Treatment of spontaneous pneumothorax: the clinician's perspective on pneumothorax management.
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Algorithms↗
Biomedical subjects
A C Miller
Publications and source records attributed to A C Miller.
Active management of labor: does it make a difference?
OBJECTIVE: Our goal was to evaluate whether active management of labor lowers cesarean section rates, shortens the length of labor, and overcomes any negative effects of epidural analgesia on nulliparous labor. STUDY DESIGN: We randomly assigned 405 low-risk term nulliparous patients to either an active management of labor (n = 200) or our usual care control protocol (n = 205). Patients who were undergoing active management of labor were diagnosed as being in labor on the basis of having painful palpable contractions accompanied by 80% cervical effacement, underwent early amniotomy, and were treated with high-dose oxytocin for failure to progress adequately in labor. RESULTS: The cesarean section rate in the active management of labor group was lower than that of controls but not significantly so (active management, 7.5%; controls, 11.7%; p = 0.36). The length of labor in the active management group was shortened by 1.7 hours (from 11.4 to 9.7 hours, p = 0.001). Fifty-five percent of patients received epidural analgesics; a reduction in length of labor persisted despite the use of epidural analgesics (active management 11.2 hours vs control 13.3 hours, p = 0.001). A significantly greater proportion of active management patients were delivered by 12 hours compared with controls (75% vs 58%, p = 0.01); this difference also persisted despite the use of epidural analgesics (66% vs 51%, p = 0.03). CONCLUSIONS: Patients undergoing active management had shortened labors and were more likely to be delivered within 12 hours, differences that persisted despite the use of epidural analgesics. There was a trend toward a reduced rate of cesarean section.
Adolescent↗
The effects of epidural analgesia on uterine activity and labor.
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Journal Article↗
Modulation of radiation response of human tumour cells by the differentiation inducers, phenylacetate and phenylbutyrate.
The aromatic fatty acids phenylacetate (PA) and phenylbutyrate (PB) are novel antitumour agents currently under clinical evaluation. Their ability to induce tumour differentiation in laboratory models and their low clinical toxicity profile makes them promising candidates for combination with conventional therapies. In the present studies, we characterized the interactions between these aromatic fatty acids and radiation, using as a model cell lines derived from cancers of the prostate, breast, brain and colon. Analysis of the radiation response of the tumour lines using the linear-quadratic model, demonstrated that cellular exposure to pharmacological, non-toxic concentrations of either PA or PB resulted in time-dependent and contrasting changes in radiation response. While drug pretreatment for 24 h reduced radiation sensitivity (significant alterations in both alpha and beta parameters), pre treatment for 72 h significantly increased radiosensitivity (significant alterations in alpha and beta parameters). In replicating tumour cells, these changes were accompanied by a gradual G1-phase arrest. Cytostasis alone, however, could not explain radiosensitization, as similar alterations in radiation response were documented also in non-cycling cells. Modulation of tumour radiobiology by PA and PB was tightly correlated with early rise followed by decline in intracellular glutathione levels and the activity of antioxidant enzymes such as catalase, superoxide dismutase, glutathione reductase, glutathione peroxidase and glutathione S-transferase. Although in vitro findings identify the aromatic fatty acids PA and PB as a new class of non-toxic modulators of radiation response, the antagonistic effect of these compounds on radiation response needs further examination. Our data strongly suggest that for PA or PB to have a role in clinical radiotherapy, appropriate scheduling of combination therapies must take into account their time-dependent effects in order to achieve clinical radiosensitization.
Antimetabolites, Antineoplastic↗
Pain, anxiety, and cooperativeness in children with cerebral palsy after rhizotomy: changes throughout rehabilitation.
Assessed pain, anxiety, physical functioning, and cooperativeness in 32 children with spastic cerebral palsy. This is the first study to assess children throughout rehabilitation following selective posterior rhizotomy. Results of the Observational Scale of Behavioral Distress and observer Likert ratings confirmed the hypothesis that children's pain and anxiety decrease over time. Children's physical functioning and cooperativeness improve over time. No significant correlation was found between pain and changes in physical functioning. Cognitive impairment, parental involvement, and children's pain behaviors explained 77% and 56% of the variance in two forms of cooperativeness. Research and clinical implications are discussed, and special considerations regarding pain assessment and management in this population are addressed.
Adaptation, Psychological↗
To everything turn, turn, turn.... An overview of continuous lateral rotational therapy.
Continuous lateral rotational therapy can be a significant adjunct in the care of the critically ill patient. CLRT has a great impact on both patient outcomes as well as cost containment in the care of the critically ill. These systems should be used with clear guidelines to determine when CLRT is indicated, its therapeutic benefit, and when to discontinue the therapy. Much research is needed to validate efficacy of particular systems, cost-effectiveness, and necessary frequency and degree of rotation to attain optimal clinical benefits.
