Challenges in Medicine: The Odyssey of a Patient with Isolated IgG4-Related Eosinophilic Angiocentric Fibrosis Presenting as a Locally Destructive Sinonasal Mass.

Eosinophilic angiocentric fibrosis (EAF) is an exceeding rare clinical entity and is considered a part of the spectrum of IgG4-related disease (IgG4RD). We hereby present such an unusual case of a 60-year-old female who presented to us with recurrent sinonasal mass, after a decade long haul of multiple clinical evaluations, biopsies, and debulking surgery without a definitive diagnosis. Over this period, the mass eroded through the ethmoid cells along with nasal septal destruction leading to saddle nose deformity, extended superiorly through the cribriform plates to right frontal lobe, and compressed the optic nerve leading to visual loss. Although initial biopsy was negative, repeat biopsy was performed owing to high clinical suspicion due to all the classic histopathological findings compatible with the diagnosis of eosinophilic angiocentric fibrosis IgG4-related disease (EAF-IgG4RD). Steroids are the recommended first-line therapy; however, our case was resistant to steroids needing rituximab to halt the disease progression. Our case interestingly also had T-cell clonality and isolated isocitrate dehydrogenase 2 enzyme mutation on next-generation sequencing, suggesting a possible role of novel molecular-targeted therapies in this rare disease. This case highlights the clinical challenges physicians face towards diagnosing and treating EAF-IgG4RD, emphasizing the need for high clinical suspicion and the possible role of targeted therapies for this rare disease.

Non-invasive peripheral focused ultrasound neuromodulation of the celiac plexus ameliorates symptoms in a rat model of inflammatory bowel disease.

NEW FINDINGS: What is the central question of this study? Does peripheral non-invasive focused ultrasound targeted to the celiac plexus improve inflammatory bowel disease? What is the main finding and its importance? Peripheral non-invasive focused ultrasound targeted to the celiac plexus in a rat model of ulcerative colitis improved stool consistency and reduced stool bloodiness, which coincided with a longer and healthier colon than in animals without focused ultrasound treatment. The findings suggest that this novel neuromodulatory technology could serve as a plausible therapeutic approach for improving symptoms of inflammatory bowel disease. ABSTRACT: Individuals suffering from inflammatory bowel disease (IBD) experience significantly diminished quality of life. Here, we aim to stimulate the celiac plexus with non-invasive peripheral focused ultrasound (FUS) to modulate the enteric cholinergic anti-inflammatory pathway. This approach may have clinical utility as an efficacious IBD treatment given the non-invasive and targeted nature of this therapy. We employed the dextran sodium sulfate (DSS) model of colitis, administering lower (5%) and higher (7%) doses to rats in drinking water. FUS on the celiac plexus administered twice a day for 12 consecutive days to rats with severe IBD improved stool consistency scores from 2.2 ± 1 to 1.0 ± 0.0 with peak efficacy on day 5 and maximum reduction in gross bleeding scores from 1.8 ± 0.8 to 0.8 ± 0.8 on day 6. Similar improvements were seen in animals in the low dose DSS group, who received FUS only once daily for 12 days. Moreover, animals in the high dose DSS group receiving FUS twice daily maintained colon length (17.7 ± 2.5 cm), while rats drinking DSS without FUS exhibited marked damage and shortening of the colon (13.8 ± 0.6 cm) as expected. Inflammatory cytokines such as interleukin (IL)-1ß, IL-6, IL-17, tumour necrosis factor-α and interferon-γ were reduced with DSS but coincided with control levels after FUS, which is plausibly due to a loss of colon crypts in the former and healthier crypts in the latter. Lastly, overall, these results suggest non-invasive FUS of peripheral ganglion can deliver precision therapy to improve IBD symptomology.

Spontaneous Rupture of Mesenteric Vasculature Associated with Fibromuscular Dysplasia in a 28-Year-Old Male.

