Mesothelioma: Drug treatment and other interventions.

Malignant mesothelioma was reported to be a tumor of the pleura for which there is no satisfactory treatment. It was also reported to be almost universally fatal, regardless of the stage of the tumor at the time of diagnosis. Due to the dismal prognosis for patients with this malignant disease, a new mode of treatment is desperately needed. Current drugs and other interventional modalities which include surgery, chemotherapy and radiation therapy are discussed below. However, in some patients none of these modalities are superior to absence of treatment. Discussed within this article are single agent and combined chemomodality therapy studies, target ligands, radiation-sensitizing and antiviral agents, multimodality and gene therapy, and chemoresistance.

Glioma: Novel considerations and treatment modalities.

Glioma tumors often evade traditional cancer treatments and quickly invade healthy brain tissue. Current clinical perspective focuses on the invasiveness of glioma cells which follow distinct anatomic structures within the central nervous system. Advances in magnetic resonance imaging have made it the procedure of choice for identifying brainstem gliomas and classifying them anatomically. Etiologic considerations include adhesion, migration, invasiveness, cell proliferation, angiogenesis and neurotoxin release. This review examines various novel interventions used in treating these deadly growths to prolong life. Recent interventional studies, detecting the cancer's unique characteristics, include the mechanisms that help it survive and spread throughout the brain. Current therapies include those that target glioma cells only, limit the spread of the cancer or block molecules which sustain the tumor. A variety of specific agents, general chemotherapy, radiotherapy and surgery are discussed.

Acute tumor lysis syndrome: considerations of cause and prevention.

The need for better chemotherapeutic interventional modalities with adjunctive biotherapy and/or immunotherapy to confront oncologic disease processes will continue into the new millennium. Unfortunately, existing problems encountered as a consequence to chemotherapy centering on acute tumor lysis syndrome (ATLS) will also continue. ATLS results when cytotoxic agents lyse, or lacerate, outer plasma membranes of numerous cancerous cells. Eventually, their contents spill into the bloodstream, indirectly causing kidney damage. This article reviews the induction of ATLS caused by cytotoxic agents and its prevention and/or control. The association of ATLS with the administration of chemotherapeutic agents must be considered when treating various types of cancer.

Disseminated intravascular coagulation: diagnosis, treatment and related pathophysiology.

This review presents a current evaluation of disseminated intravascular coagulopathy from approaches involving clinical and differential diagnosis, pharmacological treatment, biological markers, disease effects on various organs, risk factors and related pathophysiological conditions. While the optimal regimens for treatment with blood components and the absolute indications for anticoagulant and antifibrinolytic treatments are unknown, various studies are discussed which offer promising new drugs for the present and the future. Associations between this disease and other pathophysiologies are presented which provoke new perspective and insight into disease occurrence and progression.

Multiple linear regression analysis of blood pressure, hypertrophy, calcium and cadmium in hypertensive and non-hypertensive states.

High blood pressure causes heart disease and remains a major public health issue. This paper expands mathematically and mechanically on environmental heavy metal exposure and heart disease. In rabbits, mean blood pressure was measured by direct puncture of the middle ear artery. Measurements of calcium and cadmium levels were made by flame atomic absorption spectrophotometry in tissue from hypertensive and non-hypertensive rabbits. Relationships between blood pressure, hypertrophy, calcium and cadmium were tested using multiple regression analysis. Multiple linear relationships occurred showing the dependence of high blood pressure on hypertrophy, calcium and cadmium: hypertrophy on calcium, cadmium and high blood pressure; and calcium on cadmium, high blood pressure and hypertrophy. These data provide insight into the mechanism of elevated blood pressure on heavy metal and calcium accumulation, and cardiac hypertrophy.

Vascular chemical sulfhydryl alkylation in vitro: alterations in intracellular calcium and cAMP and cGMP metabolism.

This study examined the effect of N-ethylmaleimide (NEM, 10(-7) M) on agonist-induced contraction and the relaxation following drug-washout, of vascular smooth muscle (VSM) segments derived from hypertensive rabbits. Mean blood pressure increase was produced either by renal constriction plus contralateral nephrectomy, or by cadmium acetate ingestion. Freely-ionized calcium (45Ca)flux, cyclic 3':5'-guanosine monophosphate (cGMP), and cyclic 3':5' adenosine monophosphate (cAMP), were analyzed. NEM was used as a stereoselective probe to clarify the role of sulfhydryl (SH) groups in hypertension. Contractile response to norepinephrine (NE, 5.9 x 10(-7) M), angiotensin II (AT, 9.8 x 10(-8) M), and potassium chloride (KCl, 2.2 x 10(-2) M) were significantly depressed in hypertensive tissue. Exposure to NEM, before agonist challenge, caused an even greater depression in contractile response. As for the normotensive group, an inhibition of relaxation occurred when NEM was added after the development of a maximal contractile response to NE, AT or KCl. Changes in contractile ability and in relaxation were attributed to specific alterations in calcium distribution. These alterations were examined by 45Ca washout components and were related to cAMP and cGMP metabolism. These results suggest a regulatory role of SH groups in contraction and relaxation and a modification of this role in hypertension.

