[Family therapy within the treatment of eating disorders]. / Familientherapie bei Ess-Störungen.

The families of patients suffering from eating disorders such as Anorexia nervosa (AN) und Bulimia nervosa (BN) are, owing to the illness, subject to considerable emotional strain and are furthermore often characterised by significant structures and patterns of interaction within the family. Consequently the inclusion of patients' family members, whose status can be seen as increasingly gaining in scientific approval, plays an important role within both diagnosis and therapy. Of particular importance is the medical informative discussion with both patients and their parents which takes place in a primarily medical context and aims to develop and increase therapy motivation. For this purpose the doctor should possess basic knowledge concerning dialogue management with families, as will be presented in the current article. Within further stages of the therapeutic process the spectrum of interventions at the level of the family ranges from educational and supportive measures to family therapy in a more narrow sense, which is carried out by specialist psychotherapists either as outpatient-treatment or within the framework of therapy with inpatients of a clinic.

C1840-T mutation in the human skeletal muscle ryanodine receptor gene: frequency in northern German families susceptible to malignant hyperthermia and the relationship to in vitro contracture response.

In swine, a point mutation in the ryanodine receptor gene can account for all cases of malignant hyperthermia (MH). The frequency of a corresponding mutation in humans (C1840-T) and its relationship to the in vitro contracture profile is unknown. We screened 192 patients from 28 unrelated northern German families for the C1840-T mutation in the human ryanodine receptor gene and tested for MH susceptibility using the in vitro contracture test (IVCT) according to the European MH Protocol. In our patients 106 revealed MH susceptible (MHS), 56 MH nonsusceptible and 30 MH equivocal status following IVCT. In each family one or two individuals had developed clinical signs of MH or a MH crisis. All of these patients were classified MHS. The C1840-T mutation was found in 2 of 28 families (7.1%). All eight individuals of the two families characterized by this mutation revealed MHS status following IVCT. The thresholds for halothane- and caffeine-induced contractures as well as the contracture profiles following cumulative (0.4-10.0 mumol/l every 3 min) and bolus (10 mumol/l) administration of ryanodine were found to be similar in MHS patients with and without the C1840-T mutation. In conclusion, the C1840-T mutation in the human ryanodine receptor gene is a rare abnormality in MHS families. Similar contracture profiles in the presence and absence of this mutation might imply no major functional role with respect to the contracture response. At present, molecular genetic analysis cannot replace IVCT to discover MH susceptibility in humans.

A mechanism of haloalkene-induced renal carcinogenesis.

Several halogenated alkenes are nephrotoxic; some others induce renal tubular adenocarcinomas in rodents after lifelong administration. A bioactivation mechanism accounting for the organ-selective tumor induction has been elucidated: conjugation of the parent compounds with glutathione (GSH), catalyzed by hepatic GSH S-transferases, results in the formation of haloalkyl and halovinyl glutathione S-conjugates. Formation of S-conjugates (identified by NMR and mass spectrometry) could be demonstrated with trichloroethene, tetrachloroethene, hexachlorobutadiene, perfluoropropene, trichlorotrifluoropropene, and dichloroacetylene in incubations with rat liver microsomes and in the isolated perfused rat liver. The GSH conjugates formed are eliminated from the rat liver with the bile and may be translocated to the kidney, intact or after metabolism to the corresponding cysteine S-conjugates that are metabolized in the kidney by renal tubular cysteine conjugate beta-lyase (beta-lyase) to reactive intermediates, most likely thioacylchlorides and thioketenes. Interaction of these potent electrophiles with DNA [demonstrated for intermediates formed from S-(1,2,3,4,4-pentachlorobutadienyl)-L-cysteine] causes mutagenicity in bacteria, genotoxicity in cultured renal cells, and cytotoxicity in kidney cells. As an alternative to beta-lyase-catalyzed cleavage, the cysteine S-conjugates may be acetylated to the corresponding mercapturic acids, which have been identified in urine. The ability of the kidney to concentrate GSH and cysteine S-conjugates and the intensive metabolism of GSH S-conjugates to cysteine S-conjugates in this organ are evidently responsible for the organotropic carcinogenicity.

Fulminant malignant hyperthermia associated with ketoacidotic diabetic coma.

