Novel Indane-Containing NBTIs with Potent Anti-Gram-Negative Activity and Minimal hERG Inhibition.

Novel bacterial topoisomerase inhibitors (NBTIs) make up a promising new class of antibiotics with the potential to combat the growing threat of antimicrobial resistance. Two key challenges in the development of NBTIs have been to obtain broad spectrum activity against multidrug-resistant Gram-negative bacteria and to diminish inhibition of the hERG cardiac ion channel. Here we report the optimization of a series of NBTIs bearing a novel indane DNA intercalating moiety.

Ouabain Reverts CUS-Induced Disruption of the HPA Axis and Avoids Long-Term Spatial Memory Deficits.

Ouabain (OUA) is a cardiotonic steroid that modulates Na+, K+ -ATPase activity. OUA has been identified as an endogenous substance that is present in human plasma, and it has been shown to be associated with the response to acute stress in both animals and humans. Chronic stress is a major aggravating factor in psychiatric disorders, including depression and anxiety.

Consequences of the Lack of TNFR1 in Ouabain Response in the Hippocampus of C57BL/6J Mice.

Ouabain is a cardiac glycoside that has a protective effect against neuroinflammation at low doses through Na/K-ATPase signaling and that can activate tumor necrosis factor (TNF) in the brain. TNF plays an essential role in neuroinflammation and regulates glutamate receptors by acting on two different receptors (tumor necrosis factor receptor 1 [TNFR1] and TNFR2) that have distinct functions and expression. The activation of constitutively and ubiquitously expressed TNFR1 leads to the expression of pro-inflammatory cytokines.

Tackling recalcitrant Pseudomonas aeruginosa infections in critical illness via anti-virulence monotherapy.

Intestinal barrier derangement allows intestinal bacteria and their products to translocate to the systemic circulation. Pseudomonas aeruginosa (PA) superimposed infection in critically ill patients increases gut permeability and leads to gut-driven sepsis. PA infections are challenging due to multi-drug resistance (MDR), biofilms, and/or antibiotic tolerance.

Proteomic analysis reveals rattlesnake venom modulation of proteins associated with cardiac tissue damage in mouse hearts.

Snake envenomation is a common but neglected disease that affects millions of people around the world annually. Among venomous snake species in Brazil, the tropical rattlesnake (Crotalus durissus terrificus) accounts for the highest number of fatal envenomations and is responsible for the second highest number of bites. Snake venoms are complex secretions which, upon injection, trigger diverse physiological effects that can cause significant injury or death.

Influence of Nitric Oxide-Cyclic GMP and Oxidative STRESS on Amyloid-β Peptide Induced Decrease of Na,K-ATPase Activity in Rat Hippocampal Slices.

Amyloid-β peptide (Aβ) has been shown to cause synaptic dysfunction and can render neurons vulnerable to excitotoxicity and oxidative stress. Na,K-ATPase plays an important role to maintain cell ionic equilibrium and it can be modulated by N-methyl-D-aspartate (NMDA)-nitric oxide (NO)-cyclic GMP pathway. Disruption of NO synthase (NOS) activity and reactive oxygen species (ROS) production could lead to changes in Na,K-ATPase isoforms' activities that may be detrimental to the cells.

Post-Operative All-Cause Mortality in Elderly Patients Undergoing Abdominal Emergency Surgery: Role of Charlson Comorbidity Index.

(1) Background: The Charlson comorbidity index (CCI) score has been shown to predict 10-year all-cause mortality, but its validity is a matter of debate in surgical patients. We wanted to evaluate CCI on predicting all-cause mortality in elderly patients undergoing emergency abdominal surgery (EAS); (2) Methods: This retrospective single center study included all patients aged 65 years or older consecutively admitted from January 2017 to December 2019, who underwent EAS and were discharged alive. CCI was calculated by using of the International Classification of Diseases, 9th Revision, Clinical Modification codes.

Case report of gastrointestinal localization of SARS-CoV-2 and open abdomen technique in an Italian emergency surgery department for gastrointestinal bleeding.

This article aims to present the case of a man affected by SARS CoV-2 and to discuss the association between this manifestation, viral infection and Open Abodmen. A 52 years old Caucasian man, affected by SARS CoV-2 infection, was admitted to the Emergency department of Arcispedale Sant'Anna of Ferrara for epigastralgia followed by syncopal episode, vomiting and diarrhea with bloody stools. The next day the patient underwent colonoscopy, which detected an ulceration proximally to the ileocecal valve without active bleeding.

