Cholesteryl ester transfer protein activity enhances plasma cholesteryl ester formation. Studies in CETP transgenic mice and human genetic CETP deficiency

The plasma cholesteryl ester transfer protein (CETP) promotes the removal of HDL cholesteryl esters and is thought to stimulate reverse cholesterol transport (RCT). However, mechanisms by which CETP may stimulate RCT are poorly understood. Thus, we examined the relationship between plasma CETP expression and plasma cholesteryl ester formation in CETP transgenic (Tg) mice, hamsters, and human subjects with genetic CETP deficiency. Incubation of CETP Tg mouse plasma showed a 20% to 40% increase in plasma cholesterol esterification rate (CER, P < .05) compared with control mice. Injection of a neutralizing CETP monoclonal antibody (MAb) (TP2) into natural flanking region CETP Tg mice resulted in an increase in plasma free cholesterol (FC) concentration, FC/CE ratio, FC/phosphatidylcholine ratio, and hepatic CETP mRNA. In hamsters, CETP inhibition also resulted in an increase in plasma FC/phosphatidylcholine ratio and increased CETP mRNA in adipose tissue. In humans with two common CETP gene mutations (an intron 14 splicing defect and a D442G missense mutation), mean plasma CERs were 39 and 60, respectively, compared with 89 nmol x mL-1 x h-1 in normal subjects. By contrast, lecithin:cholesterol acyltransferase (LCAT) mass was normal in CETP-deficient subjects. MAb neutralization of CETP activity in incubated human plasma did not alter the LCAT reaction, even after supplementation with discoidal HDL and VLDL. Thus, genetic alterations in CETP levels lead to secondary changes in the plasma LCAT reaction, possibly because of remodeling of HDL by CETP acting in concert with other factors in vivo. In human genetic CETP deficiency, a moderate impairment in the plasma LCAT reaction may contribute to a defect in RCT, providing a potential mechanism to explain the recently observed excess of coronary heart disease in these subjects.     

Clinical and laboratory evaluation of a closed enteral feeding system under cyclic feeding conditions: a microbial and cost evaluation

Cyclic feeding schedules are now commonly used in conjunction with closed enteral feeding systems. Some manufacturers and clinicians have speculated that closed system cyclic feeding may promote formula contamination via retrograde movement of bacteria during the "no-flow" periods. Using both laboratory and clinical settings, our study evaluated whether retrograde bacterial movement under "no-flow" conditions results in contamination of closed system feeding containers. The clinical phase was conducted with 57 closed system feeding containers used to feed nursing home residents. In both laboratory and clinical testing there was no evidence of container contamination at 36-48 h, nor was there evidence of retrograde movement of bacteria beyond the drip chamber. Formula waste and costs were also analyzed using several 24- or 36-h hang time scenarios. Provided the appropriate container size is used, potential cost savings between $67 to $135 per patient per month may be achieved with the 36-h hang time scenarios. Retrograde movement of bacteria does not appear to be a source of closed system feeding container contamination in systems that incorporate a drip chamber. Using the appropriate size feeding container and systems with at least a 36-h hang time will result in significant cost savings.     

Sexual differentiation of the vertebrate brain: principles and mechanisms

A wide variety of sexual dimorphisms, structural differences between the sexes, have been described in the brains of many vertebrate species, including humans. In animal models of neural sexual dimorphism, gonadal steroid hormones, specifically androgens, play a crucial role in engendering these differences by masculinizing the nervous system of males. Usually, the androgen must act early in life, often during the fetal period to masculinize the nervous system and behavior. However, there are a few examples of androgen, in adulthood, masculinizing both the structure of the nervous system and behavior. In the modal pattern, androgens are required both during development and adulthood to fully masculinize brain structure and behavior. In rodent models of neural sexual dimorphism, it is often the aromatized metabolites of androgen, i.e., estrogens, which interact with estrogen receptors to masculinize the brain, but there is little evidence that aromatized metabolites of androgen play this role in primates, including humans. There are other animal models where androgens themselves masculinize the nervous system through interaction with androgen receptors. In the course of masculinizing the nervous system, steroids can affect a wide variety of cellular mechanisms, including neurogenesis, cell death, cell migration, synapse formation, synapse elimination, and cell differentiation. In animal models, there are no known examples where only a single neural center displays sexual dimorphism. Rather, each case of sexual dimorphism seems to be part of a distributed network of sexually dimorphic neuronal populations which normally interact with each other. Finally, there is ample evidence of sexual dimorphism in the human brain, as sex differences in behavior would require, but there has not yet been any definitive proof that steroids acting early in development directly masculinize the human brain.     

Application of the new classification for cancer of the cardia

BACKGROUND: Cancer of the cardia is now topographically classified into three types: type I, with the tumor center in the distal esophagus treated with subtotal esophagectomy; type II, arising at the gastroesophageal junction and treated with distal esophagectomy and either proximal or total gastrectomy; and type III, subcardial cancer treated with extended total gastrectomy. Our objective was to review the new classifications and compare the outcomes in patients grouped and treated according to these classifications. METHODS: Seventy-four patients with cancer of the cardia--15 with type I, 30 with type II, and 29 with type III cancer--underwent surgical resection at our institution between 1992 and 1997. Postoperative complications, UICC stages, and survival (Kaplan-Meier) were compared. RESULTS: The majority of patients with type I (73%) or type II (53%) cancer had stage I or II tumors, but only 27% of patients with type III cancer had this tumor stage (P < .05). Overall 30-day mortality was 4% and morbidity was 31%. Curative resections were performed in 73% (54 of 74) of the patients with 3-year survival rates of 72% (type I), 68% (type II), and 61% (type III). CONCLUSION: The recommended therapy for the different types of cancer of the cardia results in acceptable morbidity, mortality, and survival rates.     

