Mild Acute Inflammation Research Articles

Mild exogenous inflammation blunts neural signatures of bounded evidence accumulation and reward prediction error processing in healthy male participants

BackgroundAltered neural haemodynamic activity during decision making and learning has been linked to the effects of inflammation on mood and motivated behaviours. So far, it has been reported that blunted mesolimbic dopamine reward signals are associated with inflammation-induced anhedonia and apathy. Nonetheless, it is still unclear whether inflammation impacts neural activity underpinning decision dynamics. The process of decision making involves integration of noisy evidence from the environment until a critical threshold of evidence is reached. There is growing empirical evidence that such process, which is usually referred to as bounded accumulation of decision evidence, is affected in the context of mental illness. MethodsIn a randomised, placebo-controlled, crossover study, 19 healthy male participants were allocated to placebo and typhoid vaccination. Three to four hours post-injection, participants performed a probabilistic reversal-learning task during functional magnetic resonance imaging. To capture the hidden neurocognitive operations underpinning decision-making, we devised a hybrid sequential sampling and reinforcement learning computational model. We conducted whole brain analyses informed by the modelling results to investigate the effects of inflammation on the efficiency of decision dynamics and reward learning. ResultsWe found that during the decision phase of the task, typhoid vaccination attenuated neural signatures of bounded evidence accumulation in the dorsomedial prefrontal cortex, only for decisions requiring short integration time. Consistent with prior work, we showed that, in the outcome phase, mild acute inflammation blunted the reward prediction error in the bilateral ventral striatum and amygdala. ConclusionsOur study extends current insights into the effects of inflammation on the neural mechanisms of decision making and shows that exogenous inflammation alters neural activity indexing efficiency of evidence integration, as a function of choice discriminability. Moreover, we replicate previous findings that inflammation blunts striatal reward prediction error signals.

Chronic electrical stimulation with a peripheral suprachoroidal retinal implant: a preclinical safety study of neuroprotective stimulation.

Extraocular electrical stimulation is known to provide neuroprotection for retinal cells in retinal and optic nerve diseases. Currently, the treatment approach requires patients to set up extraocular electrodes and stimulate potentially weekly due to the lack of an implantable stimulation device. Hence, a minimally-invasive implant was developed to provide chronic electrical stimulation to the retina, potentially improving patient compliance for long-term use. The aim of the present study was to determine the surgical and stimulation safety of this novel device designed for neuroprotective stimulation. Eight normally sighted adult feline subjects were monocularly implanted in the suprachoroidal space in the peripheral retina for 9-39weeks. Charge balanced, biphasic, current pulses (100μA, 500 µs pulse width and 50 pulses/s) were delivered continuously to platinum electrodes for 3-34weeks. Electrode impedances were measured hourly. Retinal structure and function were assessed at 1-, 2-, 4-, 6- and 8-month using electroretinography, optical coherence tomography and fundus photography. Retina and fibrotic thickness were measured from histological sections. Randomized, blinded histopathological assessments of stimulated and non-stimulated retina were performed. All subjects tolerated the surgical and stimulation procedure with no evidence of discomfort or unexpected adverse outcomes. The device position was stable after a post-surgery settling period. Median electrode impedance remained within a consistent range (5-10kΩ) over time. There was no change in retinal thickness or function relative to baseline and fellow eyes. Fibrotic capsule thickness was equivalent between stimulated and non-stimulated tissue and helps to hold the device in place. There was no scarring, insertion trauma, necrosis, retinal damage or fibroblastic response in any retinal samples from implanted eyes, whilst 19% had a minimal histiocytic response, 19% had minimal to mild acute inflammation and 28% had minimal to mild chronic inflammation. Chronic suprathreshold electrical stimulation of the retina using a minimally invasive device evoked a mild tissue response and no adverse clinical findings. Peripheral suprachoroidal electrical stimulation with an implanted device could potentially be an alternative approach to transcorneal electrical stimulation for delivering neuroprotective stimulation.

Antitumor and off-target effects of cholesterol-conjugated let-7a mimics in an orthotopic hepatocellular carcinoma xenograft nude mouse model.

The antitumor effects of two intravenous dosing regimens of Chol-let-7a on heptocellular carcinoma growth were compared using an orthotopic xenograft mouse model. Off-targets were analyzed with histopathological and ultrapathological features of heparenal tissue and cells in the Chol-let-7a-, Chol-miRCtrl-, and saline-treated (blank) xenograft mice and normal control mice. Then, let-7a abundance in orthotopic tumors, corresponding paracancerous hepatic tissue, and normal liver tissue from healthy nude mice was examined by reverse transcription-polymerase chain reaction. The distribution of Chol-let-7a and Chol-miRCtrl in vivo was examined by whole-animal imaging and frozen-sections observation. The experiments were approved by the Institutional Research Board of Peking Union Medical College Hospital. Continuous treatment with Chol-let-7a resulted in tumors that were 35.86% and 40.02% the size of those in the Chol-miRCtrl and blank xenograft group (P < 0.01 and P < 0.01, respectively), while intermittent dosing with Chol-let-7a resulted in tumors that were 65.42% and 56.66% the size of those in the Chol-miRCtrl and the blank control group, respectively (P < 0.05 and P < 0.05). In addition, some histopathological and ultrapathological features were only observed after treatment with the two cholesterol-conjugated molecules, however mild with intermittent dosing Chol-let-7a treatment, such as diffuse sinusoidal dilation and edema, primarily around the centrolobular vein in heptic tissues; mild hypercellularity with dilated capillary lumens in the renal tissue; and some organelle abnormalities found in heptic and renal cells. Furthermore, whole-animal imaging showed that Chol-let-7a and Chol-miRCtrl were predominantly distributed in the liver, kidney, and bladder regions after injection, and that the concentration of Chol-let-7a and Chol-miRCtrl in the kidney and the bladder decreased much slowly in the xenograft animals, especially in the Chol-miRCtrl group. Finally, RT-PCR analysis showed that let-7a levels were significantly increased in Chol-let-7a-treated xenografts compared with Chol-miRCtrl group (P=0.003) and blank xenograft group (P=0.001); however, the level was only equivalent to 50.6% and 40.7% of that in paracancerous hepatic tissue and hepatic tissue in normal mice, respectively. Chol-let-7a, administered either continuously or intermittently, showed effective antitumor efficacy. Chol-let-7a had some off-target effects, such as mild acute hepatitis-like inflammation and non-specific drug-induced kidney injury. The intermittent dosing regimen resulted in less damage than the continuous regimen, while maintaining relatively satisfactory antitumor efficacy, which could be useful for the investigation and possible clinical use of miRNA treatment regimens in the future.

