Pseudomonas aeruginosa Endocarditis With a Large Mitral Valve Vegetation Causing Severe Mitral Valve Regurgitation and Cardiogenic Shock.

Infective endocarditis (IE) is characterized by the inflammation of the inner layer of the heart that can be caused by different pathogens. Pseudomonas aeruginosa is an uncommon source of IE. The clinical presentation is highly dependent on the patient's medical history, societal factors, and valve involvement. This infection is associated with many unfavorable complications and high mortality rates. We present a case of P. aeruginosa endocarditis causing severe mitral valve regurgitation, leading to cardiogenic shock and an eventual replacement of the mitral valve. Prompt and sensitive antibiotics in combination with surgical consultation are vital to the survival of this condition.

Exploring the Esterase Catalytic Activity of Minimalist Heptapeptide Amyloid Fibers.

This paper investigates the esterase activity of minimalist amyloid fibers composed of short seven-residue peptides, IHIHIHI (IH7) and IHIHIQI (IH7Q), with a particular focus on the role of the sixth residue position within the peptide sequence. Through computational simulations and analyses, we explore the molecular mechanisms underlying catalysis in these amyloid-based enzymes. Contrary to initial hypotheses, our study reveals that the twist angle of the fiber, and thus the catalytic site's environment, is not notably affected by the sixth residue. Instead, the sixth residue interacts with the p-nitrophenylacetate (pNPA) substrate, particularly through its -NO2 group, potentially enhancing catalysis. Quantum mechanics/molecular mechanics (QM/MM) simulations of the reaction mechanism suggest that the polarizing effect of glutamine enhances catalytic activity by forming a stabilizing network of hydrogen bonds with pNPA, leading to lower energy barriers and a more exergonic reaction. Our findings provide valuable insights into the intricate interplay between peptide sequence, structural arrangement, and catalytic function in amyloid-based enzymes, offering potentially valuable information for the design and optimization of biomimetic catalysts.

Computational modelling of supramolecular metallopeptide assemblies.

Among the important questions in supramolecular peptide self-assemblies are their interactions with metallic compounds and ions. In the last decade, intensive efforts have been devoted to understanding the structural properties of these interactions including their dynamical and catalytic impact in natural and de novo systems. Since structural insights from experimental approaches could be particularly challenging, computational chemistry methods are interesting complementary tools. Here, we present the general multiscale strategies we developed and applied for the study of metallopeptide assemblies. These strategies include prediction of metal binding site, docking of metallic moieties, classical and accelerated molecular dynamics and finally QM/MM calculations. The systems of choice for this chapter are, on one side, peptides involved in neurodegenerative diseases and, on the other, de novo fibrillar systems with catalytic properties. Both successes and remaining challenges are highlighted so that the protocol could be apply to other system of this kind.

Genome resources for three modern cotton lines guide future breeding efforts.

Cotton (Gossypium hirsutum L.) is the key renewable fibre crop worldwide, yet its yield and fibre quality show high variability due to genotype-specific traits and complex interactions among cultivars, management practices and environmental factors. Modern breeding practices may limit future yield gains due to a narrow founding gene pool. Precision breeding and biotechnological approaches offer potential solutions, contingent on accurate cultivar-specific data. Here we address this need by generating high-quality reference genomes for three modern cotton cultivars ('UGA230', 'UA48' and 'CSX8308') and updating the 'TM-1' cotton genetic standard reference. Despite hypothesized genetic uniformity, considerable sequence and structural variation was observed among the four genomes, which overlap with ancient and ongoing genomic introgressions from 'Pima' cotton, gene regulatory mechanisms and phenotypic trait divergence. Differentially expressed genes across fibre development correlate with fibre production, potentially contributing to the distinctive fibre quality traits observed in modern cotton cultivars. These genomes and comparative analyses provide a valuable foundation for future genetic endeavours to enhance global cotton yield and sustainability.

Light-Chain (AL) Cardiac Amyloidosis Presenting as Heart Failure With Reduced Ejection Fraction.

Systemic amyloidosis is caused by the extracellular deposition of misfolded proteins in various organs and usually leads to organ dysfunction. The two common subtypes include light-chain amyloidosis and transthyretin amyloidosis. Deposition of these proteins in the heart can lead to infiltrative and restrictive cardiomyopathy, commonly manifesting as heart failure with preserved ejection fraction. However, systolic heart failure with reduced ejection fraction is mainly seen in the advanced stages of the disease. Here, we present the case of a 53-year-old female who presented with new-onset heart failure with reduced ejection fraction with no prior symptoms or diagnosis of amyloidosis and diastolic dysfunction.

