Two different corticosteroid-binding globulin variants that lack cortisol-binding activity in a greek woman.

BACKGROUND: Corticosteroid-binding globulin (CBG), encoded by SERPINA6, is the principal plasma binding protein for cortisol. Most nonsynonymous single-nucleotide polymorphisms that alter the production or function of CBG occur rarely, and their clinical significance remains obscure. METHODS: Serum and DNA were obtained from a Greek woman with low morning cortisol levels and from family members. SERPINA6 exons were sequenced, and serum CBG was measured by ELISA and cortisol-binding capacity assay. Recombinant CBG variants were produced for detailed functional studies. RESULTS: A novel heterozygous c.1282G>C transversion in exon 5 of SERPINA6, resulting in a p.Trp393Ser (W371S) substitution, was identified in the proband, who was also heterozygous for single-nucleotide polymorphisms encoding the CBG Lyon (D367N) and CBG A224S variants. The proband had no measurable plasma cortisol-binding activity despite a CBG level of 273 nm by ELISA. She inherited CBG W371S from her mother whose plasma cortisol-binding capacity was approximately 50% lower than the CBG measurements by ELISA (314 nm). The proband's father and four children were heterozygous for CBG D367N; their CBG levels by ELISA were normal, but corresponding cortisol-binding capacity measurements were 50% lower. Pedigree analysis revealed that W371S segregates with A224 and that D367N and W371S segregate separately. Recombinant CBG D367N and CBG W371S had no measureable cortisol-binding activity. CONCLUSION: A new CBG Athens (W371S) variant that lacks cortisol-binding activity has been identified in a carrier of the cortisol-binding deficient CBG Lyon (D367N) variant. Analyses of CBG levels in this pedigree illustrate how immunoassays fail to accurately reflect cortisol-binding activity.

Effects of the selective alpha 1a-adrenoceptor antagonist silodosin on ECGs of healthy men in a randomized, double-blind, placebo- and moxifloxacin-controlled study.

In order to determine the effects of therapeutic and supratherapeutic doses of silodosin on QT interval, healthy men (N = 186; aged 18-45 years) were randomized to receive silodosin (8 or 24 mg) or placebo for 5 days or moxifloxacin 400 mg (positive control, known to prolong QT) once on day 5. At baseline and on day 5, five ECGs were recorded 0.25 h before dosing and 1, 1.5, 2, 3, 4, 6, 8, 10, and 23.5 h after dosing. Adjusted mean differences (analysis of covariance) between silodosin and placebo in the change in individual heart rate-corrected QTc (QTcI) from baseline to day 5 were <5 ms at all times (all 90% confidence interval (CI) upper limits <10 ms). The QTcI difference for moxifloxacin compared with placebo often exceeded 5 ms, establishing assay sensitivity. For silodosin, no statistically or clinically significant correlation was seen between plasma concentration and QTcI, and no clinically important effects on heart rate, PR segment, QRS complex, or morphologic ECG data were observed.

Differentiation of fluid, visual, and simultaneous cognitive tasks.

The constructs of fluid reasoning and spatial visualization (Horn, 1989) as well as the construct of simultaneous processing (Luria, 1966) have been tapped by various cognitive assessment batteries. In order to determine whether these constructs could be differentiated from one another, factor analyses of subtest scores from six cognitive tasks were conducted. Fluid reasoning, spatial visualization, and simultaneous processing emerged as separate factors in the analysis, supporting the hypothesis that these constructs can be differentiated in psychoeducational testing. These results extend the findings of a preliminary study which found factorial differentiation between fluid and simultaneous reasoning.

Perceived ability and level of education as predictors of traditional and practical adult problem solving.

Sixty adults (ages 19 to 80) were divided into three age groups. Each individual completed the Problem Solving Inventory (PSI), which assesses an individual's self-perception of problem-solving ability, prior to completing two types of problems, including concept-identification tasks and six everyday, practical problems. When the level of education across the younger, middle-aged, and older adults was controlled, older individuals perceived themselves as better problem solvers, and they were more confident in their problem-solving abilities than the other age groups. Additionally, these older adults with relatively high levels of education took more time to complete the concept-identification tasks but did not make more errors or need more choices to solve these tasks. Similarly, the older participants performed as well as either of the other age groups on the everyday, practical problems.

Myogenic expression of an injectable protease-resistant growth hormone-releasing hormone augments long-term growth in pigs.

