Congenital thrombotic thrombocytopenic purpura caused by new compound heterozygous mutations of the ADAMTS13 gene

Upshaw-Schulman syndrome (USS) is due to severe congenital deficiency of von Willebrand factor (VWF)-cleaving protease ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type 1 domains, nr 13) activity resulting in the presence of unusually large forms of VWF in the circulation, causing intravascular platelet clumping and thrombotic microangiopathy. Our patient, a 26-year-old man, had attacks of thrombotic thrombocytopenic purpura (TTP) with thrombocytopenia and a urine dipstick positive for hemoglobin (4+), often as the only sign of hemolytic activity. He had ADAMTS13 activity of <1% of normal plasma without the presence of inhibitors of ADAMTS13. ADAMTS13 deficiency was caused by two new mutations of the ADAMTS13 gene: a deletion of a single nucleotide in exon17 (c. 2042 delA) leading to a frameshift (K681C fs X16), and a missense mutation in exon 25 (c.3368G>A) leading to p.R1123H. This case report confirms the importance of the analysis of the ADAMTS13 activity and its inhibitor in patients who have episodes of TTP, with a very low platelet count and sometimes without the classic biochemical signs of hemolysis.

A novel paradigm for patient-cooperative control of upper-limb rehabilitation robots

Early intervention and intensive therapy improve the outcome of neuromuscular rehabilitation. There are indications that where a patient is motivated and premeditates their movement, the recovery is more effective. Therefore, a strategy for patient-cooperative control of rehabilitation devices for upper extremities is proposed and evaluated. The strategy is based on the minimal intervention principle allowing an efficient exploitation of task space redundancies and resulting in user-driven movement trajectories. The patient's effort is taken into consideration by enabling the machine to comply with forces exerted by the user. The interaction is enhanced through a multimodal display and a virtually generated environment that includes haptic, visual and sound modalities.

Congenital factor XIII deficiency in Pakistan: characterization of seven families and identification of four novel mutations

Deficiency of coagulation factor XIII (FXIII) belongs to the rare bleeding disorders and its incidence is higher in populations with consanguineous marriages. The aims of this study were to characterize patients and relatives from seven families with suspected FXIII deficiency from Pakistan and to identify the underlying mutations. As a first indicator of FXIII deficiency, a 5M urea clot solubility test was used. Plasma FXIII A- and B-subunit antigen levels were determined by ELISA. FXIII activity was measured with an incorporation assay. Sequencing of all exons and intron/exon boundaries of F13A was performed, and a novel splice site defect was confirmed by RT-PCR analysis. Genetic analysis revealed six different mutations in the F13A gene. Two splice site mutations were detected, a novel c.1460+1G>A mutation in the first nucleotide of intron 11 and a previously reported c.2045G>A mutation in the last nucleotide of exon 14. Neither of them was expressed at protein level. A novel nonsense mutation in exon 4, c.567T>A, p.Cys188X, was identified, leading in homozygous form to severe FXIII deficiency. Two novel missense mutations were found in exons 8 and 9, c.1040C>A, p.Ala346Asp and c.1126T>C, p.Trp375Arg, and a previously reported missense mutation in exon 10, c.1241C>T, p.Ser413Leu. All patients homozygous for these missense mutations presented with severe FXIII deficiency. We have analysed a cohort of 27 individuals and reported four novel mutations leading to congenital FXIII deficiency.

Clinical Significance of 3D Ultrasound Compared to MRI in Uterine Malformations

Purpose: Congenital uterine anomalies often remain asymptomatic until they cause problems, for example during pregnancy. We studied the diagnostic aspects of two- and three-dimensional ultrasound and MRI. Materials and Methods: 63 women referred for suspected uterine anomalies were studied: In the first group (until July 2008) with 2 D-US and MRI, in the second group (from August 2008) additionally with 3 D-US; these women also had diagnostic or therapeutic operative confirmation. In the third group, only 3D-US was used. Results: In all women 3D-US was possible and successful. The most common anomaly was a subseptate uterus, while a septate uterus was less frequent, and uterus bicornis (unicollis) and uterus didelphys (bicornis bicollis) were rare. The women in the first two groups all underwent at least diagnostic hysteroscopy, and some (subseptate or septate uterus) underwent operative hysteroscopy. After preoperative volume imaging, laparoscopies were required less often. 3D-US diagnoses as judged by intraoperative findings were correct in 100 % of cases, while the MRI diagnoses in the same group were correct in only 7/13 cases. Conclusion: Since the introduction of volume imaging (MRI, later 3 D-US), laparoscopy during hysteroscopic septum resection was not necessary in the majority of cases. 3D-US brings the diagnostics of uterine anomalies back into the hands of the gynecologist and can provide the gynecological surgeon with a higher subjective degree of certainty during operative hysteroscopy.