Spontaneous rupture of mesenteric vasculature associated with fibromuscular dysplasia is an unreported phenomenon. We describe a case in a 28-year-old male with a history of chronic abdominal pain who presented to our facility in hemorrhagic shock secondary to a ruptured transverse mesocolon middle colic aneurysm status postemergent transverse colectomy. He was found to have chronic vertebral, renovisceral, and iliac aneurysms as well as acute superior and inferior mesenteric artery dissection and chronic bilateral vertebral artery dissections. He subsequently developed disseminated intravascular coagulopathy, resulting in saddle pulmonary embolus as well as right renal artery and splenic artery thrombosis. Ultimately, the patient expired.

IFN-γ and IL-17A regulate intestinal crypt production of CXCL10 in the healthy and inflamed colon.

During intestinal inflammation, immature cells within the intestinal crypt are called upon to replenish lost epithelial cell populations, promote tissue regeneration, and restore barrier integrity. Inflammatory mediators including TH1/TH17-associated cytokines influence tissue health and regenerative processes, yet how these cytokines directly influence the colon crypt epithelium and whether the crypt remains responsive to these cytokines during active damage and repair, remain unclear. Here, using laser-capture microdissection and primary colon organoid culture, we show that the cytokine milieu regulates the ability of the colonic crypt epithelium to participate in proinflammatory signaling. IFN-γ induces the TH1-recruiting, proinflammatory chemokine CXCL10/IP10 in primary murine intestinal crypt epithelium. CXCL10 was also induced in colonic organoids derived from mice with active, experimentally induced colitis, suggesting that the crypt can actively secrete CXCL10 in select cytokine environments during colitis. Colon expression of cxcl10 further increased during infectious and noninfectious colitis in Il17a-/- mice, demonstrating that IL-17A exerts a negative effect on CXCL10 in vivo. Furthermore, IL-17A directly antagonized CXCL10 production in ex vivo organoid cultures derived from healthy murine colons. Interestingly, direct antagonism of CXCL10 was not observed in organoids derived from colitic mouse colons bearing active lesions. These data, highlighting the complex interplay between the cytokine milieu and crypt epithelia, demonstrate proinflammatory chemokines can be induced within the colonic crypt and suggest the crypt remains responsive to cytokine modulation during inflammation.NEW & NOTEWORTHY Upon damage, the intestinal epithelium regenerates to restore barrier function. Here we observe that the local colonic cytokine milieu controls the production of procolitic chemokines within the crypt base and colon crypts remain responsive to cytokines during inflammation. IFN-γ promotes, while IL-17 antagonizes, CXCL10 production in healthy colonic crypts, while responses to cytokines differ in inflamed colon epithelium. These data reveal novel insight into colon crypt responses and inflammation-relevant alterations in signaling.

Successful Combined Heart and Kidney Transplantation in Patient With Fabry's Disease: A Case Report.

Fabry's disease is a X-linked hereditary disease that causes the accumulation of glycosphingolipids in tissues and organs, including the kidneys and heart. This can result in both chronic kidney disease and cardiac dysfunction, including arrhythmias and heart failure. We describe a case of a 62-year-old male with Fabry's disease undergoing successful combined heart and kidney transplantation for chronic renal failure and low-output systolic heart failure. The patient has normal cardiac function and normal renal function 7 years after transplantation, while being maintained on enzyme replacement therapy with recombinant human alpha-galactosidase A. Fabry's disease is not a contraindication for organ transplantation, even in patients presenting with both renal failure and heart failure.

DNA damage response genes mark the early transition from colitis to neoplasia in colitis-associated colon cancer.

