Screening for Malignant Hyperpyrexia

The methods used to screen patients for malignant hyperpyrexia at present are not sufficiently accurate. This paper reports more specific methods of detecting patients liable to develop malignant hyperpyrexia. A motor-point muscle biopsy is performed for histopathological examination and to detect muscle contracture in vitro after exposure to halothane and suxamethonium.     

Identification of Susceptibility to Malignant Hyperpyrexia

While the serum level of creatine phosphokinase is useful as a screening test for malignant hyperpyrexia it does not provide certain identification of susceptible individuals. A much more accurate prediction may be made by pharmacological testing in vitro of muscle biopsy specimens. Individuals susceptible to malignant hyperpyrexia have muscle with heightened sensitivity to halothane, caffeine, succinylcholine, potassium chloride, and temperature change. Use of this test allows separation of susceptible individuals from those not at risk in families of patients who have experienced malignant hyperpyrexia.     

Procaine in Malignant Hyperpyrexia

The caffeine contracture of normal human muscle, which has been used as a model for malignant hyperpyrexia, is greatly potentiated by halothane. Prior administration of procaine markedly reduces the halothane-potentiated caffeine contracture, and procaine given at the height of the contracture induces relaxation. Lignocaine, on the other hand, produces a variable response and sometimes increases the contracture.The muscle from a patient with an inherited susceptibility to malignant hyperpyrexia contracted spontaneously with halothane alone, and this contracture was reversed by procaine.These experiments support the therapeutic use of procaine in malignant hyperpyrexia.     

Hyperpyrexia During Anaesthesia

Work in pigs has shown that malignant hyperpyrexia during anaesthesia may occur without suxamethonium having been given. A virtually constant feature in reported cases and in our own observations is that all subjects developing hyperpyrexia had received nitrous oxide and halothane.     

Evaluation of creatinine phosphokinase in screening patients for malignant hyperpyrexia.

Evidence is presented that serum creatinine phosphokinase (CPK) activity is of no direct value in screening patients for susceptibility to malignant hyperpyrexia and does not correlate with halothane-induced muscle contracture or the presence of myopathy. Widely differing CPK values were found at different times in the same people. In most "malignant hyperpyrexia" families the susceptible patients had either normal or inconsistently raised CPK values.     

Biochemical Basis of Malignant Hyperpyrexia

Pharmacologically-induced muscle contracture in vitro has been used as a model to study the biochemical basis of malignant hyperpyrexia. In 15 susceptible subjects halothane, succinylcholine, and potassium chloride all produced an abnormal muscle contracture, and the caffeine-induced contracture was greater than normal. The contractures were reproducible only in the presence of extracellular calcium ions. The fact that such dissimilar pharmacological stimuli all induced contracture in the affected muscle suggests that the essential abnormality in the muscle cell in malignant hyperpyrexia is an impaired binding of calcium ions to the membranes of the sarcoplasmic reticulum and the sarcolemma. Exposure of these membranes to halothane, succinylcholine, and other anaesthetic agents then leads to a rapid and abnormally large release of calcium into the myoplasm, which in turn gives rise to all the clinical features of the syndrome.     

Anaesthetic-induced Malignant Hyperpyrexia: A Suggested Method of Treatment

Experiments in susceptible Landrace pigs have shown that procaine blocks the initiation of anaesthetic-induced malignant hyperpyrexia by both halothane and succinylcholine. Pretreatment with curare prevents only the trigger action of succinylcholine. In a preliminary study procaine was used to treat the established syndrome in five pigs, two of which survived. On the basis of these findings a treatment regimen can be suggested for patients who develop malignant hyperpyrexia.     

Calmodulin and malignant hyperpyrexia

The function of calmodulin as a biological regulator is linked to the level of free Ca2+ in the cell, and there is evidence that calmodulin may itself be involved in the control of the movements of cellular Ca2+. Malignant hyperpyrexia, on the other hand, is caused by a disturbance in the level of myoplasmic Ca2+. We have investigated the possibility that calmodulin may be involved in malignant hyperpyrexia by studying the trifluoperazine-induced inhibition of calmodulin activation by phosphodiesterase, using crude and purified calmodulin preparations from control and MH-susceptible pigs. No abnormality was found in the pattern of either calmodulin activation or trifluoperazine-induced inhibition in MH muscle.     

