Molecular and phylogenetic analyses of human Parvovirus B19 isolated from Brazilian patients with sickle cell disease and beta-thalassemia major and healthy blood donors

Human Parvovirus B19 (B19V) is a recognized cause of life-threatening conditions among patients with hemoglobinopathies. This study investigates B19V infection in patients with sickle cell disease and beta-thalassemia using different experimental approaches. A total of 183 individuals (144 with sickle cell disease and 39 with beta-thalassemia major) and 100 healthy blood donors were examined for B19V using anti-B19V IgG enzyme immunoassay, quantitative PCR, DNA sequencing, and phylogenetic analysis. Viremia was documented in 18.6% of patients and 1% of donors, and was generally characterized by low viral load (VL); however, acute infections were also observed. Anti-B19V IgG was detected in 65.9% of patients with sickle cell disease and in 60% of donors, whereas the patients with thalassemia exhibited relatively low seroreactivity. The seroprevalence varied among the different age groups. In patients, it progressively increased with age, whereas in donors it reached a plateau. Based on partial NS1 fragments, all isolates detected were classified as subgenotype 1A with a tendency to elicit genetically complex infections. Interestingly, quasispecies occurred in the plasma of not only patients but also donors with even higher heterogeneity. The partial NS1 sequence examined did not exhibit positive selection. Quantitation of B19V with a conservative probe is a technically and practically useful approach. The extensive spread of B19V subgenotype 1A in patients and donors and its recent introduction into the countryside of the Sao Paulo State, Brazil were demonstrated; however, it is difficult to establish a relationship between viral sequences and the clinical outcomes of the infection. J. Med. Virol. 84:16521665, 2012. (c) 2012 Wiley Periodicals, Inc.

Secondary prevention through cardiac rehabilitation: physical activity counselling and exercise training: key components of the position paper from the Cardiac Rehabilitation Section of the European Association of Cardiovascular Prevention and Rehabilitation

Cardiac patients after an acute event and/or with chronic heart disease deserve special attention to restore their quality of life and to maintain or improve functional capacity. They require counselling to avoid recurrence through a combination of adherence to a medication plan and adoption of a healthy lifestyle. These secondary prevention targets are included in the overall goal of cardiac rehabilitation (CR). Cardiac rehabilitation can be viewed as the clinical application of preventive care by means of a professional multi-disciplinary integrated approach for comprehensive risk reduction and global long-term care of cardiac patients. The CR approach is delivered in tandem with a flexible follow-up strategy and easy access to a specialized team. To promote implementation of cardiac prevention and rehabilitation, the CR Section of the EACPR (European Association of Cardiovascular Prevention and Rehabilitation) has recently completed a Position Paper, entitled 'Secondary prevention through cardiac rehabilitation: A condition-oriented approach'. Components of multidisciplinary CR for seven clinical presentations have been addressed. Components include patient assessment, physical activity counselling, exercise training, diet/nutritional counselling, weight control management, lipid management, blood pressure monitoring, smoking cessation, and psychosocial management. Cardiac rehabilitation services are by definition multi-factorial and comprehensive, with physical activity counselling and exercise training as central components in all rehabilitation and preventive interventions. Many of the risk factor improvements occurring in CR can be mediated through exercise training programmes. This call-for-action paper presents the key components of a CR programme: physical activity counselling and exercise training. It summarizes current evidence-based best practice for the wide range of patient presentations of interest to the general cardiology community.

Amicrobial pustulosis-like rash in a patient with Crohn's disease under anti-TNF-alpha blocker

Amicrobial pustulosis of the folds (APF) is a recently described entity characterized by relapsing pustular lesions predominantly involving the cutaneous flexures and scalp. This disease typically occurs in association with systemic lupus erythematosus and a variety of other autoimmune diseases. We here describe an APF-like pustular eruption predominantly affecting the scalp, face and trunk, occurring during long-term infliximab treatment for Crohn's disease. Immunohistochemical staining of skin biopsy specimens for myxovirus resistance protein A, a marker for type 1 interferon-inducible proteins, showed increased staining in the epidermis and dermal mononuclear inflammatory infiltrate. Our observation further extends the spectrum of cutaneous adverse reactions potentially related to anti-tumor necrosis factor-α, the clinical context in which APF can occur as well as its clinical presentations.

