Nailfold Videocapillaroscopy Findings in Bradykinin-Mediated Angioedema.

BACKGROUND AND OBJECTIVE: Hereditary angioedema with C1-inhibitor deficiency (C1-INH-HAE) and acquired angioedema related to angiotensin-converting enzyme (ACE) inhibitors (ACEI-AAE) are types of bradykinin-mediated angioedema without wheals characterized by recurrent swelling episodes. Recent evidence suggests that a state of "vascular preconditioning" predisposes individuals to attacks, although no data are available on possible structural alterations of the vessels. Objective: This study aims to compare the features of nailfold capillaries to highlight possible structural anomalies between patients affected by C1-INH-HAE and controls and between patients with ACEI-AAE and hypertensive controls. METHODS: We used nailfold videocapillaroscopy (NVC) to assess the following: apical, internal, and external diameter; loop length; intercapillary distance; and capillary density, distribution, and morphology. Plasma levels of vascular endothelial growth factor (VEGF) A, VEGF-C, angiopoietin (Ang) 1, and Ang2 were also measured. RESULTS: Compared with healthy controls (n=28), C1-INH-HAE patients (n = 34) were characterized by significant structural alterations of the capillaries, such as greater intercapillary distance (216 vs 190 µm), increased apical, internal, and external diameter (28 vs 22 µm; 22 vs 20 µm; and 81 vs 65 µm, respectively), decreased density (4 vs 5 capillaries/mm2), more irregular capillary distribution, and more tortuous morphology. Apical diameter was enlarged in patients with ≥12 attacks per year. In ACEI-AAE patients, NVC showed no alterations with respect to hypertensive controls. NVC performed in 2 C1-INH-HAE patients during attacks showed no changes compared with the remission phase. CONCLUSIONS: We detected major structural capillary alterations in C1-INH-HAE patients, thus confirming the involvement of microcirculation in the pathogenesis of angioedema.

Angiotensin-Converting Enzyme Inhibitor-Associated Angioedema: From Bed to Bench.

BACKGROUND AND OBJECTIVE: Angiotensin-converting enzyme inhibitor-associated angioedema (ACEI-AAE) affects 0.1%-0.7% of patients treated with ACEIs. While previous research suggests that angioedema attacks result from increased vascular permeability, the pathogenesis is not completely understood. Objective: This study aimed to describe the clinical, genetic, and laboratory parameters of ACEI-AAE patients and to investigate the role of vascular endothelial growth factors A and C (VEGF-A and VEGF-C), angiopoietins 1 and 2 (Ang1/Ang2), and secretory phospholipase A2 (sPLA2) in the pathogenesis of ACEI-AAE. METHODS: The clinical and laboratory data of ACEI-AAE patients were collected from 2 angioedema reference centers. Healthy volunteers and ACEI-treated patients without angioedema were enrolled to compare laboratory parameters. Genetic analyses to detect mutations in the genes SERPING1, ANGPT1, PLG, and F12 were performed in a subset of patients. RESULTS: A total of 51 patients (57% male) were diagnosed with ACEI-AAE. The average time to onset of symptoms from the start of ACEI therapy was 3 years (range, 30 days-20 years). The most commonly affected sites were the lips (74.5%), tongue (51.9%), and face (41.2%). Switching from ACEIs to sartans was not associated with an increased risk of angioedema in patients with a history of ACEIAAE. VEGF-A, VEGF-C, and sPLA2 plasma levels were higher in ACEI-AAE patients than in the controls. Ang1/2 concentrations remained unchanged. No mutations were detected in the genes analyzed. CONCLUSIONS: Our data suggest that sartans are a safe therapeutic alternative in ACEI-AAE patients. Increased concentrations of VEGF-A, VEGF-C, and sPLA2 in ACEI-AAE patients suggest a possible role of these mediators in the pathogenesis of ACEI-AAE.

Radiation Engineering of Multifunctional Nanogels.

Nanogels combine the favourable properties of hydrogels with those of colloids. They can be soft and conformable, stimuli-responsive and highly permeable, and can expose a large surface with functional groups for conjugation to small and large molecules, and even macromolecules. They are among the very few systems that can be generated and used as aqueous dispersions. Nanogels are emerging materials for targeted drug delivery and bio-imaging, but they have also shown potential for water purification and in catalysis. The possibility of manufacturing nanogels with a simple process and at relatively low cost is a key criterion for their continued development and successful application. This paper highlights the most important structural features of nanogels related to their distinctive properties, and briefly presents the most common manufacturing strategies. It then focuses on synthetic approaches that are based on the irradiation of dilute aqueous polymer solutions using high-energy photons or electron beams. The reactions constituting the basis for nanogel formation and the approaches for controlling particle size and functionality are discussed in the context of a qualitative analysis of the kinetics of the various reactions.

