OBJECTIVE:Malignant hyperthermia (MH) is a classically unapparent pharmacogenetic disorder of the skeletal muscles triggered by inhalational anesthetics or depolarizing muscle relaxants. The disposition to MH is inherited in an autosomal-dominant manner and is primarily due to mutations in the gene for the ryanodine receptor type 1 (RyR1). The present study intended to analyze whether mild muscular symptoms (elevation of the resting CK, cramps in the calves, slight calf hypertrophy) may be associated with susceptibility to MH and/or with histopathological changes.METHODS:A muscle biopsy was taken from 12 out of 44 blood relatives (three generations) of a large family and was investigated with the halothane/caffeine in vitro contracture test (IVCT). Afterwards a histological, histochemical and immunhistological examination was performed. Altogether in 29 persons the DNA was analyzed for mutations in the RyR1-gene.RESULTS:Eight persons were diagnosed as susceptible to MH (MHS) by the IVCT, 4 were MH negative. All MHS persons carried the MH causative c.6617C > T (Thr2206Met) mutation and showed slight clinical signs of a myopathy as well as mild biopsy changes with isolated hypotrophic fibers and disseminated small areas with reduction of oxidative staining (multi-minicore like lesions). The Thr2206Met mutation was identified in another further 9 relatives who also experienced mild myopathological features. Clinical MH incidents were not reported in this large family.CONCLUSION:The RyR1 Thr2206Met mutation is one of the most frequent mutations in the European MH population but carriers are normally healthy. In this study we could demonstrate that the MH causative Thr2206Met mutation may also be associated both with clinical symptoms of a mild myopathy and histopathological changes in the oxidative inter myofibrillar network.

Eine Herzbeteiligung ist bei der fazioskapulohumeralen Muskeldystrophie (FSHD) im Gegensatz zu anderen Muskeldystrophien nicht näher beschrieben. Wir berichten über eine 71-jährige Frau mit progredienter Herzinsuffizienz bei FSHD, die bei einer der beiden ebenfalls an dieser Erkrankung leidenden Töchter molekulargenetisch nachgewiesen worden ist. Die Verstorbene zeigte autoptisch neben Veränderungen an der quergestreiften Muskulatur, die auch fokale entzündliche Infiltrate insbesondere an der Zwerchfellmuskulatur einschließen, eine Beteiligung der Herzmuskulatur. Histologisch gleicht das Bild am Herzen dem einer primären Kardiomyopathie, jedoch ohne Erhöhung der Herzmasse. Sowohl klinisch als auch morphologisch ist der Tod dieser Patientin Folge der Herzerkrankung

Cardiac involvement is well known in a number of skeletomuscular diseases but not in facio-scapulohumeral muscular dystrophy (FSHD). We report on a 71 year old woman with progressive cardiac insufficiency in FSHD, which was also confirmed by molecular analysis in one of the two daughters affected by the disease. Autopsy of the deceased patient showed the typical changes in skeletal muscles including focal inflammatory infiltrates in the diaphragm and, in addition, cardiac muscular involvement. The histological changes resembled those seen in primary cardiomyopathy despite the normal muscle mass volume. Both clinically and morphologically, the cardiac disease was the cause of death in this patient with FSHD.

In this immunohistochemical study, the age- and stage-dependent accumulation of advanced glycation end-products (AGEs) in Alzheimer's disease (AD) and their relation to the formation of neurofibrillary tangles and neuronal cell death was investigated. For this purpose, the distribution of AGEs in neurons and glia was analyzed in the auditory association area of superior temporal gyrus (Brodmann area 22) of young and old non-demented controls and compared with early- and late-stage AD. A possible co-localization of AGEs with typical hallmarks of AD, such as hyperphosphorylated tau (as a marker for disturbed kinase/phosphatase activity), nNOS (as a marker for nitroxidative stress) and caspase-3 (as a marker of apoptotic cell death), was also investigated. Our results show that the percentage of AGE-positive neurons (and astroglia) increase both with age and, in AD patients, with the progression of the disease (Braak stages). Interestingly, nearly all if those neurons which show diffuse cytosolic AGE immunoreactivity also contain hyperphosphoryated tau, suggesting a link between AGE accumulation and the formation of early neurofibrillary tangles. Many, but not all, neurons show a co-localization of AGEs with other markers of neurodegeneration, such as nNOS and caspase-3.

