Blockade of CD47 function attenuates restenosis by promoting smooth muscle cell efferocytosis and inhibiting their migration and proliferation.

Cluster of differentiation 47 (CD47) plays an important role in the pathophysiology of various diseases including atherosclerosis but its role in neointimal hyperplasia which contributes to restenosis has not been studied. Using molecular approaches in combination with a mouse vascular endothelial denudation model, we studied the role of CD47 in injury-induced neointimal hyperplasia. We determined that thrombin-induced CD47 expression both in human aortic smooth muscle cells (HASMCs) and mouse aortic smooth muscle cells. In exploring the mechanisms, we found that the protease-activated receptor 1-Gα protein q/11 (Gαq/11)-phospholipase Cß3-nuclear factor of activated T cells c1 signaling axis regulates thrombin-induced CD47 expression in HASMCs. Depletion of CD47 levels using its siRNA or interference of its function by its blocking antibody (bAb) blunted thrombin-induced migration and proliferation of HASMCs and mouse aortic smooth muscle cells. In addition, we found that thrombin-induced HASMC migration requires CD47 interaction with integrin ß3. On the other hand, thrombin-induced HASMC proliferation was dependent on CD47's role in nuclear export and degradation of cyclin-dependent kinase-interacting protein 1. In addition, suppression of CD47 function by its bAb rescued HASMC efferocytosis from inhibition by thrombin. We also found that vascular injury induces CD47 expression in intimal SMCs and that inhibition of CD47 function by its bAb, while alleviating injury-induced inhibition of SMC efferocytosis, attenuated SMC migration, and proliferation resulting in reduced neointima formation. Thus, these findings reveal a pathological role for CD47 in neointimal hyperplasia.

Deficiency of M-LP/Mpv17L leads to development of ß-cell hyperplasia and improved glucose tolerance via activation of the Wnt and TGF-ß pathways.

M-LP/Mpv17L is a protein that was initially identified during screening of age-dependently expressed genes in mice. We have recently demonstrated that M-LP/Mpv17L-knockout (M-LP/Mpv17L-KO) in human hepatoma cells leads to a reduction of cellular cyclic nucleotide phosphodiesterase (PDE) activity, and that in vitro-synthesized M-LP/Mpv17L possesses PDE activity. These findings suggest that M-LP/Mpv17L functions as an atypical PDE, even though it has none of the well-conserved catalytic region or other structural motifs characteristic of the PDE family. In this study, we found that M-LP/Mpv17L-KO mice developed ß-cell hyperplasia and improved glucose tolerance. Deficiency of M-LP/Mpv17L in islets from KO mice at early postnatal stages or siRNA-mediated suppression of M-LP/Mpv17L in rat insulinoma cells led to marked upregulation of lymphoid enhancer binding factor 1 (Lef1) and transcription factor 7 (Tcf7), key nuclear effectors in the Wnt signaling pathway, and some of the factors essential for the development and maintenance of ß-cells. Moreover, at the protein level, increases in the levels of phosphorylated ß-catenin and glycogen synthase kinase-3ß (GSK-3ß) were observed, indicating activation of the Wnt and TGF-ß signaling pathways. Taken together, these findings suggest that protein kinase A (PKA)-dependent phosphorylations of ß-catenin and GSK-3ß, the key mediators of the Wnt and/or TGF-ß signaling pathways, are the most upstream events triggering ß-cell hyperplasia and improved glucose tolerance caused by M-LP/Mpv17L deficiency.

The Use of Infant Pulmonary Function Tests in the Diagnosis of Neuroendocrine Cell Hyperplasia of Infancy.

