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Biomedical subjects

J S Jacob

Publications and source records attributed to J S Jacob.

At least 19 recordsLinked to original sources
PubMed2003

Evaluation of anhydride oligomers within polymer microsphere blends and their impact on bioadhesion and drug delivery in vitro.

The effect of the addition of small molecular weight anhydride oligomers to polymer microspheres was evaluated and increased bioadhesion of the composite was demonstrated. Blends of low molecular weight anhydride oligomers with thermoplastic poly(fumaric-co-sebacic anhydride) [p(FASA)] and polycaprolactone were examined. The effects of anhydride oligomers on polymer microsphere degradation, crystallinity, and surface morphology were also explored. The results demonstrated that fumaric anhydride oligomer remained within polymer microspheres for several hours after exposure to phosphate buffer, formed a homogenous crystalline blend, increased bioadhesion as measured on rat intestine, and enhanced drug delivery in vitro as measured by the everted sac technique.

Anhydrides↗
PubMed2001

Increased atherosclerosis in myeloperoxidase-deficient mice.

Myeloperoxidase (MPO), a heme enzyme secreted by activated phagocytes, generates an array of oxidants proposed to play critical roles in host defense and local tissue damage. Both MPO and its reaction products are present in human atherosclerotic plaque, and it has been proposed that MPO oxidatively modifies targets in the artery wall. We have now generated MPO-deficient mice, and show here that neutrophils from homozygous mutants lack peroxidase and chlorination activity in vitro and fail to generate chlorotyrosine or to kill Candida albicans in vivo. To examine the potential role of MPO in atherosclerosis, we subjected LDL receptor-deficient mice to lethal irradiation, repopulated their marrow with MPO-deficient or wild-type cells, and provided them a high-fat, high-cholesterol diet for 14 weeks. White cell counts and plasma lipoprotein profiles were similar between the two groups at sacrifice. Cross-sectional analysis of the aorta indicated that lesions in MPO-deficient mice were about 50% larger than controls. Similar results were obtained in a genetic cross with LDL receptor-deficient mice. In contrast to advanced human atherosclerotic lesions, the chlorotyrosine content of aortic lesions from wild-type as well as MPO-deficient mice was essentially undetectable. These data suggest an unexpected, protective role for MPO-generated reactive intermediates in murine atherosclerosis. They also identify an important distinction between murine and human atherosclerosis with regard to the potential involvement of MPO in protein oxidation.

Animals↗
PubMed2000

In situ tumor vaccination with interleukin-12-encapsulated biodegradable microspheres: induction of tumor regression and potent antitumor immunity.

An alternative technology for the local and sustained delivery of cytokines to tumors for cancer immunotherapy was evaluated and shown here to induce tumor regression, suppression of metastasis, and development of systemic antitumor immunity. Treatment of tumor-bearing BALB/c mice with a single intratumoral injection of biodegradable polylactic acid microspheres loaded with recombinant interleukin-12 (IL-12) promoted complete regression of the primary tumor and prevented the metastatic spread to the lung. Mice that experienced tumor regression after being treated rejected a subsequent challenge with live tumor cells, which indicated the development of systemic antitumor immunity. In situ tumor vaccination, ie., injection of IL-12 microspheres into existing tumors, was superior to vaccination of mice with mixtures of tumor cells (live or irradiated) and IL-12 microspheres in inducing systemic antitumor immunity. The sustained release of IL-12 from the microspheres was superior to bolus injection of free IL-12, and intratumoral delivery of microspheres was more effective than other routes of administration. These studies establish the utility of biodegradable polymer microspheres as a clinically feasible alternative to systemic cytokine therapy and cytokine gene-modified cell vaccines for the treatment of neoplastic disease.

Absorbable Implants↗
PubMed2000

Nanosphere based oral insulin delivery.

Zinc insulin is successfully encapsulated in various polyester and polyanhydride nanosphere formulations using Phase Inversion Nanoencapsulation (PIN). The encapsulated insulin maintains its biological activity and is released from the nanospheres over a span of approximately 6 h. A specific formulation, 1.6% zinc insulin in poly(lactide-co-glycolide) (PLGA) with fumaric anhydride oligimer and iron oxide additives has been shown to be active orally. This formulation is shown to have 11.4% of the efficacy of intraperitoneally delivered zinc insulin and is able to control plasma glucose levels when faced with a simultaneously administered glucose challenge. A number of properties of this formulation, including size, release kinetics, bioadhesiveness and ability to traverse the gastrointestinal epithelium, are likely to contribute to its oral efficacy.

Administration, Oral↗
PubMed2000

The integration of digital camera derived images with a computer based diabetes register for use in retinal screening.