Oral mucosal morphea: a new variant

Morphea is a cutaneous disorder characterized by an excessive collagen deposition. While in almost all cases the sclerosing process exclusively affects the skin, there are anecdotal cases in which associated mucosal involvement has been described. We here report the case of a woman developing a whitish indurated plaque over the left upper vestibular mucosa and hard palate leading to dental mobility and exposure of the roots of several teeth. Cone beam computed tomography of the left maxilla showed bone resorption involving the upper cuspid to the second molar region with widened periodontal ligament spaces, while light microscopy studies demonstrated epithelial atrophy and fibrosis of the dermis extending into the submucosa with hyalinization of subepithelial collagen. Our observation expands the spectrum of clinical presentations of morphea and provides the first example of isolated oral morphea. Its recognition is important to avoid significant local complications.

Establishment of diagnostic criteria for feline nonflea-induced hypersensitivity dermatitis

Hypersensitivity dermatitides (HD) are commonly seen in cats, and they are usually caused by environmental, food and/or flea allergens. Affected cats normally present with one of the following clinical reaction patterns: head and neck excoriations, usually symmetrical self-induced alopecia, eosinophilic skin lesions or miliary dermatitis. Importantly, none of these clinical presentations is considered to be pathognomonic for HD skin diseases, and the diagnosis of HD is usually based on the exclusion of other pruritic diseases and on a positive response to therapy. The objectives of this study were to propose sets of criteria for the diagnosis of nonflea-induced HD (NFHD). We recruited 501 cats with pruritus and skin lesions and compared clinical parameters between cats with NFHD (encompassing those with nonflea, nonfood HD and those with food HD), flea HD and other pruritic conditions. Using simulated annealing techniques, we established two sets of proposed criteria for the following two different clinical situations: (i) the diagnosis of NFHD in a population of pruritic cats; and (ii) the diagnosis of NFHD after exclusion of cats with flea HD. These criteria sets were associated with good sensitivity and specificity and may be useful for homogeneity of enrolment in clinical trials and to evaluate the probability of diagnosis of NFHD in clinical practice. Finally, these criteria were not useful to differentiate cats with NFHD from those with food HD.

Cross-sectional observational study of 208 patients with non-classical urea cycle disorders

Urea cycle disorders (UCDs) are inherited disorders of ammonia detoxification often regarded as mainly of relevance to pediatricians. Based on an increasing number of case studies it has become obvious that a significant number of UCD patients are affected by their disease in a non-classical way: presenting outside the newborn period, following a mild course, presenting with unusual clinical features, or asymptomatic patients with only biochemical signs of a UCD. These patients are surviving into adolescence and adulthood, rendering this group of diseases clinically relevant to adult physicians as well as pediatricians. In preparation for an international workshop we collected data on all patients with non-classical UCDs treated by the participants in 20 European metabolic centres. Information was collected on a cohort of 208 patients 50% of which were ≥ 16 years old. The largest subgroup (121 patients) had X-linked ornithine transcarbamylase deficiency (OTCD) of whom 83 were female and 29% of these were asymptomatic. In index patients, there was a mean delay from first symptoms to diagnosis of 1.6 years. Cognitive impairment was present in 36% of all patients including female OTCD patients (in 31%) and those 41 patients identified presymptomatically following positive newborn screening (in 12%). In conclusion, UCD patients with non-classical clinical presentations require the interest and care of adult physicians and have a high risk of neurological complications. To improve the outcome of UCDs, a greater awareness by health professionals of the importance of hyperammonemia and UCDs, and ultimately avoidance of the still long delay to correctly diagnose the patients, is crucial.

