Management of Pregnancy and Delivery in Patients With Hereditary Angioedema Due to C1 Inhibitor Deficiency.

BACKGROUND AND OBJECTIVE: There is little information on pregnancy and delivery in patients with hereditary angioedema due to C1 inhibitor deficiency (C1INH-HAE). The aim of this study was to describe the effect of pregnancy and deliveries on symptoms of C1INH-HAE and review the need for and safety of treatments available during the study period. METHODS: Retrospective review using a purpose-designed questionnaire of 61 C1INH-HAE patients from 5 hospitals specialized in the management of HAE in Spain. The outcomes measured were number of pregnancies, changes in symptoms during pregnancy and delivery, mode of delivery, type of anesthesia during delivery, treatments received, and tolerance of treatments. RESULTS: We reviewed 125 full-term pregnancies (89 without a prior diagnosis of C1INH-HAE), 14 miscarriages, and 4 induced abortions. Patients reported an increased frequency of C1INH-HAE symptoms in 59.2% of pregnancies (74/125) and the presence of symptoms throughout pregnancy in 40% (50/125). Prophylactic C1INH-HAE therapy was used during 9 (7.2%) of the 125 pregnancies. Nine patients--in 11 pregnancies (8.8 %)--received treatment for acute attacks. Most deliveries (n=110, 88%) were vaginal. A cesarean section was necessary in 15 cases (12%). Short-term prophylaxis with pdhC1INH was administered before 14 deliveries (11.2 %); 111 deliveries (88.8 %) were performed without premedication and were well tolerated. Anesthesia was used in 51 deliveries (40.8%). CONCLUSIONS: Pregnancy has a variable influence on the clinical expression of C1INH-HAE. Attacks tend to occur more frequently but not to increase in severity. Vaginal delivery was mostly well tolerated. pdhC1INH prophylaxis should be administered prior to cesarean delivery and is also recommended before vaginal delivery if there are additional risk factors. pdhC1INH should always be available in the delivery room.

Clinical Pattern and Acute and Long-term Management of Hereditary Angioedema Due to C1-Esterase Inhibitor Deficiency.

BACKGROUND: Hereditary angioedema due to C1-esterase inhibitor deficiency (HAE-C1-INH) is a life-threatening disease. OBJECTIVES: To describe the clinical characteristics and management of patients with HAE-C1-INH during routine clinical practice. METHODS: An observational, retrospective study was performed in patients with HAE-C1-INH. Demographic, clinical, and analytical data were collected from 2 periods: period A (October 2009-September 2010) and period B (October 2007-September 2009). RESULTS: We studied 112 patients with HAE-C1-INH (57.1% females). Age at onset of symptoms was 14.4 years (lower in patients who had experienced attacks in the previous year). In period B (n=87), 62.1% of patients presented at least 1 edema attack (median, 3.5 attacks/patient/2 years), and 19.1% of attacks were treated. In period A (n=77), 58.4% of patients were on maintenance therapy. Stanozolol was the most widely used drug (48.9%), with a mean weekly dose of 6.7 mg. At least 1 attack was recorded in 72.7% of patients (median, 3.0 attacks/patient/year), and 31.5% of the attacks were treated. Treatment of acute attacks increased by 12.4%. CONCLUSION: Age at onset of symptoms is associated with clinical expression of disease. The higher age at onset of symptoms, the fewer number of attacks per patient and year, and the lower dose of attenuated androgens necessary to control the disease than in other series lead us to hypothesize that HAE-C1-INH could have a less severe expression in Spain. Acute attacks seem to be treated increasingly often.

Estimating influenza vaccine effectiveness in Spain using sentinel surveillance data.

