Bile acids and their receptors: modulators and therapeutic targets in liver inflammation

Bile acids participate in the intestinal emulsion, digestion, and absorption of lipids and fat-soluble vitamins. When present in high concentrations, as in cholestatic liver diseases, bile acids can damage cells and cause inflammation. After the discovery of bile acids receptors about two decades ago, bile acids are considered signaling molecules. Besides regulating bile acid, xenobiotic, and nutrient metabolism, bile acids and their receptors have shown immunomodulatory properties and have been proposed as therapeutic targets for inflammatory diseases of the liver. This review focuses on bile acid-related signaling pathways that affect inflammation in the liver and provides an overview of the preclinical and clinical applications of modulators of these pathways for the treatment of cholestatic and autoimmune liver diseases

Endothelial dysfunction markers as a therapeutic target for Sildenafil treatment and effects on metabolic control in type 2 diabetes

Endothelial dysfunction (ED) plays a role in diabetic cardiovascular complications. Hyperglycemia increases cytockines involved in vascular inflammation. Inhibition of phosphodiesterase type 5 (PDE5) exerts a relaxation on corpora cavernosa and has cardioprotective properties. The effect of chronic sildenafil treatment, on ED markers and metabolic parameters in a non-randomized study on men with type 2 diabetes (T2DM), was investigated

Eros e thanatos: alle radici della famiglia, della vita e della morte. Una declinazione psichiatrico-forense.

Although every homicide is a tragic event, the ones committed by psychiatric patients have a special impact on public opinion, where they are perceived as unforeseeable, irrational, even threatening. Particularly disturbing are the homicide-suicides that happen within the family, which is usually viewed as a refuge in which affections are cultivated. It is in this refuge indeed, that sometimes not only the flowers of love, but also the deadly berries of thanatos grow. From time immemorial poets have known that one can lose one’s mind through love or hate and that it is not always possible “to find it again on the moon” or, in contemporary fashion, at the psychiatrists, who do their best to interpret this magma of love and hate, life and death. In literature we can find several attempts to classify homicide-suicide on the bases of the psychiatric disorder of the killer, the relationship between killer and victim and possible trigger events, in order to help clinicians to establish the risk of the occurrence. A part from the many cases of infanticide, a profile that emerges from this analysis, is that of the elderly depressed man who kills the sick wife that he is caring for. The purpose of our work is to analyse an uxoricide and failed suicide case within our forensic practice, committed by a man, almost 70 years old, who was no longer capable of taking care of a wife, who was suffering from dementia, was not self-sufficient and who was due to be admitted to an elderly clinic within a few days. In order to understand this case, be it on a clinical or forensic level, we tried to identify the psychopathological signs and symptoms of the patient that could result in a disorder, but primarily to elucidate the mental and motivational dynamics that brought him to kill his wife. We also tried to evaluate how much these dynamics affected his capacity. The story emerged from the patient under observation was that of a great love that could not end and above all that could not end with the abandonment and betrayal of a defenceless wife. The dynamics he presented were on one side those of “I can neither save you nor abandon you” and, on the other side, of “nec tecum nec sine te vivere possum”. It is at this level that the question of the differential diagnosis crops up, between euthanasia as a gesture of love or a depressive anguish that renders the patient unable to be indicted.Benché qualsiasi omicidio sia un evento tragico, quelli commessi da persone riconosciute affette da un disturbo psichiatrico hanno in genere uno speciale impatto sull’opinione pubblica, che li percepisce come imprevedibili, irrazionali, per certi versi minacciosi. Particolarmente perturbanti sono gli omicidi-suicidi che avvengono all’interno della famiglia, che ognuno di noi vive come rifugio in cui coltivare i propri affetti; ma è proprio in questo rifugio che talvolta non crescono solo i fiori dell’amore, ma anche le mortali bacche di thanatos. Da sempre i poeti sanno che si può perdere il senno per amore o per odio e che non sempre si riesce a ritrovarlo sulla luna né, più modernamente, dagli psichiatri, che tuttavia si sforzano di interpretare questo magma di amore e di odio, di vita e di morte. Vari sono stati i tentativi classificativi che hanno preso in considerazione la patologia psichiatrica del perpetratore, la relazione tra questi e la vittima ed eventuali fattori precipitanti, al fine di aiutare i clinici a stabilire il rischio che tali eventi si verifichino. Accanto a vari casi di figlicidio, un profilo che si è delineato da queste analisi è quello di uomini anziani, depressi, che uccidono le proprie mogli ammalate, di cui si erano sempre presi cura. Scopo del nostro lavoro è l’analisi di un caso di uxoricidio e mancato suicidio giunto alla nostra osservazione psichiatrico-forense, compiuto da un signore settantenne, che non poteva più assistere una moglie ormai demente, non autosufficiente e che entro pochi giorni sarebbe stata ricoverata in una casa di riposo. Al fine di comprendere questo caso sia sul piano clinico che forense abbiamo cercato non solo di evidenziare i segni e sintomi psicopatologici del Periziando codificabili in un disturbo, ma soprattutto di mettere in luce le dinamiche mentali e motivazionali che lo hanno portato a porre fine alla vita della moglie e di valutare quanto tutto ciò abbia inciso sulla sua capacità di intendere e di volere. Dal racconto del Periziando emergeva la storia di un grande amore che non poteva finire, che soprattutto non poteva finire con l’abbandono-tradimento di una moglie inerme. Le dinamiche da lui presentate erano quelle del “né ti posso salvare né ti posso abbandonare” e specularmente del “nec tecum nec sine te vivere possum”. È a questo livello che si è posto il quesito diagnostico differenziale tra un gesto di amore che si fa eutanasia o un’angoscia depressiva che rende l’interessato non imputabile