Inverse sex-based expression profiles of PTEN and Klotho in mice.

Sex differences are considered predictive factors in the development of several neurological diseases, which are also known to coincide with impaired phosphoinositide 3-kinase (PI3K)-AKT pathway activity, an essential signaling cascade involved in the control of several cellular functions such as autophagy and apoptosis. Here, under physiological conditions, we show important sex differences in the underlying balancing mechanisms that lead to similar AKT activity levels and autophagy and apoptosis processes in the two sexes. We demonstrate inverse sex-based expression of PTEN and Klotho, two important proteins that are known to negatively regulate the AKT pathway, and inverse sex-dependent levels of mTOR and FoxO3a activity.

Selective Inhibitors of G2019S-LRRK2 Kinase Activity.

Pathogenic variants in the leucine-rich repeat kinase 2 (LRRK2) gene have been identified that increase the risk for developing Parkinson's disease in a dominantly inherited fashion. These pathogenic variants, of which G2019S is the most common, cause abnormally high kinase activity, and compounds that inhibit this activity are being pursued as potentially disease-modifying therapeutics. Because LRRK2 regulates important cellular processes, developing inhibitors that can selectively target the pathogenic variant while sparing normal LRRK2 activity could offer potential advantages in heterozygous carriers.

Effects of Physical Exercise on Autophagy and Apoptosis in Aged Brain: Human and Animal Studies.

The aging process is characterized by a series of molecular and cellular changes over the years that could culminate in the deterioration of physiological parameters important to keeping an organism alive and healthy. Physical exercise, defined as planned, structured and repetitive physical activity, has been an important force to alter physiology and brain development during the process of human beings' evolution. Among several aspects of aging, the aim of this review is to discuss the balance between two vital cellular processes such as autophagy and apoptosis, based on the fact that physical exercise as a non-pharmacological strategy seems to rescue the imbalance between autophagy and apoptosis during aging.

The impact of rattlesnake venom on mice cerebellum proteomics points to synaptic inhibition and tissue damage.

Snake envenomation is responsible for more than 130,000 deaths worldwide. In Brazil, the Crotalus rattlesnake is responsible for the second largest number of accidental snake bites in the country. Although there are many descriptions of the clinical and biochemical effects of Crotalus envenoming, there are few works describing the molecular events in the central nervous system of an organism due to envenomation.

Delayed Rupture of a Normal Appearing Spleen After Trauma: Is Our Knowledge Enough? Two Case Reports.

BACKGROUND Non-operative management is considered the gold standard for hemodynamically stable patients with splenic injuries. Delayed splenic rupture is a well-known complication of non-operative management in splenic trauma, with a relevant impact on mortality and morbidity. Most of the reported cases of delayed splenic rupture presented splenic injury at admission imaging or no imaging investigations were performed.

Evaluation of hemodynamic impact of absorbable sutures in native arteriovenous fistulas: A retrospective study.

One of the major causes of arteriovenous fistula failure is the venous stenosis due to aggressive neointimal hyperplasia. The aim of the study was to assess the arteriovenous fistula maturation comparing absorbable sutures and non-absorbable ones in native vessels. Surgeries performed during a period of 24 months by a single team of expert surgeons were evaluated.

Structure-guided design of antibacterials that allosterically inhibit DNA gyrase.

A series of DNA gyrase inhibitors were designed based on the X-ray structure of a parent thiophene scaffold with the objective to improve biochemical and whole-cell antibacterial activity, while reducing cardiac ion channel activity. The binding mode and overall design hypothesis of one series was confirmed with a co-crystal structure with DNA gyrase. Although some analogs retained both biochemical activity and whole-cell antibacterial activity, we were unable to significantly improve the activity of the series and analogs retained activity against the cardiac ion channels, therefore we stopped optimization efforts.

Evaluation on prognostic efficacy of lymph nodes ratio (LNR) and log odds of positive lymph nodes (LODDS) in complicated colon cancer: the first study in emergency surgery.

Background: Lymph node involvement is one of the most important prognostic factors in colon cancer. Twelve is considered the minimum number of lymph nodes necessary to retain reliable tumour staging, but several factors can potentially influence the lymph node harvesting. Emergent surgery for complicated colon cancer (perforation, occlusion, bleeding) could represent an obstacle to reach the benchmark of 12 nodes with an accurate lymphadenectomy.

