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Biomedical subjects

R H Clark

Publications and source records attributed to R H Clark.

At least 73 records · Page 4Linked to original sources
PubMed1991

Phosphorylation of neuromodulin (GAP-43) by casein kinase II. Identification of phosphorylation sites and regulation by calmodulin.

Neuromodulin (P-57, GAP-43, B-50, F-1) is a neurospecific calmodulin-binding protein believed to play a role in regulation of neurite outgrowth and neuroplasticity. Neuromodulin is phosphorylated by protein kinase C, and this phosphorylation prevents calmodulin from binding to neuromodulin (Alexander, K. A., Cimler, B. M., Meier, K. E. & Storm, D. R. (1987) J. Biol. Chem. 262, 6108-6113). The only other protein kinase known to phosphorylate neuromodulin is casein kinase II (Pisano, M. R., Hegazy, M. G., Reimann, E. M. & Dokas, L. A. (1988) Biochem. Biophys. Res. Commun. 155, 1207-1212). Phosphoamino acid analyses revealed that casein kinase II modified serine and threonine residues in both native bovine and recombinant mouse neuromodulin. Two serines located in the C-terminal end of neuromodulin, Ser-192 and Ser-193, were identified as the major casein kinase II phosphorylation sites. Thr-88, Thr-89, or Thr-95 were identified as minor casein kinase II phosphorylation sites. Phosphorylation by casein kinase II did not affect the ability of neuromodulin to bind to calmodulin-Sepharose. However, calmodulin did inhibit the phosphorylation of neuromodulin by casein kinase II with a Ki of 1-2 microM. Calmodulin inhibition of casein kinase II phosphorylation was due to calmodulin binding to neuromodulin rather than to the protein kinase. These data suggest that the minimal secondary and tertiary structure exhibited by neuromodulin may be sufficient to juxtapose its calmodulin-binding domain, located at the N-terminal end, with the neuromodulin casein kinase II phosphorylation sites at the C-terminal end of the protein. We propose that calmodulin regulates casein kinase II phosphorylation of neuromodulin by binding to neuromodulin and sterically hindering the interaction of casein kinase II with its phosphorylation sites on neuromodulin.

Amino Acid Sequence↗
PubMed1991

High-frequency oscillatory ventilation versus intermittent mandatory ventilation: early hemodynamic effects in the premature baboon with hyaline membrane disease.

We studied the hemodynamic consequences during the first 24 h of life in premature baboons (140 d) with hyaline membrane disease that were treated with high-frequency oscillatory ventilation (HFOV) or conventional intermittent mandatory ventilation (IMV). Cardiac output and organ blood flow were measured at three time-points using the radiolabeled microsphere technique. Seven of seven HFOV and six of eight IMV animals survived the 24-h period. By design, initial mean airway pressure (Paw) was higher in the HFOV group (p less than 0.01). HFOV Paw was progressively reduced during the study period because of improving oxygenation as measured by the arterial to alveolar oxygen ratio. In contrast, it was necessary to increase Paw in the IMV animals to maintain the arterial to alveolar oxygen ratio. By 23 h, the IMV group required higher Paw than the HFOV group (p less than 0.05) and had a lower arterial to alveolar oxygen ratio (p less than 0.05). We found no significant differences in left ventricular output, effective systemic flow, organ blood flow, or central venous pressure between the two groups at 3, 8, or 23 h. The HFOV strategy used in our study resulted in significant improvement in oxygenation during the initial 24 h of treatment without adverse effect on left ventricular output, cerebral blood flow, or central venous pressure. We conclude that when appropriate changes in Paw are made during HFOV in response to improvement in arterial oxygenation and changes in lung inflation as assessed by chest radiographs HFOV can be achieved without depressing cardiovascular dynamics more than during conventional therapy with IMV.

Animals↗
PubMed1991

High-frequency ventilation: issues of strategy.

