Association between probable REM sleep behavior disorder and increased dermal alpha-synuclein deposition in Parkinson's disease.

INTRODUCTION: Many patients with Parkinson's disease suffer from REM sleep behavior disorder, potentially preceding the onset of motor symptoms. Phospho-alpha-synuclein is detectable in skin biopsies of patients with isolated REM sleep behavior disorder several years prior to the onset of manifest PD, but information on the association between dermal phospho-alpha-synuclein deposition and REM sleep behavior disorder in patients with manifest PD is limited. We therefore aimed to investigate the alpha-synuclein burden in dermal peripheral nerve fibers in patients with Parkinson's disease with and without REM sleep behavior disorder. METHODS: Patients with Parkinson's disease (n = 43) who had undergone skin biopsy for the immunohistochemical detection of phosphorylated alpha-synuclein were screened for REM sleep behavior disorder using RBDSQ and Mayo Sleep Questionnaire. Skin biopsies from 43 patients with isolated polysomnography-confirmed REM sleep behavior disorder were used as comparators. RESULTS: Dermal alpha-synuclein deposition was more frequently found (81.8% vs. 52.4%, p = 0.05) and was more abundant (p = 0.01) in patients with Parkinson's disease suffering from probable REM sleep behavior disorder compared to patients without REM sleep behavior disorder and was similar to patients with isolated REM sleep behavior disorder (79.1%). CONCLUSION: The phenotype of REM sleep behavior disorder is associated with high amounts of dermal alpha-synuclein deposition, demonstrating a strong involvement of peripheral nerves in patients with this non-motor symptom and may argue in favor of REM sleep behavior disorder as an indicator of a "body-predominant" subtype of Parkinson's disease.

Ancient noeggerathialean reveals the seed plant sister group diversified alongside the primary seed plant radiation.

Noeggerathiales are enigmatic plants that existed during Carboniferous and Permian times, ∼323 to 252 Mya. Although their morphology, diversity, and distribution are well known, their systematic affinity remained enigmatic because their anatomy was unknown. Here, we report from a 298-My-old volcanic ash deposit, an in situ, complete, anatomically preserved noeggerathialean. The plant resolves the group's affinity and places it in a key evolutionary position within the seed plant sister group. Paratingia wuhaia sp. nov. is a small tree producing gymnospermous wood with a crown of pinnate, compound megaphyllous leaves and fertile shoots each with Ω-shaped vascular bundles. The heterosporous (containing both microspores and megaspores), bisporangiate fertile shoots appear cylindrical and cone-like, but their bilateral vasculature demonstrates that they are complex, three-dimensional sporophylls, representing leaf homologs that are unique to Noeggerathiales. The combination of heterospory and gymnospermous wood confirms that Paratingia, and thus the Noeggerathiales, are progymnosperms. Progymnosperms constitute the seed plant stem group, and Paratingia extends their range 60 My, to the end of the Permian. Cladistic analysis resolves the position of the Noeggerathiales as the most derived members of a heterosporous progymnosperm clade that are the seed plant sister group, altering our understanding of the relationships within the seed plant stem lineage and the transition from pteridophytic spore-based reproduction to the seed. Permian Noeggerathiales show that the heterosporous progymnosperm sister group to seed plants diversified alongside the primary radiation of seed plants for ∼110 My, independently evolving sophisticated cone-like fertile organs from modified leaves.

[Diagnostics of Wilson's disease]. / Diagnostik des Morbus Wilson.

Wilson's disease is a rare genetic but treatable metabolic disorder which has a favorable prognosis when diagnosed early and treated adequately. Therefore, knowledge of this rare clinical condition and a reliable diagnosis are indispensable. The diagnostic work-up is initiated in cases of unexplained acute or chronic liver disease and/or an extrapyramidal motor disturbance occurring mostly between the 5th and 45th years of life. Manifestations with initial symptoms have occasionally been observed at an age younger than 1 year and later than 70 years. Immediate biochemical and genetic examinations for early diagnosis are essential. Further test methods, such as liver and transcranial sonography, cerebral magnetic resonance imaging (MRI) and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET), 123I-beta-CIT and 123I-iodobenzamide (IBZM) single photon emission computed tomography (SPECT), electrophysiology as well as fine motor tests are unspecific but can be used to test for organ damage and for monitoring of progress. Immediate initiation of a therapy is required and justified on the basis of a confirmed diagnosis.

