Rapid identification of goblet cells in unstained colon thin sections by means of quantum cascade laser-based infrared microspectroscopy.

Changes in the volume covered by mucin-secreting goblet cell regions within colon thin sections may serve as a means to differentiate between ulcerative colitis and infectious colitis. Here we show that rapid, quantum cascade laser-based mid-infrared microspectroscopy might be able to contribute to the differential diagnosis of colitis ulcerosa, an inflammatory bowel disease. Infrared hyperspectral images of mouse colon thin sections were obtained within 7.5 minutes per section with a pixel size of 3.65 × 3.65 µm(2) and a field of view of 2.8 × 3.1 mm(2). The spectra were processed by training a random decision forest classifier on the basis of k-means clustering on one thin section. The trained algorithm was then applied to 5 further thin sections for a blinded validation and it was able to identify goblet cells in all sections. The rapid identification of goblet cells within these unstained, paraffinized thin sections of colon tissue was enabled by the high content of glycopeptides within the goblet cells as revealed by the pronounced spectral signatures in the 7.6 µm-8.6 µm and the 9.2 µm-9.7 µm wavelength ranges of the electromagnetic spectrum. More so, the simple calculation of the ratio between the absorbance values at 9.29 µm and 8.47 µm provides the potential to further shorten the time for measurement and analysis of a thin section down to well below 1 minute.

An intronic base alteration of the CHRNE gene leading to a congenital myasthenic syndrome.

Reported is a patient with a congenital myasthenic syndrome due to two compound heterozygous mutations of the CHRNE gene. The molecular consequences of a novel intronic base alteration (CHRNE IVS5-16GA) remote from the splice acceptor site were investigated in vivo and in vitro. In conclusion, RNA analysis may be necessary to reveal unexpected splicing aberrations due to intronic mutations that are not part of the consensus splice site.

High dose vitamin E therapy in amyotrophic lateral sclerosis as add-on therapy to riluzole: results of a placebo-controlled double-blind study.

UNLABELLED: Increasing evidence has suggested that oxidative stress may be involved in the pathogenesis of amyotrophic lateral sclerosis (ALS). The antioxidant vitamin E (alpha-tocopherol) has been shown to slow down the onset and progression of the paralysis in transgenic mice expressing a mutation in the superoxide dismutase gene found in certain forms of familial ALS. The current study, a double blind, placebo-controlled, randomised, stratified, parallel-group clinical trial, was designed to determine whether vitamin E (5000 mg per day) may be efficacious in slowing down disease progression when added to riluzole. METHODS: 160 patients in 6 German centres with either probable or definite ALS (according to the El Escorial Criteria) and a disease duration of less than 5 years, treated with riluzole, were included in this study and were randomly assigned to receive either alpha-tocopherol (5000 mg per day) or placebo for 18 months. The Primary outcome measure was survival, calculating time to death, tracheostomy or permanent assisted ventilation, according to the WFN-Criteria of clinical trials. Secondary outcome measures were the rate of deterioration of function assessed by the modified Norris limb and bulbar scales, manual muscle testing (BMRC), spasticity scale, ventilatory function and the Sickness Impact Profile (SIP ALS/19). Patients were assessed at entry and every 4 months thereafter during the study period until month 16 and at a final visit at month 18. Vitamin E samples were taken for compliance check and Quality Control of the trial. For Safety, a physical examination was performed at baseline and then every visit until the treatment discontinuation at month 18. Height and weight were recorded at baseline and weight alone at the follow-up visits. A neurological examination as well as vital signs (heart rate and blood pressure), an ECG and VEP's were recorded at each visit. Furthermore, spontaneously reported adverse experiences and serious adverse events were documented and standard laboratory tests including liver function tests performed. For Statistical Analysis, the population to be considered for the primary outcome measure was an "intent-to-treat" (ITT) population which included all randomised patients who had received at least one treatment dose (n = 160 patients). For the secondary outcome measures, a two way analysis of variance was performed on a patient population that included all randomised patients who had at least one assessment after inclusion. RESULTS: Concerning the primary endpoint, no significant difference between placebo and treatment group could be detected either with the stratified Logrank or the Wilcoxon test. The functional assessments showed a marginal trend in favour of vitamin E, without reaching significance. CONCLUSION: Neither the primary nor the secondary outcome measures could determine whether a megadose of vitamin E is efficacious in slowing disease progression in ALS as an add-on therapy to riluzol. Larger or longer studies might be needed. However, administration of this megadose does not seem to have any significant side effects in this patient population.

