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R J White

Publications and source records attributed to R J White.

At least 91 records · Page 5Linked to original sources
PubMed1996

Cerebral resuscitation from cardiac arrest: treatment potentials.

In 1961, in Pittsburgh, PA, "cerebral" was added to the cardiopulmonary resuscitation system (CPR --> CPCR). Cerebral recovery is dependent on arrest and cardiopulmonary resuscitation times, and numerous factors related to basic, advanced, and prolonged life support. Postischemic-anoxic encephalopathy (the cerebral postresuscitation disease or syndrome) is complex and multifactorial. The prevention or mitigation of this syndrome requires that there be development and trials of special, multifaceted, combination treatments. The selection of therapies to mitigate the postresuscitation syndrome should continue to be based on mechanistic rationale. Therapy based on a single mechanism, however, is unlikely to be maximally effective. For logistic reasons, the limit for neurologic recovery after 5 mins of arrest must be extended to achieve functionally and histologically normal human brains after 10 to 20 mins of circulatory arrest. This goal has been approached, but not quite reached. Treatment effects on process variables give clues, but long-term outcome evaluation is needed for documentation of efficacy and to improve clinical results. Goals have crystallized for clinically relevant cardiac arrest-intensive care outcome models in large animals. These studies are expensive, but essential, because positive treatment effects cannot always be confirmed in the rat forebrain ischemia model. Except for a still-elusive breakthrough effect, randomized clinical trials of CPCR are limited in their ability to statistically document the effectiveness of treatments found to be beneficial in controlled outcome models in large animals. Clinical studies of feasibility, side effects, and acceptability are essential. Hypertensive reperfusion overcomes multifocal no-reflow and improves outcome. Physical combination treatments, such as mild resuscitative (early postarrest) hypothermia (34 degrees C) plus cerebral blood flow promotion (e.g., with hypertension, hemodilution, and normocapnia), each having multiple beneficial effects, achieved complete functional and near-complete histologic recovery of the dog brain after 11 mins of normothermic, ventricular fibrillation cardiac arrest. Calcium entry blockers appear promising as a treatment for postischemic-anoxic encephalopathy. However, the majority of single or multiple drug treatments explored so far have failed to improve neurologic outcome. Assembling and evaluating combination treatments in further animal studies and determining clinical feasibility inside and outside hospitals are challenges for the near future. Treatments without permanent beneficial effects may at least extend the therapeutic window. All of these investigations will require coordinated efforts by multiple research groups, pursuing systematic, multilevel research--from cell cultures to rats, to large animals, and to clinical trials. There are still many gaps in our knowledge about optimizing extracerebral life support for cerebral outcome.

Animals↗
PubMed1996

Resuscitative hypothermia.

Resuscitative (postinsult) hypothermia is less well studied than protective-preservative (pre- and intra-arrest) hypothermia. The latter is in wide clinical use, particularly for protecting the brain during cardiac surgery. Resuscitative hypothermia was explored in the 1950s and then lay dormant until the 1980s when it was revived. This change occurred through the discoveries of brain damage mitigating effects after cardiac arrest in dogs, and after forebrain ischemia in rats, of mild (34 degrees C) hypothermia (which is safe), and of benefits derived from moderate hypothermia (30 degrees C) after traumatic brain injury or focal brain ischemia in various species. The idea that protection-preservation or resuscitation by hypothermia is mainly explained by its ability to reduce cerebral oxygen demand has been replaced by an increasingly documented synergism of many beneficial mechanisms. Deleterious chemical cascades during and after these insults are suppressed even by mild hypothermia. Prolonged moderate hypothermia carries some risks, e.g., arrhythmias, infection and coagulopathies. These side effects need further study. In global brain ischemia, protective-preservative mild hypothermia provides lasting mitigation of brain damage. Resuscitative mild hypothermia, however, may be beneficial in terms of long-term outcome or may merely delay the inevitable loss of selectively vulnerable neurons. Even if the latter is true, mild hypothermia may extend the therapeutic window for other interventions. This extension of the therapeutic window requires further documentation. After normothermic cardiac arrest of 11 mins in dogs, mild resuscitative hypothermia from 15 mins to 12 hours after reperfusion plus cerebral blood flow promotion normalized functional recovery with the least histologic damage seen thus far. Optimal duration of, and rewarming methods from, resuscitative hypothermia need clarification. The earliest possible induction of mild hypothermia after cardiac arrest seems desirable. Head-neck surface cooling alone is too slow. Among many clinically feasible rapid cooling methods, carotid cold flush and peritoneal cooling look promising. After traumatic brain injury or focal brain ischemia, which seem to still benefit from even later cooling, surface cooling methods may be adequate. Resuscitative hypothermia after cardiac arrest, traumatic brain injury, or focal brain ischemia should be considered for clinical trials.

