Efficacy of omalizumab in severe asthma with fungal sensitisation: a case report.

Severe asthma with fungal sensitisation (SAFS) is characterized by poor symptoms control and frequent hospital admissions for exacerbations despite treatment with high dose inhaled steroids, long-acting beta-2 agonists and leukotriene receptor antagonists. Treatment with oral steroids is usually necessary and courses of antifungal therapy may improve asthma symptoms. We report a case refractory to conventional inhaled therapies, continuous oral steroids and antifungal therapy courses, who was effectively treated with omalizumab.

Alzheimer disease: from biomarkers to diagnosis.

The discovery of biomarkers, considered as surrogate markers of the underlying pathological changes, led an international work group (IWG) to propose a new conceptual framework for AD in 2007 Dubois et al. (2007). According to the IWG, AD is now defined as a dual clinico-biological entity that can be recognized in vivo, prior to the onset of the dementia syndrome, on the basis of: i) a specific core clinical phenotype comprised of an amnestic syndrome of the hippocampal type and ii) supportive evidence from biomarkers reflecting the location or the nature of Alzheimer-type changes. Therefore, AD is diagnosed with the same criteria throughout all symptomatic phases of the disease based on the biologically-based approach to diagnosis independent of clinical expression of disease severity. The definitions were further clarified in 2010 (Dubois et al., 2010). Although the new criteria are proposed for research purposes, we encourage expert centres with adequate resources to begin to use the proposed algorithm in order to move the field forward and facilitate translation into clinical practice.

Air pollution ultrafine particles: toxicity beyond the lung.

BACKGROUND: Ultrafine particles or nanoparticles (UFPs or PM0.1) are the fraction of ambient particulates with an aerodynamic diameter smaller than 0.1 microm. Currently UFPs are emerging as the most abundant particulate pollutants in urban and industrial areas, as their exposures have increased dramatically because of anthropogenic sources such as internal combustion engines, power plants, incinerators and many other sources of thermo-degradation. Ultrafine particles have been less studied than PM2.5 and PM10 particulates, mass concentrations of particles smaller than 2.5 and 10 microm, respectively. OBJECTIVE, EVIDENCE AND INFORMATION SOURCES: We examined the current scientific literature about the health effects of ultrafine particles exposure. STATE OF THE ART: UFPs are able to inhibit phagocytosis, and to stimulate inflammatory responses, damaging epithelial cells and potentially gaining access to the interstitium. They could be responsible for consistent reductions in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) in patients with asthma. Chronic exposure to UFPs can produce deleterious effects on the lung, also causing oxidative stress and enhancing pro-inflammatory effects in airways of COPD patients. Cardiovascular detrimental consequences due to UFPs exposure have observed in epidemiological studies, and could likely be explained by translocation of UFPs from the respiratory epithelium towards circulation and subsequent toxicity to vascular endothelium; alteration of blood coagulation; triggering of autonomic nervous system reflexes eventually altering the cardiac frequency and function. Once deposited deeply into the lung, UFPs--in contrast to larger-sized particles--appear to access to the blood circulation by different transfer routes and mechanisms, resulting in distribution throughout the body, including the brain, with potential neurotoxic consequences. PERSPECTIVES AND CONCLUSIONS: UFPs represent an area of toxicology of emerging concern. A new concept of environmental medicine would help in understanding not only the environmental mechanisms of disease, but also in developing specific preventive or therapeutic strategies for minimizing the dangerous influence of pollution on health.

Diagnostic imaging of hepatic tuberculosis: case series.