Diimidazo[1,2-c:4'',5''-e]pyrimidines: adenosine agonist activity demonstrated by microphysiometry

Vertigo and dizziness are not common in childhood, but are probably present more often than was formerly thought. These symptoms caused mainly by o700is media and middle ear effusion, two of the most common diseases in children, have been neglected for a long time, both in the literature and in practice, until recently. The purpose of this study was to determine objectively the incidence of balance-related symptoms in children with long-lasting middle ear effusion and to discover whether these symptoms resolve after the insertion of ventilation tubes. One hundred thirty-six children, ages 4 to 9 years, were given electronystagmographic tests and the Bruininks-Oseretsky tests for motor proficiency before and after tube ventilation of the middle ear. The results were compared with those in 74 healthy children with no history of middle ear diseases. Pathologic findings were found in 58% of the children with chronic middle ear effusion, as compared with only 4% of the control group. The symptoms and signs of balance disturbances resolved in 96% of the children after ventilation tube insertion. The results of this study indicate that balance-related symptoms often encountered in young children may result from chronic middle ear effusion and that these symptoms will resolve after evacuation of the effusion and ventilation of the middle ear.     

Disturbances of affective prosody in patients with schizophrenia; a cross sectional study

The solutions of nine alpha, omega-bis(3-alkyl(aryl)-4,5-dihydro-1H-1,2,4-triazol-5-on-4-yl) alkanes were titrated with tetrabutylammoniumhydroxide (TBAH) in methanol, using potentiometric methods. The half neutralization potentials values were found for all cases. Potentiometric titration curves of compounds in methanol with 0.03 M TBAH are similar to those of weak acids obtained in aqueous media with strong bases. Methanol is found to be a suitable medium for the weakly acidic compounds titrated since they are poorly dissolved in other organic solvents. A comparison among the compounds having the same alkyl chains between the two ring systems has shown that basicity increases and acidity decreases as the size of alkyl chains increases. However, the compound with a substituted phenyl group was found to be the most acidic one among the examined compounds indicating that phenyl group donates ring electrons less effectively to the system. This can be attributed to the stability of the benzene ring.     

Possible existence of quaternary structure in the high-affinity serotonin transport complex

During exercise, dynamic hyperinflation-induced intrinsic positive end-expiratory pressure (PEEPi) and decreased dynamic lung compliance (CL,dyn) of patients with chronic obstructive pulmonary disease (COPD) increase the elastic work of inspiration (Wi) more than would be predicted from the increase in tidal volume (VT). This contributes significantly to their exertional breathlessness. In 10 stable patients with COPD, the dynamic Wi was measured during incremental bicycle exercise to exhaustion. The total Wi was then partitioned into the portion required to overcome PEEPi (Wi,PEEPi) and nonPEEPi elastic load (Wi,nonPEEPi). The latter is used to overcome the increase in the total respiratory system elastance during inflation. From resting breathing to peak exercise, Wi more than doubled (p<0.001). This increase was largely due to Wi,PEEPi, which significantly rose from 1.7+/-0.3 to 5.3+/-0.8 L x cm H2O(-1) (p<0.001). In comparison, Wi,nonPEEPi increased from only 3.0+/-0.4 to 5.1+/-0.5 L x cm H2O(-1) (p<0.01). Consequently, Wi,PEEPi as a fraction of total Wi increased from 35.5+/-5.6 to 51.0+/-3.3% (p<0.02). In addition, the measured Wi,nonPEEPi at peak exercise, when expressed as a percentage of its value during resting breathing, was 25% more than that predicted from the increase in VT alone. Assuming a constant chest wall compliance, this can be attributed to the exercise-induced decrease in CL,dyn, which was 0.27+/-0.04 and 0.17+/-0.02 L x cm H2O(-1) (p<0.01), respectively, during resting breathing and peak exercise. In conclusion, the dynamic hyperinflation-induced intrinsic positive end-expiratory pressure is more important than the increase in tidal volume in raising the work of inspiration during exercise in patients with chronic obstructive pulmonary disease; the decrease in dynamic lung compliance plays a definite but less important role.     

Loss of heterozygosity at 5q21-22 (adenomatous polyposis coli gene region) in oral squamous cell carcinoma is common and correlated with advanced disease

We determined the frequency of loss of heterozygosity (LOH) at chromosome 5q21-22 (adenomatous polyposis gene region) in oral SCC from 49 patients using PCR-based assays. Of 43 informative (heterozygous) tumors, 41.9% [95% confidence interval (CI)=27.0, 57.9] contained LOH at 5q21-22. LOH at 5q21-22 was strongly associated with stage at diagnosis: 100%, (3/3), 50% (13/26), and 14% (2/14) of tumors from patients with distant metastases, regional spread, and localized disease, respectively, contained this genetic alteration (P=0.01). There were no statistically significant associations between LOH at 5q21-22 and other patient or tumor characteristics, but LOH was more commonly found in the tumors of heavy smokers, infrequent alcohol consumers, and in tumors containing either p53 mutations or HPV-DNA. In univariate analyses, LOH at 5q21-22 was associated with poor prognosis (hazard ratio=1.8, 95%, CI 0.8, 4.5); this relationship did not persist after adjustment for stage of disease (hazard ratio=1.1, 95% CI=0.4, 3.1). These data provide further evidence that inactivation of the APC gene and/or other genes at 5q21-22 is common and may be involved in the development and/or progression of oral SCC. Larger studies are needed to determine whether LOH at 5q21-22 is linked to known oral SCC etiologic factors and/or the prognosis of oral SCC patients, as well as to genetic instability at other loci involved in these malignancies.