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Biomedical subjects

R J White

Publications and source records attributed to R J White.

At least 73 records · Page 4Linked to original sources
PubMed1997

Future directions for resuscitation research. V. Ultra-advanced life support.

Standard external cardiopulmonary resuscitation (SECPR) frequently produces very low perfusion pressures, which are inadequate to achieve restoration of spontaneous circulation (ROSC) and intact survival, particularly when the heart is diseased. Ultra-advanced life support (UALS) techniques may allow support of vital organ systems until either the heart recovers or cardiac repair or replacement is performed. Closed-chest emergency cardiopulmonary bypass (CPB) provides control of blood flow, pressure, composition and temperature, but has so far been applied relatively late. This additional low-flow time may preclude conscious survival. An easy, quick method for vessel access and a small preprimed system that could be taken into the field are needed. Open-chest CPR (OCCPR) is physiologically superior to SECPR, but has also been initiated too late in prior studies. Its application in the field has recently proven feasible. Variations of OCCPR, which deserve clinical trials inside and outside hospitals, include 'minimally invasive direct cardiac massage' (MIDCM), using a pocket-size plunger-like device inserted via a small incision and 'direct mechanical ventricular actuation' (DMVA), using a machine that pneumatically drives a cup placed around the heart. Other novel UALS approaches for further research include the use of an aortic balloon catheter to improve coronary and cerebral blood flow during SECPR, aortic flush techniques and a double-balloon aortic catheter that could allow separate perfusion (and cooling) of the heart, brain and viscera for optimal resuscitation of each. Decision-making, initiation of UALS methods and diagnostic evaluations must be rapid to maximize the potential for ROSC and facilitate decision-making regarding long-term circulatory support versus withdrawal of life support for hopeless cases. Research and development of UALS techniques needs to be coordinated with cerebral resuscitation research.

Cardiopulmonary Resuscitation↗
PubMed1997

Seasonal levels of reproductive hormones and their relationship to the antler cycle of male and female reindeer (Rangifer tarandus).

Seasonal levels of LH, FSH, testosterone (T), estradiol, progesterone (P), and prolactin (PRL) were determined in the plasma of five adult bulls, and five barren and four pregnant cows of Alaskan reindeer (Rangifer tarandus), which were sampled every 3 weeks for 54 weeks. The male reproductive axis was sequentially activated; LH peaked in May-June (2 ng/ml), FSH in June (51 ng/ml), and T in September (11.8 ng/ml). LH levels in females reached a maximum in both groups at the end of August (the beginning of the rut). Seasonal variation in FSH was minimal in pregnant cows, but exhibited one elevation (41 ng/ml) in barren ones in November. T levels in cows remained at barely detectable levels. The decrease of T values observed in both groups in December and March was not significant. PRL peaked in May in cows (135 ng/ml pregnant, 140 ng/ml non-pregnant) and in June in bulls (92 ng/ml). Estradiol was highest in bulls in the rut (August), in non-pregnant cows in January and in pregnant cows in April, shortly before parturition. P levels in the pregnant cows rose from September and peaked (9 ng/ml) shortly before parturition in April. In the non-pregnant females P values increased and decreased several times before peaking (5 ng/ml) in March. In the males, the variation of T and estradiol levels correlated relatively well with the antler cycle but in the females the variation of neither estradiol, progesterone nor T appeared to be related to mineralization or casting of antlers.

Animals↗
PubMed1996

Presence of pro-forms of decorin and biglycan in human articular cartilage.

