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Biomedical subjects

J Riley

Publications and source records attributed to J Riley.

At least 37 records · Page 2Linked to original sources

Pharmacokinetics and toxic effects of nifedipine in massive overdose.

A 57-year-old man took 30 x 20 mg nifedipine retarded release tablets. He developed hypotension, tachycardia and flushing, but remained in sinus rhythm. The concentration of nifedipine 10 h after overdose was 604 micrograms 1-1, and of the M-I metabolite 110 micrograms 1-1. Log concentration time curves were linear from 10-72 h for nifedipine, with a half-life of 7.5 h; and for M-I with a half-life of 8.2 h. On this evidence, oral absorption of nifedipine retarded release is complete by 10 h. There was no evidence of saturation of nifedipine or M-I metabolism, even at concentrations ten times above the therapeutic concentration.

Drug Overdose

Effects of cilofungin (LY121019) on carbohydrate and sterol composition of Candida albicans.

Cilofungin (LY 121019) is a novel analogue of echinocandin B with potent activity against Candida albicans. The effects of cilofungin on the sterol and cell wall carbohydrate composition of Candida albicans were investigated. Exposure of Candida albicans to cilofungin resulted in a 55-60% decrease in ergosterol and a 4-13% decrease in lanosterol content relative to controls. Carbohydrate analysis revealed a 72-79% decrease in glucan content and no significant decrease in mannan or chitin content relative to controls. These studies suggest that cilofungin specifically inhibits glucan synthesis in Candida albicans and thus may be less toxic to mammalian cells. The effects of cilofungin on sterol composition may be non-specific and will require additional investigation.

Candida albicans

Further evidence for the protective role of sub-parietal cell membranous secretory product on the cuticle of a pentastomid arthropod parasite developing in its rodent intermediate host.

The pentastomid parasite Porocephalus crotali, develops to an infective stage within a granulomatous lesion in the tissues of rodent intermediate hosts. A conspicuous layer of sub-parietal cell (SPC) secretory product, which coats the intermoult cuticle up to a depth of 12 microns, is described. Around the first five nymphal instars this material consists of an amorphous matrix with distinctive electron-lucid lacunae, but that around later instars (six and seven), while retaining much of the original morphology, possesses a significant membranous component. Host effector cells, most notably eosinophils and macrophage/epithelioid cells, are frequently completely enveloped by SPC secretion but invariably appear unreactive to it. Host cells may penetrate to the outermost layer of the epicuticle but again but again cytotoxic activity is absent. During ecdysis, effector cells are recruited to the intercuticular space where widespread degranulation is evident. Some of this is specifically directed against the underside of the cast cuticle, but not against the newly exposed cuticle. Protracted degranulation eventually reduces the cast cuticle to fragments which are endocytosed by giant cells. 1 cm long infective (seventh-stage) nymphs, which retain the sixth stage cuticle as a protective sheath, are largely devoid of membranous secretion and these were dissected from cysts, washed, and surgically transplanted into the body cavities of naive and infected mice. Pronounced differences in the onset and intensity of the subsequent inflammatory response in the two categories of host indicate some form of specific recognition. In both groups of mice though, the cuticle is an eventual target for attack by effector cells, and parasites are killed. The protective function of SPC secretion is discussed.

Animals

Dyspnea in aging rats due to disseminated intravascular coagulation (DIC).

During an 18-month oncogenicity study using rats, approximately 10% of the animals developed a form of respiratory distress very similar to that seen in the terminal stages of chronic respiratory disease, commonly associated with Mycoplasma pulmonis infection. Investigation of the lungs of the affected rats revealed not only that they did not have the consolidation usually associated with chronic respiratory disease, but they also appeared macroscopically normal. Further investigation of a number of cases revealed systemic intravascular thrombus formation of the type usually referred to as disseminated intravascular coagulation. Using an antiserum to fibrin we have demonstrated the presence of intravascular fibrin deposits in the lungs of the affected rats and have shown them to be the same as experimentally induced intravascular fibrin deposits induced in rat lungs by the administration of thrombin after blocking the fibrinolytic system. This is the first example of such a phenomenon being recorded in aging rats.

Aging

Amelioration of established Sendai viral pneumonia in the nude mouse using a monoclonal antibody to the virus fusion protein.