Comparison of adenylate kinase from normal and malignant hyperpyrexic porcine muscle

Adenylate kinase has been implicated as a key factor in malignant hyperpyrexia, a complication of general anaesthesia which is usually triggered by the anaesthetic drug, halothane. Because of this, the enzyme was purified from both malignant hyperpyrexia susceptible and control porcine muscle. Electrophoretic studies, amino acid analysis, and peptide mapping of the purified enzymes revealed no significant differences between the two preparations. Both enzymes responded similarly to halothane and to the three sulfhydryl reacting reagents which were tested and they also showed an identical affinity for the substrate AMP. It is concluded that porcine MH is not due to an abnormality in the enzyme AK.     

Hereditary malignant hyperpyrexia associated with muscle adenylate kinase deficiency

Summary Muscle adenylate kinase deficiency was recognized in a family, in which two children died due to malignant hyperpyrexia following halothane anesthesia.Supported by the Deutsche Forschungsgemeinschaft.     

Calmodulin in porcine malignant hyperpyrexia

The anaesthetic complication malignant hyperpyrexia (MH) is due to an elevation of the myoplasmic Ca2+ concentration. Examination of calmodulin isolated from MH susceptible swine suggests that the disorder in calcium regulation in MH is not due to an abnormality in calmodulin.     

The effects of chlorbutol on skeletal muscle sarcoplasmic reticulum function in porcine malignant hyperpyrexia

1. Chlorbutol, a muscle relaxant, inhibits the in vitro muscle hypercontractility which is characteristic of the anaesthetic complication, malignant hyperpyrexia (MH). 2. Studies on isolated sarcoplasmic reticulum vesicles have shown that this effect of chlorbutol in MH is not due to a modification of Ca2+-transport mechanisms.     

The effects of calmodulin antagonist drugs on isolated sarcoplasmic reticulum from malignant hyperpyrexia susceptible swine

1. Because calcium antagonist drugs increase contracture in both control and malignant hyperpyrexia susceptible (MHS) skeletal muscle, the effect of these drugs on the sarcoplasmic reticulum (SR) was investigated. 2. The calmodulin antagonist drugs inhibited the Ca2+ dependent ATPase activity and the ATP-dependent Ca2+ uptake, and accelerated the efflux of Ca2+ from isolated SR preparations from both control and MHS skeletal muscle. These effects of calmodulin antagonist drugs on SR Ca2+ transport functions were consistent with their in vitro pharmacological effects on control and MHS muscle.     

Freeman-Sheldon (whistling face) syndrome with hyperpyrexia in the newborn: case report

Freeman Sheldon syndrome (FSS) is a rare, multiple congenital contracture syndrome that is relatively well-known, since affected children have a striking appearance. This entity was historically referred to as the "whistling-face syndrome". Malignant hyperthermia and hyperpyrexia have been documented in FSS after general anesthesia related to the neuropathy. We report a male neonate with FSS and hyperpyrexia without anesthesia. To our knowledge, our patient is the first in the literature with hyperpyrexia in the newborn period without anesthesia.     

The blockade of serotonin uptake into synaptosomes:relationship to an interaction with monoamine oxidase inhibitors.

To test the hypothesis that the hyperpyrexia produced by meperidine and detromethorphan in rabbits pretreated with a monoamine oxidase inhibitor is related to inhibition of neuronal uptake of serotonin (5-hydroxytryptamine (5-HT)), fluoxetine (Lilly 110140) was studied. This potent and specific 5-HT neuronal uptake blocker was administered to phenelzine-pretreated rabbits and found to produce a lethal hyperpyrexia in doses equal to or greater than 2.5 mg/kg. The order of potency in blocking 5-[14C]HT uptake into synaptosomes prepared from rabbits was: fluoxetine greater than meperidine = dextromethorphan = levorphanol greater than anileridine greater than alphaprodine greater than morphine. Since fluoxetine, meperidine, and dextromethorphan produce hyperpyrexia in phenelzine-pretreated rabbits, whereas anileridine, alphaprodine, and morphine do not, there appears to be some correlation between the hyperpyrexic response and inhibition of 5-HT uptake. The exception is levorphanol, which is not hyperpyrexic despite being equipotent with meperidine and dextromethorphan in inhibiting 5-HT uptake. The ineffectiveness of levorphanol in producing hyperpyrexia may be due to its marked depressant properties, since the addition of another depressant drug (pentobarbital) antagonized the hyperpyrexic effect of meperidine.     