BACKGROUND: Infant pulmonary function tests (iPFTs) in subjects with neuroendocrine cell hyperplasia of infancy (NEHI) have demonstrated substantial expiratory airflow obstruction and air trapping. RESEARCH QUESTION: Can indices from iPFTs be used in the diagnosis of NEHI? STUDY DESIGN AND METHODS: This is an observational case-control study evaluating iPFT results from a registry of patients assessed at the Hadassah Hebrew University Medical Center between 2008 and 2018. iPFTs results in infants with NEHI were compared to two disease control infant groups (infants evaluated for recurrent wheezing and infants evaluated due to prematurity) and a spirometry control group of infants with normal expiratory airflow, using the Kruskal-Wallis test. Receiver operating characteristic (ROC) curves were used to assess the diagnostic accuracy of iPFT indices. RESULTS: We evaluated iPFT data in 481 infants (15, NEHI; 292, wheezing; 128, premature; and 46, spirometry control group). Infants with NEHI had significantly increased trapped air volumes (median functional residual capacity measured with infant whole-body plethysmography [FRCpleth] was 199% predicted; median ratio of residual volume to total lung capacity was 59% predicted) when compared with results in all evaluated groups of infants (P < .001), including multiple pairwise comparisons. Airflow limitation was demonstrated in infants with NEHI when compared with the infants in the spirometry control group but was similar to the two disease control groups. FRCpleth had the best discriminatory ability for NEHI diagnosis, with an FRCpleth ≥ 150% predicted demonstrating a ROC of 0.91 (95% CI, 0.82-1.00), sensitivity of 86.7% (95% CI, 59.5%-98.3%), and specificity of 95.5% (95% CI, 93.2%-97.3%). INTERPRETATION: Findings on iPFTs of markedly increased air trapping, out of proportion to the degree of airflow limitation, are characteristic of infants with NEHI. iPFT results demonstrating an FRCpleth ≥ 150% predicted are highly specific for NEHI and may aid in early diagnosis. Further research is required to confirm these findings in a prospective cohort and to understand the pathophysiologic explanation for these findings.

Coexistence of atypical adenomatous hyperplasia, minimally invasive adenocarcinoma and invasive adenocarcinoma: Gene mutation analysis.

Multiple primary lung cancer (MPLC) refers to the simultaneous occurrence of two or more lung primary malignant tumors in one individual. The detection rate of MPLC has increased significantly in recent years, and the distinction between MPLC and lung metastasis has strong clinical significance. Whole exome sequencing (WES) can clearly identify the heterogeneity between MPLC nodules. Here, we report a case of a 50-year-old Asian female without a history of smoking. She underwent a lung computed tomography (CT) scan and three ground-glass nodules (GGNs) were found which were pathologically confirmed as atypical adenomatous hyperplasia (AAH), minimally invasive adenocarcinoma (MIA) and invasive adenocarcinoma (IA), respectively. We performed WES on the three pulmonary nodules and analyzed the sequencing results. We believe that this is the first published report of a case of "three phases" of lung adenocarcinoma analyzed by WES. Under the same genetic background and internal environment, these three nodules showed significant genetic differences and developed into "three phases" of lung adenocarcinoma. Analysis of the WES results supported the lung adenocarcinoma model from AAH to MIA and IA, and explored possible potential driver genes and therapeutic targets. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: We used WES to analyze the gene mutation status of three tumors in one individual. We found that even if under the same genetic background, AAH, MIA and IA showed significant genetic differences and developed into "three phases" of lung adenocarcinoma. WHAT THIS STUDY ADDS: Analysis of the WES results supported the lung adenocarcinoma model from AAH to MIA and IA, and explored possible potential driver genes and therapeutic targets.

Targeting Smad-Mediated TGFß Pathway in Coronary Artery Bypass Graft.