Malignant hyperthermia (MH) in humans is usually triggered by volatile anaesthetics and depolarizing muscle relaxants. However, other factors or drugs (e.g. cresol) are thought to induce MH. We report a case of fulminant MH associated with a ketoacidotic diabetic coma. After therapy for diabetic coma with insulin (containing the preservative cresol) and electrolyte solutions was started, the patient complained of increasing myalgia, developed a high fever and respiratory and metabolic acidosis and lost consciousness. MH was treated immediately with dantrolene; the patient recovered within 14 days. Five months later the patient was diagnosed as MH-susceptible by the in vitro caffeine and halothane contracture test. This case supports the assessment that MH and diabetes are associated diseases and that cresol could possibly trigger MH. Furthermore, therapy with dantrolene has been demonstrated to be beneficial in the treatment of MH associated with diabetic coma.

Cytotoxicity of cysteine S-conjugates: structure-activity relationships.

The cytotoxicity of cysteine S-conjugates was investigated in freshly isolated rat renal proximal tubule cells. The study was designed to determine the contribution of the thiols and of the acylating intermediates formed by cysteine conjugate beta-lyase to the initiation of cytotoxicity. Cell viability was determined by trypan blue exclusion and by lactate dehydrogenase leakage. The S-conjugates S-(1,2,2-trichlorovinyl)-L-cysteine, S-(1,2,3,3,3-pentachloro-prop-1-enyl)-L-cysteine and S-(1,2,3,4,4-pentachlorobuta-1,3-dienyl)-L-cysteine, at a concentration of 0.2 mM, reduced cell viability compared to controls from 85% to less than 50% after 3 h. The alpha-chlorinated enethiols formed from these S-conjugates are transformed to acylating intermediates. The S-conjugate S-(2-chlorovinyl)-L-cysteine forms an enethiol, which cannot transform to an acylating intermediate and did not reduce cell viability at 0.2 mM; at 1 mM, it resulted in a very slight reduction of cell viability after 3 h. S-(pentachlorophenyl)-L-cysteine and S-benzyl-L-cysteine, which form stable thiols after metabolism by beta-lyase, were not cytotoxic at a concentration of 1 mM. The direct acting S-(2-chloroethyl)-L-cysteine (0.2 mM) reduced cell viability after 3 h from 85% to 90% (control) to 40%. The results obtained suggest that reactions of the initial thiol-metabolites with biological macromolecules do not contribute to the induction of cytotoxicity by cysteine S-conjugates and indicate that acylating intermediates formed by cysteine conjugate R-lyase induce cytotoxic effects by non-selective acylation of cellular macromolecules.

[Are monamine oxidase inhibitors in disposition to malignant hyperthermia contraindicated? Discussion based on a case report]. / Sind Monoaminoxidase-Hemmstoffe bei Disposition zu maligner Hyperthermie kontraindiziert? Diskussion anhand eines Fallberichts.

We report on a young patient with a positive family history for malignant hyperthermia (MH), who was diagnosed as susceptible to MH in our malignant hyperthermia laboratory by the in vitro-contracture test. Prior to the investigation of MH-susceptibility, the patient had been on medication with moclobemide, a monoamine oxidase (MAO) inhibitor, over a period of 13 months for treatment of a hyperactivity disorder. During the therapy with moclobemide no signs of relevant side effects were observed. However, some authors regard MAO-inhibitors as MH-triggering agents. The risk of MH-patients due to the therapy with MAO-inhibitors and the association between MH and the neuroleptic malignant syndrome is discussed in this case report.

Effects of the serotonin2 receptor agonist DOI on skeletal muscle specimens from malignant hyperthermia-susceptible patients.