The Histopathology of Anorectal Neisseria gonorrhoeae Infection.

Neisseria gonorrhoeae infection of the anorectal tract is often asymptomatic and infrequently biopsied, but pathologists can be tasked with identifying the histologic features of possible infection. The study was undertaken to better characterize clinical and morphologic features of confirmed anorectal gonococcal infection. From 2011 to 2020, 201 positive gonococcal nucleic acid amplification testing samples from 174 patients collected from the distal colorectum and/or anus were matched to eight patients with concurrent biopsy specimens of the distal anorectum. Complete demographic, clinical, and infectious information was collected for each biopsied patient. The histomorphologic features of each biopsy were systematically tabulated. All eight gonococcal cases were obtained from men who have sex with men. Each case showed at least mild acute inflammation with moderate activity identified in one case with concurrent cytomegalovirus infection. Intense lymphoplasmacytic infiltration was not commonly seen (two of eight). Half of the cases showed mucosal ulceration, and seven of eight cases demonstrated lymphoid aggregates. The microscopic features are mild compared with other well-described types of infectious proctitis, with most cases displaying mild acute inflammation and scattered lymphoid aggregates. These findings highlight the importance of obtaining a complete patient history and recommending additional infectious workup even when only subtle changes are present.

Acute peripheral inflammation does not change cerebral glucose metabolism

AbstractBackgroundNeuroinflammation is a phenomenon already described in the brain of Alzheimer's disease (AD) individuals, with sustained neuroinflammatory response being detrimental. The effect of peripheral inflammation in AD is less understood. In fact, central nervous system (CNS) is protected from peripheral inflammation by the blood‐brain barrier. However, we recently demonstrated that severe sepsis causes acute brain metabolic disturbances, evidencing the CNS invasion of inflammatory mediators may affect brain function. Nevertheless, whether mild acute peripheral inflammation affects brain metabolism remains unclear. Objective: Here, we aimed at investigating the impact of mild acute peritonitis on brain energetic metabolism. Hypothesis: We hypothesized that mild peripheral inflammation will cause widespread brain glucose hypometabolism.MethodAdult male Wistar rats were randomly separated into carrageenan group, a model of mild acute peripheral inflammation (n=6), and control group (n=6). Peritonitis was induced by the administration of 500 µg of intraperitoneal (i.p.) carrageenan, while the control group was i.p. injected with 500 µl of saline. In vivo cerebral glucose metabolism was assessed using (18F)FDG‐microPET 4 h after inflammatory induction, which represents the first peak of inflammation. The peripheral inflammatory process was evaluated by analyzing the peritoneal lavage in a Flow Cytometer 48 h after the scanning i.p. injections, the second of peak of inflammation,ResultThe animals treated with carrageenan presented a 5‐fold increase in macrophages numbers (p&lt;0,05) and a 2‐fold increase in monocytes numbers (p&gt;0,05). However, our data showed that carrageenan‐induced peripheral inflammation did not cause acute changes in the whole brain glucose metabolism (p&gt;0,05). Further regional analysis, in frontal and temporoparietal cortices, striatum, hippocampus, cerebellum, thalamus and hypothalamus, did not identify any difference between groups.ConclusionMild acute peripheral inflammation does not change brain glucose metabolism. Further evaluation aiming to investigate long‐term consequences of sustained mild inflammation are needed.

S1783 Recurrent Metastatic Appendiceal Adenocarcinoma Presenting as Non-Specific Colitis – A Case Report