Revascularization surgeries such as coronary artery bypass grafting (CABG) are sometimes necessary to manage coronary heart disease (CHD). However, more than half of these surgeries fail within 10 years due to the development of intimal hyperplasia (IH) among others. The cytokine transforming growth factor-beta (TGFß) and its signaling components have been found to be upregulated in diseased or injured vessels, and to promote IH after grafting. Interventions that globally inhibit TGFß in CABG have yielded contrasting outcomes in in vitro and in vivo studies including clinical trials. With advances in molecular biology, it becomes clear that TGFß exhibits both protective and damaging roles, and only specific components such as some Smad-dependent TGFß signaling mediate vascular IH. The activin receptor-like kinase (ALK)-mediated Smad-dependent TGFß signaling pathways have been found to be activated in human vascular smooth muscle cells (VSMCs) following injury and in hyperplastic preimplantation vein grafts. It appears that focused targeting of TGFß pathway constitutes a promising therapeutic target to improve the outcome of CABG. This study dissects the role of TGFß pathway in CABG failure, with particular emphasis on the therapeutic potentials of specific targeting of Smad-dependent and ALK-mediated signaling.

Warburg-like Metabolic Reprogramming in Aging Intestinal Stem Cells Contributes to Tissue Hyperplasia.

In many tissues, stem cell (SC) proliferation is dynamically adjusted to regenerative needs. How SCs adapt their metabolism to meet the demands of proliferation and how changes in such adaptive mechanisms contribute to age-related dysfunction remain poorly understood. Here, we identify mitochondrial Ca2+ uptake as a central coordinator of SC metabolism. Live imaging of genetically encoded metabolite sensors in intestinal SCs (ISCs) of Drosophila reveals that mitochondrial Ca2+ uptake transiently adapts electron transport chain flux to match energetic demand upon proliferative activation. This tight metabolic adaptation is lost in ISCs of old flies, as declines in mitochondrial Ca2+ uptake promote a "Warburg-like" metabolic reprogramming toward aerobic glycolysis. This switch mimics metabolic reprogramming by the oncogene RasV12 and enhances ISC hyperplasia. Our data identify a critical mechanism for metabolic adaptation of tissue SCs and reveal how its decline sets aging SCs on a metabolic trajectory reminiscent of that seen upon oncogenic transformation.

Vitamin D deficiency serves as a precursor to stunted growth and central adiposity in zebrafish.

Emerging evidence demonstrates the importance of sufficient vitamin D (1α, 25-dihydroxyvitamin D3) levels during early life stage development with deficiencies associated with long-term effects into adulthood. While vitamin D has traditionally been associated with mineral ion homeostasis, accumulating evidence suggests non-calcemic roles for vitamin D including metabolic homeostasis. In this study, we examined the hypothesis that vitamin D deficiency (VDD) during early life stage development precedes metabolic disruption. Three dietary cohorts of zebrafish were placed on engineered diets including a standard laboratory control diet, a vitamin D null diet, and a vitamin D enriched diet. Zebrafish grown on a vitamin D null diet between 2-12 months post fertilization (mpf) exhibited diminished somatic growth and enhanced central adiposity associated with accumulation and enlargement of visceral and subcutaneous adipose depots indicative of both adipocyte hypertrophy and hyperplasia. VDD zebrafish exhibited elevated hepatic triglycerides, attenuated plasma free fatty acids and attenuated lipoprotein lipase activity consistent with hallmarks of dyslipidemia. VDD induced dysregulation of gene networks associated with growth hormone and insulin signaling, including induction of suppressor of cytokine signaling. These findings indicate that early developmental VDD impacts metabolic health by disrupting the balance between somatic growth and adipose accumulation.

Fu's subcutaneous needling for subcutaneous adhesions and scar hyperplasia in the neck region: A case report.

