Breakthroughs in Alzheimer's Research: A Path to a More Promising Future?

Background: Alzheimer's disease (AD) is a widespread neurodegenerative disorder with a significant global impact, affecting approximately 50 million individuals, and projections estimate that up to 152 million people will be affected by 2050. AD is characterized by beta-amyloid plaques and tau tangles in the brain, leading to cognitive decline. Summary: Recent research on AD has made significant strides, including the development of an "amyloid clock" biomarker that tracks AD progression through positron emission tomography (PET) scans. Surf4 and other genes have been discovered to play a role in regulating beta-amyloid toxicity, while inhibiting the enzyme hexokinase-2 has shown positive results in preclinical studies. New brain mapping techniques have identified early brain-based causes of cognitive changes in AD, and biomarkers such as neuronal pentraxin protein Nptx2 and astrocytic 7-subunit of the nicotinic acetylcholine receptors (7nAChRs) show potential for early detection. Other approaches, such as replenishing the enzyme Tip60, selectively degrading the modified protein p-p38 with PRZ-18002, and targeting the protein voltage-dependent anion channel-1 (VDAC1), have shown promise in enhancing cognitive function and preventing pathophysiological alterations linked to AD. Baseline blood samples and other biomarkers such as urine formic acid, p-tau 198, microRNAs, and glial fibrillary acidic protein (GFAP) have also been discovered for early detection and intervention of AD. Additionally, recent FDA approvals for medications such as aducanumab and lecanemab provide options for reducing AD symptoms and improving function, while clinical trials for dementia vaccines show promise for the nasal and beta-amyloid 40 vaccines as well as vaccinations targeting tau. Key Messages: These advancements in AD research, including biomarker discovery and the development of disease-modifying treatments, are crucial steps towards improving the lives of those affected by AD and finding a cure for this debilitating disease.

Comment on "Inclisiran siRNA technology in the management of dyslipidemia: A narrative review of clinical trials".

The study "Inclisiran siRNA technology in the management of dyslipidemia: A narrative review of clinical trials" evaluates inclisiran's efficacy and safety in reducing LDL cholesterol levels across diverse patient populations. Twelve clinical trials were reviewed, demonstrating consistent LDL-C reduction, even in statin intolerance or resistance cases, with sustained efficacy observed over various durations, some extending up to four years. Inclisiran exhibited a favorable safety profile, suggesting its potential as a well-tolerated treatment option. Despite promising findings, the limitations include the short duration of some trials and the exclusion of non-English language studies, warranting further research. Future studies should focus on the long-term safety and efficacy in diverse patient populations and explore the broader clinical implications of inclisiran. Although inclisiran shows promise in dyslipidemia management, comprehensive research is needed to understand its full potential in cardiovascular medicine.

Ultrasound renal denervation: the future of hypertension management?

BACKGROUND: Hypertension, a leading cause of global mortality and morbidity, affects approximately 1.28 billion adults worldwide, with most cases occurring in low- and middle-income countries. Despite several methods for managing mild to moderate hypertension, effective management of severe or resistant hypertension remains challenging. Renal denervation, a promising non-pharmacological technique, has emerged as a potential solution. MAIN BODY: Renal denervation works by modifying the renal sympathetic nerve supply through techniques such as ultrasound, radiofrequency energy, or injection of neurolytic agents, reducing blood pressure. Clinical trials, including the RADIANCE series, have shown consistent effectiveness of ultrasound renal denervation in lowering blood pressure, especially in patients who were previously unresponsive to anti-hypertensive medications. After a follow-up of 2 months, mean ambulatory systolic blood pressure during the daytime decreased significantly in the ultrasound renal denervation group compared to the sham group. However, further research is needed to determine renal denervation's long-term safety and efficacy. CONCLUSIONS: In conclusion, renal denervation holds great potential in improving the treatment of uncontrolled or resistant hypertension treatment, but more investigations and trials are necessary to establish its effectiveness and safety.

A Rare Case of Severe Isolated Right Heart Failure with Secundum Type Atrial Septal Defect and Mitral Regurgitation Without Pulmonary Hypertension.

