Gaetana Di Fede

Impact of chronic psychosocial stress on autonomic cardiovascular regulation in otherwise healthy subjects

Elevated psychosocial stress might favor the occurrence of cardiovascular disease; however, mechanisms are incompletely understood. We hypothesized that patients (n=126; 44±1 years of age) referred to an internal medicine clinic because of symptoms related to chronic psychosocial stress would demonstrate signs of autonomic dysregulation compared with controls (n=132; 42±1 years of age). We used autoregressive spectral analysis of RR interval variability to obtain indirect markers of sympathetic and of vagal (respectively, low-frequency and high-frequency components, both expressed in normalized units) oscillatory modulation of sinoatrial node, as well as of sympathetic vasomotor regulation (low-frequency component of systolic arterial pressure variability) and of cardiac baroreflex sensitivity (&agr;-index). Higher values of systolic and diastolic arterial pressure (respectively, 124±1 versus 117±1 mm Hg and 80±1 versus 75±1 mm Hg; both P<0.001), altered markers of autonomic regulation (increased normalized low-frequency and reduced high-frequency component of RR variability, P<0.005; increased-low frequency component of systolic arterial pressure variability, P<0.002), and reduced baroreflex sensitivity (19.3±1.4 versus 23.0±2.0 ms/mm Hg; P<0.05) were observed in patients compared with controls. Autonomic responses to active standing were also blunted in stressed patients. Autonomic markers were significantly correlated to stress perception score and were capable of discriminating between controls and patients with a high degree of accuracy. Chronic real-life stress in humans appears associated to increased arterial pressure and to impaired autonomic regulation of cardiovascular functions. The combination of sympathetic predominance, vagal withdrawal, and blunted baroreflex sensitivity might represent a treatable mechanistic link between psychosocial factors and future incidence of hypertension.

Evaluation of serum s-IgE/total IgE ratio in predicting clinical response to allergen-specific immunotherapy.

BACKGROUND To date, no predictive tests for the clinical response to allergen-specific immunotherapy (ASI) are available. Therefore an in vivo or in vitro test would be of great value. OBJECTIVE We sought to evaluate pretreatment parameters used in diagnosing allergic rhinitis and determining serum specific IgE (s-IgE) levels, serum total IgE (t-IgE) levels, and blood eosinophil counts and to identify whether can be used to predict clinical improvement in monosensitized patients with allergic rhinitis with or without asthma treated with immunotherapy. METHODS We analyzed 279 patients who had undergone 4 years of ASI administered either by means of the subcutaneous immunotherapy (76 patients) or sublingual immunotherapy (203 patients) routes. Serum t-IgE and s-IgE levels, blood eosinophil counts, and serum s-IgE/t-IgE ratios were calculated and tested for correlation with clinical response to ASI. Receiver operating characteristic curves were determined. Predicted probabilities and predictive areas under the curve were calculated. RESULTS The clinical response to ASI was effective in 145 (52.0%) of 279 total patients, 42 (55.2%) of 76 patients treated with subcutaneous immunotherapy, and 103 (50.7%) of 203 patients treated with sublingual immunotherapy. A significant correlation was found between the serum s-IgE/t-IgE ratio and the clinical response to ASI, with high ratios (>16.2) associated with an effective response. The sensitivity and specificity of the area under the curve of the ratio were higher than those of serum s-IgE and t-IgE alone. CONCLUSION The calculation of the serum s-IgE/t-IgE ratio for predicting the clinical response to ASI offers an advantage over measuring t-IgE and s-IgE levels in monosensitized patients for the following allergens: grass, Parietaria judaica, Olea europea, and house dust mite.