[Therapeutic management in early disease stages of systemic sclerosis : early diagnosis - early symptoms - early problems]. / Therapeutische Strategien im Frühstadium der systemischen Sklerose : Frühe Diagnose - frühe Symptome - frühe Probleme.

Increasing knowledge about the rare disease systemic sclerosis and improved diagnostic methods in the course of recent decades has led to the possibility of diagnosing systemic sclerosis at earlier disease stages. However, earlier diagnosis has an impact on routine clinical care of affected patients, and rheumatologists need to know about early symptoms, their diagnosis, and clinical management. In this review, the therapeutic management of early disease stages is described. In particular, we focus on diagnostic tools which should be included in a "basic assessment" of systemic sclerosis and discuss the diagnosis and treatment options of early symptoms such as Raynaud phenomenon, puffy fingers and hand edema, digital ulcers, calcinosis cutis, and cardiopulmonary, renal, and gastrointestinal involvement. Finally, the options of early immunosuppressive treatment and autologous stem cell transplantation for patients with rapid progressive and severe disease are reviewed.

[Wilson's disease]. / Morbus Wilson.

Wilson's disease is a rare autosomal recessive disorder of hepatic copper transport leading to a biliary excretion inhibition of copper. Overload of the metal mainly in liver and basal ganglia leads to hepatic but also to extrapyramidal motor as well as psychiatric clinical symptoms. Diagnosis is based on clinical suspicion, parameters of copper metabolism, ophthalmic examination and a liver biopsy. A radiocopper test is able to identify patients even with inconsistent laboratory results. For initial assessment and follow-up neurophysiological investigation and MRI are recommended additionally. Genetic analysis can be helpful to detect asymptomatic relatives of the index patient. Dependent on the stage of the disease for therapy chelating drugs and zinc are possible but must be given lifelong without longer interruptions. With early diagnosis and consequent treatment the prognosis of Wilson's disease is excellent and usually the need for liver transplantation can be prevented.

[Correlation of clinical aspects as well as genotype and phenotype in Wilson's disease on the basis of epidemiologic, clinical and cranial MRI findings]. / Klinische und Genotyp-Phänotyp-Korrelation epidemiologischer, bildgebender und neurologischer Befunde bei Patienten mit Morbus Wilson.

Wilson's disease, a rare autosomal recessive disorder of hepatic copper transport, is characterized by a varying pattern of hepatic, neurologic and psychiatric symptoms. Currently, about 250 causative mutations of the ATP 7B gene are known. However, a correlation between genotype and phenotype according to these mutations is not yet clear. To elucidate a possible correlation in this study 39 patients with Wilson's disease were subdivided into three groups according to the underlying mutation in group I for homocygote respectively group II for compound heterocygote mutation in H1069Q and group III for other mutations. Clinical subtype and extent of neurologic disturbance as well as epidemiologic aspects, presence of psychiatric symptoms, results of acustically evoked potentials (Wave III, interpeak latency III-V) and findings of cranial MRI were considered. While psychopathological symptoms, the results of acustically evoked potentials and cranial MRI show a correlation to the clinical subtype of Wilson's disease there was no genotype-phenotype correlation on the basis of the mutation in H1069Q. The qualitative and quantitative pattern of results do not show any significant differences in the three groups of genotype. Thus, the time of treatment onset still has most influence on the extent of clinical manifestation and reversibility of the toxic copper accumulation.

[Tumour necrosis factor receptor-associated periodic syndrome. A rare differential diagnosis of multiple sclerosis]. / TNF-Rezeptor-assoziiertes periodisches Syndrom. Seltene Differenzialdiagnose der Multiplen Sklerose.

Tumour necrosis factor receptor-associated periodic syndrome (TRAPS), a rare autosomal dominant disorder, is characterised by recurrent attacks of fever, myalgias, and abdominal pain. However, manifestations in the central nervous system are hardly known. We describe a family in which one of three affected members developed central nervous system symptoms. First diagnosed as multiple sclerosis (MS), the demyelinisation seems to be a feature of TRAPS rather than MS. The syndrome is discussed as a rare differential diagnosis of MS.