Introduction: Malignancies of the appendix are rare and there is a known association of appendicular carcinoid of the appendix and Crohn's disease. Appendicular carcinoid can be mixed with mucinous adenocarcinoma in both primary and metastatic lesions. We present an unusual case of a patient who presented with nonspecific colitis as a manifestation of recurrent metastatic appendiceal adenocarcinoma. Case Description/Methods: A 57-year-old male patient presented with 2 weeks of left lower quadrant pain, diarrhea, and hematochezia. Two years prior to this presentation, he had a perforated appendicitis due to poorly differential adenocarcinoma and goblet cell carcinoid. He was then found to have peritoneal metastasis treated with omentectomy, right hemicolectomy, multiple peritonectomy, and hyperthermic intraperitoneal chemotherapy. He also had multiple intra-abdominal abscesses requiring drainage and a Colo-cutaneous fistula requiring closure. A CT scan showed distal sigmoid colon and rectal thickening. Colonoscopy with biopsies of the terminal ileum showed mild acute inflammation, atypical submucosal glands suspicious for mucinous adenocarcinoma and acute colitis of the entire colon and rectum. After ruling out infectious etiologies, he was started on a prednisone taper with significant improvement in his symptoms. He was then referred to an outside institution for surgical considerations. However, he continued to have intermittent abdominal pain workup revealed a new peritoneal nodule consistent with his prior adenocarcinoma. He was given FOLFOX and bevacizumab for chemotherapy for metastatic disease as he was not a surgical candidate. Discussion: Appendicular carcinoid can be associated with Crohn’s colitis and this has been reported in the literature. This a unique case in which patient had a nonspecific inflammatory colitis which responded well to corticosteroid treatment and imaging identified recurrence of appendicular mucinous adenocarcinoma. If infectious etiologies for non-specific colitis have been excluded, thorough evaluation needs to be performed to rule out metastatic disease in patients with appendicular adenocarcinoma and/or carcinoid as treatment options can vary.

S1483 A 20-Year-OId Female With Obstructive Jaundice and a Pancreatic Head Mass: A Case Report of Type 2 Autoimmune Pancreatitis

Introduction: Autoimmune pancreatitis (AIP) is a form of chronic pancreatitis that may be associated with IgG4 laden lymphoplasmacytic infiltration and fibrosis in multiple organs. It accounts for only a small percentage of all patients with chronic pancreatitis. It can present with abdominal pain, jaundice, recurrent acute pancreatitis, or clinical findings similar to pancreatic cancer. Radiologic findings can also be similar to the above. Therefore, it is important to fully understand the radiologic and histologic nuances of AIP. We review a case of a 20-year-old female who presented with abdominal pain and jaundice who was subsequently diagnosed with Type 2 AIP. Case Description/Methods: A patient with no known past medical history presented with one week of abdominal pain. Imaging demonstrated a normal appearing pancreas with a nodular area of soft tissue fullness at the junction of the pancreatic head and body. Patient returned a few weeks later with jaundice. Endoscopic retrograde cholangiopancreatography (ERCP) revealed a significant biliary stricture which was stented. EUS with biopsies demonstrated mild acute on chronic inflammation of the ampulla and mild acute inflammation of the pancreatic head as well as benign pancreatic parenchyma with edema, very focal fibrosis, and focal neutrophilic infiltrate in acini and intralobular small ducts. Steroids were prescribed leading to resolution of signs and symptoms. Discussion: Initial presentation of AIP can mimic that of other pancreatic pathology so further imaging with biopsy is necessary to make a final diagnosis. Type 1 and Type 2 AIP both have histologic findings of periductal infiltration of plasma cells and lymphocytes, peculiar storiform fibrosis, and venulitis. Type 1 typically has a high number of IgG4 positive plasma cells and can be associated with various systemic lesions related to IgG4 positive cell infiltrates. Type 2 is known for intraluminal and intraepithelial neutrophils in small to medium ducts and acini causing destruction of the duct lumen and is considered a pancreatic specific disease. In both types imaging tends to show diffuse parenchymal enlargement with delayed enhancement and ductal strictures without significant upstream dilatation. Treatment of AIP consists of steroids with Type 1 known to have relapses requiring re-treatment. Based on the histologic and radiologic findings a presumptive diagnosis of Type 2 AIP was made. Response to steroid treatment and no evidence of relapse confirmed the diagnosis.Figure 1.: A single severe stenosis seen in the lower third of the common bile duct.

Leukemoid Reaction in a Case of Chronic Cholecystitis With Focal Mild Acute Inflammation

Leukemoid reaction is a rare condition of marked increase of the white blood cells (WBC) in the peripheral blood, mostly more than 50 × 109/L. Although its most common cause is infection, acute or chronic cholecystitis has been hardly mentioned. This report aimed to present the leukemoid reaction found in a Thai who had chronic cholecystitis with focal acute inflammation. A 74-year-old woman had low-graded fever and generalized vague abdominal discomfort for 2 days. The physical examination showed the body temperature 37.7 °C and unremarkable abdominal signs. Her blood tests showed: hemoglobin 9.0 g/L, WBC 52.48 × 109/L, neutrophil 91%, band form 1%, platelet 434 × 109/L, and alkaline phosphatase (ALP) 290 U/L. The blood cultures yielded no growth. The computed tomography of the abdomen revealed 2 stones in the common bile duct (CBD) causing obstruction; the gall bladder (GB) showed mild dilatation with thin wall containing multiple small gall stones; no pericholecystic fluid and normal size of spleen. She promptly underwent operative cholecystectomy, CBD choledochoscopy, stones removal and T-tube choledochostomy. Along with the surgery, intravenous ertapenem was also administered. The pathology of the gall bladder was chronic cholecystitis with focal mild acute inflammation. With these therapies, fever daily decreased and finally disappeared within 5 days meanwhile the WBC count also gradually diminished every day till 8.04 × 109/L within 7 days. The WBC count was still normal one month later. The diagnosis of leukemoid reaction was concluded and it was presumably be associated with chronic calculous cholecystitis with focal acute inflammation although the BCR-ABL translocation had never been explored.&#x0D;

Poly(amino acid) based fibrous membranes with tuneable in vivo biodegradation.