Hereditary ovarian cancer

At least 10% of ovarian tumors are hereditary and associated with highly penetrant, autosomal, dominant genetic predisposition. Three clinical manifestations of hereditary ovarian cancer have been identified: site-specific ovarian cancer, hereditary breast and/or ovarian cancer (HBOC) and hereditary non-polyposis colorectal cancer (HNPCC) syndromes. BRCA germline mutations account for more than 90% of all hereditary epithelial ovarian tumors whereas most of the remaining 10% are caused by MLH1 and MSH2 mutations, which are susceptibility genes of HNPCC. Genetic testing is available for each of the three hereditary syndromes above mentioned. The recommendations for OC surveillance in high-risk women having a strong family history or BRCA mutation carriers include transvaginal pelvic ultrasound with color Doppler and serum CA125 every 6 months. Bilateral salpingo-oophorectomy appears to be effective to reduce the risk of ovarian cancer in BRCA mutation carriers. Hysterosalpingo-oophorectomy should be considered in HNPCC women who undergo surgery for colorectal carcinoma.

Milder forms of atherogenic dyslipidemia in ovulatory versus anovulatory polycystic ovary syndrome phenotype

BACKGROUND Dyslipidemia is common in women with polycystic ovary syndrome (PCOS) but its prevalence in different PCOS phenotypes is still largely unknown. METHODS We measured plasma lipids and lipoproteins in 35 anovulatory PCOS (age: 25 +/- 6 years, BMI: 28 +/- 6 kg/m(2)), 15 ovulatory PCOS (age: 30 +/- 6 years, BMI: 25 +/- 3 kg/m(2)) and 27 healthy women (controls) age- and BMI-matched with ovulatory PCOS. PCOS was diagnosed by the presence of clinical or biologic hyperandrogenism associated with chronic anovulation and/or polycystic ovaries at ultrasound. In women with normal menses chronic anovulation was indicated by low serum progesterone levels (<9.54 nmol/l) during midluteal phase (days 21-24) in two consecutive menstrual cycles. RESULTS Total cholesterol, triglycerides and low-density lipoprotein (LDL)-cholesterol levels increased and high-density lipoprotein (HDL)-cholesterol decreased from controls to ovulatory and then to anovulatory PCOS (all P < 0.05). Levels of lipoprotein(a) (Lp(a)) and small, dense LDL increased (P < 0.0001 for both) and LDL size reduced (P < 0.005) between groups. Insulin resistance (by HOMA) showed a positive correlation with triglycerides and small, dense LDL and an inverse correlation with HDL-cholesterol and LDL size (P < 0.05 for all) in both PCOS phenotypes. No significant correlations were found with testosterone levels. At multivariate analysis, insulin resistance was independently associated with HDL-cholesterol and small, dense LDL in both PCOS phenotypes and with triglyceride concentrations in ovulatory PCOS only. CONCLUSIONS Women with ovulatory PCOS showed milder forms of atherogenic dyslipidemia than anovulatory PCOS and this seemed to be related to the extent of insulin resistance. Future prospective studies are needed to assess the relative contribution of such alterations on cardiovascular risk.

A Cytologic Assay for Diagnosis of Food Hypersensitivity in Patients With Irritable Bowel Syndrome

BACKGROUND & AIMS A percentage of patients with symptoms of irritable bowel syndrome (IBS) suffer from food hypersensitivity (FH) and improve on a food-elimination diet. No assays have satisfactory levels of sensitivity for identifying patients with FH. We evaluated the efficacy of an in vitro basophil activation assay in the diagnosis of FH in IBS-like patients. METHODS Blood samples were collected from 120 consecutive patients diagnosed with IBS according to Rome II criteria. We analyzed in vitro activation of basophils by food allergens (based on levels of CD63 expression), as well as total and food-specific immunoglobulin (Ig)E levels in serum. Effects of elimination diets and double-blind food challenges were used as standards for FH diagnosis. RESULTS Twenty-four of the patients (20%) had FH (cows milk and/or wheat hypersensitivity); their symptom scores improved significantly when they were placed on an elimination diet. Patients with FH differed from other IBS patients in that they had a longer duration of clinical history, a history of FH as children, and an increased frequency of self-reported FH; they also had hypersensitivities to other antigens (eg, egg or soy). The basophil activation assay diagnosed FH with 86% sensitivity, 88% specificity, and 87% accuracy; this level of sensitivity was significantly higher than that of serum total IgE or food-specific IgE assays. CONCLUSIONS A cytometric assay that quantifies basophils after stimulation with food antigens based on cell-surface expression of CD63 had high levels of sensitivity, specificity, and accuracy in diagnosing FH. This assay might be used to diagnose FH in patients with IBS-like symptoms.