We aimed to estimate influenza vaccine effectiveness (VE) against laboratory-confirmed influenza during three influenza seasons (2010/11 to 2012/2013) in Spain using surveillance data and to compare the results with data obtained by the cycEVA study, the Spanish component of the Influenza Monitoring Vaccine Effectiveness (I-MOVE) network. We used the test-negative case­control design, with data from the Spanish Influenza Sentinel Surveillance System (SISS) or from the cycEVA study. Cases were laboratory-confirmed influenza patients with the predominant influenza virus of each season, and controls were those testing negative for any influenza virus. We calculated the overall and age-specific adjusted VE. Although the number of patients recorded in the SISS was three times higher than that in the cycEVA study, the quality of information for important variables, i.e. vaccination status and laboratory results, was high in both studies. Overall, the SISS and cycEVA influenza VE estimates were largely similar during the study period. For elderly patients (> 59 years), the SISS estimates were slightly lower than those of cycEVA, and estimates for children (0­14 years) were higher using SISS in two of the three seasons studied. Enhancing the SISS by collecting the date of influenza vaccination and reducing the percentage of patients with incomplete information would optimise the system to provide reliable annual influenza VE estimates to guide influenza vaccination policies.

Piperacillin-induced DRESS: distinguishing features observed in a clinical and allergy study of 8 patients.

BACKGROUND: DRESS (drug reaction with eosinophilia and systemic symptoms) syndrome is characterized by fever, rash, eosinophilia, and multiorgan failure. Previous reports have described differences in clinical and laboratory findings of DRESS syndrome depending on the inducing drug. Piperacillin has been reported as the drug responsible for this syndrome in 3 patients. OBJECTIVE: To analyze and describe the clinical, laboratory, and allergy study findings of piperacillin-induced DRESS. PATIENTS AND METHODS: Retrospective case series of patients diagnosed with DRESS associated with piperacillin-tazobactam (Pip/Taz) according to the Kardaun diagnostic score criteria. Assessment of causality was established using the Spanish Pharmacovigilance System and the lymphocyte transformation test (LTT). The allergy study included skin and epicutaneous tests. RESULTS: Eight patients were diagnosed with DRESS due to Pip/Taz (3 probable and 5 definite cases). Skin rash was observed in all cases and facial edema in 50%; the mean latency period was 18 days. Fever was present in 7 patients. Liver and kidney injuries were detected in 6 and 3 patients, respectively. All patients had eosinophilia and a full recovery. The LTT to Pip/Taz was strongly positive in all patients, with a stimulation index of over 6. Three of 3 patients had a positive intradermal test to Pip/Taz, and 1 of 4 had a positive patch test. All patients had a negative LTT to carbapenems. CONCLUSIONS: We have reported on the first case series of piperacillin-induced DRESS. A latency period of 18 days, skin rash, eosinophilia, fever, liver injury, and good prognosis were the most common features. The allergy study, and the LTT in particular, was highly useful for identifying Pip/Taz as the culprit drug and piperacillin as the responsible active ingredient.

Management of dental-oral procedures in patients with hereditary angioedema due to C1 inhibitor deficiency.

BACKGROUND: Hereditary angioedema due to C1 inhibitor deficiency (HAE-C1-INH) has considerable implications for dental health care providers, since dental procedures may trigger severe and even life-threatening episodes. The aim of the present study was to analyze the efficacy and safety of premedication with attenuated androgens (AAs), plasma-derived human C1 esterase inhibitor concentrate (pdhC1INH), or both to prevent the development of upper airway angioedema after dental-oral procedures in patients with HAE-C1-INH. MATERIAL AND METHODS: All dental-oral procedures performed on patients with HAE-C1-INH who were followed up at La Paz University Hospital, Madrid, Spain were reviewed. Demographic data, maintenance treatment, preprocedure prophylaxis, disease severity, and occurrence of upper airway angioedema were recorded. RESULTS: Twenty-four patients (14 male/10 female; mean age, 42.6 years) underwent 66 procedures. Most procedures were performed on patients with severe HAE-C1-INH (20 procedures) or moderate HAE-C1-INH (26 procedures). Only 9 procedures were performed without short-term prophylaxis. Mild upper airway angioedema developed after 3 procedures performed without short-term prophylaxis in patients with minimal or asymptomatic HAE-C1-INH. A statistically significant association was found between development of mild postprocedure upper airway angioedema and lack of maintenance treatment with AA, lack of increased dose of preprocedure AA, and failure to administer preprocedure pdhC1INH (P = .002, Fisher exact test). CONCLUSIONS: Increased doses of prophylactic AA, administration of pdhC1INH, or both were good options for ambulatory management of dental-oral procedures in patients with HAE-C1-INH. Prophylaxis with pdC1INH or increased doses of AA is advisable before dental-oral procedures, even in patients with low disease severity.

Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part II. Treatment, follow-up, and special situations.

BACKGROUND: There are no previous Spanish guidelines or consensus statements on bradykinin-induced angioedema. AIM: To draft a consensus statement on the management and treatment of angioedema mediated by bradykinin in light of currently available scientific evidence and the experience of experts. This statement will serve as a guideline to health professionals. METHODS: The consensus was led by the Spanish Study Group on Bradykinin-Induced Angioedema, a working group of the Spanish Society of Allergology and Clinical Immunology. A review was conducted of scientific papers on different types of bradykinin-induced angioedema (hereditary and acquired angioedema due to C1 inhibitor deficiency, hereditary angioedema related to estrogens, angioedema induced by angiotensin-converting enzyme inhibitors). Several discussion meetings were held to reach the consensus. RESULTS: Treatment approaches are discussed, and the consensus reached is described. Specific situations are addressed, namely, pregnancy, contraception, travelling, blood donation, and organ transplantation. CONCLUSIONS: A review of and consensus on treatment of bradykinin-induced angioedema is presented.

Consensus statement on the diagnosis, management, and treatment of angioedema mediated by bradykinin. Part I. Classification, epidemiology, pathophysiology, genetics, clinical symptoms, and diagnosis.

BACKGROUND: There are no Spanish guidelines or consensus statement on bradykinin-induced angioedema. AIM: To review the pathophysiology, genetics, and clinical symptoms of the different types of bradykinin-induced angioedema and to draft a consensus statement in light of currently available scientific evidence and the experience of experts. This statement will serve as a guideline to health professionals. METHODS: The consensus was led by the Spanish Study Group on Bradykinin-Induced Angioedema (SGBA), a working group of the Spanish Society of Allergology and Clinical Immunology. A review was conducted of scientific papers on different types of bradykinin-induced angioedema (hereditary and acquired angioedema due to C1 inhibitor deficiency, hereditary angioedema related to estrogens, angioedema induced by angiotensin-converting enzyme inhibitors). Several discussion meetings of the SGBA were held in Madrid to reach the consensus. RESULTS: The pathophysiology, genetics, and clinical symptoms of the different types of angioedema are reviewed. Diagnostic approaches are discussed and the consensus reached is described. CONCLUSIONS: A review of bradykinin-induced angioedema and a consensus on diagnosis are presented.

Multiple acute parasitization by Anisakis simplex.

Hypersensitivity to Anisakis is an increasingly prominent medical problem throughout the world, due to a better understanding of diseases induced by parasites and to modern culinary habits of eating raw or undercooked fish. We describe the case of a patient who presented epigastric pain, wheals, erythema, and pruritus 3 hours after the ingestion of fish. More than 200 larvae were obtained by endoscopy. However, the patient only developed an immune response with specific immunoglobulin E and eosinophilia peaking at day 18 and decreasing during the 17-month follow-up. Only eosinophilia reached normal limits.

Use of the lymphocyte transformation test in the diagnosis of DRESS syndrome induced by ceftriaxone and piperacillin-tazobactam: two case reports.

Drug-related rash with eosinophilia and systemic symptoms (DRESS) syndrome, or drug-induced hypersensitivity syndrome (DIHS), is a life-threatening multiorgan systemic reaction characterized by rash, fever, lymphadenopathy, hepatitis, and leukocytosis with eosinophilia. Aromatic anticonvulsant drugs and allopurinol have been reported to be the most frequent eliciting agents. Our search of the literature revealed only 2 cases induced by piperacillin and 1 case by ceftriaxone.We present 2 cases of DRESS syndrome induced by the beta-lactam drugs ceftriaxone and piperacillin-tazobactam. An allergological workup including skin prick test, intradermal tests, patch tests, and lymphocyte transformation test (LTT) was performed. LTT was shown to be a useful technique in both cases to help to identify the drugs involved.

Silicon substituted hydroxyapatite/VEGF scaffolds stimulate bone regeneration in osteoporotic sheep.