Although each high-frequency ventilator has functional characteristics that are design related, it now appears that when used with similar treatment strategies and within their functional limitations, similar clinical outcomes can be realized. Optimized treatment protocols must vary depending on the pulmonary disease to be treated, with strategies during treatment for pulmonary injury different from those used in pulmonary injury prevention. It is still unclear whether any one particular high-frequency ventilator will have specific disadvantages that cannot be overcome by device modification and that are inherent in a particular HFV methodology. Experimental and clinical data suggest that HFV will contribute significantly in reducing neonatal pulmonary morbidity and aid in the prevention of chronic pulmonary disease.

Clinical Protocols↗
PubMed1990

High-frequency oscillatory ventilation and extracorporeal membrane oxygenation for the treatment of acute neonatal respiratory failure.

Forty-six (92%) outborn and four (8%) inborn term or near-term neonates were admitted for extracorporeal membrane oxygenation (ECMO) treatment to a neonatal intensive care unit between July 1, 1985, and November 1, 1987. All infants had PAO2-PaO2 greater than or equal to 600 mm Hg in spite of aggressive conventional ventilatory and pharmacologic therapy. All patients were offered rescue treatment with high-frequency oscillatory ventilation (HFOV), and only if there was no improvement in PAO2-PaO2 with HFOV were infants treated using ECMO. Four patients died before receiving an adequate trial of HFOV and before emergency ECMO support could be initiated; 21 patients, all of whom survived to hospital discharge, responded to HFOV; 25 patients ultimately required ECMO therapy for cardiopulmonary support, with 22 (88%) surviving to discharge. Neonates responding to HFOV were of slightly younger gestational age (38 +/- 2 weeks vs 40 +/- 2 weeks, mean +/- SD; P less than .001) and more frequently had clinical evidence of pneumonia (11 of 21 vs 2 of 25; P less than .002). There was no statistically significant difference in outcome with respect to the number of ventilator days, hospital days, or survival between patients responding to HFOV and patients who required ECMO. Morbidity was increased in ECMO patients, with bleeding abnormalities, seizures, and renal failure occurring more frequently than in HFOV-treated infants. Overall, 92% (46 of 50) of the patients were treated with a staged protocol using HFOV before ECMO. A total of 46% (21 of 46) responded to HFOV treatment alone and did not require ECMO therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Extracorporeal Membrane Oxygenation↗
PubMed1989

A phase II trial of intermittent leukocyte interferon and high dose chlorambucil in the treatment of non-Hodgkin's lymphoma resistant to conventional therapy.

Thirteen patients with advanced non-Hodgkin's lymphoma who previously failed conventional chemotherapy protocols were treated with a combination of alpha-interferon (IFN) 6,000,000 units i.m. days 1-5 and 8, plus chlorambucil (CLB) 16 mg/m2 days 5-9 repeated every 4 weeks. There were five complete responses (CRs) and one partial response (PR) (46% total responses) with mean duration of remission of 456+ days. Responses were obtained in low and intermediate grade lymphomas. Toxicity was acceptable and easily managed. It is unlikely that IFN alone using this low dose intermittent schedule is responsible for the remissions. The combination of the two agents appears to be an effective treatment modality. IFN may be functioning as a biological response modifier when used in combination with a cytotoxic agent.

Adult↗
PubMed1989

Role of lung injury in the pathogenesis of hyaline membrane disease in premature baboons.