[Hypertension therapy in patients with renal artery stenosis]

Renovascular hypertension is due to reduced renal parenchymal perfusion. The correct diagnosis can be difficult. It is important to note that the demonstration of renal artery stenosis in a patient with hypertension does not necessarily constitute renovascular hypertension. Often, clinically nonsignificant and asymptomatic renal artery stenosis are found in patients with essential hypertension, or renal failure of other origin. Renovascular disease is a complex disorder with various clinical presentations. In patients with significant renovascular hypertension plasma renin is increased. For this reason the therapy aims to block the renin-angiotensin-aldosterone system. Bilateral renal artery stenosis causes renal sodium retention. In this situation a diuretic drug has to be added to the therapy. Endovascular or surgical therapy has to be considered in patients with flash pulmonary edema or fibromuscular dysplasia. The control of cardiovascular risk factors is important.

The Oklahoma Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome Registry: the Swiss connection

OBJECTIVES: Thrombotic thrombocytopenic purpura (TTP) was initially described as an uncommon and usually fatal disorder. With effective treatment it is more frequently diagnosed, the clinical presentations are more diverse, and long-term sequelae are becoming recognized. METHODS: Patient data are from The Oklahoma TTP-hemolytic uremic syndrome (HUS) Registry, an inception cohort of 348 consecutive patients with their first episode of clinically diagnosed TTP or HUS, 1989-2006. The Registry enrolls all patients in a defined region who are diagnosed with TTP or HUS and for whom plasma exchange treatment is requested. ADAMTS13 activity has been analyzed on 235 (93%) of 254 patients since 1995 at the University of Berne, Switzerland. Patients are described by clinical categories, related to their associated conditions and clinically apparent etiologies, and by the presence of severe ADAMTS13 deficiency. RESULTS AND CONCLUSIONS: The clinical spectrum of syndromes described as TTP is variable with multiple etiologies. Advances in clinical and laboratory investigation have provided better understanding of the pathogenesis of these syndromes, their clinical evaluation and management, and their long-term outcomes. In addition to new information about TTP, these studies provide a model for translational research to define the complete community spectrum of uncommon disorders.

Long-term outcome of acute spinal cord ischemia syndrome

BACKGROUND AND PURPOSE: Current knowledge of long-term outcome in patients with acute spinal cord ischemia syndrome (ASCIS) is based on few studies with small sample sizes and <2 years' follow-up. Therefore, we analyzed clinical features and outcome of all types of ASCIS to define predictors of recovery. METHODS: From January 1990 through October 2002, 57 patients with ASCIS were admitted to our center. Follow-up data were available for 54. Neurological syndrome and initial degree of impairment were defined according to American Spinal Injury Association (ASIA)/International Medical Society of Paraplegia criteria. Functional outcome was assessed by walking ability and bladder control. RESULTS: Mean age was 59.4 years; 29 were women; and mean follow-up was 4.5 years. The origin was atherosclerosis in 33.3%, aortic pathology in 15.8%, degenerative spine disease in 15.8%, cardiac embolism in 3.5%, systemic hypotension in 1.8%, epidural anesthesia in 1.8%, and cryptogenic in 28%. The initial motor deficit was severe in 30% (ASIA grades A and B), moderate in 28% (ASIA C), and mild in 42% (ASIA D). At follow-up, 41% had regained full walking ability, 30% were able to walk with aids, 20% were wheelchair bound, and 9% had died. Severe initial impairment (ASIA A and B) and female sex were independent predictors of unfavorable outcome (P=0.012 and P=0.043). CONCLUSIONS: Considering a broad spectrum of clinical presentations and origins, the outcome in our study was more favorable than in previous studies reporting on ASCIS subgroups with more severe initial deficits.