The pathological effect of parainfluenza type I (Sendai virus) is known to be a bronchopneumonia, which becomes a chronic pneumonia in the immunodeficient athymic (nude) mouse. The severity of this established chronic pneumonia can be dramatically altered by providing the nude mouse with humoral monoclonal antibodies which are neutralizing, and are directed against the fusion protein, of the virus. The alveolitis, which is a significant part of the pathology, is suppressed due to a reduction (greater than 90%) in the number of virus-infected alveolar macrophages present in the alveoli. This clearly identifies the infected alveolar macrophage as the primary effector cell in the pathogenesis of alveolitis caused by parainfluenza virus type I. The implications of using virus-neutralizing monoclonal antibodies, which have little immunomodulatory toxicity, in the treatment of viral pneumonias are discussed.

Animals

Diagnosis of alpha 1-antitrypsin deficiency by enzymatic amplification of human genomic DNA and direct sequencing of polymerase chain reaction products.

We have compared sequencing of cloned "polymerase chain reaction" (PCR) products and the direct sequencing of PCR products in the examination of individuals from six families affected with alpha 1-antitrypsin (AAT) deficiency. In families where paternity was in question we confirmed consanguinity by DNA fingerprinting using a panel of locus-specific minisatellite probes. We demonstrate that direct sequencing of PCR amplification products is the method of choice for the absolutely specific diagnosis of AAT deficiency and can distinguish normals, heterozygotes and homozygotes in a single, rapid and facile assay. Furthermore, we demonstrate the reproducibility of the PCR and a rapid DNA isolation procedure. We have also shown that two loci can be simultaneously amplified and that the PCR product from each locus can be independently examined by direct DNA sequencing.

Base Sequence

Studies on the host/parasite interface during the development of a pentastomid arthropod parasite in rodent intermediate hosts, with observations on protective surface membranes.

The changing structure of the cuticle of the arthropod pentastomid parasite Porocephalus crotali, during growth to the infective stage in mouse and rattlesnake hosts, is described. The outermost cuticulin layer of the cuticle in instars II-VI is elevated to form a dense mat of epicuticular hairs. Since the VI larval cuticle is retained by the infective (VII) nymph as a protective sheath, effectively all stages in mice present a hairy surface to the host and this may constitute a physical barrier to inflammatory cells. The entire surface is overlain by a triple-track 'unit' membrane whose biophysical properties resemble those of a conventional plasma membrane, and there is evidence to suggest that this membrane is susceptible to immune attack. Under natural circumstances, epicuticular hairs entrap secretion, delivered to the cuticle via innumerable minute ducts which communicate with tegumental secretory cells termed subparietal cells (SPC). SPC synthesize lamellate droplets which unfold on the cuticle to constitute a layer of protective polymorphic vesicles. By contrast, infective nymphs in snakes possess a smooth cuticle and SPC membranous secretion is stacked over the entire surface, in sheets up to 20 deep. The function of the lipid and protein components of SPC secretion is discussed.

Animals

Fine structural aspects of secretory processes in a pentastomid arthropod parasite in its mouse and rattlesnake hosts.

The histology and development of three extensive glands in the porocephalid pentastomid Porocephalus crotali is described by light and electron microscopy, during growth of the parasite to an infective stage in the tissues of mouse; the infective stage in rattlesnake definitive hosts is also included. These glands elaborate excretory/secretory components which are channelled, via chitin-lined efferent ductules, on to the parasite cuticle. Hook and frontal glands are relatively compact, and within each gland ductules serving individual secretory lobules collect into common ducts which discharge over each of the four hooks, or at the anterior margin of the cephalothorax respectively. Subparietal gland cell lobules, composed of two large and two small secretory cells, are distributed under the cuticle and each is served by a single efferent ductule; these erupt over the entire cuticle. The large cells in subparietal glands secrete lamellate droplets which coat the cuticle with thin layers. Identical cells are found in hook and frontal glands, in addition to to three morphologically distinct types of protein secretory cell. Preliminary data on the composition and immunological properties of the various secretory products are presented.

Animals

Light microscope observations of granulomatous reactions against developing Porocephalus crotali (Pentastomida: Porocephalida) in mouse and rat.

