Eosinophilic vasculitis: an inhabitual and resistant manifestation of a vasculitis

A 55-year-old woman was referred because of diffuse pruritic erythematous lesions and an ischemic process of the third finger of her right hand. She was known to have anaemia secondary to hypermenorrhea. She presented six months before admission with a cutaneous infiltration on the left cubital cavity after a paravenous leakage of intravenous iron substitution. She then reported a progressive pruritic erythematous swelling of her left arm and lower extremities and trunk. Skin biopsy of a lesion on the right leg revealed a fibrillar, small-vessel vasculitis containing many eosinophils.Two months later she reported Raynaud symptoms in both hands, with a persistent violaceous coloration of the skin and cold sensation of her third digit of the right hand. A round 1.5 cm well-delimited swelling on the medial site of the left elbow was noted. The third digit of her right hand was cold and of violet colour. Eosinophilia (19 % of total leucocytes) was present. Doppler-duplex arterial examination of the upper extremities showed an occlusion of the cubital artery down to the palmar arcade on the right arm. Selective angiography of the right subclavian and brachial arteries showed diffuse alteration of the blood flow in the cubital artery and hand, with fine collateral circulation in the carpal region. Neither secondary causes of hypereosinophilia nor a myeloproliferative process was found. Considering the skin biopsy results and having excluded other causes of eosinophilia, we assumed the diagnosis of an eosinophilic vasculitis. Treatment with tacrolimus and high dose steroids was started, the latter tapered within 12 months and then stopped, but a dramatic flare-up of the vasculitis with Raynaud phenomenon occurred. A new immunosuppressive approach with steroids and methotrexate was then introduced. This case of aggressive eosinophilic vasculitis is difficult to classify into the usual forms of vasculitis and constitutes a therapeutic challenge given the resistance to current immunosuppressive regimens.

Absence of prosthesis-patient mismatch with the new generation of Edwards stented aortic bioprosthesis

Prosthesis-patient mismatch (PPM) remains a controversial issue with the most recent stented biological valves. We analyzed the incidence of PPM after implantation of the Carpentier-Edwards Perimount Magna Ease aortic valve (PMEAV) bioprosthesis and assessed the early clinical outcome. Two hundred and seventy consecutive patients who received a PMEAV bioprosthesis between January 2007 and July 2008 were analyzed. Pre-, peri- and postoperative data were assessed and echocardiographic as well as clinical follow-up was performed. Mean age was 72+/-9 years, 168 (62.2%) were males. Fifty-seven patients (21.1%) were below 65 years of age. Absence of PPM, corresponding to an indexed effective orifice area >0.85 cm(2)/m(2), was 99.5%. Observed in-hospital mortality was 2.2% (six patients), with a predicted mortality according to the additive EuroSCORE of 7.6+/-3.1%. At echocardiographic assessment after a mean follow-up period of 150+/-91 days, mean transvalvular gradient was 11.8+/-4.8 mmHg (all valve sizes). No paravalvular leakage was seen. Nine patients died during follow-up. The Carpentier-Edwards PMEAV bioprosthesis shows excellent hemodynamic performance. This valve can be implanted in all sizes with an incidence of severe PPM below 0.5%.

Automated cement segmentation in vertebroplasty

Vertebroplasty is a minimally invasive procedure with many benefits; however, the procedure is not without risks and potential complications, of which leakage of the cement out of the vertebral body and into the surrounding tissues is one of the most serious. Cement can leak into the spinal canal, venous system, soft tissues, lungs and intradiscal space, causing serious neurological complications, tissue necrosis or pulmonary embolism. We present a method for automatic segmentation and tracking of bone cement during vertebroplasty procedures, as a first step towards developing a warning system to avoid cement leakage outside the vertebral body. We show that by using active contours based on level sets the shape of the injected cement can be accurately detected. The model has been improved for segmentation as proposed in our previous work by including a term that restricts the level set function to the vertebral body. The method has been applied to a set of real intra-operative X-ray images and the results show that the algorithm can successfully detect different shapes with blurred and not well-defined boundaries, where the classical active contours segmentation is not applicable. The method has been positively evaluated by physicians.

