Nitrogen dioxide pollution increases vulnerability to COVID-19 through altered immune function.

Previous ecological studies suggest the existence of possible interplays between the exposure to air pollutants and SARS-CoV-2 infection. Confirmations at individual level, however, are lacking. To explore the relationships between previous exposure to particulate matter < 10 µm (PM10) and nitrogen dioxide (NO2), the clinical outcome following hospital admittance, and lymphocyte subsets in COVID-19 patients with pneumonia. In 147 geocoded patients, we assessed the individual exposure to PM10 and NO2 in the 2 weeks before hospital admittance. We divided subjects according to the clinical outcome (i.e., discharge at home vs in-hospital death), and explored the lymphocyte-related immune function as an index possibly affecting individual vulnerability to the infection. As compared with discharged subjects, patients who underwent in-hospital death presented neutrophilia, lymphopenia, lower number of T CD45, CD3, CD4, CD16/56 + CD3 + , and B CD19 + cells, and higher previous exposure to NO2, but not PM10. Age and previous NO2 exposure were independent predictors for mortality. NO2 concentrations were also negatively related with the number of CD45, CD3, and CD4 cells. Previous NO2 exposure is a co-factor independently affecting the mortality risk in infected individuals, through negative immune effects. Lymphopenia and altered lymphocyte subsets might precede viral infection due to nonmodifiable (i.e., age) and external (i.e., air pollution) factors. Thus, decreasing the burden of air pollutants should be a valuable primary prevention measure to reduce individual susceptibility to SARS-CoV-2 infection and mortality.

Effect of a Low Glycemic Index Mediterranean Diet on Non-Alcoholic Fatty Liver Disease. A Randomized Controlled Clinici Trial.

INTRODUCTION: Non-Alcoholic Fatty Liver Disease (NAFLD) is currently the most common form of liver disease worldwide affecting all ages and ethnic groups and it has become a consistent threat even in young people. Our aim was to estimate the effect of a Low Glycemic Index Mediterranean Diet (LGIMD) on the NAFLD score as measured by a Liver Ultrasonography (LUS). DESIGN: NUTRIzione in EPAtologia (NUTRIEPA) is a population-based Double-Blind RCT. Data were collected in 2011 and analyzed in 2013-14. SETTING/PARTICIPANTS: 98 men and women coming from Putignano (Puglia, Southern Italy) were drawn from a previous randomly sampled population-based study and identified as having moderate or severe NAFLD. INTERVENTION: The intervention strategy was the assignment of a LGIMD or a control diet. OUTCOME MEASURES: The main outcome measure was NAFLD score, defined by LUS. RESULTS: After randomization, 50 subjects were assigned to a LGIMD and 48 to a control diet. The study lasted six months and all participants were subject to monthly controls/checks. Adherence to the LGIMD as measured by Mediterranean Adequacy Index (MAI) showed a median of 10.1. A negative interaction between time and LGIMD on the NAFLD score (-4.14, 95% CI -6.78,-1.49) was observed, and became more evident at the sixth month (-4.43, 95%CI -7.15, -1.71). A positive effect of the interaction among LGIMD, time and age (Third month: 0.07, 95% CI 0.02, 0.12; Sixth month: 0.08, 95% CI 0.03,0.13) was also observed. CONCLUSIONS: LGIMD was found to decrease the NAFLD score in a relatively short time. Encouraging those subjects who do not seek medical attention but still have NAFLD to follow a LGIMD and other life-style interventions, may reduce the degree of severity of the disease. Dietary intervention of this kind, could also form the cornerstone of primary prevention of Type 2 Diabetes Mellitus (T2DM) and cardiovascular disease.

Control of infectious mortality due to carbapenemase-producing Klebsiella pneumoniae in hematopoietic stem cell transplantation.

