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.

Spindle cell oncocytoma of the pituitary gland with follicle-like component: organotypic differentiation to support its origin from folliculo-stellate cells

Spindle cell oncocytoma (SCO) is a rare, non-adenomatous tumor originating from the anterior pituitary gland. Composed of fusiform, mitochondrion-rich cells sharing several immunophenotypic and ultrastructural properties with folliculo-stellate cells (FSC), SCO has been proposed to represent a neoplastic counterpart of the latter. To date, however, SCO has failed to meet one criterion commonly used in histological-based taxonomy and diagnostics; that of recapitulating any of FSCs' morphologically defined developmental or physiological states. We describe a unique example of SCO wherein a conventional fascicular texture was seen coexisting with and organically merging into follicle-like arrangements. The sellar tumor of 2.7 × 2.6 × 2.5 cm was transphenoidally resected from a 55-year old female. Preoperative magnetic resonance imaging indicated an isointense, contrast enhancing mass with suprasellar extension. Histology showed multiple rudimentary to well-formed, follicle-like cavities on a classical spindle cell background; while all the participating cells exhibited an SCO immunophenotype, including positivity for S100 protein, vimentin, EMA, Bcl-2, and TTF-1, as well as staining with the antimitochondrial antibody 113-1. Conversely no expression of GFAP, follicular-epithelial cytokeratin, carcinoembryonic antigen, or anterior pituitary hormones was detected. Ultrastructurally, tumor cells facing follicular lumina displayed organelles of epithelial specialization, in particular surface microvilli and apical tight junctions. This constellation is felt to be reminiscent of FSCs' metaplastic transition to follicular epithelium, as observed during embryonic development and physiological renewal of the hormone-secreting parenchyma. Such finding is apt to being read as a supporting argument for SCO's descent from the FSC lineage.

Compression hosiery for occupational leg symptoms and leg volume: a randomized crossover trial in a cohort of hairdressers

OBJECTIVE: Occupational leg symptoms are highly prevalent in the general population and impair the psychic state of health. We investigated hairdressers, a cohort exposed to prolonged standing during work, in a randomized crossover trial. We hypothesized that hairdressers wearing low-strength compression hosiery would benefit from less leg volume increase and discomfort. METHODS: One hundred and eight hairdressers were randomized to wear medical compression stockings (MCS; 15-20 mmHg) in a crossover study. The effect of MCS on symptoms and on lower leg volume was compared with no compression treatment. Symptoms were assessed with a comprehensive questionnaire, categorized using factor analysis with varimax rotation and correlated with leg volume changes. RESULTS: Wearing MCS reduced the symptom score for pain and feelings of swelling (range 0-4) by an average of 0.22 (12%, P < 0.001). Sleep disturbance, feeling of unattractive legs and depressiveness improved with MCS compared with no MCS. Subjects initially obliged to refrain from wearing stockings showed a significant decrease of pain and feelings of swelling as well (by 0.10 [6%], P = 0.015). Wearing MCS was associated with a decrease of lower leg volume by an average of 19 mL (P < 0.001), with preference in older hairdressers (P < 0.001). The effects of wearing MCS on symptoms and on leg volume were not correlated with each other. CONCLUSIONS: Individuals working in a standing profession experience leg pain, feelings of swelling, heaviness and various other disturbing feelings. These symptoms can be alleviated by wearing low-strength MCS.

Thoracic radionecrosis following repeated cardiac catheterization

Radiodermatitis is a known complication in patients having undergone radiotherapy. It usually appears 2 to 5 years after irradiation. We are reporting on a case of radiodermatitis that occurred within months after coronary dilatation and stenting. It started with painful swelling, followed by a typical appearance on the skin surface. Histological finding confirmed the diagnosis. However, magnetic resonance imaging showed changes in the subcutaneous tissue extending into the ribs. A radical debridement was performed including removal of a partially necrotic 4th rib. The defect was closed with a latissimus dorsi transposition flap. Our findings are compared with the literature reports.

Impairment of mitochondrial tRNAIle processing by a novel mutation associated with chronic progressive external ophthalmoplegia

We report a sporadic case of chronic progressive external ophthalmoplegia associated with ragged red fibers. The patient presented with enlarged mitochondria with deranged internal architecture and crystalline inclusions. Biochemical studies showed reduced activities of complex I, III and IV in skeletal muscle. Molecular genetic analysis of all mitochondrial tRNAs revealed a G to A transition at nt 4308; the G is a highly conserved nucleotide that participates in a GC base-pair in the T-stem of mammalian mitochondrial tRNA(Ile). The mutation was detected at a high level (approx. 50%) in muscle but not in blood. The mutation co-segregated with the phenotype, as the mutation was absent from blood and muscle in the patient's healthy mother. Functional characterization of the mutation revealed a six-fold reduced rate of tRNA(Ile) precursor 3' end maturation in vitro by tRNAse Z. Furthermore, the mutated tRNA(Ile) displays local structural differences from wild-type. These results suggest that structural perturbations reduce efficiency of tRNA(Ile) precursor 3' end processing and contribute to the molecular pathomechanism of this mutation.