The development of granulomatous reactions against moulting nymphal pentastomids (Porocephalus crotali) in the tissues of rat and mouse intermediate hosts is described. Adipose tissue and lungs are favoured sites for encystment accounting for 70% of larvae. Six moults separate the primary larva from the final infective stage which first appears about 80 days post-infection (p.i.) and is fully infective by day 120. Larvae, and particularly their cast cuticles, are the foci of granulomatous reactions characterized by an intense eosinophilia. During ecdysis, large numbers of eosinophils permeate the entire lesion but, significantly, degranulation is limited to the underside of cast cuticles where the resultant debris is endocytosed by macrophage/epithelioid cells. A pronounced asymmetry in the granulomatous lesion, evident even in the earliest cysts, results from the accumulation of individual epithelioid granulomas associated with cuticle fragments close to the ventral side of the developing parasite; each is circumscribed by fibrosis. External to this region are extensive tracts of tissue composed of mature plasma cells. Particularly in rats, large numbers of partially degranulated mast cells (= globule leucocytes) also surround cuticle granulomas, and mast cell granules can accumulate within macrophages and fibroblasts. Inflammation slowly subsides once the infective stage is attained. This 1 cm-long larva resides in a thin, fibrotic, C-shaped cyst and can remain viable for years: uniquely this instar retains its last moulted cuticle as a protective sheath. Nymphal instars II-VI feed predominantly upon eosinophils but we do not yet know whether this requirement is obligate.

Adipose Tissue

Polyamine depletion and growth inhibition in Candida albicans and Candida tropicalis by alpha-difluoromethylornithine and cyclohexylamine.

The ability of two known inhibitors of polyamine synthesis, alpha-difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase (ODC), and cyclohexylamine, an inhibitor of spermidine synthase, to inhibit the in vitro growth and polyamine synthesis of clinical isolates of Candida tropicalis and Candida albicans was examined. Treatment of C. tropicalis and C. albicans with either DFMO or cyclohexylamine resulted in depletion of cellular polyamines and inhibition of growth. The growth inhibition produced by each of these compounds was completely reversed by exogenous polyamines. Depletion of polyamines by low concentrations of DFMO significantly enhanced the growth inhibitory activity of cyclohexylamine versus C. albicans. DFMO inhibited ODC activity in both C. albicans and C. tropicalis. These findings document the ability of cyclohexylamine and DFMO to inhibit polyamine synthesis and growth in clinically important species of Candida.

Candida

Growth inhibition of pathogenic yeast isolates by alpha-difluoromethylornithine: an inhibition of ornithine decarboxylase.

A large body of evidence exists suggesting that polyamines can play essential roles in cellular growth and differentiation. We examined the ability of alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase, the major rate-limiting enzyme in polyamine biosynthesis, to inhibit the growth of Candida albicans, C. tropicalis, and C. parapsilosis. Substantial growth-inhibition was observed for all three species at DFMO concentrations ranging from 1 to 100 mM. C. tropicalis was significantly more susceptible to DFMO than C. albicans or C. parapsilosis. Depletion of cellular polyamine pools was seen in all 3 species following exposure to DFMO and polyamine depletion enhanced the susceptibility of the organisms to DFMO. The action of DFMO was specifically antagonized by exogenous polyamines. These data suggest that polyamines are important in the growth of Candida spp. and that inhibitors of polyamine biosynthesis may be useful as antifungal agents.

Candida

Circuit for the electromanipulation of plant protoplasts.

An electric circuit for plant protoplast manipulation is described. The circuit used readily available materials and was designed for use in teaching. This integrated circuit can be placed in a single small box with controls for the aligning voltage, the aligning frequency, the pulse voltage, and the pulse timing. The circuit can be supplied by any suitable source of dc power and can be easily altered for individual requirements. The circuit, as presented here, can be assembled for less than $250.

Cell Fusion

An algorithm for the management of ureteral calculi.

We evaluated 158 patients with ureteral calculi (28 impacted in the ureteropelvic junction, 42 in the upper, 29 middle and 36 lower third of the ureter, and 23 in the intramural tunnel) treated by extracorporeal shock wave lithotripsy, percutaneous ultrasonic lithotripsy, ureteroscopic methods, chemolysis or surgery. Of the patients 92.5 per cent were treated successfully by endourological methods. Twelve patients (7.5 per cent) required an operation. Extracorporeal shock wave lithotripsy was successful in 61 per cent of the patients without placement of a ureteral stent and in 100 per cent in whom stent placement or stone dislodgement was successful. Ureteroscopic removal was successful in 52 of 56 patients with lower third and intravesical tunnel ureteral calculi. An algorithm for ureteral calculi management is developed, which emphasizes stent bypass and extracorporeal shock wave lithotripsy for upper third or ureteropelvic junction calculi, ureteroscopic removal or stent bypass with extracorporeal shock wave lithotripsy for middle third calculi, and ureteroscopic techniques for lower third and intramural tunnel calculi. Percutaneous ultrasonic lithotripsy, chemolysis and surgery are recommended as complementary methods.

Algorithms