RATIONALE: Lymphadenectomy for tongue cancer in the neck region is often accompanied by local impaired mobility, gland damage, difficult in swallowing, and postoperative complication and seriously affects patients life quality. We reported a case of subcutaneous adhesions and scar hyperplasia in the neck region after lymphadenectomy for tongue lesions accompanied by impaired neck mobility and difficult in swallowing was treated using Fu's subcutaneous needling (FSN) treatment. PATIENT CONCERNS: A 55-year-old male with tongue cancer received surgical intervention with lymphadenectomy 8 years ago was revealed a 15 cm-long curved surgical incision in the neck region and surrounded by numerous scar tissues. DIAGNOSIS: Post-operation subcutaneous adhesions and scar hyperplasia in the neck region after lymphadenectomy was diagnosed. INTERVENTIONS: FSN treatment was performed 2 to 3 times per week for 1 month to sway the affected tightened muscle and dissociate the superficial fascia beneath the scar resulted in a considerable improvement in neck movement. OUTCOMES: The Vancouver Scar Scale (VSS) was as follows: color (M) - 1; vascular distribution (V) - 0, thickness (H) - 2, and flexibility (P) - 4, with a total of 7 points before FSN treatment. The VSS after 1 month of FSN treatment was as follows: M1, V0, H2, and P2, with a total of 5 points. Neck mobility in different directions, i.e., stretching to the back of the neck and laterally bending the neck to the left and/or right side, was improved (P < .05). LESSONS: At present, treatment of chronic scar hyperplasia has certain side effects and limitations. FSN is safe and convenient, with minimal destruction of the superficial fascia, having evident effects of dissociating tissue adhesion under scars and compensating for deficiencies in scar hyperplasia treatment. It can provide new ideas for future treatments.

Autophagy plays a positive role in induction of epidermal proliferation.

Autophagy is a multistage catabolic process that mediates stress responses. However, the role of autophagy in epidermal proliferation, particularly under conditions when the epidermis becomes "activated" (hyperproliferative), remains unclear. We have shown that inhibition of Beclin 1, a key activator in the initiation phase of autophagy, attenuates imiquimod (IMQ)-induced epidermal hyperplasia in adult mice as well as naturally occurring hyperproliferation in neonatal mouse epidermis. Inhibition of Beclin 1 did not change the levels of several key inflammatory molecules or the numbers of immune cells in lesional skins. This indicates that autophagy does not affect inflammatory regulators in IMQ-treated mouse skin. Bioinformatic analysis combined with gene expression quantitative assays, revealed that a deficiency in autophagy decreases the expression of PDZ Binding Kinase (PBK), a regulator of the cell cycle, in mouse epidermis and human epidermal keratinocytes (HEKs). Interestingly, the decrease in PBK results in inhibition of proliferation in HEKs and such reduced proliferation can be rescued by activation of p38, the downstream signaling of PBK. Collectively, autophagy plays a positive role in epidermal proliferation, which is in part via regulating PBK expression.

Route-specific association of progestin therapy and concurrent metformin use in obese women with complex atypical hyperplasia.

INTRODUCTION: Previous studies have suggested that metformin use may enhance the therapeutic effect of progestin therapy for endometrial hyperplasia or malignancy. However, it is not known how the impact of concurrent metformin may be altered by route of progestin therapy, either locally via an intrauterine device or systemically. This study examined the effectiveness of concurrent metformin use and progestin therapy for women with complex atypical hyperplasia stratified by progestin route (systemic vs local). METHODS: This single-institution retrospective study examined consecutive women with complex atypical hyperplasia who received progestin therapy from 2003 to 2018. Time-dependent analyses for complete response rate were performed comparing concurrent metformin users versus non-users in the oral progestin group and in the levonorgestrel-releasing intrauterine device group. RESULTS: Across the study cohort (n=245), there were 137 (55.9%) women who responded to progestin therapy. In the oral progestin group (n=176), the median age and body mass index were 36 years and 37.7 kg/m2, respectively. 36 (20.5%) of women on oral progestins also took metformin. After controlling for diabetes status, women taking both oral progestins and metformin had a complete response rate similar to those not taking metformin (6 month cumulative rates, 23.1% vs 27.8%, adjusted hazard ratio (aHR) 0.71, 95% confidence interval (95% CI) 0.36 to 1.41). In the levonorgestrel-releasing intrauterine device group (n=69), the median age and body mass index were 35 years and 39.9 kg/m2, respectively. There were 15 (21.7%) women who took metformin in addition to the levonorgestrel-releasing intrauterine device. After controlling for diabetes status, women who had the levonorgestrel-releasing intrauterine device and took metformin had a significantly higher complete response rate compared with those not taking metformin (6 month cumulative rates, 86.7% vs 58.9%, aHR 2.31, 95% CI 1.09 to 4.89). CONCLUSION: In a predominantly obese population, concurrent metformin may possibly offer treatment benefit when used with the levonorgestrel-releasing intrauterine device.

