Nanoparticle-derived non-viral genetic transfection at the blood-brain barrier to enable neuronal growth factor delivery by secretion from brain endothelium.

Brain capillary endothelial cells form the blood-brain barrier (BBB) that denotes a major restraint for drug entry to the brain. The identification of many new targets to treat diseases in the brain demands novel thinking in drug design as new therapeutics could often be proteins and molecules of genetic origins like siRNA, miRNA and cDNA. Such molecules are otherwise prevented from entry into the brain unless encapsulated in drug carriers. The desirable entry of such large, hydrophilic molecules should be made by formulation of particular drug carriers that will enable their transport into the brain endothelium, or even through the endothelium and into the brain. This manuscript reviews the potential of different drug-carriers for therapy to the brain with respect to their targetability, biocompatibility, toxicity and biodegradability.

Comparative plasma concentration profiles after i.v., i.m. and rectal administration of pethidine in children.

Plasma concentration-time curves of pethidine and norpethidine were studied in 25 children allocated after operation to three groups to receive pethidine 1 mg kg-1 i.v., i.m. or rectally. Peak concentrations occurred after 5 +/- 1, 10 +/- 2, and 60 +/- 10 min, respectively, while the maximum concentrations amounted to 2800 +/- 462, 1609 +/- 367 and 531 +/- 179 nmol litre-1, respectively. The area under the curve (0-240 min) was similarly reduced in the group with rectal administration (P less than 0.05). Compared with the i.v. data, approximately 40% systemic availability occurred after rectal application, although considerable individual variation was noted. In one child very high plasma concentrations were observed after rectal administration, possibly as a result of redistribution/recirculation phenomena. The average results are similar to those obtained when other opioids are given rectally.

Mycobacterium paratuberculosis in the semen and genital organs of a semen-donor bull.

Mycobacterium paratuberculosis, the cause of Johne's disease, was isolated from the feces of a donor bull in an artificial insemination stud. During isolation and observation for 21 months, the organism was recovered from all of 26 fecal samples and from 8 of 31 semen samples. At necropsy, it was isolated from the intestine and adjacent lymph nodes, lung, spleen, seminal vesicles, and prostate gland but not from the testicles. We concluded that routine fecal cultures at bull studs will reveal infected bulls before they become genitally infected and shed M paratuberculosis in semen.

Susceptibility of the lemming (Dicrostonyx rubricatus) to Mycobacterium paratuberculosis.

The susceptibility of the lemming (Dicrostonyx rubricatus) to Mycobacterium paratuberculosis was studied. Twelve lemmings were exposed to cultural material of M paratuberculosis and were necropsied at 40- to 260-day intervals after exposure. Selected tissues were examined bacteriologically and histologically. Mycobacterium paratuberculosis was recovered from all exposed lemmings except the one necropsied 40 days after exposure. Pathologic changes typical of paratuberculosis were seen in a few lemmings. Clinical signs of disease were not seen. Rate of growth and general appearance of the exposed lemmings and the normal controls did not differ. The extent of infection in this species of lemming was similar to that seen in exposed hamsters.

Mammary gland exposure of cows to Mycobacterium paratuberculosis.

Mycobacterium paratuberculosis injected into the mammary gland was transported to the supramammary lymph nodes in 5 of 6 cows and to the intestine of 1 cow. The bacillus caused hypersensitivity to johnin and stimulated the production of complement-fixing antibodies. Apparently, the bacillus is not a cause mastitis.

Effect of dexamethasone on Mycobacterium paratuberculosis infection in hamsters.

Sixty hamsters were randomly divided into 4 equal groups: group 1--given only dexamethasone, group 2--given dexamethasone and exposed to Mycobacterium paratuberculosis, group 3--exposed to M paratuberculosis but not treated, and group 4--used as normal controls. Group 2 hamsters (treated with dexamethasone and exposed to the bacterium) had significantly higher bacterial counts in spleen and aggregated lymphatic nodules (Peyser's patches) than did those in group 3. None of the hamsters exposed to M paratuberculosis (groups 2 and 3) developed clinical signs of disease. All hamsters treated with the drug (groups 1 and 2) grew more slowly than did the hamsters not treated.

Skin testing, fecal culture, and lymphocyte immunostimulation in cattle inoculated with Mycobacterium paratuberculosis.

Fourteen calves at 21 days of age were experimentally inoculated with 100 mg (wet weight) of Mycobacterium paratuberculosis. Three calves were inoculated orally, 4 intravenously, and 7 subcutaneously. Lymphocyte immunostimulation, fecal culture, and intradermal tuberculin skin testing were done between 112 to 150 days following exposure. Lymphocyte immunostimulation test results, conducted at 112 days after inoculation, showed all animals positive to Mycobacterium avium purified protein derivative. Fecal culture results, taken at 120 days after inoculation, showed that 2 of 3 animals inoculated intravenously were positive, whereas only 2 of 7 inoculated subcutaneously were positive (8 of 14 total were positive). Intradermal skin testing results at 150 days with M avium purified protein derivative showed 13 of the 14 calves were positive. Calves were examined at necropsy 153 days after inoculation, and M paratuberculosis was isolated from tissues of each of the 14 calves.

Subcutaneous exposure of calves to Myobacterium paratuberculosis compared with intravenous and oral exposures.

Three groups of calves, 21 days of age, were exposed to Mycobacterium paratuberculosis by oral, intravenous, and subcutaneous routes. Fecal cultural examination and intradermal tests were made, and at 150 days after exposure, the calves were euthanatized and tissues were collected for histopathologic and bacteriologic cultural examination. Calves in the 3 groups were infected. Those exposed intravenously had significantly higher colony counts than did either of the other groups. There was no significant difference between colony counts of cultures from tissues of calves exposed orally and those of calves exposed subcutaneously.

Susceptibility of the Mongolian gerbil (Meriones unguiculatus) to Mycobacterium paratuberculosis.

Mongolian gerbils (Meriones unguiculatus) were exposed to Mycobacterium paratuberculosis by intraperitoneal and oral routes. Fourteen weeks after exposure, the gerbils were necropsied and tissues were cultured and examined microscopically. Results of the study showed that gerbils can be infected with M paratuberculosis but are not suitable for studies of paratuberculosis.

Intravenous johnin and tuberculin tests in cattle vaccinated with Mycobacterium paratuberculosis cells and subsequently inoculated with Mycobacterium bovis.

Calves at 30 days of age were vaccinated with a killed whole-cell Mycobacterium paratuberculosis vaccine. Four months later, these calves were inoculated with Mycobacterium bovis. The intravenous tuberculin and johnin tests were applied both before and after inoculation. The results of the hematologic investigation had extremes at both high and low values and were too unsuitable for statistical analysis. The intravenous tuberculin test is considered unsuitable for diagnosis of bovine tuberculosis in cattle vaccinated against paratuberculosis.

Effect of aflatoxin on susceptibility of hamsters to Mycobacterium paratuberculosis.

After oral administration of Mycobacterium paratuberculosis to hamsters, the organism passed the epithelial barrier of the intestine, and infection was established in the small intestine and mesenteric lymph nodes. The addition of aflatoxin to the ration of hamsters did not increase their susceptibility to M paratuberculosis but, rather, seemed to decrease susceptibility to the bacillus. Hamsters not treated with aflatoxin and infected with M paratuberculosis had higher bacterial counts in intestinal tract and mesenteric lymph node on necropsy than did infected hamsters that had been treated with aflatoxin. Aflatoxin-treated hamsters grew slowly, had an unthrifty appearance, and developed lesions of megalocytosis regardless of whether they were infected with M paratuberculosis.