IL-17RA-Mediated Epithelial Cell Activity Prevents Severe Inflammatory Response to Helicobacter pylori Infection.

Helicobacter pylori is a Gram-negative pathogen that colonizes the stomach, induces inflammation, and drives pathological changes in the stomach tissue, including gastric cancer. As the principal cytokine produced by Th17 cells, IL-17 mediates protective immunity against pathogens by inducing the activation and mobilization of neutrophils. Whereas IL-17A is largely produced by lymphocytes, the IL-17 receptor is expressed in epithelial cells, fibroblasts, and hematopoietic cells. Loss of the IL-17RA in mice results in impaired antimicrobial responses to extracellular bacteria. In the context of H. pylori infection, this is compounded by extensive inflammation in Il17ra-/- mice. In this study, Foxa3creIl17rafl/fl (Il17raΔGI-Epi) and Il17rafl/fl (control) mice were used to test the hypothesis that IL-17RA signaling, specifically in epithelial cells, protects against severe inflammation after H. pylori infection. The data indicate that Il17raΔGI-Epi mice develop increased inflammation compared with controls. Despite reduced Pigr expression, levels of IgA increased in the gastric wash, suggesting significant increase in Ag-specific activation of the T follicular helper/B cell axis. Gene expression analysis of stomach tissues indicate that both acute and chronic responses are significantly increased in Il17raΔGI-Epi mice compared with controls. These data suggest that a deficiency of IL-17RA in epithelial cells is sufficient to drive chronic inflammation and hyperactivation of the Th17/T follicular helper/B cell axis but is not required for recruitment of polymorphonuclear neutrophils. Furthermore, the data suggest that fibroblasts can produce chemokines in response to IL-17 and may contribute to H. pylori-induced inflammation through this pathway.

Essential role of Helicobacter pylori apolipoprotein N-acyltransferase (Lnt) in stomach colonization.

Bacterial lipoproteins are post-translationally modified with acyl chains, anchoring these proteins to bacterial membranes. In Gram-negative bacteria, three enzymes complete the modifications. Lgt (which adds two acyl chains) and LspA (which removes the signal peptide) are essential. Lnt (which adds a third acyl chain) is not essential in certain bacteria including Francisella tularensis, Neisseria gonorrhoeae, and Acinetobacter baumannii. Deleting lnt results in mild to severe physiologic changes. We previously showed lnt is not essential for Helicobacter pylori growth in vitro. Here, the physiologic consequences of deleting lnt in H. pylori and the role of Lnt in the host response to H. pylori were examined using in vitro and in vivo models. Comparing wild-type, Δlnt, and complemented mutant H. pylori, no changes in growth rates or sensitivity to acid or antibiotics were observed. Since deleting lnt changes the number of acyl chains on lipoproteins and the number of acyl chains on lipoproteins impacts the innate immune response through Toll-like receptor 2 (TLR2) signaling, primary human gastric epithelial cells were treated with a purified lipoprotein from wild-type or lnt mutant H. pylori. Differential gene expression analysis indicated that lipoprotein from the lnt mutant induced a more robust TLR2 response. In a complementary approach, we infected wild-type and Tlr2-/- mice and found that both the wild-type and complemented mutant strains successfully colonized the animals. However, the lnt mutant strain was unable to colonize either mouse strain. These results show that lnt is essential for H. pylori colonization and identifies lipoprotein synthesis as a target for therapeutic intervention.

Interim outcomes of mechanical thrombectomy for deep vein thrombosis from the All-Comer CLOUT Registry.