Carbapenemase-producing Klebsiella pneumoniae (KPC-Kp) infections are an emerging cause of death after hematopoietic stem cell transplantation (HSCT). In allogeneic transplants, mortality rate may rise up to 60%. We retrospectively evaluated 540 patients receiving a transplant from an auto- or an allogeneic source between January 2011 and October 2015. After an Institutional increase in the prevalence of KPC-Kp bloodstream infections (BSI) in June 2012, from July 2012, 366 consecutive patients received the following preventive measures: (i) weekly rectal swabs for surveillance; (ii) contact precautions in carriers (iii) early-targeted therapy in neutropenic febrile carriers. Molecular typing identified KPC-Kp clone ST512 as the main clone responsible for colonization, BSI and outbreaks. After the introduction of these preventive measures, the cumulative incidence of KPC-Kp BSI (P=0.01) and septic shocks (P=0.01) at 1 year after HSCT was significantly reduced. KPC-Kp infection-mortality dropped from 62.5% (pre-intervention) to 16.6% (post-intervention). Day 100 transplant-related mortality and KPC-Kp infection-related mortality after allogeneic HSCT were reduced from 22% to 10% (P=0.001) and from 4% to 1% (P=0.04), respectively. None of the pre-HSCT carriers was excluded from transplant. These results suggest that active surveillance, contact precautions and early-targeted therapies, may efficiently control KPC-Kp spread and related mortality even after allogeneic HSCT.

Sirolimus-based graft-versus-host disease prophylaxis promotes the in vivo expansion of regulatory T cells and permits peripheral blood stem cell transplantation from haploidentical donors.

Hematopoietic stem cell transplantation (HSCT) from human leukocyte antigen (HLA) haploidentical family donors is a promising therapeutic option for high-risk hematologic malignancies. Here we explored in 121 patients, mostly with advanced stage diseases, a sirolimus-based, calcineurin-inhibitor-free prophylaxis of graft-versus-host disease (GvHD) to allow the infusion of unmanipulated peripheral blood stem cell (PBSC) grafts from partially HLA-matched family donors (TrRaMM study, Eudract 2007-5477-54). Conditioning regimen was based on treosulfan and fludarabine, and GvHD prophylaxis on antithymocyte globulin Fresenius (ATG-F), rituximab and oral administration of sirolimus and mycophenolate. Neutrophil and platelet engraftment occurred in median at 17 and 19 days after HSCT, respectively, and full donor chimerism was documented in patients' bone marrow since the first post-transplant evaluation. T-cell immune reconstitution was rapid, and high frequencies of circulating functional T-regulatory cells (Treg) were documented during sirolimus prophylaxis. Incidence of acute GvHD grade II-IV was 35%, and occurrence and severity correlated negatively with Treg frequency. Chronic GvHD incidence was 47%. At 3 years after HSCT, transpant-related mortality was 31%, relapse incidence 48% and overall survival 25%. In conclusion, GvHD prophylaxis with sirolimus-mycophenolate-ATG-F-rituximab promotes a rapid immune reconstitution skewed toward Tregs, allowing the infusion of unmanipulated haploidentical PBSC grafts.

Prolonged ingestion of ovalbumin diet by sensitized mice improves the metabolic consequences induced by experimental food allergy.

The prevalence of food allergy is rising in the western world. Allergen restriction is the chosen treatment in this condition, but continuous ingestion of the antigen has shown positive results in clinical trials. In a previous study, we have shown several allergic and metabolic alterations after 7 days of ovalbumin (OVA) ingestion by sensitized mice. The aim of this study was to investigate whether prolonged ingestion of antigen by sensitized mice would reverse the metabolic consequences caused by experimental food allergy. For this, allergic and metabolic parameters were analysed after prolonged ingestion of an OVA diet by OVA-sensitized mice. As shown previously, after 7 days of OVA consumption, sensitized mice showed increased serum levels of anti-OVA immunoglobulin (Ig)E and IgG1, aversion to the antigen ingestion, marked body and adipose tissue weight loss, followed by adipose tissue inflammation and decreased serum levels of adipokines, glucose and triglycerides. However, after 14 days of oral challenge, sensitized mice showed an anti-OVA IgE level similar to the mice that were only sensitized, but the specific IgG1 did not change. With this prolonged ingestion of OVA, sensitized mice were protected from OVA-induced anaphylaxis when the antigen was given systemically at a dose of 2 mg/animal. Moreover, various parameters analysed were significantly ameliorated, including adipose tissue inflammation, body and adipose tissue loss, as well as serum levels of adipokines and triglycerides. Therefore, our data suggest that prolonged ingestion of OVA by sensitized mice results in an improvement of the metabolic consequences caused by experimental food allergy.