[Classical crossed pontine syndromes]. / Klassische alternierende Syndrome der Brücke. Eine historisch-kritische und topodiagnostische Analyse.

Definitions of classical crossed brainstem syndromes in the modern neurological literature are often inaccurate and inconsistent. As a result, different clinical syndromes are designated with the same eponym, other crossed syndromes are nearly completely forgotten. In this study, the original historical publications on the classical alternating pontine syndromes of Foville, Millard-Gubler, Raymond, Raymond-Cestan, Brissaud-Sicard, Gasperini, Grenet and Gelle were reviewed and critically analysed. Their anatomic basis and etiology, and the main publications about each syndrome were discussed. We conclude that the syndromes of Foville, Millard-Gubler, Raymond, Raymond-Cestan and Brissaud-Sicard are interpreted in their essential parts concurring to their historical descriptions. Crossed syndromes of Foville and Millard-Gubler are occasionally mixed up with each other. The syndromes in the last decades described as crossed syndromes of Gasperini and Grenet were, however, never described by Gasperini and Grenet. The existence of the Gelle's as "paralysie alterné de l'acoustique" postulated syndrome seems to be very questionable.

[Unilateral amaurosis as the only focal symptom caused by dissection of the common carotid artery]. / Unilaterale Amaurose als einziges fokales Zeichen einer Carotis-communis-Dissektion.

BACKGROUND: Central retinal artery occlusion with persistent amaurosis as the only focal symptom caused by dissection of the internal carotid artery has occasionally been reported. Central retinal artery occlusion due to a common carotid artery dissection has been diagnosed only very rarely. CASE REPORT: We describe a patient presenting with cervical pain, headache and unilateral amaurosis due to a thrombosis of the central retinal artery caused by a common carotid artery dissection, as demonstrated on MR imaging. No other neurological deficits could be detected. The patient underwent an anticoagulative treatment without improvement of his vision, but also without the appearance of further neurological symptoms. CONCLUSION: In monocular visual loss combined with cervical pain or headache, carotid artery dissection should be considered. Early treatment might be of crucial importance for the prevention of a devastating hemispheric stroke.

Serial magnet resonance angiography in patients with vasculitis and vasculitis-like angiopathy of the central nervous system.

The purpose of the study was to examine the value of the non-invasive magnet resonance angiography (MRA) in the follow-up of cerebral vasculitis (CV) and vasculitis-like angiopathy. We performed follow-up MRA (TOF 3D), MRI and transcranial doppler ultrasound (TCD) in the patients with isolated angiitis of the CNS (2/6), Crohn-disease-associated CV (1/6), and reversible arterial vasoconstriction (RAV) of the CNS (1 migraine, 1 eclampsia and 1 toxic encephalopathy) (3/6). In all patients with RAV MRA showed a complete remission of the vascular alterations after treatment. In the patients with isolated angiitis of the CNS and Crohn-disease-associated CV, partly regressive and partly progressive changes were demonstrated. The MR-angiographically detectable vascular alterations corresponded to the clinical course of the disease, as well as to TCD in all our patients. Success of therapeutic procedures, the need and the intensity of further drug administration could be estimated. The MRA appears to be a valuable non-invasive method in the follow-up of patients with CV and RAV.

[The clinical spectrum of limb-girdle muscular dystrophies type 2I in cases of a mutation in the "fukutin-related- protein"-gene]. / Klinisches Spektrum der Gliedergürtelmuskeldystrophie Typ 2I bei Mutation im "Fukutin-Related-Protein"-Gen.

