Reference point insensitive molecular data analysis.

MOTIVATION: In biomedicine, every molecular measurement is relative to a reference point, like a fixed aliquot of RNA extracted from a tissue, a defined number of blood cells, or a defined volume of biofluid. Reference points are often chosen for practical reasons. For example, we might want to assess the metabolome of a diseased organ but can only measure metabolites in blood or urine. In this case, the observable data only indirectly reflects the disease state. The statistical implications of these discrepancies in reference points have not yet been discussed. RESULTS: Here, we show that reference point discrepancies compromise the performance of regression models like the LASSO. As an alternative, we suggest zero-sum regression for a reference point insensitive analysis. We show that zero-sum regression is superior to the LASSO in case of a poor choice of reference point both in simulations and in an application that integrates intestinal microbiome analysis with metabolomics. Moreover, we describe a novel coordinate descent based algorithm to fit zero-sum elastic nets. AVAILABILITY AND IMPLEMENTATION: The R-package "zeroSum" can be downloaded at https://github.com/rehbergT/zeroSum Moreover, we provide all R-scripts and data used to produce the results of this manuscript as Supplementary Material CONTACT: Michael.Altenbuchinger@ukr.de, Thorsten.Rehberg@ukr.de and Rainer.Spang@ukr.deSupplementary information: Supplementary material is available at Bioinformatics online.

Rifaximin preserves intestinal microbiota balance in patients undergoing allogeneic stem cell transplantation.

Intestinal dysbiosis has been associated with acute gastrointestinal GvHD and poor outcome following allogeneic stem cell transplantation (ASCT). To assess the effect of a switch in 2012 from ciprofloxacin/metronidazole to rifaximin for gut decontamination on intestinal microbiota composition and ASCT outcome, we retrospectively analyzed 394 patients receiving ASCT from September 2008 through June 2015. In 131 and 90 patients, respectively, urinary 3-indoxyl sulfate levels and intestinal enterococcal load were measured before conditioning and weekly within the first 28 days after ASCT. The use of rifaximin correlated with lower enterococcal positivity (6.9 vs 21.9%, P=0.05) and higher urinary 3-indoxyl sulfate concentrations (10.5 vs 4.6 µmoL/mmoL crea, P<0.001) after ASCT. Patients on rifaximin showed lower 1-year transplant-related mortality (P=0.04) and higher overall survival (P=0.008). Treatment of infectious complications with systemic antibiotics did not abrogate the beneficial effects of rifaximin on intestinal microbiota composition in the early course of ASCT and outcome. The data underscore the importance of maintaining a diverse population of symbiotic and mutualistic bacteria in the gut on ASCT outcome.

[Value of colour Doppler ultrasonography in relation to clinical pretest probability in giant cell (temporal) arteritis]. / Wertigkeit der farbkodierten Duplexsonographie in Abhängigkeit der klinischen Vortest-Wahrscheinlichkeit bei Riesenzellarteriitis.