[Therapeutic management of necrotizing neck infections]. / Therapeutisches Management nekrotisierender Weichteilinfektionen des Halses.

BACKGROUND: Necrotizing neck infections are uncommon soft-tissue infections, usually caused by virulent, toxin producing bacteria. Necrotizing fasciitis represents a special form of necrotizing soft tissue infection with a mortality rate of up to 76% even though aggressive therapy is recommended. PATIENTS AND METHODS: In the last 2 years we treated four patients with severe necrotizing neck infections and five suffering from necrotizing fasciitis. RESULTS: Microbiological analysis revealed mixed infections with Candida albicans, Streptococcus pyogenes, Fusobacterium, Proprioni bacteria and Staphylococcus. The surgical management was not only restricted to drainage, but also included functional neck dissection in order minimize the spread of the disease. Eight of our patients recovered completely, but one died due to toxic shock as consequence of a delayed in therapy. CONCLUSION: Complete recovery of patients suffering from necrotizing fasciitis depends on early and aggressive surgical therapy including neck dissection and drainage as well as an interdisciplinary strategy of conservative therapy. Hyperbaric oxygen should be considered as a treatment adjunct in patients with necrotizing fasciitis if surgery and antibiotic treatment fail.

[Primary nasal epithelial cells and fibroblasts have inflammation-inducing functions]. / Primäre nasale Epithelzellen und Fibroblasten haben entzündungsfördernde Eigenschaften.

BACKGROUND: The appearance of neutrophils in rhinitis and sinusitis led to the working hypothesis that neutrophil-specific attractants commonly called chemokines are generated by stimulation with proinflammatory cytokines and bacteria. The receptor mechanism of chemokine synthesis by bacterial products is under discussion and still has to be elucidated. PATIENTS AND METHODS: The primary nasal cultures of epithelial cells and fibroblasts ( n=4) were incubated with TNF-alpha (tumor necrosis factor) for 24 and 72 h. Bacterial stimulation of the cell cultures was performed by adding supernatants from the mucoid phenotype of Pseudomonas aeruginosa (PA01) in dilution 1:5 for 24 and 72 h. Supernatants were collected and the concentration of the chemokines interleukin-8 (IL-8), GRO-alpha (growth-related oncogene-alpha), and ENA-78 (epithelial neutrophil-activating peptide) were determined by ELISA technique. Our results revealed that the protein concentration of the chemokines GRO-alpha and IL-8 was upregulated by TNF-alpha as well as by bacterial supernatants in epithelial cells. CONCLUSION: We conclude that GRO-alpha and IL-8 were inducible by bacterial supernatants in nasal epithelial cells and fibroblasts.

Neutrophil chemokines in cultured nasal fibroblasts.

BACKGROUND: To gain insight into the mechanisms responsible for tissue neutrophil immigration in sinusitis, primary nasal fibroblasts are analyzed for synthesizing and delivering neutrophil chemokines. METHODS: Primary nasal fibroblast cell culture was treated with tumor necrosis factor (TNF)-alpha concentrations of 20 and 200 ng/ml for 2, 8, 24 and 72 h. Chemokine concentrations in supernatants were determined by enzyme-linked immunoassay (ELISA) and chemokine mRNA expression in fibroblasts was measured by reverse transcriptase polymerase chain reaction (RT-PCR). Biological chemotactic activity was identified by three-step high-performance liquid chromatography (HPLC) and by bioassay measuring neutrophil chemotaxis in a single Boyden chamber system. RESULTS: Interleukin (IL)-8 and growth-related oncogene (GRO)-alpha were induced in nasal fibroblast culture by proinflammatory stimulus. After 24 h of stimulation neutrophil chemotactic activity only was detected for IL-8. Granulocyte chemotactic protein (GCP)-2 mRNA was already significantly up-regulated after 2 h of stimulation. CONCLUSION: Induction of IL-8 protein dominates chemokine synthesis 24 and 72 h after stimulation, whereas induction of GCP-2 mRNA seems to have a role in the early phase after 2 h of exposition with TNF-alpha.

Percutaneous endovascular abdominal aortic aneurysm repair.