BACKGROUND: Hepatic tuberculosis (TB) shows non-specific symptoms, and liver imaging may provide diagnostic clues. Here we describe a series of patients with hepatic TB showing characteristic radiological findings. METHODS: Single-centre retrospective evaluation of patients with hepatic TB diagnosed over a period of 16 years who underwent ultrasound, computed tomography (CT) and/or magnetic resonance imaging (MRI). Hepatic lesions were classified as miliary, nodular, serohepatic or cholangitis. RESULTS: Of 14 patients with hepatic TB, five were co-infected with the human immunodeficiency virus. All patients had additional extrahepatic TB localisations. An interferon-gamma release assay was performed in 11/14 patients, ultrasound and CT were available for all patients and MRI for four. Observed patterns were miliary (n = 6) with multiple nodules < 2 cm; nodular (n = 5), characterised by a variable number of nodules (2-7 cm); and serohepatic (n = 3), with multiple nodular subcapsular lesions with a thin, smooth wall. Shared findings were hypoechoic lesions on ultrasound, hypodense lesions with ring enhancement on CT, while MRI lesions were hypointense on T1- and hyperintense on T2-weighted images. CONCLUSIONS: Ultrasound, CT and MRI can independently contribute to detection of hepatic TB. While a miliary pattern or calcifications are characteristic, no pattern is completely pathognomonic and the diagnosis depends on microbiological evidence. Particularly in risk groups, characteristic radiological findings may prompt targeted diagnostic work-up.

Respiratory allergy in agriculture.

Allergic respiratory diseases in farmers may be caused by exposures to many organic substances. Potentially inhalable particulate material of biologic origin are referred to collectively as organic dust, whose composition includes also molds and other microorganisms. Organic dust may evoke immuno-allergic reactions and cause rhinitis, asthma and extrinsic allergic alveolitis. The agricultural work environment represents a risk factor for these diseases, whose occupational origins are often overlooked by clinicians. Prevalence studies of respiratory allergic diseases among agricultural workers are advocated for the development of prevention strategies.

Ultrastructural localization of BHRF1: an Epstein-Barr virus gene product which has homology with bcl-2.

BHRF1 is an Epstein-Barr virus encoded protein which has a 38% sequence similarity with bcl-2 over the carboxyl portion. Like bcl-2, BHRF1 has been shown to suppress programmed cell death from apoptosis. Previously BHRF1 has been detected in mitochondrial, microsomal, and nuclear compartments by cell fractionation analysis. In this study we have used the technique of immunoelectron microscopy to define the ultrastructural distribution of the BHRF1 product in the EBV converted cell lines B95.8 and P3HR-1. The BHRF1 product was localized at the periphery of the mitochondria in a pattern similar to that of bcl-2 and by analogy with bcl-2 this is likely to be the functional destination. Sequence analysis of the BHRF1 protein disclosed similarity with the recently described bcl-2 homologues bcl-x (32%) and bax (34%) over the carboxyl portion, with several domains of complete identity. BHRF1 appears to be a member of a gene family involved in the regulation of programmed cell death. The identity between BHRF1 and bcl-2, an apparent shared ability to abrogate apoptosis, and the common ultrastructural localization is compelling and suggests that bcl-2 and BHRF1 are both functionally and mechanistically similar.

Phase I clinical and pharmacokinetic study of bcl-2 antisense oligonucleotide therapy in patients with non-Hodgkin's lymphoma.

PURPOSE: To evaluate the pharmacokinetics and toxicity of an antisense oligonucleotide targeting bcl-2 in patients with non-Hodgkin's lymphoma (NHL) and to determine efficacy using clinical and biologic end points. PATIENTS AND METHODS: Twenty-one patients with Bcl-2-positive relapsed NHL received a 14-day subcutaneous infusion of G3139, an 18-mer phosphorothioate oligonucleotide complementary to the first six codons of the bcl-2 open reading frame. Plasma pharmacokinetics were measured by anion exchange high-performance liquid chromatography. Response was assessed by computed tomography. Changes in Bcl-2 expression were measured by fluorescence-activated cell sorting of patients' tumor samples. RESULTS: Eight cohorts of patients received doses between 4. 6 and 195.8 mg/m(2)/d. No significant systemic toxicity was seen at doses up to 110.4 mg/m(2)/d. All patients displayed skin inflammation at the subcutaneous infusion site. Dose-limiting toxicities were thrombocytopenia, hypotension, fever, and asthenia. The maximum-tolerated dose was 147.2 mg/m(2)/d. Plasma levels of G3139 equivalent to the efficacious plasma concentration in in vivo models were produced with doses above 36.8 mg/m(2)/d. Plasma levels associated with dose-limiting toxicity were greater than 4 microg/mL. By standard criteria, there was one complete response, 2 minor responses, nine cases of stable disease, and nine cases of progressive disease. Bcl-2 protein was reduced in seven of 16 assessable patients. This reduction occurred in tumor cells derived from lymph nodes in two patients and from peripheral blood or bone marrow mononuclear cell populations in the remaining five patients. CONCLUSION: Bcl-2 antisense therapy is feasible and shows potential for antitumor activity in NHL. Downregulation of Bcl-2 protein suggests a specific antisense mechanism.