BACKGROUND: Colour Doppler sonography (CDS) is an established technique in the diagnosis of giant-cell (temporal) arteritis (GCA). The predictive value of its diagnostic criteria for GCA (halo sign or stenosis) is related to the pretest probability (PTP), a measure of probability of presence of a target disease before the result of a diagnostic test is known. PATIENTS AND METHODS: A total of 182 (average age 69 years, 69% women) patients of the Rheumatology Center Baden-Württemberg were investigated. Based on the diagnostic criteria of the American College of Rheumatology (ACR) they were assigned to one of three groups, before a CDS was performed: group 1 (n= 139) patients with "isolated" polymyalgia rheumatica (PMR) and a low PTP for GCA; group 2 (n=19) patients with intermediate PTP and nonspecific headache and fewer than three ACR criteria for GCA); and group 3 (n=224) patients with a high PTP and new headache loclized to the temporal artery and at least three ACR criteria for GCA. RESULTS: The halo sign (periluminal dark halo) of more than 0.3 mm was present in 26% of group 1. 42% of those in group 2 and 83% of those in group 3. A stenosis or occlusion of the temporal artery was present in 3.5% (group 1), 5% (group 2) and 46% (group 3), respectively. 3 of 24 patients of group 3 also had a stenosis of the axillary or brachial artery. Concordance between clinical criteria and CDS (normal CDS in patients with PMR but no headache or abnormal CDS and clinically suspected BCA was found in 123 of 182 patients (67.5%). In these patients biopsy of the temporal artery ("gold standard" for the diagnosis of GCA) was not recommended. Temporal artery biopsy was, however, recommended in all patients with discordant findings (abnormal CDS with PMR but no headache or normal CDS with clinically suspected GCA, and also those with intermediary PTP (32%). A biopsy was performed in 42 of these patients after informed consent had been obtained. This demonstrated vasculitis in 11 of 25 patients with PMR (PPV in group 1: 0.44). But biopsies were negative in all four patients with clinically suspected GCA and normal CDS (NPV in group 3:1). In the intermediary group biopsy demonstrated vasculitits in 5 of 6 patients with an abnormal CDS (PPV 0.63), while 4 of 5 patients with a normal CDS had a normal biopsy (NPV 0.8). CONCLUSION: Taking into account pretest probability, an RCA can be accurately diagnosed or excluded by CDS in two thirds of patients without biopsy. When performed by an experienced investigator CDS is a basic part in the diagnosis of CDA.

[Digital ischemia in a gardener: is rose cutting a vascular risk factor?]. / Akrale Durchblutungsstörungen bei einer Hobbygärtnerin: Rosenschneiden als vaskulärer Risikofaktor?

HISTORY AND ADMISSION FINDINGS: A 48-year-old right handed gardener presented with a white discoloration and numbness of her left ring finger. She reported cutting her roses without protection gloves so repetitive scratchy lesions especially of her left hand occurred. INVESTIGATIONS: On examination the pulse of the left radial artery was absent. Allen's test showed a dominant ulnar supply of the palmar arch. Duplex ultrasound demonstrated an occluded aneurysm of the distal portion of the left radial artery. Furthermore there were occlusions of the first and fourth digital artery on MR angiography probably due to distal emboli of the radial aneurysm. TREATMENT AND COURSE: After exclusion of systemic disease or vasculitis, an repetitive trauma due to rose thorns was supposed to be the cause of the radial aneurysm. Anticoagulation therapy was initiated and infusion of prostaglanden E1 was performed over 7 days. The digital ischemia resolved within a few days. Therefore a surgical procedure was not recommended. CONCLUSIONS: In the presence of a radial artery aneurysm an occupational and recreational trauma history should be sought after.

[Haemorrhagic diathesis as an early symptom of systemic amyloidosis]. / Hämorrhagische Diathese als Frühsymptom einer systemischen Amyloidose.

HISTORY: A 63-year-old man, known to have Bechterev's disease was admitted because of weight gain and nocturnal sweating. He also had signs of heart failure with progressive exertional dyspnoea. Many months previously numerous bleedings had occurred in the skin, predominantly the face (periorbital and perioral), the inguinal region and the penis. INVESTIGATIONS: Extensive diagnostic test failed to find any evidence of tumor. The Rumpel-Leede tourniquet test was positive, while platelet functions was normal, suggesting vascular disease. The skin biopsy showed many perivascular amyloid deposits (AL). Immunochemical differentiation also demonstrated the same amyloid in rectal and hepatic biopsies. But there was AA amyloid in a hepatic artery. Immunophoresis indicated a biclonal gammopahty of unknown significance. DIAGNOSIS, TREATMENT AND COURSE: These findings indicated the diagnosis of primary AL amyloidosis associated with a gammopathy of unknown significance and a secondary AA amyloidosis in the presence of chronic Bechterev s disease. The clinical picture also showed cardiac complications, predominantly heart failure and numerous previous myocardial infarctions without S-T elevations. Echocardiography, which revealed marked thickening of the left ventricle with a restrictive filling pattern, suggested cardiac co-morbidity. The patient underwent chemotherapy with melphalan and prednisone but had a sudden cardiac death. CONCLUSION: In a case of bleeding of unknown cause systemic amyloidosis should be considered in the differential diagnosis. A tendency towards bleeding, as in this patient, may be the first sign of amyloidosis, which ist often diagnosed quite late in the course of the disease.