The proteoglycans decorin and biglycan in extracts of human articular cartilage were analysed by SDS/PAGE and immunoblotting, using antisera raised to peptide sequences present in the pro-regions and the mature core proteins. In adult cartilage, both pro-forms and mature processed forms of the proteoglycan core protein were observed for both decorin and biglycan. In the case of biglycan, it was also shown that additional proteolytic processing takes place after removal of the propeptide and that this accounts for the presence of non-glycanated forms of the molecule. For both decorin and biglycan, the relative abundance of the pro-forms was much less in the juvenile than the adult. Different adult connective tissues, including meniscus, tendon and intervertebral disc were also examined for the presence of pro-forms of the proteoglycans. While the mature form of decorin was present at a similar level in extracts of all tissues examined, the pro-form was only detected in the articular cartilage. In the case of biglycan, the abundance of the mature form was more varied, with high levels in articular cartilage, intermediate levels in meniscus and the annulus fibrosus of the intervertebral disc, low levels in the nucleus pulposus of the intervertebral disc, and non-detectable levels in the patellar tendon. The pro-form of biglycan was detected in the disc tissue extracts, albeit at a lower level than in articular cartilage, but was not detected in the meniscus or tendon. The proportion of the pro-form relative to the mature form of biglycan was, however, higher in the nucleus pulposus of the intervertebral disc than in articular cartilage. Thus, the persistence of pro-forms of both decorin and biglycan is a feature of the extracellular matrix of some connective tissues, although their abundance is both tissue- and age-dependent, with adult articular cartilage being a particularly rich source.

Adult↗
PubMed1996

Mitochondrial depolarization in glutamate-stimulated neurons: an early signal specific to excitotoxin exposure.

A brief exposure to high concentrations of glutamate kills cultured forebrain neurons by an excitotoxic process that is dependent on Ca2+ influx through the NMDA receptor. In this study, we have measured striking changes in mitochondrial function during and immediately after intense glutamate receptor activation. Using indo-1 microfluorometry and a specific inhibitor of the mitochondrial Na+/Ca2+ exchanger, CGP-37157, we have demonstrated that mitochondria accumulate large quantities of Ca2+ during a toxic glutamate stimulus and further that Ca2+ efflux from mitochondria contributes to the prolonged [Ca2+]i elevation after glutamate removal. We then used JC-1 (5,5',6,6'-tetrachloro-1,1',3,3'-tetraethylbenzimidazolocarbocyanine+ ++ iodide), a ratiometric indicator of mitochondrial membrane potential (delta psi), to show that Ca2+ accumulation within the organelle dissipates delta psi. The abrupt loss of delta psi after glutamate stimulation did not occur in the presence of MK801 or in the absence of extracellular Ca2+. The mitochondrial depolarization was also cyclosporin A-sensitive, indicating a probable role for the permeability transition pore. Hence mitochondrial Ca2+ accumulation and the subsequent permeability transition may be a critical early event specific to the NMDA receptor-mediated excitotoxic cascade.

Animals↗
PubMed1996

Repression of RNA polymerase III transcription by the retinoblastoma protein.

Transcription by RNA polymerase (pol) III is under cell-cycle control, being higher in S and G2 than in G0 and early G1 phases. Many transformed cell types have elevated pol III activity, presumably to sustain sufficient protein synthesis for unrestrained growth. The retinoblastoma tumour-suppressor protein (Rb) restricts cellular proliferation, and is often found mutated in transformed cells. Here we demonstrate that Rb can repress the level of transcription from pol III templates both in vitro and vivo. Analysis of Rb-deficient SAOS2 cells and primary fibroblasts from Rb-/- mice demonstrates elevated levels of pol III activity in the absence of functional Rb protein. Rb-induced repression of pol III activity is alleviated by mutations in the Rb pocket domain that occur naturally in tumours, and by viral transforming proteins that bind and inactivate Rb. These results implicate repression of pol III transcription as a mechanism for Rb-induced growth arrest, and suggest that restraining protein biosynthesis may be important in the prevention of tumour development.

Adenovirus E1A Proteins↗
PubMed1996

Changes with age in the structure of fibromodulin in human articular cartilage.