AVE 0991, a non-peptide mimic of angiotensin-(1-7) effects, attenuates pulmonary remodelling in a model of chronic asthma.

BACKGROUND AND PURPOSE: AVE 0991 (AVE) is a non-peptide compound, mimic of the angiotensin (Ang)-(1-7) actions in many tissues and pathophysiological states. Here, we have investigated the effect of AVE on pulmonary remodelling in a murine model of ovalbumin (OVA)-induced chronic allergic lung inflammation. EXPERIMENTAL APPROACH: We used BALB/c mice (6-8 weeks old) and induced chronic allergic lung inflammation by OVA sensitization (20 µg·mouse(-1) , i.p., four times, 14 days apart) and OVA challenge (1%, nebulised during 30 min, three times per·week, for 4 weeks). Control and AVE groups were given saline i.p and challenged with saline. AVE treatment (1 mg·kg(-1) ·per day, s.c.) or saline (100 µL·kg(-1) ·per day, s.c.) was given during the challenge period. Mice were anaesthetized 72 h after the last challenge and blood and lungs collected. In some animals, primary bronchi were isolated to test contractile responses. Cytokines were evaluated in bronchoalveolar lavage (BAL) and lung homogenates. KEY RESULTS: Treatment with AVE of OVA sensitised and challenged mice attenuated the altered contractile response to carbachol in bronchial rings and reversed the increased airway wall and pulmonary vasculature thickness and right ventricular hypertrophy. Furthermore, AVE reduced IL-5 and increased IL-10 levels in the BAL, accompanied by decreased Ang II levels in lungs. CONCLUSIONS AND IMPLICATIONS: AVE treatment prevented pulmonary remodelling, inflammation and right ventricular hypertrophy in OVA mice, suggesting that Ang-(1-7) receptor agonists are a new possibility for the treatment of pulmonary remodelling induced by chronic asthma.

Predicting the Clinical Outcome of Allogeneic Hematopoietic Stem Cell Transplantation: The Long and Winding Road toward Validated Immune Biomarkers.

The clinical outcome of allogeneic hematopoietic stem cell transplantation (HSCT) is strongly influenced from the potential complications arising during the delicate phase of post-transplant immune restoration. The quantitative aspects of immune-cell repopulation after HSCT and the qualitative features their functional restitution have been extensively reported. Nevertheless, measurable immune biomarkers predicting the clinical outcome of HSCT await formal validation. The aim of this review is an appraisal of most studies published so far on the predictive value of different T and NK-cell biomarkers after HSCT with emphasis on defined thresholds endorsed by multivariate analysis.

Relationship among fatty liver, adipose tissue distribution and metabolic profile in moderately obese children: an ultrasonographic study.

We examined the relationship between moderate obesity and glucose metabolism, insulin sensitivity and suspected fatty liver in children. We measured body mass index (BMI), z-score BMI, caliper skinfold thickness, waist and hip circumference in 94 participants (mean age 9.7 +/-2.2 years). Fasting blood glucose, insulin, HOMA score, lipid profile and transaminases (ALT, AST) were measured. Fatty liver and skinfold thickness were evaluated by means of ultrasound. The z-score BMI was 2.01 +/-0.39 (mean +/- SD), and the duration of obesity was 4.3+/-3.03 years. A positive correlation was found between caliper and US skinfold thickness for tricipital (r= 0.33; p= 0.003) and sovrailiac skinfold (r= 0.34; p=0.003). Fatty liver was diagnosed in 64% of children and it was positively related to anthropometric measurements. The three sub-groups--group 0 (normal US liver and normal transaminases); group 1 (US fatty liver and normal transaminases); group 2 (US fatty liver and elevated transaminases)--showed a difference concerning z-score BMI, insulin and HOMA parameters (Tukey test: z score BMI group 1 vs group 0 and 2 vs group 0; serum insulin: group 2 vs group 1 and group 2 vs group 0; HOMA IR: group 2 vs group 1 and group 2 vs group 0). Moderately obese children with steatosis exhibited a clear increase of insulin and insulin resistance which represents indices of a future metabolic syndrome. In addition, it is important to perform a liver ultrasound since transaminases seems to be not adequate for the diagnosis of fatty liver.