Interaction of lipopolysaccharide endotoxin produced from Escherichia coli with D-tubocurarine at the nicotinic2 receptor and adenosine 3':5' cyclic monophosphate during physiological contraction in skeletal muscle.

In this report the murine model of endotoxicosis was used to evaluate hyposensitivity to the neuromuscular relaxant D-tubocurarine (dTC). This hyposensitivity was expressed in terms of a decreased potency to dTC. A rightward shift of the dose-response curve due to endotoxin was observed. Mice were subjected to cumulative intraperitoneal doses of Escherichia coli endotoxin over a 2-wk period. The interaction between endotoxin and dTC was examined during an acute (1 wk) and chronic (2 wk) period of endotoxicosis. Muscle twitch analyses were performed and samples of gastrocnemius muscle were assayed for adenosine 3':5' cyclic monophosphate (cAMP) by [125I]radioimmunoassay. A parallel shift in the dose-response curve occurred in the endotoxin group subjected to doses corresponding to one-third the dose evoking 50% lethality for 2 wk. Both skeletal muscle tension and cAMP levels decreased as cumulative endotoxin doses increased. A relationship between decreasing cAMP levels and increasing dTC and effective dose required to achieve 50% muscle paralysis values was thought to be evoked by the agonistic activity of E. coli endotoxin leading to desensitizing of adenylate cyclase. The perturbations of the classical second messenger cAMP system by endotoxin may be responsible for skeletal muscle dysfunction observed in immunocompromised patients.

Calcium accumulation in experimental hypertension.

At present, the significance of calcium accumulation in the aetiology of coronary artery disease (CAD) in humans is not known, except only to exacerbate the condition. In an attempt to understand ionic disturbances in vasculature derived from cardiovascular abnormalities, soft tissues from hypertensive models were examined. The study hypothesis was to see if basic cardiovascular regulatory sites in hypertensive models accumulated greater amounts of Ca2+. Calcium levels were measured by flame atomic absorption spectrophotometry in tissue derived from two types of hypertensive rabbits. Both models of hypertension developed mean arterial pressures of at least 50 mm Hg greater than those of controls over a 5-wk period. Significant increases in calcium levels were found in left ventricle and aorta derived from both hypertensive groups compared with controls. Renal cortex and medulla were not significantly different among any of the groups. These levels corroborate the findings of others which show increased calcium levels in cardiovascular tissues in experimental hypertension in rabbits. Although there have been several studies that have shown the relationship between calcium, hypertension and CAD, this is the first study to look at calcium accumulation rather that the effects of calcium channel blockers. The link between hypertension and calcium accumulation in a number of tissues may be important in the development of CAD and other cardiac dysfunction.

Multiple linear regression analysis of hypertrophy, calcium and cadmium in hypertensive and non-hypertensive states.

Heart disease remains a major public health issue. In this study we aimed to achieve a greater mathematical and mechanistic understanding of the relationship between exposure to heavy metals and heart disease. Measurements of calcium and cadmium levels were made by flame atomic absorption spectrophotometry in tissue from hypertensive and non-hypertensive rabbits. Relationships between hypertrophy, calcium and cadmium were tested using multiple regression analysis. Multiple linear relationships occurred that showed the dependence of hypertrophy on calcium and cadmium levels, and of calcium accumulation on cadmium and hypertrophy. These data provide an insight into the mechanisms of heavy metal accumulation and the development of cardiovascular hypertrophy.

Co-modulation between acetylcholinesterase and cyclic nucleotide signal transduction systems in burn trauma.