In this prospective, nonrandomized study, we compared outcome with percutaneous femoral artery closure to that with open femoral arteriotomy in 95 patients who underwent endovascular AAA repair. Devices were introduced using 22 Fr and/or 16 Fr sheaths. The 8 Fr/10 Fr Perclose devices (Perclose Inc., Redwood City, CA) were used in an off-label "preclose technique." Thirty-three patients had bilateral open femoral arteriotomies, 44 patients had bilateral attempted percutaneous closure, and 18 patients had open femoral arteriotomy on one side and attempted percutaneous closure on the other side. Percutaneous closure was successful in 85% (47/55) of 16 Fr sheaths and 64% (29/45) of 22 Fr sheaths (p < 0.027). Bilateral percutaneous closure was successful in 63% (28/44) of patients. Conversion to open femoral arteriotomy due to bleeding occurred in 24 of 106 percutaneous attempts. There were no dissections, arterial thromboses, or pseudoaneurysms associated with percutaneous arterial closure. Wound complications were seen in 3.6% (3/84) of open arteriotomies and 0.9% (1/106) of all percutaneous attempts and arterial closures (p > 0.05). Gender, previous femoral access, obesity, and iliac occlusive disease were not predictive of percutaneous failure. Procedural success for percutaneous AAA repair is affected by sheath size. Devices delivered through 16 Fr or smaller sheaths will have successful femoral artery closure rates of at least 85%.

External iliac artery-to-internal iliac artery endograft: a novel approach to preserve pelvic inflow in aortoiliac stent grafting.

PURPOSE: To describe four patients with abdominal aortic aneurysm and bilateral common iliac artery aneurysms repaired by coil embolization of the ipsilateral internal iliac artery, aortouniiliac endograft extended to the ipsilateral external iliac artery, femorofemoral bypass grafting, and a contralateral external iliac to internal iliac stent graft to preserve pelvic perfusion. METHODS: Four patients with multiple risk factors, abdominal aortic aneurysm (mean diameter, 6.6 cm), and bilateral common iliac artery aneurysms were evaluated with contrast-enhanced computed tomography scanning, arteriography, and intravascular ultrasonography. Aortobiiliac endovascular abdominal aortic aneurysm repair was not feasible because of extension of the common iliac artery aneurysms to the iliac bifurcation bilaterally. RESULTS: The abdominal aortic aneurysms were repaired with an aortouniiliac endograft. The ipsilateral common iliac artery aneurysms were treated by coil embolization of the internal iliac artery and extension of the endograft to the external iliac artery. The contralateral common iliac artery aneurysms were excluded by a custom-made stent graft (n = 2) or a commercial stent graft (n = 2) from the external iliac artery to the internal iliac artery, which preserved pelvic inflow via retrograde perfusion from the femorofemoral bypass. Mean length of stay was 3.5 days. One patient had hip claudication. Follow-up (mean 10 months, range 6 to 17) demonstrated exclusion of the abdominal aortic aneurysm and common iliac artery aneurysms with no endoleak and patent external iliac artery-to-internal iliac artery endografts in all patients. CONCLUSION: Patients with bilateral common iliac artery aneurysms that extend to the iliac bifurcation may be excluded from endovascular abdominal aortic aneurysm repair because of concerns regarding pelvic ischemia after occlusion of both internal iliac arteries. External iliac artery-to-internal iliac artery endografting is a feasible alternative to maintain pelvic perfusion and still allow endograft repair of the abdominal aortic aneurysm in these patients.

High prevalence of the H1069Q mutation in East German patients with Wilson disease: rapid detection of mutations by limited sequencing and phenotype-genotype analysis.