Effects after daily use of washing products on infants aged 0-52 weeks.

AIM: This paper evaluates the parents and medical satisfaction in the daily use of some bath products on 606 newborns/infants, during a randomized controlled trial. METHODS: All the subjects recruited were randomly allocated to one group. All children daily used Johnson's Baby products for 8 weeks. RESULTS: Parents increased satisfaction level during the study, and pediatricians declared that the products used were without secondary effects on the body skin of newborn children, especially in 186 newborns (92 female plus 94 male) aged 0-4 weeks. CONCLSIONS: These results suggest that the products used are indicated in daily wash use from the first days of life.

Main characteristics of hepatocellular carcinoma and cirrhosis and therapeutic approaches.

Between 1995 and 1997 we studied 100 patients with hepatocarcinoma (HCC) and cirrhosis. Of these 74 were males and 26 females with a mean age of 66 years. 13% patients were only HbsAg positive, 75% only anti-HCV positive, 6% HbsAg and anti-HCV and the etiology in 6% of cases was alcoholic. Alpha-foetoprotein was >400 ng/ml in only 18% of cases and portal thrombosis was present in 12%. Mononodular HCC was observed in 63% of cases (small HCC in only 38%) and in 79% was localized to the right lobe. Of the mononodular types, 70% were shown by echography to be hypoechoic, 6% hysoechoic, 6% hyperechoic and 17% mixed patterns. Histologically, 49% were well-differentiated, 45% moderately-differentiated and 6% poorly-differentiated. No correlation was found between histologic pattern and number of nodules. Well-differentiated HCC was found in 51% of mononodular types and in 46% of multinodular types. Moderately-differentiated HCC was detected in 46% and 43% respectively and poorly-differentiated HCC in 3% and 11% respectively. No correlation was found between number of nodules and the degree of Edmonson.

Treatment of patients with advanced gastric carcinoma with a 5-fluorouracil-based or a cisplatin-based regimen: two parallel randomized phase II studies.

BACKGROUND: Although many drug combination therapies have been proposed, there is no standard therapy for patients with advanced gastric carcinoma. The superiority of combination therapy over monochemotherapy has not been demonstrated convincingly. To explore the role of monochemotherapy, the authors evaluated 5-fluorouracil (5-FU), modulated by 6S-leucovorin (6S-LV) and a cisplatin-containing regimen, which was comprised of epirubicin, etoposide, and cisplatin with the addition of the reversal agent lonidamine (EEP-L). METHODS: After stratification according to performance status (PS) and resection of the primary tumor, 72 patients with advanced gastric carcinoma were randomized to 2 parallel Phase II trials with 5-FU/6S-LV and EEP-L, respectively. Thirty-six patients in Study A received bolus 6S-LV, 100 mg/m2, followed by bolus 5-FU, 370 mg/m2, on Days 1-5 and 36 others in Study B received epirubicin, 30 mg/m2, on Days 1 and 5; etoposide, 100 mg/m2, on Days 1, 3, and 5; cisplatin, 30 mg/m2, on Days 2 and 4; and lonidamine, 150 mg/day. RESULTS: There were 6 partial responses (18.2%) (95% confidence interval [CI] +/- 13.2) in Study A and 7 partial responses (21.9%) (95% CI +/- 14.3) in Study B. Partial responses were more frequent in patients with resected tumors or with an Eastern Cooperative Oncology Group PS of 0-1. The median duration of response was 8.8 and 8.3 months, respectively, in Study A and Study B. The median survival reached 8 months in Study A and 9 months in Study B. In the whole population of patients survival was significantly higher in patients with a PS of 0-1 (P < 0.05). Patients with a PS of 0-1 and a resected tumor had the significantly longest survival both in EEP-L treated patients and in all evaluable patients in the two studies. The most frequent World Health Organization Grade 3-4 toxic effects were gastrointestinal in Study A and hematologic in Study B. No treatment-related death was observed. CONCLUSIONS: The efficacy of 5-FU, modulated with 6S-LV, is moderate in patients with advanced gastric carcinoma, similar to cisplatin-containing regimens. PS and other prognostic factors could influence the response rate, which does not appear to be a reliable parameter for evaluating the outcome of chemotherapy trials.

