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PubMed2002

RYR1 mutations causing central core disease are associated with more severe malignant hyperthermia in vitro contracture test phenotypes.

Malignant hyperthermia (MH) and central core disease (CCD) are autosomal dominant disorders of skeletal muscle. Susceptibility to MH is only apparent after exposure to volatile anesthetics and/or depolarizing muscle relaxants. CCD patients present with diffuse muscular weakness but are also at risk of MH. Mutations in RYR1 (19q13.1), encoding a skeletal muscle calcium release channel (ryanodine receptor), account for the majority of MH and CCD cases. Fifteen RYR1 N-terminal mutations are considered causative of MH susceptibility, five of which are also associated with CCD. In the first extensive UK population survey, eight of 15 mutations were detected in 85 out of 297 (29%) unrelated MH susceptible cases, with G2434R detected in 53 cases (18%). Mutation type was shown to affect significantly MH phenotypes (in vitro contracture test (IVCT) response to caffeine, halothane, and ryanodine). RYR1 mutations associated with both CCD and MH (R163C, R2163H, R2435H) had more severe caffeine and halothane response phenotypes than those associated with MH alone. Mutations near the amino terminal (R163C, G341R) had a relatively greater effect on responses to caffeine than halothane, with a significantly increased caffeine:halothane tension ratio compared to G2434R of the central domain. All phenotypes were more severe in males than females, and were also affected by muscle specimen size and viability. Discordance between RYR1 genotype and IVCT phenotype was observed in seven families (nine individuals), with five false-positives and four false-negatives. This represents the most extensive study of MH patient clinical and genetic data to date and demonstrates that RYR1 mutations involved in CCD are those associated with one end of the spectrum of MH IVCT phenotypes.

Anesthetics, Inhalation↗
PubMed2005

Homozygous microdeletion of chromosome 4q11-q12 causes severe limb-girdle muscular dystrophy type 2E with joint hyperlaxity and contractures.

Microdeletion syndromes are commonly transmitted as dominant traits and are frequently associated with variably expressed pleiotropic phenotypes. Nonlethal homozygous microdeletions, on the other hand, are very rare. Here, we delineate the fifth and so far largest homozygous microdeletion in nonmalignancies of approximately 400 kb on chromosome 4q11-q12 in a large consanguineous East-Anatolian family with six affected patients. The deleted region contains the beta-sarcoglycan gene (SGCB), the predicted gene SPATA18 (spermatogenesis associated 18 homolog) and several expressed sequence tags. Patients presented with a severe and progressive Duchenne-like muscular dystrophy phenotype, a combination of hyperlaxity and joint contractures, chest pain, palpitations, and dyspnea.

Adolescent↗
PubMed1982

Concepts of multiple congenital contractures (arthrogryposis) in man and animals.

This is a concept of multiple congenital contractures, based upon clinical experience with the malformation and available literature, leading to a conception of the multiple categories of etiology, which cause neuropathic or myopathic muscle weakness or limb immobilization. The muscle weakness and imbalance of muscle power around the joints elicits a physiological compensatory collagenic response, which replaces atrophied muscle fibers with connective tissue and thickens the joint capsule sufficiently to result in prenatal fixation of limb segments at the joint.

Animals↗
PubMed1984

Transient length responses of heart muscle in Ba2+-contracture to step tension reductions.

The transient length response of the cat papillary muscle in Ba2+-contracture to step tension reduction was found to comprise four different phases. It is tentatively suggested that the transient response is mostly determined by the kinetics of the attachment and detachment of cross-bridges between actin and myosin filaments, which vary appreciably with activation level of the muscle.

Animals↗
PubMed1985

Force and membrane potential in acetylcholine and potassium contractures of denervated mouse muscles.