OBJECTIVES: The multicenter, prospective, single arm CLOUT registry assesses the safety and effectiveness of the ClotTriever System (Inari Medical, Irvine, CA) for the treatment of acute and nonacute lower extremity deep vein thrombosis (DVT) in all-comer patients. Reported here are the outcomes of the first 250 patients. METHODS: All-comer patients with lower extremity DVT were enrolled, including those with bilateral DVT, those with previously failed DVT treatment, and regardless of symptom duration. The primary effectiveness end point is complete or near-complete (≥75%) thrombus removal determined by independent core laboratory-adjudicated Marder scores. Safety outcomes include serious adverse events through 30 days and clinical outcomes include post-thrombotic syndrome severity, symptoms, pain, and quality of life through 6 months. RESULTS: The median age was 62 years and 40% of patients had contraindications to thrombolytics. A range of thrombus chronicity (33% acute, 35% subacute, 32% chronic) was observed. No patients received thrombolytics and 99.6% were treated in a single session. The median thrombectomy time was 28 minutes. The primary effectiveness end point was achieved in 86% of limbs. Through 30 days, one device-related serious adverse event occurred. At 6 months, 24% of patients had post-thrombotic syndrome. Significant and sustained improvements were observed in all clinical outcomes, including the Revised Venous Clinical Severity Score, the numeric pain rating scale, and the EuroQol Group 5-Dimension Self-Report Questionnaire. CONCLUSIONS: The 6-month outcomes from the all-comer CLOUT registry with a range of thrombus chronicities demonstrate favorable effectiveness, safety, and sustained clinical improvements.

Cytoplasmic Autoinhibition in HCN Channels is Regulated by the Transmembrane Region.

Hyperpolarization-activated cation-nonselective (HCN) channels regulate electrical activity in the brain and heart in a cAMP-dependent manner. The voltage-gating of these channels is mediated by a transmembrane (TM) region but is additionally regulated by direct binding of cAMP to a cyclic nucleotide-binding (CNB) fold in the cytoplasmic C-terminal region. Cyclic AMP potentiation has been explained by an autoinhibition model which views the unliganded CNB fold as an inhibitory module whose influence is disrupted by cAMP binding. However, the HCN2 subtype uses two other CNB fold-mediated mechanisms called open-state trapping and Quick-Activation to respectively slow the deactivation kinetics and speed the activation kinetics, against predictions of an autoinhibition model. To test how these multiple mechanisms are influenced by the TM region, we replaced the TM region of HCN2 with that of HCN4. This HCN4 TM-replacement preserved cAMP potentiation but augmented the magnitude of autoinhibition by the unliganded CNB fold; it moreover disrupted open-state trapping and Quick-Activation so that autoinhibition became the dominant mechanism contributed by the C-terminal region to determine kinetics. Truncation within the CNB fold partially relieved this augmented autoinhibition. This argues against the C-terminal region acting like a portable module with consistent effects on TM regions of different subtypes. Our findings provide evidence that functional interactions between the HCN2 TM region and C-terminal region govern multiple CNB fold-mediated mechanisms, implying that the molecular mechanisms of autoinhibition, open-state trapping, and Quick-Activation include participation of TM region structures.

Hospital Enforcement of Early Cholecystectomy for Acute Cholecystitis.

International guidelines state that early laparoscopic cholecystectomy (ELC) is appropriate for all severity grades of acute cholecystitis and leads to reduced hospital stays and costs. A multicenter prospective randomized controlled trial recommends ELC over delayed laparoscopic cholecystectomy (DLC) management because in addition to reduced hospital stays and costs, ELC also leads to reduced patient morbidity. Therefore, ELC is standard of care for acute cholecystitis. We hypothesize that 1) international guidelines are not presently followed and that 2) a quality improvement (QI) project enforcing ELC for acute cholecystitis will increase rates of ELC management. A retrospective chart review of all surgical consults for cholecystitis from January 2016 to December 2018 was undertaken. A total of 307 patients diagnosed with acute cholecystitis were included. ELC was defined as cholecystectomy within hospital admission. Pre-QI ELC versus DLC rates were 77.4 per cent (233/301) versus 22.6 per cent (68/301). Eight DLC patients (11.8%) returned to the ED after discharge secondary to persistent signs and symptoms of cholecystitis and 62.5 per cent (5/8) received an immediate cholecystectomy before their elective surgery date. After QI initiatives, ELC rates rose to 100 per cent (6/6). These data show there was a lack of consistent ELC management of acute cholecystitis.

