Imported human rabies in Switzerland, 2012: a diagnostic conundrum.

Human rabies is rare in Western Europe. It is not easily recognized in the absence of a history of exposure. We describe the clinical course, diagnosis and follow-up of an imported human rabies case in Switzerland. The patient, a U.S. citizen, presented at an outpatient clinic in Iraq with pain in his right shoulder on July 5, 2012. On July 8 he was transferred to a hospital in the United Arab Emirates, where he exhibited progressive encephalitis with coma. On July 29, he was transferred to a hospital in Switzerland, where he died on July 31, 2012. The autopsy showed severe encephalitis. Rabies was diagnosed by the rapid fluorescent focus inhibition test (RFFIT) and confirmed by fluorescence antibody testing (FAT) in brain smears and immunohistochemistry on paraffin-embedded brain sections. The viral strain was characterized by RT-PCR followed by sequencing and phylogenetic analysis as an American bat rabies strain associated with Tadarida brasiliensis. Close contacts and exposed health care workers received postexposure prophylaxis (PEP).

[New anticoagulants - direct factor Xa-inhibitors]. / Neue Antikoagulantien - die Anti-Faktor Xa-Antagonisten.

The direct oral factor Xa-inhibitors are at present in clinical use as antithrombotics, after their efficiency and safety have been proved in clinical studies. Three products are actually in the market, rivaroxaban (Xarelto®) apixaban (Eliquis®) and edoxaban (Lixiana®). Efficacy and safety have been tested for rivaroxaban and apixaban in large study programmes with more than 60'000 patients each. For edoxaban large phase III studies are under way. Based on these data rivaroxaban was registered in the EU and CH for primary prophylaxis against thrombosis after major orthopaedic surgery, such as hip- and knee-joint protheses, for treatment and prophylaxis of deep vein thrombosis and pulmonary embolism and for prophylaxis against thromboembolic stroke in patients with atrial fibrillation. Apixaban is presently registered in the EU and CH for prophylaxis against thrombosis after major orthopaedic surgery, Edoxaban is registered only in Japan for the same indication. These products have been shown to be non-inferior or superior compared with vitamin K antagonists or low-molecular weight heparins, they are administered once or twice a day, they do not need laboratory monitoring. But they have disadvantages also, they depend on renal clearance, they can interact with other medicaments and they lack a specific antidote. In total, though, they are considered as a progress for the appropriate patients in terms of quality of treatment.

Rhinofacial Conidiobolus coronatus infection presenting with nasal enlargement.

Rhinofacial Conidiobolus coronatus infection is a rare form of zygomycosis in humans living in the northern hemispheres. Most human cases are observed in the periequatorial areas of Africa, Asia, or South America. Only limited information regarding optimal treatment is available. We report a case of rhinofacial C. coronatus infection in an emigrated Sudanese patient. The infection was successfully treated with terbinafin and itraconazole for 12 months. Diagnosis was confirmed by microbiological culture from a tissue biopsy. Antimicrobial susceptibility testing of this organism was not predictive of optimal therapy.

Venous thromboembolism prophylaxis in acutely ill medical patients: definite need for improvement.

AIM OF THE STUDY: To examine the frequency and adequacy of thromboprophylaxis in acutely ill medical patients hospitalized in eight Swiss medical hospitals. METHODS: A cross-sectional study of 1372 patients from eight Swiss hospitals was carried out. After exclusion of patients (275) given therapeutic anticoagulation, 1097 patients were audited. The adequacy of thromboprophylaxis was assessed by comparison with predefined explicit criteria. RESULTS: Of 1097 patients, 542 (49.4%) received thromboprophylaxis. According to the explicit criteria, 644 (58.7%) should have been on prophylaxis (P < 0.001, when compared with the rate observed). The rate of prevention differed widely between hospitals (from 29.4 to 88.6%) with no difference between teaching and nonteaching hospitals. According to the explicit criteria, a substantial proportion (44.9%) of the patients who should have been treated were not. Conversely, 41.3% of the patients were unnecessarily treated. CONCLUSIONS: Even though the appropriateness of the explicit criteria used could be challenged, our data suggest that the current practice is associated with important uncertainty leading to both overuse and underuse of thromboprophylaxis in patients hospitalized in medical wards. More efforts are urgently needed to develop new or endorse existing explicit, evidence-based criteria and guidelines for thromboprophylaxis in this population of patients.