Neuropathologische Untersuchungen sollen dazu beitragen,die Ursachen der zentralnervösen Komplikationen nachHerzoperationen aufzudecken und die Rate der postoperativenneurologisch-kognitiven Störungen zu reduzieren. Unter diesemAspekt haben wir die Gehirne von 262 nach herzchirurgischenOperationen (Bypass-, Klappenoperationen undHerztransplantationen) Verstorbenen untersucht. Es finden sichZirkulationsstörungen (Makro- und Mikroblutungen, Infarkte,Subarachnoidalblutungen, hypoxämische Hirnschäden) in 128 Fällen(49%), davon kommen 33 Fälle als Todesursache in Betracht(12,6%). Als Ursachen der Infarkte sind neben einerstenosierenden Arteriosklerose von Hirnarterien undThromboembolien (Operationsgebiet, Myokardinfarkte) in seltenenFällen Fettembolien (2), Fremdkörperembolien (1) undMikroembolien durch Megakaryozyten zu nennen. Weiterhin bestehenentzündliche Veränderungen in 17 Fällen, davon meistSeptikopyämien (12 Fälle) durch Pilze oder Bakterien, und in 5Fällen ließen sich Gliaknötchen als mögliches Substrat einerviralen oder Autoimmunencephalitis (Bickerstaff) nachweisen. AlsNebenbefund fand sich noch ein Morbus Alzheimer (37 Fälle, 14%des Materials) bei älteren Patienten, zum Teil mit einerAmyloidangiopatie, jedoch nicht als Todesursache und nicht alsUrsache größerer Hirnblutungen. Da die Arbeit eineAutopsiestudie darstellt, ist eine Übertragung der gefundenenVeränderungen auf die Gesamtgruppe der operierten Herzpatientenmit neurologisch-kognitiven Störungen nur bedingt möglich ist.Auf jeden Fall spielen im eigenen Material umfangreichemikroembolische Ereignisse (Fettembolie, Fremdkörperembolie),wie sie oft in der Literatur angegeben werden, keineentscheidende Rolle. Es finden sich aber, in unterschiedlicherHäufigkeit in den einzelnen untersuchten Operationsgruppen,besonders nach Klappenoperationen, Mikroblutungen der weißenSubstanz, die nicht zum Tode führen. Sie könnten, ebenso wie diegelegentlich auftretenden Gliaknötchen, nach Resorption undVernarbung postoperativ bei den Patienten neurologisch-kognitive Störungen verursachen.

The identification of PTTG (human Securin) by differential display RT-PCR in rat pituitary adenomas and its cloning from a rat pituitary tumor cell line was the initial step in understanding its function and investigating its role as a potential oncogene in different kind of neoplasias. As far as pituitary adenomas are concerned, it was found that PTTG was overexpressed in about 90% of all adenoma subtypes. A correlation between PTTG and bFGF mRNAs was described by using a semiquantitative PCR. In addition, it was shown that bFGF stimulates lactotroph proliferation, prolactin secretion and angiogenesis in pituitary adenomas and precedes increased pituitary PTTG mRNA expression in vivo. On the other hand, bFGF was directly upregulated by Securin in PTTG transformed NIH3T3 fibroblasts. As a conclusion it could be suggested the existence of an endocrine loop between PTTG and bFGF. In our study, performed in a total number of 103 biopsied pituitary adenomas, we tried to evaluate through RT-PCR possible correlations among the mRNAs of PTTG, bFGF and IGF-1. Our results agree with these of a previous investigation in respect to the mRNAs of bFGF and PTTG. However our data support further a noteworthy positive correlation between PTTG and IGF-1 in most adenoma subtypes. As it was previously suggested, IGF-1 could be a potential candidate in pituitary tumor formation. We propose therefore a possible significant role of IGF-1, in respect to PTTG overexpression, in the development of these tumors.

Neuropathological studies may contribute to the discovery of central nervous system complications after heart surgery and thus help to reduce the incidence of postoperative neurological or cognitive disturbances. We examined the brains of 262 such patients operated for coronary bypass, valve replacement, or heart transplantation. Circulatory disturbances (macro- and microhemorrhages, infarcts, subarachnoid hemorrhages, and hypoxemic brain damage) were present in 128 cases (49%), as the cause of death in 33 cases (12.6%). The infarcts were caused by local arteriosclerosis of brain arteries, arterial emboli originating from the operative sites or myocardial infarctions, or by fat emboli, foreign body emboli or megakaryocytic capillary emboli in rare cases. Inflammatory disturbances were present in 17 cases and consisted of fungal or bacterial septicopyemic changes (12) or of glial nodules (5) as the substrate of a viral or autoimmunencephalitis (Bickerstaff). An incidental finding was Alzheimer's disease in 37 cases (14% of the material) of elderly patients, often associated with cerebral amyloid angiopathy but not as cause of death or cause of macroscopic brain hemorrhage. Since we have conducted an autopsy study, there is a limitation to transfer the documented changes to the total group of post-cardiac surgery patients with neurologic and cognitive deficits. Contrary to some previous reports, histologically overt microembolic phenomena do not seem to play a major role in our material. On the other hand, careful scrutiny revealed non-fatal white matter microhemorrhages of varying frequency in the different groups, especially after valve operations. These as well as the occasional glial nodules, after resorption and microscarring, could well be the cause of slight neurologic and cognitive impairments.