Anal Mucinous Adenocarcinoma Presenting as a Superficial Lesion Without Luminal Involvement.

Anal mucinous adenocarcinoma arises from mucin-secreting columnar epithelium within anal glands and is extremely rare, comprising 2%-3% of all gastrointestinal malignancies. We present a unique case of 65-year-old developmentally disabled man with complaint of rectal pain. Examination showed an excoriated erythematous perianal region with mucinous film and subdermal nodularity. Surgical pathology of the lesion revealed poorly differentiated mucinous adenocarcinoma of intestinal type. Subsequent colonoscopy was without findings of intraluminal lesions. He established with oncology and later underwent a positron emission tomography scan that showed extensive metastasis. This case highlights a unique presentation of de novo mucinous adenocarcinoma with luminal sparing.

Colonizing the Unlikely: Brachyspira in an Immunocompetent Patient.

Chronic diarrhea is a common condition that medical professionals often encounter. We present an unusual case of chronic diarrhea in a relatively young, immunocompetent man that was attributed to Brachyspira. The patient's clinical presentation was not specific, and he underwent workup for common infectious, inflammatory, and autoimmune causes, all unrevealing. During colonoscopy, no abnormalities were detected; however, histopathology revealed the presence of Brachyspira. Following a course of metronidazole, the patient showed marked improvement in his diarrhea. It is worth noting that the patient's social history did not align with the established risk factors mentioned in the existing literature.

Interventions targeting social determinants of mental disorders and the Sustainable Development Goals: a systematic review of reviews.

Globally, mental disorders account for almost 20% of disease burden and there is growing evidence that mental disorders are socially determined. Tackling the United Nations Sustainable Development Goals (UN SDGs), which address social determinants of mental disorders, may be an effective way to reduce the global burden of mental disorders. We conducted a systematic review of reviews to examine the evidence base for interventions that map onto the UN SDGs and seek to improve mental health through targeting known social determinants of mental disorders. We included 101 reviews in the final review, covering demographic, economic, environmental events, neighborhood, and sociocultural domains. This review presents interventions with the strongest evidence base for the prevention of mental disorders and highlights synergies where addressing the UN SDGs can be beneficial for mental health.

Genetics of Gallstone Disease and Their Clinical Significance: A Narrative Review.

Gallstone (GS) disease is common and arises from a combination of genetic and environmental factors. Although genetic abnormalities specifically leading to cholesterol GSs are rare, there are clinically significant gene variants associated with cholesterol GSs. In contrast, most bilirubin GSs can be attributed to genetic defects. The pathogenesis of cholesterol and bilirubin GSs differs greatly. Cholesterol GSs are notably influenced by genetic variants within the ABC protein superfamily, including ABCG8, ABCG5, ABCB4, and ABCB11, as well as genes from the apolipoprotein family such as ApoB100 and ApoE (especially the E3/E3 and E3/E4 variants), and members of the MUC family. Conversely, bilirubin GSs are associated with genetic variants in highly expressed hepatic genes, notably UGT1A1, ABCC2 (MRP2), ABCC3 (MRP3), CFTR, and MUC, alongside genetic defects linked to hemolytic anemias and conditions impacting erythropoiesis. While genetic cases constitute a small portion of GS disease, recognizing genetic predisposition is essential for proper diagnosis, treatment, and genetic counseling.

A Novel Home for Hemangiomas: Sclerosing Hemangioma in the Pancreas.

Pancreatic hemangiomas, predominantly in female patients, are rare benign vascular tumors. We report a unique case of an incidentally discovered pancreatic sclerosing hemangioma. The patient's clinical presentation and imaging were concerning for an abdominal mass. Endoscopic ultrasound and histopathology confirmed the pancreatic sclerosing hemangioma. Because there were no complications, surgery was not performed, and the patient was monitored. Biopsy confirmation is crucial to rule out malignancy and avoid unnecessary surgical resection.

Tailored synthesis of NdMnxFe1-xO3 perovskite nanoparticles with oxygen-vacancy defects for lithium-ion battery anodes.