Silicon-substituted hydroxyapatite (SiHA) macroporous scaffolds have been prepared by robocasting. In order to optimize their bone regeneration properties, we have manufactured these scaffolds presenting different microstructures: nanocrystalline and crystalline. Moreover, their surfaces have been decorated with vascular endothelial growth factor (VEGF) to evaluate the potential coupling between vascularization and bone regeneration. In vitro cell culture tests evidence that nanocrystalline SiHA hinders pre-osteblast proliferation, whereas the presence of VEGF enhances the biological functions of both endothelial cells and pre-osteoblasts. The bone regeneration capability has been evaluated using an osteoporotic sheep model. In vivo observations strongly correlate with in vitro cell culture tests. Those scaffolds made of nanocrystalline SiHA were colonized by fibrous tissue, promoted inflammatory response and fostered osteoclast recruitment. These observations discard nanocystalline SiHA as a suitable material for bone regeneration purposes. On the contrary, those scaffolds made of crystalline SiHA and decorated with VEGF exhibited bone regeneration properties, with high ossification degree, thicker trabeculae and higher presence of osteoblasts and blood vessels. Considering these results, macroporous scaffolds made of SiHA and decorated with VEGF are suitable bone grafts for regeneration purposes, even in adverse pathological scenarios such as osteoporosis. STATEMENT OF SIGNIFICANCE: For the first time, the in vivo behavior of scaffolds made of silicon substituted hydroxyapatites (SiHA) has been evaluated under osteoporosis conditions. In order to optimize the bone regeneration properties of these bioceramics, 3D macroporous scaffolds have been manufactured by robocasting and implanted in osteoporotic sheep. Our experimental design shed light on the important issue of the biological response of nano-sized bioceramics vs highly crystalline bioceramics, as well as on the importance of coupling vascularization and bone growth processes by decorating SiHA scaffolds with vascular endothelial growth factor.

Diagnosis of aspirin-induced asthma combining the bronchial and the oral challenge tests: a pilot study.

BACKGROUND: We investigated the usefulness of the bronchial challenge (BC) with lysine-acetylsalicylate (L-ASA) in the diagnosis of aspirin-exacerbated respiratory disease (AERD) using a protocol that combined both the oral challenge (OC) and the BC tests. METHODS: Adult asthmatic patients with suspected AERD who underwent BC with L-ASA were included in the study. If the BC result with L-ASA was negative, an OC was carried out to establish the diagnosis. AERD was ruled out if both the BC and the OC results were negative (nonresponders). Both responders and nonresponders were compared for age, gender, a personal or family history of atopy, underlying disease, current asthma treatment, and presence of nasal polyps. Six patients with asthma but no suggestive history of AERD were included as controls. RESULTS: Twenty-two patients completed the study. Ten patients tested positive to the BC and/or OC (responders), whereas 12 did not (nonresponders). Seven out of the 10 responders had a positive BC result and 3 a positive OC result. After BC, 4 patients had an early asthmatic response, 1 had a dual response, and 2 had isolated late responses. No significant differences were observed in the aforementioned variables between responders and nonresponders. The results of both challenges were negative in the 6 controls. CONCLUSIONS: The BC had a high positive predictive value, was safe, and when negative, the subsequent OC did not result in any severe adverse reactions. The BC elicited an isolated late asthmatic response that has not been previously described in the literature.

Synergistic effect of Si-hydroxyapatite coating and VEGF adsorption on Ti6Al4V-ELI scaffolds for bone regeneration in an osteoporotic bone environment.

The osteogenic and angiogenic responses to metal macroporous scaffolds coated with silicon substituted hydroxyapatite (SiHA) and decorated with vascular endothelial growth factor (VEGF) have been evaluated in vitro and in vivo. Ti6Al4V-ELI scaffolds were prepared by electron beam melting and subsequently coated with Ca10(PO4)5.6(SiO4)0.4(OH)1.6 following a dip coating method. In vitro studies demonstrated that SiHA stimulates the proliferation of MC3T3-E1 pre-osteoblastic cells, whereas the adsorption of VEGF stimulates the proliferation of EC2 mature endothelial cells. In vivo studies were carried out in an osteoporotic sheep model, evidencing that only the simultaneous presence of both components led to a significant increase of new tissue formation in osteoporotic bone. STATEMENT OF SIGNIFICANCE: Reconstruction of bones after severe trauma or tumors extirpation is one of the most challenging tasks in the field of orthopedic surgery. This scenario is even more complicated in the case of osteoporotic patients, since their bone regeneration capability is decreased. In this work we present a porous implant that promotes bone regeneration even in osteoporotic bone. By coating the implant with osteogenic bioceramics such as silicon substituted hydroxyapatite and subsequent adsorption of vascular endothelial growth factor, these implants stimulate the bone ingrowth when they are implanted in osteoporotic sheep.

