Dopaminergic-GABAergic interplay and alcohol binge drinking

© 2019 Elsevier Ltd The dopamine D 3 receptor (D 3 R), in the nucleus accumbens (NAc), plays an important role in alcohol reward mechanisms. The major neuronal type within the NAc is the GABAergic medium spiny neuron (MSN), whose activity is regulated by dopaminergic inputs. We previously reported that genetic deletion or pharmacological blockade of D 3 R increases GABA A α6 subunit in the ventral striatum. Here we tested the hypothesis that D 3 R-dependent changes in GABA A α6 subunit in the NAc affect voluntary alcohol intake, by influencing the inhibitory transmission of MSNs. We performed in vivo and ex vivo experiments in D 3 R knockout (D 3 R −/− ) mice and wild type littermates (D 3 R +/+ ). Ro 15-4513, a high affinity α6-GABA A ligand was used to study α6 activity. At baseline, NAc α6 expression was negligible in D 3 R +/+ , whereas it was robust in D 3 R −/− ; other relevant GABA A subunits were not changed. In situ hybridization and qPCR confirmed α6 subunit mRNA expression especially in the NAc. In the drinking-in-the-dark paradigm, systemic administration of Ro 15-4513 inhibited alcohol intake in D 3 R +/+ , but increased it in D 3 R −/− ; this was confirmed by intra-NAc administration of Ro 15-4513 and furosemide, a selective α6-GABA A antagonist. Whole-cell patch-clamp showed peak amplitudes of miniature inhibitory postsynaptic currents in NAc medium spiny neurons higher in D 3 R −/− compared to D 3 R +/+ ; Ro 15-4513 reduced the peak amplitude in the NAc of D 3 R −/− , but not in D 3 R +/+ . We conclude that D 3 R-dependent enhanced expression of α6 GABA A subunit inhibits voluntary alcohol intake by increasing GABA inhibition in the NAc

Retinal Protection and Distribution of Curcumin in Vitro and in Vivo

Diabetic retinopathy (DR), a secondary complication of diabetes, is a leading cause of irreversible blindness accounting for 5% of world blindness cases in working age. Oxidative stress and inflammation are considered causes of DR. Curcumin, a product with anti-oxidant and anti-inflammatory properties, is currently proposed as oral supplementation therapy for retinal degenerative diseases, including DR. In this study we predicted the pharmacodynamic profile of curcumin through an in silico approach. Furthermore, we tested the anti-oxidant and anti-inflammatory activity of curcumin on human retinal pigmented epithelial cells exposed to oxidative stress, human retinal endothelial and human retinal pericytes (HRPCs) cultured with high glucose. Because currently marketed curcumin nutraceutical products have not been so far evaluated for their ocular bioavailability; we assessed retinal distribution of curcumin, following oral administration, in rabbit eye. Curcumin (10 μM) decreased significantly (p < 0.01) ROS concentration and TNF-α release in retinal pigmented epithelial cells and retinal endothelial cells, respectively. The same curcumin concentration significantly (p < 0.01) protected retinal pericytes from high glucose damage as assessed by cell viability and LDH release. Among the tested formulations, only that containing a hydrophilic carrier provided therapeutic levels of curcumin in rabbit retina. In conclusion, our data suggest that curcumin, when properly formulated, may be of value in clinical practice to manage retinal diseases

Incidence of pleural mesothelioma in a community exposed to fibres with fluoro-edenitic composition in Biancavilla (Sicily, Italy)

Introduction. Amphibolic fibres with fluoro-edenitic composition characterize Biancavilla soil, including the major quarry from which building materials have been extensively extracted. These fibres induce mesothelioma in experimental animals and their in vitro biological action is similar to that of crocidolite.Materials and methods. Malignant mesothelioma case series and incidence were examined to evaluate the disease burden on Biancavilla inhabitants. Results. The incidence of pleural mesothelioma in Biancavilla is steadily higher than in the Sicilian Region, risk estimates are more elevated in women than in men, the most affected age class is constituted by subjects aged less than 50.Discussion and conclusions. Environmental exposure to fibres with fluoro-edenitic composition appears to be causally related to the elevated mesothelioma occurrence in Biancavilla. In this frame, environmental clean-up is the main goal to be pursued in public health terms. A contribution of scientific research to public health decision making with respect to priority setting for environmental clean-up can derive from some further selected epidemiological investigations

Neutralization, effector function and immune imprinting of Omicron variants

Currently circulating SARS-CoV-2 variants have acquired convergent mutations at hot spots in the receptor-binding domain$^{1}$ (RBD) of the spike protein. The effects of these mutations on viral infection and transmission and the efficacy of vaccines and therapies remains poorly understood. Here we demonstrate that recently emerged BQ.1.1 and XBB.1.5 variants bind host ACE2 with high affinity and promote membrane fusion more efficiently than earlier Omicron variants. Structures of the BQ.1.1, XBB.1 and BN.1 RBDs bound to the fragment antigen-binding region of the S309 antibody (the parent antibody for sotrovimab) and human ACE2 explain the preservation of antibody binding through conformational selection, altered ACE2 recognition and immune evasion. We show that sotrovimab binds avidly to all Omicron variants, promotes Fc-dependent effector functions and protects mice challenged with BQ.1.1 and hamsters challenged with XBB.1.5. Vaccine-elicited human plasma antibodies cross-react with and trigger effector functions against current Omicron variants, despite a reduced neutralizing activity, suggesting a mechanism of protection against disease, exemplified by S309. Cross-reactive RBD-directed human memory B cells remained dominant even after two exposures to Omicron spikes, underscoring the role of persistent immune imprinting