In this work two types of biodegradable polysuccinimide-based, electrospun fibrous membranes are presented. One contains disulfide bonds exhibiting a shorter (3 days) in vivo biodegradation time, while the other one has alkyl crosslinks and a longer biodegradation time (more than 7 days). According to the mechanical measurements, the tensile strength of the membranes is comparable to those of soft the connective tissues and visceral tissues. Furthermore, the suture retention test suggests, that the membranes would withstand surgical handling and in vivo fixation. The in vivo biocompatibility study demonstrates how membranes undergo in vivo hydrolysis and by the 3rd day they become poly(aspartic acid) fibrous membranes, which can be then enzymatically degraded. After one week, the disulfide crosslinked membranes almost completely degrade, while the alkyl-chain crosslinked ones mildly lose their integrity as the surrounding tissue invades them. Histopathology revealed mild acute inflammation, which diminished to a minimal level after seven days.

Lymphogranuloma venereum (LGV) of the anorectum: evaluation of clinicopathological associations and the utility of a novel RNA in-situ hybridisation stain.

Recent studies from multiple global regions have reported a resurgence of lymphogranuloma venereum (LGV) proctitis, which is caused by Chlamydia trachomatis (CT). LGV proctitis is histologically indistinguishable from other forms of sexually transmitted proctitis and is difficult to differentiate from inflammatory bowel disease. While immunohistochemical stains are available for syphilis, there is no commonly available stain for the tissue identification of CT. From 200 positive CT nucleic acid tests (NAT) from anorectal swabs, we identified 12 patients with biopsies collected from the distal colorectum or anus within 90days of the positive NAT. We collected basic demographic information and tabulated clinical and histological findings. We examined the performance of a novel RNA in-situ hybridisation (ISH) stain targeting CT 23s rRNA on these 12 cases and 10 controls from the anorectum. All 12 patients were male; nine were HIV+, two had concurrent gonococcal infection, one had concurrent syphilis and one had cytomegalovirus co-infection. The majority of biopsies (11 of 12) showed mild or moderate acute inflammation, had a prominent lymphoplasmacytic infiltrate (eight of 11) and lacked marked crypt distortion (10 of 10). The RNA ISH stain was positive in 10 of 12 cases (sensitivity 83%). One case showed equivocal staining. No controls showed definitive positive staining (specificity 100%). One had equivocal staining. Our series showed that anorectal LGV had similar histological findings to those of prior STI proctitis series predominantly comprised of syphilis. The novel RNA ISH stain was sensitive and specific and may show utility in differentiating types of STI proctitis.

MiR-21 mediates nickel nanoparticle-induced pulmonary injury and fibrosis

We and other groups have demonstrated that exposure to nickel nanoparticles (Nano-Ni) results in severe and persistent lung inflammation and fibrosis, but the underlying mechanisms remain unclear. Here, we propose that miR-21 may play an important role in Nano-Ni-induced lung inflammation, injury, and fibrosis. Our dose- and time-response studies demonstrated that exposure of C57BL/6J (WT) mice to Nano-Ni resulted in upregulation of miR-21, proinflammatory cytokines, and profibrotic mediators. Histologically, exposure to Nano-Ni caused severe pulmonary inflammation and fibrosis. Based on the dose- and time-response studies, we chose a dose of 50 µg of Nano-Ni per mouse to compare the effects of Nano-Ni on WT with those on miR-21 KO mouse lungs. At day 3 post-exposure, Nano-Ni caused severe acute lung inflammation and injury that were reflected by increased neutrophil count, CXCL1/KC level, LDH activity, total protein concentration, MMP-2/9 protein levels and activities, and proinflammatory cytokines in the BALF or lung tissues from WT mice, which were confirmed histologically. Although Nano-Ni had similar effects on miR-21 KO mice, the above-mentioned levels were significantly lower than those in WT mice. Histologically, lungs from WT mice exposed to Nano-Ni had infiltration of a large number of polymorphonuclear (PMN) cells and macrophages in the alveolar space and interstitial tissues. However, exposure of miR-21 KO mice to Nano-Ni only caused mild acute lung inflammation and injury. At day 42 post-exposure, Nano-Ni caused extensive pulmonary fibrosis and chronic inflammation in the WT mouse lungs. However, exposure of miR-21 KO mice to Nano-Ni only caused mild lung fibrosis and chronic lung inflammation. Our results also showed that exposure to Nano-Ni caused upregulation of TGF-β1, phospho-Smad2, COL1A1, and COL3A1 in both WT and miR-21 KO mouse lungs. However, levels were significantly lower in miR-21 KO mice than in WT mice, except TGF-β1, which was similar in both kinds of mice. Decreased expression of Smad7 was observed in WT mouse lungs, but not in miR-21 KO mice. Our results demonstrated that knocking out miR-21 ameliorated Nano-Ni-induced pulmonary inflammation, injury, and fibrosis, suggesting the important role of miR-21 in Nano-Ni-induced pulmonary toxicity.

Cervical Epidural and Subarachnoid Catheter Placement in Standing Adult Horses.