Exeter district provides a retinal screening service based on a mobile non-mydriatic camera operated by a dedicated retinal screener visiting general practices on a 2-yearly cycle. Digital attachments to eye cameras can now provide a cost effective alternative to the use of film in population based eye screening programmes. Whilst the manufacturers of digital cameras provide a database for the storage of pictures, the images do not as yet interface readily with the rest of the patient's computer held data or allow for a sophisticated grading, reporting and administration system. The system described is a development of the Exeter diabetes register (EXSYST) which can import digitally derived pictures from either Ris-Lite TM and Imagenet TM camera systems or scanned Polaroids Pictures can be reported by the screener, checked by a consultant ophthalmologist via the hospital network, and a report, consisting of colour pictures, map of relevant pathology and referral recommendations produced. This concise report can be hard copied inexpensively on a high resolution ink-jet printer to be returned to the patient's general practitioner. Eye images remain available within the hospital diabetes centre computer network to facilitate shared care. This integrated system would form an ideal platform for the addition of computer based pathology recognition and total paperless transmission when suitable links to GP surgeries become available.

Blindness↗
PubMed1999

Correlation of two bioadhesion assays: the everted sac technique and the CAHN microbalance.

This contribution correlates two in vitro methods utilized to determine bioadhesion. One method, the everted intestinal sac technique, is a passive test for bioadhesion involving several polymer microspheres and a section of everted intestinal tissue. The other method, the CAHN microbalance, employs a CAHN dynamic contact angle analyzer with modified software to record the tensile forces measured as a single polymer microsphere is pulled from intestinal tissue. This study demonstrates that CAHN and everted sac experiments yield similar results when used to quantify the bioadhesive nature of polymer microsphere systems. A polymer showing high adhesion in one method also demonstrates high bioadhesion in the other method; polymers that exhibit high fracture strength and tensile work measurements with the CAHN microbalance also yield high binding percentages with the everted sac method. The polymers tested and reported here are poly(caprolactone) and different copolymer ratios of poly(fumaric-co-sebacic anhydride). The results of this correlation demonstrate that each method alone is a valuable indicator of bioadhesion.

Adhesiveness↗
PubMed1998

Cytokine immunotherapy of cancer with controlled release biodegradable microspheres in a human tumor xenograft/SCID mouse model.

A novel biodegradable poly(lactic acid) microsphere formulation was evaluated for in vivo cytokine immunotherapy of cancer in a human tumor xenograft/ severe combined immunodeficiency (SCID) mouse model. Co-injection of interleukin-2 (IL-2)-loaded microspheres with tumor cells into a subcutaneous site resulted in the complete suppression of tumor engraftment in 80% of animals. In contrast, bovine-serum-albumin(BSA)-loaded particles or bolus injections of poly(ethylene glycol)/IL-2 were ineffective in preventing tumor growth. The antitumor effect of IL-2 released by the microspheres was shown to be mediated by the mouse natural killer cells. This is the first evidence that the rejection of human tumor xenografts can be provoked by the sustained in vivo delivery of IL-2 from biodegradable microspheres. The use of poly(lactic acid) microspheres to deliver cytokines to the tumor environment could provide a safer and simpler alternative to gene therapy protocols in the treatment of cancer.

Animals↗
PubMed1997

Biologically erodable microspheres as potential oral drug delivery systems.

Biologically adhesive delivery systems offer important advantages over conventional drug delivery systems. Here we show that engineered polymer microspheres made of biologically erodable polymers, which display strong adhesive interactions with gastrointestinal mucus and cellular linings, can traverse both the mucosal absorptive epithelium and the follicle-associated epithelium covering the lymphoid tissue of Peyer's patches. The polymers maintain contact with intestinal epithelium for extended periods of time and actually penetrate it, through and between cells. Thus, once loaded with compounds of pharmacological interest, the microspheres could be developed as delivery systems to transfer biologically active molecules to the circulation. We show that these microspheres increase the absorption of three model substances of widely different molecular size: dicumarol, insulin and plasmid DNA.

Adhesiveness↗
PubMed1996

Human phagocytes employ the myeloperoxidase-hydrogen peroxide system to synthesize dityrosine, trityrosine, pulcherosine, and isodityrosine by a tyrosyl radical-dependent pathway.