In this study, we synthesize nanostructured NdMnxFe1-xO3 perovskites using a facile method to produce materials for the high-working-efficiency anodes of Li-ion batteries. A series of characterization assessments (e.g., X-ray diffraction (XRD), X-ray photoelectron spectroscopy (XPS), and electron microscopy) were conducted, and the results confirmed the efficacious partial replacement of Fe ions with Mn ions in the NdFeO3 perovskite structure, occurrence of both amorphous and crystalline structures, presence of oxygen vacancies (VO), and interconnection between nanoparticles. The possibility of Mn ion replacement significantly affects the size, amount of VO, and ratio of amorphous phase in NdMnxFe1-xO3 perovskites. The NdMnxFe1-xO3 perovskite with x = 0.3 presents a notable electrochemical performance, including low charge transfer resistance, durable Coulombic efficiency, first-rate capacity reservation, high pseudo-behavior, and elongated 150-cycle service life, whereas no discernible capacity deterioration is observed. The reversible capacity of the anode after the 150th-cylcle was 713 mAh g-1, which represents a high-capacity value. The outstanding electrochemical efficiency resulted from the optimum presence of VO, interconnection between the nanoparticles, and distinctive properties of the NdFeO3 perovskite. The interconnection between nanoparticles was advantageous for forming a large electrolyte-electrode contact area, improving Li-ion diffusion rates, and enhancing pseudocapacitive effect. The attributes of perovskite crystals, coexistence of Mn and Fe throughout the charge/discharge process, and optimum VO precluded the electrode devastation that caused the Li2O-phase decomposition catalysis, enabling favorable reversible Li storage.

In situ magnesiothermic reduction synthesis of a Ge@C composite for high-performance lithium-ion batterie anodes.

Metallothermic, especially magnesiothermic, solid-state reactions have been widely applied to synthesize various materials. However, further investigations regarding the use of this method for composite syntheses are needed because of the high reactivity of magnesium. Herein, we report an in situ magnesiothermic reduction to synthesize a composite of Ge@C as an anode material for lithium-ion batteries. The obtained electrode delivered a specific capacity of 454.2 mAh·g-1 after 200 cycles at a specific current of 1000 mA·g-1. The stable electrochemical performance and good rate performance of the electrode (432.3 mAh·g-1 at a specific current of 5000 mA·g-1) are attributed to the enhancement in distribution and chemical contact between Ge nanoparticles and the biomass-based carbon matrix. A comparison with other synthesis routes has been conducted to demonstrate the effectiveness of contact formation during in situ synthesis.

From an Hsp90 - binding protein to a peptide drug.

The Lpl proteins represent a class of lipoproteins that was first described in the opportunistic bacterial pathogen Staphylococcus aureus, where they contribute to pathogenicity by enhancing F-actin levels of host epithelial cells and thereby increasing S. aureus internalization. The model Lpl protein, Lpl1 was shown to interact with the human heat shock proteins Hsp90α and Hsp90ß, suggesting that this interaction may trigger all observed activities. Here we synthesized Lpl1-derived peptides of different lengths and identified two overlapping peptides, namely, L13 and L15, which interacted with Hsp90α. Unlike Lpl1, the two peptides not only decreased F-actin levels and S. aureus internalization in epithelial cells but they also decreased phagocytosis by human CD14+ monocytes. The well-known Hsp90 inhibitor, geldanamycin, showed a similar effect. The peptides not only interacted directly with Hsp90α, but also with the mother protein Lpl1. While L15 and L13 significantly decreased lethality of S. aureus bacteremia in an insect model, geldanamycin did not. In a mouse bacteremia model L15 was found to significantly decreased weight loss and lethality. Although the molecular bases of the L15 effect is still elusive, in vitro data indicate that simultaneous treatment of host immune cells with L15 or L13 and S. aureus significantly increase IL-6 production. L15 and L13 represent not antibiotics but they cause a significant reduction in virulence of multidrug-resistant S. aureus strains in in vivo models. In this capacity, they can be an important drug alone or additive with other agents.

Bacterial Lipoproteins Shift Cellular Metabolism to Glycolysis in Macrophages Causing Bone Erosion.

