4WD to Travel Inside the 5-HT1A Receptor World

5-HT1A receptor is one of the most important members of the numerous families of serotoninergic receptors. Though it was the first 5-HT receptor to be identified and cloned, the knowledge of its activation/transduction mechanisms, mediated effects, and connection with other systems is still uncompleted. For this reason, relevant is the study of the four Ws of the title: first of all “who” this receptor is, then “why” it continues to be a so attractive target after several years after its identification, then “where” is 5-HT1A receptor expressed within the body, and, finally, “what” effects this receptor can elicit under physiological and pathological conditions. Obviously, more and more potent, safe, and selective “drugs” might be discovered once the responses to these questions are given

Antagonism/Agonism modulation to build novel antihypertensives selectively triggering i1-imidazoline receptor activation

Pharmacological studies have suggested that I1-imidazoline receptors are involved in the regulation of cardiovascular function and that selective I1-agonists, devoid of the side effects associated with the common hypotensive α2-adrenoreceptor agonists, might be considered as a second generation of centrally acting antihypertensives. Therefore, in the present study, inspired by the antihypertensive behavior of our selective I1-agonist 4, we designed, prepared, and studied the novel analogues 5-9. A selective I1-profile, associated with significant hemodinamic effects, was displayed by 5, 8, and 9. Interestingly, the highest potency and longest lasting activity displayed by 8 (carbomethyline) suggested that van der Waals interactions, promoted by the ortho methyl decoration of its aromatic moiety, are particularly advantageous. In addition, in analogy to what was noted for (S)-(+)-4, the observation that only (S)-(+)-8 displayed significant hemodynamic effects unequivocally confirmed the stereospecific nature of the I1 proteins

Outcomes and Predictors of Mortality in Patients With KPC-Kp Infections Treated With Meropenem Vaborbactam: An Observational Multicenter Study

Background Meropenem-vaborbactam is a recent and promising option for the treatment of KPC-producing Klebsiella pneumoniae (KPC-Kp) infections, including those resistant to ceftazidime-avibactam.Methods We conducted a retrospective analysis of observational data from 19 Italian hospitals on use and outcomes of patients treated with meropenem-vaborbactam for at least >= 24 hours for KPC-Kp infections. Crude and propensity-weighted multiple Cox regression models were performed to ascertain risk factors independently associated with 30-day mortality.Results The cohort included 342 adults with bloodstream infections (n = 172) and nonbacteremic infections (n = 170), of which 107 were lower respiratory tract infections, 30 were complicated urinary tract infections, and 33 were infections involving other sites. Most infections (62.3%) were managed with meropenem-vaborbactam monotherapy, or in combination with at least 1 other active drug (usually fosfomycin, tigecycline, or gentamicin) (37.7%). The 30-day mortality rate was 31.6% (108/342). In multiple Cox regression model, 30-day mortality was independently associated with septic shock at infection onset, Charlson comorbidity index >= 3, dialysis, concomitant COVID-19, and INCREMENT score >= 8. Administration of meropenem-vaborbactam within 48 hours from infection onset was a negative predictor of mortality. All predictors, except administration of meropenem-vaborbactam within 48 hours, remained significant when the multiple Cox regression model was repeated after adjustment for the propensity score for receipt of combination therapy.Conclusions Despite the limits of a retrospective study, the data derived from this multicenter cohort provide additional evidence on the efficacy of meropenem-vaborbactam in treating severe KPC-Kp infections, even when used as monotherapy

Ceftolozane/Tazobactam for Treatment of Severe ESBL-Producing Enterobacterales Infections: A Multicenter Nationwide Clinical Experience (CEFTABUSE II Study)