Early recoil after balloon angioplasty of tibial artery obstructions in patients with critical limb ischemia.

PURPOSE To assess the extent of early recoil in patients with critical limb ischemia (CLI) undergoing conventional tibial balloon angioplasty. METHODS Our hypothesis was that early recoil, defined as lumen compromise >10%, is frequent and accounts for considerable luminal narrowing after tibial angioplasty, promoting restenosis. To test this theory, 30 consecutive CLI patients (18 men; mean age 76.2±12.1 years) were angiographically evaluated immediately after tibial balloon angioplasty and 15 minutes later. Half the patients were diabetics. Target lesions included anterior and posterior tibial arteries and the peroneal artery with / without the tibioperoneal trunk. Mean tibial lesion length was 83.8 mm. Early elastic recoil was determined on the basis of minimal lumen diameter (MLD) measurements at baseline (MLDbaseline), immediately after tibial balloon angioplasty (MLDpostdilation), and 15 minutes thereafter (MLD15min). RESULTS Elastic recoil was observed in 29 (97%) patients with a mean luminal compromise of 29% according to MLD measurements (MLDbaseline 0.23 mm, MLD postdilation 2.0 mm, and MLD15min 1.47 mm). CONCLUSION Early recoil is frequently observed in CLI patients undergoing tibial angioplasty and may significantly contribute to restenosis. These findings support the role of dedicated mechanical scaffolding approaches for the prevention of restenosis in tibial arteries.

IN.PACT Amphirion paclitaxel eluting balloon versus standard percutaneous transluminal angioplasty for infrapopliteal revascularization of critical limb ischemia: rationale and protocol for an ongoing randomized controlled trial

BACKGROUND The effectiveness and durability of endovascular revascularization therapies for chronic critical limb ischemia (CLI) are challenged by the extensive burden of infrapopliteal arterial disease and lesion-related characteristics (e.g., severe calcification, chronic total occlusions), which frequently result in poor clinical outcomes. While infrapopliteal vessel patency directly affects pain relief and wound healing, sustained patency and extravascular care both contribute to the ultimate "patient-centric" outcomes of functional limb preservation, mobility and quality of life (QoL). METHODS/DESIGN IN.PACT DEEP is a 2:1 randomized controlled trial designed to assess the efficacy and safety of infrapopliteal arterial revascularization between the IN.PACT Amphirion™ paclitaxel drug-eluting balloon (IA-DEB) and standard balloon angioplasty (PTA) in patients with Rutherford Class 4-5-6 CLI. DISCUSSION This multicenter trial has enrolled 358 patients at 13 European centers with independent angiographic core lab adjudication of the primary efficacy endpoint of target lesion late luminal loss (LLL) and clinically driven target lesion revascularization (TLR) in major amputation-free surviving patients through 12-months. An independent wound core lab will evaluate all ischemic wounds to assess the extent of healing and time to healing at 1, 6, and 12 months. A QoL questionnaire including a pain scale will assess changes from baseline scores through 12 months. A Clinical Events Committee and Data Safety Monitoring Board will adjudicate the composite primary safety endpoints of all-cause death, major amputation, and clinically driven TLR at 6 months and other trial endpoints and supervise patient safety throughout the study. All patients will be followed for 5 years. A literature review is presented of the current status of endovascular treatment of CLI with drug-eluting balloon and standard PTA. The rationale and design of the IN.PACT DEEP Trial are discussed. IN.PACT DEEP is a milestone, prospective, randomized, robust, independent core lab-adjudicated CLI trial that will evaluate the role of a new infrapopliteal revascularization technology, the IA-DEB, compared to PTA. It will assess the overall impact on infrapopliteal artery patency, limb salvage, wound healing, pain control, QoL, and patient mobility. The 1-year results of the adjudicated co-primary and secondary endpoints will be available in 2014. TRIAL REGISTRATION NCT00941733

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.