LGMD2I, linked to chromosome 19q13.3, is caused by mutations in the fukutin related protein (FKRP) gene. This myopathy has a variable clinical course with weakness and wasting of the shoulder girdle muscles and proximal extremities, calf hypertrophy, and elevated serum CK. We describe five patients from four families harboring the typical C826A mutation in the FKRP gene. Three patients showed the typical clinical features of LGMD2I. One patient had prominent exercise-induced myalgia in addition to a limb-girdle syndrome. Another patient had myalgia, cramps, elevated serum CK and dilatative cardiomyopathy without muscle weakness and wasting. Thus, the phenotype of the C826A mutation in the FKRP gene is apparently not restricted to a clinical limb girdle syndrome.

[Avellis' syndrome in brainstem infarctions]. / Avellis-Syndrom bei Hirnstammischämien.

In 1891 Georg Avellis described a so-called "laryngeal hemiplegia" that can be caused by peripheral lesions of the vagal and glossopharyngeal nerves and rarely by infarctions of the medulla oblongata, thus representing a classical brainstem syndrome. In this study we describe two patients with an Avellis' syndrome caused by brainstem ischemia. Contemporary publications about Avellis' syndrome in brainstem lesions seem to be very inhomogenous. They report various diseases with unilateral laryngeal palsy due to nucleus ambiguus lesions with diverse additional neurological symptoms. We conclude that according to Avellis' original description only the combination of ipsilateral palatolaryngeal paresis and contralateral hemiparesis and/or hemihypesthesia should to be interpreted as Avellis' syndrome.

[Classical crossed syndromes of the medulla oblongata. A historical and topodiagnostic discussion]. / Klassische alternierende Medulla-oblongata-Syndrome - Eine historisch-kritische und topodiagnostische Analyse -

Historical publications of the classical alternating medulla oblongata syndromes of Wallenberg, Babinski-Nageotte, Cestan-Chenais, Hughlings Jackson, Avellis, Schmidt, Dejerine, Spiller and Tapia were reviewed and critically analysed. We compare these descriptions with descriptions of the brainstem syndromes in well-known modern German, English and Russian neurological textbooks. The anatomic basis and etiology of the alternating medullar syndromes, and the main publications relating to these syndromes were discussed. Causes of the inconsistencies of the modern and historical descriptions of these syndromes might be an ignorance of the historical references. Progress and development of the clinical neurology and neuroanatomy in the late twentieth century, however, has also lead to correction and perfection of some historical descriptions in the modern neurological literature.

[Facioscapulohumeral muscular dystrophy. The spectrum of clinical manifestations and molecular genetic changes]. / Fazioskapulohumerale Muskeldystrophie. Spektrum der klinischen Manifestationen und molekulargenetischen Veränderungen.

Although the gene for facioscapulohumeral muscular dystrophy (FSHD) has not been identified so far, 4q35 deletion represents a diagnostic marker of the disease. In the present study, 46 consecutive symptomatic patients with 4q35 FSHD deletions or typical FSHD clinical features were evaluated. The patients were divided into three groups: 33 patients (72%) with typical FSHD phenotype and 4q35 FSHD deletion, eight (17%) with atypical (non-Landouzy-Dejerine) FSHD phenotype but with 4q35 FSHD deletion, and five patients (11%) with the typical FSHD phenotype but without FSHD 4q35 deletion. Apparently, the 4q35 deletion is associated not only with Landouzy-Dejerine FSHD but also with a variety of "atypical" FSHD forms. On the other hand, the Landouzy-Dejerine FSHD phenotype is possibly a polyetiological syndrome caused in some patients by other genetic effects than 4q35 deletion.

[Hauptmann-Thannhauser muscular dystrophy and differential diagnosis of myopathies associated with contractures]. / Die Hauptmann-Thannhauser-Muskeldystrophie und Differenzialdiagnosen von Myopathien mit Kontrakturen.