Horses underwent either cervical epidural space (CES) catheterization or subarachnoid space (SAS) catheterization while restrained in stocks, under deep sedation (detomidine and morphine) and local anesthesia (mepivacaine 2%) block. Catheters were placed under ultrasound guidance with visualization of the dura, SAS, and spinal cord between the first (C1) and second (C2) cervical vertebrae. Following sedation and sterile skin preparation, operator 1 placed under ultrasound guidance, a 6- or 8-inch Tuohy needle with the bevel oriented caudally. For CES, a 6-inch Touhy needle was used with the hanging drop technique to detect negative pressure, and operator 2 then passed the epidural catheter into the CES. For SAS, following puncture of the dura, cerebrospinal fluid (CSF) was aspirated prior to placement of the epidural catheter. Placement into either CES or SAS was confirmed with plain and contrast radiography. Catheters were wrapped for the duration of the study. CSF cytology was assessed up to every 24 h for the study period. Horses were assessed daily for signs of discomfort, neck pain, catheter insertion site swelling, or changes in behavior. A complete postmortem assessment of the spinal tissues was performed at the end of the study period (72 h). Two horses had CES catheters and five horses had SAS catheters placed successfully. All horses tolerated the catheter well for the duration of the study with no signs of discomfort. Ultrasound was essential to assist placement, and radiography confirmed the anatomical location of the catheters. CSF parameters did not change over the study period (P > 0.9). There was evidence of mild meningeal acute inflammation in one horse and hemorrhage in another consistent with mechanical trauma. Placement of an indwelling CES or SAS catheter appears to be safe, technically simple, and well tolerated in standing sedated normal horses.

Blood Pressure Maintained in Response to a Hypotensive Stimulus During Mild Acute Inflammation

IntroductionSevere acute inflammation such as sepsis disrupts autonomic nervous system function and jeopardizes blood pressure regulation. Severe experimental inflammation (endotoxin) blunts the vascular baroreflex to increase muscle sympathetic nerve activity in response to reductions in blood pressure and abolishes baroreflex control of heart rate. Whether mild acute inflammation alters the ability to maintain blood pressure and peripherally vasoconstrict during a hypotensive challenge is unknown.PurposeDetermine whether mild acute inflammation alters the ability to maintain blood pressure and peripherally vasoconstrict during lower body negative pressure (LBNP).MethodsThirteen young, healthy adults (26 ± 4.5 yrs; male n=5; 21.3 ± 2.0 kg/m2) completed assessments before (baseline) and 24h after the induction of acute inflammation via typhoid vaccination. Measures were completed after 10 min rest (rest) and after 2 minutes of equilibration to −20 mmHg of LBNP. Measures included brachial blood flow via ultrasonography and brachial blood pressure and heart rate via an automatic blood pressure cuff. Conductance was calculated as blood flow/mean arterial pressure (MAP). ELISAs were performed on serum blood samples from baseline and 24h to assess inflammatory markers C‐reactive protein (CRP) and interleukin‐6 (IL‐6).ResultsAcute inflammation was evident at 24h by increases in IL‐6 (0.98 ± 0.55 to 1.78 ± 0.68 pg/mL, p&lt;0.01) and CRP (0.42 ± 0.98 to 1.30 ± 1.44 mg/L, p=0.02). Acute inflammation did not alter the blood flow, conductance, diameter, or MAP response to LBNP (see table , p for interactions &gt;0.05). Blood flow, conductance, and velocity were lower during LBNP compared to rest (p&lt;0.01) whereas brachial diameter and MAP were maintained (p&gt;0.05). Heart rate was elevated at 24h and increased during LBNP at baseline (p&lt;0.01) but did not change during LBNP at 24h (interaction p&lt;0.01).ConclusionThe ability of young adults to respond to a hypotensive challenge and maintain blood pressure was preserved during mild acute inflammation, however, the heart rate response was altered. Our data may suggest that mild acute inflammation alters baroreflex control of the heart rate response to a hypotensive challenge. Hemodynamic response to LBNP at baseline and during acute inflammation. Baseline 24H p‐value Rest LBNP Rest LBNP Visit LBNP Interaction Brachial blood flow, mL/min 47.0 ± 14.4 40.8 ± 11.8 45.4 ± 14.2 42.0 ± 16 0.94 0.04 0.56 Conductance, mL/min/mmHg 52.2 ± 15.5 44.7 ± 11.9 49.8 ± 14.3 46.5 ± 16.6 0.93 0.03 0.46 Brachial diameter, mm 3.81 ± 0.85 3.83 ± 0.87 3.89 ± 0.84 3.81 ± 0.81 0.46 0.62 0.12 Mean velocity, cm/s 7.5 ± 3.3 6.4 ± 2.9 6.8 ± 3 6.4 ± 2.6 0.35 0.04 0.44 MAP, mmHg 90 ± 9 91 ± 8 91 ± 6 90 ± 7 0.81 0.87 0.23 Heart rate, bpm 52 ± 11 57 ± 11 56 ± 12 57 ± 12 0.08 &lt;0.01 &lt;0.01 Data mean ± standard deviation. MAP, mean arterial pressure.

2445 Appendiceal Pathology in Women with Endometriosis

Study Objective To report the prevalence of abnormal appendiceal pathology in women with pelvic pain and pathology-confirmed pelvic endometriosis. Design Retrospective case series. Setting Tertiary care referral center. Patients or Participants Forty patients with pelvic pain undergoing laparoscopy for possible endometriosis with concomitant laparoscopic appendectomy during a 5 month period. Interventions Laparoscopic excision of suspected endometriosis with concomitant laparoscopic appendectomy on patients with visible abnormalities of the appendix. Measurements and Main Results Forty patients underwent laparoscopic excision of suspected endometriosis with visible abnormalities involving the appendix and were treated with concomitant laparoscopic appendectomy. Of this subgroup, thirty-eight patients had pelvic endometriosis and eighteen patients (47.3%) had appendiceal pathology: seven (18%) with pathology-confirmed appendiceal endometriosis, three (7.9%) with carcinoid neuroendocrine tumor, two (5.3%) with acute appendicitis, two (5.3%) with mild acute inflammation, two (5.3%) with lymphoid hyperplasia, and two (5.3%) with fibrous obliteration. The prevalence of appendiceal pathology in patients with pelvic endometriosis was 47.3%. Conclusion Appendiceal pathology may be a contributing factor to pelvic pain in women with endometriosis and should be routinely inspected for visible abnormalities.