To test the hypothesis that hyaline membrane disease (HMD) has a multifactorial etiology in which barotrauma plays a major role, we compared the immediate institution of high-frequency oscillatory ventilation (HFOV; 15 Hz, n = 5) with positive-pressure ventilation with positive end-expiratory pressure (PPV; n = 7) in premature baboons (140-days gestation) with HMD. Measurements of ventilation settings and physiological parameters were obtained and arterial-to-alveolar O2 (PaO2-to-PAO2) ratio and oxygenation index [(PaO2/PAO2)-to-mean airway pressure ratio (IO2)] were calculated. At death (24 h), static pressure-volume (PV) curves were performed, and phospholipids (PL) and platelet-activating factor (PAF) were measured in lung lavage fluid. Morphological inflation patterns were analyzed using a panel of standards. By design, mean airway pressure was initially higher (19 vs. 13 cmH2O) in the HFOV animals. PaO2-to-PAO2 ratio and IO2 progressively deteriorated in the PPV animals and then stabilized at significantly lower levels than with HFOV. PV curves from HFOV animals had significant increases in lung volume at maximum distending pressure, deflation volume at 10 cmH2O, and hysteresis area compared with PPV, which showed no hysteresis. Seven of seven PPV and only one of five HFOV animals had morphological findings of HMD. PL amount and composition in both groups were consistent with immaturity, even though the quantity was significantly greater in the PPV group. PAF was present (greater than or equal to 0.10 pmol) in six of seven PPV and in the only HFOV animal with HMD. We conclude that HFOV protected PL-deficient premature baboons from changes in gas exchange, lung mechanics, and morphology typical of HMD in this model.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Influence of ventilatory technique on pulmonary baroinjury in baboons with hyaline membrane disease.

To assess the influence of ventilatory technique on pulmonary baroinjury in experimental hyaline membrane disease, we randomized 24 premature baboons to six treatment groups according to ventilator (PPV, positive pressure ventilator; HFO, high frequency oscillator; HFI, high frequency flow interrupter) and O2 therapy FIO2 as clinically indicated, or FIO2 1.0). PaCO2 was adjusted by varying pressure amplitude, and for PPV, also by rate (less than 60/min). HFO and HFI were set at a frequency of 10 Hz. Animals were cared for with standard NICU techniques until death or sacrifice at 11 days. One animal died at delivery and was excluded from data analysis. There were no intergroup differences in Paw, Pa/AO2, PaCO2 or oxygenation index (IO2 = [Pa/AO2]/Paw) prior to death of the first study animal at 13 h. Animals who subsequently developed airleak had higher Paw, lower Pa/AO2 and lower IO2 during this period. The degree of airleak was significantly less with HFO compared to PPV or HFI. The effect of O2 exposure did not appear different with respect to the degree of airleak or the frequency of severe tracheal injury, although survival was shortened. Severe tracheal injury was more frequent with HFI compared to PPV or HFO. BPD was found only in 100% O2 exposed animals surviving greater than 1 wk. Management of premature baboons with HFO and appropriate O2 resulted in less severe airleak, 100% survival, and no evidence of severe tracheal injury or BPD. These outcomes were not achieved with clinically similar strategies using PPV or HFI.

Animals↗
PubMed1988

Tracheal and bronchial injury in high-frequency oscillatory ventilation and high-frequency flow interruption compared with conventional positive-pressure ventilation.

We compared the histopathologic changes in the airways of premature baboons treated with conventional positive-pressure ventilation (PPV) with those seen after high-frequency oscillatory ventilation (HFOV) and high-frequency flow interruption (HFFI). Twenty-six animals were treated with ventilation for 24 hours (five PPV, 10 HFOV, 11 HFFI), and 18 were treated with ventilation for 96 hours (six PPV, six HFOV, six HFFI). A semiquantitative scoring system was used to grade tissue changes in the trachea, carina, and both main-stem bronchi. Alterations were produced by all forms of mechanical ventilation. The degree of injury was similar and relatively mild for the PPV- and HFOV-treated animals at both 24 and 96 hours. Eleven of 17 baboons treated with HFFI ventilation (8/11 at 24 hours; 3/6 at 96 hours) had severe airway damage characterized by diffuse submucosal necrosis, extensive hemorrhage, dense polymorphonuclear leukocyte infiltration, sloughed epithelium, focal basophilia, and intraluminal debris. HFOV resulted in no greater degree of airway damage than did PPV. The use of HFFI, with the particular strategy we employed, resulted in a far greater degree of damage than either PPV (P less than 0.01) or HFOV.

Animals↗
PubMed1987

Immunologic studies of subjects with asthma exposed to formaldehyde and urea-formaldehyde foam insulation (UFFI) off products.

