The Ramus Intermedius: A Bridge to Survival in the Setting of Triple-Vessel Total Occlusion.

Coronary artery disease continues to remain the leading cause of mortality worldwide. Coronary blood supply is provided through the right and left main coronary arteries. The left main coronary artery (LMCA) in turn gives rise to the left anterior descending (LAD) and left circumflex (LCX) arteries. In some cases, LMCA may trifurcate into the ramus intermedius (RI) in addition to the LAD and LCX arteries. Atherosclerotic plaque formation and rupture with subsequent clot formation and occlusion of coronary arteries are the underlying mechanisms of myocardial infarction. Though the clinical implications of the presence of ramus intermedius (RI) are controversial some data suggest that the RI is associated with an increased risk of atherosclerotic plaque formation in the LMCA and the proximal LAD. Conversely, it has been proposed that the RI provides an additional collateral source of blood supply to the myocardium and may potentially contribute to improved survival. Case reports tout the benefits of RI, specifically in the setting of multivessel coronary artery occlusions. Whether it increases the risk of atherosclerotic plaque formation or whether it is protective has yet to be determined. We present a case of a 58-year-old male who presented with acute coronary syndrome and cardiogenic shock due to total ostial occlusion of LAD. The patient had also chronic total occlusions of the right coronary artery and LCX but a patent RI, which was the only source of blood supply to the myocardium and practically determined the patient's survival. Additionally, we performed a literature review to identify similar cases, to support RI's potentially protective role in enhancing survival.

Gastric Antral Vascular Ectasia: Resolution of Bleeding and Stabilization of Hematocrit Following Orthotopic Liver Transplantation.

Gastric Antral Vascular Ectasia (GAVE) is an uncommon cause of chronic gastrointestinal bleeding and iron deficiency anemia in the geriatric population. It is often associated with cirrhosis of the liver and is hypothesized to result from synthetic liver dysfunction. Treatment options include argon plasma coagulation, endoscopic band ligation, and radiofrequency ablation. An orthotopic liver transplant may be effective for patients with advanced liver disease. In this case report, we describe a 60-year-old woman with a history of cirrhosis secondary to nonalcohol-related steatohepatitis (NASH) and GAVE syndrome who presented with abdominal pain and melena. She had multiple prior episodes of gastrointestinal bleeding, leading to long-term transfusion dependency. An urgent esophagogastroduodenoscopy revealed the presence of GAVE with active bleeding. The patient was supported with blood transfusions and transferred to a transplant center, where she underwent orthotopic liver transplantation. Following the transplantation, her hemoglobin levels improved and remained stable. She was no longer noted to require any further blood transfusions during outpatient follow-up visits. This case report substantiates the role of synthetic liver dysfunction in the development of GAVE. Also, it suggests that patients with advanced cirrhosis and refractory GAVE may benefit from liver transplantation as a potential treatment option.

Relationship of pain relief with catastrophizing following interventional pain procedures for low back pain.

INTRODUCTION: Catastrophizing is associated with worse pain outcomes after various procedures suggesting its utility in predicting response. However, the stability of pain catastrophizing as a static predictor has been challenged. We assess, among patients undergoing steroid injections for chronic low back pain (cLBP), whether catastrophizing changes with the clinical response to pain interventions. METHODS: This prospective study enrolled patients undergoing fluoroscopic-guided injections for cLBP. Patients filled out Brief Pain Inventory (BPI) and Pain Catastrophizing Scale (PCS) at baseline and 1-month follow-up. We assessed the change in PCS scores from pre-injection to post-injection and examined its predictors. We also examined the correlation of various domains of BPI, such as pain severity and effect on Relationships, Enjoyment, and Mood (REM), with PCS scores at baseline and follow-up. RESULTS: 128 patients were enrolled. Mean (SD) PCS and pain severity scores at baseline were 22.38 (±13.58) and 5.56 (±1.82), respectively. Follow-up PCS and pain severity scores were 19.76 (±15.25) and 4.42 (±2.38), respectively. The change in PCS pre-injection to post-injection was not significant (p=0.12). Multiple regression models revealed baseline PCS and REM domain of BPI as the most important predictors of change in PCS after injection. Pain severity, activity-related pain, age, sex, insurance status, depression, prior surgery, opioid use, or prior interventions did not predict change in PCS score. In correlation analysis, change in PCS was moderately correlated with change in pain (r=0.38), but weakly correlated with baseline pain in all pain domains. CONCLUSIONS: PCS showed non-significant improvement following steroid injections; the study was not powered for this outcome. Follow-up PCS scores were predicted by the REM domain of BPI, rather than pain severity. Larger studies are needed to evaluate a statistically significant and clinically meaningful change in catastrophizing scores following pain interventions.