Epidemiology of cholelithiasis in southern Italy. Part II: Risk factors.

OBJECTIVE: To determine behavioural, dietary and other common factors associated with new cases of gallstones, diagnosed by ultrasonography, in a prospective cohort study conducted in southern Italy. SUBJECTS AND METHODS: Between May 1985 and June 1986, systematic sampling from the electoral register of Castellana, a small town in southern Italy, yielded 2472 subjects who had had their gallbladder checked for gallstones by ultrasonography. Between May 1992 and June 1993, 1962 out of the 2235 (87.7%) subjects without gallstones at baseline agreed to a further ultrasound examination. At the first survey a standardized questionnaire was administered, inquiring about medical history, diet, cigarette smoking and other behavioural characteristics. Height and weight were also measured, and blood levels of glucose, cholesterol, HDL-cholesterol and triglycerides were determined by standard methods. The same variables were measured at the second survey. The diagnosis of gallstones was made with the same echograph by echographists working in the same department. Multiple logistic regression was used to determine which factors measured at the first survey were associated with the incident cases of gallstones. RESULTS: One hundred and four subjects had developed gallstones, an incidence of 9.7 per 1000 persons per year. Age, body mass index (BMI), weight change, a history of diabetes, constipation (shown by use of laxatives), cigarette smoking, years of schooling, consumption of fried foods and excessive oil, and pregnancy in females, were positively associated with the incidence of gallstones. Consumption of wine, coffee, fish and wholemeal bread was inversely associated. Sex, family history of cholelithiasis, use of oral contraceptives and serum lipids were not independent risk factors for gallstones. CONCLUSION: The results of this study confirm many gallstone-associated factors reported in previous cross-sectional and case-control studies, as well as in other cohort studies based on the clinical diagnosis of gallstones, such as BMI, ageing and wine consumption. Furthermore, use of laxatives, considered a proxy of constipation, appears to be another important independent risk factor for gallstones.

Effect of cisplatin in advanced colorectal cancer resistant to 5-fluorouracil plus (S)-leucovorin.

Modulation of 5-fluorouracil (5-FU) is currently being investigated in advanced colorectal cancer. In an attempt to improve the results obtainable for the association of 5-FU and leucovorin, we decided to add cisplatin to 5-FU and (6S)-leucovorin (S-LV) after disease progression. The hypothesis was that a pharmacological enhancement of the efficacy of 5-FU would result in responses in 5-FU-unresponsive patients or in a second response in previously responding patients. A group of 28 5-FU+S-LV-pretreated patients, with advanced measurable colorectal cancer, were treated with 80 mg/m2 cisplatin on day 1, 80 mg/m2 S-LV and 370 mg/m2 5-FU as an i. v. bolus for 5 consecutive days every 4 weeks. We obtained 3 partial responses (response rate: 11 +/- 11%), while 11 patients had stable disease (39 +/- 18%). Among the 3 responders, 1 patient had earlier achieved a partial response, a second stable disease and 1 had disease progression after the previous 5-FU+S-LV treatment. The median survival time for all 28 patients was 11 months. Toxicity was minimal and consisted of mild and reversible gastrointestinal symptoms and myelosuppression. We believe that further studies must be carried out to establish the real impact of the synergism between cisplatin, 5-FU and S-LV in untreated patients.

Advanced non-small-cell lung cancer (NSCLC) treated with folinic acid (F), fluorouracil (FU), vincristine (O), and mitomycin-C (Mi), (F-FOMi).

Thirty-one patients with advanced non-small-cell lung cancer (NSCLC) were treated with a combination of folinic acid, fluorouracil, vincristine, and mitomycin (F-FOMi). Eight partial responses (26%), eight stable disease (26%), and 15 progressive disease (48%) were obtained. Patients with performance status (PS) 0-1 had a significantly better response rate than those with PS 2-3. Overall actuarial survival was 10 months. Toxicity was mild and mainly gastrointestinal with mucositis and diarrhea. F-FOMi seems to be comparable to regimens more widely used in the treatment of NSCLC.

Salvage chemotherapy with mitoxantrone and mitomycin with or without methotrexate in advanced breast cancer.

