific transport of 125I-Mal-BSA is detected across bovine lung microvascular endothelial cell monolayers, only paracellular and/or fluid-phase transport. Low temperatures reduce BSA transport by 5-fold and Mal-BSA by 2-fold. Interestingly, 3-fold more native BSA is transported than Mal-BSA at 37 degrees C, whereas at 8-10 degrees C they are nearly equal, suggesting facilitation of BSA transport. Cumulatively, it appears that gp30 and gp18 mediate the binding, endocytosis, and degradation of modified albumins, whereas albondin mediates native albumin binding which significantly enhances its transcytosis and capillary permeability.

OBJECTIVE

Postoperative intrahepatic recurrence of human hepatocellular carcinoma is high. Recently, the relationship between proliferating cell activity in the cirrhotic liver and occurrence or recurrence of hepatocellular carcinoma has been reported.

METHODS

One hundred two resected cases of small hepatocellular carcinoma of < 3 cm in diameter without venous invasion or intrahepatic metastasis were examined to ascertain the factors affecting postoperative intrahepatic recurrence.

RESULTS

Cumulative intrahepatic recurrence rates at 1, 3, and 5 years after surgery were 12.0%, 57.2%, and 67.6%, respectively. The log-rank test indicated that serum albumin levels of < 3.7 g/dL, alanine aminotransferase levels of more than 54 IU/L, active inflammation in the nontumorous portion, and high proliferating cell nuclear antigen labeling index in the nontumorous portion >> 23.2%) were significant risk factors for recurrence. Tumor factors, including tumor size, histological grade, or alpha-fetoprotein level, were not significant risk factors. Cox's proportional hazard model identified that serum albumin level and alanine aminotransferase level were independently associated with intrahepatic recurrence after hepatectomy.

CONCLUSIONS

This study suggests that the principal cause linked to either a recurrence or a second new growth of hepatocellular carcinoma in the remnant liver after hepatectomy was the state of the underlying liver parenchyma as well as other tumor factors per se.

BACKGROUND

Surgical site infection (SSI) is an infection occurring in an incisional wound within 30 days of surgery and significantly effects patient recovery and hospital resources.

OBJECTIVE

This study sought to determine the relationship between preoperative serum albumin and SSI.

METHODS

A study of 524 patients who underwent gastrointestinal surgery in 4 institutions was performed. Patients were identified using a prospective SSI database and hospital records. Serum albumin was determined preoperatively in all patients. Hypoalbuminemia was defined as albumin <30 mg/dL. Data are presented as median (interquartile range) and a difference between groups was examined using Mann-Whitney U and Fisher exact test and multiple logistic regression analysis.

RESULTS

A total of 105 patients developed a SSI (20%). The median time to the development of SSI was 7 (5-10) days. Having an emergency procedure (P = 0.003), having a procedure over 3 hours in duration (P = 0.047), being American Society of Anaesthetics grade 3 (P = 0.03) and not receiving preoperative antibiotics (P = 0.007) were associated with SSI while having a laparoscopic procedure reduced the likelihood of SSI (P = 0.004). Patients who developed a SSI had a lower preoperative serum albumin (30 [25-34.5] vs. 36 [32-39], P < 0.001). On multivariate analysis, hypoalbuminemia was an independent risk factor for SSI development (relative risk, RR = 5.68, 95% confidence interval: 3.45-9.35, P < 0.001). Albumin <30 mg/dL was associated with an increased rate of deep versus superficial SSI (P = 0.002). The duration of inpatient stay was negatively correlated with preoperative albumin (R = -0.319, P < 0.001).

CONCLUSIONS

Hypoalbuminemia is an independent risk factor for the development of SSI following gastrointestinal surgery and is associated with deeper SSI and prolonged inpatient stay.