Myeloperoxidase, a heme protein secreted by activated phagocytes, may be a catalyst for lipoprotein oxidation in vivo. Active myeloperoxidase is a component of human atherosclerotic lesions, and atherosclerotic tissue exhibits selective enrichment of protein dityrosine cross-links, a well characterized product of myeloperoxidase. Tyrosylation of lipoproteins with peroxidase-generated tyrosyl radical generates multiple protein-bound tyrosine oxidation products in addition to dityrosine. The structural characterization of these products would thus serve as an important step in determining the role of myeloperoxidase in lipoprotein oxidation in the artery wall. We now report the identification and characterization of four distinct tyrosyl radical addition products generated by human phagocytes. Activated neutrophils synthesized three major fluorescent products from -tyrosine; on reverse phase HPLC, each compound coeluted with fluorescent oxidation products formed by myeloperoxidase. We purified the oxidation products to apparent homogeneity by cation and anion exchange chromatographies and identified the compounds as dityrosine (3,3'-dityrosine), trityrosine (3,3',5',3"-trityrosine) and pulcherosine (5-[4"-(2-carboxy-2-aminoethyl)phenoxy]3, 3'-dityrosine) by high resolution NMR spectroscopy and mass spectrometry. Additionally, we have found that dityrosine is a precursor to trityrosine, but not pulcherosine. In a search for a precursor to pulcherosine, we identified isodityrosine (3-[4'-(2-carboxy-2-aminoethyl)phenoxy]tyrosine), a non-fluorescent product of L-tyrosine oxidation by human phagocytes. Our results represent the first identification of this family of tyrosyl radical addition products in a mammalian system. Moreover, these compounds may serve as markers specific for tyrosyl radical-mediated oxidative damage in atherosclerosis and other inflammatory conditions.

Free Radicals↗
PubMed1994

Double-walled polymer microspheres for controlled drug release.

One approach to the controlled release of drugs involves incorporation of the drug molecules into the matrix of microscopic polymer spheres or capsules. Existing methods for preparing such microparticles do not, however, always guarantee a constant release rate, for example because drug molecules may be trapped preferentially at the surface, because they have to diffuse through an increasing thickness of polymer when the particles are non-eroding or because the surface area changes for eroding particles. In other situations pulsed release may be required--an application to which simple polymer microspheres do not readily lend themselves. Multi-walled microspheres might solve some of these problems. Here we describe a one-step process for preparing double-walled polymer microspheres with diameters ranging from about 20 to 1,000 micrometers. Our technique involves the phase separation of a polymer mixture owing to solvent evaporation: with an appropriate choice of interfacial tensions and evaporation rate, a spherical droplet of one polymer becomes coated with a highly uniform layer of the other. This process, which might be adapted to yield multi-walled microspheres, should make possible the engineering of highly specific drug-release properties.

Drug Delivery Systems↗
PubMed1991

Screening for treatable diabetic retinopathy: a comparison of different methods.

The results of the screening of 3318 diabetic patients for sight-threatening diabetic retinopathy in three UK centres are reported. The aims of the study were to determine the extent of diabetic retinopathy in the screened population and to assess the relative effectiveness of different screening methods in appropriately referring cases from a diabetic population, in a context very close to a routine clinical service. Patients were assessed by ophthalmoscopic examination by an ophthalmological clinical assistant. The clinical assistants' referral grades formed the reference standard against which to assess the effectiveness of other screening methods including ophthalmoscopy by primary screeners who were general practitioners (GPs), ophthalmic opticians and hospital physicians, and the assessment by consultant ophthalmologists of non-mydriatic Polaroid fundus photography. The performance of primary screeners based on ophthalmoscopy ranged from a sensitivity of 0.41, with a specificity of 0.89, for one of the GP groups, to a sensitivity of 0.67, with a specificity of 0.96, for the hospital physician group. The performance of the non-mydriatic camera ranged from a sensitivity of 0.35, with a specificity of 0.95, to a sensitivity of 0.67, with a specificity of 0.98.

Aged↗
PubMed1989

Bacterial contamination of intraocular and extraocular fluids during extracapsular cataract extraction.

Fluid aspirated from the anterior chamber and fluid drained from the conjunctival sac during 101 extracapsular cataract operations was examined for bacterial contamination. Bacteria were grown by enrichment culture from the conjunctival sac of 90 eyes and from the anterior chamber aspirate of 29 eyes. Conjunctival fluid, stained with fluorescein, was demonstrated to flow into the anterior chamber during the aspiration stage of extracapsular cataract extraction and during intraocular lens implantation. It is suggested that this fluid from the conjunctival sac, contaminated with bacteria, routinely enters the anterior chamber during extracapsular cataract extraction and is the likely source of some cases of post-operative endophthalmitis.

Anterior Chamber↗
PubMed1988

Supramolecular structure of the thylakoid membrane of Prochlorothrix hollandica: a chlorophyll b-containing prokaryote.