Comparison of the Sensititre YeastOne colorimetric antifungal panel with the modified Clinical and Laboratory Standards Institute broth microdilution (M38-A) method for antifungal susceptibility testing of dermatophytes.

BACKGROUND: To compare the susceptibility of different dermatophyte species to itraconazole (I), fluconazole (F) and voriconazole (V) by the modified reference (microdilution, CLSI M38-A) and the colorimetric method Sensititre YeastOne. The microdilution method is not very practical for use in routine susceptibility testing in the clinical laboratory, thus necessitating the use of other methods. METHODS: We studied a total of 46 dermatophyte strains isolated from clinical specimens. The microdilution reference susceptibility testing was performed following the CLSI M38-A document, using I, F and V drugs. The MIC were defined as the lowest drug concentration that produced 100% (I and V) and 50% inhibition (F) after 72 h incubation at 35 degrees C. The Sensititre MIC were detected by a change in color from pink to blue or purple. RESULTS: Agreement levels between the 2 methods (+/-2 dilutions) for I, F and V were 30, 53.3 and 83.3%, 0, 12.5 and 66.6% and 37.5, 44.4 and 75% for Trichophyton mentagrophytes, Trichophyton rubrum and Microsporumgypseum, respectively. The MIC(50/90) (mg/l) of I, F and V for T. mentagrophytes were 0.25/0.5, 16/64 and 0.12/0.25 by the microdilution method and 0.016/0.06, 8/16 and 0.03/0.06 by the Sensititre method. The MIC for I, F and V for T. rubrum were 0.25/1, 8/64 and 0.25/0.5 by the microdilution and 0.008/0.03, 2/8, 0.016/0.03 by the Sensititre method. For M. gypseum, MIC were 0.5/1 (I), /256 (F) and 0.25/1 (V) as well as 0.016/0.25 (I), 16/256 (F) and 0.06/0.25 (V) by the microdilution and Sensititre methods, respectively. CONCLUSIONS: The MICs obtained were lower by the Sensititre than the microdilution method. The best correlation between both methods was obtained for V in T. mentagrophytes (>80%), but was low for T. rubrum. Although the Sensititre method is easy to use in a clinical laboratory, it shows poor agreement with the reference method for dermatophytes.

Response of macrophages and neural cells in contact with reduced graphene oxide microfibers.

Graphene-based materials are revealing a great promise for biomedical applications and demonstrating attractiveness for neural repair. In the context of neural tissue damage, the dialogue between neural and immune cells appears critical for driving regeneration, thus making the understanding of their relations pivotal. Herein, the acute response of RAW-264.7 macrophages on nanostructured reduced graphene oxide (rGO) microfibers has been evaluated through the analysis of cell parameters including proliferation, viability, intracellular content of reactive oxygen species, cell cycle, apoptosis, and cell size and complexity. The influence of the direct contact of rGO microfibers on their polarization towards M1 and M2 phenotypes has been studied by analyses of both M1 (CD80) and M2 (CD163) markers and the secretion of the inflammatory cytokines TNF-α and IL-6. Finally, the capability of these rGO microfibers to regulate neural stem cell differentiation has been also evaluated. Findings reveal that rGO microfibers inhibit the proliferation of RAW-264.7 macrophages without affecting their viability and cell cycle profiles. The presence of M1 and M2 macrophages on these microfibers was confirmed after 24 and 48 h, respectively, accompanied by a decrease in TNF-α and an increase in IL-6 cytokine secretion. These rGO microfibers were also able to support the formation of a highly interconnected neural culture composed of both neurons (map2+ cells) and glial cells (vimentin+ cells). These findings encourage further investigation of these microfibers as attractive biomaterials to interact with immune and neural cells, attempting to support wound healing and tissue repair after implantation.

Associations among pollen sensitizations from different botanical species in patients living in the northern area of Madrid.