We investigated blood-brain barrier (BBB) function in relation to Alzheimer's disease (AD) and vascular dementia (VAD) in the very elderly. Sixty-five 85-year-old persons from a population-based sample were followed for 3 years; 29 were demented at age 85 (13 with AD, 14 with VAD, and 2 with other dementias), 7 developed dementia during follow-up, and 29 remained nondemented. CSF/serum albumin ratio was used as as a measure of BBB function. Dementia was defined according to the DSM-III-R, AD according to the NINCDS-ADRDA criteria, and VAD according to the NINDS-Association Internationale pour la Recherche et l'Enseignement en Neurosciences (AIREN) criteria. Mean CSF/serum albumin ratio was higher in all dementias (8.5 +/- 4.3; p = 0.007) and in the subtypes AD (8.9 +/- 5.3; p = 0.046) and VAD (8.7 +/- 3.5; p = 0.002) than in nondemented individuals (versus 6.5 +/- 2.0), but it was not related to dementia severity. Nondemented women at age 85 (n = 3) who developed dementia during the follow-up had a higher CSF/serum albumin ratio than those not developing dementia (10.4 +/- 2.0 versus 6.0 +/- 1.9; p = 0.007). Nondemented individuals lacking the apolipoprotein E epsilon3 allele (n = 4) had a higher CSF/serum albumin ratio (9.3 +/- 0.8 versus 6.6 +/- 2.1; p = 0.029) than other individuals. A relative BBB dysfunction is associated with both AD and VAD among very elderly individuals. This finding is possibly found early in the disease before the onset of clinical dementia.

Normal human liver tissue and cultured human hepatocytes are valuable models to study xenobiotic metabolism and toxicity, but they only have a limited in vitro life-span and are not readily available. This report describes the establishment of replicative cultures of human adult liver epithelial cells in serum-free medium. The longevity of three of these cultures, derived from different donors, was extended by introduction of the simian virus 40 large T antigen gene. Two cell lines, THLE-2 and -3, established with a recombinant simian virus 40 large T antigen virus have undergone>> 100 population doublings, are nontumorigenic when injected into athymic nude mice, have near-diploid karyotypes, and do not express alpha-fetoprotein. The cells express cytokeratin 18 and albumin in early passage, whereas higher-passage cells in logarithmic-phase growth also express cytokeratin 19. THLE-2 and -3 cells metabolize benzo[a]pyrene, N-nitrosodimethylamine, and aflatoxin B1 to their ultimate carcinogenic metabolites that adduct DNA, which indicates functional cytochrome P450 pathways. Other enzymes involved in metabolism of chemical carcinogens, such as epoxide hydrolase, NADPH cytochrome P450 reductase, superoxide dismutase, catalase, glutathione S-transferases, and glutathione peroxidase are also retained by THLE cells. Thus, these immortalized human liver cells constitute an in vitro model for pharmacotoxicological studies and for the investigation of etiology and pathogenesis of human hepatocellular carcinoma.

OBJECTIVE

To examine the effects of testosterone administration to older hypogonadal males (bioavailable testosterone less than 70 ng/dL).

METHODS

Alternate-case controlled trial.

METHODS

St. Louis University.

METHODS

Eight males (mean age 77.6 +/- 2.3 years) who received testosterone and six males (mean age 76 +/- 2.3 years) who served as controls. Selected from alumni of the SHEP trial and attendees at the St. Louis University Impotence Clinic.

METHODS

Testosterone enanthate (200 mg/mL) was administered intramuscularly to the treatment group every 2 weeks for 3 months.

METHODS

Serum testosterone, bioavailable testosterone and estradiol, weight, % body fat, right hand muscle strength, balance, cholesterol, HDL-cholesterol, hematocrit, BUN, creatinine, albumin, calcium, PTH, 25(OH) vitamin D, 1,25(OH)2 vitamin D, osteocalcin, prostate-specific antigen, and fructosamine.

RESULTS

Males who received testosterone had a significant increase in testosterone and bioavailable testosterone concentration, hematocrit, right hand muscle strength and osteocalcin concentration. They had a decrease in cholesterol (without a change in HDL-cholesterol) levels and decreased BUN/Creatinine ratios.

CONCLUSIONS

These preliminary findings support the need for long term studies of testosterone therapy in older hypogonadal males.

OBJECTIVE

To determine the activity and toxicity of doxorubicin in combination with cisplatin and etoposide in patients with small-cell prostate carcinoma (SCPCa) and to characterize the clinicopathologic features of SCPCa.