Efficacy of subcutaneous immunoglobulins in primary immunodeficiency with Crohn's-like phenotype: report of a case.

Common variable immune deficiency (CVID) is the most frequent primary immunodeficiency in adults. In CVID, the prevalence of gastrointestinal manifestations ranges between 2 and 50% with a complication-related morbidity second only to that of the respiratory tract. In some cases, clinical and endoscopic features are undistinguishable from those of inflammatory bowel disease (IBD). We describe the case of a 28-year-old man in which a diagnosis of Crohn's disease was firstly suspected. Subsequently, a diagnosis of Crohn's-like disease in a patient with CVID was made and a replacement therapy with human normal immunoglobulin intravenously was started. Unfortunately, serum IgG levels remained below 2.0 g/l in pre-infusional controls with persistence of gastrointestinal symptoms and malnutrition despite anti-inflammatory therapy (mesalazine, corticosteroids). Then, the patient began treatment with human normal immunoglobulins administered subcutaneously. The follow-up visits showed a progressive increase in serum IgG. Moreover, the patient reported improvement of gastrointestinal symptoms with reduction of diarrhoea, and laboratory tests showed a progressive and significant improvement. We confirm that therapy with subcutaneously administered immunoglobulins is safe and effective. In addition, our observations indicate that, for patients with CVID and enteropathic complications, replacement therapy with subcutaneous IgG may be the treatment of choice.

Thymoma-associated immunodeficiency: a syndrome characterized by severe alterations in NK, T and B-cells and progressive increase in naïve CD8+ T Cells.

Thymomas are rare tumours that sustain T-lymphopoiesis and trigger a variety of autoimmune diseases and immunodeficiencies, including a fatal hypogammaglobulinemia, namely Goods Syndrome (GS). Due to its rarity, GS has been poorly investigated and immunological features, as well as pathogenetic mechanisms underlying this syndrome, are unclear. We studied 30 thymoma patients by performing an immunological assessment, including immunophenotype and analysis of T cell repertoire (TCR). Development of GS was characterized by a progressive decrease in B, CD4 T and NK lymphocytes. These alterations paired with accumulation of CD8+CD45RA+ T cells that showed a polyclonal repertoire without expansions of specific clonotypes. GS is defined as hypogammaglobulinemia with thymoma. Here, we show for the first time that this syndrome is characterized by a severe loss of CD4+, NK and B cells. Furthermore, the accumulation of CD8+CD45RA+ T lymphocytes parallels these changes; this accumulation may have a role in determining the disease and can be used to monitor clinical stages of immunodeficiency in thymoma.

Abciximab in rescue coronary angioplasty after full-dose tissue-type plasminogen activator.

BACKGROUND: Rescue angioplasty is a complex procedure because of frequent reocclusions secondary to a paradoxical pro-thrombotic effect brought about by thrombolytic therapy. Administration of abciximab may improve procedural results but its utilization in this setting is limited by the potential hemorrhagic risk. Very few data on this approach are currently available in the medical literature. METHODS: After failed full-dose tissue-type plasminogen activator (tPA), 30 patients (23 males, 7 females, mean age 64 +/- 13 years) referred for rescue angioplasty received abciximab (0.25 mg/kg bolus + 0.125 mcg/kg/min x 12 hour infusion) (Abc+ group). The procedural results, hemorrhagic complications and in-hospital outcome observed in these patients were compared to those of 35 patients submitted to rescue angioplasty in the same time period (1997-1999) who did not receive abciximab (Abc- group). RESULTS: In the Abc+ group, 11 patients (37%) were in Killip class 3-4, 14 (47%) had multivessel disease, and 4 (13%) had previous bypass surgery. In all Abc+ patients, factors suggestive of procedural failure were present (i.e. saphenous vein graft occlusion, intraluminal thrombus, dissection, reocclusion, slow flow). The periprocedural heparin dose was 5,000 IU in Abc+ and 100 IU/kg in Abc-patients (range 5,000-10,000 IU). The procedure was successful in 29 Abc+ (97%) and in 34 Abc- patients (97%). A hemoglobin drop > 5 g occurred in 3 Abc+ (10%) and in 4 Abc- patients (11%) with a similar incidence of blood transfusion in the two groups. In all these cases, significant bleeding occurred at the vascular access site. There were 2 in-hospital deaths in Abc+ and 1 in Abc- patients. CONCLUSIONS. Selected patients undergoing rescue angioplasty may be treated with abciximab without an undue increase in hemorrhagic complications. Larger studies are needed to confirm the feasibility of this approach and to assess its potential benefits.

