Absorption and urinary excretion of the coffee diterpenes cafestol and kahweol in healthy ileostomy volunteers

Epidermal growth factor (EGF) has been found to induce enhanced gap junctional intercellular communication (GJIC) in the human kidney epithelial cell line K7. This is in contrast to what is reported for other cell types, which all show decreased GJIC in response to EGF. In the present study it is shown that 12-O-tetradecanoylphorbol-13-acetate (TPA) and EGF induce similar phosphorylation pattern of the gap junction protein connexin43 (Cx43) in K7 cells, although their effects on GJIC are opposite. Tyrosine phosphorylation of a 42 kD protein was observed to be induced concomitantly with phosphorylation of Cx43. EGF was however found to induce only serine phosphorylation of Cx43, indicating that the tyrosine kinase activity of the EGF receptor was not directly affecting the gap junction protein. The 42 kD protein phosphorylated on tyrosine was identified to be a mitogen activated protein (MAP) kinase. Both EGF and TPA was found to activate MAP kinase in these cells. Phosphorylation of Cx43 and enhancement of GJIC in response to EGF occurred with difference in time course. Phosphorylation of Cx43 was completed within 15 min, while the enhanced GJIC appeared 2-3 h later. It is therefore possible that regulation of synthesis or transport of Cx43 is responsible for the increase in GJIC, rather than direct involvement of Cx43 phosphorylation. This is in support of our previous finding that protein synthesis is necessary for EGF induced upregulation of GJIC in K7 cells.     

Double patch closure of ventricular septal defect with increased pulmonary vascular resistance

BACKGROUND: Closure of a large ventricular septal defect (VSD) in children with elevated pulmonary vascular resistance is associated with significant morbidity and mortality. Pulmonary hypertensive episodes continue to be a major cause of postoperative morbidity and mortality. We designed a fenestrated flap valve double VSD patch in an effort to decrease the morbidity and mortality associated with the closure of a large VSD with elevated pulmonary vascular resistance. METHODS: Eighteen children (mean age, 5.7 years) with a large VSD and elevated pulmonary vascular resistance (mean, 11.4 Wood units) underwent double patch VSD closure using moderately hypothermic cardiopulmonary bypass and cardioplegic arrest. The routine VSD patch was fenestrated (4 to 6 mm) and on the left ventricular side of the patch, a second, smaller patch was attached to the fenestration along its superior margin before closure of the VSD. RESULTS: All children survived operation and were weaned from inotropic and ventilator support within 48 hours postoperatively. Postoperative pulmonary artery pressures were significantly lower than preoperative values. One child died 9 months postoperatively. CONCLUSIONS: Closure of a large VSD in children with elevated pulmonary vascular resistance can be performed with low morbidity and mortality when a flap valve double VSD patch is used.     

Sentinel node localization in patients with breast cancer

BACKGROUND: Intraoperative lymphatic mapping and identification of the first draining lymph node (the sentinel node) may allow some patients with breast cancer to avoid the morbidity of formal axillary clearance. The aim of this pilot study was to establish the reliability of the technique in predicting axillary node status. METHODS: Sixty-eight consecutive patients with breast cancer, 38 undergoing mastectomy and 30 wide local excision, were included. Some 2-4 ml of 2.5 per cent Patent Blue dye was injected into adjacent breast tissue on the axillary side of the primary tumour. After 5-10 min, the axilla was explored. Blue-stained lymphatics were dissected to the sentinel node, which was removed for frozen-section examination, followed by routine histology. Formal axillary dissection was then completed. RESULTS: A sentinel lymph node was identified successfully in 56 (82 per cent) of 68 patients. Histology of the sentinel node accurately predicted axillary node status in 53 (95 per cent). There were three false negatives (5 per cent). In each case, only a single non-sentinel node was tumour positive. Sensitivity and specificity were 83 and 100 per cent respectively. CONCLUSION: This technique would allow a selective policy of formal axillary dissection in only node-positive patients; however, further experience and refinement are needed.     

Dilutional and modified ultrafiltration reduces pulmonary hypertension after operations for congenital heart disease: a prospective randomized study

OBJECTIVE: A prospective randomized study was performed to test whether removal of endothelin-1, by ultrafiltration techniques, will reduce pulmonary hypertension after operations for congenital heart disease. METHODS: Twenty-four patients with pulmonary hypertension (systolic pulmonary/systemic arterial pressure ratio > 60%) undergoing cardiac operations were randomized into a control group (n = 12) having conventional ultrafiltration and an experimental group (n = 12) undergoing dilutional ultrafiltration during and modified ultrafiltration after cardiopulmonary bypass. Plasma endothelin-1, nitric oxide metabolites, and cyclic guanosine monophosphate were assayed before bypass, 10 minutes into bypass, after bypass, and 0, 3, 6, and 12 hours after the operation in both groups, as well as in the ultrafiltrates and after modified ultrafiltration in the experimental group. Both groups received alpha-blockers (chlorpromazine and/or prazosin) postoperatively using the same guidelines. RESULTS: The ultrafiltrates contained significant amounts of endothelin-1 (1.81 +/- 0.86 pg/ml, dilutional, and 6.44 +/- 1.82 pg/ml, modified ultrafiltrate). Endothelin-1 and the pulmonary/systemic pressure ratio were significantly lower in experimental compared with control patients. Nitric oxide metabolites and cyclic guanosine monophosphate increased similarly in both groups for 12 hours after the operation (p = not significant). Three of 12 control patients (25%) but no experimental patients had pulmonary hypertensive crises (p = 0.07). The experimental patients required significantly less ventilatory support (67 +/- 47 hours vs 178 +/- 139 hours for control patients, p = 0.048). CONCLUSIONS: Dilutional and modified ultrafiltration reduce endothelin-1 and the pulmonary/systemic pressure ratio postoperatively and may become an important adjunct for preventing pulmonary hypertension after operations for congenital heart disease in high-risk patients.     