Nephrolithiasis in a 17-Year-Old Male With Seckel Syndrome and Horseshoe Kidneys: Case Report and Review of the Literature.

We report the case of a 17-year-old male with Seckel syndrome and horseshoe kidneys which had a 7 mm kidney stone in the lower pole calyx of the right moiety. The patient had a history of rotoscoliosis with 60° dextroconvex curvature and hepatic steatosis. Attempted ureteroscopy was unsuccessful due to stone location and anatomy. Percutaneous nephrolithotomy was ultimately required. This case highlights the difficulties of endoscopic treatments of renal calculi in patients with abnormal renal anatomy and dysmorphia. To our knowledge, this is the first reported case of nephrolithiasis in a patient with Seckel syndrome and horseshoe kidneys.

Density dependent re-tuning of autoreactive T cells alleviates their pathogenicity in a lymphopenic environment.

Peripheral T cell tolerance is challenging to induce in partially lymphopenic hosts and this is relevant for clinical situations involving transplant tolerance. While the shortage of regulatory cells is thought to be one reason for this, T cell-intrinsic tolerance processes such as anergy are also poorly triggered in such hosts. In order to understand the latter, we used a T cell deficient mouse model system where adoptively transferred autoreactive T cells are significantly tolerized in a cell intrinsic fashion, without differentiation to regulatory T cells. Intriguingly these T cells often retain sufficient effector functions to trigger autoimmune pathology. Here we find that the high population density of the autoreactive T cells that accumulated in such a host limits the progression of the cell-intrinsic tolerance process in T cells. Accordingly, reducing the cell density during a second transfer allowed T cells to further tune down their responsiveness to antigenic stimulation. The retuning of T cells was reflected by a loss of the T cell's abilities to proliferate, produces cytokines or help B cells. We further suggest, based on altering the levels of chronic antigen using miniosmotic pumps, that the effects of cell-density on T cell re-tuning may reflect the effective changes in the antigen dose perceived by individual T cells. This could proportionally elicit more negative feedback downstream of the TCR. Consistent with this, the retuned T cells showed signaling defects both proximal and distal to the TCR. Therefore, similar to the immunogenic activation of T cells, cell-intrinsic T cell tolerance may also involve a quantitative and progressive process of tuning down its antigen-responsiveness. The progress of such tuning seems to be stabilized at multiple intermediate stages by factors such as cell density, rather than just absolute antigen levels.

Safety and Efficacy of Stereotactic Ablative Radiation Therapy for Renal Cell Carcinoma Extracranial Metastases.

PURPOSE: Renal cell carcinoma is refractory to conventional radiation therapy but responds to higher doses per fraction. However, the dosimetric data and clinical factors affecting local control (LC) are largely unknown. We aimed to evaluate the safety and efficacy of stereotactic ablative radiation therapy (SAbR) for extracranial renal cell carcinoma metastases. METHODS AND MATERIALS: We reviewed 175 metastatic lesions from 84 patients treated with SAbR between 2005 and 2015. LC and toxicity after SAbR were assessed with Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 and Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Predictors of local failure were analyzed with χ2, Kaplan-Meier, and log-rank tests. RESULTS: In most cases (74%), SAbR was delivered with total doses of 40 to 60 Gy, 30 to 54 Gy, and 20 to 40 Gy in 5 fractions, 3 fractions, and a single fraction, respectively. The median biologically effective dose (BED) using the universal survival model was 134.5 Gy. The 1-year LC rate after SAbR was 91.2% (95% confidence interval, 84.9%-95.0%; median follow-up, 16.7 months). Local failures were associated with prior radiation therapy (hazard ratio [HR], 10.49; P<.0001), palliative-intent radiation therapy (HR, 4.63; P=.0189), spinal location (HR, 5.36; P=.0041), previous systemic therapy status (0-1 vs >1; HR, 3.52; P=.0217), and BED <115 Gy (HR, 3.45; P=.0254). Dose received by 99% of the target volume was the strongest dosimetric predictor for LC. Upon multivariate analysis, dose received by 99% of the target volume greater than BED of 98.7 Gy and systemic therapy status remained significant (HR, 0.12 and 3.64, with P=.0014 and P=.0472, respectively). Acute and late grade 3 toxicities attributed to SAbR were observed in 3 patients (1.7%) and 5 patients (2.9%), respectively. CONCLUSIONS: SAbR demonstrated excellent LC of metastatic renal cell carcinoma with a favorable safety profile when an adequate dose and coverage were applied. Multimodality treatment with surgery should be considered for reirradiation or vertebral metastasis. A higher radiation dose may be required in patients who received previous systemic therapies.