An anti-peptide antibody was raised in a rabbit against the carboxy terminal region of the human fibromodulin core protein. The antibody was purified from other components of the resulting antiserum by affinity chromatography using the immobilized peptide, and was used to study the structural heterogeneity of fibromodulin extracted from human articular cartilage of different ages by the use of immunoblotting following sodium dodecyl sulfate polyacrylamide gel electrophoresis analysis of the extracted macromolecules. In the fetus and neonate, fibromodulin was visualized as a diffuse component with a relative molecular weight of 70-110 kDa, whereas in the mature adult a more discrete component of smaller size was apparent with a relative molecular weight of 67 kDa. The size of the fibromodulin from mature adult cartilage could not be altered by pretreatment of the samples with keratanase II or endo-beta-galactosidase before analysis. In contrast, the size of the fibromodulin from younger cartilage could be decreased with both glycosidases, with the endo-beta-galactosidase yielding a smaller product than the keratanase. The size of the product resulting from endo-beta-galactosidase treatment of the fibromodulin from young cartilage was the same as that of the intact fibromodulin from mature adult cartilage. Thus, fibromodulin is present in human articular cartilage at all ages, but the extracted molecules only appear to exist in a proteoglycan form possessing keratan sulfate chains in the juvenile and young adult, and the size of these chains decreases with age. In the mature adult the fibromodulin does not possess either keratan sulfate or non-sulfated polylactosamine chains, though it appears to possess the same number of N-linked oligosaccharides as its counterparts from the younger tissue, but they are not modified further. The majority of the fibromodulin extracted from arthritic cartilage is of the same size as that found in the normal mature adult, although there is evidence for proteolytic processing. The degree of such processing is greater for the fibromodulin obtained from the cartilage of rheumatoid arthritic joints than osteoarthritic joints.

Acetylglucosaminidase↗
PubMed1996

The isolation and transplantation of the brain. An historical perspective emphasizing the surgical solutions to the design of these classical models.

Following an historical review of earlier attempts to develop separated head and brain preparations and their contributions to modern-day understanding of the neurophysiology and neurochemistry of the central nervous system, the experiments that eventually led to the first successful total isolation of the mammalian brain are presented. The operative strategies emphasizing the anatomical and physiological problems requiring solution that resulted in vascular and neurogenic separation from the parent body and cephalon are described. The innovative engineering concepts that were utilized in the design of miniaturized equipment to maintain the isolated brain in a living state under conditions of cross circulation, extracorporeal artificial perfusion and transplantation are elaborated. Investigations employing isolated brain and cephalic preparation documenting tissue substrate requirements, metabolic and rheological conditions prevailing at various low temperatures and the immunologically privileged state of the separated organ are briefly presented. The unique opportunities these isolated brain models offer for study are emphasized as well as the complexity of their surgical preparation, which, to date, has limited their universal applications.

Animals↗
PubMed1996

Characterization of siamycin I, a human immunodeficiency virus fusion inhibitor.

The human immunodeficiency virus (HIV) fusion inhibitor siamycin I, a 21-residue tricyclic peptide, was identified from a Streptomyces culture by using a cell fusion assay involving cocultivation of HeLa-CD4+ cells and monkey kidney (BSC-1) cells expressing the HIV envelope gp160. Siamycin I is effective against acute HIV type 1 (HIV-1) and HIV-2 infections, with 50% effective doses ranging from 0.05 to 5.7 microM, and the concentration resulting in a 50% decrease in cell viability in the absence of viral infection is 150 microM in CEM-SS cells. Siamycin I inhibits fusion between C8166 cells and CEM-SS cells chronically infected with HIV (50% effective dose of 0.08 microM) but has no effect on Sendai virus-induced fusion or murine myoblast fusion. Siamycin I does not inhibit gp120 binding to CD4 in either gp120- or CD4-based capture enzyme-linked immunosorbent assays. Inhibition of HIV-induced fusion by this compound is reversible, suggesting that siamycin I binds noncovalently. An HIV-1 resistant variant was selected by in vitro passage of virus in the presence of increasing concentrations of siamycin I. Drug susceptibility studies on a chimeric virus containing the envelope gene from the siamycin I-resistant variant indicate that resistance maps to the gp160 gene. Envelope-deficient HIV complemented with gp160 from siamycin I-resistant HIV also displayed a resistant phenotype upon infection of HeLa-CD4-LTR-beta-gal cells. A comparison of the DNA sequences of the envelope genes from the resistant and parent viruses revealed a total of six amino acid changes. Together these results indicate that siamycin I interacts with the HIV envelope protein.