Clinical approach to the patient with blood eosinophilia.

Increased blood eosinophil count may be caused by a range of diseases, from allergic disorders to malignant tumors. The allergist is often consulted to evaluate patients with this finding and he should not only rule out the presence of allergy, but through a detailed history taking and physical examination, he should provide a list of likely causes of the patient blood eosinophilia. Importantly used drugs capable of inducing blood eosinophilia and common parasitic infections that might be the culprit.

Increase in CD45RO+ cells and activated eosinophils in chronic allergic conjunctivitis.

We assessed the infiltration of CD45RO+ cells in conjunctival biopsies of fifteen subjects affected by seasonal allergic conjunctivitis by means of immunohistochemistry. Correlations between infiltration of CD45RO+ cells and serum and mucosal indices of eosinophilic activation were investigated. The study was performed in autumn and all selected patients showed <> also in absence of sensitising pollens. Fifteen healthy subjects were used as controls. The semi-quantitative count of CD45RO+ cells in biopsy specimens demonstrated that positive cells were higher in allergic patients than in controls (p < 0.001) and EG2+ eosinophils were present only in biopsies of allergic patients. Furthermore, a statistically significant positive correlation (r = 0.73; p < 0.001) between CD45RO+ lymphocytes and EG2 positive eosinophils, was observed in the biopsies of allergic patients. Total serum IgE significantly correlated with CD45RO+ cells (r = 0.61; p < 0.02) and EG2+ eosinophils (r = 0.67; p < 0.01) in the conjunctiva. On the other hand serum ECP did not correlate with any histological and immunohistochemical parameters in the conjunctival biopsies. The present study shows that mild symptoms in SCA patients out of pollen season are associated with inflammation of the conjunctiva as shown by an increased number of CD45RO and EG2 positive cells.

Allergen immunotherapy: an effective immune-modifier.

Allergen-specific immunotherapy (IT) consists in administering gradually increasing doses of an allergen extract to sensitive patients. This practice results in ameliorating symptoms associated with the subsequent exposure to the causative allergen. Presently, the lack of therapies which affect the pathogenesis of the disease make IT the only treatment that may improve the natural course of allergic diseases.

Occupational asthma due to low molecular weight agents.

Occupational asthma is defined as variable airflow obstruction and airways hyperresponsiveness caused by exposure to agents present in the workplace. Low molecular weight agents such as isocyanates, aldehydes, anhydrides, colophony, dyes, persulphate, amines, acrylates and metals are steadily increasing as causative agents of occupational asthma. Isocyanates, aldehydes and anhydrides my cause sensitisation through an IgE mediated response in some workers. These agents act as haptens which combine with a carrier protein to form a complete antigen. Assays for the detection of specific IgE are standardized for very few agents and have a good specificity, but poor sensitivity. The diagnosis of occupational asthma relies not only on a suggestive hystory showing that asthma is caused or exacerbated specifically by work exposure, but in most cases needs to be confirmed by objective means. Combined monitoring of lung function parameters, such as peak expiratory flow rate at the work site and non specific bronchial hyperresponsiveness during and away from exposure, is necessary. The "gold standard" for confirming a diagnosis in an individual worker still remains the specific bronchoprovocation test, which has now reached a high degree of sensitivity, specificity and reproducibility for agents such a s isocyanates. In occupation asthma due to low molecular weight agents there are no individual risk factors which could predict the susceptibility to develop the disease. The primary prevention is based on appropriate interventions tn the workplace. The strict medical surveillance of workers may allow the early diagnosis and removal from further exposure in order to prevent morbidity and disability.