The Peri-Implant Sulcus Compared with Internal Implant and Suprastructure Components: A Microbiological Analysis

Purpose: A recent in vivo study has shown considerable contamination of internal implant and suprastructure components with great biodiversity, indicating bacterial leakage along the implant-abutment interface, abutment-prosthesis interface, and restorative margins. The goal of the present study was to compare microbiologically the peri-implant sulcus to these internal components on implants with no clinical signs of peri-implantitis and in function for many years. Checkerboard DNA-DNA hybridization was used to identify and quantify 40 species. Material and Methods: Fifty-eight turned titanium Brånemark implants in eight systemically healthy patients (seven women, one man) under regular supportive care were examined. All implants had been placed in the maxilla and loaded with a screw-retained full-arch bridge for an average of 9.6 years. Gingival fluid samples were collected from the deepest sulcus per implant for microbiological analysis. As all fixed restorations were removed, the cotton pellet enclosed in the intra-coronal compartment and the abutment screw were retrieved and microbiologically evaluated. Results: The pellet enclosed in the suprastructure was very similar to the peri-implant sulcus in terms of bacterial detection frequencies and levels for practically all the species included in the panel. Yet, there was virtually no microbial link between these compartments. When comparing the abutment screw to the peri-implant sulcus, the majority of the species were less frequently found, and in lower numbers at the former. However, a relevant link in counts for a lot of bacteria was described between these compartments. Even though all implants in the present study showed no clinical signs of peri-implantitis, the high prevalence of numerous species associated with pathology was striking. Conclusions: Intra-coronal compartments of screw-retained fixed restorations were heavily contaminated. The restorative margin may have been the principal pathway for bacterial leakage. Contamination of abutment screws most likely occurred from the peri-implant sulcus via the implant-abutment interface and abutment-prosthesis interface.

The role of warning behaviors in threat assessment: an exploration and suggested typology

The concept of warning behaviors offers an additional perspective in threat assessment. Warning behaviors are acts which constitute evidence of increasing or accelerating risk. They are acute, dynamic, and particularly toxic changes in patterns of behavior which may aid in structuring a professional's judgment that an individual of concern now poses a threat - whether the actual target has been identified or not. They require an operational response. A typology of eight warning behaviors for assessing the threat of intended violence is proposed: pathway, fixation, identification, novel aggression, energy burst, leakage, directly communicated threat, and last resort warning behaviors. Previous research on risk factors associated with such warning behaviors is reviewed, and examples of each warning behavior from various intended violence cases are presented, including public figure assassination, adolescent and adult mass murder, corporate celebrity stalking, and both domestic and foreign acts of terrorism. Practical applications and future research into warning behaviors are suggested. Copyright © 2011 John Wiley & Sons, Ltd.

Tight junctions in brain barriers during central nervous system inflammation

Homeostasis within the central nervous system (CNS) is a prerequisite to elicit proper neuronal function. The CNS is tightly sealed from the changeable milieu of the blood stream by the blood-brain barrier (BBB) and the blood-cerebrospinal fluid (CSF) barrier (BCSFB). Whereas the BBB is established by specialized endothelial cells of CNS microvessels, the BCSFB is formed by the epithelial cells of the choroid plexus. Both constitute physical barriers by a complex network of tight junctions (TJs) between adjacent cells. During many CNS inflammatory disorders, such as multiple sclerosis, human immunodeficiency virus infection, or Alzheimer's disease, production of pro-inflammatory cytokines, matrix metalloproteases, and reactive oxygen species are responsible for alterations of CNS barriers. Barrier dysfunction can contribute to neurological disorders in a passive way by vascular leakage of blood-borne molecules into the CNS and in an active way by guiding the migration of inflammatory cells into the CNS. Both ways may directly be linked to alterations in molecular composition, function, and dynamics of the TJ proteins. This review summarizes current knowledge on the cellular and molecular aspects of the functional and dysfunctional TJ complexes at the BBB and the BCSFB, with a particular emphasis on CNS inflammation and the role of reactive oxygen species.

[Historical review and future orientations of the conventional vascular microanastomoses]

Microvascular surgery has become an important method for reconstructing surgical defects due to trauma, tumors or after burn. The most important factor for successful free flap transfer is a well-executed anastomosis. The time needed to perform the anastomosis and the failure rate are not negligible despite the high level of operator's experience. During the history, many alternatives were tried to help the microsurgeon and to reduce the complications. A Medline literature search was performed to find articles dealing with non-suture methods of microvascular anastomosis. Many historical books were also included. The non-suture techniques can be divided into four groups based on the used mechanism of sutures: double intubation including tubes and stents, intubation-eversion including simple rings, double eversion including staples and double rings, and wall adjustement with adhesives or laser. All these techniques were able to produce a faster and easier microvascular anastomosis. Nevertheless, disadvantages of the suturless techniques include toxicity, high cost, leakage or aneurysm formation. More refinement is needed before their widespread adoption. Thus, laser-assisted microvascular anastomosis using 1,9 μm diode laser appeared to be a safe and reliable help for the microsurgeon and may be further developed in the near future.