There has been concern in recent years as to the health hazards of exposure to potentially carcinogenic or immunotoxic substances in the environment. This study was done to determine the effects of exposure to urea-formaldehyde foam insulation (UFFI) off products on various hematologic and immunologic parameters in subjects with asthma: complete blood count and differential, erythrocyte sedimentation rate, lymphocyte subpopulations (E-rosetting, T3, T4, T8, B73.1, and Fc receptor positive lymphocytes and large granular lymphocytes), lymphocyte response to phytohemagglutinin and formalin-treated red blood cells (Form-RBC), serum antibody against the Thomsen-Friedenreich RBC antigen and against Form-RBC, and natural killer (NK), interferon (IFN)-boosted NK (IFN-NK), and antibody-dependent cell-mediated cytotoxicity. Four control subjects with asthma from conventionally insulated homes (control group) and 23 subjects with asthma from UFFI-insulated homes (home group) were exposed to placebo, formaldehyde, dust, and UFFI off gas at levels ordinarily found in UFFI-containing homes for four separate periods in an environmental chamber. Immunologic testing was carried out before the exposure series and 1 day after completion 7 days later as part of an investigation of respiratory and possible allergic effects of such exposure. Data from the UFFI-insulated home group were not significantly different from data of the normal conventionally insulated home control group for any of the variables studied, either before or after UFFI exposure. Paired t tests comparing data from each of the two groups before and after UFFI exposure demonstrated minimal but statistically significant increases in percent eosinophils and T8 positive cells in the UFFI-insulated home group only. Although NK, relative NK, and IFN-NK were normal in all groups, IFN-NK assays by use of a low concentration of alpha-interferon demonstrated a statistically significant decrease in NK response to IFN in both the control and UFFI-insulated home groups after UFFI exposure. These differences were not observed at optimum levels of IFN stimulation. These data indicate that long-term exposure to UFFI off products in the home apparently had no effect on the immunologic parameters studied. Short-term exposure resulted in minor immunologic changes in this subject population.

Antibody Formation↗
PubMed1987

Tracheal and bronchial injury in high-frequency oscillatory ventilation compared with conventional positive pressure ventilation.

We compared airway histopathologic findings in premature baboons given standard positive pressure ventilation with those seen after high-frequency oscillatory ventilation. Six animals received standard frequency conventional ventilation for a mean of 9.2 days; seven received high-frequency oscillatory ventilation at 10 Hz using a piston oscillator for a mean of 10.2 days; five baboons served as controls, and were killed immediately after birth. A semiquantitative histopathologic scoring system was used to grade tissue changes in the trachea, carina, and both mainstem bronchi. Compared with the nonventilated control animals, injury was produced with both forms of mechanical ventilation (P less than 0.01 for both instruments); however, the degree of damage was mild, with no significant difference in the extent of injury between the two treatment groups. High-frequency oscillatory ventilation appears to result in no greater degree of airway damage than conventional positive pressure ventilation.

Animals↗
PubMed1987

cis-platinum, 5-fluorouracil, and hydroxyurea in the treatment of advanced non-small-cell lung cancer. A phase II study.

Sixteen patients with advanced non-small-cell lung cancer were treated with the combination of cis-platinum, 5-fluorouracil, and hydroxyurea. There were two complete responses (lasting 16 weeks each) and one partial response (lasting 12 weeks). Toxicity was manageable, but responders were unable to tolerate further therapy. Despite the obtaining of complete responses, the overall benefit of this particular combination requires further clinical investigation.

Adenocarcinoma↗
PubMed1987

Extracorporeal membrane oxygenation and high-frequency oscillatory ventilation: potential therapeutic relationships.

Eighteen neonates 33 to 42 wk gestational age with severe respiratory failure were referred for extracorporeal membrane oxygenation (ECMO). Sixteen ultimately met the ECMO criteria, of whom 15 were first offered high-frequency oscillatory ventilation (HFOV). Seven responded to HFOV alone and did not require ECMO treatment. Eight of the nine remaining patients were placed on ECMO support with HOFV. Infants who responded to HFOV alone tended to have pneumonia more than meconium aspiration, to be smaller and more immature, to have higher Apgar scores, and to have suffered severe hypoxia (alveolar-arterial oxygen pressure difference over 600 torr) for less time than the ECMO group. Although patient numbers are small, a trend is noted which favors HFOV treatment alone in terms of the duration of HFOV, the total duration of assisted ventilation, the rapidity with which extubation was accomplished, and the length of hospital stay.