BACKGROUND: Administration of serotonin2 (5-HT2) receptor agonists in pigs triggers malignant hyperthermia (MH) and psychotic-like behavior. Both can be reduced by 5-HT2 receptor antagonists. Furthermore, an increase in the plasma concentration of 5-HT has been found during onset of halothane-induced MH in pigs. Therefore, in this study, the in vitro effects of the 5-HT2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) were investigated in muscle specimens from MH-susceptible (MHS) and -negative (MHN) patients. METHODS: After MH classification using the caffeine-halothane contracture test (CHCT), surplus muscle specimens from 23 MHS and 17 MHN patients were used to examine the effects of DOI. In the first study, DOI was added to the bath in a concentration of 0.02 mM. In a second experiment, muscles were preincubated for 60 min with 0.02 mM DOI, and subsequently, halothane was added incrementally to the organ bath (0.11-0.22-0.44 mM) for 15 min according to the CHCT protocol. The in vitro effects of DOI on contracture development and muscle twitch were measured for 120 min in both investigations. RESULTS: Muscle specimens form all patients developed contractures after administration of DOI, characterized by a significantly earlier development of contracture in MHS (16.8 +/- 1.7 min) than in MHN (66.3 +/- 5.8 min) muscles (P < 0.05). There was no overlap between the groups in the range of times. The onset of contracture development after DOI was prolonged by halothane in specimens from MHN patients (89.7 +/- 5.6 min) but not MHS patients. Preincubation with DOI increased the halothane-induced contractures in specimens from MHS patients compared to the results of the CHCT. The contracture development in specimens from MHS patients was larger than from MHN patients. At the end of the experiment, contractures had reached a maximum of 12.9 +/- 1.1 mN in specimens from MHS and 5.3 +/- 0.6 mN in MHN patients (P < 0.05). The additional administration of halothane led to significantly increased contractures in specimens from MHS individuals (15.9 +/- 0.9 mN) at 120 min. However, the contracture development decreased significantly to 3.1 +/- 0.4 mN in MHN muscles. Muscle twitch after DOI administration was reduced significantly in specimens from MHS and MHN patients. CONCLUSIONS: A functional or structural altered serotonin system might be involved in the development of MH in humans.

Inositol 1,4,5-trisphosphate in blood and skeletal muscle in human malignant hyperthermia.

The in vitro contracture test (IVCT) is the only available diagnostic method at present for evaluation of malignant hyperthermia (MH) susceptibility. However, the disadvantage of the IVCT is that it is invasive. Several studies suggest that an altered inositol phosphate system is involved in the development of MH. A greater concentration of inositol 1,4,5-trisphosphate (1,4,5-IP3) was found in MH susceptible (MHS) than in normal (MHN) skeletal muscles. In this study the concentrations of 1,4,5-IP3 in blood samples and skeletal muscle specimens of identical patients were measured in an attempt to define susceptibility to MH. Muscle biopsies were obtained from 34 patients with clinical suspicion of MH. Patients were first classified as MHS (n = 19), MHN (n = 8) or MH equivocal (MHE; n = 7) by the standard IVCT. For detection of 1,4,5-IP3 concentrations, blood samples were obtained and an additional muscle specimen was excised. After sample preparation, concentrations of 1,4,5-IP3 were measured using radioimmunoassay. In blood samples, concentrations of 1,4,5-IP3 were similar in all individuals tested for MH susceptibility and in control patients not tested for MH susceptibility (n = 44). In skeletal muscle, 1,4,5-IP3 concentrations were significantly higher in MHS than in MHE or MHN patients, respectively. Each MHS sample contained more 1,4,5-IP3 than the highest concentration measured in MHN muscle. Defining arbitrary thresholds for 1,4,5-IP3 concentration in skeletal muscles in order to discriminate between MHS and MHN status, it was possible to assign three MHE patients to MHS and four to MHN. This study supports the hypothesis that an altered inositol phosphate system might be involved in MH. However, measurement of 1,4,5-IP3 concentration in a simple blood sample preparation is not reliable for MH susceptibility screening.

Rhabdomyolysis following severe physical exercise in a patient with predisposition to malignant hyperthermia.

A 21-year-old man suffered from exertional heat stroke with impaired consciousness and rhabdomyolysis after strenuous physical exercise. Within two weeks the patient recovered completely without any specific therapy. Based on the symptoms and laboratory investigations, this episode suggested a moderate form of malignant hyperthermia. An in vitro contracture test was performed and a predisposition to malignant hyperthermia was diagnosed; other muscular diseases were excluded by histological examination. At present, the in vitro contracture test is the only method used to determine susceptibility to malignant hyperthermia and should be performed when the diagnosis is suggested on clinical grounds.