Critical Illness↗
Tumor radiosensitization based on the use of inhibitors of the mevalonate pathway of cholesterol synthesis.
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Adenocarcinoma↗
Transcriptional upregulation of gamma-globin by phenylbutyrate and analogous aromatic fatty acids.
Phenylbutyrate has been shown recently to induce fetal hemoglobin (HbF) production in patients with sickle cell anemia and beta thalassemia. We have now examined related aromatic fatty acids in order to define the range of active structures and identify plausible mechanisms of action. Structure-function analysis revealed that for effective stimulation of HbF in erythroid precursors: (1) the ideal length for the aliphatic side chain is four carbons; (2) oxygen or sulfur substitutions in the carboxylic chain are allowed, as evidenced by the equal or increased activity of phenoxypropionate, benzylthioglycolate, and benzyloxyacetate compared with phenylbutyrate; and (3) blocking the carboxylate group by conversion to the amide form greatly reduces potency. Molecular analysis indicated that the prototype agent, phenylbutyrate, increases HbF production through transcriptional activation of the gamma-globin gene. The latter contains a butyrate responsive promoter known to up-regulate transcription in the presence of short-chain fatty acids of three to five carbons. To determine whether stimulation of an element in this promoter by phenylbutyrate and its analogues might contribute to their mechanism of action, we used a transient expression system involving K562 erythroleukemia cells transfected with a luciferase reporter gene driven by the minimum gamma-globin promoter. Transcriptional activation in this experimental system correlated well with the capacity of an aromatic fatty acid to increase HbF production in erythroid precursors (r = 0.94). Our studies identify potent analogues of phenylbutyrate for the treatment of beta-chain hemoglobinopathies, and suggest that stimulation of a butyrate responsive promoter may be responsible for their activity.
Cells, Cultured↗
Cytoskeletal architecture in mouse lung epithelial cells is regulated by protein-kinase C-alpha and calpain II.
Brief exposure to 12-O-tetradecanoylphorbol 13-acetate (TPA) caused a uniformly flattened population of mouse lung epithelial cells to become more heterogeneous; some cells rounded up, and others detached to overlap with flatter cells. Actin stress fiber organization was disrupted, and F-actin accumulated in lemellipodia. Vinculin dissociated from the focal adhesion plaques to diffuse throughout the cytoplasm. Inhibition of protein kinase C (PKC) activity blocked these effects of TPA. After 8 h of TPA exposure, actin filaments reassembled and vinculin again localized to the cell periphery. Calpain inhibition attenuated the decrease of PKC-alpha protein and PKC activity from the membrane fraction, and prevented the redistribution of cytoskeletal elements. Talin immunostaining was widespread throughout control cells but was localized to the periphery 8 h after treatment with TPA or with inhibitors of PKC and calpain. Both vinculin and talin concentrations increased with prolonged TPA treatment. PKC-zeta and calpain II were not appreciably affected by TPA exposure. Translocation of PKC-alpha to the membrane, followed by its calpain-induced downmodulation, is apparently required for the reversible pattern of cytoskeletal changes caused by TPA.
Animals↗
Management of spontaneous pneumothorax: back to the future.
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Diagnosis, Differential↗
Arterial blood gas analysis in the assessment of suspected acute pulmonary embolism.
PURPOSE: The utility of arterial blood gas levels in excluding the diagnosis of acute pulmonary embolism (PE) was evaluated. METHODS: Data are from the Prospective Investigation of Pulmonary Embolism Diagnosis (PIOPED). PE was diagnosed or excluded by pulmonary angiography. Among 330 patients with no prior cardiopulmonary disease, 130 patients had PE and 200 did not. Among 438 patients with prior cardiopulmonary disease, 147 had PE and 291 did not. Definitions were low PaO2 (< 80 mm Hg), low PaCO2 (< 35 mm Hg), and high alveolar-arterial oxygen gradient (P(A-a)O2 [> 20 mm Hg]). RESULTS: Among patients with no prior cardiopulmonary disease who had values of the PaO2 and PaCO2 that were not low and a P(A-a)O2 that was normal, 16 of 42 or 38% (95% confidence interval [CI] = 24 to 54%) had PE. Among patients with prior cardiopulmonary disease who had PaO2 and PaCO2 values that were not low and a P(A-a)O2 that was normal, 4 of 28 or 14% (95% CI = 4 to 33%) had PE. Other combinations of blood gas levels and the P(A-a)O2 gradient, failed to exclude PE in larger percentages of patients. CONCLUSION: With various combinations of the PaO2 of 80 mm Hg or more, the PaCO2 of 35 mm Hg or higher, and the P(A-a)O2 gradient of 20 mm Hg or less, PE could not be excluded in more than 30% of patients with no prior cardiopulmonary disease and PE could not be excluded in more than 14% of patients with prior cardiopulmonary disease. Blood gas levels, therefore, are of insufficient discriminant value to permit exclusion of the diagnosis of PE.
