The epistatic interaction between the dopamine D3 receptor and dysbindin-1 modulates higher-order cognitive functions in mice and humans.

The dopamine D2 and D3 receptors are implicated in schizophrenia and its pharmacological treatments. These receptors undergo intracellular trafficking processes that are modulated by dysbindin-1 (Dys). Indeed, Dys variants alter cognitive responses to antipsychotic drugs through D2-mediated mechanisms. However, the mechanism by which Dys might selectively interfere with the D3 receptor subtype is unknown. Here, we revealed an interaction between functional genetic variants altering Dys and D3. Specifically, both in patients with schizophrenia and in genetically modified mice, concomitant reduction in D3 and Dys functionality was associated with improved executive and working memory abilities. This D3/Dys interaction produced a D2/D3 imbalance favoring increased D2 signaling in the prefrontal cortex (PFC) but not in the striatum. No epistatic effects on the clinical positive and negative syndrome scale (PANSS) scores were evident, while only marginal effects on sensorimotor gating, locomotor functions, and social behavior were observed in mice. This genetic interaction between D3 and Dys suggests the D2/D3 imbalance in the PFC as a target for patient stratification and procognitive treatments in schizophrenia.

What We Know About the Pathogenesis of Idiopathic Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic progressive lung disease of unknown cause, occurring in adults, limited to the lungs and associated with the pathologic and radiologic pattern of usual interstitial pneumonia. Prognosis is poor, and most patients die of respiratory failure within 3 to 6 years from the onset of symptoms. Although our understanding of the pathogenesis of IPF has improved over the past two decades, the mechanisms responsible for this disorder have not been clearly defined. Aging is the single most important risk factor, but genetic, environmental, and diverse exogenous factors such as smoking, viral infections, chronic tissue injury (i.e., gastroesophageal reflux disease, traction injury) play contributory roles. In this review, we focus on pathogenetic mechanisms that we think are crucial for the initiation of the fibrotic process and for its progressive evolution. In the early stage of the disease, in the context of the permissive genetic background combined with the presence of specific risk factors, alveolar epithelial cells play a leading role. Subsequent evolution of the fibrotic process and its lethal progression is likely due to the abnormal tissue repair process that takes place in the lung and to the inability to counteract this process. In this phase of the disease, fibroblasts assume a crucial role. Current pharmacological treatment strategies for IPF have only modest value, principally by slowing the course of disease progression. Unfortunately, improvement or cure has not yet been achieved with pharmacological agents. The challenge for the future is to improve the comprehension of the mechanisms involved in the inception and evolution of IPF and their articulated interactions. This is fundamental not only to conceive and develop new drugs against this dreadful disease but also to apply different therapeutic approaches such as drug repositioning and personalized therapies in the management of IPF.

Designing a new scoring system (QualyP Score) correlating the management of cardiopulmonary bypass to postoperative outcomes.

AIM: The aim of this study was to ascertain if a score, directly derived from CPB records, could correlate to major postoperative outcomes. METHODS: An additive score (QualyP Score) was created from 10 parameters: peak lactate value during CPB, peak VCO(2)i, lowest DO(2)i/VCO(2)i, peak respiratory quotient, CPB time, cross-clamp time, lowest CPB temperature, circulatory arrest, ultrafiltration during CPB, number of packed red cells transfused intraoperatively. The PerfSCORE was calculated, as well. Multivariable logistic regression models were built to detect the independent predictors of: peak lactate >3 mmol/L during the first three postoperative days; the incidence of acute kidney injury network (AKIN) 1-2-3; respiratory insufficiency; mortality. RESULTS: The mean score was 4.8±2.6 (0-10). A QualyP Score ≥1 was predictive of postoperative acidosis (OR=1.595). A score ≥2 was predictive of AKIN 2 (OR=1.268) and respiratory insufficiency (OR=1.526). A score ≥5 was predictive of AKIN 3 (OR=1.848) and mortality (OR=1.497). CONCLUSIONS: QualyP Score may help to provide a quality marker of perfusion, emphasizing the need for goal-directed perfusion strategies.

[Technic for repair of laparoceles by an extraperitoneal approach]. / Tecnica di riparazione dei laparoceli per via extraperitoneale.

The authors report their experience with a technique for reconstruction of the abdominal wall, without opening the peritoneal sac, in patients with ventral hernia. After detailing the basic principles and advantages of the technique, they conclude by stating that it constitutes an effective procedure for repair of ventral hernias of the median line without endoabdominal morbid associations.

[Retroperitoneal tumors in children: clinical diagnostic problems (author's transl)]. / Sui tumori retroperitoneali nell'infanzia.

Starting from two recent observations of retroperitoneal tumors in the pediatric age group (a nephroblastoma and a ganglioneuroma), the authors illustrate the main characteristics of these malignancies and emphasize the difficulties often encountered in differential diagnosis.