In vitro diagnosis of malignant hyperthermia susceptibility with ryanodine-induced contractures in human skeletal muscles.

The in vitro contracture test with ryanodine is a new method to distinguish malignant hyperthermia (MH) susceptible (MHS) from normal (MHN) patients. The purpose of our investigation was to determine whether smaller concentrations of ryanodine than those used previously may result in a better differentiation. We performed a ryanodine contracture test (RCT) using concentrations of 1 and 2 microM in muscle specimens of 41 MHS, 58 MHN, and 19 MH-equivocal (MHE) patients. Nine patients were excluded from the study due to neuromuscular diseases. All contracture levels (i.e., start of contractures, contractures of 0.2 g and 1.0 g) were attained significantly earlier in MHS than in MHN muscles at both concentrations of ryanodine. Using a ryanodine concentration of 2 microM, all contracture levels were reached significantly faster than with 1 microM. There was no overlap in the range of times between groups at all contracture levels with ryanodine 1 and 2 microM. The median threshold times for all MHE patients were always between those of MHS and MHN. Defining arbitrarily threshold times for MHS and MHN, an assignment of MHE patients to either MHS or MHN using 1 or 2 microM ryanodine was possible in most cases. Ryanodine administration at a concentration of 1 microM led to a better distinction of MHS from MHN patients than 2 microM. The RCT with ryanodine 1 microM should therefore be added to the current diagnostic methods.

RSV bronchiolitis and risk of wheeze and allergic sensitisation in the first year of life.

Severe respiratory syncytial virus (RSV) infection has been hypothesised to be a risk factor for the development of allergy and asthma, but epidemiological studies in older children have been inconclusive. The current study hypothesises that the effect of RSV bronchiolitis might be most prominent during the first year after bronchiolitis. Forty-two infants had experienced RSV bronchiolitis severe enough to cause hospitalisation. For each child with RSV infection, two controls were acquired from a birth cohort and matched for date of birth and sex. All the children were followed prospectively and underwent a follow-up examination at a mean age of 1 yr, which included physical examination, and serum immunoglobulin (Ig) E tests for common food and inhaled allergens. Risk factors for the development of recurrent wheezing and IgE antibodies were analysed for the whole group of 126 children. A positive test for IgE antibodies was noted in 14 of 42 (33%) RSV children and in 2 of 84 (2.3%) children in the control group. RSV bronchiolitis was the most important risk factor for allergic sensitisation. Likewise, 13 children (15.5%) of the RSV group and three (3.6%) children of the control group suffered from recurrent wheezing, and RSV bronchiolitis posed a considerable risk for recurrent wheezing. Severe respiratory syncytial virus bronchiolitis during the first year of life is an important risk factor for the development of recurrent wheezing and sensitisation to common allergens during the subsequent year.

Severe respiratory syncytial virus infections and reduced interferon-gamma generation in vitro.

To study the consequences of the interaction of respiratory syncytial virus (RSV) with dendritic cells in vitro, we established a model of the primary immune response using dendritic cells, autologous naive T cells and the superantigen toxic shock syndrome toxin 1 (TSST 1). About 10% of the naive T cells express the T cell receptor chain Vbeta2. These cells were stimulated by TSST 1 and could be analysed by flow cytometry. Cultures infected with RSV produced significantly less interferon-gamma compared to uninfected cultures. In a first set of experiments we evaluated whether this culture model using isolated CD4(+) CD45RA(+) T cells, in fact, reflects the primary immune response. In a prospective study, cells were isolated from 13 children at birth, at 1 year of age and at 4 years of age. RSV reduced interferon-gamma production at all the age groups analysed and the results were stable over time within a given individual. In a second set of experiments, we asked whether clinical differences in the course of RSV infection are due to variations in the cellular immune response. At the age of 1 year (5-9 months after the RSV epidemic) dendritic cells and naive T cells were obtained from 27 children with a history of bronchiolitis, from 15 children with a benign course of RSV infection and from 26 controls without RSV infection. The frequency of interferon-gamma-producing cells in RSV infected cultures was significantly lower (P < 0.001) in cultures from children with a history of RSV bronchiolitis compared to children with mild RSV infection. Cultures from children without infection displayed a wide range of results. Overall, interferon-gamma generation in this group was still lower (P < 0.05) than in the group with mild RSV infection. Because we have ruled out that memory cells play a role in the experiments performed, the most likely explanation for our results is that a high generation of interferon-gamma in the primary immune response protects from severe RSV mediated disease.