Animals↗
PubMed1996

Effects of head down tilt on hemodynamics, fluid volumes, and plasma Na-K pump inhibitor in rats.

BACKGROUND: Hindquarter suspension in rats has been used as a model of simulated weightlessness (SW) for ground based study of the effects of microgravity on the cardiovascular system (CVS). METHODS: Using this rat model of SW we tested the hypothesis that CVS deconditioning following spaceflight results, in part, from a decrease in the circulating concentration of sodium-potassium pump inhibitor (SPI). Control rats similarly prepared were not suspended. RESULTS: During the first hour of suspension, central venous pressure (CVP), blood pressure (BP), heart rate (HR), cardiac output (CO), plasma volume (PV), extracellular fluid volume (ECFV), urine output (UV), atrial natriuretic peptide (ANP), and the plasma level of SPI increased. Plasma renin activity (PRA) and myocardial Na+, K(+)-ATPase activity (NKA) decreased. By the end of 4 h of SW, the changes in CVP, BP, HR, ECFV, and UV persisted, but PV, plasma ANP and SPI, and myocardial NKA activity returned to control levels. By the end of 1 d of SW, ECFV and plasma SPI levels had decreased but the myocardial NKA had not increased. At day 4, CVP and BP were the same as in control sham treated rats. Plasma SPI levels were decreased at day 4 but the myocardial NKA was not different, whereas renal NKA was increased. At day 7, myocardial NKA and renal NKA were increased and vascular smooth muscle cell (VSMC) membrane potentials were hyperpolarized. CONCLUSIONS: These data indicate that prolonged SW causes a decrease in plasma SPI level which, by hyperpolarizing VSMC, may play a role in the CVS deconditioning seen in astronauts following spaceflight.

Animals↗
PubMed1995

Cell cycle regulation of RNA polymerase III transcription.

Inactivation of the TATA-binding protein-containing complex TFIIIB contributes to the mitotic repression of RNA polymerase III transcription, both in frogs and in humans (J. M. Gottesfeld, V. J. Wolf, T. Dang, D. J. Forbes, and P. Hartl, Science 263:81-84, 1994; R. J. White, T. M. Gottlieb, C. S. Downes, and S. P. Jackson, Mol. Cell. Biol. 15:1983-1992, 1995). Using extracts of synchronized proliferating HeLa cells, we show that TFIIIB activity remains low during the early part of G1 phase and increases only gradually as cells approach S phase. As a result, the transcription of all class III genes tested is significantly less active in early G1 than it is in S or G2 phase, both in vitro and in vivo. The increased activity of TFIIIB as cells progress through interphase appears to be due to changes in the TATA-binding protein-associated components of this complex. The data suggest that TFIIIB is an important target for the cell cycle regulation of RNA polymerase III transcription during both mitosis and interphase of actively proliferating HeLa cells.

Cell Cycle↗
PubMed1995

Mitotic regulation of a TATA-binding-protein-containing complex.