Thirty-three patients with advanced and refractory breast cancer were treated with two mitoxantrone-containing regimens (mitoxantrone plus mitomycin and mitoxantrone plus mitomycin plus methotrexate). All patients had received previous chemotherapy with cyclophosphamide, methotrexate and fluorouracil (CMF); cyclophosphamide, adriamycin and fluorouracil (CAF); or CMF and CAF. Partial response occurred in five patients (15 +/- 12%), stable disease occurred in 15 patients (45 +/- 17%) and progressive disease occurred in 13 patients (40 +/- 17%). The median duration of response was 5 months. The median actuarial survival was 11 months. Toxicity was mild, even in patients who had previously received anthracyclines; generally it was mainly hematological. We thus recommend mitoxantrone-containing regimens as salvage chemotherapy in advanced breast cancer.

Association of epirubicin, etoposide and cisplatin in gastric cancer. A phase II study.

Cisplatin-based drug combinations are now currently investigated in an attempt to surpass the results obtainable by 5-FU alone or by 5-FU-containing regimens. We evaluated 29 patients with advanced and measurable gastric adenocarcinoma treated with etoposide, epirubicin and cisplatin. One patient had complete response (3 +/- 7%); 9 patients had partial response (31 +/- 17%); 5 patients (17 +/- 14%) were considered stable (S) and 14 (48 +/- 18%) were classified as progressive. The average survival time for the entire group was 11 months with 25% of the patients alive at 24 months. We feel that cisplatin-containing regimens are promising and deserve further investigations. To clearly explore the potential innovative role of these regimens randomized trials versus FAM or 5-FU alone are mandatory.

[Echography in the study of adenopathies of the upper abdomen]. / L'ecografia nello studio delle adenopatie dell'addome superiore.

Four-hundred eighty-five patients underwent US examination; 183 of them had gastric cancer, 239 colorectal cancer, 38 pancreatic cancer, 11 esophageal cancer, and 14 had gastric lymphoma. All patients underwent surgery. In 95 cases fine-needle biopsy under US guidance was performed. Lymphadenopathies were classified by the criteria proposed by Yoshinaka et al., type I: poorly-defined borders, diffuse internal echoes; type II: well-defined borders, diffuse internal echoes; type III: well-defined borders, notchings, strong internal echoes. Twenty/twenty-nine type I, 66/98 type II, and 39/43 type III adenopathies were found to be neoplasm-positive. Of 73 patients with adenopathy from gastric cancer, 9 were type I, 42 were type II, and 22 were type III (183 patients examined); of 9 patients with adenopathy from esophageal cancer, 7 were type II and 2 were type III (11 patients examined); of 48 patients with adenopathy from colorectal cancer, 5 were type I, 28 were type II, and 15 were type III (239 patients examined); of 29 patients with adenopathy from pancreatic cancer, 7 were type I, 18 were type II, and 4 were type III (38 patients examined); finally, of 11 patients with adenopathy from gastric lymphoma, 8 were type I, and 3 were type II (14 patients examined). The relationship between US and pathology was possible from a statistical point of view only. Type I lymphadenopathies seem to suggest lymphomatous involvement, whereas type III ones suggest metastatic involvement. US is a valid approach method, which must be supported by other investigation techniques--e.g., CT and lymphography--in order to avoid high false-negative percentages.

Advanced colon cancer: staging and prognosis by CEA test.

The carcinoembryonic antigen (CEA) test was studied in 54 patients with advanced stages of colon cancer which was treated with high doses of folinic acid + fluorouracil. The CEA test correlates evaluated included: prognostic value, performance status, metastatic pattern, histologic grading, predictive value for response to chemotherapy, and value differences in cases with partial response to therapy. CEA levels less than 5 ng/ml corresponded to a greater survival time than did levels greater than 5 ng/ml. A correlation of CEA with performance status and with metastatic pattern was demonstrated. A progressive increase in average CEA values corresponded to increases in neoplastic mass. Although CEA levels were not found to be an index for predicting the response to chemotherapy, there was a significant different between pre- and posttreatment levels for partial response. The results suggest that CEA offers an additional criterion for evaluating the response of colon cancer to chemotherapy and it also has a role in the staging of advanced disease.