[Repeated attacks of pain in the nipple of a pregnant woman. Unusual manifestation of Raynaud's phenomenon]. / Anfallsartige Brustwarzenschmerzen bei einer schwangeren Patientin. Ungewöhnliche Manifestation eines Raynaud-Phänomens.

HISTORY AND FINDINGS: A 38-year-old woman, in her 13th week of pregnancy, presented for angiological investigation of repeated episodes of pain in the right index finger. She also reported painful paleness of the right nipple evoked particularly by cold. This was her fifth pregnancy; she had miscarried twice. The nipple pain occurred spasmodically and in three phases, while the left nipple was unaffected. The attacks lasted c. 15 min, progressing from an ischemic to a hyperemic phase, accompanied by unbearable pain. When first examined there was circumscribed, purplish network-patterned discoloration of the right hand with blackened discoloration of the distal nail-bed of the index finger. INVESTIGATIONS: Duplex-sonography revealed patency of the large arteries of the arm and hand. Transesophageal echocardiography showed a persistent foramen ovale and echo-density suspected to be a right atrial thrombus. Laboratory tests demonstrated anticardiolipin antibodies, suggesting an antiphospholipid syndrome. TREATMENT AND COURSE: On administration of low-molecular heparin, its dosage weight-adjusted, and 100 mg aspirin daily the discoloration of the finger quickly disappeared, but Raynaud's syndrome remained unchanged until she had stopped breast feeding (left breast only) after 8 months. A healthy girl had been delivered by cesarean section in the 39th week, weighing 3100 g. There were no further thromboembolic complications. CONCLUSION: This very rare case of Raynaud's phenomenon in a nipple was associated with an anti-phospholipid syndrome.

[Deep venous thrombosis of the leg. Will it be acute ambulatory therapy in the future?]. / Tiefe Beinvenenthrombose. Akuttherapie in Zukunft ambulant?

Early diagnosis and treatment of deep venous thrombosis (DVT) in the leg is of decisive importance, in particular in view of the potentially life-threatening complication of pulmonary embolism. The establishment of the diagnosis if often difficult since in the early stage symptoms may be non-existent or few (50%). The most important therapeutic measure is compression. Acute medication is initiated within the first 24 hours with unfractionated conventional heparin administered as a continuous i.v. infusion or intermittent s.c. injections. An initial bolus injection is followed by continuous infusion of 30,000-40,000 units of heparin. More recent data show that low-molecular-weight heparins are as effective as conventional heparin and are easier to apply, making acute treatment on an ambulatory basis feasible. Conversion to anticoagulation treatment is effected with gradually increasing doses, and must overlap heparin for at least 4-5 days. The duration of treatment is determined by the nature of the thrombosis, with recommendations ranging from 3 to 12 months. A shortened in-hospital treatment with early mobilization is considered to be of benefit to the patient.

[Critical ischaemia of the limbs and localized livedo in a case of ergotism]. / Kritische Extremitätenischämie und lokalisierte Livedo bei sporadischem Ergotismus.