Prochlorothrix hollandica is a newly described photosynthetic prokaryote, which contains chlorophylls a and b. In this paper we report the results of freeze fracture and freeze etch studies of the organization of the photosynthetic thylakoid membranes of Prochlorothrix. These membranes exhibit four distinct fracture faces in freeze fractured preparations, two of which are derived from membrane splitting in stacked regions of the thylakoid membrane, and two of which are derived from nonstacked regions. The existence of these four faces confirms that the thylakoid membranes of Prochlorothrix, like those of green plants, display true membrane stacking and have different internal composition in stacked and non-stacked regions, a phenomenon that has been given the name lateral heterogeneity. The general details of these fracture faces are similar to those of green plants, although the intramembrane particles of Prochlorothrix are generally smaller than those of green plants by as much as 30%. Freeze etched membrane surfaces have also been studied, and the results of these studies confirm freeze fracture observations. The outer surface of the thylakoid membrane displays both small (less than 8.0 nm) and large (greater than 10.0 nm) particles. The inner surface of the thylakoid membrane is covered with tetrameric particles, which are concentrated into stacked membrane regions, a situation that is similar to the inner surfaces of the thylakoid membranes of green plants. These tetramers have never before been reported in a prokaryote. The photosynthetic membranes of Prochlorothrix therefore represent a prokaryotic system that is remarkably similar, in structural terms, to the photosynthetic membranes found in chloroplasts of green plants.

Chloroplasts↗
PubMed1986

Heliobacterium chlorum: cell organization and structure.

The basic cellular organization of Heliobacterium chlorum is described using the freeze-etching technique. Internal cell membranes have not been observed in most cells, leading to the conclusion that the photosynthetic apparatus of these organisms must be localized in the cell membrane of the bacterium. The two fracture faces of the cell membrane are markedly different. The cytoplasmic (PF) face is covered with densely packed particles averaging 8 nm in diameter, while the exoplasmic (EF) face contains far fewer particles, averaging approximately 10 nm in diameter. Although a few differentiated regions were noted within these fracture faces, the overall appearance of the cell membrane was remarkably uniform. The Heliobacterium chlorum cell wall is a strikingly regular structure, composed of repeating subunits arranged in a rectangular pattern at a spacing of 11 nm in either direction. We have isolated cell wall fragments by brief sonication in distilled water, and visualized the cell wall structure by negative staining as well as deep-etching.

Bacteria↗
PubMed1986

The effects of galactolipid depletion on the structure of a photosynthetic membrane.

The galactolipids monogalactosyldiglyceride and digalactosyldiglyceride together comprise more than 77% of the photosynthetic membrane lipids of higher plant chloroplasts. We have isolated a lipase from the chloroplasts of runner beans (Phaseolus vulgaris) which is highly specific for these galactolipids. This galactolipase promotes the hydrolysis of monogalactosyldiglyceride and digalactosyldiglyceride, in the process liberating two free fatty acids into the membrane bilayer, leaving the residual galactosyl glyceride group to diffuse into the aqueous bulk phase. Isolated spinach photosynthetic membranes were treated with this enzyme preparation and changes in membrane composition were studied with thin layer chromatography (for lipids), gel electrophoresis (proteins), and freeze-etching (membrane structure). After 30 min of lipolysis, nearly 100% of the galactolipids had been converted into membrane-associated fatty acids and water-soluble galactosyl glycerides. SDS PAGE showed that two proteins, one of which is possibly associated with the reaction center of photosystem II, were removed by the treatment. Despite the minor nature of changes in membrane protein composition, freeze-fracture and freeze-etch studies showed that striking changes in membrane structure had taken place. The large freeze-fracture particle on the E fracture face had disappeared in stacked regions of the membrane system. In addition, a tetrameric particle visible at the inner surface of the membrane had apparently dissociated into individual monomeric particles. The fact that these two structures are so dramatically affected by the loss of galactolipids strongly suggests that these lipids play a crucial role in maintaining their structure. Both structures are believed to be different views of the same transmembrane unit: a membrane-spanning complex associated with photosystem II. Our results are consistent with two possible interpretations: the intramembrane particles may be lipidic in nature, and hence lipolysis causes their disappearance; or galactolipids are necessary for the organization of a complex photosystem II-associated structure which is composed of a number of different molecular species.

Carboxylic Ester Hydrolases↗
PubMed1985

The Rhodopseudomonas viridis photosynthetic membrane: arrangement in situ.

The organization of photosynthetic membranes in the cytoplasm of the photosynthetic bacterium Rh. viridis has been examined by several techniques for electron microscopy. Thin sections of membrane stacks show that the regular lattice of membrane subunits reported in other studies can be observed in thin section. Tilting of sections in the electron microscope shows that the regular lattices of several membranes overlap in a way that suggests they are in register with each other. This observation can be confirmed by freeze-fracture images in which a regular arrangement of membrane lattices can be observed, each perfectly aligned. Analysis of the spacings of membrane pairs shows that the photosynthetic membranes of Rh. viridis are very closely apposed. The mean diameter of two membranes is 160A, and the average space between two such membranes is only 42A. When a recently developed atomic level model of Rh. viridis reaction center is superimposed against these spacings, each reaction center extends from the surface of its respective membrane far enough to make contact with an apposing membrane. The limited free space between membranes and regular alignment of lattices has a number of implications for how this membrane is organized to carry out the process of energy transfer.

Bacteriorhodopsins↗