Monitoring thrombin generation by electrochemistry: development of an amperometric biosensor screening test for plasma and whole blood

BACKGROUND: Complete investigation of thrombophilic or hemorrhagic clinical presentations is a time-, apparatus-, and cost-intensive process. Sensitive screening tests for characterizing the overall function of the hemostatic system, or defined parts of it, would be very useful. For this purpose, we are developing an electrochemical biosensor system that allows measurement of thrombin generation in whole blood as well as in plasma. METHODS: The measuring system consists of a single-use electrochemical sensor in the shape of a strip and a measuring unit connected to a personal computer, recording the electrical signal. Blood is added to a specific reagent mixture immobilized in dry form on the strip, including a coagulation activator (e.g., tissue factor or silica) and an electrogenic substrate specific to thrombin. RESULTS: Increasing thrombin concentrations gave standard curves with progressively increasing maximal current and decreasing time to reach the peak. Because the measurement was unaffected by color or turbidity, any type of blood sample could be analyzed: platelet-poor plasma, platelet-rich plasma, and whole blood. The test strips with the predried reagents were stable when stored for several months before testing. Analysis of the combined results obtained with different activators allowed discrimination between defects of the extrinsic, intrinsic, and common coagulation pathways. Activated protein C (APC) predried on the strips allowed identification of APC-resistance in plasma and whole blood samples. CONCLUSIONS: The biosensor system provides a new method for assessing thrombin generation in plasma or whole blood samples as small as 10 microL. The assay is easy to use, thus allowing it to be performed in a point-of-care setting.

Long-term outcomes of patients receiving zotarolimus-eluting stents in ST elevation myocardial infarction, non-ST elevation acute coronary syndrome, and stable angina: data from the Resolute program

BACKGROUND Outcome data are limited in patients with ST-segment elevation acute myocardial infarction (STEMI) or other acute coronary syndromes (ACSs) who receive a drug-eluting stent (DES). Data suggest that first generation DES is associated with an increased risk of stent thrombosis when used in STEMI. Whether this observation persists with newer generation DES is unknown. The study objective was to analyze the two-year safety and effectiveness of Resolute™ zotarolimus-eluting stents (R-ZESs) implanted for STEMI, ACS without ST segment elevation (non-STEACS), and stable angina (SA). METHODS Data from the Resolute program (Resolute All Comers and Resolute International) were pooled and patients with R-ZES implantation were categorized by indication: STEMI (n=335), non-STEACS (n=1416), and SA (n=1260). RESULTS Mean age was 59.8±11.3 years (STEMI), 63.8±11.6 (non-STEACS), and 64.9±10.1 (SA). Fewer STEMI patients had diabetes (19.1% vs. 28.5% vs. 29.2%; P<0.001), prior MI (11.3% vs. 27.2% vs. 29.4%; P<0.001), or previous revascularization (11.3% vs. 27.9% vs. 37.6%; P<0.001). Two-year definite/probable stent thrombosis occurred in 2.4% (STEMI), 1.2% (non-STEACS) and 1.1% (SA) of patients with late/very late stent thrombosis (days 31-720) rates of 0.6% (STEMI and non-STEACS) and 0.4% (SA) (P=NS). The two-year mortality rate was 2.1% (STEMI), 4.8% (non-STEACS) and 3.7% (SA) (P=NS). Death or target vessel re-infarction occurred in 3.9% (STEMI), 8.7% (non-STEACS) and 7.3% (SA) (P=0.012). CONCLUSION R-ZES in STEMI and in other clinical presentations is effective and safe. Long term outcomes are favorable with an extremely rare incidence of late and very late stent thrombosis following R-ZES implantation across indications.

Diagnosis and Treatment of Venous Malformations Consensus Document of the International Union of Phlebology (IUP): updated 2013