HISTORY AND ADMISSION FINDINGS: A 57-year-old woman, a heavy smoker and migraine sufferer, was admitted with severe resting pain in the right forefoot and painful localized tendril-shaped reddening on the right thigh. She had regularly been taking 1-2 mg ergotamine tartrate, several analgesics, some containing caffeine, and selective serotonin-uptake inhibitors. Clinical examination found all limbs to be cool. On the right leg the pulse was not palpable below the inguinal line, and the reddening corresponded to localized livedo. INVESTIGATIONS: The peripheral Doppler pressure indicated critical perfusion reduction in the right leg with a tibiobrachial pressure ratio of 0.14. Colour-coded duplex sonography showed generalized vasoconstriction with filiform hourglass stenosis of the right proximal superficial femoral artery without atherosclerotic changes. The history of drug intake and the characteristic sonographic findings indicated ergotism and an arteriography was deemed unnecessary. TREATMENT AND COURSE: All ergotamine and caffeine containing drugs were discontinued and the patient urged to stop smoking. Amlidopine, 2.5 mg orally, and prostaglandin E1, 60 microgram i.v., were administered daily. The resting pain was much reduced after the first infusion and the painful livedo disappeared. The documented high-grade stenosis of the right superficial femoral artery was reduced to 25-50% by the third day of infusion. At the end of 10 daily infusions both the Doppler pressure and the duplex sonography had become normal. Pizotifen was given for the migraine and the serotonin re-uptake inhibitor sertralin was discontinued. CONCLUSION: An interaction of the serotonin re-uptake inhibitor with ergotamine was presumably responsible for the development of ergotism under >>therapeutic<< ergotamine dosage. Vasospastic stenoses and occlusions can be demonstrated by duplex sonography and may in future not require additional angiographic confirmation. Intravenous rather than intraarterial infusion of prostaglandin is to be preferred if vessels at many sites are affected. Livedo is a transitory sign of ergotism.

[Value of color-coded duplex ultrasound in patients with polymyalgia rheumatica without signs of temporal arteritis]. / Stellenwert der farbkodierten Duplexsonographie bei Patienten mit Polymyalgia rheumatica ohne klinische Zeichen einer Arteriitis temporalis.

BACKGROUND AND OBJECTIVE: Recent studies have described characteristic sonographic signs in patients with manifest temporal arteritis (TA). It was the aim of this study to determine whether sonography can identify TA without clinical signs but biopsy evidence of giant-cell arteritis in patients with rheumatic polymyalgia (RP). PATIENTS AND METHODS: 22 patients (14 women, 8 men; average age 67.4 +/- 9.1 years) with RP but no clinical signs of TA were prospectively examined for TA by colour-coded duplex sonography (ATL HDI 3000, linear 12-5 Mhz) before temporal artery biopsy was taken. If there was clinical suspicion of extratemporal involvement, other vessels were also examined selectively. The biopsy was taken from a site identified by the sonography. A definitive diagnosis of TA was made only if there was a positive biopsy. RESULTS: In seven of the 22 patients (32%) sonography showed an echo-poor halo around the lumen of the temporal artery. Five of these seven patients also had histological evidence of giant-cell arteritis. Conversely, all of the five patients had abnormal sonographic findings, namely a marked halo with a minimal thickness of 0.7 mm. Two of the five patients also had temporal artery stenosis, i.e. there was a 100% sensitivity and 80% specificity with respect to the halo sign in conformance with the histology. Two patients with TA were also shown sonographically to have stenosis in arteries of the shoulder girdle and arm. Stenoses in the renal and mesenteric arteries as well of the coeliac trunk were demonstrated in one patient. CONCLUSIONS: Colour-coded sonography with a high-frequency transducer head probably provides reliable diagnosis of TA in patients with RP, even in the absence of clinical signs of vascular inflammation. It remains to be proven whether sonography without biopsy is reliable enough for the diagnosis and treatment of asymptomatic TA.

[Guidelines for prevention of thrombosis in orthopedics]. / Leitlinien zur Thromboseprophylaxe in der Orthopädie.