Characterization of the terminal cisternae and longitudinal tubules of sarcoplasmic reticulum from malignant hyperpyrexia susceptible porcine skeletal muscle

1. The sarcoplasmic reticulum (SR) from malignant hyperpyrexia susceptible (MHS) and control porcine skeletal muscle was separated into vesicular fractions enriched in the membrane elements of the terminal cisternae and longitudinal tubules. 2. The two membrane preparations were highly purified and had distinctive features which were associated with their origins in the SR membraneous network. 3. Calsequestrin and calcium were enriched in the terminal cisternae fraction (HSR), in comparison to longitudinal tubule preparations (LSR). 4. The HSR membrane also had a greater total capacity to store Ca2+ and Ca2+ release was more rapid than from LSR preparations. 5. No distinction could be made between the membrane morphology, Ca2+ -fluxes or Ca2+ -dependent ATPase activities, associated with these functionally distinct regions of MHS and control preparations.     

Anatamo-pathological aspects of malignant ovarian tumors in children. Apropos of 16 cases

The authors present 16 cases of malignant ovarian tumors in childhood, censed in Pasteur Institute - Tunis. These tumors are scarce, and present in the literature only 3% of the malignant tumors in childhood. In this series, germ cell tumors are the most frequent and present 81.25% of these cases, of which 43.75% of dysgerminoma. Gonadal stromal tumors are more scarce (6.25%). The prognosis of these tumors was transformed by the radiation therapy in dysgerminoma, and the chemotherapy in the other germ cell tumors. These tumors must be diagnosed and treated early.     

How should clinical data be included in experimental studies of cancer immunology?

Patients diagnosed with the same malignant disease are often heterogeneous with regard to age, complications, malignant cell morphology and tumor histology, disease stage, prognostic parameters, and previous therapy. Many of these factors can affect immunocompetent cells or influence the malignant cell susceptibility to immunotherapy. Summaries of relevant clinical information should therefore be included in cancer immunology studies to increase the present as well as the future scientific impact. Guidelines for selection of relevant information are suggested in the article.     

Methyl p-hydroxyphenyllactate. An inhibitor of cell growth and proliferation and an endogenous ligand for nuclear type-II binding sites

We previously described and partially characterized endogenous ligands for nuclear type II sites in normal and malignant tissues. Chromatography of these ligands on Sephadex LH-20 revealed that two peaks with binding activity (alpha and beta) could be resolved. The beta-peak component was present in all normal tissues that we examined, but not in malignant tissues, and it inhibited the growth of MCF-7 human breast cancer cells in vitro. Conversely, the alpha-peak component was found to be present in both normal and malignant tissues, and did not inhibit MCF-7 cell growth. The present studies describe the purification and identification of the alpha-peak and beta-peak components in bovine serum and an assessment of the effects of these compounds on normal and malignant cell growth. Gas chromatography-mass spectroscopy analysis of the purified beta-peak component demonstrated that the compound was methyl p-hydroxyphenyllactate (MeHPLA). Competition analysis revealed that MeHPLA binds to nuclear type II sites with a high binding affinity, while physiological levels of this compound blocked estradiol stimulation of uterine growth in vivo and inhibited the growth of MCF-7 human breast cancer cells in vitro. The alpha-peak component was found to be the corresponding acid, p-hydroxyphenyllactic acid (HPLA). This compound interacted with nuclear type II sites with a relatively low affinity and did not block uterotropic response to estradiol or inhibit MCF-7 cell growth. These studies demonstrate that HPLA and MeHPLA are ligands for nuclear type II sites and that MeHPLA may be a very important regulator of normal and malignant cell growth.     

Levels of sister-chromatid exchanges in hybrids between Bloom syndrome B-lymphoblastoid cells and various cell lines with lymphoid malignancy

The present study has been undertaken to examine the effect of cell hybridization of Bloom syndrome (BS) B-lymphoblastoid cell lines (LCLs) and various cell lines from lymphoid malignancies in order to clarify the relationship between sister-chromatoid exchange (SCE) and malignant conditions. Cell hybridization studies have shown that though BS high-SCE frequencies were completed by fusion with normal cells, fusion with various malignant cell lines did not result in complete normalization of BS SCEs, with 15-30 SCEs remaining per hybrid cell, demonstrating possibly common defects in DNA of BS and malignant cells. These findings strongly support the idea that the characteristic high SCE frequency in BS cells has some connection with the malignant condition, and that at least one step in carcinogenesis is either accompanied by the production of SCEs, or that SCEs themselves cause such a step to occur.