Simple renal cysts in hypertensive patients: relation between cyst growing and anti-hypertensive therapy.

The study investigates relationship between simple renal cyst enlargement studied by ultrasonography and anti-hypertensive treatment. To this purpose we enrolled 42 patients with newly diagnosed hypertension affected by simple renal cysts. Fourteen were randomly assigned to treatment with ACE-Inhibitors (group 1), twelve to diuretics (group 2) and sixteen to Ca-Antagonists (group 3). Patient performed a basal ultrasonography to evaluate basal cyst dimension before starting anti-hypertensive treatment. Following 12 months of the anti-hypertensive regimen, a new echograph was performed to evaluate changes in cyst size. A control group consisting of 15 patients with normal blood pressure and simple renal cysts was enrolled (group 0). An enlargement of cysts was detected in all patients. However, the enlargement observed in patients treated by Ca-Antagonists was significantly greater than that observed in the other groups (p<0.05). Our study supports the hypothesis that Ca-Antagonists may favor cyst enlargement by enhancing cyclic AMP production. In fact, cAMP and cAMP agonists stimulate fluid secretion by lining cells of the cyst wall, inducing cyst enlargement.

Diffusion-weighted MR imaging in the evaluation of renal tumours.

The aim of this study was to evaluate the capability and the reliability of diffusion-weighted MR imaging to differentiate benign from malignant renal lesions. Twenty healthy volunteers and 48 patients with known renal lesions underwent MR of the kidneys by using a 1.5 T superconductive magnet. Diffusion-weighted images (DWI) were obtained on the axial plane during breathhold (17 s) with a SE EPI single shot sequence using a b value of 500 s/mm2. One region of interest (ROI) (lesions < than 3 cm) or 3 ROI (lesions > than 3 cm) were placed within the lesion for the measurement of apparent diffusion coefficient (ADC). ADC map was obtained at each slice position. Mean ADC value in normal renal parenchyma was 2.2 +/- 0.20 x 10(-3) mm2/s, while ADC values in simple cysts (n = 20) were higher (mean ADC values 3.65 +/- 0.09 x 10(-3) mm2/s). Solid benign and malignant renal tumors (n = 19) showed a mean ADC value of 1.7 +/- 0.48 x 10(-3) mm2/sec. The comparison between ADC values in normal parenchyma group and tumour group were found to be statistically significant (p < 0.0001). ADC values of cystic renal cell carcinomas were higher than those of clear cell carcinomas (p < 0.001). In conclusion, DW MRI of the kidney seems to be a reliable means for differentiating normal renal parenchyma from different renal tumors.

Treatment of obstetric and gynecologic infections with meropenem: comparison with imipenem/cilastatin.

The aim of this study was to compare the clinical and bacteriologic efficacy of meropenem with imipenem/cilastatin in the treatment of obstetric and gynecologic infections. This was a controlled, multicenter, randomized study with two parallel groups and a follow-up period of up to 4 weeks. A total of 105 hospital in-patients requiring antibacterial parenteral therapy were enrolled, 52 in the meropenem group and 53 in the imipenem/cilastatin group. Both drugs were administered at 0.5 g every 8 hours, by slow intravenous infusion over 20-30 minutes; for meropenem the administration by intravenous bolus injection (over approximately 5 minutes) was allowed. The mean duration of therapy was 5 days for both treatments. At the end of treatment, all 46 evaluable patients in the meropenem treatment group had a satisfactory clinical response, while in the imipenem/cilastatin group 5/49 patients were clinical failures. The difference between the treatment groups in clinical response was statistically significant (100% vs 89.8%; p=.026). A similar result was seen in the intention-to-treat analysis (98% vs 84.6%; p=0.017). Both treatments were well tolerated, but fewer meropenem patients experienced treatment-related adverse events in comparison with imipenem/cilastatin (11.5% vs 15.1%).

