Effect of platelet-activating factor on secretion of mucous glycoprotein from chinchilla middle ear epithelial cells in vitro

Platelet-activating factor (PAF) is a naturally occurring phospholipid that acts as a pleiotropic mediator and mediates cell-cell reactions under physiological and pathological conditions. Recently, it has been shown that PAF is a strong secretagogue of mucous glycoprotein in the airways, suggesting its role in mucous glycoprotein secretion and the pathogenesis of otitis media with effusion. In the current study, we examined the effect of PAF on mucous glycoprotein secretion in cultured chinchilla middle ear epithelial cells. PAF at 1 M significantly stimulated mucous glycoprotein secretion from cultured chinchilla middle ear epithelial cells. This action was concentration-dependent, with secretions reaching near maximum when the cells were incubated with PAF at 100 M. In a time-dependent study, PAF demonstrated an initial rapid stimulation of mucous glycoprotein secretion, followed by a gradual increase thereafter. A six-fold increase was seen in the first 2 h compared with controls. Cycloheximide, a protein synthesis inhibitor, demonstrated an inhibitory effect on PAF-stimulated mucous glycoprotein secretion in this study. These findings suggest that PAF plays an important role in the pathogenesis of otitis media with effusion by stimulating mucous glycoprotein secretion in vitro.Supported by NIH grant P0I-D000133 from the National Institute on Deafness and Other Communication Disorders.     

Synthesis of a series ofcis-diamminedichloro-platinum (II) complexes linked to uracil and uridine as candidate antitumor agents

The search for platinum (II)-based compounds with improved therapeutic properties was prompted to design and synthesize a new family of water-soluble, third generation cis-diamminedichloroplatinum (II) complexes linked to uracil and uridine. Six heretofore undescribed uracil and uridine-platinum (II) complexes are; [N-(2-aminoethyl)uracil-5-carboxamide]dichloroplatinum (II) (3a), [N-(2-aminoethyl)uracil-6-carboxamide]dichloroplatinum (II) (3b), [5-(2-aminoethyl)carbamoyl-2′,3′,5′,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl) carbamoylu-carbamoyl-2′,3′,5′,-tri-O-acetyluridine] dichloroplatinum (II) (6b), [5-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7a), [6-(2-aminoethyl)carbamoyluridine]dichloroplatinum (II) (7b). These analogues were prepared from the key starting materials, 5-carboxyuracil (1a) and 6-carboxyuracil (1b) which were reacted with ethylenediamine to afford the respective N-(2-aminoethyl)uracil-5-carboxamide (2a) and N-(2-aminoethyl)uracil-6-carboxamide (2b). The cisplatin complexes3a and3b were obtained through the reaction of the respective2a and2b with potassium tetrachloroplatinate (II). The heterocyclic nucleic acid bases1a and1b were efficiently introduced on the β-D-ribose ring via a Vorbruggen-type nucleoside coupling procedure with hexamethyldisilazane, trimethylchlorosilane and stannicchloride under anhydrous acetonitrile to yield the stereospecific β-anomeric 5-carboxy-2′,3′,5′-tri-0-acetyluridine (4a) and 6-carboxy-2′,3′,5′-tri-0-acetyluridine (4b), respectively. The nucleosides4a and4b were coupled with ethylenediamine to provide the respective 5-(2-aminoethyl)carbamoyl-2′,3′,5′-tri-0-acetyluridine (5a) and 6-(2-aminoethyl)carbamoyl-2′,3′,5′-tri-0-acetyluridine (5b). The diamino-uridines5a and5b were reacted with potassium tetrachloroplatinate (II) to give the novel nucleoside complexes,6a and6b, respectively which were deacetylated into the free nucleosides,7a and7b by the treatment with CH₃ONa. The antitumor activities were evaluated against three cell lines (K-562, FM-3A and P-388).     

Radiolabeling of Methylphosphonate and Phosphorothioate Oligonucleotides and Evaluation of Their Transport in Everted Rat Jejunum Sacs

Purpose. The therapeutic use of antisense oligonucleotides will likely involve their administration over protracted periods of time. The oral route of drug dosing offers many advantages over other possible routes when chronic drug administration is necessary. However, little is known about the potential for oligonucleotide uptake from the gastrointestinal tract. This issue is addressed in the current work. Methods. We have developed a simple procedure for radiolabeling oligonucleotides by reductive alkylation with ¹⁴C-formaldehyde. We have utilized this approach, as well as 5 addition of fluorophores, to prepare labeled methylphosphonate and phosphorothioate oligonucleotides for use in intestinal transport studies. An everted rat gut sac model was employed to compare the transport of oligonucleotides to that of model compounds whose permeation properties are better understood. Results. We demonstrate that both methylphosphonate and phosphorothioate oligonucleotides are passively transported across the intestinal epithelium, probably by a paracellular route. The rates of transport for both types of oligonucleotides were similar, and were significantly greater than that of the very high MW polymer blue dextran, but were lower than the transport rate of valproic acid, a low MW compound known to have high oral availability. Conclusions. A significant degree of permeation of oligonucleotides across the gastrointestinal epithelium does occur, but it is still unclear whether this is sufficient to permit effective oral administration of oligonucleotides as drugs.     