A Rare Case of a 54-year-old Male with Vocal Cord Paralysis Secondary to Left Atrial Enlargement.

Ortner's syndrome, a rare condition characterized by hoarseness due to left recurrent laryngeal nerve palsy caused by cardiovascular structural compression, is typically associated with an enlarged left atrium secondary to conditions like mitral stenosis. However, recent studies propose additional causes, including compression between the dilated pulmonary artery and the aorta. We present a case of a 54-year-old male with Ortner's syndrome secondary to severe mitral regurgitation and pulmonary hypertension. Our patient presented with a one-month history of progressive dyspnea and hoarseness. Diagnostic imaging revealed cardiac enlargement, left vocal cord paralysis, and severe mitral valve pathology. A transesophageal echocardiogram revealed mitral valve prolapse and severe flail motion of the anterior leaflet. Further assessments through catheterizations confirmed severely elevated right ventricular systolic pressures and pulmonary hypertension. Attempts at mitral valve replacement were hindered by persistently elevated pulmonary pressures, necessitating transfer for specialized care. Our case highlights the broad differentials for hoarseness, emphasizing rare cardiovascular origins such as Ortner's syndrome, involving compression of the left recurrent laryngeal nerve. Early identification is essential, often necessitating comprehensive head and neck examination and radiological studies. While management depends on nerve injury duration, a timely intervention targeting the underlying cardiovascular pathology, including appropriate medical therapy and surgical approaches, can potentially alleviate or reverse nerve damage. Furthermore, our case underscores the significance of initiating guideline-directed medical therapy early in chronic cardiovascular conditions to mitigate cardiac remodeling and prevent complications like left recurrent laryngeal nerve palsy. Timely identification and targeted management of underlying cardiovascular etiologies are crucial in preventing Ortner's syndrome.

Benign Pneumoperitoneum Following Mitral Valve Replacement.

The pneumoperitoneum refers to the presence of free air inside the abdominal cavity. This finding is usually a sequela of a gastrointestinal tract perforation. Still, in rare instances, it can present after cardiac surgery due to the proximity of the peritoneal cavity and pericardium, allowing air to enter the peritoneal cavity. Our patient was a 63-year-old female who initially presented for revision of the mitral valve replacement. A chest X-ray on postoperative day 13 revealed a 6.6 cm lucency under the right diaphragm suggestive of pneumoperitoneum. She was discharged after serial chest X-rays revealed a decrease in the size of the pneumoperitoneum. Twelve days later, our patient was readmitted, as another chest X-ray revealed that the size of the pneumoperitoneum was again increasing. An endoscopy was performed, but it did not reveal any lesions or etiology that would lead to a leak from the gastrointestinal tract. Finally, due to the benign nature of the pneumoperitoneum and the decrease in its size over the following days, we opted for conservative management, and she was discharged again. This case emphasizes the rare occurrence of benign pneumoperitoneum post-mitral valve surgery. While surgery may not always be required for asymptomatic cases, careful vigilance post-cardiac surgery remains crucial to detect potential abdominal complications promptly.

Proceed with Caution: Social Acceptability of Forestry Practices in Puerto Rico among Members of Local Environmental Organizations, Academia and Professional Associations.

Social acceptability of forestry practices plays a key role in defining sustainable forestry policies and strategies. In this study an online survey was distributed among members of environmental, non-governmental, professional, and academic organizations to assess the acceptability of forestry practices in Puerto Rico among members of civic society interested in environmental management issues. Participants were asked about their perception of forest uses, their preference of tree harvesting technologies, methods that may apply in small scale wood production settings, and trust in organizations providing forest information. We also inquired about attitudes towards economic activity in forests and the impact of such activity on recreation and biodiversity. The results show that even though participants do not place a high priority on economic development through forestry activities, acceptance of forest management for wood harvesting will be possible by considering adherence to particular forestry technologies and methods to safeguard current recreation activities and biodiversity conservation. Social acceptability information would be worthwhile when seeking consensus among a broader group of local stakeholders. As a next step we suggest the creation of a council constituted by diverse forestry sector stakeholders that would engage in a strategic planning exercise to delineate a clear road map that can guide short and long-term sustainable forest management, including wood industry development.

Antisense oligonucleotides restore excitability, GABA signalling and sodium current density in a Dravet syndrome model.