Acute Disease↗
Increased susceptibility of ras-transformed cells to phenylacetate is associated with inhibition of p21ras isoprenylation and phenotypic reversion.
Alterations in the expression of ras oncogenes are characteristic of a wide variety of human neoplasms. Accumulating evidence has linked elevated ras expression with disease progression and with failure of tumors to respond to conventional therapies, including radiotherapy and certain chemotherapies. These observations led us to investigate the response of ras-transformed cells to the differentiation-inducer phenylacetate (PA). Using gene transfer models, we show that PA caused cytostasis in ras-transformed mesenchymal cells, associated with increased expression of 2',5'-oligoadenylate synthetase, an enzyme implicated in negative growth control. PA also induced phenotypic reversion characterized by loss of anchorage-independent growth, reduced invasiveness and increased expression of collagen alpha type I, a marker of cell differentiation. The anti-tumor activity of PA was observed in cases involving either Ha- or Ki-ras and was independent of the mode of oncogene activation. Interestingly, in contrast to their relative resistance to radiation and doxorubicin, ras-transformed cells were significantly more sensitive to PA than their parental cells. The profound changes in tumor cell and molecular biology were associated with reduced isoprenylation of the ras-encoded p21. Our results indicate that PA can suppress the growth of ras-transformed cells, resistant otherwise to free-radical based therapies, through interference with p21ras isoprenylation, critical to signal transduction and maintenance of the malignant phenotype.
3T3 Cells↗
Very early changes in pulmonary protein kinase C-alpha and calpain II contents following injection of butylated hydroxytoluene (BHT) into mice.
Butylated hydroxytoluene (BHT)-induced lung damage in mice is an excellent model system for studying mechanisms of chemically-induced, reversible alveolar injury. Changes in the pulmonary contents of protein kinase C (PKC) and the calcium-dependent protease, calpain, were previously noted during the repair phase following BHT-induced pneumotoxicity. Calpain is believed to initiate PKC down-regulation. PKC-alpha is the major PKC isozyme and calpain II the major calpain isozyme in mouse lung. We have now studied the time course of these enzymatic changes in detail. Pulmonary PKC-alpha concentrations decreased as early as 45 min after an i.p. injection of 200 mg/kg BHT. Calpain II levels rose within the first 40 min after BHT injection, and then declined below control levels. The rapidity of these changes implies a role of these enzymes in mediating the onset of injury. Lung damage and repair, as estimated by measuring the lung weight/body weight ratio, is maximal 6 days after administration of this dose of BHT. The extent of the decreased PKC-alpha and calpain II concentrations at this time was linearly related to the estimated degree of injury based on increased lung weight. This correlation suggests the value of monitoring these enzymes as putative early biomarkers of alveolar injury.
Animals↗
Tumor resistance to oxidative stress: association with ras oncogene expression and reversal by lovastatin, an inhibitor of p21ras isoprenylation.
The ras oncogene family has been implicated in tumor resistance to ionizing radiotherapy. Using the gene-transfer model, we show here that ras expression may also affect cell responses to chemical inducers of oxidative stress. Studies involving human osteosarcoma subclones, which vary in their levels of EJras expression, revealed a tight correlation between the amounts of ras-encoded mRNA and p21 produced, and the degree of resistance to doxorubicin or hydrogen peroxide. Differences in response could not be explained by increased activity of anti-oxidant enzymes such as superoxide dismutase, glutathione reductase, glutathione S-transferase or glutathione peroxidase. Moreover, there were no significant differences in glutathione levels. Although the resistant cells had elevated levels of gamma-glutamyl-transferase mRNA indicative of an increased rate of glutathione turnover, this elevation was not specific for ras-transfected cell lines. Lovastatin, an inhibitor of protein isoprenylation critical for p21ras membrane association and function, restored the sensitivity of ras-transformed cells to doxorubicin and hydrogen peroxide. The data indicate that pharmacological agents affecting ras expression may enhance responses of some human tumors to free-radical-mediated chemotherapies.
Doxorubicin↗
Transcriptional upregulation of TGF-alpha by phenylacetate and phenylbutyrate is associated with differentiation of human melanoma cells.