A shape-based machine learning tool for drug design

Building predictive models for iterative drug design in the absence of a known target protein structure is an important challenge. We present a novel technique, Compass, that removes a major obstacle to accurate prediction by automatically selecting conformations and alignments of molecules without the benefit of a characterized active site. The technique combines explicit representation of molecular shape with neural network learning methods to produce highly predictive models, even across chemically distinct classes of molecules. We apply the method to predicting human perception of musk odor and show how the resulting models can provide graphical guidance for chemical modifications.     

In vitro displacement of phenytoin from protein binding by nonsteroidal antiinflammatory drugs tolmetin, ibuprofen, and naproxen in normal and uremic sera

Displacement of phenytoin (90% bound to albumin) by other highly albumin-bound drugs like salicylate has been well documented. Other widely used nonsteroidal antiinflammatory drugs like tolmetin, ibuprofen, and naproxen are also strongly bound to albumin and can potentially displace phenytoin. However, phenytoin-ibuprofen interaction has been poorly studied in the past, and interaction of phenytoin with tolmetin or naproxen has not been studied before. For normal serum pool (albumin 3.7 g/dl), we observed significant increases in free phenytoin concentrations only with antiinflammatory drug concentrations at the upper end of therapeutic or above therapeutic concentrations. However, for the uremic pool (albumin 2.9 g/dl), displacement of phenytoin was significant even at the lower end of therapeutic concentrations of those antiinflammatory drugs. Of the three antiinflammatory drugs we studied, ibuprofen caused the highest displacement of phenytoin.     

Induction of ermAMR from a clinical strain of Enterococcus faecalis by 16-membered-ring macrolide antibiotics

We cloned the MLSB resistance determinant by PCR from a clinical isolate of Enterococcus faecalis 373, which is induced more strongly by a 16-membered-ring macrolide, tylosin, than by erythromycin. To elucidate the molecular basis of resistance of E. faecalis 373, we analyzed the cloned gene, designated ermAMR, by site-directed mutagenesis and reporter gene assay. Our results showed that an arginine-to-cysteine change in the seventh codon of the putative leader peptide endowed tylosin with resistance inducibility and that TAAA duplication enabled the control region to express the downstream methylase gene at a drastically increased level.     

Synthesis of phosphoramide mustard analogues of daunomycin and carminomycin

New phosphoramide mustards (6-8) have been prepared from the antibiotics 2 and 3, and from 5. The mixture of cyclophosphamides could be separated by preparative layer and column chromatography. The assignments of configuration to the isomeric phosphoramidates was based on the magnetic anisotropy of the P = O bond. The synthesized compounds 6a,b-8a,b (mixture of isomers) were tested for inhibitory activity on the [3H]-thymidine incorporation into the DNA of tumor cells, using ovarian carcinoma cell line.     

Ultrastructural features of cystic and merogonic stages of Hepatozoon sipedon (Apicomplexa: Adeleorina) in northern leopard frogs (Rana pipiens) and northern water snakes (Nerodia sipedon) from Ontario, Canada

This article describes the long-term consequences of successful cardiovascular disease (CVD) prevention and its influence on premature mortality in Finland, with special reference to North Karelia. Active community-based CVD prevention began in 1972 in the province of North Karelia (population, 180,000). Since 1977, active preventive work has been carried out nationwide, taking advantage of the experience from North Karelia, which continued as a demonstration area for integrated prevention of noncommunicable diseases. Comprehensive community-based interventions as part of WHO interhealth and CINDI programmes in North Karelia and nationwide aimed at changing the target risk factors and health behaviours (serum cholesterol, blood pressure, smoking, diet) at the population level. Age-adjusted mortality rates for CVD, coronary heart disease (CHD), cerebrovascular disease, all cancers, lung cancer, accidents and violence, and all causes in the population aged 35-64 years from the pre-programme period (1969-71) to 1995 were the main measures of the outcome. Among men there was a great reduction in deaths from CHD, CVD, cancer, and all causes in the whole country. From 1969-71 to 1995 the age-standardized CHD mortality (per 100,000) decreased in North Karelia by 73% (from 672 to 185) and nationwide by 65% (from 465 to 165). The reduction in CVD mortality was of the same magnitude. Among men, CHD mortality decreased in the 1970s, as did lung cancer mortality in the 1980s and 1990s, significantly more in North Karelia than in all of Finland. Among women there was a great reduction in CVD (including CHD and stroke) mortality and all-causes mortality, but only a small reduction in cancer mortality. These results show that a major reduction in CVD mortality among the working-age population can take place in association with active reduction of major risk factors, with a favourable impact on cancer and all-causes mortality.