Hauptmann-Thannhauser muscular dystrophy is characterized by the clinical triad of early-onset contractures of elbow, Achilles tendons, and cervical spine, slowly progressive humeroperoneal muscle wasting and weakness, and life-threatening cardiac involvement with conduction blocks manifesting in the third decade. Hauptmann-Thannhauser muscular dystrophy is due to mutations in the LMNA gene affecting the nuclear envelope proteins lamin A and C. We present a 16-year-old German boy with typical muscular involvement and contractures and typical course of Hauptmann-Thannhauser muscular dystrophy due to the novel missense mutation R401C. The data of this family suggest a lower penetrance of muscular and especially cardiac symptoms than expected. Autosomal-dominant Hauptmann-Thannhauser muscular dystrophy and X-chromosomal Emery-Dreifuss muscular dystrophy are not clearly distinguishable by phenotypic criteria. Other muscular diseases associated with contractures and congenital or childhood onset are reviewed.

Higher proportion of mitochondrial A3243G mutation in blood than in skeletal muscle in a patient with cardiomyopathy and hearing loss.

Phenotypes of individuals with the mitochondrial A3243G mutation and amount of mutant DNA in different tissues can be very variable, but the proportion of mutant DNA was consistantly lower in blood than muscle in previously studied patients. We detected the A3243G mutation in a 54-year-old patient with cardiomyopathy and hearing loss, where the amount of mutant DNA was higher in blood (19%) than in muscle (6%). This shows that the level of A3243G mutation is not always lower in rapidly dividing tissues such as blood than in muscle, as has been presumed until now.

Mitochondrial 3243 A-->G mutation (MELAS mutation) associated with painful muscle stiffness.

The mitochondrial mutation A-->G at nucleotide position 3243 is associated with mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS) and other mitochondrial encephalomyopathies. We found this mutation in a 61-year-old patient who developed at the age of 54 a myopathy with painful muscle stiffness as the predominant symptom. Additionally hypacusis, a mild hemisensory syndrome and impaired glucose tolerance were present. Muscle histopathology showed few ragged red fibers. The mutation was detected heteroplasmatically in DNA from muscle and blood. So far painful muscle stiffness has not been a known phenotype of the 3243 mutation.

Increase of mitochondria in vasa nervorum of cases with mitochondrial myopathy, Kearns-Sayre syndrome, progressive external ophthalmoplegia and MELAS.

Previous studies on patients with mitochondrial myopathy, encephalopathy, lactic acidosis, and stroke-like episodes (MELAS) revealed accumulations of mitochondria in endothelial cells, smooth muscle cells of pial arterioles, and small intracerebral arteries up to 250 microns in diameter; in pericytes of capillaries, endothelial cells, and smooth muscle cells of small blood vessels in skeletal muscle; and according to preliminary results also in endothelial and smooth muscle cells of capillaries and arterioles in sural nerves. These mitochondria do not show the prominent paracrystalline inclusions which are seen in striated muscle fibres and led to the identification of this group of disorders. To corroborate our preliminary findings in peripheral nerves, additional cases have been evaluated morphometrically by electron microscopy including cases in which mitochondrial DNA (mtDNA) mutations have been identified. In fact, an increase of the mean number and an enlargement of the mean cross-sectional area of mitochondria was noted in endothelial and smooth muscle cells of endoneurial and epineurial arterioles, and in endothelial cells and in pericytes of capillaries in sural nerves of the 20 cases with mitochondrial disorders studied. This increase was statistically significant compared to the control group. However, due to heteroplasmia, which is a common feature in mitochondrial disorders, and because of the limited number of measurable blood vessels and cases, no significant differences could be detected between the various types of mitochondrial diseases which were characterized by different point mutations or deletions of mtDNA. Our findings suggest that the mitochondria play a significant role in the pathogenesis not only of myopathic and encephalopathic symptoms, but also in the pathogenesis of peripheral neuropathy which appears to be regularly associated with mitochondrial disorders.