Effects of low frequency electromagnetic fields on expression of lymphocyte subsets and production of cytokines of men and women employed in a museum.

The objective of this study was to analyse the immune response to electromagnetic fields (ELMFs) in seven men and eight women employed in a museum. The workers were exposed in a room to an ELMFs (range 0.2-3.6 microT and 40-120 V/m) induced by 50 Hz electricity for 20 h a week. Control groups consisted of 47 women and 39 men with a similar percentage of atopic subjects, age (range 30-51 years) and smoking habits of the workers included in the study. Levels of blood lead (Pb) and urinary trans-trans muconic acid, a metabolite of benzene (markers of exposure to traffic and smoking) of the control and exposed groups were similar. Lymphocyte subsets were determined in men and women using conjugated antibodies. Serum interleukin (IL) 4 and interferon gamma and their 'in vitro' production by peripheral mononuclear blood cells (PMBCs) stimulated by phytohemoglutinin (PHA), as well as blastogenesis of PMBCs induced by PHA, were determined in women only. ELMF-exposed women showed a significant reduction in the percentage of B and NK CD3(-)-CD25+ lymphocytes and a slight reduction of CD16(+)-56+ NK lymphocytes. They also showed significantly lower levels of interferon gamma in serum, or produced in the supernatants by PMBCs both spontaneously and stimulated by PHA, while they did not show significant changes in serum and 'in vitro' produced IL-4, or in blastogenesis of PMBCs. Men working in the museum showed, in relation to the controls, a statistically significant reduction in both number and percentage of CD16(+)- CD56+ and CD3(-)-CD25+ lymphocyte subsets. On the whole, this investigation demonstrates a reduction of blood NK lymphocytes and of the production of interferon gamma in workers exposed to low frequency ELMFs. Recent studies have shown that stress and poor lifestyle induce the reduction of blood cytotoxic activities possibly acting on nervous functions. This may suggest that ELMFs reduces blood NK lymphocytes by combined effects on the immune and nervous systems.

Effect of natural allergen exposure on non-specific bronchial reactivity in asthmatic farmers.

The aim of the study was to assess the seasonal variability of non-specific bronchial reactivity (NSBR) evaluated with methacholine in asthmatic farmers allergic to pollens. Twenty farmers (16 male and four female) with allergy to pollens, e.g. 'Graminae' and 'Parietaria', entered the study. None of the patients had been previously treated with specific immunotherapy. Patients underwent a methacholine challenge at the first visit and then in the subsequent seasons. Four groups of tests were obtained according to the period when the challenge was performed. Group 1: challenges performed in December, January and February; group 2 in March, April and May; group 3 in June, July and August; group 4 in September, October and November. PD20 values were expressed as the natural logarithm of the cumulative dose of methacholine causing at least a 20% fall in FEV1. Bronchial hyperreactivity was highest in summer, followed by spring and autumn; in winter it was much lower. Multiple group analysis (ANOVA) showed statistically significant differences between the groups (P < 0.01). When the groups were compared individually, statistically significant differences existed only between group 1 (winter) and each of the other groups, respectively 2 (spring) (P = 0.02), 3 (summer) (P = 0.004) and 4 (autumn) (P = 0.02). The results underlined the importance of allergic inflammation in determining changes in NSBR. In the region where the study was carried out (central Italy), the grass and Paretaria pollination lasts from March to November. Therefore, farmers had a progressive increase in NSBR from spring to summer and a decrease in fall as a consequence of the varying pollen concentration in different seasons. The level of allergen exposure is, in fact, the main factor that determines the severity of bronchial inflammation, thus affecting NSBR.