Acute hemorrhagic edema of young children: a concise narrative review

Acute hemorrhagic edema of young children is an uncommon but likely underestimated cutaneous leukocytoclastic vasculitis. The condition typically affects infants 6-24 months of age with a history of recent respiratory illness with or without course of antibiotics. The diagnosis is made in children, mostly nontoxic in appearance, presenting with nonpruritic, large, round, red to purpuric plaques predominantly over the cheeks, ears, and extremities, with relative sparing of the trunk, often with a target-like appearance, and edema of the distal extremities, ears, and face that is mostly non-pitting, indurative, and tender. In boys, the lesions sometimes involve the scrotum and, more rarely, the penis. Fever, typically of low grade, is often present. Involvement of body systems other than skin is uncommon, and spontaneous recovery usually occurs within 6-21 days without sequelae. In this condition, laboratory tests are non-contributory: total blood cell count is often normal, although leukocytosis and thrombocytosis are sometimes found, clotting studies are normal, erythrocyte sedimentation rate and C-reactive protein test are normal or slightly elevated, complement level is normal, autoantibodies are absent, and urinalysis is usually normal. Experienced physicians rapidly consider the possible diagnosis of acute hemorrhagic edema when presented with a nontoxic young child having large targetoid purpuric lesions and indurative swelling, which is non-pitting in character, and make the diagnosis either on the basis of clinical findings alone or supported by a skin biopsy study.

Mitochondrial translation in trypanosomatids: a novel target for chemotherapy?

Trypanosomatids cause widespread disease in humans and animals. Treatment of many of these diseases is hampered by the lack of efficient and safe drugs. New strategies for drug development are therefore urgently needed. It has long been known that the single mitochondrion of trypanosomatids exhibits many unique features. Recently, the mitochondrial translation machinery of trypanosomatids has been the focus of several studies, which revealed interesting variations to the mammalian system. It is the aim of this article to review these unique features and to discuss them in the larger biological context. It is our opinion that some of these features represent promising novel targets for chemotherapeutic intervention that should be studied in more detail.

Organelle segregation into Plasmodium liver stage merozoites

The liver stage of the Plasmodium parasite remains one of the most promising targets for intervention against malaria as it is clinically silent, precedes the symptomatic blood stage and represents a bottleneck in the parasite life cycle. However, many aspects of the development of the parasite during this stage are far from understood. During the liver stage, the parasite undergoes extensive replication, forming tens of thousands of infectious merozoites from each invading sporozoite. This implies a very efficient and accurate process of cytokinesis and thus also of organelle development and segregation. We have generated for the first time Plasmodium berghei double-fluorescent parasite lines, allowing visualization of the apicoplast, mitochondria and nuclei in live liver stage parasites. Using these we have seen that in parallel with nuclear division, the apicoplast and mitochondrion become two extensively branched and intertwining structures. The organelles then undergo impressive morphological and positional changes prior to cell division. To form merozoites, the parasite undergoes cytokinesis and the complex process of organelle development and segregation into the forming daughter merozoites could be analysed in detail using the newly generated transgenic parasites.

