Inhibition of matrix metalloproteinases by lung TIMP-1 gene transfer or doxycycline aggravates pulmonary hypertension in rats

Chronic hypoxic pulmonary hypertension (PH) results from persistent vasoconstriction, excess muscularization, and extracellular matrix remodeling of pulmonary arteries. The matrix metalloproteinases (MMPs) are a family of proteinases implicated in extracellular matrix turnover and hence in smooth muscle and endothelial cell migration and proliferation. Because MMP expression and activity are increased in PH, we designed the present study to investigate whether inhibition of lung MMPs in rats subjected to chronic hypoxia (CH) contributes to or protects against vascular remodeling and PH. To achieve lung MMP inhibition, rats exposed to 10% O(2) for 15 days were treated with either doxycycline (20 mg/kg per day by gavage starting 2 days before and continuing throughout the CH period) or a single dose of recombinant adenovirus (Ad) for the human tissue inhibitors of metalloproteinases-1 (hTIMP-1) gene (Ad.hTIMP-1, 10(8) plaque-forming units given intratracheally 2 days before CH initiation). Control groups either received no treatment or were treated with an adenovirus containing no gene in the expression cassette (Ad.Null). Efficacy of hTIMP-1 gene transfer was assessed both by ELISA on bronchoalveolar lavages and by hTIMP-1 immunofluorescence on lung sections. MMP inhibition in lungs was evaluated by in situ zymography and gelatinolytic activity assessment using [(3)H]gelatin. Rats treated with either doxycycline or Ad.hTIMP-1 had higher pulmonary artery pressure and right heart ventricular hypertrophy more severe than their respective controls. Worsening of PH was associated with increased muscularization and periadventitial collagen accumulation in distal arteries. In conclusion, our study provides compelling evidence that MMPs play a pivotal role in protecting against pulmonary artery remodeling.     

Bacterial infection as a complication of liver transplantation: epidemiology and risk factors

A retrospective survey was undertaken to characterize the epidemiology of bacterial infection in 79 patients who underwent 103 operations for orthotopic liver transplantation. Fifty-four patients (68%) developed 115 bacterial infections (1.46 episodes per patient), and seven patients died as a result of these infections. Fifty-three percent of bacterial infections occurred within 2 weeks after transplantation and were designated as early infections. The most common sites of infection were the abdomen (35 cases), the bloodstream (31 cases), and the surgical wound (19 cases). Aerobic enteric gram-negative bacilli were the predominant pathogens, and other pathogenic organisms were enterococci, staphylococci, and Pseudomonas bacteria. Logistic regression analysis identified prolonged duration of surgery (greater than or equal to 8 hours) and an elevated bilirubin level (greater than or equal to 12 mg/dL) as risk factors for early bacterial infection at any site; risk factors for abdominal or wound infection were prolonged duration of surgery, increased operative transfusion requirement (greater than or equal to 2 blood volumes), and prior hepatobiliary surgery. Awareness of the sites, pathogens, and time of onset of bacterial infection provides a basis for improved prophylaxis and empiric therapy.     

Nontypable Haemophilus influenzae (biotype 4) as a neonatal, maternal, and genital pathogen

Between 1976 and 1981 Haemophilus influenzae was identified in 16 women with postpartum bacteremia and 36 neonates with bacteremia or meningitis. H. influenzae was also recovered from neonatal or genital cultures of 50 additional patients. By counter-immunoelectrophoresis 17% of neonatal isolates from blood or cerebrospinal fluid (CSF) were type b. All remaining strains (94% overall) were nontypable (NT). Of the NT blood or CSF isolates, 38% belonged to biotype 4. Of all the NT biotype 4 isolates referred to the Centers for Disease Control during the study, 82% were of genital, neonatal, or maternal origin, a finding that suggests that this isolate is a genital biotype. Clinical disease was similar to that observed in patients infected with group B Streptococcus except for the infrequent (11%) occurrence of meningitis. Maternal bacteremia resulted in mild febrile illness, while neonatal bacteremia was associated with a high incidence of shock, respiratory distress (50%), and death (30%). H. influenzae bacteremia in these two patient groups was rare in Houston before 1976, but since then it has been responsible for 2.5% of cases of significant bacteremia. NT H. influenzae should be recognized as a definite neonatal, maternal, and genital pathogen.     