The aromatic fatty acids phenylacetate (PA) and phenylbutyrate (PB) induce tumour cell differentiation in experimental models and both are currently in clinical trials. The purpose of this study was to determine the effect of these antitumour agents on the expression of transforming growth factor-alpha (TGF-alpha) in neoplastic cells. Treatment of human melanoma 1011 cultures with either PA or PB caused over 40-fold increase in TGF-alpha biosynthesis and secretion into the media. Whereas elevation in TGF-alpha mRNA steady-state levels became evident within 6-12 h and reached peak quantities the following day, the amounts of its coded protein increased gradually over a period of 5 days of treatment. Further molecular analysis revealed that regulation of TGF-alpha expression occurred at the transcriptional level. In contrast to TGF-alpha, expression of its receptor remained below detectable levels, indicating that an autocrine loop involving this growth factor is unlikely. Interestingly, the increase in TGF-alpha production paralleled drug-induced cytostasis and differentiation defined by morphological changes and increased melanogenesis. Like PA and PB, other differentiation inducers such as all-trans-retinoic acid, dimethyl sulfoxide, and 5-aza-2'-deoxycytidine, all induced TGF-alpha expression in the melanoma cells. The close association between enhanced TGF-alpha production and melanoma cell differentiation suggests that this growth factor, often linked to mitogenesis, may play a novel role in tumour differentiation by PA and PB.
Antineoplastic Agents↗
Brain mRNA from infants of aluminium-exposed lactating rabbits.
The neurotoxicity of aluminium (Al) involves bundling of neurofilaments, increased chromatin binding and decreased protein synthesis in Al injected rabbits. Thus, using an amphipathic Al ligand, maltol, experiments were carried out to examine whether or not administration of Al to lactating mother rabbits reduces brain protein synthesis in their offspring. Lactating mother rabbits received s.c. injections 3 times weekly of aluminium (Al) maltolate (1 mg Al/kg body wt) or an equivalent weight of maltol, for 4 weeks post-partum. Polysome preparations were obtained from the brain of their infants in order to assess mRNA translation in cell-free protein synthesizing systems. The brain polysomes showed a statistically significant reduction in the incorporation of [14C]leucine into protein. The poly (A)+ and poly (A)- fractions obtained from these polysomes showed reductions of 44% or more in the incorporation of [35S]methionine into protein. A variety of products separated by SDS-polyacrylamide gel electrophoresis all exhibited decreased labelling. These experiments suggest that infant rabbits exposed to a highly neurotoxic form of Al in milk exhibit changes in brain protein synthesis which resemble those in infants injected directly with Al.
Aluminum Compounds↗
Acute spinal cord injury and neurogenic shock in pregnancy.
A case of a pregnant woman with a subluxation of C-6 on C-7 with acute quadriplegia and sensory loss to the T-10 dermatome is described. Hemodynamic and fetal monitoring during the 3-week period of neurogenic shock resulted in good maternal and fetal outcomes. Pulmonary complications and anesthetic issues are important aspects of the care of these critically ill patients. Major trauma is a common cause of death and disability in young adults and may contribute to as much as 15 percent of nonobstetric maternal deaths. Spinal cord injuries involve young women in 15 percent of cases. The literature is replete with information on the obstetric management of patients with preexisting spinal cord injury (1-4) but there is little on the management and special problems of the pregnant patient with acute spinal cord trauma. We report here the management of a case of acute cord transection accompanied by spinal shock and discuss the specific maternal as well as fetal considerations in this syndrome.
Acute Disease↗
Strain-related differences in the pneumotoxic effects of chronically administered butylated hydroxytoluene on protein kinase C and calpain.
BALB/cBy (BALB) and CXB H mice responded similarly to a single intraperitoneal injection of butylated hydroxytoluene (BHT). This transient pneumotoxicity was characterized by an elevated lung weight and alveolar damage. These changes were accompanied by alterations in the calcium second messenger pathway, namely, two- to five-fold decreases in the activities and pulmonary content of protein kinase C alpha (PKC alpha) and calcium-dependent protease isozyme II (calpain II). BALB and CXB H mice varied in their responsiveness to a chronic (4-6 weekly injections) BHT regimen. CXB H mice became tolerant to BHT and all of the above parameters had returned to control values when examined after the last injection. Chronic BHT administration also failed to enhance lung tumor multiplicity in CXB H mice when the first BHT injection was preceded by the carcinogen, urethane. In contrast, the additional BHT doses potentiated the pathological and biochemical alterations in BALB mice above that found with acute treatment. This included a chronic inflammatory response characterized by the presence of activated macrophages, and a lung tumor multiplicity that was 3-fold greater than in BALB mice receiving urethane alone. One BHT injection increased calpain II mRNA in both strains (1.5- to 3-fold); mRNA declined following multiple BHT injections in BALB mice, but remained elevated in CXB H mice. Studies with the cytochrome P450 inhibitor, piperonyl butoxide, indicated that metabolism of BHT was required for both its acute and chronic effects. We conclude the following: (i) Differences between inbred mice in their susceptibility to chronic pneumotoxicant exposure may exist even when they respond similarly to an acute exposure of the same agent; (ii) A chronic inflammatory state involving a high concentration of activated macrophages may play an important role in tumor enhancement by a non-carcinogen; (iii) The protein contents of PKC alpha and calpain II decrease during BHT-induced lung damage.
Animals↗