BACKGROUND/AIMS: Wilson disease is caused by a large number of different mutations in the ATP7B gene. Wilson disease patients from a homogeneous ethnical background (Saxonia) were studied for distribution and phenotypes of ATP7B mutations. METHODS: Eighty-two patients were analyzed. The H1069Q mutation was assayed by a polymerase chain reaction-based restriction fragment length polymorphism test. Exons 8 and 15 were sequenced in all, and the entire gene in 30, non-H1069Q-homozygotes. RESULTS: Four novel and 12 known mutations were found. Thirty-two (39%) Wilson disease patients were homozygous and 39 (48%) heterozygous for the H1069Q mutation (allele frequency 63%). Together with sequence analysis of exons 8 and 15 mutations in both alleles were identified in 65% of patients. Only one patient had both mutations at other locations. In H1069Q homozygotes symptoms started later (21.3+/-7.2 years) than in H1069Q compound heterozygotes (14.6+/-5.8, P<0.001) or H1069Q negatives (10+/-4.4, P<0.001), and they had more frequently neurologic symptoms (93 vs. 47%, P<0.001) and Kayser-Fleischer rings (82 vs. 51%, P<0.001). Mutation status did not correlate with liver biopsy findings, serum ceruloplasmin levels or (64)Cu-assay results. CONCLUSIONS: In spite of many known ATP7B mutations, only few occur in this homogeneous population. Limited genetic testing is useful to confirm Wilson disease in this population.

[Topical Mitomycin C for the prophylaxis of recurrent haze after excimer laser photorefractive keratectomy (PRK) - a pilotstudy of 5 patients]. / Topisches Mitomycin C zur Rezidivprophylaxe von Haze nach erneuter Excimer-Laser-photorefraktiver Keratektomie (PRK) - Klinische Pilotstudie an 5 Patienten.

PURPOSE: Corneal haze is a severe complication after excimer laser PRK and may lead to a compromised visual performance and regression. Currently, corticosteroids are topically applied to inhibit the appearance of haze. However, this therapy is not always successful in preventing haze. Various animal studies have shown that topical applied mitomycin C reduces keratocyte activity and collagen synthesis and subsequently haze. MATERIAL AND METHODS: We have treated 5 patients (5 eyes) with severe haze and regression after PRK. In all eyes we have mechanically debrided the haze and 0.02 % mitomycin C was applied to the area of previous ablation for 1 minute. In 2 eyes we have only performed the debridement, whereas in 3 eyes we also have performed a re-PRK after the laser ablation the mitomycin was applied. The postop follow-up was 9 months. RESULTS: In all eyes the surgery and the postop time was without any complications. The haze could be removed in all eyes completely and in the entire postop period recurrent haze was not more than trace. Regression could be eliminated in the three eyes with a re-PRK, whereas the 2 eyes without re-PRK still remained myop. We could not observe any mitomycin C associated complications on the conjunctiva or cornea. CONCLUSION: Topical applied mitomycin C seems to be a promising therapy to prevent recurrent haze after a second PRK procedure. As mitomycin C can be associated with a variety of serious complications, it should only be used in patients with high risk of haze.

[Hypercarotenemia, amenorrhea and a vegetarian diet]. / Hypercarotinémie, aménorrhée et régime végétarien.

In order to analyse the role of hypercarotenemia in amenorrhoea, we have studied the ovarian function of 20 patients presenting with hypercarotenemia (serum carotene greater than 5 mumol/l). 12 of these were complaining of secondary amenorrhoea (group I), 7 with a normal weight (group I A) and 5 with a weight below 85% of ideal weight (group I B). Another group of 8 patients had normal menstrual cycles and a body weight within normal limits (group II). Group I presented an ovarian insufficiency of hypothalamic origin with an increase in the FSH/LH ratio. The patients in group I A although of normal weight differed from group II by a history of important weight variations, strenuous sports activity and an essentially vegetarian diet, the most likely reason for their hypercarotenemia. The high carotene levels however do not seem to be directly responsible for the amenorrhoea, in view of the normal menstrual cycles of the patients in group II. Hypercarotenemia can be considered as a biologic marker of weight loss with fat mobilisation and low T3 levels. It can also be due to a vegetarian diet. The latter may be an aetiological factor in anovulation by increasing faecal excretion of oestrogens and thus decreasing blood levels of oestradiol particularly when associated with other compounding factors such as excessive physical activity, loss of weight or affective problems.

Hamartoma of the spleen with haematological symptoms.