1840 Salivary Gland Choristoma: A Rare Finding at Gastroesophageal Junction

INTRODUCTION: Choristoma is tumor-like outgrowth of heterotopic and mature tissue located at anatomically unusual sites. Heterotopic salivary gland tissue (HSGT) has been most commonly described in head and neck region but can rarely involve gastrointestinal (GI) tract with a few cases reported in the literature. CASE DESCRIPTION/METHODS: An 87-year-old female with past medical history of gastroesophageal reflux disease (GERD), hypertension, and chronic kidney disease was admitted for an acute DVT. Due to worsening anemia, she underwent an upper endoscopy that showed a small nodularity at the GE junction (Figure 1a), a large hiatal hernia, and reflux esophagitis in the lower one-third of the esophagus (Figure 1b). Biopsy of the nodule demonstrated an esophagogastric junction-type mucosa with mild to moderate chronic inflammation, mild acute inflammation and focal glandular tissue consistent with heterotopic salivary gland tissue (Figure 1c, d). No intestinal metaplasia or dysplasia were noted. DISCUSSION: Salivary gland choristoma at the gastroesophageal junction (GEJ) is an extremely rare entity, with only one case reported in the English literature. Additionally, two other cases of HSGT at GEJ not in the form of choristoma were described in the same report. All of the cases had a medical history of GERD. One of the HSGT cases had reflux esophagitis while the other had Barret’s esophagus with high-grade dysplasia. Similarly, our patient had a history of GERD with reflux esophagitis. She was diagnosed incidentally, through an EGD-guided biopsy of the nodule to exclude malignancy. It is well-known that intestinal columnar metaplasia at the GEJ can occur secondary to chronic acid exposure and inflammation in the setting of GERD. The origin of these intestinal glandular cells remains unknown. Furthermore, pancreatic acinar metaplasia at the GEJ is a relatively common finding, but the causative relationship between GERD and pancreatic acinar metaplasia is obscure. Salivary gland choristoma of the GEJ could be a metaplastic change in the setting chronic inflammation as a result of reflux esophagitis. However, the biological and clinical significance of this finding is yet to be investigated.

The opposing effects of acute inflammation and iron deficiency anemia on serum hepcidin and iron absorption in young women.

Hepatic hepcidin synthesis is stimulated by inflammation but inhibited during iron deficiency anemia (IDA). In humans, the relative strength of these opposing signals on serum hepcidin and the net effect on iron absorption and systemic iron recycling is uncertain. In this prospective, 45-day study, in young women (n=46; age 18-49 years) with or without IDA, we compared iron and inflammation markers, serum hepcidin and erythrocyte iron incorporation from 57Fe-labeled test meals, before and 8, 24 and 36 hours (h) after influenza/DPT vaccination as an acute inflammatory stimulus. Compared to baseline, at 24-36 h after vaccination: 1) interleukin-6 increased 2-3-fold in both groups (P<0.001); 2) serum hepcidin increased >2-fold in the non-anemic group (P<0.001), but did not significantly change in the IDA group; 3) serum iron decreased in the non-anemic group (P<0.05) but did not change in the IDA group; and 4) erythrocyte iron incorporation did not change in either of the two groups, but was approximately 2-fold higher in the IDA group both before and after vaccination (P<0.001). In this study, mild acute inflammation did not increase serum hepcidin in women with IDA, suggesting low iron status and erythropoietic drive offset the inflammatory stimulus on hepcidin expression. In non-anemic women, inflammation increased serum hepcidin and produced mild hypoferremia, but did not reduce dietary iron absorption, suggesting iron-recycling macrophages are more sensitive than the enterocyte to high serum hepcidin during inflammation. The study was registered as a prospective observational trial at clinicaltrials.gov identifier: 02175888. The study was funded by the International Atomic Energy Agency.

Comparative mouse lung injury by nickel nanoparticles with differential surface modification