Pharmacokinetics of sumatriptan in non-respondent and in adverse drug reaction reporting migraine patients

Sumatriptan is a selectiveagonist of 5HT1 (1B/1D) receptors,which has proved to be effectiveand safe for the acute treatment ofmigraine attacks. Nevertheless, itsuse by migraine sufferers is stilllimited and some patients consideradverse reactions related to sumatriptan,especially chest symptoms,unacceptable even if not serious.Moreover, in clinical trials, almostone third and one sixth of patients,respectively, fail to experienceheadache relief either after oral orafter subcutaneous sumatriptanadministration. Our aim was to verifywhether differencies in sumatriptanpharmacokinetics couldexplain non-response and/oradverse drug reactions. Sumatriptanlevels were determined by HPLCwith electrochemical detection.Pharmacokinetic parameters werecalculated using a computer program(PK Solutions 2.0; non compartmentalPharmacokinetics DataAnalysis). After oral administration,sumatriptan is rapidly absorbed andsometimes displays multiple peaksof plasma concentration. This “multiplepeaking” gives rise to considerableinter-subject variability inthe time of reaching maximumplasma concentration.Pharmacokinetic parameters ofsumatriptan, both after oral andsubcutaneous administration, weresimilar in the three patient groups.Blood pressure and heart rate didnot show any significant differencesbetween groups. Pharmacokineticparameters and bioavailability ofsumatriptan did not seem to be correlatedeither to the lack of efficacyor the appearance of side effects.These results could depend on thelimited number of patients studied

Assessment of the Coagulation Profile in Canine Multiple Myeloma: A Cohort Investigation in 234 Dogs

Hypercoagulability in canine multiple myeloma (MM) as described in humans has not been reported and prognostic factors related to hemostasis have not been investigated. Aims of this study were: to describe the haemostatic profile in dogs with MM, to detect a possible hypercoagulable state, and to assess whether coagulation parameters have prognostic value. Haemostatic alteration at the initial visit of dogs affected by MM (Group 1, n = 78) were retrieved from the electronic data- base (P.O.A. System-Plus 9.0®) of the San Marco Veterinary Clinic, between 2002–2015. Dogs with MM met the following criteria: bone marrow plasma cells ≥ 15%, osteolytic lesions, serum mono-biclonal gammopathy and extensive coagulation profile including platelet count, aPTT, PT, fibrinogen, thrombin time (TT), FPDs, D-Dimer and antithrombin (AT). Two groups of dogs individually matched for age, breed, and sex were used as controls: healthy dogs (Group 2, n = 78) and sick dogs without MM (Group 3, n = 78). In addition, the hemostatic profile between clinical bleeding (B-MM, n = 45) (e.g., gum bleeding, epistaxis) and no- clinical bleeding (NB-MM, n = 33) dogs with MM was evaluated. Kruskal-Wallis and Wilcoxon-Mann-Whitney tests were used to compare groups. Risk to death at 90 days after diagnosis within B-MM and NB-MM dogs was evaluated by Pearson's X2 test. ROC curves were used to identify the best analyte to predict death. Prothrombin time and aPTT were increased (p = 0.001) in Group 1 vs groups 2 and 3, TT was increased (p = 0.001) in Group 1 vs 3. The platelet count and AT concentration were decreased in Group 1 vs groups 2 and 3 (p = 0.001). Fibrinogen concentration was decreased in Group 1 vs 3 (p = 0.01). No differences between Groups 1 vs groups 2 and 3 for FDPs and D-dimer were observed. Platelet count and AT concentrations were decreased in B-MM vs NB-MM (p = 0.04; p = 0.026); PT and aPTT and were increased in B-MM vs NB-MM (p = 0.026; p = 0.03). No differences between B-MM and NB-MM were observed for TT, FDPs, D-Dimer. B-MM dogs showed lower mortality rate in respect to NB-MM patient (p < 0.028). The TT resulted the best haemostatic analyte in predicting death in dogs affected with MM (p < 0.04; AUC 64%; 95% CI = 0.48–0.82). Primary and secondary haemostasis are compromised in dogs with MM while tertiary haemostasis appears unaffected. The hypercoagulable state, opposite to humans, is unlikely in dogs with MM. Surprisingly, dogs with MM and clinical bleeding apparently have protective effect against death. The prediction of mortality in canine MM was related to TT