Signal transduction systems (sts(s)) and acetylcholinesterase (AChE) levels in skeletal muscle distantly located from the site of large body surface area (BSA) burns are due to the systemic effects of burn trauma. Evaluating the guanylate and adenylate cyclase sts(s), by measuring adenosine 3':5'-phosphate (cyclic AMP) and guanosine 3':5'-phosphate (cyclic GMP) by radioimmunoassay with polymorphic forms of AChE demonstrated that the various systems (i.e., cyclic GMP and AChE) interact while under the duress of burn trauma. This trauma emanates from large skin burns (30-50% BSA) that have induced a chronic burn trauma response at postburn day 21. This study showed that a system, with a minimum of 2 components, regulated cyclic AMP levels. This paper provides insight into our current understanding of the effects of burn trauma on cellular signalling and discusses some of the potential implications of recent findings on long term rehabilitative care.

Indirect talk of signalling systems in endotoxicosis: cross-talk alternatives.

This work evaluated indirect talk, a system of communication between two secondary messengers which uses a third modulating messenger/compound for communication. It expands on our previous report (6) of mean levels and univariate linear/non-linear relationships. It presents results using multivariate testing with vectorial modeling. The signal transduction systems (sts) studied through 125I-radioimmunoassay involved: adenosine 3':5' -cyclic monophosphate (cAMP); and the guanylate cyclase sts via guanine 3':5' -cyclic monophosphate (cGMP). Through multivariate testing, the dependency of a specified parameter was determined relative to two or more independent parameters. The contributing aspects of each of the independent variables were assigned to either 2- or 3-dimensional axes. Through the vector analyses the topic of indirect talk was well aspected. Multivariate equations showed that communication between two systems occurred. Vectorial analysis showed that the direct/indirect mechanism of that communication (namely, indirect talk) occurred. Such analysis leads to a greater understanding of endotoxemia that adversely affects skeletal muscle.

Polyinositol interrelationships in skeletal muscle under the duress of burn trauma.

Skeletal muscle weakness is a common problem among burn patients. An understanding of the changes that occur in the phosphatidyl inositol signal transducing system (sts) in skeletal muscle may identify pharmacological agents that would prove useful in the treatment of these patients. This report examines changes that occur in the interrelationships between the polyinositol phosphates of skeletal muscle due to the systemic effects of large body surface area (% BSA) burns. Burn injury was applied to predefined areas corresponding to 0, 20 and 50 per cent BSA of the dorsal and ventral skin surfaces of mice. At postburn day 21, polyinositol phosphate levels were measured in the gastrocnemius muscle by the incorporation of myo[2-(3)H]inositol with separation of the phosphates by anion-exchange chromatography. All data were analysed using analysis of variance and curve fitting routines. In the gastrocnemius, a number of interrelationships were found between the polyinositol phosphates. A relationship between inositol 1 phosphate (I1P) and inositol was the only relationship that was found in all three groups. However, a number of other relationships existed in the 20 and 50 per cent BSA burn group. These data illustrate that changes in polyinositol interrelationships occur in the phosphatidyl inositol signal transducing system due to the systemic effects of large per cent BSA burns.

Multiple stepwise regression analysis of physiologic tension and secondary messengers in chronic burn trauma.

In this report, we have used a multiple stepwise regression analysis to determine the best derived multivariate equation between a dependent and multiple independent parameters. All parameters were derived from harvested gastrocnemius muscle subjected to chronic burn trauma. Correlations between seven different parameters were tested. Physiologic tension, calcium, adenosine 3':5' cyclic monophosphate (cAMP), inositol 1,4,5-triphosphate (IP3) and its catabolites comprised one large data matrix. From it, the various parameters were substituted as the dependent variable. The remaining parameters all comprised a multiple independent group. From such a format, the stepwise regression was run. The simultaneous co-governing of independent parameters over one dependent parameter provides a means of mathematically proving multiple correlations. Such findings provide a new perspective in interpreting chemical signalling.

E. coli endotoxin affinity at the nicotinic2 receptor: receptor theory revisited, ilumina nostros occulae.

This paper examines the interaction of endotoxin at the nicotinic2 receptor (ACh-Rpost) with the adenylate cyclase signal transduction system in skeletal muscle. It reports the drug-receptor (DR) dissociation constant (K, 0.05020 +/- .0015 mg/kg) for E. coli endotoxin. It expands on a previous report (1) which presented the relevance of skeletal muscle cAMP as a metabolic indicator and second messenger influenced by endotoxicosis. The use of a murine endotoxic model allowed for the measuring of K for the antagonist. DR affinity measures which relied on the constrained-slope Schild plot measured it. This report assessed dose-response relations of the competitive antagonist dTC (AN) and their modification (AN') by advancing endotoxicosis. The presence of endotoxin at a fixed final concentration (i.e., 7.75 mg/kg) within the body at the end of a two week period caused a rightward shift in the dTC dose-response curve. Endotoxin desensitized cAMP and caused the dTC curve to be shifted rightward. This report differs from typical pharmacological applications where standard agonist curves are obtainable in the presence of an antagonist. This in vivo model did not allow for the measurement of agonist ACh concentration. Therefore, the use of a pair of compounds (i.e., antagonistic dTC and agonistic endotoxin) and their effects (i.e., suppression of active tension and cAMP desensitization, respectively) allowed us to quantitate K. In summary, this report supports the hypothesis linking the nicotinic2 receptor to the adenylate cyclase signal transduction system and illustrates that endotoxicosis perturbed both.