METHODS

Patients with SCPCa (pure or mixed), measurable disease, good organ function, and no prior treatment with doxorubicin, etoposide, or cisplatin were treated every 4 weeks with doxorubicin 50 mg/m(2) as a 24-hour intravenous (IV) infusion followed by etoposide 120 mg/m(2)/d and cisplatin 25 mg/m(2)/d IV on days 2 to 4.

RESULTS

Thirty-eight patients (36 assessable for response) were treated for a median of four cycles. Twenty-nine (81%) of 36 patients had prior hormonal therapy. Study patients had visceral metastases, lytic bone disease, and relatively low serum prostate-specific antigen (PSA). We observed 22 partial responses (response rate, 61% in an intent-to-treat analysis); toxicity was severe (grade 3 or 4 neutropenia 100%, thrombocytopenia 66%, mucositis 21%, and infection 68%). Three patients died of toxicity. Median time to progression and overall survival time were 5.8 months and 10.5 months, respectively. Performance status, serum albumin, and number of organs involved (but not PSA, carcinoembryonic antigen, or neuroendocrine markers) were predictors of survival.

CONCLUSIONS

SCPCa presents unique clinicopathologic features. Addition of doxorubicin to the etoposide/cisplatin regimen caused higher toxicity in this patient population and failed to improve outcome. Given these results, we do not recommend further development of this regimen for patients with SCPCa. Improvement in therapy will come from understanding the biology of SCPCa progression and integrating new targeted therapies into the treatment of SCPCa.

BACKGROUND

Human serum albumin (HSA) is an abundant plasma protein that binds a wide variety of hydrophobic ligands including fatty acids, bilirubin, thyroxine and hemin. Although HSA-heme complexes do not bind oxygen reversibly, it may be possible to develop modified HSA proteins or heme groups that will confer this ability on the complex.

RESULTS

We present here the crystal structure of a ternary HSA-hemin-myristate complex, formed at a 1:1:4 molar ratio, that contains a single hemin group bound to subdomain IB and myristate bound at six sites. The complex displays a conformation that is intermediate between defatted HSA and HSA-fatty acid complexes; this is likely to be due to low myristate occupancy in the fatty acid binding sites that drive the conformational change. The hemin group is bound within a narrow D-shaped hydrophobic cavity which usually accommodates fatty acid; the hemin propionate groups are coordinated by a triad of basic residues at the pocket entrance. The iron atom in the centre of the hemin is coordinated by Tyr161.

CONCLUSIONS

The structure of the HSA-hemin-myristate complex (PDB ID 1o9x) reveals the key polar and hydrophobic interactions that determine the hemin-binding specificity of HSA. The details of the hemin-binding environment of HSA provide a structural foundation for efforts to modify the protein and/or the heme molecule in order to engineer complexes that have favourable oxygen-binding properties.

The surface and internal morphology, drug distribution and release kinetics at 22 degrees C of polyesters such as PCL (polycaprolactone) and PLGA (poly(DL-lactic-co-glycolic acid)) 65:35 microspheres containing BSA (bovine serum albumin) have been investigated in order to understand the relationship amongst morphology, drug distribution and in vitro release profiles and to develop controlled release devices for marine fishes in tropical area. CLSM (confocal laser scanning microscope) micrographs reveal that the polyvinylalcohol (PVA as an emulsifier) concentration in the external water phase strongly influences drug distribution within microspheres and release profiles. The presence of PVA in the internal water phase enhances the stabilization of inner water droplets against coalescence. This results in a more uniform drug distribution and a slower BSA release. Different oil-phase volumes and polymer concentrations yield different solvent exchange and precipitation mechanisms, which lead to different morphologies. A low oil-phase volume yields microspheres with a porous matrix and defective skin surface, which gives a high initial BSA burst as well as a fast release profile. Microspheres fabricated from a low polymer concentration have less defective skin surface, but with a less tortuous inner matrix which results in a more rapid BSA release. A higher BSA loading yields a larger concentration gradient between the emulsion droplet and the continuous water phase as well as between the microspheres and the in vitro medium. The former results in a lower encapsulation efficiency, whereas the latter yields a faster initial burst and a more rapid release profile. High stirring speed can reduce microsphere size, but decreases the yield of microspheres.