Venous malformations (VMs) are the most common vascular developmental anomalies (birth defects) . These defects are caused by developmental arrest of the venous system during various stages of embryogenesis. VMs remain a difficult diagnostic and therapeutic challenge due to the wide range of clinical presentations, unpredictable clinical course, erratic response to the treatment with high recurrence/persistence rates, high morbidity following non-specific conventional treatment, and confusing terminology. The Consensus Panel reviewed the recent scientific literature up to the year 2013 to update a previous IUP Consensus (2009) on the same subject. ISSVA Classification with special merits for the differentiation between the congenital vascular malformation (CVM) and vascular tumors was reinforced with an additional review on syndrome-based classification. A "modified" Hamburg classification was adopted to emphasize the importance of extratruncular vs. truncular sub-types of VMs. This incorporated the embryological origin, morphological differences, unique characteristics, prognosis and recurrence rates of VMs based on this embryological classification. The definition and classification of VMs were strengthened with the addition of angiographic data that determines the hemodynamic characteristics, the anatomical pattern of draining veins and hence the risk of complication following sclerotherapy. The hemolymphatic malformations, a combined condition incorporating LMs and other CVMs, were illustrated as a separate topic to differentiate from isolated VMs and to rectify the existing confusion with name-based eponyms such as Klippel-Trenaunay syndrome. Contemporary concepts on VMs were updated with new data including genetic findings linked to the etiology of CVMs and chronic cerebrospinal venous insufficiency. Besides, newly established information on coagulopathy including the role of D-Dimer was thoroughly reviewed to provide guidelines on investigations and anticoagulation therapy in the management of VMs. Congenital vascular bone syndrome resulting in angio-osteo-hyper/hypotrophy and (lateral) marginal vein was separately reviewed. Background data on arterio-venous malformations was included to differentiate this anomaly from syndrome-based VMs. For the treatment, a new section on laser therapy and also a practical guideline for follow up assessment were added to strengthen the management principle of the multidisciplinary approach. All other therapeutic modalities were thoroughly updated to accommodate a changing concept through the years.

Eosinophilia in Dermatologic Disorders

Eosinophil infiltration can be observed in skin disorders, such as allergic/immunologic, autoimmune, infectious, and neoplastic diseases. Clinical presentations are variable and include eczematous, papular, urticarial, bullous, nodular, and fibrotic lesions; pruritus is a common symptom in all. In this review, we present representative eosinophilic skin diseases according to their clinical pattern, together with histologic findings and diagnostic procedures. We also discuss the potential roles of eosinophils in the pathogenesis of dermatologic disorder. Current pathogenesis-based diagnostic and therapeutic approaches are outlined.

Use of Recombinant Virus Replicon Particles for Vaccination against Mycobacterium ulcerans Disease.

Buruli ulcer, caused by infection with Mycobacterium ulcerans, is a necrotizing disease of the skin and subcutaneous tissue, which is most prevalent in rural regions of West African countries. The majority of clinical presentations seen in patients are ulcers on limbs that can be treated by eight weeks of antibiotic therapy. Nevertheless, scarring and permanent disabilities occur frequently and Buruli ulcer still causes high morbidity. A vaccine against the disease is so far not available but would be of great benefit if used for prophylaxis as well as therapy. In the present study, vesicular stomatitis virus-based RNA replicon particles encoding the M. ulcerans proteins MUL2232 and MUL3720 were generated and the expression of the recombinant antigens characterized in vitro. Immunisation of mice with the recombinant replicon particles elicited antibodies that reacted with the endogenous antigens of M. ulcerans cells. A prime-boost immunization regimen with MUL2232-recombinant replicon particles and recombinant MUL2232 protein induced a strong immune response but only slightly reduced bacterial multiplication in a mouse model of M. ulcerans infection. We conclude that a monovalent vaccine based on the MUL2232 antigen will probably not sufficiently control M. ulcerans infection in humans.

Mapping a gene causing cerebral cavernous malformation to 7q11.2-q21.

Cerebral cavernous malformation is a common disease of the brain vasculature of unknown cause characterized by dilated thin-walled sinusoidal vessels (caverns); these lesions cause varying clinical presentations which include headache, seizure, and hemorrhagic stroke. This disorder is frequently familial, with autosomal dominant inheritance. Using a general linkage approach in two extended cavernous malformation kindreds, we have identified linkage of this trait to chromosome 7q11.2-q21. Multipoint linkage analysis yields a peak logarithm of odds (lod) score of 6.88 with zero recombination with locus D7S669 and localizes the gene to a 7-cM region in the interval between loci ELN and D7S802.