Dravet syndrome is an intractable developmental and epileptic encephalopathy caused by de novo variants in SCN1A resulting in haploinsufficiency of the voltage-gated sodium channel Nav1.1. We showed previously that administration of the antisense oligonucleotide STK-001, also called ASO-22, generated using targeted augmentation of nuclear gene output technology to prevent inclusion of the nonsense-mediated decay, or poison, exon 20N in human SCN1A, increased productive Scn1a transcript and Nav1.1 expression and reduced the incidence of electrographic seizures and sudden unexpected death in epilepsy in a mouse model of Dravet syndrome. Here, we investigated the mechanism of action of ASO-84, a surrogate for ASO-22 that also targets splicing of SCN1A exon 20N, in Scn1a+/- Dravet syndrome mouse brain. Scn1a +/- Dravet syndrome and wild-type mice received a single intracerebroventricular injection of antisense oligonucleotide or vehicle at postnatal Day 2. We examined the electrophysiological properties of cortical pyramidal neurons and parvalbumin-positive fast-spiking interneurons in brain slices at postnatal Days 21-25 and measured sodium currents in parvalbumin-positive interneurons acutely dissociated from postnatal Day 21-25 brain slices. We show that, in untreated Dravet syndrome mice, intrinsic cortical pyramidal neuron excitability was unchanged while cortical parvalbumin-positive interneurons showed biphasic excitability with initial hyperexcitability followed by hypoexcitability and depolarization block. Dravet syndrome parvalbumin-positive interneuron sodium current density was decreased compared to wild-type. GABAergic signalling to cortical pyramidal neurons was reduced in Dravet syndrome mice, suggesting decreased GABA release from interneurons. ASO-84 treatment restored action potential firing, sodium current density and GABAergic signalling in Dravet syndrome parvalbumin-positive interneurons. Our work suggests that interneuron excitability is selectively affected by ASO-84. This new work provides critical insights into the mechanism of action of this antisense oligonucleotide and supports the potential of antisense oligonucleotide-mediated upregulation of Nav1.1 as a successful strategy to treat Dravet syndrome.

Acute Pancreatitis-Induced Thrombosis of Celiac Artery: An Unusual Complication of Acute Pancreatitis.

Acute pancreatitis can lead to both local and systemic complications, including pseudocysts, biliary obstruction, duodenal obstruction, sepsis, necrosis, vascular complications, and multiorgan failure. Vascular complications following acute pancreatitis are associated with a high risk of morbidity and mortality due to their thrombotic and hemorrhagic effects. When thrombosis is present, it usually involves the splanchnic venous system, but it is rarely seen in the arterial system. Celiac artery thrombosis is rare with only a few cases reported in the literature. In this case, we present a 65-year-old Hispanic female who presented to the emergency department with abdominal pain and nausea, with computed tomography angiography (CTA) of the abdomen revealing acute pancreatitis with thrombosis of the celiac artery, which was managed with anticoagulation.

Astrocytes: Role in pathogenesis and effect of commonly misused drugs in the HIV infected brain.

The roles of astrocytes as reservoirs and producers of a subset of viral proteins in the HIV infected brain have been studied extensively as a key to understanding HIV-associated neurocognitive disorders (HAND). However, their comprehensive role in the context of intersecting substance use and neurocircuitry of the reward pathway and HAND has yet to be fully explained. Use of methamphetamines, cocaine, or opioids in the context of HIV infection have been shown to lead to a faster progression of HAND. Glutamatergic, dopaminergic, and GABAergic systems are implicated in the development of HAND-induced cognitive impairments. A thorough review of scientific literature exploring the variety of mechanisms in which these drugs exert their effects on the HIV brain and astrocytes has revealed marked areas of convergence in overexcitation leading to increased drug-seeking behavior, inflammation, apoptosis, and irreversible neurotoxicity. The present review investigates astrocytes, the neural pathways, and mechanisms of drug disruption that ultimately play a larger holistic role in terms of HIV progression and drug use. There are opportunities for future research, therapeutic intervention, and preventive strategies to diminish HAND in the subset population of patients with HIV and substance use disorder.

Acute Fulminant Cerebral Edema Caused by Influenza Type B in an 18-Year-Old Female: A Rare Case.

Most influenza B infections are self-limited, but in some instances, they can cause substantial morbidity and mortality due to complications. Acute fulminant cerebral edema (AFCE) is one of the rare complications. AFCE, a consequence of acute encephalitis, presents as acute onset of alteration in mental status, seizure, and/or headache followed by rapidly progressive encephalopathy, often leading to death. The exact pathophysiology of AFCE is unknown, but many pathomechanisms have been proposed. We present a case of an 18-year-old female in excellent physical condition who presented with respiratory insufficiency after being recently diagnosed with influenza B infection. Three days later, she developed acute encephalopathy, leading to brain death. To our knowledge, this rare case of AFCE developing following influenza B infection is the first reported case outside the pediatric population.