Typically, right heart failure (RHF) may occur following left heart failure (LHF) in chronic volume overload states such as chronic severe mitral regurgitation (MR) through chronically elevated pulmonary pressures. In Lutembacher syndrome (LS), the direct shunting through a secundum type atrial septal defect (ASD) results in congestive heart failure in the setting of severe mitral stenosis (MS) with or without elevated pulmonary arterial or venous pressures. We report a rare case of severe isolated RHF and bi-atrial enlargement resulting from the direct shunting through a secundum type ASD in the presence of a severe eccentric primary MR. There are no significant cases documented like this after a thorough search using PubMed, Medline, and Google Scholar. A review of the literature suggests that LS is also caused by a combination of mitral regurgitation and a secundum-type atrial septal defect without mitral stenosis, though rarely. Because this is a primary MR, we feel it is a case of LS with MR, ruling out a combination of secondary MR and secundum-type atrial septal defect.

Evaluation of potential bacterial protease inhibitor properties of selected hydroxyquinoline derivatives: an in silico docking and molecular dynamics simulation approach.

Antimicrobial drug resistance (AMR) is a severe global threat to public health. The increasing emergence of drug-resistant bacteria requires the discovery of novel antibacterial agents. Quinoline derivatives have previously been reported to exhibit antimalarial, antiviral, antitumor, antiulcer, antioxidant and, most interestingly, antibacterial properties. In this study, we evaluated the binding affinity of three newly designed hydroxyquinolines derived from sulfanilamide (1), 4-amino benzoic acid (2) and sulfanilic acid (3) towards five bacterial protein targets (PDB ID: 1JIJ, 3VOB, 1ZI0, 6F86, 4CJN). The three derivatives were designed considering the amino acid residues identified at the active site of each protein involved in the binding of each co-crystallized ligand and drug-likeness properties. The ligands displayed binding energy values with the target proteins ranging from -2.17 to -8.45 kcal/mol. Compounds (1) and (3) showed the best binding scores towards 1ZI0/3VOB and 1JIJ/4CJN, respectively, which may serve as new antibiotic scaffolds. Our in silico results suggest that sulfanilamide (1) or sulfanilic acid (3) hydroxyquinoline derivatives have the potential to be developed as bacterial inhibitors, particularly MRSA inhibitors. But before that, it must go through the proper preclinical and clinical trials for further scientific validation. Further experimental studies are warranted to explore the antibacterial potential of these compounds through preclinical and clinical studies.Communicated by Ramaswamy H. Sarma.

Oral Erythromycin Improves the Quality of Endoscopy in Upper Gastrointestinal Bleeding Patients.

Background Upper gastrointestinal bleeding is a life-threatening emergency. Endoscopy is the therapeutic and diagnostic procedure of choice after initial stabilization of the patient. But the presence of retained blood, blood products, and other residual material in the stomach is a big challenge for endoscopists during urgent endoscopy after acute upper gastrointestinal bleeding. Intravenous erythromycin before endoscopy improves the visualization of gastric and duodenal mucosa in these patients. Use of oral erythromycin is more easy and convenient, so the objective of our study was to assess the effects of oral erythromycin on quality of endoscopy in upper gastrointestinal bleeding patients. Methods This interventional study was conducted at the Department of Medicine, POF Hospital Wah Cantt, Pakistan from January 2019 to December 2019. Patients with clinical evidence of acute upper gastrointestinal bleeding within 12 hours were inducted consecutively. Patients were randomly assigned to erythromycin (500 mg) suspension or placebo, orally three hours before endoscopy. One endoscopist performed all the procedures with the same double-channel video endoscope. The primary endpoint was endoscopic quality. The secondary endpoints were the need for second-look endoscopy within 48 hours, endoscopy related complications, therapeutic procedure performed or not during endoscopy, number of blood transfusions, and length of hospital stay. Results A total of 60 patients were included in the study; 30 received erythromycin and 30 received placebo. Out of these, 60% were male and 40% were female. The mean age was 53.68 ± 16.64. Quality of endoscopy was much better in the erythromycin group (83.3%) as compared to placebo (40%). Erythromycin did not shorten the endoscopic duration (15.53 vs. 14.33 minutes in the placebo group; p=0.216) and length of hospital stay (5.23 in erythromycin vs. 5.40 days in placebo group; p=0.807). Statistically no significant association was found between use of erythromycin and establishment of cause of bleed, need for second-look endoscopy, number of blood transfusions and number of endoscopic therapeutic procedures. Conclusion Erythromycin oral suspension before endoscopy in patients with acute upper gastrointestinal bleeding produced good quality of endoscopy in our study. It improved the visualization of gastric and duodenal mucosa significantly. However, it did not shorten the duration of endoscopy or hospital stay. There was no significant difference in number of second-look endoscopies and blood transfusions as well.