Administration of azobenzenearsonate (ABA)-coupled syngeneic spleen cells intravenously to A/J mice leads to the generation of suppressor T cells (Ts1) which exhibit specific binding to ABA-bovine serum albumin (BSA)-coated dishes. These Ts1 share idiotypic determinants with the major cross-reactive idiotype (CRI) of the anti-ABA antibodies of A/J mice, and also produce a soluble suppressor factor (TsF) bearing CRI and I-J subregion-coded determinants. Injection of this TsF into naive A/J mice elicits a second set of specific suppressor cells (Ts2) which are not lysed by anti-CRI antibody plus C, and which do not bind to ABA-BSA-coated dishes. However, in contrast with Ts1, these Ts2 do bind to plates bearing CRI+ anti-ABA immunoglobulin. Thus, Ts2 exhibit anti-idiotypic specificity. These data indicate that antigen elicits the production of a soluble T cell product bearing both variable portion of the Ig heavy chain (VH) and I-J subregion-coded determinants which serves to communicate between T cell subsets to establish an idiotype-anti-idiotype regulatory pathway.

A chymotrypsinlike protease with an Mr of 95,000 was extracted from Treponema denticola ATCC 35405 and was partially purified by preparative sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The proteolytic activity was detected in an electrophoretogram containing polyacrylamide that was conjugated to bovine serum albumin. A single band of activity was detected when the T. denticola extract was solubilized and electrophoresed in the presence of sodium dodecyl sulfate. No activity was found in extracts of Treponema vincentii. The enzyme hydrolyzed transferrin, fibrinogen, alpha 1-antitrypsin, immunoglobulin A, immunoglobulin G, gelatin, bovine serum albumin, and a synthetic peptide containing phenylalanine. It did not degrade collagen or synthetic substrates containing arginine or proline. For the hydrolysis of azocoll, the pH optimum of the enzyme was 7.5. Heating at temperatures above 50 degrees C destroyed the activity. Reducing agents and the chelators EDTA and ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid increased the enzyme activity, while phenylmethylsulfonyl fluoride, L-1-tosylamide-2-phenylethyl chloromethyl ketone, sulfhydryl reagents, and human serum reduced activity. The ability of the enzyme to hydrolyze a number of humoral proteins suggests that it may be involved in spirochete invasiveness and tissue destruction.

Glycated albumin is thought to more accurately reflect glycemic control in diabetic hemodialysis patients than hemoglobin A(1c) because of shortened red cell survival. To test this, glycated hemoglobin and albumin levels were measured in blood samples collected from 307 diabetic subjects of whom 258 were on hemodialysis and 49 were without overt renal disease. In diabetic subjects with renal disease, relative to those without, the mean serum glucose and glycated albumin concentrations were significantly higher while hemoglobin A(1c) tended to be lower. The glycated albumin to hemoglobin A(1c) ratio was significantly increased in dialysis patients compared with the controls. Hemoglobin A(1c) was positively associated with hemoglobin and negatively associated with the erythropoietin dose in hemodialysis patients, whereas these factors and serum albumin did not significantly impact glycated albumin levels. Using best-fit multivariate models, dialysis status significantly impacted hemoglobin A(1c) levels without a significant effect on glycated albumin. Our results show that in diabetic hemodialysis patients, hemoglobin A(1c) levels significantly underestimate glycemic control while those of glycated albumin more accurately reflect this control.