Wound protectors mitigate superficial surgical site infections after pancreatoduodenectomy

Background

Whether the choice of antibiotic prophylaxis, the type of incision, or the use of wound protectors decreases surgical site infections (SSIs) in patients undergoing pancreatoduodenectomy (PD) remains unknown.

Variation of the genetic expression pattern after exposure to estradiol-17beta and 4-nonylphenol in male zebrafish (Danio rerio)

There is much concern about the increasing presence in the environment of synthetic chemicals that are able to disrupt the endocrine system. Among these compounds, 4-nonylphenol (4-NP) is one of the most studied xenoestrogens, due to its widespread accumulation in water sediment and consequent presence in fatty acid of aquatic organisms. Here, we have used a zebrafish microarray representing 16,399 genes to study the effects of 4-NP and estradiol-17β (E2) in adult male zebrafish in order to elucidate the mechanism of action of 4-NP compared with that of E2. The microarray results showed that both 4-NP and E2 induced a strong expression of vitellogenin (VTG), the sex related precursor of the yolk proteins in oviparous vertebrates. Both treatments induced elevated protein turnover upregulating genes involved in proteolysis and those that are constituents of the ribosome. Many genes regulated by 4-NP and E2 are involved in energy metabolism, oxidative stress defense mechanisms, xenobiotic metabolism, and lipid metabolism. A different pattern of expression in the two treatments was found for genes involved in oxidative stress, since E2 seems to induce the mechanism of detoxification, while 4-NP seems to inhibit this protective mechanism of the cell.Overall, these findings demonstrate that the microarray approach can contribute significantly to the understanding of expression patterns induced by E2 and 4-NP in male zebrafish. The results also demonstrate that 4-NP is able to act through an alternative pattern to that of estradiol-17β, modulating the expression of the same genes in a different manner.     

Heterogenity of serotypes of Neisseria meningitidis that cause endemic disease.

Three collections of strains of Neisseria meningitidis that caused meningococcal disease during nonepidemic periods were serotyped to determine whether serotypes that cause endemic disease are more heterogeneous than those responsible for epidemic disease. Thirty-four strains isolated from pediatric patients in Houston, Texas, from February 1977 to March 1978 were of three separate serogroups and 11 serotypes; 27 contemporary (1977-1978) strains from predominantly military populations, obtained nationwide, were of six serogroups and six serotypes, while 11 strains isolated at military posts in the southwest United States from 1970 through 1976 were of four serogroups and five serotypes. Between 9% and 20% of the strains were nontypable, while type II strains which were responsible for the epidemics in the Northern and Western Hemispheres earlier in the 1970's, accounted for only 20%-44% of the strains. In contast to epidemics, which appear to be caused by a single serotype, endemic meningococcal disease appears to be caused by a broad, heterogeneous distribution of serotypes. Thus, development of a serotype-specific vaccine may have limited application to the prevention of endemic meningococcal disease.     

Embolisation procedures in congenital heart disease.

Eight therapeutic embolisation procedures were performed by the transcutaneous catheter technique in seven patients with congenital heart disease. After surgical correction of tetralogy of Fallot (four patients), catheter embolisation was used to occlude two large aortopulmonary collaterals (one patient), three small aortopulmonary collaterals (one patient), and two Blalock-Taussig shunts (two patients). In two patients congenital coronary anomalies were occluded--a coronary arteriovenous malformation and a coronary artery/bronchial artery anastomosis. In one patient a pulmonary arteriovenous malformation was embolised. Detachable balloons were used to occlude six large arteries, the three small arteries were occluded with small gelfoam fragments, and the pulmonary arteriovenous malformation was occluded with multiple steel coils and large gelfoam pieces. Successful occlusion was achieved in all cases. No complications were encountered and the procedure was well tolerated even in the two patients receiving postoperative intensive care. Therapeutic embolisation in suitable cases is a safe and effective alternative to surgery and the detachable balloon technique is effective in occluding high flow vessels.