BackgroundPrevious studies have demonstrated that exposure to nickel nanoparticles (Nano-Ni) causes oxidative stress and severe, persistent lung inflammation, which are strongly associated with pulmonary toxicity. However, few studies have investigated whether surface modification of Nano-Ni could alter Nano-Ni-induced lung injury, inflammation, and fibrosis in vivo. Here, we propose that alteration of physicochemical properties of Nano-Ni through modification of Nano-Ni surface may change Nano-Ni-induced lung injury, inflammation, and fibrosis.MethodsAt first, dose–response and time-response studies were performed to observe lung inflammation and injury caused by Nano-Ni. In the dose–response studies, mice were intratracheally instilled with 0, 10, 20, 50, and 100 μg per mouse of Nano-Ni and sacrificed at day 3 post-exposure. In the time-response studies, mice were intratracheally instilled with 50 µg per mouse of Nano-Ni and sacrificed at days 1, 3, 7, 14, 28, and 42 post-instillation. At the end of the experiment, mice were bronchoalveolar lavaged (BAL) and the neutrophil count, CXCL1/KC level, LDH activity, and concentration of total protein in the BAL fluid (BALF) were determined. In the comparative studies, mice were intratracheally instilled with 50 μg per mouse of Nano-Ni or with the same molar concentration of Ni as Nano-Ni of either partially [O]-passivated Nano-Ni (Nano-Ni–P) or carbon-coated Nano-Ni (Nano-Ni–C). At day 3 post-exposure, BAL was performed and the above cellular and biochemical parameters in the BALF were analyzed. The MMP-2/9 protein levels and activities in the BALF and mouse lung tissues were also determined. Mouse lung tissues were also collected for H&E staining, and measurement of thiobarbituric acid reactive substances (TBARS) and 8-hydroxy-2′-deoxyguanosine (8-OHdG) in the genomic DNA. At day 42 post-exposure, mouse right lung tissues were collected for H&E and Trichrome stainings, and left lung tissues were collected to determine the hydroxyproline content.ResultsExposure of mice to Nano-Ni resulted in a dose–response increase in acute lung inflammation and injury reflected by increased neutrophil count, CXCL1/KC level, LDH activity, and concentration of total protein in the BALF. The time-response study showed that Nano-Ni-induced acute lung inflammation and injury appeared as early as day 1, peaked at day 3, and attenuated at day 7 post-instillation. Although the neutrophil count, CXCL1/KC level, LDH activity, and concentration of total protein in the BALF dramatically decreased over the time, their levels were still higher than those of the controls even at day 42 post-exposure. Based on the results of the dose- and time-response studies, we chose a dose of 50 µg per mouse of Nano-Ni, and day 3 post-exposure as short-term and day 42 post-exposure as long-term to compare the effects of Nano-Ni, Nano-Ni–P, and Nano-Ni–C on mouse lungs. At day 3 post-exposure, 50 μg per mouse of Nano-Ni caused acute lung inflammation and injury that were reflected by increased neutrophil count, CXCL1/KC level, LDH activity, concentration of total protein, and MMP-2/9 protein levels and activities in the BALF. Nano-Ni exposure also caused increased MMP-2/9 activities in the mouse lung tissues. Histologically, infiltration of large numbers of neutrophils and macrophages in the alveolar space and interstitial tissues was observed in mouse lungs exposed to Nano-Ni. Nano-Ni–P exposure caused similar acute lung inflammation and injury as Nano-Ni. However, exposure to Nano-Ni–C only caused mild acute lung inflammation and injury. At day 42 post-exposure, Nano-Ni caused extensive interstitial fibrosis and proliferation of interstitial cells with inflammatory cells infiltrating the alveolar septa and alveolar space. Lung fibrosis was also observed in Nano-Ni–P-exposed lungs, but to a much lesser degree. Only slight or no lung fibrosis was observed in Nano-Ni–C-exposed lungs. Nano-Ni and Nano-Ni–P, but not Nano-Ni–C, caused significantly elevated levels of TBARS in mouse lung tissues and 8-OHdG in mouse lung tissue genomic DNA, suggesting that Nano-Ni and Nano-Ni–P induce lipid peroxidation and oxidative DNA damage in mouse lung tissues, while Nano-Ni–C does not.ConclusionOur results demonstrate that short-term Nano-Ni exposure causes acute lung inflammation and injury, while long-term Nano-Ni exposure causes chronic lung inflammation and fibrosis. Surface modification of Nano-Ni alleviates Nano-Ni-induced pulmonary effects; partially passivated Nano-Ni causes similar effects as Nano-Ni, but the chronic inflammation and fibrosis were at a much lesser degree. Carbon coating significantly alleviates Nano-Ni-induced acute and chronic lung inflammation and injury.

Home-Made Tooth Whitener: An Unusual Cause of Dysphagia

A 54 yo female with a history of presumed reflux that did not improve despite being on omeprazole 40mg daily was evaluated for a several month history of worsening dysphagia to solids only. An upper endoscopy showed diffuse proximal esophageal fibrosis with two rings that caused moderate to severe obstruction in the proximal and middle esophagus. Balloon dilation using a 6-7-8 mm dilator was required to traverse the stricture. The rest of the esophagus also showed extensive scarring and trachealization with minimal to completely absent peristalsis. Biopsies showed benign squamous mucosa with focal mild acute inflammation and was negative for features of eosinophilic esophagitis, dysplasia, malignancy and organisms. No obvious risk factor or etiology were identified. She denied any history of radiation. Chest CT was negative for extrinsic pathology. On further questioning the patient admitted to using a diluted form of cleaning bleach to whiten her teeth. She reported using this concoction for the past 6-8 months several times per week. Due to resultant burning in the mouth she would subsequently swallow this solution. The patient is currently undergoing twice monthly dilation of her esophagus with mild improvement in her dysphagia. House hold bleach is a strong alkali with a pH of 12 to 13, depending on the strength, that usually contains approximately 5.25% sodium hypochlorite. Bleach ingestion has been rarely reported to cause severe esophageal injury. Considering absence of other causes in our patient we construed that the repetitive ingestion of small amounts of bleach over time caused esophageal injury which likely lead to fibrosis and eventual stricture formation. In some severe cases of alkali ingestion esophageal stent placement or even esophagectomy may be required. In addition patients who suffer esophageal damage from alkali ingestion have an increased risk of corrosive-induced carcinoma (CIC) that can be as high as 1000 fold. However, no official guidelines for the surveillance of CIC have been established. On review of the literature no cases like this have been reported. This practice may potentially be more prevalent in our region and lack of awareness amongst patients may lead to more cases in the future. This case emphasizes the importance of history taking and highlights an additional risk factor for physicians to rule out amongst patients presenting with dysphagia and esophageal stricture without any obvious etiology.1713_A Figure 1. Esophageal Ring.1713_B Figure 2. Trachealization of the Esophagus.