Differences in interregional brain connectivity in children with unilateral hearing loss.

OBJECTIVES: To identify functional network architecture differences in the brains of children with unilateral hearing loss (UHL) using resting-state functional-connectivity magnetic resonance imaging (rs-fcMRI). STUDY DESIGN: Prospective observational study. METHODS: Children (7 to 17 years of age) with severe to profound hearing loss in one ear, along with their normal hearing (NH) siblings, were recruited and imaged using rs-fcMRI. Eleven children had right UHL; nine had left UHL; and 13 had normal hearing. Forty-one brain regions of interest culled from established brain networks such as the default mode (DMN); cingulo-opercular (CON); and frontoparietal networks (FPN); as well as regions for language, phonological, and visual processing, were analyzed using regionwise correlations and conjunction analysis to determine differences in functional connectivity between the UHL and normal hearing children. RESULTS: When compared to the NH group, children with UHL showed increased connectivity patterns between multiple networks, such as between the CON and visual processing centers. However, there were decreased, as well as aberrant connectivity patterns with the coactivation of the DMN and FPN, a relationship that usually is negatively correlated. CONCLUSION: Children with UHL demonstrate multiple functional connectivity differences between brain networks involved with executive function, cognition, and language comprehension that may represent adaptive as well as maladaptive changes. These findings suggest that possible interventions or habilitation, beyond amplification, might be able to affect some children's requirement for additional help at school. LEVEL OF EVIDENCE: 3b. Laryngoscope, 127:2636-2645, 2017.

A study on verifying the effectiveness of 4-week composite weight-loss dietary supplement ingestion on body composition and blood lipid changes in middle-aged women.

PURPOSE: The purpose of this study was to investigate the effectiveness of a composite weight-loss dietary supplement on body composition and blood lipid changes in middle-aged women. METHODS: Thirty seven middle-aged women living in the Kyunggi area participated in this study and they were randomly divided into 2 groups (Dietary supplement ingestion group; DG, n = 20 and Placebo group; PG, n = 17). Blood draw and dual energy x-ray (DEXA) measurements were conducted to examine changes in body composition and blood lipids. RESULTS: There were no significant changes in weight and BMI in both groups. There was an interaction between the composite weight-loss dietary supplement intake and lean body mass in DG and there was a significant decrease in percent body fat in DG. Blood lipid changes in the study results showed that there was no significant difference in TC, TG, and LDL in both groups; however, there was a significant interaction between the composite weight-loss dietary supplement intake and HDL-C as well as an increase in the HDL-C of DG. CONCLUSION: In conclusion, it seems that 4-week ingestion of the composite weight-loss dietary supplement decreased body fat, increased lean body mass, and increased HDL-C. Therefore, the composite weight-loss dietary supplement is expected to prevent obesity and induce health improvements in middle-aged women.

FILLERS-Q: an instrument for assessing patient experiences after treatment with facial injectable soft tissue fillers.

Patient-reported outcomes data are limited after injectable soft tissue filler treatment. Patient-reported outcome measures (PROMs) are becoming integral to medical practices in other specialties and will become so as well in facial plastic surgery. The obvious differences in types of disorders treated and the outcomes of primary importance seen between general medical/surgical and facial plastic surgery practices make institution of standard outcomes studies difficult in facial plastic surgery. However, understanding the patient's experience and satisfaction with treatment is essential to continue to provide excellent care to facial aesthetic patients. This article describes use of a new survey instrument, Facial Injectables: Longevity, Late and Early Reactions and Satisfaction Questionnaire (FILLERS-Q), in assessing patient response to facial injections of soft tissue fillers. FILLERS-Q is a 43-item questionnaire that captures patient demographics (4 items), patient satisfaction with treatment (10 items), procedure-related events (3 to 7 items), impact on relationships (9 to 15 items), and economic considerations related to dermal filler treatment (3 to 7 items). The results provide a "snapshot" of patients treated in an individual surgeon's practice.