Modulation of ryanodine-induced contractures in human skeletal muscle pretreated with dantrolene.

Dantrolene seems to be the causal therapy in malignant hyperthermia (MH) crisis but the complex mechanisms of MH and dantrolene therapy are still not fully understood. The influence of dantrolene on ryanodine-induced contractures has been reported in animal studies only. In the present study 20 patients from 17 families were tested for MH using the protocol of the European Malignant Hyperthermia Group. In addition ryanodine-induced contractures were evaluated following bolus application of 10.0 mumol.l-1 ryanodine. After pretreatment with 1 mumol.l-1 dantrolene ryanodine-provoked contractures developed significantly later in MHS (15.8 +/- 1.8 min) and MHN (46.0 +/- 4.2 min) muscle specimens than after ryanodine alone (MHS 4.8 +/- 0.7 min. (MHN 13.7 +/- 0.9 min). They were no longer observed in either group after pretreatment with 5 mumol.l-1 dantrolene. We conclude that dantrolene is able to attenuate ryanodine-induced contractures dose-dependently, and therefore it is speculated that dantrolene could specifically act at the ryanodine receptor binding site.

High-purity ryanodine and 9,21-dehydroryanodine for in vitro diagnosis of malignant hyperthermia in man.

Susceptibility to malignant hyperthermia (MH) is currently diagnosed by the in vitro contracture test (IVCT) in skeletal muscle. However, this test does not possess absolute specificity. Thus, in addition to the established procedure, the "ryanodine contracture test" has been proposed to improve discrimination between MH-susceptible (MHS) and normal (MHN) patients. In all previous studies, the ryanodine used was a mixture consisting of high-purity ryanodine (HPR) and 9,21-dehydroryanodine (DHR). Therefore, in this study the effects of both substances were investigated in concentrations of 2, 5 and 10 mumol litre-1. With all concentrations, contractures appeared earlier in MHS than in MHN muscles, but these differences were significant at all contracture levels with HPR only. Moreover, with the smallest concentration (2 mumol litre-1), the best discrimination between MHS and MHN was observed. Classification of MH-equivocal patients (MHE) as MHS or MHN seems to be possible with the use of ryanodine-induced contractures. The contracture test with HPR should therefore be added to the established procedure of the IVCT.

[Effects of serotonin 2 receptor agonists on skeletal muscle preparations in patients with a disposition toward malignant hyperthermia]. / Effekte von Serotonin2-Rezeptoragonisten auf Skelett-muskelpräparate von Patienten mit Disposition zu maligner Hyperthermie.

In pigs genetically susceptible to malignant hyperthermia (MH), it has been shown that serotonin (5-HT2) receptor agonists can induce MH and "psychotic" behaviour. Both can be prevented by 5-HT2 receptor antagonists. Furthermore, free levels of serotonin in plasma increased concomitantly with clinical and laboratory parameters during halothane-induced MH in pigs. In this study the in vitro-effects of the 5-HT2 receptor agonist1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane (DOI) were investigated in muscle specimens of MH-susceptible (MHS) and normal (MHN) patients. METHODS. Muscle biopsies were obtained from 37 patients aged 5-69 years (23.6 +/- 5.3 years) with clinical suspicion for MH. The patients were first classified as MHS, MHN or MHE (MH equivocal) by the in vitro contracture test (IVCT) according to the European MH protocol. After MH classification, surplus muscle specimens were subjected to the DOI study. DOI was added to the organ bath in a concentration of 0.02 mmol/l. The in vitro effects on contracture development and muscle twitch were observed for 120 min. RESULTS. Muscle specimens of all patients developed contractures after administration of DOI. However, DOI produced an earlier development of contracture in MHS (17.0 +/- 1.8 min; n = 17) than in MHN (64.7 +/- 5.9 min; n = 15) muscles. In MHS muscles, contractures were more distinct than in MHN muscles; at the end of the experiment, contractures had reached a maximum of 12.5 +/- 0.9 mN in MHS and 5.1 +/- 0.7 mN in MHN muscles. Muscle twitch following DOI administration was reduced significantly in both MHS and MHN muscles. The results of four MHE muscles were comparable with MHS. CONCLUSION. The present study supports the assumption that an altered serotonin system might be involved in the development of MH. In further studies it should investigated whether 5-HT2 receptors of skeletal muscles from MHS subjects are disordered in function or structure. 5-HT2 receptor agonists should be considered as MH-triggering agents.