Carbon sequestration in Himalaya's alpine meadows: Mitigating cropping encroachment on pastures in Northern Pakistan

Rangelands store about 30% of the world’s carbon and support over 120 million pastoralists globally. Adjusting the management of remote alpine pastures bears a substantial climate change mitigation potential that can provide livelihood support for marginalized pastoralists through carbon payment. Landless pastoralists in Northern Pakistan seek higher income by cropping potatoes and peas over alpine pastures. However, tilling steep slopes without terracing exposes soil to erosion. Moreover, yields decline rapidly requiring increasing fertilizer inputs. Under these conditions, carbon payment could be a feasible option to compensate pastoralists for renouncing hazardous cropping while favoring pastoral activities. The study quantifies and compares C on cropped and grazed land. The hypothesis was that cropping on alpine pastures reduces former carbon storage. The study area located in the Naran valley of the Pakistani Himalayas receives an annual average of 819 mm of rain and 764 mm of snow. Average temperatures remain below 0°C from November to March while frost may occur all year round. A total of 72 soil core samples were collected discriminating land use (cropping, pasture), aspect (North, South), elevation (low 3000, middle 3100, and high 3200 m a.s.l.), and soil depth (shallow 0-10, deep 10-30 cm). Thirty six biomass samples were collected over the same independent variables (except for soil depth) using a 10x10x20 cm steal box inserted in the ground for each sample. Aboveground biomass and coarse roots were separated from the soil aggregate and oven-dried. Soil organic carbon (SOC) and biomass carbon (BC) were estimated through a potassium dichromate oxidation treatment. The samples were collected during the second week of October 2010 at the end of the grazing and cropping season and before the first snowfall. The data was statistically analyzed by means of a one-way analysis of variance. Results show that all variables taken separately have a significant effect on mean SOC [%]: crop/pasture 1.33/1.6, North/South 1.61/1.32, low/middle/high 1.09/1.62/1.68, shallow/deep 1.4/1.53. However, for BC, only land use has a significant effect with more than twice the amount of carbon in pastures [g m-2]: crop/pasture 127/318. These preliminary findings suggest that preventing the conversion of pastures into cropping fields in the Naran valley avoids an average loss of 12.2 t C ha-1 or 44.8 t CO2eq ha-1 representing a foreseeable compensation of 672 € ha-1 for the Naran landless pastoralists who would renounce cropping. The ongoing study shall provide a complete picture for carbon payment integrating key aspects such as the rate of cropping encroachment over pastures per year, the methane leakage from the system due to livestock enteric fermentation, the expected cropping income vs. livestock income and the transaction costs of implementing the mitigation project, certifying it, and verifying carbon credits. A net present value over an infinite time horizon for the mitigation scenario shall be estimated on an iterative simulation to consider weather and price uncertainties. The study will also provide an estimate of the minimum price of carbon at which pastoralists would consider engaging in the mitigation activity.

Deforestation and forest degradation monitoring and assessment of biomass and carbon stock of lowland rainforest in the Analanjirofo region, Madagascar

Madagascar is currently developing a policy and strategies to enhance the sustainable management of its natural resources, encouraged by United Nations Framework Convention on Climate Change (UNFCCC) and REDD. To set up a sustainable financing scheme methodologies have to be provided that estimate, prevent and mitigate leakage, develop national and regional baselines, and estimate carbon benefits. With this research study this challenge was tried to be addressed by analysing a lowland rainforest in the Analanjirofo region in the district of Soanierana Ivongo, North East of Madagascar. For two distinguished forest degradation stages: “low degraded forest” and “degraded forest” aboveground biomass and carbon stock was assessed. The corresponding rates of carbon within those two classes were calculated and linked to a multi-temporal set of SPOT satellite data acquired in 1991, 2004 and 2009. Deforestation and particularly degradation and the related carbon stock developments were analysed. With the assessed data for the 3 years 1991, 2004 and 2009 it was possible to model a baseline and to develop a forest prediction for 2020 for Analanjirofo region in the district of Soanierana Ivongo. These results, developed applying robust methods, may provide important spatial information regarding the priorities in planning and implementation of future REDD+ activities in the area.