The mitotic state is associated with a generalized repression of transcription. We show that mitotic repression of RNA polymerase III transcription can be reproduced by using extracts of synchronized HeLa cells. We have used this system to investigate the molecular basis of transcriptional repression during mitosis. We find a specific decrease in the activity of the TATA-binding-protein (TBP)-containing complex TFIIIB. TBP itself is hyperphosphorylated at mitosis, but this does not appear to account for the loss of TFIIIB activity. Instead, one or more TBP-associated components appear to be regulated. The data suggest that changes in the activity of TBP-associated components contribute to the coordinate repression of gene expression that occurs at mitosis.

Base Sequence↗
PubMed1995

Mitochondria and Na+/Ca2+ exchange buffer glutamate-induced calcium loads in cultured cortical neurons.

Utilizing Indo-1 microfluorimetry, we have investigated the role of mitochondria and Na+/Ca2+ exchange in buffering calcium loads induced by glutamate stimulation or depolarization of cultured rat forebrain neurons. A 15 sec pulse of 3 microM glutamate or 50 mM potassium with veratridine was followed by a 2 min wash with a solution containing either Na(+)-free buffer or the mitochondrial uncoupler carbonyl cyanide p-trifluoromethoxyphenylhydrazone (FCCP), or both. For glutamate-induced Ca2+ loads, a Na(+)-free wash delayed recovery to baseline by twofold, mitochondrial uncoupling delayed recovery by greater than fourfold, and the combined treatment essentially prevented recovery of [Ca2+]i for the duration of the wash. Although the depolarization stimulus was able to elicit a larger peak [Ca2+]i, the neurons required significantly less time to recover from depolarization-induced Ca2+ loads after identical wash manipulations, indicating a fundamental difference between calcium loads induced by glutamate as opposed to those induced by depolarization. We show evidence that the delayed recovery is not primarily the result of perturbations in intracellular pH regulation and have also demonstrated that a substantial portion of the delayed recovery is independent of Ca2+ entry during the washout phase. We conclude that glutamate and depolarization both induce Ca2+ loads whose buffering is critically dependent on functional mitochondria and secondarily reliant on Na+/Ca2+ exchange. The two systems overlap and seem to be responsible for buffering most of the glutamate-induced Ca2+ load, because manipulations that compromised both systems completely disabled the neurons' ability to recover [Ca2+]i to baseline.

Adenosine Triphosphate↗
PubMed1994

Differential regulation of RNA polymerases I, II, and III by the TBP-binding repressor Dr1.

RNA polymerases I, II, and III each use the TATA-binding protein (TBP). Regulators that target this shared factor may therefore provide a means to coordinate the activities of the three nuclear RNA polymerases. The repressor Dr1 binds to TBP and blocks the interaction of TBP with polymerase II- and polymerase III-specific factors. This enables Dr1 to coordinately regulate transcription by RNA polymerases II and III. Under the same conditions, Dr1 does not inhibit polymerase I transcription. By selectively repressing polymerases II and III, Dr1 may shift the physiological balance of transcriptional output in favor of polymerase I.

Base Sequence↗
PubMed1994

The effect of nebulized salbutamol therapy on the incidence of postoperative chest infection in high risk patients.

Patients who smoke heavily and those with pre-existing airflow obstruction are at particular risk of postoperative respiratory infection following upper abdominal surgery. This invariably prolongs hospital stay and increases morbidity. In order to determine whether high dose bronchodilator therapy in the perioperative period reduced the risk of infection, all patients undergoing elective upper abdominal surgery were assessed for risk of developing postoperative infection. Fifty-three patients were identified as high risk according to previously published criteria and were randomly allocated to receive nebulized salbutamol (5 mg) or saline placebo 6 hourly for 48 h beginning 1 h preoperatively. There was no difference in rates of postoperative chest infection in the two groups and this study, therefore, provides no support for the routine preoperative use of bronchodilators in these patients.

Aged↗
PubMed1994

Intracranial suppuration: a modern decade of postoperative subdural empyema and epidural abscess.