A Survey Study of Surgeons and Anesthesiologists Regarding Perioperative Multimodal Analgesia for Opioid-Tolerant Patients.

PURPOSE: Perioperative pain management of opioid-tolerant patients can be challenging. Although regional anesthesia and multimodal analgesics may be beneficial, these modalities are often underused. It is unclear whether practice patterns for perioperative pain management are determined by the knowledge, attitudes, and beliefs of surgeons and anesthesiologists. DESIGN: Descriptive survey. METHODS: Using a Qualtrics survey, we polled a randomly selected group of 25 surgeons and 25 anesthesiologists regarding their knowledge, attitudes, beliefs, and practices for pain management in an opioid-tolerant patient. FINDINGS: Of 25, 23 anesthesiologists and 18/25 surgeons responded to the survey. Demographics were similar between the 2 groups. Most of the participant surgeons and anesthesiologists believed that pain management may be challenging in an opioid-tolerant patient. However, only 56% of surgeons would recommend a preoperative pain consultation. Most surgeons and anesthesiologists believed in the efficacy of regional anesthetics. However, 43% of surgeons would not advocate for a regional block, perhaps due to their perception of the added perioperative time. Multimodal analgesics were widely accepted by both surgeons and anesthesiologists. CONCLUSIONS: There is an urgent need to reinforce the importance of patient-centered care, with a specific focus on addressing knowledge gaps and improving perceptions for all the members of the team, including surgeons, anesthesiologists, and perioperative nursing teams, if optimal outcomes are to be achieved for our patients.

Analysis of the interplay between MeCP2 and histone H1 during in vitro differentiation of human ReNCell neural progenitor cells.

An immortalized neural cell line derived from the human ventral mesencephalon, called ReNCell, and its MeCP2 knock out were used. With it, we characterized the chromatin compositional transitions undergone during differentiation, with special emphasis on linker histones. While the WT cells displayed the development of dendrites and axons the KO cells did not, despite undergoing differentiation as monitored by NeuN. ReNCell expressed minimal amounts of histone H1.0 and their linker histone complement consisted mainly of histone H1.2, H1.4 and H1.5. The overall level of histone H1 exhibited a trend to increase during the differentiation of MeCP2 KO cells. The phosphorylation levels of histone H1 proteins decreased dramatically during ReNCell's cell differentiation independently of the presence of MeCP2. Immunofluorescence analysis showed that MeCP2 exhibits an extensive co-localization with linker histones. Interestingly, the average size of the nucleus decreased during differentiation but in the MeCP2 KO cells, the smaller size of the nuclei at the start of differentiation increased by almost 40% after differentiation by 8 days (8 DIV). In summary, our data provide a compelling perspective on the dynamic changes of H1 histones during neural differentiation, coupled with the intricate interplay between H1 variants and MeCP2.Abbreviations: ACN, acetonitrile; A230, absorbance at 230 nm; bFGF, basic fibroblast growth factor; CM, chicken erythrocyte histone marker; CNS, central nervous system; CRISPR, clustered regulated interspaced short palindromic repeatsDAPI, 4,'6-diaminidino-2-phenylindole; DIV, days in vitro (days after differentiation is induced); DMEM, Dulbecco's modified Eagle medium; EGF, epidermal growth factor; ESC, embryonic stem cell; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GFAP, glial fibrillary acidic proteinHPLC, high-performance liquid chromatography; IF, immunofluorescence; iPSCs, induced pluripotent stem cells; MAP2, microtubule-associated protein 2; MBD, methyl-binding domain; MeCP2, methyl-CpG binding protein 2; MS, mass spectrometry; NCP, nucleosome core particle; NeuN, neuron nuclear antigen; NPC, neural progenitor cellPAGE, polyacrylamide gel electrophoresis; PBS, phosphate buffered saline; PFA, paraformaldehyde; PTM, posttranslational modification; RP-HPLC, reversed phase HPLC; ReNCells, ReNCells VM; RPLP0, ribosomal protein lateral stalk subunit P0; RT-qPCR, reverse transcription quantitative polymerase-chain reaction; RTT, Rett Syndrome; SDS, sodium dodecyl sulphate; TAD, topologically associating domain; Triple KO, triple knockout.