Belonging to a group of membrane proteins, bacterial lipoproteins (LPPs) are defined by a unique lipid structure at their N-terminus providing the anchor in the bacterial cell membrane. In Gram-positive bacteria, LPPs play a key role in host immune activation triggered through a Toll-like receptor 2 (TLR2)-mediated action resulting in macrophage stimulation and subsequent tissue damage demonstrated in in vivo experimental models. Yet the physiologic links between LPP activation, cytokine release, and any underlying switches in cellular metabolism remain unclear. In this study, we demonstrate that Staphylococcus aureus Lpl1 not only triggers cytokine production but also confers a shift toward fermentative metabolism in bone marrow-derived macrophages (BMDMs). Lpl1 consists of di- and tri-acylated LPP variants; hence, the synthetic P2C and P3C, mimicking di-and tri-acylated LPPs, were employed to reveal their effect on BMDMs. Compared to P3C, P2C was found to shift the metabolism of BMDMs and the human mature monocytic MonoMac 6 (MM6) cells more profoundly toward the fermentative pathway, as indicated by lactate accumulation, glucose consumption, pH reduction, and oxygen consumption. In vivo, P2C caused more severe joint inflammation, bone erosion, and lactate and malate accumulation than P3C. These observed P2C effects were completely abrogated in monocyte/macrophage-depleted mice. Taken together, these findings now solidly confirm the hypothesized link between LPP exposure, a macrophage metabolic shift toward fermentation, and ensuing bone destruction. IMPORTANCE Osteomyelitis caused by S. aureus is a severe infection of the bone, typically associated with severe bone function impairment, therapeutic failure, high morbidity, invalidity, and occasionally even death. The hallmark of staphylococcal osteomyelitis is the destruction of the cortical bone structures, yet the mechanisms contributing to this pathology are hitherto poorly understood. One bacterial membrane constituent found in all bacteria is bacterial lipoproteins (LPPs). Previously, we have shown that injection of purified S. aureus LPPs into wild-type mouse knee joints caused a TLR2-dependent chronic destructive arthritis but failed to elicit such effect in monocyte/macrophage-depleted mice. This observation stirred our interest in investigating the interaction of LPPs and macrophages and analyzing the underlying physiological mechanisms. This ascertainment of LPP-induced changes in the physiology of macrophages provides an important clue in the understanding of the mechanisms of bone disintegration, opening novel avenues to manage the course of S. aureus disease.

A Case of Herpes Simplex Virus Colitis in an Immunosuppressed Patient.

Herpes simplex virus (HSV) can cause severe disseminated infections in immunocompromised patients. Gastrointestinal tract involvement seldom includes the colon. We present a rare case of disseminated cutaneous HSV infection with concomitant colonic involvement in an immunosuppressed patient. The patient's clinical presentation and computerized tomography (CT) findings were concerning for colitis. She failed to improve on antibiotic therapy and subsequently underwent flexible sigmoidoscopy. Gross findings and histopathology were consistent with herpes simplex virus colitis. It is essential to recognize this pathology in immunocompromised patients to evaluate the need to hold immunosuppressive therapy and ensure successful treatment to prevent fatal outcomes.

Staphylococcus aureus lipoproteins in infectious diseases.

Infections with the Gram-positive bacterial pathogen Staphylococcus aureus remain a major challenge for the healthcare system and demand new treatment options. The increasing antibiotic resistance of S. aureus poses additional challenges, consequently inflicting a huge strain in the society due to enormous healthcare costs. S. aureus expresses multiple molecules, including bacterial lipoproteins (Lpps), which play a role not only in immune response but also in disease pathogenesis. S. aureus Lpps, the predominant ligands of TLR2, are important for bacterial survival as they maintain the metabolic activity of the bacteria. Moreover, Lpps possess many diverse properties that are of vital importance for the bacteria. They also contribute to host cell invasion but so far their role in different staphylococcal infections has not been fully defined. In this review, we summarize the current knowledge about S. aureus Lpps and their distinct roles in various infectious disease animal models, such as septic arthritis, sepsis, and skin and soft tissue infections. The molecular and cellular response of the host to S. aureus Lpp exposure is also a primary focus.

Phenol-soluble modulin α and ß display divergent roles in mice with staphylococcal septic arthritis.

Phenol-soluble modulin α (PSMα) is identified as potent virulence factors in Staphylococcus aureus (S. aureus) infections. Very little is known about the role of PSMß which belongs to the same toxin family. Here we compared the role of PSMs in S. aureus-induced septic arthritis in a murine model using three isogenic S. aureus strains differing in the expression of PSMs (Newman, Δpsmα, and Δpsmß). The effects of PSMs on neutrophil NADPH-oxidase activity were determined in vitro. We show that the PSMα activates neutrophils via the formyl peptide receptor (FPR) 2 and reduces their NADPH-oxidase activity in response to the phorbol ester PMA. Despite being a poor neutrophil activator, PSMß has the ability to reduce the neutrophil activating effect of PSMα and to partly reverse the effect of PSMα on the neutrophil response to PMA. Mice infected with S. aureus lacking PSMα had better weight development and lower bacterial burden in the kidneys compared to mice infected with the parental strain, whereas mice infected with bacteria lacking PSMß strain developed more severe septic arthritis accompanied with higher IL-6 and KC. We conclude that PSMα and PSMß play distinct roles in septic arthritis: PSMα aggravates systemic infection, whereas PSMß protects arthritis development.

Ionically cross-linked alginate-chitosan core-shell hydrogel beads for oral delivery of insulin.