Prolonged course of pure red cell aplasia after erythropoietin therapy.

Pure red cell aplasia (PRCA) caused by neutralising anti-erythropoietin antibodies is a very rare disease. Since 1998, an increased incidence of PRCA in patients with kidney failure following treatment with recombinant human erythropoietin (rhEpo) has been reported, mostly in Europe. In most cases, PRCA was cured by immunosuppressive therapy, immunoglobulins, plasmapheresis or renal transplantation. We report an exceptionally prolonged course of PRCA over 68 months despite renal transplantation and different immunosuppressive regimens.

Factor Xa and thrombin, but not factor VIIa, elicit specific cellular responses in dermal fibroblasts.

UNLABELLED: Coagulation factors (F)VIIa, FXa and thrombin are implicated in cellular responses in vascular, mesenchymal and inflammatory cells. Fibroblasts are the most abundant cells in connective tissue, and damage to blood vessels places coagulation factors in contact with these and other cell types. OBJECTIVES: To investigate cellular responses of primary dermal fibroblasts to FVIIa, FXa and thrombin by following changes in expression of candidate proteins: monocyte chemotactic protein-1 (MCP-1), interleukin-8 (IL-8), interleukin-6 (IL-6) and vascular endothelial growth factor (VEGF), and to determine the expression of receptors implicated in signaling by these coagulation factors. METHODS: Steady-state mRNA levels were quantified by RNase protection assay, and protein secretion by ELISA. PAR gene expression was assessed by ribonuclease protection assay and conventional and quantitative reverse-transcription-polymerase chain reaction. RESULTS: FVIIa did not induce the candidate genes. In contrast, FXa and thrombin induced MCP-1 mRNA and protein secretion strongly, IL-8 moderately, and IL-6 weakly. Neither FXa nor thrombin induced VEGF mRNA or protein secretion, although FXa induced VEGF protein secretion in lung fibroblasts. Comparison of the presence of candidate receptors in the two fibroblast subtypes demonstrated higher levels of PAR-1 and PAR-3 in lung fibroblasts relative to their dermal counterparts and the additional expression of PAR-2. CONCLUSIONS: FXa and thrombin induce expression of MCP-1, IL-8 and IL-6, and distribution and expression of PARs on dermal fibroblasts is reduced relative to their lung counterparts. Tissue origin may influence the cellular response of fibroblasts to coagulation proteases.

Successful reintroduction of methotrexate after acute pneumonitis in a patient with acute lymphoblastic leukemia.

Low-dose methotrexate (MTX) is used as disease-modifying therapy in severe rheumatoid arthritis and as maintenance treatment in patients with complete remission of acute lymphoblastic leukemia (ALL). It is generally well tolerated, but in 27% of patients acute pneumonitis leads to discontinuation of treatment. We describe a 56-year-old female patient with newly diagnosed pre-B-ALL. She was treated with induction chemotherapy in July 1999 which lead to complete remission. Maintenance treatment with low-dose MTX and 6-mercaptopurine (6-MP) was started in December 1999. In April 2000 she was hospitalized because of fever, cough, and rapidly progressive dyspnea. No pathogens could be cultured from blood or bronchoalveolar lavage fluid. Computed tomography of the lungs revealed interstitial infiltration and ground-glass opacities. Acute pneumonitis was diagnosed, and MTX was stopped. Prednisone therapy lead to rapid clinical amelioration of dyspnea and hypoxemia. Since for this patient there was no alternative leukemia therapy, MTX was successfully reintroduced in August 2000 without reappearance of any respiratory symptoms. We discuss risk profile, clinical and histological presentation, and therapy of MTX-induced pneumonitis. To our knowledge, this is the first patient with ALL in whom successful reintroduction of MTX after severe pneumonitis has been reported.

Pulmonary granulomas after tumour necrosis factor alpha antagonist therapy.

Tumour necrosis factor alpha (TNFalpha) antagonists are an established therapeutic option in Crohn's disease and rheumatoid arthritis. In recently published studies these agents have been used with great success, but little is known about any side effects or long term consequences. They increase the frequency of infections with mycobacteria, where TNFalpha is thought to be an important host defence factor. We describe one patient who was treated with TNFalpha antagonists and later developed pulmonary granulomas with caseating necrosis without detection of mycobacteria or any other pathogens. Possible mechanisms involved in this newly recognised side effect are discussed.