Anti-Bacterial Agents↗
PubMed1996

Resuscitation from severe brain trauma.

Severe traumatic brain injuries are extremely heterogeneous. At least seven of the secondary derangements in the brain that have been identified as occurring after most traumatic brain injuries also occur after cardiac arrest. These secondary derangements include posttraumatic brain ischemia. In addition, traumatic brain injury causes insults not present after cardiac arrest, i.e., mechanical tissue injury (including axonal injury and hemorrhages), followed by inflammation, brain swelling, and brain herniation. Brain herniation, in the absence of a mass lesion, is due to a still-to-be-clarified mix of edema and increased cerebral blood flow and blood volume. Glutamate release immediately after traumatic brain injury is proven. Late excitotoxicity needs exploration. Inflammation is a trigger for repair mechanisms. In the 1950s and 1960s, traumatic brain injury with coma was treated empirically with prolonged moderate hypothermia and intracranial pressure monitoring and control. Moderate hypothermia (30 degrees to 32 degrees C), but not mild hypothermia, can help prevent increases in intracranial pressure. How to achieve optimized hypothermia and rewarming without delayed brain herniation remains a challenge for research. Deoxyribonucleic acid (DNA) damage and triggering of programmed cell death (apoptosis) by trauma deserve exploration. Rodent models of cortical contusion are being used effectively to clarify the molecular and cellular responses of brain tissue to trauma and to study axonal and dendritic injury. However, in order to optimize therapeutic manipulations of posttraumatic intracranial dynamics and solve the problem of brain herniation, it may be necessary to use traumatic brain injury models in large animals (e.g., the dog), with long-term intensive care. Stepwise measures to prevent lethal brain swelling after traumatic brain injury need experimental exploration, based on the multifactorial mechanisms of brain swelling. Novel treatments have so far influenced primarily healthy tissue; future explorations should benefit damaged tissue in the penumbra zones and in remote brain regions. The prehospital arena is unexplored territory for traumatic brain injury research.

Animals↗
PubMed1996

Cerebral resuscitation from cardiac arrest: pathophysiologic mechanisms.

Both the period of total circulatory arrest to the brain and postischemic-anoxic encephalopathy (cerebral postresuscitation syndrome or disease), after normothermic cardiac arrests of between 5 and 20 mins (no-flow), contribute to complex physiologic and chemical derangements. The best documented derangements include the delayed protracted inhomogeneous cerebral hypoperfusion (despite controlled normotension), excitotoxicity as an explanation for selectively vulnerable brain regions and neurons, and free radical-triggered chemical cascades to lipid peroxidation of membranes. Protracted hypoxemia without cardiac arrest (e.g., very high altitude) can cause angiogenesis; the trigger of it, which lyses basement membranes, might be a factor in post-cardiac arrest encephalopathy. Questions to be explored include: What are the changes and effects on outcome of neurotransmitters (other than glutamate), of catecholamines, of vascular changes (microinfarcts seen after asphyxia), osmotic gradients, free-radical reactions, DNA cleavage, and transient extracerebral organ malfunction? For future mechanism-oriented studies of the brain after cardiac arrest and innovative cardiopulmonary-cerebral resuscitation, increasingly reproducible outcome models of temporary global brain ischemia in rats and dogs are now available. Disagreements exist between experienced investigative groups on the most informative method for quantitative evaluation of morphologic brain damage. There is agreement on the desirability of using not only functional deficit and chemical changes, but also morphologic damage as end points.

Altitude Sickness↗