Preparation of intact bovine tail intervertebral discs for organ culture

The intervertebral disc (IVD) is the joint of the spine connecting vertebra to vertebra. It functions to transmit loading of the spine and give flexibility to the spine. It composes of three compartments: the innermost nucleus pulposus (NP) encompassing by the annulus fibrosus (AF), and two cartilaginous endplates connecting the NP and AF to the vertebral body on both sides. Discogenic pain possibly caused by degenerative intervertebral disc disease (DDD) and disc herniations has been identified as a major problem in our modern society. To study possible mechanisms of IVD degeneration, in vitro organ culture systems with live disc cells are highly appealing. The in vitro culture of intact bovine coccygeal IVDs has advanced to a relevant model system, which allows the study of mechano-biological aspects in a well-controlled physiological and mechanical environment. Bovine tail IVDs can be obtained relatively easy in higher numbers and are very similar to the human lumbar IVDs with respect to cell density, cell population and dimensions. However, previous bovine caudal IVD harvesting techniques retaining cartilaginous endplates and bony endplates failed after 1-2 days of culture since the nutrition pathways were obviously blocked by clotted blood. IVDs are the biggest avascular organs, thus, the nutrients to the cells in the NP are solely dependent on diffusion via the capillary buds from the adjacent vertebral body. Presence of bone debris and clotted blood on the endplate surfaces can hinder nutrient diffusion into the center of the disc and compromise cell viability. Our group established a relatively quick protocol to "crack"-out the IVDs from the tail with a low risk for contamination. We are able to permeabilize the freshly-cut bony endplate surfaces by using a surgical jet lavage system, which removes the blood clots and cutting debris and very efficiently reopens the nutrition diffusion pathway to the center of the IVD. The presence of growth plates on both sides of the vertebral bone has to be avoided and to be removed prior to culture. In this video, we outline the crucial steps during preparation and demonstrate the key to a successful organ culture maintaining high cell viability for 14 days under free swelling culture. The culture time could be extended when appropriate mechanical environment can be maintained by using mechanical loading bioreactor. The technique demonstrated here can be extended to other animal species such as porcine, ovine and leporine caudal and lumbar IVD isolation.

Analgesic and anti-inflammatory actions of robenacoxib in acute joint inflammation in dog

The objectives of this study were to establish dose-response and blood concentration-response relationships for robenacoxib, a novel nonsteroidal anti-inflammatory drug with selectivity for inhibition of the cyclooxygenase (COX)-2 isoenzyme, in a canine model of synovitis. Acute synovitis of the stifle joint was induced by intra-articular injection of sodium urate crystals. Robenacoxib (0.25, 0.5, 1.0, 2.0 and 4.0 mg/kg), placebo and meloxicam (0.2 mg/kg) were administered subcutaneously (s.c.) 3 h after the urate crystals. Pharmacodynamic endpoints included data from forceplate analyses, clinical orthopaedic examinations and time course of inhibition of COX-1 and COX-2 in ex vivo whole blood assays. Blood was collected for pharmacokinetics. Robenacoxib produced dose-related improvement in weight-bearing, pain and swelling as assessed objectively by forceplate analysis (estimated ED(50) was 1.23 mg/kg for z peak force) and subjectively by clinical orthopaedic assessments. The analgesic and anti-inflammatory effects of robenacoxib were significantly superior to placebo (0.25-4 mg/kg robenacoxib) and were non-inferior to meloxicam (0.5-4 mg/kg robenacoxib). All dosages of robenacoxib produced significant dose-related inhibition of COX-2 (estimated ED(50) was 0.52 mg/kg) but no inhibition of COX-1. At a dosage of 1-2 mg/kg administered s.c., robenacoxib should be at least as effective as 0.2 mg/kg of meloxicam in suppressing acute joint pain and inflammation in dogs.

Biomaterials for Intervertebral Disc Regeneration

The intervertebral disc (IVD) is a complex avascular organ of viscoelastic properties. The current research focus is to regenerate and to partially restore a degenerated IVD by ‘smart’ biomaterials in combination of cell therapy and/or growth factors. For the two tissues of the IVD, that is, the nucleus pulposus (NP) and the annulus fibrosus (AF), biomaterials of different mechanical properties are needed. The ideal biomaterial to restore the water-rich NP and the tensile-force resistant AF has not been identified yet. The lack of blood vessels and the relative scarcity of specially adapted cells of the IVD organ demand novel concepts of tissue-engineered biological approaches to regenerate or replace the IVD. Injectable biodegradable hydrogels with swelling properties are in focus for NP replacement, whereas electrospun biphasic composites and silk, among other biodegradable polymers, are discussed for AF reinforcement.

Hereditary angioedema (HAE) in children and adolescents--a consensus on therapeutic strategies

Hereditary angioedema due to C1 inhibitor (C1 esterase inhibitor) deficiency (types I and II HAE-C1-INH) is a rare disease that usually presents during childhood or adolescence with intermittent episodes of potentially life-threatening angioedema. Diagnosis as early as possible is important to avoid ineffective therapies and to properly treat swelling attacks. At a consensus meeting in June 2011, pediatricians and dermatologists from Germany, Austria, and Switzerland reviewed the currently available literature, including published international consensus recommendations for HAE therapy across all age groups. Published recommendations cannot be unconditionally adopted for pediatric patients in German-speaking countries given the current approval status of HAE drugs. This article provides an overview and discusses drugs available for HAE therapy, their approval status, and study results obtained in adult and pediatric patients. Recommendations for developing appropriate treatment strategies in the management of HAE in pediatric patients in German-speaking countries are provided.Conclusion Currently, plasma-derived C1 inhibitor concentrate is considered the best available option for the treatment of acute HAE-C1-INH attacks in pediatric patients in German-speaking countries, as well as for short-term and long-term prophylaxis.