Food-additive-induced urticaria : A survey of 838 patients with recurrent chronic idiopathic urticaria

Background: Recurrent chronic idiopathic urticaria (RCIU) is a common skin condition that affects 0.1–3% of the population in the USA and Europe and accounts for nearly 75% of all ‘ordinary’ chronic urticaria (CU) cases. Methods: We studied 838 consecutive patients with RCIU referred to hospital between 1998 and 2003. Patients with known causes of CU were excluded. Clinical history, physical examination, and symptom diaries were evaluated during two periods, a diet-free period (1 week) and a food-additive-free diet (FAFD) period (4 weeks), respectively, and two double-blind placebo-controlled (DBPC) challenges of six food additives were administered. The first DBPC challenge included a mixture of the six food additives (DBPCmixed) given to all patients. The second DBPC challenge comprised the single food additives, administered at increasing doses (DBPCsingle) to patients with a positive DBPCmixed test and 105 patients with a negative DBPCmixed test, as a control. Results: The DBPCmixed challenge was positive in 116 patients. None of the 105 control patients had a positive DBPCsingle test. Only 31 DBPCsingle tests were positive in patients with positive DBPCmixed challenge. Twenty-four of the 116 patients showing a positive DBPCmixed challenge also had a positive DBPCsingle result. Conclusions: Our results confirmed that food additive hypersensitivity reactions occurred in few RCIU patients using DBPCsingle challenge. The combination of the results of FAFD and DBPCmixed challenge seems to be of considerable practical interest for allergists, internists and dermatologists, rather than the data of clinical history and the results of DBPCsingle challenge, in patients with RCIU.

Fecal Assays Detect Hypersensitivity to Cow's Milk Protein and Gluten in Adults With Irritable Bowel Syndrome

BACKGROUND & AIMS Some patients with irritable bowel syndrome (IBS)-like symptoms suffer from food hypersensitivity (FH); their symptoms improve when they are placed on elimination diets. No assays identify patients with FH with satisfactory levels of sensitivity. We determined the frequency of FH among patients with symptoms of IBS and the ability of fecal assays for tryptase, eosinophil cationic protein (ECP), or calprotectin to diagnose FH. METHODS The study included 160 patients with IBS, 40 patients with other gastrointestinal diseases, and 50 healthy individuals (controls). At the start of the study, patients completed a symptom severity questionnaire, fecal samples were assayed, and levels of specific immunoglobulin E were measured. Patients were observed for 4 weeks, placed on an elimination diet (without cows milk and derivatives, wheat, egg, tomato, and chocolate) for 4 weeks, and kept a diet diary. Those who reported improvements after the elimination diet period were then diagnosed with FH, based on the results of a double-blind, placebo-controlled, oral food challenge (with cows milk proteins and then with wheat proteins). RESULTS Forty of the patients with IBS (25%) were found to have FH. Levels of fecal ECP and tryptase were significantly higher among patients with IBS and FH than those without FH. The ECP assay was the most accurate assay for diagnosis of FH, showing 65% sensitivity and 91% specificity. CONCLUSIONS Twenty-five percent of patients with IBS have FH. These patients had increased levels of fecal ECP and tryptase, indicating that they might cause inflammation in patients with IBS. Fecal assays for ECP could be used to identify FH in patients with IBS.