1. 4-(N-2-Aminoethyl2'-pyridyl disulphide)-7-nitrobenzo-2-oxa-1,3-diazole (compound I) was synthesized and evaluated as a fluorescent labelling reagent for thiol groups. 2. The design of compound (I) as one example of a general type of reporter group delivery reagent (2-pyridyl-S-S-X, where X contains an environmentally sensitive spectroscopic probe) is discussed. 3. The electronic absorption spectrum of compound (I) was determined over a wide range of pH and the spectral changes that accompany its reaction with low-molecular-weight thiols, e.g. L-cysteine, and with papain (EC 3.4.22.2) and bovine serum albumin are discussed. 4. A new value of epsilon343 for 2-thiopyridone (Py-2-SH) was determined as 8.08 X 10(3) +/- 0.08 X 10(3)M-1-cm-1. 5. Spectral analysis of the reactions of compound (I) with L-cysteine and with papain (in the pH range 3.5-8.0) showed that even under equimolar conditions the reaction (thiol-disulphide interchange to release Py-2-SH) is essentially stoicheimoetric and probably proceeds by specific attack at the sulphur atom distal from the pyridyl ring of compound (I). 6. The fluorescence-emission spectra of compound (I) and of the products of its reaction with papain and with ficin (EC 3.4.22.3) were determined. Compound (I) is highly fluorescent in aqueous solution. Excitation within the intense visible absorption band (lambda max. 481 nm, epsilon max. 2.52 X 10(4)M-1-cm-1) provides green fluorescence with an emission maximum at 540 nm. Both papain and ficin labelled by reaction with compound (I) are characterized by fluorescence-emission maxima (535 nm and 530 nm respectively) of even higher intensity. The fluorescence emission of the product of the reaction of papain with compound (I) was shown to be 25 times more intense than that of the product of the reaction of papain with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (Nbd chloride). 7. The second-order rate constants (k2) for the reactions of compound (I) and of Nbd chloride with GSH, papain, albumin, ficin, 2-benzimidazolylmethanethiol and 2-benzimidazolylethanethiol were determined at 25.0 degrees C and various pH values. At pH4 the values of k2(compound I)/k2(Nbd chloride) are: GSH, 288; albumin, 36; papain 3 X 10(3); ficin, 3 X 10(4). 8. The pH-k2 profiles for the reactions of compound (I) and of Nbd chloride with the two 2-benzimidazolylalkanethiols were determined. Of the four profiles only that for the reaction of compound (I) with 2-benzimidazolylmethanethiol is characterized by a striking rate maximum in acidic media.

Prolonged Q-T interval predicts severe arrhythmias and sudden death, and has been shown to occur in alcoholic liver disease and cirrhotic patients who are candidates for liver transplantation. This study first evaluated the prevalence of prolonged Q-T interval in a large population of unselected patients with cirrhosis, and assessed the relationship between abnormal Q-T, etiology, and severity of liver disease and mortality of patients. Possible causes of Q-T abnormality were also explored. Ninety-four patients with cirrhosis without overt heart disease and 37 control subjects with mild chronic active hepatitis were enrolled. Rate-corrected Q-T interval (Q-Tc) was assessed along with routine liver tests, Child-Pugh score, serum bile salts, electrolytes and creatinine, plasma renin activity, aldosterone, norepinephrine, atrial natriuretic factor and, gonadal hormones. Q-Tc was longer in patients with cirrhosis than in controls (440.3 +/- 3.2 vs. 393.6 +/- 3.7 ms; P < .001) and prolonged >> 440 ms) in 44 patients (46.8%) and 2 controls (5.4%; P < .001). Q-Tc length was not influenced by the etiology of cirrhosis and correlated with Child-Pugh score (r = .53; P < .001), liver tests such as prothrombin activity, and serum concentrations of albumin and bilirubin, plasma bile salts, and plasma norepinephrine. Multivariate analysis showed that only Child-Pugh score and plasma norepinephrine were independently correlated with Q-Tc duration. Over a median follow-up period of 19 months (range, 2-33 months), patients with Q-Tc longer than 440 ms had a significantly lower survival rate than those with normal Q-Tc. Q-T interval is frequently prolonged in patients with cirrhosis, regardless the etiology of the disease, worsens in parallel with the severity of the disease, and may have an important prognostic meaning. In addition to other undefined factors related to the severity of cirrhosis, sympathoadrenergic hyperactivity may play a pathogenetic role.