A Call To Action: Cholangiocarcinoma in the Setting of Sustained Hepatitis C Virologic Response - Case Report and Review of Literature.

The incidence of cholangiocarcinoma, an aggressive malignancy with poor prognosis, is increasing. Hepatitis B and C have been well established as predisposing factors for this malignancy. The availability and efficacy of treatment for hepatitis C infection has led to a substantial reduction in viral hepatitis-related cholangiocarcinoma mortality. Despite treatment, the potential for developing cholangiocarcinoma continues to exist for patients with underlying cirrhosis. We present a patient who was effectively treated for hepatitis C with direct-acting antiviral therapy eight years prior. He presented with malaise, fatigue, and an unintentional weight loss of 40 pounds. Imaging revealed a metastatic malignancy, and a liver biopsy confirmed the diagnosis of cholangiocarcinoma and the absence of underlying cirrhosis in the background liver. This case highlights the persistent risk of developing cholangiocarcinoma despite achieving sustained virological response to treatment for hepatitis C. We review the associated literature and briefly discuss the predisposing conditions that might result in such an outcome. We also encourage the need for long-term surveillance for such patients and the importance of conducting more multi-center studies to identify at-risk patients and develop cost-effective screening protocols.

Gastrointestinal Bleeding as Initial Manifestation of Injection Drug Use-Associated Amyloidosis.

Systemic amyloidosis has been reported in the context of injection drug use, usually related to ongoing chronic inflammation and persistent cutaneous infections. The kidneys are almost always the first organs affected in that setting. Involvement of the gastrointestinal tract is less common and rarely the initial site of presentation. We present a case of systemic amyloidosis that primarily manifested in the gastrointestinal tract, occurring in the setting of chronic injection drug use. The patient's hemoglobin level dropped progressively over time due to ongoing, slow gastrointestinal bleeding, prompting an endoscopic examination that ultimately confirmed the presence of gastrointestinal amyloidosis. As the overall prognosis for gastrointestinal amyloidosis is poor, early diagnosis and treatment are essential to decelerate the progression of the disease.

Late-Onset Hemorrhagic Pericardial Effusion and Cardiac Tamponade Associated With Immune Checkpoint Inhibitors: Case Report and Literature Review.

Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that target T lymphocytes and stimulate the immune system. However, the use of ICIs is associated with immune-related adverse events (irAEs). Pericardial disease is a cardiovascular irAEs that can present as cardiac tamponade. The precise mechanisms underlying pericardial complications are not fully understood. Late-onset hemorrhagic pericardial effusion associated with ICIs is quite rare; the mechanism and predisposing factors are yet to be determined. This case report describes a patient with diffuse large B-cell lymphoma (DLBCL) who received pembrolizumab for 390 days and subsequently developed cardiac tamponade caused by hemorrhagic pericardial effusion. The purpose of this report is to raise awareness about the occurrence of late-onset cardiac tamponade and provide a summary of available data on patients who experienced hemorrhagic pericardial effusion during ICI treatment.