Ouabain increases neuronal branching in hippocampus and improves spatial memory.

Previous research shows Ouabain (OUA) to bind Na, K-ATPase, thereby triggering a number of signaling pathways, including the transcription factors NFᴋB and CREB. These transcription factors play a key role in the regulation of BDNF and WNT-β-catenin signaling cascades, which are involved in neuroprotection and memory regulation. This study investigated the effects of OUA (10 nM) in the modulation of the principal signaling pathways involved in morphological plasticity and memory formation in the hippocampus of adult rats.

Intermittent fasting uncovers and rescues cognitive phenotypes in PTEN neuronal haploinsufficient mice.

Phosphatase and tensin homolog (PTEN) is an important protein with key modulatory functions in cell growth and survival. PTEN is crucial during embryogenesis and plays a key role in the central nervous system (CNS), where it directly modulates neuronal development and synaptic plasticity. Loss of PTEN signaling function is associated with cognitive deficits and synaptic plasticity impairment.

Do I Need to Operate on That in the Middle of the Night? Development of a Nomogram for the Diagnosis of Severe Acute Cholecystitis.

Background: Some authors have proposed different predictive factors of severe acute cholecystitis, but generally, the results of risk analyses are expressed as odds ratios, which makes it difficult to apply in the clinical practice of the acute care surgeon. The severe form of acute cholecystitis should include both gangrenous and phlegmonous cholecystitis, due to their severe clinical course, and cholecystectomy should not be delayed. The aim of this study was to create a nomogram to obtain a graphical tool to compute the probability of having a severe acute cholecystitis.

A rare diaphragmatic hernia with a delayed presentation of intestinal symptoms following spleno-distal pancreatectomy: a case report.

Acquired diaphragmatic hernia, non-related to trauma, is a very rare condition. It can constitute a therapeutic problem and the surgical solution is not always immediately clear. We report the case of a 73-year-old woman with a history of spleno-distal pancreatectomy for a neuroendocrine tumour performed in 2009, who came back to Emergency Room 2 years later, complaining of abdominal pain.

Discovery of 5-substituent-N-arylbenzamide derivatives as potent, selective and orally bioavailable LRRK2 inhibitors.

Leucine-rich repeat kinase 2 (LRRK2) has been suggested as a potential therapeutic target for Parkinson's disease. Herein we report the discovery of 5-substituent-N-arylbenzamide derivatives as novel LRRK2 inhibitors. Extensive SAR study led to the discovery of compounds 8e, which demonstrated potent LRRK2 inhibition activity, high selectivity across the kinome, good brain exposure, and high oral bioavailability.

Delayed diagnosis of blunt carotid trauma in a seat belt syndrome with associated abdominal wall injury A case report.

Unlabelled: The aim of this case report is to be aware of occult carotid lesions in thoracic- abdominal trauma because, carotid artery injury consequent to blunt trauma is rare, affecting less than 1% of patients as reported in literature. A 45-years-old female, involved in a traffic accident, arrived to Emergency Room hemodynamically stable, with a Glasgow Coma Scale of 15, complaining abdominal pain, without any neurological signs. She underwent Computed Tomography (CT) scan that showed a complete disruption of left abdominal wall muscles, associated with massive bowel loops herniation.

Motor control exercises of the lumbar-pelvic region improve respiratory function in obese men. A pilot study.

Purpose: Obese subjects have decreased pulmonary function. The hypothesis of our study was that poor coordination of the lumbar-pelvic musculature secondary to obesity may hinder the synergic activation of the respiratory muscles. The aim of the paper was to evaluate whether specific motor control exercises of the lumbar-pelvic musculature were able to improve respiratory function.

Asymptomatic and early pseudoaneurysm of posterior superior pancreaticoduodenal artery and right gastric artery complicating acute pancreatitis: A case report.

Introduction: Arterial pseudoaneurysm is a rare and life-threatening complication of pancreatitis, seen more often in chronic than in acute pancreatitis. It involves mostly the splenic artery, while only in 10% of the case it appears in pancreaticoduodenal and gastric artery. This case report described an asymptomatic pseudoaneurysm of the posterior superior pancreaticoduodenal artery and of the right gastric artery, which occurred after 13days from the episode of acute pancreatitis and, then it was treated with vascular angioembolization.