Multivariate and vectorial analysis of pharmacological signalling: diaphragm inositol 1,4,5-triphosphate under the duress of burn trauma.

Aberrant signal transduction processes within the diaphragm contribute to the weakness of this primary muscle involved in respiration. The importance of this report emphasizes how scald burn injury manifests distant systemic effects which impact on respiration. Scald burn injury from hot water is a common type of thermal injury in three specific patient groups: young children, the elderly, and the mentally and physically handicapped. Multivariate and vectorial analyses are presented within this paper with application to the effects of burn trauma on pharmacological signal transduction systems in the diaphragm. Multivariate equations showed the dependence of IP, on three to five independent variables. The independent variables included: burn size, glycerophosphate, and other polyinositols (inositol 1,4 biphosphate (I1,4P2), inositol 1 phosphate (I1P) and inositol). Graphic illustration of the equations used vectorial analysis. The multivariate analysis gives rise to a wider class of contributing factors than those observed using standard univariate relationships. This may be useful clinically in the identification of therapeutic agents for the treatment of respiratory problems in burn patients.

Divalent cations in hypertension with implications to heart disease: calcium, cadmium interactions.

Heart disease still pervades all socioeconomic classes within the United States. Understanding the effects of environmentally-related pathogenesis (e.g., heavy metal accumulation) may aid in developing novel treatments for the prevention of heart dysfunction. The aim of this report was to use experimental investigation in an attempt to expand upon the multivariate importance of divalent cation interactions in the development of heart disease. Calcium and cadmium levels were measured by flame atomic absorption spectrophotometry in various tissues derived from two types of hypertensive rabbit models. Both models of hypertension developed mean arterial pressures of at least 50 mm mercury greater than those of controls over a 5 week period. Interrelationships between calcium and cadmium levels were found to exist for both hypertensive groups in the left ventricle, aorta, and renal medulla. The renal cortex showed no such interrelationship for the renal hypertensive group. Multiple interrelationships between calcium and cadmium levels and hypertrophy were also observed. These studies related the importance of endogenous or exogenous (viz, environmental) factors governing cadmium and calcium accumulation in hypertensive rabbits. The resulting relationships between divalent cations and hypertrophy were presented to draw attention to areas which remain unexplored with perspective to cardiovascular disease.

Dysfunctional metabolism induced by the systemic effects of burn trauma: the role of rates of polyinositol and glycerophosphate formation in diaphragm.

Common complications among patients with burns are respiratory problems. Inspiration for breathing normally is facilitated by diaphragmatic contractility. However, in burn trauma numerous factors impose on skeletal muscle activity and chest wall function. These present limitations to surgical procedures requiring anesthesia. The hypothesis of this study was that the systemic effects of increasing burn size may result in metabolic changes in the polyinositol part of the phosphatidyl inositol signal transduction system in diaphragm. In this report, rate changes in polyinositol phosphates (i.e., inositol triphosphate (IP3), inositol 1,4 biphosphate (I1,4P2), inositol 1 phosphate (I1P), and inositol) that occurred in diaphragm subjected to the systemic effects of burn trauma were examined. Third-degree burn injury was applied by scalding predefined areas (i.e., 0%, 20%, and 50% body surface area) on the dorsal and ventral surfaces of mice. At postburn day 21 tissues were harvested and the levels of the polyinositol phosphates were measured by incorporation of myo-[2-3H]-inositol with separation of the phosphates by anion-exchange chromatography. All actual levels and rates of formation were analyzed with standard statistical tests and curve-fitting routines. Rate changes of the labelled [3H]-polyinositol phosphates were determined for the control, 20%, and 50% groups. These data show that rate changes occur in the polyinositol part of the phosphatidyl signal transduction system and are caused by the systemic effects of large percent body surface area burns. The changes that occur in the polyinositol phosphates provide insight into dysfunctional processes that can affect skeletal muscle physiology. The long-term goal of these studies is that they will lead to therapeutic advancements in the treatment of respiratory dysfunction in patients with burns.