Attenuation of serotonin-induced contractures in skeletal muscle from malignant hyperthermia-susceptible patients with dantrolene.

BACKGROUND: Porcine malignant hyperthermia (MH) can be triggered by administration of certain serotonin2 receptor agonists. Pretreatment with dantrolene completely abolished serotonin-induced MH. The purpose of this study was to investigate the effects of the serotonin2 receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) in skeletal muscle specimens from MH-susceptible (MHS) and MH-nonsusceptible (MHN) patients following pretreatment with dantrolene. METHOD: We used muscle specimens surplus to diagnostic requirements from 12 MHS and 13 MHN patients in this study. In the first experiment, DOI 0.02 mM was added to the organ bath. In the second experiment, muscle specimens were preincubated with dantrolene 0.5 microM or 1.0 microM, respectively, for 10 min before DOI 0.02 mM was administered. RESULTS: Administration of DOI 0.02 mM induced contractures in muscle specimens from MHS and MHN patients. Contracture development started significantly earlier in MHS than in MHN specimens. In MHS muscle the maximum contracture was significantly greater than in MHN. Pretreatment with dantrolene significantly delayed the start of contracture development in MHS muscles, whereas in MHN muscles no contractures were observed after dantrolene. The contracture maximum was significantly reduced in MHS. CONCLUSION: The acceleration of DOI-induced contracture development in skeletal muscle specimens from MHS patients indicates that an altered serotonin system might be involved in human MH. Dantrolene effectively delayed serotonin-induced contractures. Further investigations are needed to determine whether serotonin2 receptors of skeletal muscle from MHS subjects are altered in function or structure, or whether this response is a secondary phenomenon.

[Incidence of disposition for malignant hyperthermia in patients with neuromuscular diseases]. / Inzidenz der Disposition zur malignen Hyperthermie bei Patienten mit neuromuskulären Erkrankungen.

PURPOSE: It has been suggested that malignant hyperthermia (MH) occurs more frequent in patients with neuromuscular diseases (NMD) than in patients without NMD when they are exposed to volatile anaesthetics and/or succinylcholine. However, whereas central core disease (CCD) and MH susceptibility (MHS) are closely associated, the relationship between MH and other NMD is still uncertain. The purpose of this study was to evaluate the MH status of individuals with specific NMD with the in vitro contracture test (IVCT) and to ascertain the risk for MH in individuals with NMD. METHODS: After institutional approval and informed consent, 29 patients of 3-59 years of age (27.2 +/- 17.3) with clinical suspicion for NMD and MH were enrolled in this prospective study. After excision of a skeletal muscle sample from M. vastus lateralis, patients were first classified as MHS, MH-equivocal (MHE) and MH-normal (MHN) by the IVCT according to the European MH protocol. Additionally, small muscle samples were excised from each patient for histological, histochemical and morphometric examination. RESULTS: Fourteen patients were diagnosed by the IVCT as MHS and 9 as MHN. In 6 patients MH status was equivocal. In six patients CCD was diagnosed, in 14 individuals muscular dystrophies and in 5 patients myotonias. Two patients had unspecific myopathies and one patient a carnitine deficiency syndrome. One patient with Friedreich's ataxia was investigated because of a MH crisis and classified as MHE. All CCD patients and two of three individuals with Duchenne's muscular dystrophy were tested as MHS. CONCLUSION: In this study 69% of the NMD patients were diagnosed as susceptible to MH with the IVCT. These results suggest, that NMD patients bear a high risk for MH. On the other hand, it has been discussed that in vitro contracture testing is not specific in NMD patients because skeletal muscle specimens from these patients have an elevated in vitro sensitivity. However, regarding our results and from a clinical point of view, patients with NMD should be treated like MHS individuals, unless they have undergone IVCT and were classified as MH-normal.