The ANS- (1-anilino-8-naphthalene sulfonate) anion is strongly, dominantly bound to cationic groups of water-soluble proteins and polyamino acids through ion pair formation. This mode of ANS- binding, broad and pH dependent, is expressed by the quite rigorous stoichiometry of ANS- bound with respect to the available summed number of H+ titrated lysine, histidine, and arginine groups. By titration calorimetry, the integral or overall enthalpies of ANS- binding to four proteins, bovine serum albumin, lysozyme, papain, and protease omega, were arithmetic sums of individual ANS(-)-polyamino acid sidechain binding enthalpies (polyhistidine, polyarginine, polylysine), weighted by numbers of such cationic groups of each protein (additivity of binding enthalpies). ANS- binding energetics to both classes of macromolecules, cationic proteins and synthetic cationic polyamino acids, is reinforced by the organic moiety (anilinonaphthalene) of ANS-. In a much narrower range of binding, where ANS- is sometimes assumed to act as a hydrophobic probe, ANS- may become fluorescent. However, the broad overall range is sharply dependent on electrostatic, ion pair formation, where the organic sulfonate group is the major determinant of binding.

In a prospective study of 7735 middle-aged British men (British Regional Heart Study) 660 died during an average follow-up period of 9.2 years. There was a marked increase in mortality rate with decreasing serum albumin concentrations that persisted even after adjustment for age, social class, town of residence, cigarette smoking, serum total cholesterol, systolic blood pressure, serum total calcium, and forced expiratory volume in 1 s. When serum albumin concentration was less than 40 g/l, the mortality rate was 23/1000 per year compared with 4/1000 per year for a concentration equal to or above 48 g/l. A similar pattern was observed for cardiovascular, cancer, and other deaths. The associations persisted for cardiovascular disease and cancer even when deaths within the first five years of follow-up were excluded. These results must be interpreted with caution since there was no prior hypothesis concerning serum albumin. However, the strength of the association between serum albumin and mortality seems to be comparable with that for cigarette smoking.

After more than two decades of nutritional awareness, we designed a prospective study to determine whether malnutrition is still a significant issue in hospitalized patients. Patients admitted to an intensive care unit (ICU) were divided into well-nourished and malnourished groups, according to their nutritional status as assessed by serum albumin level and weight/height ratio. Severity of illness, as assessed by the Therapeutic Intervention Scoring System (TISS), was used to further stratify the study population. All patients were followed clinically until discharge or death and their outcome recorded. Of 129 patients studied, 43% were malnourished. Length of hospital stay (p = n.s.), incidence of complications (p < 0.01), and number of patients not discharged from hospital (p < 0.05) were greater in the malnourished patients than in the well-nourished. In patients with less severe degrees of illness, the existence of malnutrition led to a worse outcome than in sicker patients. To further assess the clinical setting in which hospital-related malnutrition develops or is exacerbated, postoperative patients admitted to the ICU (n = 66) were also studied in a nutritional survey; the results of this survey indicate that: (a) the incidence of malnutrition in the surgical population is similar to that in the whole study population, and (b) hospital-related malnutrition in surgical patients mainly develops during their preoperative stay in general wards. Whereas our conclusion that patients' outcome is adversely affected by a poor nutritional status is not new or startling, malnutrition continues to be a persistent problem in hospitalized patients, which can be readily identified using simple and easily available indices and, furthermore, readily treated.