Background. Few data are reported in the literature about the outcome of patients with severe extended-spectrum beta-lactamase-producing Enterobacterales (ESBL-E) infections treated with ceftolozane/tazobactam (C/T), in empiric or definitive therapy.Methods. A multicenter retrospective study was performed in Italy (June 2016-June 2019). Successful clinical outcome was defined as complete resolution of clinical signs/symptoms related to ESBL-E infection and lack of microbiological evidence of infection. The primary end point was to identify predictors of clinical failure of C/T therapy.Results. C/T treatment was documented in 153 patients: pneumonia was the most common diagnosis (n = 46, 30%), followed by 34 cases of complicated urinary tract infections (22.2%). Septic shock was observed in 42 (27.5%) patients. C/T was used as empiric therapy in 46 (30%) patients and as monotherapy in 127 (83%) patients. Favorable clinical outcome was observed in 128 (83.7%) patients; 25 patients were considered to have failed C/T therapy. Overall, 30-day mortality was reported for 15 (9.8%) patients. At multivariate analysis, Charlson comorbidity index >4 (odds ratio [OR], 2.3; 95% confidence interval [CI], 1.9-3.5; P = .02), septic shock (OR, 6.2; 95% CI, 3.8-7.9; P < .001), and continuous renal replacement therapy (OR, 3.1; 95% CI, 1.9-5.3; P = .001) were independently associated with clinical failure, whereas empiric therapy displaying in vitro activity (OR, 0.12; 95% CI, 0.01-0.34; P < .001) and adequate source control of infection (OR, 0.42; 95% CI, 0.14-0.55; P < .001) were associated with clinical success.Conclusions. Data show that C/T could be a valid option in empiric and/or targeted therapy in patients with severe infections caused by ESBL-producing Enterobacterales. Clinicians should be aware of the risk of clinical failure with standard-dose C/T therapy in septic patients receiving CRRT

Migration and wintering patterns of Golden Plover, Pluvialis apricaria, in the Northern part of Modena province (Northern Italy)

The authors present the results on the migration and wintering patterns of Golden Plover. There are differences on biometrics between juv (immature)/adults. The juv are mainly significantly present in autumn and the adults in spring migration. We found a significant differences in the weights with adults weighing much more than young ones perhaps demonstrating a different migration pattern

Time-budget of dabbling ducks migrating through Modena province in springtime

The authors report first data of Time budget activity in the pre-breeding migration of 6 dabbling ducks migrating through Modena province. Figures of 8,356 ducks were gathered in the main peak of migration (February-March). Sampling method suggested by Altmann (1974) was used. The main behaviors observed were: sleeping, swimming and feeding; contra courtship, and vigilance were insignificant, it could mean that the migrating birds are all paired. We remark the drop of Anas querquedula that few years ago was the dominant duck migrating in Modena province

La classificazione della pericolosità radon nella pianificazione territoriale finalizzata alla gestione del rischio. Classification of radon hazard in urban planning focused to risk management

""\\"Questo contributo tratta della valutazione della pericolosità radon nella pianificazione territoriale. Sulla base delle esperienze maturate in Europa e negli Stati Uniti, si propone di associare le misure di concentrazione del radon nel suolo, effettuate alla profondità minima di 80 cm, con la determinazione della permeabilità ai gas del terreno, per il calcolo degli indici RP e RI. Il valore di questi parametri consente la classificazione del rischio in un sito dove è previsto un futuro sviluppo edilizio e la predisposizione preventiva d’accorgimenti tecnici per controllare i successivi livelli di radon indoor. L’applicazione di questo metodo a due siti-pilota (la Valle della Caffarella e il Parco della Resistenza) ubicati in Italia centrale e caratterizzati da diversi assetti geologici, dimostra che l’introduzione del parametro permeabilità aiuta a descrivere meglio il livello di rischio, riducendo la variabilità stagionale che interessa le misure. A scopo precauzionale, si suggerisce di moltiplicare per 2 gli indici RP ottenuti per le misure estive (svolte nei mesi di luglio e agosto) e per 1.5 quelli di giugno e settembre, così da evitare di sottostimare le concentrazioni di radon nel suolo e gli indici radon relativi a questi periodi, rispetto alle condizioni medie annue o ai massimi invernali.. . \\"""""\\"This work deals with the evaluation of radon hazard in urban planning. According to the experiences developed in Europe and in the United States, we propose to associate the measurement of soil radon concentration at the minimum depth of 80 cm with the determination of soil gas permeability in order to calculate RP and RI radon indices. The values of these indices allow classifying the radon risk of a future building site and planning technical actions to reduce and control indoor radon levels. The application of this procedure to two test-sites (Valle della Caffarella and Parco della Resistenza) located in central Italy and characterised by different geological setting and bedrock, demonstrate that the introduction of the intrinsic permeability helps to better describe the level of risk, reducing the seasonal variability that affects measurements. With a precautionary spirit, we suggest that a correction coefficient should be employed to summer measurements in order to minimise the underestimation of soil radon and radon indices that is commonly observed in dry and warm periods. July and August RP indices should be multiplied by 2, whereas June and September values times 1.5. No corrections are needed for winter determinations when highest values are reached. \\""

Il rischio radon in edilizia. Proposta di codifica di un protocollo per la classificazione del rischio.