Depolarization and contracture force (P) provoked by acetylcholine (ACh) and by K ions were studied in bundles dissected from mouse soleus muscles that had been denervated for 4-7 days. Cl-free solutions were used. The muscle fibres were depolarized by solutions containing 150 mM K or 10 microM ACh to nearly zero mV resulting in maximum P (Pmax). Threshold P was produced when the membrane was depolarized to more than about -60 mV by both agents. 50% Pmax was produced by [K] causing the membrane to depolarize to -42 mV, whereas a potential more positive than -20 mV was required for 50% Pmax to be produced when ACh was used. The rate of depolarization was always higher for ACh than for K. Pretreatment by 0.05 microM ACh (about threshold for P) did not affect the P-[K] relation appreciably showing that ACh did not "stabilize" the membrane. Nearly equal P was provoked by successive applications of just suprathreshold agent concentrations when the order of application was ACh----K but not with the reverse order. Hypertonicity (by addition of 300 mM sucrose to all solutions) caused PACh to decrease and PK to increase. It was concluded that the ACh receptors are located in the surface membrane of the muscle fibres, not in the T-system membranes.

Acetylcholine↗
PubMed1976

The effect of muscle extracts on the contracture response of skeletal muscle to acetylcholine.

Preincubation of normal rat soleus muscles in vitro with homogenates prepared from mixed leg muscles which had been denervated 4 days previously resulted in an increase in the contracture response to acetylcholine. After 30 min incubation a 1.5-fold increase was observed. Homogenates of normally innervated muscles did not increase the response. The active principles of the denervated muscles were found to reside in the "cytosol" fraction. An approximately 2-fold increase was observed upon incubation with the cytosol for 30 min; incubation for longer periods resulted in a subsequent decrease in the response. The effect of the denervated muscle cytosol was concentration-dependent and heat-labile. Normal muscle cytosol also increased the soleus muscle response to acetylcholine but this fraction was less effective than denervated muscle cytosol. The response of control muscles incubated in Krebs-Henseleit solution was found to decrease with time. Commercially obtained phospholipases C and D increased the response of normal soleus muscles approximatley 2-fold. Phospholipase A, lipase, trypsin, collagenase and a bacterial protease had no effect, lysozyme produced a small but consistent increase in the response to acetylcholine.

Acetylcholine↗
PubMedDate not supplied

[Evaluation of elasticity by means of length-tension relationships in a model of isolated ventricular myocardium from rat and cat papillary muscle under conditions of contracture (author's transl)].

Increase of Ca2+ concentration to 7.5 mM in the presence of 10 mM or 20 mM caffeine shifted length-tension relationships of 5 rat trabecular muscles and 5 cat papillary muscles to higher tensions. At 1max diastolic tension was enhanced from (formula: see text), for all measured points of stress-strain relationships after the increase of diastolic tension by caffeine and Ca2+ as well as under control conditions. The function E = f (sigma) = b (sigma - c) was computed by linear regression analysis (0.99 greater than r2 greater than 0.96). The average value of constant b was 13.89 +/- 2.01 in control curves of rat trabecular muscles and 13.42 +/- 1.98 in curves with 10 mM caffeine and 7.5 mM Ca2+. Likewise, in cat papillary muscles 20 mM caffeine and 7.5 mM Ca2+ did not alter the stiffness constant b in a statistically significant manner (control: 16.63 +/- 3.03, caffeine: 16.43 +/- 3.02). The results demonstrate that the stiffness constant b cannot indicate acute variations of the length-tension relationships due to caffeine and Ca2+ and may result in overestimating of myocardial distensibility. However, if the tangent modulus (E) is related to strain (epsilon), the alterations of diastolic elasticity are detectable. Mathematical considerations of these experimental results imply a new base for evaluation of diastolic elasticity of the heart by means of the tangent modulus (E). These results are of substantial importance in clinical evaluation of distensibility of myocardial tissue, as the tangent modulus related to wall stress apparently is not appropriate to realize alterations in "passive" myocardial properties due to contracture.

Animals↗
PubMedDate not supplied

Adaptation to stress exposure prevents arrhythmogenic and contractural effects of the excess of Ca2+ on the heart by the increased activity of sarcoplasmic reticulum.

Adaptation of rats to repeated short-term stress exposure prevents, to a considerable extent, contractural and arrhythmogenic effects of high concentrations of extracellular Ca2+ on isolated heart. Increased efficiency of SR Ca2(+)-pump functioning and a significant increase in Ca2+ pump resistance to autolysis are proved to play the main role in this effect.