Compressed Donut-Shaped Tablets with Zero-Order Release Kinetics

Purpose. Simple uncoated compressed tablets with a central hole (donut-shape) are proposed to provide a constant drug release over a long period of time (>20 hrs). The effect of hole size and drug solubility on the release kinetics is investigated. Methods. The donut-shaped polyethylene oxide (PEO, Mw = 4 × l0⁶) tablets (600 mg and 12 mm diameter) are bored with a drill bit (3/32, 7/64, 1/8, and 5/32). Results. The release of theophylline from the donut-shaped tablets is zero order (80 – 90% release) before rapidly decreasing. As the hole size is increased from 7/64 to 5/32, the release rate increases and the release time is shortened. However, the release of theophylline from the donut-shaped tablet with a hole size of 3/32 follows the same anomalous release profile from a tablet without a hole. As drug solubility increases, the duration of linear drug release is shortened to 65 – 70% release followed by a severe tailing at the later stage of the release. Conclusions. Donut-shaped PEO tablets with a hole provide zero-order release kinetics because the effect of the releasing surface area on the release kinetics is reduced.     

Recent trends of age-specific pneumoconiosis mortality rates in the United States, 1985-1996: coal workers' pneumoconiosis, asbestosis, and silicosis

The authors examined the temporal trends of age-specific pneumoconiosis mortality from coal worker's pneumoconiosis (CWP), asbestosis, and silicosis in the United States in 1985-1996. Mortality data were derived from the National Center for Health Statistics multiple causes of death files for the period. Age-specific mortality rates were computed for three age groups (15-44, 45-64, and > or = 65 years) among decedents with mention of CWP, asbestosis, or silicosis. Linear regression analysis was performed to examine the annual changes in age-specific mortality rates, by age group, with each specific condition. The CWP mortality rates declined significantly (p = 0.0001) in the groups 45 years old and older, but not in the age group 15-44. Asbestosis mortality rates declined significantly (p = 0.005) for the age group 45-64, while increasing (p = 0.0001) for those aged 65 years and older. However, in the younger age group 15-44, the rates showed no significant trend. Silicosis mortality rates declined significantly (p = 0.0001) for all groups. The continued occurrence of deaths from CWP, asbestosis, and silicosis among young adults may be the result of high levels of exposure to occupational risks. These results suggest that pneumoconiosis surveillance may help to evaluate the temporal pneumoconiosis mortality patterns in the United States.     

Heel pain in children. Diagnosis and treatment

Heel pain in children is common, and its evaluation is challenging. Medical history and physical examination may be unrevealing owing to children's limited communication skills. Often, advanced laboratory and imaging studies are required to make an accurate diagnosis. The most common causes of heel pain in children are apophysitis, enthesopathy, and overuse syndromes such as tendinitis. Juvenile rheumatoid arthritis is relatively uncommon. In very active children, occult fractures must also be evaluated. Pain unrelated to activity may indicate tumors, infection, or congenital problems. In general, heel pain in children is treated nonoperatively. For fractures in particular, children are less likely than adults to receive surgical treatment.     

Epidemiology of rotavirus diarrhea in Egyptian children and implications for disease control.

Reliable epidemiologic data are essential for formulating effective policy to control rotavirus disease through immunization. The objective of this study was to describe the epidemiology of rotavirus diarrhea in a population-based cohort of children under 3 years of age residing in Abu Homos, Egypt, in 1995-1996. Rotavirus diarrhea incidence rates (episodes per person-year) were 0.13 for infants aged <6 months, 0.61 for those aged 6-11 months, 0.17 for those aged 12-23 months, and 0.15 for those aged 24-35 months. Fifty-six percent of children with rotavirus diarrhea had clinical dehydration; 90% of rotavirus diarrheal episodes occurred between July and November. In infants under 1 year of age, receipt of breast milk was associated with a lower incidence of rotavirus diarrhea. No other sociodemographic or environmental factor was found to be significantly associated with rotavirus diarrhea. Of 46 rotavirus isolates with strains identified, 41 (89%) were G serotypes 1 and 2. Rotavirus diarrhea was a major cause of morbidity in this cohort. Promotion of breastfeeding may exert a protective effect in young infants in this setting, but improvements in water and sanitation are unlikely to be effective preventive measures. The use of effective immunization against rotavirus in early infancy should be considered a public health priority.     

Persistent Organochlorines in the Effluents from a Chlorine-Bleached Kraft Integrated Pulp and Paper Mill in Southeast Asia

A bleached sulfate integrated pulp and paper mill producing printing and writing paper from mixed tropical hardwood and bamboo was studied. The mill uses a “conventional bleaching sequence,” C-E-H1-H2, with an average molecular chlorine consumption of 50 kg per ton of air-dried pulp (ADP). The content of polychlorinated dibenzofurans (PCDFs) and dibenzo-p-dioxins (PCDDs) in the bleaching filtrate in terms of the nordic toxicity equivalent (N-TEQ) was 33.5, 1.15, 0.56, and 0.014 pg/L for the E, C, H1, and H2 bleaching stages, respectively. The corresponding PCDFs and PCDDs loads in ng/t ADP were in the same ranking, i.e., 670, 69, 11.2, and 0.28, respectively. The congener and isomeric pattern of PCDFs and PCDDs of the bleaching filtrate and the bleached pulp was found to be typical for the chlorine bleaching plant effluent. The obtained dioxin load formed in the mill is in agreement with Western studies for the given multiple chlorine of 0.21–0.23. The load is, however, lower than reported discharges from Scandinavian mills using 1980s bleaching technologies, but substantially higher than the discharges from mills with modern bleaching technologies. Modifications in the bleaching plant to reduce molecular chlorine use are necessary to reduce dioxin formation. Received: 15 July 1998/Accepted: 17 March 1999