Sarcina as an Unknown Culprit of Esophageal Strictures

Sarcina ventriculi is a gram positive organism that is well known to veterinarians, however the exact pathogenicity in humans is not well delineated. Several cases of human disease have been described including emphysematous gastritis, gastric ulcers and perforation, and recently esophageal pneumatosis. Here we present a case of Sarcina-associated esophageal stricture. A 65 year old woman with metastatic breast cancer and history of Schatzki ring presented with two months of progressive dysphagia. Imaging with x-ray fluoroscopy revealed an irregularly short segment stricture at the mid to distal esophagus. Esophagogastroduodenoscopy (EGD) showed a benign appearing stenosis at 32 cm that measured 3 mm in diameter and gastric ulcers. She underwent subsequent dilation under fluoroscopy with a Savary dilator up to 12 mm and was medically managed with a proton pump inhibitor. Esophageal biopsies revealed acute and chronic inflammation with rare large tetrads of bacterial cocci, morphologically consistent with Sarcina organisms. In light of Sarcina presence, she was treated with 7 days of metronidazole and ciprofloxacin. An esophageal stent was placed after serial dilation failed to improve symptoms. Unfortunately, her hospital course was complicated by acute pulmonary embolisms, hemorrhagic gastropathy, and persistent vomiting resulting in subsequent removal of the stent. Ultimately, the patient transitioned to palliative comfort care due to overall poor prognosis. Sarcina ventriculi is a well described pathogen in veterinary medicine, but its role in human disease is not as well understood. Human presentation has varied widely from gastrointestinal symptoms of nausea, vomiting, epigastric pain to emphysematous gastritis complicated by gastric perforation. EGD findings have also varied but common themes have emerged including luminal findings of retained food residue and mucosal findings of erosion and gastric ulcers. While most reported cases of Sarcina pathology have been gastric in location, very few have been esophageal. Studies of the esophageal microbiome did not identify Sarcina in patients with normal histology, which suggests that in contrast to gastric sites the organism is more likely to be a pathogen. Compared to previous esophageal pathology reported, we report a case of Sarcina that occurred in the setting of stasis as a result of esophageal stricture. It will be important to further assess the importance of Sarcina in the pathogenesis of esophageal diseases.Figure: EGD findings of severe esophageal stricture.Figure: Purple Sarcina cocci in characteristic tetrads (long arrows) are present in the luminal aspect of this gastric biopsy. Notice the large size of the organisms in comparison to the luminal bacilli (arrowheads) in the background. There is mild acute inflammation, demonstrated by the intraepithelial neutrophils (short arrows), in the adjacent gastric epithelium. Hematoxylin and eosin (H&E) stain, original magnification 600x.Figure: Esophagus squamous mucosa with luminal Sarcina organisms (long arrows). Arrowhead points to background bacilli for size comparison. H&E 600x.

A Rare Case of Abdominal Pain: Gastric Sarcoidosis With Quiescent Pulmonary Disease

A 77-year-old African American female presented with 3-weeks of epigastric abdominal pain, bilious emesis, and dysphagia to solids. Pain was sharp, mid-epigastric, 10/10 in severity, and was exacerbated by oral intake. The patient's past medical history included hypertension, coronary artery disease, and pulmonary sarcoidosis, which was diagnosed by bronchoscopy 21 years prior and treated with corticosteroids for one year. She was followed closely and was in remission for 20 years. On presentation, physical exam was significant for hyperactive bowel sounds. Lab work was within normal limits. The patient underwent endoscopy, which showed a single non-bleeding 6mm ulcer in the stomach body and mucosal erythema and nodularity in the antrum and stomach body. Biopsies revealed non-necrotizing granuloma in the gastric mucosa with mild chronic and focal acute inflammation. Gastric ulcer histology was benign. Stains were negative for H. pylori, acid-fast bacilli, and fungal organisms. The patient was started on oral prednisone 40mg daily for a diagnosis of gastric sarcoidosis. She was symptomatically improved after two days of treatment. Sarcoidosis is a chronic disease; however, about ⅔ of patients have remission within a decade after diagnosis, while only ⅓ have progressive disease that leads to organ damage. Less than 5% of patients have disease recurrence after they are in remission for more than 1 year. Recurrence of active disease in an extrapulmonary location after a prolonged period of latency from pulmonary sarcoid is extremely rare. Most cases of gastric sarcoidosis are asymptomatic and found on incidental biopsy. Symptomatic patients most often present with epigastric pain, vomiting, and weight loss. Endoscopic findings range from mucosal erythema and ulcers to nodular lesions to linitis plastica. Biopsy showing noncaseating granulomas is critical for diagnosis, but not pathognomonic. Granulomas can also be seen in Crohn's disease, tuberculosis, gastric malignancy, lymphoma, and idiopathic granulomatous gastritis. To establish a diagnosis of GI sarcoidosis, in addition to histology, other etiologies must be excluded. There also must be clinical, radiographic or histopathologic evidence of sarcoidosis in another organ system. If the GI tract is the only organ involved, sarcoidosis cannot be confirmed. Oral corticosteroids are the mainstay for treatment of symptomatic GI sarcoidosis. Improvement can be seen quickly, as shown in our patient. Surgery is reserved for refractory or life-threatening cases. This case highlights the importance of having GI sarcoidosis in the differential diagnosis for epigastric pain, despite quiescent pulmonary disease.Figure 1Figure 2Figure 3