Ileocecal Mesentery Arteriovenous Malformation as a Rare Cause of Ectopic Variceal Bleeding in a 58-Year-Old Male With Cirrhosis.

Ectopic varices can be defined as dilated portosystemic venous collaterals that are located at a site other than the esophagus or stomach. These varices can be seen in patients with underlying portal hypertension, but bleeding from them is quite rare. The bleeding usually occurs in patients with a history of intra-abdominal surgery and adhesions. These varices are commonly found in the duodenum or rectum, but they can be present anywhere along the gastrointestinal tract. Currently, there are no well-established guidelines regarding the diagnosis and management of these variceal bleeds, and further investigations with randomized controlled or large-scale trials are required. Here, we report an unusual case of ectopic variceal bleeding from an ileal arteriovenous malformation (AVM), which presented as syncope associated with an acute abdomen in a patient with no prior history of intra-abdominal surgery.

Fulminant Hepatic Failure With Minimal Alcohol Consumption in a 25-Year-Old Female With Hereditary Hemochromatosis: A Rare Case.

Hereditary hemochromatosis (HH) is an inherited disorder in which organ damage and other clinical manifestations are commonly seen in patients with a homozygous mutation involving C282Y of the HFE gene, causing increased iron absorption in the intestine. The liver is the primary site of iron deposition, and excessive iron overload can eventually lead to hepatic cirrhosis. Patients who drink significant amounts of alcohol are more likely to develop cirrhosis, and in females, it is commonly seen after menopause. We describe a young female with hereditary hemochromatosis who developed fulminant hepatic failure with minimal alcohol consumption at age 25.

Bixa orellana ethyl acetate fraction and its isolated compound ellagic acid attenuate the progression of MIA-induced osteoarthritis in rat knees.

Osteoarthritis (OA) is a pathology that is characterized by progressive erosion of articular cartilage. In this context, medicinal plants have become relevant tools regarding their potential role in the prevention and treatment of OA, being safe and effective. The aim of this work was investigate the therapeutic efficacy of the ethyl acetate fraction of Bixa orellana leaves (BoEA) and ellagic acid (ElAc) for the therapeutic treatment of OA induced by monosodium iodoacetate (MIA) in rats. The plant material was extracted via maceration with 70 % hydroalcoholic solvent (BoHE). The ethyl acetate (BoEA) fraction was by solvents in increasing order of polarity. The ElAc was identified and isolated in BoEA using high performance liquid chromatography (HPLC-DAD) and analytical curve. The OA was induced using MIA in the right knee at the knee joint. Doses of BoEA and ElAc were administered daily (every 24 h, orally) at concentrations of 50, 100 and 50 mg/kg, respectively, for 28 days after induced OA. We evaluated the animals through clinical and radiological examinations every 7 days and, on the 29th day, the animals were euthanized, the joints being removed for histopathological analysis and the serum for cytokine analysis. BoEA and ElAc compounds reduced inflammation and nociception in OA and were as effective as indomethacin in clinical parameters of joint discomfort and allodynia in rats, in addition to showing improvements in radiological and histopathological images, acting on the progress of cartilage deterioration, proving properties related to anti-inflammatory and analgesic processes, being important allies for new therapeutic interventions for the treatment of OA.

An Unusual Case of Nonbacterial Thrombotic Endocarditis Attributable to Malignancy.

Nonbacterial thrombotic endocarditis (NBTE), also known as marantic endocarditis, is a condition characterized by the deposition of thrombi and fibrin on normal or degenerated cardiac valves in the absence of microorganisms. We report a case of a 60-year-old male with nonbacterial thrombotic endocarditis found on transesophageal echocardiogram (TEE) after a normal TEE just one month prior. Our patient presented with abdominal pain associated with poor appetite and unintentional 20-pound weight loss for one month. Chest computed tomography revealed the presence of a mass-like opacification in the right lung middle lobe with moderate pericardial effusions. A biopsy of the mass confirmed malignancy consistent with lung primary adenocarcinoma. Subsequently, during hospitalization, the patient developed left lower extremity pain. Arterial ultrasound showed occlusion of the distal left popliteal artery for which he underwent thrombectomy of the left superficial femoral artery, balloon angioplasty of the left posterior tibial artery, and left popliteal artery. Repeat TEE during current hospitalization revealed a large 2 cm vegetation on the noncoronary cusp of the aortic valve. Studies for infective endocarditis were unremarkable. Subsequently, he was treated with aortic valve replacement and anticoagulation. After discharge, he returned with bilateral occipital infarcts four days later and expired.