Treatment of mastocytosis: pharmacologic basis and current concepts.

Mastocytosis is a rare, heterogeneous disorder characterized by a marked increase in mast cell density in various tissues. Mast cells from different human tissues are heterogeneous. So far, there is no cure for systemic mastocytosis. Conventional therapy is based on agents that antagonize mediators released from mast cells, drugs that inhibit the release of mediators and agents that modulate mast cell proliferation. This pharmacologic approach is satisfactory in the majority of patients with indolent mastocytosis. At the beginning of the new millennium, the therapy of severe forms of aggressive mastocytosis remains a challenge for students of this intriguing disorder.

New biodegradable hydrogels based on an acryloylated polyaspartamide cross-linked by gamma irradiation.

Alpha, beta-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA), a synthetic biocompatible macromolecule, was functionalized with glycidyl methacrylate (GMA) in order to introduce in its side chains residues having double bonds and ester groups. The copolymer (PHG), obtained from PHEA and GMA, had a degree of derivatization of 29 mol%. PHG aqueous solutions are cross-linked by gamma radiation at 0 degrees C either in the presence or absence of N,N'-methylenebisacrylamide (BIS) giving rise to new hydrogel systems. In both cases gelation occurs at quite low doses (0.26 and 0.4 kGy, respectively). The obtained networks were characterized by FT-IR spectrophotometry which confirmed that the cross-linking process involves the vinyl groups of the polymer chains. Swelling measurements evidenced the high affinity of aqueous media at different pH-values towards PHG hydrogels. The sol fractions of the irradiated samples, properly purified, were characterized by FT-IR and 1H-NMR analyses and reduced viscosity measurements. Finally, in vitro chemical or enzymatic hydrolysis studies suggested that the prepared samples undergo a partial degradation at pH 1 and 10 or after incubation with enzymes such as esterase, pepsin, and alpha-chymotrypsin.

Immunopharmacology of human mast cells and basophils.

Human mast cells and basophils play a key role in the pathogenesis of several immunological and inflammatory disorders, not only by producing inflammatory and fibrogenic mediators, but also by directly (CD40 ligand) and indirectly secreting various cytokines and chemokines. Studies carried out to evaluate the effects of drugs that modulate the release of mediators and cytokines from these cells have contributed to clarifying the biochemical mechanism by which immunological and non-immunological stimuli activate these cells. Significant differences have been documented between human mast cells and basophils as regard the pharmacological agents that modulate the release of mediators, between mast cells isolated from different anatomical sites, and between compounds of the same class of drugs. Efforts to gain insight into the biochemical events occurring during immunological activation of mast cells and basophils could lead to the identification of new biochemical targets for therapeutic interventions in several immunological disorders.

Cytarabine release from alpha, beta-poly (N-hydroxyethyl)-DL-aspartamide matrices cross-linked through gamma-radiation.

alpha, beta-Poly (N-hydroxyethyl)-DL-aspartamide solutions were cross-linked through gamma-radiation and the systems obtained were tested as matrices for drug sustained release, using cytarabine as model drug. We performed the characterization of the cross-linked polymer, both drug-loaded and unloaded. through water swelling measurements, scanning electron microscopy and X-ray analysis. Finally, we investigated the in vitro release behaviour of cytarabine.

Giardiasis as a cause of hypokalemic myopathy in congenital immunodeficiency.

Hypokalemic myopathy may occur in several infections. We report a case of severe and transient myopathy secondary to hypokalemia induced by chronic intestinal infection with Giardia lamblia in a patient with common variable hypogammaglobulinemia. Hypokalemic myopathy is documented by serum enzymes, electromyography (reduction in the number of voluntarily activated motor unit action potentials and an increase in polyphasic motor unit action potentials, and pathological changes (hematoxylin-eosin, ATPase staining). The case reported involves hypokalemic myopathy induced by giardiasis in a patient with primary immunodeficiency; the histopathological changes observed in a skin/muscle biopsy from this patient are described for the first time.

Clinical advances in mastocytosis.