Chronic intestinal inflammation predisposes patients with Inflammatory Bowel Disease (IBD) to Colitis-Associated Cancer (CAC). In the setting of chronic inflammation, microsatellite instability (MSI) results from early loss of DNA damage response (DDR) genes, ultimately leading to tumor formation. Despite continued efforts to improve early detection of high risk, pre-dysplastic regions in IBD patients, current macroscopic and genetic surveillance modalities remain limited. Therefore, understanding the regulation of key DDR genes in the progression from colitis to cancer may improve molecular surveillance of CAC. To evaluate DDR gene regulation in the transition from colitis to tumorigenesis, we utilized the well-established Azoxymethane/Dextran Sodium Sulfate (AOM/DSS) pre-clinical murine model of CAC in C57BL/6 mice. In order to assess colonic tumor burden in the setting of mutagen and intestinal irritation, tumors were visualized and graded in real time through high-resolution murine colonoscopy. Upon sacrifice, colons were opened and assessed for macroscopic tumor via high magnification surgical lenses (HMSL). Tissues were then sectioned and separated into groups based on the presence or absence of macroscopically visible tumor. Critical DDR genes were evaluated by semi-quantitative RT-PCR. Interestingly, colon tissue with macroscopically visible tumor (MVT) and colon tissue prior to observable tumor (the non-macroscopically visible tumor-developing group, NMVT) were identical in reduced mRNA expression of mlh1, anapc1, and ercc4 relative to colitic mice without mutagen, or those receiving mutagen alone. Colitis alone was sufficient to reduce colonic ercc4 expression when compared to NMVT mice. Therefore, reduced ercc4 expression may mark the early transition to CAC in a pre-clinical model, with expression reduced prior to the onset of observable tumor. Moreover, the expression of select DDR genes inversely correlated with chronicity of inflammatory disease. These data suggest ercc4 expression may define early stages in the progression to CAC.

Association of altered collagen content and lysyl oxidase expression in degenerative mitral valve disease.

BACKGROUND: Collagen cross-linking is mediated by lysyl oxidase (LOX) enzyme in the extracellular matrix (ECM) of mitral valve leaflets. Alterations in collagen content and LOX protein expression in the ECM of degenerative mitral valve may enhance leaflet expansion and disease severity. METHODS: Twenty posterior degenerative mitral valve leaflets from patients with severe mitral regurgitation were obtained at surgery. Five normal posterior mitral valve leaflets procured during autopsy served as controls. Valvular interstitial cells (VICs) density was quantified by immunohistochemistry, collagen Types I and III by picro-sirius red staining and immunohistochemistry, and proteoglycans by alcian blue staining. Protein expression of LOX and its mediator TGFß1 were quantified by immunofluorescence and gene expression by PCR. RESULTS: VIC density was increased, structural Type I collagen density was reduced, while reparative Type III collagen and proteoglycan densities were increased (P<.0001) with an increase in spongiosa layer thickness in myxomatous valves. These changes were associated with a reduction in LOX (P<.0001) and increase in TGFß1 protein expression (P<.0001). However, no significant change was seen in gene expression. Linear regression analysis identified a correlation between Type I collagen density and LOX grade (R2=0.855; P<.0001). CONCLUSIONS: Reduced Type I collagen density with a simultaneous increase in Type III collagen and proteoglycan densities possibly contributes to spongiosa layer expansion resulting in incompetent mitral valve leaflets. Observed changes in Type I and III collagen densities in Degenerative Mitral Valve Disease may be secondary to alterations in LOX protein expression, contributing to disorganization of ECM and disease severity.

Neuro-Ophthalmic Presentation of Neuro-Sweet Disease.

Acute febrile neutrophilic dermatosis (Sweet syndrome) is a systemic inflammatory condition usually associated with autoimmune or neoplastic processes and characterised by inflammatory dermatologic lesions such as erythematous plaques and papules associated with fever and leukocytosis. Neurological and ophthalmological involvement is rare. The authors describe an unusual case of Sweet syndrome associated with microscopic polyangiitis presenting with papilloedema, anterior uveitis, and skin rash. Years later, he developed acute posterior multifocal placoid pigment epitheliopathy. Treatment with immunosuppressive medications led to a relapsing remitting course with maximum benefit from use of steroids. The authors describe the difficulties in diagnosis and treatment of this rare case.

Elevated integrin α6ß4 expression is associated with venous invasion and decreased overall survival in non-small cell lung cancer.