Here, core-shell hydrogel beads for oral insulin delivery at intestine was reported, which was a target site for insulin absorption. The core-shell hydrogel beads were prepared using naturally derived alginate and chitosan polysaccharides by simple dropping technique. In order to effectively control leakage of insulin from core-shell hydrogel beads, insulin was embedded into the layered double hydroxides (LDHs). LDH/insulin-loaded complexes were firstly coated with chitosan, and then coated with alginate to generate core-shell hydrogel beads. The biocompatibility and angiogenic response of core-shell hydrogel beads were evaluated by direct contact of the beads with chick embryo chorioallantoic membrane, which indicates safety of the core-shell beads. The beads successfully retained the insulin within the core-shell structure at pH 1.2, indicating that insulin had a good protective effect in harsh acidic environments. Interestingly, insulin release starts at the simulated intestinal fluid (pH 6.8) and continue to release for 24 h in a sustained manner.

First Report of a Methicillin-Resistant, High-Level Mupirocin-Resistant Staphylococcus argenteus.

We describe the identification of a methicillin-resistant, high-level mupirocin-resistant Staphylococcus argenteus. The isolate (1801221) was characterized as t6675-ST2250-SCCmecIVc, and whole-genome sequencing revealed that the isolate possessed two plasmids. One plasmid (34,870 bp), designated p1_1801221 with rep23, harboured the mupirocin resistance (mupA) gene. The second plasmid (20,644 bp), assigned as p2_1801221 with rep5a and rep16, carried the resistance determinants for penicillin (blaZ) and cadmium (cadD). Phylogenetic analysis revealed that the isolate clustered with the European ST2250 lineage. The overall high similarity of both plasmids in S. argenteus with published DNA sequences of Staphylococcus aureus plasmids strongly suggests an interspecies transfer. The pathogenic potential, community and nosocomial spread, and acquisition of antibiotic resistance gene determinants, including the mupA gene by S. argenteus, highlight its clinical significance and the need for its correct identification.

"The Stakes Are Higher"- Patient and Caregiver Perspectives on Cystic Fibrosis Research and Personalized Medicine.

Introduction: Making bench to bedside advances in cystic fibrosis (CF) care requires the sustained engagement and trust of people living with CF. However, there is a scarcity of studies exploring their concerns and priorities regarding research and its end products. The aim of this qualitative study was to generate empirical evidence regarding patient and caregiver perspectives on cystic fibrosis research and personalized medicine to foster developments in translational research in Canada. Methods: A total of 15 focus groups were conducted, engaging 22 adults with CF and 18 caregivers (e.g., parents, siblings and partners) living in Canada. Inductive thematic analysis relied on an iterative process involving themes derived from both participant meaning-making and existing scientific literature. Participant perspectives were considered along intrapersonal, intracommunity, interpersonal, and structural lines. Results: Overall, participants described a relationship to CF research inextricable from the lived experience of CF as a lifelong progressive and terminal disease and from the goal of advancing medical science. They were enthusiastic and excited about the emergence of CFTR modulators, although they had some knowledge gaps regarding the associated research. They largely spoke to positive experiences with researcher communication but had feedback regarding informed consent processes and the return of study results. Participants also voiced concerns about structural access barriers to research and to its end products. Extensive histories of research participation, a relatively small and intercommunicative CF community, and structural overlap between research and care settings contributed to their perspectives and priorities. Conclusion: Study findings are valuable for researchers and policy-makers in CF and rare or progressive diseases more broadly. Continuing to solicit and listen to the voices of patients and caregivers is crucial for research ethics and the translation of new therapies in the area of personalized medicine.

Lipoproteins Cause Bone Resorption in a Mouse Model of Staphylococcus aureus Septic Arthritis.

Septic arthritis, most often caused by Staphylococcus aureus, is a rapidly progressive and destructive joint disease with substantial mortality and morbidity. Staphylococcus aureus lipoproteins (Lpps) are known to induce arthritis and bone destruction. Here, we aimed to investigate the bone resorptive effect of S. aureus Lpps in a murine arthritis model by intra-articular injection of purified S. aureus Lpps, synthetic lipopeptides, and live S. aureus strains. Analyses of the bone mineral density (BMD) of the distal femur bone were performed. Intra-articular injection of both live S. aureus and purified S. aureus Lpps were shown to significantly decrease total- and trabecular BMD. Liquid chromatography-mass spectrometry analyses revealed that the Lpps expressed by S. aureus SA113 strain contain both diacyl and triacyl lipid moieties. Interestingly, synthetic diacylated lipopeptide, Pam2CSK4, was more potent in inducing bone resorption than synthetic triacylated lipopeptide, Pam3CSK4. Modified lipoproteins lacking the lipid moiety were deprived of their bone resorptive abilities. Monocyte depletion by clodronate liposomes fully abrogated the bone resorptive capacity of S. aureus lipoproteins. Our data suggest that S. aureus Lpps induce bone resorption in locally-induced murine arthritis, an effect mediated by their lipid-moiety through monocytes/macrophages.