OBJECTIVE: To determinate the existence of associations among sensitizations to antigens produced by pollen grains of different botanical species as assessed by skin prick tests in patients with respiratory disorders. METHODS: Six hundred twenty nine consecutive patients living in the northern area of Madrid who underwent clinical evaluation because of rhinoconjunctivitis, and/or asthma were studied. All patients were tested with a skin prick test using a battery of inhalants including pollens, dust mites, molds and danders. The exploratory multivariate technique of Multiple Correspondence Analysis was used to compare the homogeneity of sensitizations between groups. Of the 629 patients, 459 (73.0%) had positive skin prick tests to pollen and were selected as the study group. RESULTS: The most prevalent pollen sensitization was to Gramineae pollen (83.7%) followed by Oleaceae sensitisation (75.8%). Multiple Correspondence Analysis revealed the existence of an association among pollen sensitizations, showing that they clustered two groups: sensitizations to Gramineae, Oleaceae, Cupressaceae, Chenopodiaceae, Plantaginaceae (group I), and sensitizations to Betulaceae, Platanaceae, Compositae (group II). Sensitization to Parietaria was not included in any of the sensitization groups and showed an independent behaviour. CONCLUSION: Pollen sensitizations in our area cluster into two association groups which have not previously been reported.

Glass-glass ceramic thermoseeds for hyperthermic treatment of bone tumors.

Implantable thermoseeds are synthesised from mixtures of a melt-derived glass with composition SiO(2) (40)-CaO(40)-Fe(2)O(3)(20) (mol%) and a sol-gel glass with composition SiO(2)(58)-P(2)O(5)(6)-CaO(36) (mol%). Structural, textural and magnetic properties of the samples are evaluated. In vitro bioactivity is assessed in order to determine the potential capability to bond to living bone. In spite of the low textural properties of the material, a bioactive behavior is observed as a result of the sol-gel glass content. Although the crystallization of the glass ceramic provides the magnetic phase, the presence of sol-gel glass modifies the magnetic properties, improving the heating power. For the first time, hyperthermia heating experiments as well as preliminary biocompatibility assays have been carried out for this kind of material. The ability to reach hyperthermic temperature range together with the bioactive behavior makes this biomaterial a very promising candidate for bone cancer treatment.

In vitro biocompatibility assessment of poly(epsilon-caprolactone) films using L929 mouse fibroblasts.

Biodegradable and biocompatible materials are the basis for tissue engineering. As an initial step for developing vascular grafts, the in vitro biocompatibility of poly(epsilon-caprolactone) (PCL), recently suggested for several clinical applications, was evaluated in this study using L929 mouse fibroblasts. Different cellular aspects were analyzed in order to know the cell viability during cell culture on PCL films: adhesion, proliferation, morphology, LDH release and mitochondrial function. Since topography and other surface characteristics of materials play an essential part in cell adhesion, PCL membranes with either smooth or rough surface were prepared, characterized and used to carry out cell cultures. During short culture times, PCL produced a significant stimulation of mitochondrial activity evaluated by reduction of the MTT reagent. The results provide evidences of good adhesion, growth, viability, morphology and mitochondrial activity of cells on PCL films. Therefore, it can be concluded that PCL is a suitable and biocompatible material as a scaffold for vascular graft development.

A comparison of new nonsedating and classical antihistamines in the treatment of primary acquired cold urticaria (ACU).

The efficacy of the new nonsedating antihistamines loratadine and cetirizine was compared in a randomized, single-blind, crossover, controlled study with that of the classical antihistamines cyproheptadine and ketotifen in seven patients with primary acquired cold urticaria (ACU). The patients received each of the four drugs for 14 consecutive days with a 7-day interval between drugs. We evaluated clinical symptomatology, adverse effects, minimum time of cold contact stimulation required to induce an immediate coalescent wheal (CSTT), and inhibition of histamine-induced wheal response. Both loratadine and cetirizine showed suppression of symptoms with infrequent adverse effects. Important side-effects were observed in patients receiving cyproheptadine. Improvement in CSTT was statistically significant for all drugs compared with baseline values, without differences among them. The histamine-induced skin test was significantly inhibited by all antihistamines. Wheal reductions were 34.6% for loratadine and 50.9% for cetirizine. This study suggests that both loratadine and cetirizine may be effective in the treatment of primary ACU.