Contemporary results of endovascular repair of abdominal aortic aneurysms: effect of anatomical fixation on outcomes.

PURPOSE: To report the contemporary controlled trial experience with the fully supported unibody Powerlink stent-graft for endovascular treatment of abdominal aortic aneurysm (AAA). METHODS: Between 2000 and 2008, 3 prospective multicenter trials of the Powerlink system evaluated 157 AAA patients (141 men; mean age 72.0+/-9.1 years) with mean AAA sac diameter of 5.6+/-0.9 cm who received a bifurcated stent-graft featuring anatomical fixation at the aortoiliac bifurcation and proximal sealing with extension stent-grafts as needed. Challenging infrarenal aortic neck anatomy was present in 83% of patients. Postoperative follow-up occurred at defined intervals to 5 years. RESULTS: Technical success was achieved in 99% of patients. Aneurysm exclusion was achieved in all patients over a mean procedure time of 132+/-58 minutes. No aneurysm-related deaths, ruptures, conversions, or migrations have been observed to current follow-up as these aneurysms have continued to remodel, with > or =92% of patients free from sac growth. CONCLUSION: The implant technique of placing a fully-supported unibody stent-graft at the aortoiliac bifurcation with proximal sealing appears to safely and effectively reline the aorta and exclude aneurysms. Results from controlled clinical trial experience suggest this algorithm can provide stable, secure fixation for patients with challenging infrarenal aortic neck anatomy.

Desired position, shape, and dynamic range of the normal adult eyebrow.

OBJECTIVE: To determine the resting and aesthetically desired position of the eyebrows and the range of eyebrow mobility. METHODS: Photographs were taken of 40 adult subjects in 5 poses: eyes open and eyes closed, maximum brow elevation and brow contraction, and brow positioned optimally by the subject. The height of the brow was measured relative to the orbital rim and surrounding structures in 6 locations: the medial brow, above the medial canthus, midpupil, lateral canthus, brow peak, and brow tail. RESULTS: Women desired the lower border of the brow to fall just below the orbital rim at the medial canthus, at the rim at the midpupillary line and several millimeters above the rim at the lateral canthus. Men desired a lower brow with a lower tail and a less accentuated peak. The brow peak in both women and men was just medial to the lateral canthus. Range of movement was greater medially in men and at the brow tail in women. CONCLUSIONS: The aesthetic position of the medial and central brow is relatively low. The brow peak should be just medial to the lateral canthus. Surgeons planning forehead and brow surgery should consider these parameters to avoid creating an unnatural brow appearance.

Cognitive impairment is not equal in patients with epileptic and psychogenic nonepileptic seizures.

PURPOSE: Patients with psychogenic nonepileptic seizures (PNES) and those with epileptic seizures (ES) purportedly have roughly equal neurocognitive deficits. However, recent findings suggest that patients with somatoform disorders exhibit more variable effort on neurocognitive testing than do controls. We reexamined neurocognitive function in patients with ESs and PNES by using symptom validity testing to control for variability in effort. METHODS: Patients referred for video-EEG monitoring were administered the Word Memory Test (WMT), a measure of symptom validity, as part of neuropsychological evaluation. Patients classified with ictal video-EEG recordings as having ES (n = 41) or PNES (n = 43) were compared on neurocognitive and WMT performance and demographic, psychiatric, and medical variables. RESULTS: Striking rates of WMT failure were observed in the PNES (51.2%) group, but not in the ES (8.1%) group (p = <0.001) after controlling for false-positive errors. Although the PNES and ES groups reported equivalent neurologic histories, the PNES group exhibited less objective evidence of impairment as measured by valid neuropsychological testing, MRI of the brain, and video-EEG monitoring. CONCLUSIONS: Many patients with PNES do not put forth maximal effort during neuropsychological assessment. When patients with PNES put forth valid effort, they demonstrate less objective evidence of neuropathologic injury or disease than do patients with ES. The cognitive impairment reported by this group appears to be more a function of motivational (although not necessarily intentional) factors than of verifiable neuropathology.