Optical projection tomography reveals dynamics of HEV growth after immunization with protein plus CFA and features shared with HEVs in acute autoinflammatory lymphadenopathy

The vascular-stromal compartment of lymph nodes is important for lymph node function, and high endothelial venules (HEVs) play a critical role in controlling the entry of recirculating lymphocytes. In autoimmune and autoinflammatory diseases, lymph node swelling is often accompanied by apparent HEV expansion and, potentially, targeting HEV expansion could be used therapeutically to limit autoimmunity. In previous studies using mostly flow cytometry analysis, we defined three differentially regulated phases of lymph node vascular-stromal growth: initiation, expansion, and the re-establishment of vascular quiescence and stabilization. In this study, we use optical projection tomography to better understand the morphologic aspects of HEV growth upon immunization with ovalbumin/CFA (OVA/CFA). We find HEV elongation as well as modest arborization during the initiation phase, increased arborization during the expansion phase, and, finally, vessel narrowing during the re-establishment of vascular quiescence and stabilization. We also examine acutely enlarged autoinflammatory lymph nodes induced by regulatory T cell depletion and show that HEVs are expanded and morphologically similar to the expanded HEVs in OVA/CFA-stimulated lymph nodes. These results reinforce the idea of differentially regulated, distinct phases of vascular-stromal growth after immunization and suggest that insights gained from studying immunization-induced lymph node vascular growth may help to understand how the lymph node vascular-stromal compartment could be therapeutically targeted in autoimmune and autoinflammatory diseases.

Microsurgical management of large intra-and extracranial calvarial meningiomas

Objective: Based on the largest series reported of giant intra- and extracranial calvarial meningiomas (GIECM) the purpose of the present study was to characterize the treatment and outcome data associated with patients operated on GIECM and to describe our experience in the management of this rare and therapeutically demanding tumour entity. Methods: The data of 12 patients (7/12 males, 5/12 females) with surgically treated GIECM at the University Hospitals Aachen and Bern between 1994 and 2011 were retrospectively analyzed. The mean patient age was 58 years (range, 22 to 78 years). Symptom distribution included extracranial swelling (12/12), seizures (5/12), headache (4/12), gait disturbance (3/12), dizziness (2/12), and impaired vision (1/12). GIECM were located frontal (6/12), temporal (3/12), parietal, fronto-parietal, and parieto-occipital (1/12 each). Microsurgical resection with acrylic-augmented cranioplasty was performed in all patients and 11/12 patients received dural repair with synthetic (7/11) or autologous (4/11) patch grafts. Surgical excision in two stages with primary removal of the extracranial meningioma component was undertaken in 2/12 patients, whereas preoperative embolization and postoperative radiotherapy were applied in 1/12 patient each. Results: In contrast to intradural meningiomas GIECM mainly affect male patients at a comparatively younger age. GIECM could be completely (9/12) or subtotally (3/12) resected. Surgical-associated complications included minor CSF leak (6/12), wound healing disturbance (3/12), venous engorgement, and haemorrhage (2/12 each), requiring reoperation in 3/12 cases. Histopathological examination revealed meningothelial (6/12), atypical (4/12), and transitional (1/12) GIECM. 10/12 patients exhibited excellent postoperative clinical outcome, 1/12 patient each deteriorated or died of pulmonary embolism. Conclusions: The operative management of GIECM is challenging, carries a substantial risk, and demands special strategies because of the large tumour size, anatomical involvement of scalp, calvaria, meninges, brain or vascular structures, and more frequent atypical histology. Although microsurgical resection with cranioplasty and mostly dural grafting usually results in a good clinical outcome, the potential complication rate is markedly higher when compared to smaller meningiomas without extracranial component. Preoperative embolization and staging of surgical resection are possible additional therapeutic options.

Modeling Small Molecule Elution From a Hydrogel using a Microfluidic Technique

Drug release from a fluid-contacting biomaterial is simulated using a microfluidic device with channels defined by solute-loaded hydrogel. In order to mimic a drug delivery device, a solution of poly(ethylene glycol) diacrylate (PEG-DA), solute, and photoinitiator is cured inside a microfluidic device with a channel through the center ofthe hydrogel. As water is pumped through the channel, solute diffuses out of the hydrogel and into the water. Channel sizes within the devices range from 300 µm to 1000 µm to simulate vessels within the body. The properties of the PEG hydrogel were characterizedby the extent of crosslinking, the swelling ratio, and the mesh size of the gel. The structure of the hydrogel was related to the UV exposure dosage and the initial water and solute content in the PEG-DA solution.