Life-threatening thrombocytopenia associated with acute Epstein-Barr virus infection in an older adult.

Acute Epstein-Barr virus (EBV) infection commonly induces hematological abnormalities, most notably atypical lymphocytosis ("infectious mononucleosis"). In addition, mild decreases in platelet counts are commonly encountered in uncomplicated cases; however, severe thrombocytopenia is exceedingly rare. Here, we describe a 58-year-old white man who presented with cervical lymphadenopathy, thrombocytopenia, and a bleeding diathesis with minimal platelet counts of 0.5 x 10(9)/l. The diagnosis of acute EBV was serologically confirmed. Because of the bleeding diathesis and the prior ingestion of aspirin, treatment was started with intravenous methylprednisolone and immunoglobulins. Platelet counts normalized within 7 days, and the patient fully recovered. Although more common in children, adolescents, and young adults, acute EBV infection may also occur in older adults, and this differential diagnosis should be considered in every patient presenting with acute thrombocytopenia. In this report we also briefly summarize the literature on EBV-associated severe thrombocytopenia.

Establishment and characterization of an arsenic-sensitive monoblastic leukaemia cell line (SigM5).

Few human monoblastic cell lines have been characterized to date. We have established the SigM5 cell line from a patient with acute monoblastic leukaemia (FAB M5a). Original leukaemic cells had a karyotype of 47,XY,+8, whereas the cell line showed a stemline clone of 81,XX,Y,Y,1,4,6,7,+8,+8,9,10,10,11,13,16,19[cp], with a minor sideline also present. Cytochemical staining was strongly positive with alpha-naphthylbutyrate acetate esterase, particulate positive with Sudan black and weakly positive for myeloperoxidase. Cells were positive for CD13, CD15, CD18, CD23, CD33, CD38, CD45, CD68 and myeloperoxidase. CD14 expression was 3-15%. SigM5 constitutively secreted interleukin (IL)-2, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, ferritin, lysozyme, N-elastase and neopterin upon stimulation with interferon (IFN)-gamma. Cells expressed the proinflammatory mediator macrophage migration inhibitory factor (MIF). All NADPH oxidase subunits were constitutively present, but nitroblue tetrazolium reduction was only detectable upon activation with IFN-gamma. SigM5 monoblasts were sensitive to arsenic trioxide (As2O3) previously not described to induce apoptosis in monoblastic cells. Differing considerably in morphology, immunophenotype and sensitivity to arsenics from the widely used cell lines U937, HL-60 and THP-1, SigM5 is a new monoblastic cell line useful for studying leukaemogenesis, monocyte differentiation and tumour cell susceptibility to arsenic compounds.

[Diagnosis of vitamin B12 deficiency: only apparently child's play]. / Diagnose eines Vitamin-B12-Mangels: nur scheinbar ein Kinderspiel.

We performed a systematic literature search for diagnostic criteria in establishing cobalamin deficiency. The diagnostic procedure is particularly uncertain in elderly patients with neurological symptoms and in cases with borderline cobalamin values. In any patient with suspected cobalamin deficiency we recommend analysing a full blood count and determining cobalamin concentration in a serum sample. Particularly in elderly patients and cases with neurological symptoms presenting borderline cobalamin values and no abnormalities in the blood count, we recommend further investigation with methylmalonic acid, homocystein and Schilling test. These additional tests should make it possible to decide whether to recommend lifelong substitution with cobalamin. Various cobalamin assays, Schilling test, food cobalamin test, gastroscopic evaluation and the problems surrounding these assays in the elderly are discussed. Our own experience with methylmalonic acid, homocystein determination and food cobalamin test did not reveal a simple diagnostic procedure in such cases. We conclude that there is still no "gold standard" for diagnostic procedure in the special cases mentioned.

[Visceral and neurological complications in Varicella infections of adults]. / Viszerale und neurologische Komplikationen bei Varizellen-infektionen des Erwachsenen.