""\\"La Pianificazione Territoriale, attraverso. la conoscenza degli elementi di pericolo. esistenti nell’area in esame, consente la. predisposizione di strumenti urbanistici. idonei ad assicurare la salvaguardia. della salute pubblica e dell’incolumità. delle persone e dei beni presenti.. Quest’impostazione, che vale per il. rischio idrogeologico, sismico, vulcanico,. industriale ecc., non trova adeguato. riscontro nei confronti di un altro rischio. naturale poco conosciuto e pertanto. comunemente dimenticato, che è causato. dalle emanazioni radioattive del gas. Radon e dai suoi prodotti di decadimento.. Statistiche di tipo epidemiologico indicano. il forte impatto che il Radon ha sulla salute. pubblica, stimandolo come seconda causa. di tumore al polmone dopo il fumo e. responsabile in Italia di circa 3000 decessi. \\\\\\\/ anno (WHO 2009).. Sinora, il problema dell’inquinamento. indoor da Radon nel nostro Paese è stato. appannaggio prevalentemente di due. figure professionali: il medico per l’aspetto. sanitario ed il fisico per le misure. Questo. stato di cose, particolarmente chiuso. e circoscritto, escludendo di tenere in. considerazione anche gli aspetti connessi. alle cause geologiche del fenomeno, sta. indirizzando le necessarie azioni di difesa. a soluzioni che risentono fortemente di un. approccio al problema limitato e parziale.. Poiché la distribuzione e la migrazione. del Radon sono controllate dall’assetto. geologico del territorio (natura dei terreni,. tettonica, ecc.), ne risulta che le prime. indicazioni sulla potenziale localizzazione. di zone a forte concentrazione di questo gas si possano ottenere proprio secondo. valutazioni di tipo geologico. Informazioni. più approfondite invece si ricavano. dall’esecuzione di specifici rilievi della. concentrazione di Radon nei gas del suolo. (rilievi di Soil Radon).. Pertanto, ponendo il problema. all’attenzione degli urbanisti, dei. progettisti e dei costruttori, nei territori. che sono stati preliminarmente. individuati potenzialmente a rischio,. quest’indagine dovrebbe essere compresa. tra quelle di natura geologica, necessarie. per la redazione dei piani urbanistici. particolareggiati e per la progettazione delle. costruzioni pubbliche e private. Sarebbe. pertanto auspicabile che le Associazioni. di Categoria, gli Ordini Professionali e. le Pubbliche Amministrazioni facessero. proprio e diffondessero l’ampio patrimonio. di conoscenze oggi disponibile, al fine. di tradurre consapevolmente in azioni. concrete le strategie di difesa dal rischio. naturale Radon nelle abitazioni e nei posti. di lavoro.\\""

Structural requirements for adrenergic alpha-receptorcovalent occupancy by chiral tetramine disulfides

Chiral tetramine disulfldes 3, designed to study the molecular properties of the active site of the adrenergic alpha-receptor, were synthesizedand tested on ral vas deferens preparation. The activity of the three optical isomers showed that the receptor displays an insignificantdegree ol stereoselectivity thus supporting the hypothesis that the benzylic groups of tetramine disulfides related to Benextramine donot bind at the same site that is normally occupied by the catechol nuclei of the neurotrirnsmitter. Rather, they would interact withan accessory area which appears to be insensitive to chirality efiects

Molecular properties of the adrenergic alpha-receptors.4.Topographical and structural differences betweentissue-specific binding sites as revealedby benextramine and analogues.

Until recently, it has been tacitly assurned that the postsynaptic or alpha1-adrenoreceptors of diverse biologicat origins are phar-macologicalll,similar. Quantitative evidence is now available that significant diiffcrences may exist between alpha1-adreceptors oi differenttissues and species. We submit experimental evidence which demonstrates that the alpha-receptor binding sites of the rat vas deferensand rabbit aorta or left atrium exhibit stereochemical and structural differences. Furthermore, the topographical dualism underling the respective effects oi Benextramine and AOC on rat vas deferens apply also to rabbit aorta. In addition, the tetraminedisulfides incorporating catechol nuclei showed high potency toward the alpha1-receptors of both rat vas deferens and rabbit aorta.Optimmm act\uecvity was sharply associatecl on both tissues with those 3'.4'-dihydroxybenzyl ccrnpouncls having a six- and eight-carbonchains. The mechanistic and topographicat significance of this dualism is discusse