Early Repolarization Augmentation Mimicking Pseudo-Infarction in a Patient With Diabetic Ketoacidosis and Normokalemia.

Early repolarization (ER) changes, characterized by J point elevation with or without ST-segment elevation, are dynamic in their presentation and can be exacerbated by factors such as hypothermia, hypercalcemia, vagotonia, and certain medications. There is limited research regarding the mechanism of these changes and the dynamic changes of ER secondary to diabetic ketoacidosis (DKA). This case report highlights the augmentation of early repolarization changes resembling ST-segment elevation myocardial infarction (STEMI) in a patient with DKA that resolved with the treatment of acidosis. The misinterpretation of ER changes on electrocardiogram (ECG) as STEMI or pericarditis may result in the inappropriate utilization of resources, increased patient risk, and elevated morbidity and mortality. Recognition of the potential of DKA to cause ER changes can potentially avoid these unfavorable outcomes.

Peripheral Nerve Stimulation for Pain Management: A Review.

PURPOSE OF REVIEW: Peripheral nerve stimulation has seen a recent upsurge in utilization for various chronic pain conditions, specifically from a neuropathic etiology, where a single peripheral nerve can be pinpointed as a culprit for pain. RECENT FINDINGS: There is conflicting evidence about the efficacy and long-term outcomes of peripheral nerve stimulation for chronic pain, with most studies being small sized. The focus of this article is to review available evidence for the utilization of peripheral nerve stimulation for chronic pain syndromes as well as upcoming evidence in the immediate postoperative realm. The indications for the use of PNS have expanded from neuropathic pain such as occipital neuralgia and post-amputation pain, to more widespread disease processes such as chronic low back pain. Percutaneous PNS delivered over a 60-day period may provide significant carry-over effects including pain relief, potentially avoiding the need for a permanently implanted system while enabling improved function in patients with chronic pain.

Pain Management in the Elderly: A Narrative Review.

With the increase in life expectancy in the United States, octogenarians and nonagenarians are more frequently seen in clinical practice. The elderly patients have multiple preexisting comorbidities and are on multiple medications, which can make pain management complex. Moreover, the elderly population often suffers from chronic pain related to degenerative processes, making medical management challenging. In this review, the authors collated available evidence for best practices for pain management in the elderly.

MHCII+CD80+ thymic eosinophils increase in abundance during neonatal development in mice and their accumulation is microbiota dependent.

Eosinophils are present in the thymus of mammals, yet their function at this site during homeostatic development is unknown. We used flow cytometry to determine the abundance and phenotype of eosinophils (here defined as SSchigh SiglecF+ CD11b+ CD45+ cells) in the thymus of mice during the neonatal period, the later postnatal period, and into adulthood. We show that both the total number of thymic eosinophils and their frequency among leukocytes increase over the first 2 wk of life and that their accumulation in the thymus is dependent on the presence of an intact bacterial microbiota. We report that thymic eosinophils express the interleukin-5 receptor (CD125), CD80, and IDO, and that subsets of thymic eosinophils express CD11c and major histocompatibility complex II (MHCII). We found that the frequency of MHCII-expressing thymic eosinophils increases over the first 2 wk of life, and that during this early-life period the highest frequency of MHCII-expressing thymic eosinophils is located in the inner medullary region. These data suggest a temporal and microbiota-dependent regulation of eosinophil abundance and functional capabilities in the thymus.

Ketamine Effects on Energy Metabolism, Functional Connectivity and Working Memory in Healthy Humans.