Ectopic expression of a new serum protease-resistant porcine growth hormone-releasing hormone, directed by an injectable muscle-specific synthetic promoter plasmid vector (pSP-HV-GHRH), elicits growth in pigs. A single 10 mg intramuscular injection of pSP-HV-GHRH DNA followed by electroporation in three-week-old piglets elevated serum GHRH levels by twofold to fourfold, enhanced growth hormone secretion, and increased serum insulin-like growth factor-I by threefold to sixfold over control pigs. After 65 days the average body weight of the pigs injected with pSP-HV-GHRH was approximately 37% greater than the placebo-injected controls and resulted in a significant reduction in serum urea concentration, indicating a decrease in amino acid catabolism. Evaluation of body composition indicated a uniform increase in mass, with no organomegaly or associated pathology.

The use of drug formularies in managed care.

As a way of controlling the rising costs of health care, most managed care companies have implemented drug formularies. A drug formulary is generally defined as a listing of medications the health plan will cover for reimbursement. Some medications may need authorization from the health plan before they will be dispensed. This paper argues that drug formularies contain cost while causing no physical harm to the patient. The method of research used is descriptive. The paper will examine the issue from the side of the physician, the health plan and the patient. The research includes personal interviews, anecdotal records and reviews of available literature. The findings will show that patients still have access to a wide range of therapeutic medications and do not suffer physical harm as a result of a drug formulary.

The risk of infection associated with intra-arterial catheters for cancer chemotherapy.

OBJECTIVE: To determine the frequency of, and risk factors for, infections associated with intra-arterial catheters used for cancer chemotherapy. METHODS: Between September 1992 and September 1995, we conducted a surveillance study of all 807 intra-arterial catheters placed for chemotherapy at our center. The insertion site was disinfected with povidone iodine and alcohol, and the arterial catheter was placed using maximal sterile barrier precautions. Upon removal, all intravascular segments were submitted for semi-quantitative culture. RESULTS: No episodes of catheter-related bloodstream infection (95% confidence interval [CI95], 0%-1.6%) were observed. However, the risk of colonization (>15 colony-forming units) of arterial catheters was 15% (CI95, 12%-17%). Retrospective risk-factor analysis conducted on 224 intra-arterial catheters placed for chemotherapy in 1993 showed that colonization was associated significantly with duration of catheterization (median of 1 day for culture-negative catheters vs median of 4 days for culture-positive catheters, P<.001). Age, gender, prior radiotherapy, underlying cancer, neutropenia, and hypoalbuminemia were not associated with catheter colonization. CONCLUSION: Intra-arterial catheters for cancer chemotherapy placed under maximal sterile barrier precautions for a short period of time are associated with a very low risk of bloodstream infection.

Nosocomial respiratory syncytial virus infections: prevention and control in bone marrow transplant patients.

OBJECTIVE: To assess the effectiveness of a multifaceted infection control strategy in limiting the nosocomial transmission of respiratory syncytial virus (RSV) infection to patients in a bone marrow transplant (BMT) unit. DESIGN: Before/after trial. SETTING: University-affiliated tertiary cancer center. PATIENTS: Adult BMT recipients hospitalized during two consecutive wintertime community outbreaks of RSV infection. INTERVENTIONS: An infection control strategy against nosocomial RSV infection was implemented in the BMT unit in February 1993. The strategy involved prompt identification, isolation, and cohorting of RSV-infected patients; prompt therapy with aerosolized ribavirin; use of masks and gloves by anyone entering an infected BMT patient's room; screening visitors for respiratory symptoms; restricting visitation by all children under 12 years of age and all family members and other visitors with RSV symptoms; and restricting symptomatic hospital staff from working in the BMT unit. RESULTS: After implementation of the multifaceted infection-control strategy, there were four cases of nosocomial RSV infection in 3,870 patient days (incidence density, 1.0 case/1,000 patient days) compared with 14 cases of nosocomial RSV infection in 3,152 patient days (incidence density, 4.4 cases/1,000 patient days) during the 1992-1993 RSV season (rate ratio, 4.4; 95% confidence interval [CI95]. 1.4-17.9: P < .01). This decrease in incidence occurred despite a comparable prevalence of community-acquired RSV cases between the two seasons (2.2% vs 3.2% in 1992-1993 and 1993-1994, respectively; prevalence ratio, 0.7; CI95, 0.2-2.1; P = 0.5). CONCLUSION: Institution of a multifaceted infection control strategy significantly reduced the frequency of nosocomial RSV infection in a high-risk group of adult BMT recipients.

p53 mutations in nonmelanoma skin cancer of the head and neck: molecular evidence for field cancerization.