Lung cancer carries a poor prognosis and is the most common cause of cancer-related death worldwide. The integrin α6ß4, a laminin receptor, promotes carcinoma progression in part by cooperating with various growth factor receptors to facilitate invasion and metastasis. In carcinoma cells with mutant TP53, the integrin α6ß4 promotes cell survival. TP53 mutations and integrin α6ß4 overexpression co-occur in many aggressive malignancies. Because of the high frequency of TP53 mutations in lung squamous cell carcinoma (SCC), we sought to investigate the association of integrin ß4 expression with clinicopathologic features and survival in non-small cell lung cancer (NSCLC). We constructed a lung cancer tissue microarray and stained sections for integrin ß4 subunit expression using immunohistochemistry. We found that integrin ß4 expression is elevated in SCC compared with adenocarcinoma (P<.0001), which was confirmed in external gene expression data sets (P<.0001). We also determined that integrin ß4 overexpression associates with the presence of venous invasion (P=.0048) and with reduced overall patient survival (hazard ratio, 1.46; 95% confidence interval, 1.01-2.09; P=.0422). Elevated integrin ß4 expression was also shown to associate with reduced overall survival in lung cancer gene expression data sets (hazard ratio, 1.49; 95% confidence interval, 1.31-1.69; P<.0001). Using cBioPortal, we generated a network map demonstrating the 50 most highly altered genes neighboring ITGB4 in SCC, which included laminins, collagens, CD151, genes in the EGFR and PI3K pathways, and other known signaling partners. In conclusion, we demonstrate that integrin ß4 is overexpressed in NSCLC where it is an adverse prognostic marker.

Congenital bronchial artery to pulmonary artery fistula presenting as hemoptysis.

A 51-year-old male presented with 2 weeks of hemoptysis. Pulmonary angiography was performed and identified a bronchial artery to pulmonary artery fistula of the right upper lobe. Despite angioembolization, the hemoptysis recurred 1 year later. It was hypothesized that the recurrence occurred due to retrograde filling from the pulmonary arterial side of the abnormality. Right upper lobectomy was performed and resulted in resolution of hemoptysis. We present a case report of a rare, congenital bronchial artery to pulmonary artery fistula.

An in vivo microdialysis characterization of the transient changes in the interstitial dialysate concentration of metabolites and cytokines in human skeletal muscle in response to insertion of a microdialysis probe.

Skeletal muscle has recently been described as an endocrine organ, capable of releasing cytokines and regulators of metabolism. Microdialysis of the interstitial space of skeletal muscle enables analysis of the release of such cytokines. The purpose of this study was to determine the transient changes in concentration of metabolites and cytokines in human skeletal muscle in a 7h period following the insertion of a microdialysis probe. In total, sixteen microdialysis catheters were inserted into the vastus lateralis of male participants (age 26.2±1.35y, height 180.8±3.89cm, mass 83.9±3.86kg, BMI 25.7±0.87kgm(-2), body fat 26.1±3.0%). Serial samples were analyzed by micro-enzymatic and multiplexed immunoassay. Muscle interstitial glucose and lactate levels remained stable throughout, amino acid concentrations stabilized after 2.5h, however, insertion of a microdialysis catheter induced a 29-fold increase in peak IL-6 (p<0.001) and 35-fold increase in peak IL-8 concentrations (p<0.001) above basal levels 6h post insertion. In contrast to stable amino acid, glucose and lactate concentrations after 2h, commonly reported markers of tissue homeostasis in in vivo microdialysis, the multi-fold increase in IL-6 and IL-8 following insertion of a microdialysis catheter is indicative of a sustained disturbance of tissue homeostasis.

Diverting T helper cell trafficking through increased plasticity attenuates autoimmune encephalomyelitis.