Pathological lesions in senile diabetes: possible pathogenetic interpretations.

Pathohistological alterations of the kidney and pancreas were studied in a group of elderly diabetics divided into "aged diabetics" (AD) (onset of diabetes before 60 years of age) and "senile diabetics" (SD) (onset of diabetes after 70 years of age). The control groups were formed by middle-aged non-insulin dependent diabetics (NIDDM) and non-diabetic elderly subjects. The non-diabetic elderly subjects showed no damage of pancreatic islets and the arterioles were also intact. The middle-aged NIDDM group having had diabetes for less than one year presented no alterations either. Middle-aged NIDDM patients affected by the disease for longer than 10 years, displayed the characteristic diabetic damage (hyalinization of the islets and arteriolar damage). In addition, AD presented pancreatic lesions characteristic of long-term NIDDM. SD were divided into two groups depending on the duration of disease: shorter than 6 and longer than 10 years. The former presented small islets with few fibrotic cells and arteriolar damage, while the latter presented a picture of transition between SD with duration of disease shorter than 6 years and AD. The kidney in AD and SD affected by diabetes longer than 10 years resembled the kidney of NIDDM patients. SD with duration of disease shorter than 6 years had aspecific age-related damage. These lesions seem to confirm that macroangiopathy represents the main pathogenesis of senile diabetes, being aggravated by the persisting hyperglycemia causing microangiopathy.

Comparison between serum interleukin-2 concentrations in healthy adult and elderly subjects.

The serum interleukin-2 (IL-2) concentrations were evaluated in healthy elderly patients, enrolled under the SENIEUR protocol, and healthy adult controls. The aim of the study was to ascertain whether the reduced immune response, described during aging, is linked to deficient production of IL-2 or to its receptorial deficit, or if the reduced serum IL-2 concentrations observed during aging can be used as a biological immunodeficiency marker. The results obtained did not show any significant differences between the study groups, even if mean values were slightly decreased in the elderly group, as compared to the adult one. This finding does not justify the age-dependent deficiency of the immune response, i.e., to explain this condition, one needs another pathogenetic hypothesis. It is suggested that one such hypothesis could be the alteration of IL-2 receptors which undergo major cleavage and minor re-expression in the elderly, causing this way some receptorial changes with consequent reduction of T-helper activation.

Senile diabetes and bone mineral density.

Bone mineral density was determined in a series of 67 elderly diabetics (38 males and 29 females) and 40 non-diabetic elderly subjects (20 males and 20 females) at the third medial and tenth ultradistal of the non-dominating radius using an X-ray densitometer (DEXA). Bone metabolism markers (Ct, PTH, HOP, UCA, AP, Vit-25-OH-D, BGP) were also measured. Our results indicate that there is no significant difference in values of BMD and the bone metabolism markers studied between diabetic and non-diabetic elderly subjects. We believe that senile diabetes is not a risk factor of onset and maintenance of senile osteoporosis.

Prevalence of diabetes mellitus in a sample of the elderly population of the city of Catania.

The prevalence of diabetes mellitus is increasing world-wide, even if it varies markedly in the geographical areas and populations investigated. This study is part of the Progetto Finalizzato Invecchiamento (Aging Project) of the Italian NCR (National Research Council) and is aimed at investigating the prevalence of diabetes and selected clinical characteristics in a study sample aged between 65 and 84 years of age resident in Catania (Italy). The prevalence rate for type II diabetes was 22.8% and it is certainly among the highest values recorded to date in other areas of Italy and abroad. We distinguished between two forms of diabetes in subjects >70 years of age: aged diabetes with onset in middle age (AD); and diabetes of senescence with onset after 70 years of age (DS). Prevalence rate was 18% for AD and 4.8% for DS, respectively. The age-specific rates of AD and DS show the progressive lower prevalence rates of the former and the higher rates of the latter. We assume that DS is mainly caused by atherosclerotic processes and represents the typical form of diabetes in the elderly.