Mastocytosis is a disease characterized by an abnormal proliferation of tissue mast cells. The events primarily responsible for mast cell proliferation in mastocytosis are largely unknown, but a derangement of the network involving c-kit receptor and its natural ligand (stem cell factor, which promotes mast cell growth and differentiation in man) is likely to have a primary role in this disease. Mastocytosis comprises a wide spectrum of clinical conditions determined by the degree of mast cell proliferation, the organ systems involved, the age at onset and the association with hematologic diseases. Mastocytosis can occur in a pediatric or an adult form. In both groups of patients, the disease may be limited to the skin (cutaneous mastocytosis) or be systemic, involving predominantly the bone marrow and the gastrointestinal tract. The symptoms in patients with mastocytosis are generally related to the increased release of mast-cell-derived mediators, such as histamine, prostaglandin D2, peptide leukotrienes, platelet-activating factor, heparin and proteolytic enzymes. The measurement of these chemical mediators (histamine, tryptase and prostaglandin D2 and their metabolites) in body fluids is useful for the diagnosis and the laboratory evaluation of patients with systemic mastocytosis. As little is known about the pathogenesis of the different forms of mastocytosis, the treatment of the majority of these patients is largely symptomatic.

Growth and growth hormone in children during and after therapy for acute lymphoblastic leukaemia.

Growth impairment and growth hormone (GH) deficiency have been reported in children treated for acute lymphoblastic leukaemia (ALL). We have studied growth and GH secretion in a group of 50 patients, affected by ALL, during a 2- to 5-year period after diagnosis, and in 12 "long-term-survivors". We observed a significant decrease in growth velocity during the 1st year (in particular during the first 6 months) of therapy and a catch-up growth after the end of therapy. "Long-term survivors" did not exhibit a significant reduction of height standard deviation score (SDS), as compared to height SDS at diagnosis. None of the patients showed GH deficiency. Our data indicate that chemotherapy significantly affects growth of patients treated for ALL, whereas radiotherapy-at the doses used in this study-does not induce GH deficiency, at least not within 9 years after diagnosis.

Livedo reticularis in a patient with systemic lupus erythematosus and anticardiolipin antibodies.

This report describes a case of livedo reticularis associated with increased titres of anticardiolipin antibodies (aCL) in a patient with systemic lupus erythematosus. A 38-year-old woman presented with fever, malaise, arthritis and livedo reticularis in a severe form. Antibodies to native DNA and an increased level of aCL were found. A significant positive correlation exists between livedo reticularis and elevated serum antiphospholipid activity in patients with systemic lupus erythematosus. aCL are shown to play a possible pathogenetic role in thrombotic events. This suggests that thrombosis is the underlying cause of livedo in these patients. A biopsy performed in a patient at the site where livedo was most marked showed no evidence of thrombi. It is postulated that the mechanism of livedo in lupus patients with aCL consists of both thrombosis and dysfunction in the regulation of the tone of the peripheral vascular bed.

Growth and development in white patients with sickle cell diseases.

We have evaluated height, weight, bone age, somatomedin-C levels, and pubertal development in 114 Sicilian patients affected by sickle cell diseases (SCDs). Thirty-one had homozygous sickle hemoglobin (SS), 55 S-beta 0 thalassemia, and 28 S-beta + thalassemia. In both children and adults, the mean height and weight were approximately 1 SD below the normal mean for age. The height was below the normal range only in a few subjects (8 children and 4 adult women). Somatomedin-C levels were within the normal range in most of the patients (37/44 children and 17/22 adults). Bone age revealed a slight delay in skeletal maturation (mean chronological age and bone age were 7.7 +/- 3 and 7.11 +/- 2.9 respectively; p < 0.05). Mean age at menarche was increased compared to normal subjects. Our findings show that Sicilian patients with SCD exhibit a moderate delay of growth and adolescence but attain a final height within the normal range.

Clinical value of CA 19-9 (carbohydrate antigen) in gastrointestinal adenocarcinoma.

CA 19-9 and CEA serum levels were determined before and 7 days after surgery in 140 patients with gastrointestinal adenocarcinoma, and in 70 patients with gastrointestinal non neoplastic diseases. CA 19-9 test was shown to be positive in 37.9% of colorectal cancer, in 32.6% of gastric cancer and in 77.8% of pancreatic cancer. CA 19-9 test was also shown to be more sensitive for colonic cancer with respect to rectal cancer (40.9% vs. 23.5%). CA 19-9 test is more sensitive and specific than CEA. In particular, the reported results suggest the clinical value of CA 19-9 test in the diagnosis of pancreatic adenocarcinoma and as a suitable parameter in the follow-up of gastrointestinal cancer.

[Flunitrazepam anesthesia and voluntary abortion in the first trimester (author's transl)]. / L'impiego del flunitrazepam nell'anestesia per l'interruzione volontaria della gravidanza (IVG) nel primo trimestre.

PIP: Intravenous flunitrazepam was used for 300 patients undergoing voluntary abortion by vacuum aspiration. 3 hours after the operation, all patients were completely conscious and able to leave the ward. 96.6% (288 subjects) had no memory of the procedure. Side effects were minimal and mild. Thus, this type of anesthesia is considered suitable in this type of surgery. (author's modified)^ieng