Working memory (WM) is a crucial resource for temporary memory storage and the guiding of ongoing behavior. N-methyl-D-aspartate glutamate receptors (NMDARs) are thought to support the neural underpinnings of WM. Ketamine is an NMDAR antagonist that has cognitive and behavioral effects at subanesthetic doses. To shed light on subanesthetic ketamine effects on brain function, we employed a multimodal imaging design, combining gas-free calibrated functional magnetic resonance imaging (fMRI) measurement of oxidative metabolism (CMRO 2 ), resting-state cortical functional connectivity assessed with fMRI, and WM-related fMRI. Healthy subjects participated in two scan sessions in a randomized, double-blind, placebo-controlled design. Ketamine increased CMRO 2 and cerebral blood flow (CBF) in prefrontal cortex (PFC) and other cortical regions. However, resting-state cortical functional connectivity was not affected. Ketamine did not alter CBF-CMRO 2 coupling brain-wide. Higher levels of basal CMRO 2 were associated with lower task-related PFC activation and WM accuracy impairment under both saline and ketamine conditions. These observations suggest that CMRO 2 and resting-state functional connectivity index distinct dimensions of neural activity. Ketamine’s impairment of WM-related neural activity and performance appears to be related to its ability to produce cortical metabolic activation. This work illustrates the utility of direct measurement of CMRO 2 via calibrated fMRI in studies of drugs that potentially affect neurovascular and neurometabolic coupling.

Laser-induced microinjury of the corneal basal epithelium and imaging of resident macrophage responses in a live, whole-eye preparation.

The corneal epithelium is continuously subjected to external stimuli that results in varying degrees of cellular damage. The use of live-cell imaging approaches has facilitated understanding of the cellular and molecular mechanisms underlying the corneal epithelial wound healing process. Here, we describe a live, ex vivo, whole-eye approach using laser scanning confocal microscopy to simultaneously induce and visualize short-term cellular responses following microdamage to the corneal epithelium. Live-cell imaging of corneal cell layers was enabled using the lipophilic fluorescent dyes, SGC5 or FM4-64, which, when injected into the anterior chamber of enucleated eyes, readily penetrated and labelled cell membranes. Necrotic microdamage to a defined region (30 µm x 30 µm) through the central plane of the corneal basal epithelium was induced by continuously scanning for at least one minute using high laser power and was dependent on the presence of lipophilic fluorescent dye. This whole-mount live-cell imaging and microdamage approach was used to examine the behavior of Cx3cr1:GFP-expressing resident corneal stromal macrophages (RCSMs). In undamaged corneas, RCSMs remained stationary, but exhibited a constant extension and retraction of short (~5 µm) semicircular, pseudopodia-like processes reminiscent of what has previously been reported in corneal dendritic cells. Within minutes of microdamage, nearby anterior RCSMs became highly polarized and extended projections towards the damaged region. The extension of the processes plateaued after about 30 minutes and remained stable over the course of 2-3 hours of imaging. Retrospective immunolabeling showed that these responding RCSMs were MHC class II+. This study adds to existing knowledge of immune cell behavior in response to corneal damage and introduces a simple corneal epithelial microdamage and wound healing paradigm.

Purplish Discoloration of Urine in a Patient Receiving Cefiderocol: A Rare Adverse Effect.

Drug-induced urine discoloration, although usually benign, can still raise concern in healthcare facilities. This case report presents the second case of purple urine discoloration associated with cefiderocol in a 64-year-old male admitted to the intensive care unit for ventilator-associated pneumonia. The patient required broad-spectrum antibiotic treatment with vancomycin, cefiderocol, amikacin, and micafungin. On the fourth day after initiating antibiotics, the presence of purplish urine in the foley bag was noted. Urinalysis showed 11-25 red blood cells/hpf, but cultures ruled out urinary tract infection. Further laboratory workup did not reveal any evidence of hemolysis or rhabdomyolysis. Cultures from the endotracheal aspirate grew multidrug-resistant Pseudomonas. Cefiderocol and amikacin were continued to complete a seven-day course. Two days after completion of the cefiderocol course, the urine discoloration cleared up, providing strong evidence that cefiderocol was the cause of the discoloration.