PURPOSE: The necessity of effective prevention of DVT is generally accepted. However, attitudes and beliefs concerning prophylaxis vary greatly in terms of the risk groups receiving prophylaxis and the prophylactic methodology. This paper reviews current research on the subject and seeks to provide recommendations. RESULTS: Known clinical risk factors allow the classification of patients according to high, medium and low risk of developing thromboembolism. Basic forms of prophylaxis are physiotherapy and early mobilisation. However, there are no data on the safety and efficacy of these methods. Mechanical devices used include external intermittent pneumatic compression and graduated compression stockings. Used in isolation, these methods reduce the incidence of deep vein thrombosis in low and moderate risk patients by one half or one third. There is no distinction between mechanical and pharmacological methods in terms of safety and efficacy. Furthermore, secondary effects are extremely rare. Moderate and high risk category patients should receive combined modes of mechanical and pharmacological treatment. A direct comparison of safety in moderate risk patients fixed doses of standard heparin vs. low molecular weight heparin revealed no significant differences. In the case of high risk patients, adjusted dose heparin administered subcutaneously or fixed dose low molecular heparin is recommended. A severe secondary effect of heparin-prophylaxis is heparin-induced thrombocytopenie. The optimum duration of pharmacological prophylaxis is not yet clear. CONCLUSION: The methods and duration of prophylaxis remain subject to an individual medical assessment of the clinically significant benefits in relation to the risk secondary effects of the treatment. On major questions there are significant variations in the specialist literature. This means that standards cannot be formulated, although recommendations can be given.

[The prevalence of hyperhomocysteinemia in thromboangiitis obliterans. Does homocysteine play a role pathogenetically?]. / Prävalenz der Hyperhomocysteinämie bei der Thrombangiitis obliterans. Spielt Homocystein pathogenetisch eine Rolle?

OBJECTIVE: As hyperhomocysteinaemia is known to be an important risk factor in the early onset of arteriosclerotic occlusive disease and leg-vein thrombosis, we investigated the prevalence of hyperhomocysteinaemia in patients with thromboangiitis obliterans (TAO), a condition predominantly affecting peripheral arteries and veins. PATIENTS AND METHODS: Plasma homocysteine (HC), before and after administration of methionine (0.1 g/kg) as well as serum folic acid, vitamins B6 and B12 were measured in 15 patients with TAO (12 men, 3 women; mean age 33.3 years: group 1), in 15 non-smokers without peripheral vascular disease (group 2) and 15 smokers without peripheral vascular disease (group 3). At the time of the study, of those in group 1 seven were active smokers, seven were ex-smokers and one was a non-smoker. RESULTS: Before methionine administration four patients (27%), none of the healthy non-smokers and one smoker without vascular disease (7%) had increased HC levels (> 13.9 nmol/ml). The difference between groups 1 and 2 was statistically significant (P < 0.05), but not that between groups 1 and 3 and between 2 and 3. 4 hours after methionine increased HC levels (> or = 31 nmol/ml) were measured in nine patients but in none of the healthy controls. The difference between patients and the two control groups without vascular disease was clearly significant (P = 0.0107). There was a difference in folic acid levels between the patients and the smokers without vascular disease: in eight patients (53%) the levels were in the lower third of normal, in six (40%) they were in the middle and in one (7%) in the upper third. Corresponding levels in group 3 were: four (27%), three (20%) and eight (53%). CONCLUSION: Hyperhomocysteinaemia occurs frequently in patients with TAO. It may play an important and nicotine-independent role in its pathogenesis.

[Smoking and peripheral vascular disorders]. / Rauchen und periphere Gefässleiden.

Smoking is a major risk factor for peripheral arterial occlusive disease (PAOD) and plays a crucial role in the pathogenesis of the thrombangiitis obliterans (TAO), nicotine and carboxyhemoglobin cause functional disturbances and structural damage of the endothelial cells which may initiate arteriosclerosis. Additional effects of smoking are hyperfibrinogenemia, lowering of HDL-cholesterol and increased oxidation of LDL-cholesterol. By these mechanisms, smoking influences other primary risk factors for arteriosclerosis. Patients with PAOD, who continue to smoke, have a worse clinical prognoses with higher amputation and mortality rates than those who quit smoking. The most urgent goal in the therapy of PAOD and TAO should be an immediate and complete smoking cessation. However most patients continue to smoke despite the knowledge of the hazards to their health. An appropriate approach to this addiction may be an alternative application of nicotine temporarily (transdermal by patches or chewing gum) and behavioral treatment. This combined therapy results in better success rates in terms of smoking cessation.