Bilateral Acute Iris Transillumination Associated with Moxifloxacin Antibiotic Use.

PURPOSE: To describe the clinical and demographic characteristics and associated factors leading to bilateral acute iris transillumination (BAIT) syndrome. METHODS: A retrospective review of patients with BAIT syndrome was performed. RESULTS: Thirty-five patients with a diagnosis of BAIT were identified. The median age at presentation was 53 years; 80% of the patients were female. Twenty-six patients (74%) had recent histories of systemic antibiotic treatment. Of those with such a history, 24 patients (92%) had been receiving moxifloxacin. Two patients within our cohort were prescribed moxifloxacin prophylactically prior to a systemic surgical procedure and had no evidence of systemic illness or recent viral illness. CONCLUSIONS: Our data support the notion that moxifloxacin might be associated with the onset of BAIT syndrome. Notably, within our cohort, two patients received moxifloxacin as surgical prophylaxis and subsequently developed BAIT syndrome. This could suggest a potential association between moxifloxacin and the onset of BAIT, though further studies are needed to confirm this finding.

Epilepsy and sudden unexpected death in epilepsy in a mouse model of human SCN1B-linked developmental and epileptic encephalopathy.

Voltage-gated sodium channel ß1 subunits are essential proteins that regulate excitability. They modulate sodium and potassium currents, function as cell adhesion molecules and regulate gene transcription following regulated intramembrane proteolysis. Biallelic pathogenic variants in SCN1B, encoding ß1, are linked to developmental and epileptic encephalopathy 52, with clinical features overlapping Dravet syndrome. A recessive variant, SCN1B-c.265C>T, predicting SCN1B-p.R89C, was homozygous in two children of a non-consanguineous family. One child was diagnosed with Dravet syndrome, while the other had a milder phenotype. We identified an unrelated biallelic SCN1B-c.265C>T patient with a clinically more severe phenotype than Dravet syndrome. We used CRISPR/Cas9 to knock-in SCN1B-p.R89C to the mouse Scn1b locus (Scn1bR89/C89). We then rederived the line on the C57BL/6J background to allow comparisons between Scn1bR89/R89 and Scn1bC89/C89 littermates with Scn1b+/+ and Scn1b-/- mice, which are congenic on C57BL/6J, to determine whether the SCN1B-c.265C>T variant results in loss-of-function. Scn1bC89/C89 mice have normal body weights and ∼20% premature mortality, compared with severely reduced body weight and 100% mortality in Scn1b-/- mice. ß1-p.R89C polypeptides are expressed in brain at comparable levels to wild type. In heterologous cells, ß1-p.R89C localizes to the plasma membrane and undergoes regulated intramembrane proteolysis similar to wild type. Heterologous expression of ß1-p.R89C results in sodium channel α subunit subtype specific effects on sodium current. mRNA abundance of Scn2a, Scn3a, Scn5a and Scn1b was increased in Scn1bC89/C89 somatosensory cortex, with no changes in Scn1a. In contrast, Scn1b-/- mouse somatosensory cortex is haploinsufficient for Scn1a, suggesting an additive mechanism for the severity of the null model via disrupted regulation of another Dravet syndrome gene. Scn1bC89/C89 mice are more susceptible to hyperthermia-induced seizures at post-natal Day 15 compared with Scn1bR89/R89 littermates. EEG recordings detected epileptic discharges in young adult Scn1bC89/C89 mice that coincided with convulsive seizures and myoclonic jerks. We compared seizure frequency and duration in a subset of adult Scn1bC89/C89 mice that had been exposed to hyperthermia at post-natal Day 15 versus a subset that were not hyperthermia exposed. No differences in spontaneous seizures were detected between groups. For both groups, the spontaneous seizure pattern was diurnal, occurring with higher frequency during the dark cycle. This work suggests that the SCN1B-c.265C>T variant does not result in complete loss-of-function. Scn1bC89/C89 mice more accurately model SCN1B-linked variants with incomplete loss-of-function compared with Scn1b-/- mice, which model complete loss-of-function, and thus add to our understanding of disease mechanisms as well as our ability to develop new therapeutic strategies.