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages carry distinct spike mutations resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters elicit plasma-neutralizing antibodies against Omicron BA.1, BA.2, BA.2.12.1, and BA.4/5, and that breakthrough infections, but not vaccination alone, induce neutralizing antibodies in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1, BA.2, and BA.4/5 receptor-binding domains, whereas Omicron primary infections elicit B cells of narrow specificity up to 6 months after infection. Although most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant–neutralizing antibody that is a strong candidate for clinical development

Imprinted antibody responses against SARS-CoV-2 Omicron sublineages

SARS-CoV-2 Omicron sublineages carry distinct spike mutations and represent an antigenic shift resulting in escape from antibodies induced by previous infection or vaccination. We show that hybrid immunity or vaccine boosters result in potent plasma neutralizing activity against Omicron BA.1 and BA.2 and that breakthrough infections, but not vaccination-only, induce neutralizing activity in the nasal mucosa. Consistent with immunological imprinting, most antibodies derived from memory B cells or plasma cells of Omicron breakthrough cases cross-react with the Wuhan-Hu-1, BA.1 and BA.2 receptor-binding domains whereas Omicron primary infections elicit B cells of narrow specificity. While most clinical antibodies have reduced neutralization of Omicron, we identified an ultrapotent pan-variant antibody, that is unaffected by any Omicron lineage spike mutations and is a strong candidate for clinical development

Cholecystocolonic fistula in exacerbated chronic cholecystitis: A case report

The cholecystocolonic fistula (CCF) is an atypical variant of biliary disease, and it is the second most common intestinal fistula after cholecystoduodenal fistula. Intraoperative diagnosis is frequent, which implies challenging surgical management, especially in patients, often aged, with comorbidities. The rarity of this condition, atypical and various presentation, diagnostic and management complexity, makes it a unique surgical entity. We report our experience of an 84-year-old man with a history of chronic cholecystitis who presented with nonspecific symptoms. The imaging tests aroused the suspicion of gallbladder-colic fistula in the preoperative diagnosis, facilitating the subsequent surgical treatment that confirmed the diagnosis

A dietary pattern rich in olive oil and raw vegetables is associated with lower mortality in Italian elderly subjects

Dietary habits play an important role in healthy ageing. We have investigated the role of dietary patterns on overall mortality in a large series of Italian elderly, recruited in five EPIC cohorts in Northern (Varese and Turin), Central (Florence) and Southern Italy (Naples and Ragusa).A total of 5611 subjects (72·6 % women) aged 60 years or older, enrolled in 1993–1998, were prospectively followed (median 6·2 years), with 152 deaths (98 women). Four major dietary patterns were identified by using an exploratory factor analysis based on dietary information collected at enrolment. The associations between these dietary patterns and overall mortality were evaluated by Cox models adjusted for potential confounders. The 'Olive Oil & Salad' pattern, characterised by a high consumption of olive oil, raw vegetables, soups and poultry, emerged as being inversely associated with overall mortality in both crude and adjusted models. After adjustment for gender, age and caloric intake, overall mortality was reduced by approximately 50 % in the highest quartile and a significant trend emerged (P = 0·008). This association persisted after adjusting for several additional confounders (hazard ratio (HR) 0·50; 95 % CI 0·29, 0·86; P for trend = 0·02). An association of the 'Pasta & Meat' pattern (characterised by pasta, tomato sauce, red meat, processed meat, added animal fat, white bread and wine) with increased overall mortality was also suggested, but only for the highest quartile in a multivariate model. Dietary recommendations aimed at the Italian elderly population should support a dietary pattern characterised by a high consumption of olive oil, raw vegetables and poultry

Bulky DNA adducts and breast cancer risk in the prospective EPIC-Italy study

International audienceThe role of environmental carcinogen exposure in breast cancer development has long been suspected, but no specific association has been identified so far. A few molecular epidemiology studies reported that DNA adducts detected by different methods are associated with a modest increase of breast cancer risk. We aimed to evaluate the association between bulky DNA adducts, detected by the P-postlabelling method in peripheral leukocytes, and the risk of developing breast cancer in the female Italian cohorts of the EPIC (European Prospective Investigation into Cancer and nutrition) study. By using a case-control design, breast cancer cases identified in the follow-up of over 30,000 women of EPIC-Italy study have been matched to controls by specific criteria. We measured the levels of bulky DNA adducts by the P-postlabelling method in peripheral leukocytes donated at enrolment. Conditional regression analyses adjusted for selected potential confounders were used. Results on DNA adduct levels were available for 292 cases and 292 matched controls. The mean DNA adduct levels were similar in both groups ( = 0.62). Multivariate regression analyses failed to show any significant association between bulky DNA adducts and breast cancer. Our results do not support any association of breast cancer risk with exposure to environmental carcinogens as measured through the levels of bulky DNA adducts in pre-diagnostic white blood cells. Larger studies by using different methods and/or biomarkers are needed to better evaluate the role of specific environmental carcinogens in breast carcinogenesis