Multiple and distinct p53 mutations were detected by DNA sequence analysis in tumor and adjacent nonmalignant skin samples from eight patients with nonmelanoma skin cancer of the head and neck, providing unambiguous evidence for field cancerization. The mutations consisted of C-->T transitions at dipyrimidine sequences (30% of all single base substitutions), T-->C transitions (47%), and G-->T transversions (12%), suggesting that other carcinogens may act along with UV radiation in the development of nonmelanoma skin cancer. Patient interviews revealed that, in addition to substantial exposure to solar UV radiation, most had a history of smoking and were exposed to carcinogens from industrial or agricultural sources. These data show that extensive molecular epidemiological investigations are necessary to elucidate risk factors associated with the disease in localities where patients often report substantial exposure to environmental carcinogens.

Prevention of central venous catheter-related infections by using maximal sterile barrier precautions during insertion.

OBJECTIVE: In many hospitals, the only sterile precautions used during the insertion of a nontunneled central venous catheter are sterile gloves and small sterile drapes. We investigated whether the use of maximal sterile barrier (consisting of mask, cap, sterile gloves, gown, and large drape) would lower the risk of acquiring catheter-related infections. DESIGN: Prospective randomized trial. SETTING: A 500-bed cancer referral center. METHODS: We randomized patients to have their nontunneled central catheter inserted under maximal sterile barrier precautions or control precautions (sterile gloves and small drape only). All patients were followed for 3 months postinsertion or until the catheter was removed, whichever came first. Catheter-related infections were diagnosed by quantitative catheter cultures and/or simultaneous quantitative blood cultures. RESULTS: The 176 patients whose catheters were inserted by using maximal sterile barrier precautions were comparable to the 167 control patients in underlying disease, degree of immuno-suppression, therapeutic interventions, and catheter risk factors for infections (duration and site of catheterization, number of catheter lumen, catheter insertion difficulty, reason for catheter removal). There were a total of four catheter infections in the test group and 12 in the control group (P = 0.03, chi-square test). The catheter-related septicemia rate was 6.3 times higher in the control group (P = 0.06, Fisher's exact test). Most (67%) of the catheter infections in the control group occurred during the first 2 months after insertion, whereas 25% of the catheter infections in the maximal sterile precautions group occurred during the same period (P < 0.01, Fisher's exact test). Cost-benefit analysis showed the use of such precautions to be highly cost-effective. CONCLUSION: Maximal sterile barrier precautions during the insertion of nontunneled catheters reduce the risk of catheter infection. This practice is cost-effective and is consistent with the practice of universal precautions during an invasive procedure.

A new predictive equation for resting energy expenditure in healthy individuals.

A predictive equation for resting energy expenditure (REE) was derived from data from 498 healthy subjects, including females (n = 247) and males (n = 251), aged 19-78 y (45 +/- 14 y, mean +/- SD). Normal-weight (n = 264) and obese (n = 234) individuals were studied and REE was measured by indirect calorimetry. Multiple-regression analyses were employed to drive relationships between REE and weight, height, and age for both men and women (R2 = 0.71): REE = 9.99 x weight + 6.25 x height - 4.92 x age + 166 x sex (males, 1; females, 0) - 161. Simplification of this formula and separation by sex did not affect its predictive value: REE (males) = 10 x weight (kg) + 6.25 x height (cm) - 5 x age (y) + 5; REE (females) = 10 x weight (kg) + 6.25 x height (cm) - 5 x age (y) - 161. The inclusion of relative body weight and body-weight distribution did not significantly improve the predictive value of these equations. The Harris-Benedict Equations derived in 1919 overestimated measured REE by 5% (p less than 0.01). Fat-free mass (FFM) was the best single predictor of REE (R2 = 0.64): REE = 19.7 x FFM + 413. Weight also was closely correlated with REE (R2 = 0.56): REE = 15.1 x weight + 371.

The effect of Pseudomonas aeruginosa cytotoxin and toxin A on human polymorphonuclear leukocytes.