We report the case of a 29 year old male patient with a splenic hamartoma suffering from infections, anaemia and thrombocytopenia. Shortly after surgical removal of the tumour the blood cell count was within normal range. Hamartomas of the spleen are rare benign tumour-like lesions composed mainly of vascular elements. Most of them remain small in size and asymptomatic and are therefore incidental findings at laparotomy or autopsy. However, occasionally they present with symptoms, among which haematological disturbances appear in very few cases; only 16 cases of splenic hamartomas with haematological symptoms are described in the literature. The major symptoms were anaemia and/or thrombocytopenia as well as frequent infections. After removal of these lesions the symptoms disappeared.

Cytochemical study of macrophage lysosomal inorganic trimetaphosphatase and acid phosphatase.

Cytochemical investigations have associated acid inorganic trimetaphosphatase (TMPase) activity with the lysosomes of certain cell types. We have used the modified staining technique of Berg to show that this enzyme activity is present in normal mononuclear phagocytes and macrophage cell lines. We have found this enzyme activity to be present in murine RAW264 macrophages, in human U937 macrophages, in normal human blood monocytes, and in guinea pig peritoneal macrophages. All of the RAW264 and U937 macrophages showed intense TMPase activity. Many of the human monocytes and most of the guinea pig macrophages were labeled by this method. The reaction product was associated with the lysosomes of these cell types. The lysosomal staining-pattern was similar to that of acid phosphatase. Differences with regard to Golgi staining were noted. This indicates that TMPase is a lysosomal enzyme of mammalian macrophages. The distinction between TMPase and acid phosphatase activity has been demonstrated by measuring the pH optimum of each enzyme. Using substrates identical to those of the ultrastructural cytochemistry, we show that the pH optimum of TMPase is 4.0 and that of acid phosphatase is 5.0. The enzymatic activities are therefore ultrastructurally and biochemically distinct. Following phagocytosis of latex, yeast (Saccharomyces cerevisiae), or Corynebacterium parvum, TMPase has been found to be associated with phagosomes. This enzyme may take part in the degradation of phagocytosed materials, particularly microorganisms which contain inorganic polyphosphates and metaphosphates.

Activatable esterase activity of murine natural killer cell--YAC tumour cell conjugates.

Natural killer (NK) cells have been obtained from mouse spleens and grown in vitro. These cells: retained cytotoxicity against YAC targets; and were homogeneous as judged by morphology and surface markers. The alpha-naphthol acetate esterases (ANAE) and diisopropyl-fluorophosphate (DFP)-binding proteins of NK cells, YAC cells and NK-YAC conjugates have been examined. Ultrastructural cytochemistry indicates that NK cells have two types of ANAE: an enzyme primarily associated with the granule externum and an activatable ANAE associated with the granule internum. Both of these activities are inhibited by DFP. The activatable ANAE appears during incubation of NK cells with YAC cells. DFP-binding proteins were examined by sodium dodecyl sulphate/polyacrylamide gel electrophoresis and autofluorography. NK cells and YAC cells have major DFP-binding proteins of 35 X 10(3) and 20 X 10(3) Mr, respectively. NK-YAC conjugates had a new band at 55 X 10(3) Mr. This new protein may be identical to the activatable ANAE described above. Our studies provide evidence for an NK cell esterase that becomes activated when incubated in the presence of tumour cells. This esterase may be related to the cytolytic mechanism.

Ovarian fetiform teratoma (homunculus) in a 9-year-old girl.

An infarcted ovarian mass, removed from a 9-year-old girl, was composed of a thin-walled cyst containing a fetiform structure. At its cranial pole was a ruptured cyst lined by skin and a diaphanous fibrous membrane associated with long, darkly pigmented hair. The remainder of the fetiform structure was covered by skin bearing fine lanugo hair. Rudimentary upper limb buds were present. At the caudal pole were two extremities that included feet, toes, and nails. Radiographic studies demonstrated portions of skull, vertebral, and limb bones. Microscopical examination revealed primitive brain tissue at the base of the cephalic cavity and a spinal cord along the entire length of the trunk with ganglia and peripheral nerves extending outward from it. Notochordal tissue was associated with one vertebral body. A mucus-filled endodermal tube containing glandular outgrowths also ran the length of the trunk. This patient is one of the youngest reported with an ovarian homunculus or fetiform teratoma. This specimen is among the very few recorded cases in the literature and reflects the highest degree of organized development exhibited by a single germ cell undergoing neoplasia.