How useful is the ultrastructural study of the cilia of the respiratory tract in the diagnosis of an immotile cilia syndrome?

The immotile cilia syndrome (ICS) comprises a range of congenital defects of the ciliary apparatus most probably transmitted by autosomal recessive inheritance. Because cilia occur mainly in the respiratory and genital tract, the clinical symptoms of ICS are most commonly chronic sinusitis, bronchitis, bronchiectasis and male sterility. The syndrome can be associated with a situs inversus and is then called Kartagener's syndrome. We studied the ciliary ultrastructure in airway biopsies of 5 patients suffering from chronic upper and lower respiratory tract infections. With the single exception of one female patient with confirmed ICS diagnosis (Kartagener's syndrome) the etiology of the recurrent infections was unknown. The following ciliary defects were observed: missing dynein arms, radial spoke defects, missing nexin links, microtubular transpositions, compound cilia, supernumerary, absent, or incomplete microtubules, lack of ciliary orientation and various abnormal patterns of microtubular arrangement. In no instance did a patient show only a single anomaly; defects were always combined. Missing dynein arms, radial spoke defects and microtubular transpositions have frequently been described as lesions specific for ICS. Whenever these lesions were found simultaneously in both the respiratory and genital tracts, their genetic origin cannot be doubted. In our confirmed ICS patient the outer dynein arms were not missing but were reduced in number and length in a large number of cilia. The biopsy was, however, obtained from the heavily infected maxillary sinus and it is known that inflammation can lead to a loss of dynein arms. In the light of our investigations and of a review of the published cases of ciliary anomalies, it is concluded that none of the above defects in itself is specific for ICS. They may all occur as secondary lesions or sporadically as varieties in otherwise healthy subjects. It therefore appears questionable whether ICS can be diagnosed from the ciliary ultrastructure of a single airway biopsy. Assessment of ICS cannot be based simply on the ultrastructural demonstration of a particular ciliary defect, but necessitates additional considerations particularly regarding the origin of the biopsy, the sampling procedures and quantitation of defects. It appears necessary to investigate samples from different parts of the airways and quantitatively analyze the prominent lesions.

Sleep-Disordered Breathing and Periodic Limb Movements in Narcolepsy with Cataplexy: A Systematic Analysis of 35 Consecutive Patients

Background: Disturbed sleep is a core feature of narcolepsy with cataplexy (NC). Few studies have independently assessed sleep-disordered breathing (SDB) and periodic limb movements (PLMs) in non-homogeneous series of patients with and without cataplexy. We systematically assessed both SDB and PLMs in well-defined NC patients. Methods: We analyzed the clinical and polysomnographic features of 35 consecutive NC patients (mean age 40 ± 16 years, 51% males, 23/23 hypocretin-deficient) to assess the prevalence of SDB (apnea-hypopnea index >5) and PLMs (periodic leg movements in sleep (PLMI) >15) together with their impact on nocturnal sleep and daytime sleepiness using the multiple sleep latency test. Results: 11 (31%) and 14 (40%) patients had SDB and PLMs, respectively. SDB was associated with older age (49 ± 16 vs. 35 ± 13 years, p = 0.02), higher BMI (30 ± 5 vs. 27 ± 6, p = 0.05), and a trend towards higher PLMI (25 ± 20 vs. 12 ± 23, p = 0.052), whereas PLMs with older age (50 ± 16 vs. 33 ± 11 years, p = 0.002) and reduced and fragmented sleep (e.g. sleep efficiency of 82 ± 12% vs. 91 ± 6%, p = 0.015; sleep time of 353 ± 66 vs. 395 ± 28, p = 0.010). SDB and PLMs were also mutually associated (p = 0.007), but not correlated to daytime sleepiness. Conclusions: SDB and PLMs are highly prevalent and associated in NC. Nevertheless, SDB and PLMs are rarely severe, suggesting an overall limited effect on clinical manifestations.