Animals↗
PubMed1978

[A method for the measurement of the collodiaphyseal angle in case of external rotational contracture (author's transl)].

The authors discuss the objectivity of measurements for the collodiaphyseal angle of the hip fixed in external rotation on the a.p. projection. Since the antetorsion cannot be measured because of the external rotation contracture, an alternative projection is proposed. Several pictures are demonstrated for the determination of the rotation. To find the true value of the distorted collodiaphyseal angle the authors propose a formula for the calculation on theoretical grounds. They consider this formula valuable for clinical use.

Anthropometry↗
PubMed1977

Focal contracture following injection of succinylcholine in patients with peripheral nerve injury.

Focal muscle contracture in the limb following sytemic administration of depolarizing neuromuscular blocking agents have been demonstrated experimentally with transection or crush injury of the nerve, but has rarely been observed clinically in patients with partial peripheral nerve injury. Three cases of spastic response in the hand and wrist are described in patients with subclinical chronic, subacute, and acute nerve injury, to document the occurrence of this phenomenon under various circumstances.

Adult↗
PubMed1976

The adenosine triphosphate (ATP) depletion test: comparison with the caffeine contracture test as a method of diagnosing malignant hyperthermia susceptibility.

The adenosine triphosphate (ATP depletion ratio, which is the ratio [ATP] in skeletal muscle equilibrated with carbogen and 4% halothane for 30 minutes divided by [ATP] in skeletal muscle equilibrated with carbogen alone for 30 minutes is less than normal in most but not in all rigid MHS patients. The ratio is normal in non-rigid MHS patients. This diagnostic tool is, therefore, useful in the diagnosis of rigid MH. It is not, however, such a sensitive diagnostic parameter as the caffeine contracture test.

Adenosine Triphosphate↗
PubMed1982

Comparison of the caffeine skinned fibre tension (CSFT) test with the caffeine-halothane contracture (CHC) test in the diagnosis of malignant hyperthermia.

We have compared and contrasted two diagnostic tests for Malignant Hyperthermia (MH) - the Caffeine-Halothane Contracture Test and the Caffeine Skinned Fibre Tension Test. Both tests show a strongly positive relationship both with the occurrence of MH reactions and with each other. The former test is more rapid and requires less skill. The latter test can be performed on much less muscle and permits storage of the muscle over prolonged periods of time.

Anesthesia↗
PubMed2000

[In vitro contracture test and gene typing in diagnosing malignant hyperthermia. Each as an appropriate complement to the other method].

BACKGROUND: Malignant hyperthermia (MH) is an autosomal dominantly inherited disorder, triggered in susceptible individuals by inhalation anesthetics and depolarizing muscle relaxants such as succinylcholine. Because of its high sensitivity (97-99%) and specificity (93.6%) as well as the genetic heterogeneity of MH disorder, the in vitro contracture test (IVCT) following the European-MH-Group is considered to be the "Gold Standard" for phenotypical determination of predisposed patients. On the other hand mutations in the skeletal muscle ryanodine receptor gene (RYR1) are tightly linked with MH susceptibility. After detecting a C1840T-mutation (Arg614Cys) in the RYR1 gene in one individual of a large MH family, we searched for this mutation in the remaining family members and determined the concordance with IVCT. METHODS: According to the European standard protocol for MH, 43 individuals of a large MH pedigree were assigned the status of MH susceptible (MHS),--negative (MHN) or--equivocal (MHE). The genetic investigation of 44 family members for the Arg614Cys-mutation was carried out by restriction fragment analysis: Genomic DNA was prepared from EDTA whole blood followed by amplification of a 918 bp RYR1 gene fragment by polymerase chain reaction. In presence of the Arg614Cys-mutation digestion with the restriction endonuclease Rsal would result in different DNA fragments of the amplified sequence than in absence of mutation. RESULTS: According to the response to IVCT, 25 individuals phenotypically revealed MHS, 7 MHE and 11 MHN status. Out of the 44 family members screened genetically for the Arg614Cys-mutation, the mutation was detected in 23 individuals. Out of them 19 were MHS and one was MHEc. The mutation was absent in 9 predisposed individuals, but six of them were MHE and three MHS. The mutation was also present in three individuals who had no MH screening (IVCT) before. For these last mentioned individuals the diagnosis MHS was deduced from genetic results. CONCLUSION: Based on results of IVCT the identification of a MH associated mutation in a MH-family can make and support a correct MH diagnosis and can resolve MHE findings.