Quiescence of Human Monocytes after Affinity Purification: A Novel Method Apt for Monocyte Stimulation Assays.

Several methods to isolate monocytes from whole blood have been previously published, with different advantages and disadvantages. For the purpose of cytokine release assessment upon external stimulation, the use of monocyte preparations consisting of non-activated cells is prerequisite. Affinity-isolated monocyte preparations from peripheral blood mononuclear cells (PBMCs), obtained via positive or negative selection using magnetic beads, released pro-inflammatory cytokines such as TNF-α and IL-6 even without adding external stimuli, hindering any assessment of an effect of bacterial lipoproteins on cell stimulation. Hence, the cell preparation protocol was modified by adding a quiescence step on repellent surface culture plates, dampening any monocyte pre-activation. This protocol now provides a robust method to prepare silent yet fully activatable, pure monocyte populations for further use in stimulus-elicited activation experiments.

Small Bowel Volvulus as Delayed Presentation of Undiagnosed Crohn's Disease: A Case Report.

INTRODUCTION: Emergency department (ED) visits related to flare-ups of inflammatory bowel disease (IBD) are becoming more prevalent. There are many potentially dangerous complications and sequelae of uncontrolled IBD. CASE REPORT: We report a case of a middle-aged woman who presented with a few hours of severe abdominal pain, nausea, and vomiting. Given her hemodynamic instability, she was sent urgently for computed tomography, which showed an incomplete small bowel malrotation, mesenteric volvulus, and high-grade small bowel obstruction with evolving ischemia. The patient underwent exploratory laparotomy to resect most of her small intestines. Biopsies later revealed active Crohn's disease. CONCLUSION: Patients with flare-ups of IBD are common in the ED, but very few present with a midgut volvulus later in life. Our case is unique and adds to the literature due to the dramatic consequences of undiagnosed Crohn's disease in a patient with intermittent symptoms and extensive workup spanning over two decades.

More Is Not Always Better-the Double-Headed Role of Fibronectin in Staphylococcus aureus Host Cell Invasion.

While Staphylococcus aureus has classically been considered an extracellular pathogen, these bacteria are also capable of being taken up by host cells, including nonprofessional phagocytes such as endothelial cells, epithelial cells, or osteoblasts. The intracellular S. aureus lifestyle contributes to infection development. The predominant recognition and internalization pathway appears to be the binding of the bacteria via a fibronectin bridge to the α5ß1-integrin on the host cell membrane, followed by phagocytosis. Although osteoblasts showed high expression of α5ß1-integrin and fibronectin, and bacteria adhered to osteoblasts to a high proportion, here we demonstrate by internalization assays and immunofluorescence microscopy that S. aureus was less engulfed in osteoblasts than in epithelial cells. The addition of exogenous fibronectin during the infection of cells with S. aureus resulted in an increased uptake by epithelial cells but not by osteoblasts. This contrasts with the previous conception of the uptake mechanism, where high expression of integrin and fibronectin would promote the bacterial uptake into host cells. Extracellular fibronectin surrounding osteoblasts, but not epithelial cells, is organized in a fibrillary network. The inhibition of fibril formation, the short interfering RNA-mediated reduction of fibronectin expression, and the disruption of the fibronectin-fibril meshwork all resulted in a significant increase in S. aureus uptake by osteoblasts. Thus, the network of fibronectin fibrils appears to strongly reduce the uptake of S. aureus into a given host cell, indicating that the supramolecular structure of fibronectin determines the capacity of particular host cells to internalize the pathogen. IMPORTANCE Traditionally, Staphylococcus aureus has been considered an extracellular pathogen. However, among other factors, the frequent failure of antimicrobial therapy and the ability of the pathogen to cause recurrent disease have established the concept of eukaryotic invasion of the pathogen, thereby evading the host's immune system. In the current model of host cell invasion, bacteria initially bind to α5ß1 integrin on the host cell side via a fibronectin bridge, which eventually leads to phagocytosis of S. aureus by host cells. However, in this study, we demonstrate that not the crude amount but the supramolecular structure of fibronectin molecules deposited on the eukaryotic cell surface plays an essential role in bacterial uptake by host cells. Our findings explain the large differences of S. aureus uptake efficacy in different host cell types as well as in vivo differences between courses of bacterial infections and the localization of bacteria in different clinical settings.