A New Neurorehabilitative Postsurgery Intervention for Facial Palsy Based on Smile Observation and Hand-Mouth Motor Synergies

Objective. To perform a preliminary test of a new rehabilitation treatment (FIT-SAT), based on mirror mechanisms, for gracile muscles after smile surgery. Method. A pre- and postsurgery longitudinal design was adopted to study the efficacy of FIT-SAT. Four patients with bilateral facial nerve paralysis (Moebius syndrome) were included. They underwent two surgeries with free muscle transfers, one year apart from each other. The side of the face first operated on was rehabilitated with the traditional treatment, while the second side was rehabilitated with FIT-SAT. The FIT-SAT treatment includes video clips of an actor performing a unilateral or a bilateral smile to be imitated (FIT condition). In addition to this, while smiling, the participants close their hand in order to exploit the overlapped cortical motor representation of the hand and the mouth, which may facilitate the synergistic activity of the two effectors during the early phases of recruitment of the transplanted muscles (SAT). The treatment was also aimed at avoiding undesired movements such as teeth grinding. Discussion. Results support FIT-SAT as a viable alternative for smile rehabilitation after free muscle transfer. We propose that the treatment potentiates the effect of smile observation by activating the same neural structures responsible for the execution of the smile and therefore by facilitating its production. Closing of the hand induces cortical recruitment of hand motor neurons, recruiting the transplanted muscles, and reducing the risk of associating other unwanted movements such as teeth clenching to the smile movements

Efficient reabsorption of transintestinally excreted cholesterol is a strong determinant for cholesterol disposal in mice[S]

Transintestinal cholesterol excretion (TICE) is a major route for eliminating cholesterol from the body and a potential therapeutic target for hypercholesterolemia. The underlying mechanism, however, is largely unclear, and its contribution to cholesterol disposal from the body is obscured by the counteracting process of intestinal cholesterol reabsorption. To determine the quantity of TICE independent from its reabsorption, we studied two models of decreased intestinal cholesterol absorption. Cholesterol absorption was inhibited either by ezetimibe or, indirectly, by the genetic inactivation of the intestinal apical sodium-dependent bile acid transporter (ASBT; SLC10A2). Both ezetimibe treatment and Asbt inactivation virtually abrogated fractional cholesterol absorption (from 46% to 4% and 6%, respectively). In both models, fecal neutral sterol excretion and net intestinal cholesterol balance were considerably higher than in control mice (5- and 7-fold, respectively), suggesting that, under physiological conditions, TICE is largely reabsorbed. In addition, the net intestinal cholesterol balance was increased to a similar extent but was not further increased when the models were combined, suggesting that the effect on cholesterol reabsorption was already maximal under either condition alone. On the basis of these findings, we hypothesize that the inhibition of cholesterol (re)absorption combined with stimulating TICE will be most effective in increasing cholesterol disposal

Children with facial paralysis due to Moebius syndrome exhibit reduced autonomic modulation during emotion processing

Facial mimicry is crucial in the recognition of others' emotional state. Thus, the observation of others' facial expressions activates the same neural representation of that affective state in the observer, along with related autonomic and somatic responses. What happens, therefore, when someone cannot mimic others' facial expressions? We investigated whether psychophysiological emotional responses to others' facial expressions were impaired in 13 children (9 years) with Moebius syndrome (MBS), an extremely rare neurological disorder (1/250,000 live births) characterized by congenital facial paralysis. We inspected autonomic responses and vagal regulation through facial cutaneous thermal variations and by the computation of respiratory sinus arrhythmia (RSA). These parameters provide measures of emotional arousal and show the autonomic adaptation to others' social cues. Physiological responses in children with MBS were recorded during dynamic facial expression observation and were compared to those of a control group (16 non-affected children, 9 years). There were significant group effects on thermal patterns and RSA, with lower values in children with MBS. We also observed a mild deficit in emotion recognition in these patients. Results support "embodied" theory, whereby the congenital inability to produce facial expressions induces alterations in the processing of facial expression of emotions. Such alterations may constitute a risk for emotion dysregulation

Sex differences and rehabilitation needs after hospital discharge for COVID-19: an Italian cross-sectional study

COVID-19 can result in persistent symptoms leaving potential rehabilitation needs unmet. This study aims to describe persistent symptoms and health status of individuals hospitalised for COVID-19 according to the International Classification of Functioning, Disability and Health domains of impairments, limitations in activity, and participation restrictions