A retrospective study of subdural empyema and epidural abscess spanning 11 years and encompassing 41 patients was performed, demonstrating that the clinical characteristics of intracranial suppuration have changed over time. Sinusitis and otitis media, previously the predominant etiologies, were predisposing factors in only 29% of patients. A prior craniotomy had been performed in 66% of cases and was the most common risk factor for abscess development. The postoperative patients were subjected to detailed analysis. Patients who had undergone a prior craniotomy were notable for the following features: older age, lack of fever, evidence of wound infection, frequent false-negative computed tomographic scans, and a high percentage of Gram negative aerobic organisms or skin flora as pathogens. The population at highest risk for abscess development ranged from 50 to 60 years old, older than in previous series. Older age and an advanced degree of encephalopathy were indicative of a poor prognosis. Patients with subdural empyema had a worse prognosis as well. Hyponatremia was a frequent complicating factor. A much greater percentage of Gram-negative aerobic bacteria were isolated than in previous studies. Computed tomographic scans, half of which were performed with intravenous contrast material, were nondiagnostic in 30% of patients. The mortality rate was 18.5%, and delay in treatment correlated with increased risk of poor outcome. All patients were treated with a craniotomy. Repeated operations were required in three patients and were associated with the development of intraparenchymal abscess.

Adolescent↗
PubMed1993

Non-proteoglycan forms of biglycan increase with age in human articular cartilage.

Polyclonal anti-peptide antibodies were raised to the C-terminal regions of human biglycan and decorin. These antibodies were used in immunoblotting to study structural variations with age in the proteoglycan core proteins present in extracts of human articular cartilage and intervertebral disc. Three forms of the biglycan core protein were identified. The largest form was detected only after chondroitinase treatment and represents the proteoglycan form of the molecule from which the glycosaminoglycan chains have been removed. However, chondroitinase treatment did not alter the electrophoretic mobility of the two smaller proteins, which appear to represent non-proteoglycan forms of the molecule, resulting either from a failure to substitute the intact proteoglycan core protein with glycosaminoglycan chains during its synthesis or from proteolytic processing of the intact proteoglycan causing removal of the N-terminal region bearing the glycosaminoglycan chains. The non-proteoglycan forms constituted a minor proportion of biglycan in the newborn, but were the major components in the adult. A similar trend was seen in both articular cartilage and intervertebral disc. In comparison, decorin appears to exist predominantly as a proteoglycan at all ages, with two core protein sizes being present after chondroitinase treatment. Non-proteoglycan forms were detected in the adult, but they were always a minor constituent.

Adolescent↗
PubMed1993

An evaluation of five commercial immunoassay data analysis software systems.

An evaluation of five commercial software systems used for immunoassay data analysis revealed numerous deficiencies. Often, the utility of statistical output was compromised by poor documentation. Several data sets were run through each system using a four-parameter calibration function, and the results were compared to those from an independent method. Comparable results between systems were obtained, but often several attempts at analysis were necessary. The evaluation process revealed that it is difficult to monitor the numerous options available on these types of programs, and that incorrect results could easily be obtained if comparison analyses were not used. Recommendations for improved software functionality and for using the four-parameter calibration model are presented.

Data Interpretation, Statistical↗
PubMed1992

Mechanism of TATA-binding protein recruitment to a TATA-less class III promoter.

The TATA-binding protein (TBP) is required for transcription by RNA polymerase III (pol III), even though many pol III templates, such as the adenovirus VA1 gene, lack a consensus TATA box. We show that TBP alone does not form a stable, productive interaction with VA1 DNA. However, it can be incorporated into an initiation complex if the other class III basal factors, TFIIIB and TFIIIC, are also present. TFIIIB can associate with the evolutionarily conserved C-terminal domain of TBP in the absence of DNA or TFIIIC, suggesting that TFIIIB exists in solution as a complex with TBP. The stable association of TBP with an essential component of the pol III transcription apparatus may account for the ability of TATA-less class III genes to recruit TBP.

Adenoviridae↗