Statin therapy and long-term adverse limb outcomes in patients with peripheral artery disease: insights from the REACH registry

AIMS Due to a high burden of systemic cardiovascular events, current guidelines recommend the use of statins in all patients with peripheral artery disease (PAD). We sought to study the impact of statin use on limb prognosis in patients with symptomatic PAD enrolled in the international REACH registry. METHODS Statin use was assessed at study enrolment, as well as a time-varying covariate. Rates of the primary adverse limb outcome (worsening claudication/new episode of critical limb ischaemia, new percutaneous/surgical revascularization, or amputation) at 4 years and the composite of cardiovascular death/myocardial infarction/stroke were compared among statin users vs. non-users. RESULTS A total of 5861 patients with symptomatic PAD were included. Statin use at baseline was 62.2%. Patients who were on statins had a significantly lower risk of the primary adverse limb outcome at 4 years when compared with those who were not taking statins [22.0 vs. 26.2%; hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.72-0.92; P = 0.0013]. Results were similar when statin use was considered as a time-dependent variable (P = 0.018) and on propensity analysis (P < 0.0001). The composite of cardiovascular death/myocardial infarction/stroke was similarly reduced (HR, 0.83; 95% CI, 0.73-0.96; P = 0.01). CONCLUSION Among patients with PAD in the REACH registry, statin use was associated with an ∼18% lower rate of adverse limb outcomes, including worsening symptoms, peripheral revascularization, and ischaemic amputations. These findings suggest that statin therapy not only reduces the risk of adverse cardiovascular events, but also favourably affects limb prognosis in patients with PAD.

Search for direct chargino production in anomaly-mediated supersymmetry breaking models based on a disappearing-track signature in pp collisions at sqrts=7 TeV with the ATLAS detector

A search for direct chargino production in anomaly-mediated supersymmetry breaking scenarios is performed in p p collisions at root s = 7 TeV using 4.7 fb(-1) of data collected with the ATLAS experiment at the LHC. In these models, the lightest chargino is predicted to have a lifetime long enough to be detected in the tracking detectors of collider experiments. This analysis explores such models by searching for chargino decays that result in tracks with few associated hits in the outer region of the tracking system. The transverse-momentum spectrum of candidate tracks is found to be consistent with the expectation from the Standard Model background processes and constraints on chargino properties are obtained.

Idiopathic chylothorax and lymphedema in 2 whippet littermates.

Idiopathic chylothorax and limb edema was diagnosed in two 2-year-old male whippet siblings. The fact that the 2 related animals developed similar clinical signs at a young age may suggest a congenital or hereditary etiology.

Congenital Hepatic Fibrosis in the Franches-Montagnes Horse Is Associated with the Polycystic Kidney and Hepatic Disease 1 (PKHD1) Gene

Congenital hepatic fibrosis has been described as a lethal disease with monogenic autosomal recessive inheritance in the Swiss Franches-Montagnes horse breed. We performed a genome-wide association study with 5 cases and 12 controls and detected an association on chromosome 20. Subsequent homozygosity mapping defined a critical interval of 952 kb harboring 10 annotated genes and loci including the polycystic kidney and hepatic disease 1 (autosomal recessive) gene (PKHD1). PKHD1 represents an excellent functional candidate as variants in this gene were identified in human patients with autosomal recessive polycystic kidney and hepatic disease (ARPKD) as well as several mouse and rat mutants. Whereas most pathogenic PKHD1 variants lead to polycystic defects in kidney and liver, a small subset of the human ARPKD patients have only liver symptoms, similar to our horses with congenital hepatic fibrosis. The PKHD1 gene is one of the largest genes in the genome with multiple alternative transcripts that have not yet been fully characterized. We sequenced the genomes of an affected foal and 46 control horses to establish a comprehensive list of variants in the critical interval. We identified two missense variants in the PKHD1 gene which were strongly, but not perfectly associated with congenital hepatic fibrosis. We speculate that reduced penetrance and/or potential epistatic interactions with hypothetical modifier genes may explain the imperfect association of the detected PKHD1 variants. Our data thus indicate that horses with congenital hepatic fibrosis represent an interesting large animal model for the liver-restricted subtype of human ARPKD.