Naive T helper cells differentiate into functionally distinct effector subsets that drive specialized immune responses. Recent studies indicate that some of the effector subsets have plasticity. Here, we used an EAE model and found that Th17 cells deficient in the transcription factor BCL11B upregulated the Th2-associated proteins GATA3 and IL-4 without decreasing RAR-related orphan receptor γ (RORγt), IL-17, and GM-CSF levels. Surprisingly, abnormal IL-4 production affected Th17 cell trafficking, diverting migration from the draining lymph nodes/CNS route to the mesenteric lymph nodes/gut route, which ameliorated EAE without overt colitis. T helper cell rerouting in EAE was dependent on IL-4, which enhanced retinoic acid (RA) production by dendritic cells, which further induced expression of gut-homing receptors CCR9 and α4ß7 on Bcl11b-deficient CD4+ T cells. Furthermore, IL-4 treatment or Th2 immunization of wild-type mice with EAE caused no alteration in Th17 cytokines or RORγt, but diverted T helper cell trafficking to the gut, which improved EAE outcome without overt colitis. Our data demonstrate that Th17 cells are permissive to Th2 gene expression without affecting Th17 gene expression. This Th17 plasticity has an impact on trafficking, which is a critical component of the immune response and may represent a possible avenue for treating multiple sclerosis.

Death by late-presenting Bochdalek hernia in infant soon after congenital cardiac repair.

Congenital diaphragmatic hernia (CDH) presenting beyond the neonatal period is commonly perceived to be rare. With reported frequencies of 2.6% to 20% of all CDH, it may be an overlooked cause of mortality. Variable symptomatology makes its diagnosis challenging. We report the sudden death of a 3-month-old patient shortly after hospital discharge following congenital heart surgery. Autopsy findings associated the patient's demise with migrated abdominal contents in the chest through a Bochdalek hernia defect. No indications of CDH existed before hospital discharge. Relevant issues pertaining to congenital heart disease, CDH, and importance of autopsy in this context are discussed.

IL-22BP is regulated by the inflammasome and modulates tumorigenesis in the intestine.

Chronic mucosal inflammation and tissue damage predisposes patients to the development of colorectal cancer. This association could be explained by the hypothesis that the same factors and pathways important for wound healing also promote tumorigenesis. A sensor of tissue damage should induce these factors to promote tissue repair and regulate their action to prevent development of cancer. Interleukin 22 (IL-22), a cytokine of the IL-10 superfamily, has an important role in colonic epithelial cell repair, and its levels are increased in the blood and intestine of inflammatory bowel disease patients. This cytokine can be neutralized by the soluble IL-22 receptor, known as the IL-22 binding protein (IL-22BP, also known as IL22RA2); however, the significance of endogenous IL-22BP in vivo and the pathways that regulate this receptor are unknown. Here we describe that IL-22BP has a crucial role in controlling tumorigenesis and epithelial cell proliferation in the colon. IL-22BP is highly expressed by dendritic cells in the colon in steady-state conditions. Sensing of intestinal tissue damage via the NLRP3 or NLRP6 inflammasomes led to an IL-18-dependent downregulation of IL-22BP, thereby increasing the ratio of IL-22/IL-22BP. IL-22, which is induced during intestinal tissue damage, exerted protective properties during the peak of damage, but promoted tumour development if uncontrolled during the recovery phase. Thus, the IL-22-IL-22BP axis critically regulates intestinal tissue repair and tumorigenesis in the colon.

Clinical, pathological, and molecular analyses of cardiovascular abnormalities in Costello syndrome: a Ras/MAPK pathway syndrome.