Icatibant , the bradykinin B2 receptor antagonist with target to the interconnected kinin systems

INTRODUCTION: HOE-140/ Icatibant is a selective, competitive antagonist to bradykinin (BK) against its binding to the kinin B2 receptor. Substitution of five non-proteogeneic amino acid analogues makes icatibant resistant to degradation by metalloproteases of kinin catabolism. Icatibant has clinical applications in inflammatory and vascular leakage conditions caused by an acute (non-controlled) production of kinins and their accumulation at the endothelium B2 receptor. The clinical manifestation of vascular leakage, called angioedema (AE), is characterized by edematous attacks of subcutaneous and submucosal tissues, which can cause painful intestinal consequences, and life-threatening complications if affecting the larynx. Icatibant is registered for the treatment of acute attacks of the hereditary BK-mediated AE, i.e., AE due to C1 inhibitor deficiency. AREAS COVERED: This review discusses emerging knowledge on the kinin system: kinin pharmacological properties, biochemical characteristics of the contact phase and kinin catabolism proteases. It underlines the responsibility of the kinins in AE initiation and the potency of icatibant to inhibit AE formation by kinin-receptor interactions. EXPERT OPINION: Icatibant antagonist properties protect BK-mediated AE patients against severe attacks, and could be developed for use in inflammatory conditions. More studies are required to confirm whether or not prolonged and frequent applications of icatibant could result in the impairment of the cardioprotective effect of BK.

Application of an in vitro drug screening assay based on the release of phosphoglucose isomerase to determine the structure-activity relationship of thiazolides against Echinococcus multilocularis metacestodes

OBJECTIVES: The disease alveolar echinococcosis (AE), caused by the larval stage of the cestode Echinococcus multilocularis, is fatal if treatment is unsuccessful. Current treatment options are, at best, parasitostatic, and involve taking benzimidazoles (albendazole, mebendazole) for the whole of a patient's life. In conjunction with the recent development of optimized procedures for E. multilocularis metacestode cultivation, we aimed to develop a rapid and reliable drug screening test, which enables efficient screening of a large number of compounds in a relatively short time frame. METHODS: Metacestodes were treated in vitro with albendazole, the nitro-thiazole nitazoxanide and 29 nitazoxanide derivatives. The resulting leakage of phosphoglucose isomerase (PGI) activity into the medium supernatant was measured and provided an indication of compound efficacy. RESULTS: We show that upon in vitro culture of E. multilocularis metacestodes in the presence of active drugs such as albendazole, the nitro-thiazole nitazoxanide and 30 different nitazoxanide derivatives, the activity of PGI in culture supernatants increased. The increase in PGI activity correlated with the progressive degeneration and destruction of metacestode tissue in a time- and concentration-dependent manner, which allowed us to perform a structure-activity relationship analysis on the thiazolide compounds used in this study. CONCLUSIONS: The assay presented here is inexpensive, rapid, can be used in 24- and 96-well formats and will serve as an ideal tool for first-round in vitro tests on the efficacy of large numbers of antiparasitic compounds.

miR-199a-5p regulates urothelial permeability and may play a role in bladder pain syndrome

Defects in urothelial integrity resulting in leakage and activation of underlying sensory nerves are potential causative factors of bladder pain syndrome, a clinical syndrome of pelvic pain and urinary urgency/frequency in the absence of a specific cause. Herein, we identified the microRNA miR-199a-5p as an important regulator of intercellular junctions. On overexpression in urothelial cells, it impairs correct tight junction formation and leads to increased permeability. miR-199a-5p directly targets mRNAs encoding LIN7C, ARHGAP12, PALS1, RND1, and PVRL1 and attenuates their expression levels to a similar extent. Using laser microdissection, we showed that miR-199a-5p is predominantly expressed in bladder smooth muscle but that it is also detected in mature bladder urothelium and primary urothelial cultures. In the urothelium, its expression can be up-regulated after activation of cAMP signaling pathways. While validating miR-199a-5p targets, we delineated novel functions of LIN7C and ARHGAP12 in urothelial integrity and confirmed the essential role of PALS1 in establishing and maintaining urothelial polarity and junction assembly. The present results point to a possible link between miR-199a-5p expression and the control of urothelial permeability in bladder pain syndrome. Up-regulation of miR-199a-5p and concomitant down-regulation of its multiple targets might be detrimental to the establishment of a tight urothelial barrier, leading to chronic pain.