Lamotrigine-Induced Lupus With Aseptic Meningitis and Hemophagocytic Lymphohistiocytosis.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by disordered immune activation resulting in cytokine storm and inflammation. We present a 27-year-old woman who had a fever and diffuse rash after recently starting lamotrigine. She developed meningismus and polyarthralgia. Laboratory results revealed cytopenia, elevated serum aminotransferases, hypofibrinogenemia and elevated ferritin. Cerebrospinal fluid analysis suggested aseptic meningitis. Antinuclear antibody and rheumatoid factor serologies were positive, complement levels of C3 were decreased, and antihistone antibody was negative. A bone marrow biopsy demonstrated hemophagocytic macrophages and the diagnosis of HLH was made. The patient was empirically started on high-dose intravenous dexamethasone following which both her mental status and laboratory indices markedly improved. Lamotrigine has been shown to induce lupus-like syndrome, aseptic meningitis, and HLH, but not concomitantly. Our patient was recently started on lamotrigine, likely inducing her underlying undiagnosed lupus, in addition to, resulting in aseptic meningitis and a cytokine storm leading to HLH.

Insulin Edema Syndrome due to Rapid Glucose Correction in a Diabetic Patient.

Edema resulting from the initiation of insulin therapy or intensification of glycemic control is a rare and under-recognized complication. In this report, we present a case of a 46-year-old patient with insulin-dependent diabetes mellitus (IDDM) who avoided insulin treatment due to associated peripheral edema. Though rare, this phenomenon is typically seen in patients with elevated glucose levels who are initiated on insulin treatment, resulting in rapid correction and tight control of glucose levels. The diagnosis of insulin-induced edema is made after other causes of acute edema are ruled out. Furthermore, in this case report, we will also discuss the postulated mechanisms for the edema-causing property of insulin.

Altered adult neurogenesis and gliogenesis in patients with mesial temporal lobe epilepsy.

The hippocampus is the most common seizure focus in people. In the hippocampus, aberrant neurogenesis plays a critical role in the initiation and progression of epilepsy in rodent models, but it is unknown whether this also holds true in humans. To address this question, we used immunofluorescence on control healthy hippocampus and surgical resections from mesial temporal lobe epilepsy (MTLE), plus neural stem-cell cultures and multi-electrode recordings of ex vivo hippocampal slices. We found that a longer duration of epilepsy is associated with a sharp decline in neuronal production and persistent numbers in astrogenesis. Further, immature neurons in MTLE are mostly inactive, and are not observed in cases with local epileptiform-like activity. However, immature astroglia are present in every MTLE case and their location and activity are dependent on epileptiform-like activity. Immature astroglia, rather than newborn neurons, therefore represent a potential target to continually modulate adult human neuronal hyperactivity.

Cytoplasmic switch of ARS2 isoforms promotes nonsense-mediated mRNA decay and arsenic sensitivity.

The life of RNA polymerase II (RNAPII) transcripts is shaped by the dynamic formation of mutually exclusive ribonucleoprotein complexes (RNPs) that direct transcript biogenesis and turnover. A key regulator of RNA metabolism in the nucleus is the scaffold protein ARS2 (arsenic resistance protein 2), bound to the cap binding complex (CBC). We report here that alternative splicing of ARS2's intron 5, generates cytoplasmic isoforms that lack 270 amino acids from the N-terminal of the protein and are functionally distinct from nuclear ARS2. Switching of ARS2 isoforms within the CBC in the cytoplasm has dramatic functional consequences, changing ARS2 from a NMD inhibitor to a NMD promoter that enhances the binding of UPF1 to NCBP1 and ERF1, favouring SURF complex formation, SMG7 recruitment and transcript degradation. ARS2 isoform exchange is also relevant during arsenic stress, where cytoplasmic ARS2 promotes a global response to arsenic in a CBC-independent manner. We propose that ARS2 isoform switching promotes the proper recruitment of RNP complexes during NMD and the cellular response to arsenic stress. The existence of non-redundant ARS2 isoforms is relevant for cell homeostasis, and stress response.