Cardiovascular abnormalities are important features of Costello syndrome and other Ras/MAPK pathway syndromes ("RASopathies"). We conducted clinical, pathological and molecular analyses of 146 patients with an HRAS mutation including 61 enrolled in an ongoing longitudinal study and 85 from the literature. In our study, the most common (84%) HRAS mutation was p.G12S. A congenital heart defect (CHD) was present in 27 of 61 patients (44%), usually non-progressive valvar pulmonary stenosis. Hypertrophic cardiomyopathy (HCM), typically subaortic septal hypertrophy, was noted in 37 (61%), and 5 also had a CHD (14% of those with HCM). HCM was chronic or progressive in 14 (37%), stabilized in 10 (27%), and resolved in 5 (15%) patients with HCM; follow-up data was not available in 8 (22%). Atrial tachycardia occurred in 29 (48%). Valvar pulmonary stenosis rarely progressed and atrial septal defect was uncommon. Among those with HCM, the likelihood of progressing or remaining stable was similar (37%, 41% respectively). The observation of myocardial fiber disarray in 7 of 10 (70%) genotyped specimens with Costello syndrome is consistent with sarcomeric dysfunction. Multifocal atrial tachycardia may be distinctive for Costello syndrome. Potentially serious atrial tachycardia may present in the fetus, and may continue or worsen in about one-fourth of those with arrhythmia, but is generally self-limited in the remaining three-fourths of patients. Physicians should be aware of the potential for rapid development of severe HCM in infants with Costello syndrome, and the need for cardiovascular surveillance into adulthood as the natural history continues to be delineated.

Isolated necrotizing aortitis presenting as incidental thoracoabdominal aortic aneurysm: a case report.

Noninfectious aortitis is frequently asymptomatic yet often leads to the development of ascending aortic aneurysms requiring repair. We present the case of a 64-year-old Caucasian woman who presented to our medical center with an incidentally discovered thoracoabdominal aneurysm. She had previously been in good health and had not complained of chest pain or been otherwise symptomatic. At presentation to our clinic, her ascending aorta measured 5 cm at the sinotubular junction (STJ) with dilation of her descending thoracic aorta to 6 cm. Her coronary angiogram was normal. Cross-sectional imaging was notable for thickening of the aortic wall along its length. The entity of isolated noninfectious aortitis is increasingly being recognized as an identifiable factor leading to ascending aneurysmal disease. In reviewing this case, we outline current understanding and guidelines for management and follow-up of this pathology. Operative repair of the ascending arch was conducted using an interpositional graft. The aortic valve apparatus was normal and the proximal anastomosis was created at the STJ. Intraoperatively, an inflammatory obliteration of the aortopulmonary window was noted. It was not possible to completely excise the posterior aortic wall. Our patient had an uneventful recovery and final pathology revealed necrotizing aortitis (NA). She is currently undergoing routine surveillance of her descending thoracoabdominal aneurysm. Recent case series indicate that NA is a histologically distinct process, which is associated commonly with development of ascending aneurysm, and although it is most commonly an isolated finding, it may be associated with other vascular abnormalities including stenoses of branch vessels. There is a growing body of literature suggesting that NA represents a distinct clinical entity, associated with the development of ascending aortic aneurysms. Further research is required to determine the optimal follow-up and value of medical therapies.

AAV-mediated chronic over-expression of SNAP-25 in adult rat dorsal hippocampus impairs memory-associated synaptic plasticity.

Long-term memory is formed by alterations in glutamate-dependent excitatory synaptic transmission, which is in turn regulated by synaptosomal protein of 25 kDa (SNAP-25), a key component of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor complex essential for exocytosis of neurotransmitter-filled synaptic vesicles. Both reduced and excessive SNAP-25 activity has been implicated in various disease states that involve cognitive dysfunctions such as attention deficit hyperactivity disorder, schizophrenia and Alzheimer's disease. Here, we over-express SNAP-25 in the adult rat dorsal hippocampus by infusion of a recombinant adeno-associated virus vector, to evaluate the consequence of late adolescent-adult dysfunction of the soluble N-ethylmaleimide-sensitive factor attachment protein receptor protein in the absence of developmental disruption. We report a specific and significant increase in the levels of extracellular glutamate detectable by microdialysis and a reduction in paired-pulse facilitation in the hippocampus. In addition, SNAP-25 over-expression produced cognitive deficits, delaying acquisition of a spatial map in the water maze and impairing contextual fear conditioning, both tasks known to be dorsal hippocampal dependent. The high background transmission state and pre-synaptic dysfunction likely result in interference with requisite synapse selection during spatial and fear memory consolidation. Together these studies provide the first evidence that excess SNAP-25 activity, restricted to the adult period, is sufficient to mediate significant deficits in the memory formation process.