After exposure to cytotoxin or toxin A of Pseudomonas aeruginosa, the ultrastructure of resting and phagocytosing human polymorphonuclear leukocytes (PMNL) and of cells of P. aeruginosa strain 1348A was studied by transmission (TEM) and scanning (SEM) electronmicroscopy, and by light microscopy (LM) after histochemical staining of cytoplasmic granules. Cytotoxin caused marked clumping and destruction of PMNL, pyknotic nuclear changes with bleb formation, and release of cytoplasmic granules; phagocytosis was markedly diminished. In contrast, after exposure to toxin A, PMNL phagocytosed actively, but their cytoplasmic pseudopodia were markedly irregular and their nuclei pyknotic. Colloidal-gold-labelled cytotoxin showed an affinity for the cytoplasmic membranes, nuclei and granules of PMNL. Cytotoxin had no apparent effect on cells of P. aeruginosa strain 1348A but there was polar separation of the cytoplasmic membrane in bacteria exposed to toxin A. Cytotoxin and toxin A appear to be important in the pathogenesis of infections caused by P. aeruginosa.

Effect of Kupffer cell phagocytosis of erythrocytes and erythrocyte ghosts on susceptibility to endotoxemia and bacteremia.

The phagocytosis of erythrocytes by macrophages has previously been shown to depress macrophage function. In this study we compared the effect of the phagocytosis of erythrocytes and erythrocyte ghosts by Kupffer cells on the duration of the depression of complement receptor clearance function and host defense against endotoxemia and bacteremia. Phagocytosis of erythrocytes and erythrocyte ghosts was induced in rats by the injection of rat erythrocytes or erythrocyte ghosts coated with anti-rat erythrocyte immunoglobulin G (EIgG and GIgG, respectively). The hepatic uptake of EIgG and GIgG (17.4 X 10(8)/100 g) occurred during the first 30 min after injection. The digestion of phagocytized EIgG and GIgG, as assessed by electron microscopy, was complete at 24 and 3 h after injection, respectively. The depression of Kupffer cell complement receptor clearance function caused by EIgG and GIgG returned to normal by 6 h after injection of EIgG and by 3 h after injection of GIgG. Phagocytosis of EIgG depressed the survival rate after endotoxemia and bacteremia when endotoxin or bacteria were injected at 30 min after EIgG. The survival rate returned to normal when the endotoxin and bacteria were injected at 12 and 6 h after the EIgG, respectively. Phagocytosis of GIgG did not depress the survival rate after endotoxemia and bacteremia. Thus, compared with erythrocytes, erythrocyte ghosts are more rapidly digested after phagocytosis, depress complement receptor function for a shorter period of time, and cause less depression of host defense. These findings indicate that the contents of erythrocytes play an important role in the impairment of host defense caused by the phagocytosis of erythrocytes by Kupffer cells.

Endothelial injury and pulmonary congestion characterize neurogenic pulmonary edema in rabbits.

The objectives of the present study were to determine whether an intracisternal injection of fibrinogen-sodium citrate, a model of neurogenic pulmonary edema (NPE), produces protein-rich or protein-poor pulmonary edema, and to determine whether the edema is associated with pulmonary vascular hypertension and pulmonary congestion. Fibrinogen (6-10 mg/ml) dissolved in 0.055 M sodium citrate was injected into the cisterna magna of six New Zealand White rabbits. Six additional rabbits were injected with saline to control for the effects of intracranial hypertension and pulmonary vascular hypertension. The fibrinogen-sodium citrate solution or sodium citrate alone, as opposed to saline, produced systemic and pulmonary vascular hypertension, pulmonary edema, hypoxemia, hypercapnia, and acidosis. The lungs from fibrinogen-injected rabbits were edematous, congested, and liverlike in appearance. Tracheal froth that was blood tinged and protein rich was present in five of the six rabbits. Microscopic examination of lung biopsies revealed erythrocytes and plasma in the alveoli and focal injury to the pulmonary microvascular endothelium. Fibrinogen-sodium citrate increased (P less than 0.05) the extravascular lung water (EVLW) (10.3 +/- 2.0 vs. 5.5 +/- 0.6 g, means +/- SE), lung blood weight (9.7 +/- 1.3 vs. 3.8 +/- 0.6 g), total dry lung weight (3.2 +/- 0.4 vs. 2.0 +/- 0.1 g), and the EVLW-to-blood-free dry lung weight ratio (7.0 +/- 0.8 vs. 4.0 +/- 0.3 g) from saline-control values. There was no difference in the blood-fre dry lung weight (1.4 +/- 0.1 vs. 1.3 +/- 0.1 g) between the two groups. These findings demonstrate that pulmonary congestion, pulmonary vascular hypertension, and focal endothelial injury contribute to the development of NPE.