Amino Acid Substitution↗
PubMed1998

[Compartment syndrome and Volkmann contracture--can they be prevented in supracondylar humerus fracture?].

The arterial blood supply of the arm is unique, as the collateral circulation is especially good. Because of this anatomic perculiarity it is possible to deal with lack of peripheral pulse without critical ischemia occurring in fractures in the elbow region. We present two children with supracondylar fractures of the humerus with damage to the brachial artery and the different management results. It is necessary to carry out the immediate diagnostic and therapeutic procedures in order to prevent late complications. We conclude that Volkmann's ischemic contracture can always be prevented.

Adolescent↗
PubMedDate not supplied

Inflammatory reaction and capsular contracture around smooth silicone implants.

Histologic studies were performed on capsular tissue resected from 21 patients who were implanted with smooth silicone prostheses filled with gel. The results disclosed a nonuniform response to the implants. The granulomatous reaction to the silicone showed important variations along the same surface of the implants, between the plane and the concave surfaces, between equivalent points at the right and left sides, and among the patients. Also, a significant difference was observed between reactions and capsules in early and late stages. The author believes these variations of the capsular inflammatory reaction promote different sites of contraction between cell-to-cell, or cell-to-collagen-to-cell. These adding forces result in vectors of different intensities and directions around the implants which explains the various clinical grades of capsular contracture.

Adult↗
PubMed1996

RISC (Repolarization-induced stop of caffeine-contracture) is not due to store depletion in cultured murine skeletal muscle.

We have combined the patch-clamp technique with Fura-2 measurements to investigate whether RISC (repolarization-induced stop of caffeine-contracture) is a consequence of store depletion in cultured skeletal muscles of rats and mice. Weak depolarizations (-45 to -40 mV) of long duration induced a barely detectable Ca2+ transient. Even under these conditions, caffeine-activated Ca2+transients (CafTs) were terminated upon membrane repolarization (-70 mV) at all stages of CafT. Following the peak of the CafT, massive Ca2+ release was elicited by either flash-photolysis of caged Ca2+ or further depolarization to 0 mV, demonstrating the lack of store depletion. Thus, RISC is not due primarily to store depletion but to closure of the Ca2+ release channels possibly through a mechanical interaction with voltage sensors. RISC was not present in rat heart muscle, further supporting a role of direct interaction in skeletal muscle.

Action Potentials↗
PubMed2000

Comparison of the in vitro caffeine-halothane contracture test with the Ca-induced Ca release rate test in patients suspected of having malignant hyperthermia susceptibility.

PURPOSE: We compared the results of the in vitro caffeine-halothane contracture test (CHCT) according to the protocols of the North American Malignant Hyperthermia Group (NAMHG) and the European Malignant Hyperthermia Group (EMHG) with the Ca-induced Ca release (CICR) rate test in the same patients with suspected malignant hyperthermia (MH). METHODS: Five normal controls and 16 patients suspected of having MH susceptibility were studied. Muscle biopsies were usually obtained from the musculus vastus lateralis. Diagnostic cutoff points and procedures for CHCT protocols were as described in the original and renewal versions of NAMHG and EMHGs. The CICR rate test was performed according to the protocol reported by Endo et al. RESULTS: All five normal controls and two patients with abortive MH, two with postoperative hyperthermia, and three with high serum creatine kinase levels were normal in the three tests. Three patients with MH reactions and one patient with a history of masseter spasm were classified as MH positive according to NAMHG criteria and MH susceptible and MH equivocal according to EMHG criteria. There were five cases with discordant results between the CHCT and CICR rate tests. CONCLUSION: We propose that muscle biopsy for diagnosis of MH susceptibility should combine the CHCT with the CICR rate test, which may identify the defective site of Ca release channels.

Journal Article↗