Acyl exchange between acyl-CoA and position 2 of sn-phosphatidylcholine occurs in the microsomal preparations of developing safflower cotyledons. Evidence is presented to show that the acyl exchange is catalysed by the combined back and forward reactions of an acyl-CoA:lysophosphatidylcholine acyltransferase (EC 2.3.1.23). The back reaction of the enzyme was demonstrated by the stimulation of the acyl exchange with free CoA and by the observation that the added CoA was acylated with acyl groups from position 2 of sn-phosphatidylcholine. Re-acylation of the, endogenously produced, lysophosphatidylcholine with added acyl-CoA occurred with the same specificity as that observed with added palmitoyl lysophosphatidylcholine. A similar acyl exchange, catalysed by an acyl-CoA:lysophosphatidylcholine acyltransferase, occurred in microsomal preparations of rat liver. The enzyme from safflower had a high specificity for oleate and linoleate, whereas arachidonate was the preferred acyl group in the rat liver microsomal preparations. The rate of the back reaction was 3-5% and 0.2-0.4% of the forward reaction in the microsomal preparations of safflower and rat liver respectively. Previous observations, that the acyl exchange in safflower microsomal preparations was stimulated by bovine serum albumin and sn-glycerol 3-phosphate, can now be explained by the lowered acyl-CoA concentrations in the incubation mixture with albumin and in the increase in free CoA in the presence of sn-glycerol 3-phosphate (by rapid acylation of sn-glycerol 3-phosphate with acyl groups from acyl-CoA to yield phosphatidic acid). Bovine serum albumin and sn-glycerol 3-phosphate, therefore, shift the equilibrium in acyl-CoA:lysophosphatidylcholine acyltransferase-catalysed reactions towards the rate-limiting step in the acyl exchange process, namely the removal of acyl groups from phosphatidylcholine. The possible role of the acyl exchange in the transfer of acyl groups between complex lipids is discussed.

OBJECTIVE

Controversy surrounding the efficacy of corticosteroids in severe alcoholic hepatitis (AH) persists.

OBJECTIVE

(a) to analyze individual data of patients with severe AH discriminant function (DF>> or =32 from the last three randomized controlled trials; and (b) to identify the independent prognostic factors associated with short-term survival.

METHODS

Individual data were collected from the three principal investigators. Survival analysis was performed at 28 days using the Kaplan-Meier method and log-rank test. The independent prognostic values were assessed by the proportional hazards regression model.

RESULTS

About 102 placebo and 113 corticosteroid patients with DF>> or =32 were analyzed. At 28 days, corticosteroid patients had significantly higher survival: 84.6+/-3.4% vs. 65.1+/-4.8%, P=0.001. In univariate analysis, corticosteroid treatment, age, DF, albumin, creatinine and encephalopathy were prognostic factors. In multivariate analysis, age (P=0.0001), serum creatinine (P<0.002) and corticosteroid treatment (P=0.002) were independent prognostic variables. A more dramatic decrease of median serum bilirubin values (micromol/l) was observed at 7 and 14 days in corticosteroid patients (P<0.05) : -76.5 vs. -35 and -105 vs. -45.

CONCLUSIONS

Corticosteroids improved short-term survival of patients with severe AH. Age and serum creatinine are independent prognostic factors. Corticosteroids are recommended for patients with severe AH.

About 70 to 80% of an oral dose of digoxin is absorbed, mainly in the proximal part of the small intestine. The degree of binding to serum albumin is 20 to 30%. Digoxin is extensively distributed in the tissues, as reflected by the large volume of distribution. High concentrations are found in the heart and kidneys, but the skeletal muscles form the largest digoxin storage. The half-life of elimination in healthy persons varies between 26 and 45 hours. The main route of elimination is renal excretion of digoxin, which is closely correlated with the glomerular filtration rate. In addition, some tubular secretion and perhaps tubular reabsorption occurs. Nearly all of the digoxin in the urine is excreted unchanged, with a small part as active metabolites. The clinical significance of dihydrodigoxin as a metabolite remains to be resolved. About 25 to 28% of digoxin is eliminated by nonrenal routes. Biliary excretion may rise up to 30% of a given dose, but the enterohepatic cycle seems to be of minor importance. The pharmacodynamic effects of digoxin, including toxic symptoms, are correlated with the uptake of digoxin in the heart after a single dose and with the steady state serum digoxin concentration during maintenance therapy. Impaired kidney function is the most important condition with an influence on the pharmacokinetics of digoxin. In addition to the renal clearance of creatinine, the biovailability of the digoxin formulation used, the volume of distribution, the amount of extrarenal clearance, body weight and serum albumin concentration, are other factors which may modify the serum level of digoxin. Certain drug interactions may also occur during the absorptive phase. Exact prediction of serum digoxin concentrations by various dosage calculations has not succeeded. Since many factors may influence the sensitivity of the myocardium to digoxin, measurement of serum digoxin levels in only one, but a useful criterion, when making clinical decisions about adjustment of digoxin dosage.