Birth Weight↗
PubMed1986

Pulmonary interstitial emphysema treated by high-frequency oscillatory ventilation.

Twenty-seven low birth weight infants who developed pulmonary interstitial emphysema (PIE) and respiratory failure while on conventional ventilation were treated with high-frequency oscillatory ventilation (HFOV). The mean birth weight was 1.2 kg (range 0.55 to 2) with gestational age of 28 wk (range 25 to 34). Ten patients died, six of whom had documented sepsis with shock and were therefore excluded from analysis. All patients showed initial improvement on HFOV. Surviving patients showed continued improvement in oxygenation and ventilation at increasingly lower fraction of inspired oxygen and proximal airway pressure with resolution of PIE, while nonsurvivors progressively developed chronic respiratory insufficiency with continued PIE from which recovery was not possible. Overall survival in nonseptic patients was 80% (16 of 20). We found HFOV to be effective in the treatment of PIE and hypothesize that interstitial airleak is decreased during HFOV because adequate ventilation is provided at lower peak distal airway pressures.

Critical Care↗
PubMed1984

Respiratory response to formaldehyde and off-gas of urea formaldehyde foam insulation.

In 18 subjects, 9 of whom had previously complained of various nonrespiratory adverse effects from the urea formaldehyde foam insulation (UFFI) in their homes, pulmonary function was assessed before and after exposure in a laboratory. On separate occasions formaldehyde, 1 part per million (ppm), and UFFI off-gas yielding a formaldehyde concentration of 1.2 ppm, were delivered to each subject in an environmental chamber for 90 minutes and a fume hood for 30 minutes respectively. None of the measures of pulmonary function used (forced vital capacity, forced expiratory volume in 1 second or maximal midexpiratory flow rate) showed any clinically or statistically significant response to the exposure either immediately after or 8 hours after its beginning. There were no statistically significant differences between the responses of the group that had previously complained of adverse effects and of the group that had not. There was no evidence that either formaldehyde or UFFI off-gas operates as a lower airway allergen or important bronchospastic irritant in this heterogeneous population.

Allergens↗
PubMed1984

Leukocyte interferon as a possible biological response modifier in lymphoproliferative disorders resistant to standard therapy.

In vitro and in vivo studies utilizing a combination of leukocyte interferon-alpha (IFN) and chlorambucil (CLB) were done to investigate possible synergism between a biological response modifier and a chemotherapy drug. In vitro studies utilized a human myeloid leukemia cell line (K-562) pretreated with IFN and then exposed to CLB. The combination resulted in significant depression of cell growth compared with use of IFN or CLB alone. In vivo studies involved eight heavily pretreated patients given 6 million units IFN for 5 days followed by oral CLB (16 mg/m2) for 5 days repeated every 4 weeks. Three myeloma patients had reduction in immunoglobulins and experienced clinical responses. Three of four patients with Hodgkin's disease responded after relatively short periods of treatment. One patient with a diffuse lymphocytic lymphoma had a complete unmaintained remission lasting 6 months. Toxicity was minimal, with mild fever, nausea, and vomiting. These preliminary studies suggest that IFN may be a biological response modifier when used in combination with a cytotoxic agent.

Adult↗
PubMed1984

Congenital juvenile chronic myelogenous leukemia: case report and review.

The case of a patient with ecchymosis, hepatomegaly, leukocytosis, thrombocytopenia, and anemia at birth is presented. Throughout his course, thrombocytopenia, anemia, and leukocytosis without a marked increase in the number of blast forms in either peripheral blood or bone marrow persisted until the patient developed a blast crisis shortly before his death at age 4 months. This patient is the youngest reported to have the juvenile form of chronic myelogenous leukemia and the first that in the present era can be considered congenital in origin.

Diagnosis, Differential↗