Residual vein thrombosis for assessing duration of anticoagulation after unprovoked deep vein thrombosis of the lower limbs: The extended DACUS study

The safest duration of anticoagulation after idiopathic deep vein thrombosis (DVT) is unknown. We conducted a prospective study to assess the optimal duration of vitamin K antagonist (VKA) therapy considering the risk of recurrence of thrombosis according to residual vein thrombosis (RVT). Patients with a first unprovoked DVT were evaluated for the presence of RVT after 3 months of VKA administration; those without RVT suspended VKA, while those with RVT continued oral anticoagulation for up to 2 years. Recurrent thrombosis and/or bleeding events were recorded during treatment (RVT group) and 1 year after VKA withdrawal (both groups). Among 409 patients evaluated for unprovoked DVT, 33.2% (136 of 409 patients) did not have RVT and VKA was stopped. The remaining 273 (66.8%) patients with RVT received anticoagulants for an additional 21 months; during this period of treatment, recurrent venous thromboembolism and major bleeding occurred in 4.7% and 1.1% of patients, respectively. After VKA suspension, the rates of recurrent thrombotic events were 1.4% and 10.4% in the no‐RVT and RVT groups, respectively (relative risk = 7.4; 95% confidence interval = 4.9–9.9). These results indicate that in patients without RVT, a short period of treatment with a VKA is sufficient; in those with persistent RVT, treatment extended to 2 years substantially reduces, but does not eliminate, the risk of recurrent thrombosis. Am. J. Hematol. 2011.

Leukotriene receptor antagonists in monotherapy or in combination with antihistamines in the treatment of chronic urticaria: a systematic review

In vitro and in vivo clinical and experimental data have suggested that leukotrienes play a key role in inflammatory reactions of the skin. Antileukotriene drugs, ie, leukotriene receptor antagonists and synthesis inhibitors, are a class of anti-inflammatory drugs that have shown clinical efficacy in the management of asthma and in rhinitis with asthma. We searched MEDLINE database and carried out a manual search on journals specializing in allergy and dermatology for the use of antileukotriene drugs in urticaria. Montelukast might be effective in chronic urticaria associated with aspirin (ASA) or food additive hypersensitivity or with autoreactivity to intradermal serum injection (ASST) when taken with an antihistamine but not in mild or moderate chronic idiopathic urticaria [urticaria without any possible secondary causes (ie, food additive or ASA and other NSAID hypersensitivity, or ASST)]. Evidence for the effectiveness of zafirlukast and the 5-lipoxygenase inhibitor, zileuton, in chronic urticaria is mainly anecdotal. In addition, there is anecdotal evidence of effectiveness of antileukotrienes in primary cold urticaria, delayed pressure urticaria and dermographism. No evidence exists for other physical urticarias, including cholinergic, solar and aquagenic urticarias, vibratory angioedema, and exercise-induced anaphylaxis.

Searching for wheat plants with low toxicity in celiac disease: Between direct toxicity and immunologic activation.

BACKGROUND Natural or induced variations in the noxiousness of gluten proteins for celiac disease (CD) patients are currently being investigated for their potential in breeding wheat crops with reduced toxicity. AIMS We evaluated the bread wheat line C173 for its effects on the in vitro-grown duodenal mucosa of CD patients. METHODS In vitro-grown duodenal mucosa biopsies of 19 CD patients on a gluten-free diet were exposed to peptic/tryptic-digested prolamins from bread wheat line C173 lacking gliadin-glutenin subunits, analyzed for morphology, cytokine and anti-tTG antibody production, and compared with mucosa biopsies exposed to prolamins from wild-type cv. San Pastore. RESULTS Duodenal mucosa biopsies exposed to prolamins from C173 and San Pastore released higher amounts of IFN-γ, IL-2, IL-10 and anti-tTG antibodies in the culture medium than untreated controls. The line C173 differed from cv. San Pastore as it did not produce negative effects on enterocyte height, suggesting that manipulating prolamin composition can affect innate immune responses of CD mucosa to wheat gluten. CONCLUSIONS Our data demonstrated that this gliadin-deficient wheat has a lower direct toxicity but activates an immunologic reaction of the duodenal mucosa like that of the common wheat species.