Primary varicella-zoster virus (VZV) infections in adults generally follow a more severe course than in children and are more often associated with life-threatening complications. In the years 1992 to 1995 we observed 7 immunocompetent adults with a severe course of primary VZV infection. All 7 patients presented initially with a characteristic rash. In 6 patients the diagnosis of VZV was confirmed by ELISA on material taken from the lesions, and in all of them it was confirmed by serology. The following complications were observed: pneumonia (5x), elevated liver enzymes (4x), myocarditis (1x), encephalitis (1x) and myelitis (1x). Pulmonary lesions were characterized by bilateral interstitial infiltrates on chest-x-ray and required mechanical ventilation in 2 patients. The liver enzymes were only slightly elevated and clinically not significant. Myocarditis in one case was postulated in view of elevated creatine kinase levels, ECG-repolarization changes and AV-block III which required the insertion of a transitory pacemaker. Encephalitis presented as abnormal behaviour at work followed by seizures. Myelitis was suspected due to ascending sensory motor tetraparesis and confirmed by MRI. All patients were treated with high doses of parenteral acyclovir (3 x 10 mg/kg body weight i.v. per day) for 5-12 days. 6 patients recovered completely and only the patient with myelitis has residual neurological deficits 3 months after discharge. Although we cannot exclude the possibility that supportive therapy without acyclovir would have had the same outcome, we recommend high-dose parenteral acyclovir for treatment of visceral and neurological complications in primary VZV infections in adults.

[Differential diagnostic aspects of progressive spastic paraplegia in adults with emphasis on neurometabolic diseases]. / Differentialdiagnostische Aspekte der progredienten spastischen Paraparese beim Erwachsenen mit Betonung neurometabolischer Erkrankungen.

The differential diagnosis of a progressive spastic paraparesis in the young adult is broad and includes rare neuro-metabolic diseases like cerebro-tendinous xanthomatosis, adrenomyeloneuropathy and hypovitaminosis. Their clinical presentation as well as the result of paraclinical examinations can be similar to those of multiple sclerosis. The early recognition of these diseases is important, because a dietary regimen may reduce the severity and progression of symptoms and signs and genetic counselling can be important. The relevant biochemical examinations for their detection are discussed. These neuro-metabolic diseases have to be differentiated from other neuro-degenerative diseases like amyotrophic lateral sclerosis and hereditary spastic paraplegias.

[Akinetic crisis in Parkinson disease]. / Die akinetische Krise beim Morbus Parkinson.

The akinetic crisis is an "off" state that lasts more than 48 hours with akinesia, rigidity and bradykinesia, occurring with signs of CNS dysregulation in advanced stages of Parkinson's disease. 7 akinetic crises lasting 4 to 14 days (average 9.3) were observed in 744 hospitalizations over a period of 7 years. The age of the patients with akinetic crisis and the mean duration and the severity of the disease were significantly higher than in the other patients. While bradykinesia and rigor are the most relevant clinical signs in some 40% of parkinsonian patients, 6 of our 7 patients (86%) had an akinetic-rigid form of the disease. Levodopa withdrawal preceded the akinetic crisis in 4 patients: in 3 patients the akinetic crisis occurred despite adequate dopaminergic therapy, in one patient after benzodiazepine withdrawal, in another case after gastrointestinal bleeding, and in one case without known cause. Hyperthermia, tachycardia and sweating were the most common collateral manifestations. Apomorphine given subcutaneously was effective in four cases, apomorphine and amantidine were effective in one case, and one patient died during an akinetic crisis. The akinetic crisis is a distinct form of motor fluctuation in advanced stages of Parkinson's disease, with clinical signs resembling malignant neuroleptic syndrome (NMS). While NMS is related to dopaminergic receptor blockade or dopaminergic depletion, akinetic crisis can occur despite adequate dopaminergic therapy as a symptom of severe basal ganglia dysfunction related to the advanced stages of Parkinson's disease. Outcome and therapy of akinetic crisis depend on the underlying causes.

[Differential diagnosis of chronic gait disorders of neurologic origin in old age]. / Die Differentialdiagnose neurologische bedingter chronischer Gangstörungen im Alter.

The differential diagnosis of chronic gait difficulties with falls in the elderly, due to neurological diseases, is discussed. The spectrum is quite wide and encompasses central and peripheral pathologies of the nervous system. For centrally induced gait difficulties auxiliary examinations correspond to those used in the evaluation of dementia.