Percutaneous endovascular abdominal aortic aneurysm repair.

In this prospective, nonrandomized study, we compared outcome with percutaneous femoral artery closure to that with open femoral arteriotomy in 95 patients who underwent endovascular AAA repair. Devices were introduced using 22 Fr and/or 16 Fr sheaths. The 8 Fr/10 Fr Perclose devices (Perclose Inc., Redwood City, CA) were used in an off-label "preclose technique." Thirty-three patients had bilateral open femoral arteriotomies, 44 patients had bilateral attempted percutaneous closure, and 18 patients had open femoral arteriotomy on one side and attempted percutaneous closure on the other side. Percutaneous closure was successful in 85% (47/55) of 16 Fr sheaths and 64% (29/45) of 22 Fr sheaths (p < 0.027). Bilateral percutaneous closure was successful in 63% (28/44) of patients. Conversion to open femoral arteriotomy due to bleeding occurred in 24 of 106 percutaneous attempts. There were no dissections, arterial thromboses, or pseudoaneurysms associated with percutaneous arterial closure. Wound complications were seen in 3.6% (3/84) of open arteriotomies and 0.9% (1/106) of all percutaneous attempts and arterial closures (p > 0.05). Gender, previous femoral access, obesity, and iliac occlusive disease were not predictive of percutaneous failure. Procedural success for percutaneous AAA repair is affected by sheath size. Devices delivered through 16 Fr or smaller sheaths will have successful femoral artery closure rates of at least 85%.

External iliac artery-to-internal iliac artery endograft: a novel approach to preserve pelvic inflow in aortoiliac stent grafting.

PURPOSE: To describe four patients with abdominal aortic aneurysm and bilateral common iliac artery aneurysms repaired by coil embolization of the ipsilateral internal iliac artery, aortouniiliac endograft extended to the ipsilateral external iliac artery, femorofemoral bypass grafting, and a contralateral external iliac to internal iliac stent graft to preserve pelvic perfusion. METHODS: Four patients with multiple risk factors, abdominal aortic aneurysm (mean diameter, 6.6 cm), and bilateral common iliac artery aneurysms were evaluated with contrast-enhanced computed tomography scanning, arteriography, and intravascular ultrasonography. Aortobiiliac endovascular abdominal aortic aneurysm repair was not feasible because of extension of the common iliac artery aneurysms to the iliac bifurcation bilaterally. RESULTS: The abdominal aortic aneurysms were repaired with an aortouniiliac endograft. The ipsilateral common iliac artery aneurysms were treated by coil embolization of the internal iliac artery and extension of the endograft to the external iliac artery. The contralateral common iliac artery aneurysms were excluded by a custom-made stent graft (n = 2) or a commercial stent graft (n = 2) from the external iliac artery to the internal iliac artery, which preserved pelvic inflow via retrograde perfusion from the femorofemoral bypass. Mean length of stay was 3.5 days. One patient had hip claudication. Follow-up (mean 10 months, range 6 to 17) demonstrated exclusion of the abdominal aortic aneurysm and common iliac artery aneurysms with no endoleak and patent external iliac artery-to-internal iliac artery endografts in all patients. CONCLUSION: Patients with bilateral common iliac artery aneurysms that extend to the iliac bifurcation may be excluded from endovascular abdominal aortic aneurysm repair because of concerns regarding pelvic ischemia after occlusion of both internal iliac arteries. External iliac artery-to-internal iliac artery endografting is a feasible alternative to maintain pelvic perfusion and still allow endograft repair of the abdominal aortic aneurysm in these patients.