Dysferlin is a new marker for leaky brain blood vessels in multiple sclerosis

Dysferlin is a muscle protein involved in cell membrane repair and its deficiency is associated with muscular dystrophy. We describe that dysferlin is also expressed in leaky endothelial cells. In the normal central nervous system (CNS), dysferlin is only present in endothelial cells of circumventricular organs. In the inflamed CNS of patients with multiple sclerosis (MS) or in animals with experimental autoimmune encephalomyelitis, dysferlin reactivity is induced in endothelial cells and the expression is associated with vascular leakage of serum proteins. In MS, dysferlin expression in endothelial cells is not restricted to vessels with inflammatory cuffs but is also present in noninflamed vessels. In addition, many blood vessels with perivascular inflammatory infiltrates lack dysferlin expression in inactive lesions or in the normal-appearing white matter. In vitro, dysferlin can be induced in endothelial cells by stimulation with tumor necrosis factor-alpha. Hence, dysferlin is not only a marker for leaky brain vessels, but also reveals dissociation of perivascular inflammatory infiltrates and blood-brain barrier disturbance in multiple sclerosis.

In vitro metacestodicidal activities of genistein and other isoflavones against Echinococcus multilocularis and Echinococcus granulosus

Echinococcus multilocularis and Echinococcus granulosus metacestode infections in humans cause alveolar echinococcosis and cystic echinococcosis, respectively, in which metacestode development in visceral organs often results in particular organ failure. Further, cystic hydatidosis in farm animals causes severe economic losses. Although benzimidazole derivatives such as mebendazole and albendazole are being used as therapeutic agents, there is often no complete recovery after treatment. Hence, in searching for novel treatment options, we examined the in vitro efficacies of a number of isoflavones against Echinococcus metacestodes and protoscoleces. The most prominent isoflavone, genistein, exhibits significant metacestodicidal activity in vitro. However, genistein binds to the estrogen receptor and can thus induce estrogenic effects, which is a major concern during long-term chemotherapy. We have therefore investigated the activities of a number of synthetic genistein derivatives carrying a modified estrogen receptor binding site. One of these, Rm6423, induced dramatic breakdown of the structural integrity of the metacestode germinal layer of both species within 5 to 7 days of in vitro treatment. Further, examination of the culture medium revealed increased leakage of parasite proteins into the medium during treatment, but zymography demonstrated a decrease in the activity of metalloproteases. Moreover, two of the genistein derivatives, Rm6423 and Rm6426, induced considerable damage in E. granulosus protoscoleces, rendering them nonviable. These findings demonstrate that synthetic isoflavones exhibit distinct in vitro effects on Echinococcus metacestodes and protoscoleces, which could potentially be exploited further for the development of novel chemotherapeutical tools against larval-stage Echinococcus infection.

Pulmonary capillary pressure. A review

Pulmonary capillary pressure (Pcap) is the predominant force that drives fluid out of the pulmonary capillaries into the interstitium. Increasing hydrostatic capillary pressure is directly proportional to the lung's transvascular filtration rate, and in the extreme leads to pulmonary edema. In the pulmonary circulation, blood flow arises from the transpulmonary pressure gradient, defined as the difference between pulmonary artery (diastolic) pressure and left atrial pressure. The resistance across the pulmonary vasculature consists of arterial and venous components, which interact with the capacitance of the compliant pulmonary capillaries. In pathological states such as acute respiratory distress syndrome, sepsis, and high altitude or neurogenic lung edema, the longitudinal distribution of the precapillary arterial and the postcapillary venous resistance varies. Subsequently, the relationship between Pcap and pulmonary artery occlusion pressure (PAOP) is greatly variable and Pcap can no longer be predicted from PAOP. In clinical practice, PAOP is commonly used to guide fluid therapy, and Pcap as a hemodynamic target is rarely assessed. This approach is potentially misleading. In the presence of a normal PAOP and an increased pressure gradient between Pcap and PAOP, the tendency for fluid leakage in the capillaries and subsequent edema development may substantially be underestimated. Tho-roughly validated methods have been developed to assess Pcap in humans. At the bedside, measurement of Pcap can easily be determined by analyzing a pressure transient after an acute pulmonary artery occlusion with the balloon of a Swan-Ganz catheter.