Long-term consequences of one anastomosis gastric bypass on esogastric mucosa in a preclinical rat model.

Although bariatric surgery is proven to sustain weight loss in morbidly obese patients, long-term adverse effects have yet to be fully characterized. This study compared the long-term consequences of two common forms of bariatric surgery: one-anastomosis gastric bypass (OAGB) and Roux-en-Y Gastric Bypass (RYGB) in a preclinical rat model. We evaluated the influence of biliopancreatic limb (BPL) length, malabsorption, and bile acid (BA) reflux on esogastric mucosa. After 30 weeks of follow-up, Wistar rats operated on RYGB, OAGB with a short BPL (15 cm, OAGB-15), or a long BPL (35 cm, OAGB-35), and unoperated rats exhibit no cases of esogastric cancer, metaplasia, dysplasia, or Barrett's esophagus. Compared to RYGB, OAGB-35 rats presented higher rate of esophagitis, fundic gastritis and perianastomotic foveolar hyperplasia. OAGB-35 rats also revealed the greatest weight loss and malabsorption. On the contrary, BA concentrations were the highest in the residual gastric pouch of OAGB-15 rats. Yet, no association could be established between the esogastric lesions and malabsorption, weight loss, or gastric bile acid concentrations. In conclusion, RYGB results in a better long-term outcome than OAGB, as chronic signs of biliary reflux or reactional gastritis were reported post-OAGB even after reducing the BPL length in a preclinical rat model.

Salmonella infection induced intestinal crypt hyperplasia through Wnt/ß-catenin pathway in chicken.

S. Pullorum is a causative agent of enteric disease of poultry with serious diarrhea. However, the detailed mechanism behind its injury to intestinal mucosa barrier, especially for intestinal stem cells, is unclear. In this study, S. Pullorum were orally administrated to 3 days old chicken to investigate the pathogenesis of S. Pullorum on intestinal mucosal barrier, especially on the proliferation of epithelial cells. We found that S. Pullorum could colonize in the cecum and invade into the liver through intestinal mucosa damage, which caused obvious pathological changes in liver and intestine and even leaded to death, as well as significant reduction of body weight. We also found that S. Pullorum infection enhanced the mRNA expression of IL-1ß and IL-6 through TLR4/MyD88 pathway, which was also further verified by the increased lipopolysaccharide (LPS) levels in serum. Furthermore, S. Pullorum increased the depth of crypt and density of PCNA+ cells significantly through the over-activation of Wnt/ß-catenin signaling pathway. The expression of intestinal stem cells markers Lgr5 and Bmi1 was also increased after S. Pullorum infection to support the crypt hyperplasia. In addition, we verified that S. Pullorum infection enhanced the mRNA expression of IL-1ß, TLR4, Lgr5 and Bmi1. Our study indicated that S. Pullorum infection damaged the intestinal mucosa barrier to induce diarrhea, affected the abnormal proliferation of intestinal stem cells by over-activation of Wnt/ß-catenin pathway in chicken.

Inflammation-induced IgE promotes epithelial hyperplasia and tumour growth.

IgE is the least abundant circulating antibody class but is constitutively present in healthy tissues bound to resident cells via its high-affinity receptor, FcεRI. The physiological role of endogenous IgE antibodies is unclear but it has been suggested that they provide host protection against a variety of noxious environmental substances and parasitic infections at epithelial barrier surfaces. Here we show, in mice, that skin inflammation enhances levels of IgE antibodies that have natural specificities and a repertoire, VDJ rearrangements and CDRH3 characteristics similar to those of IgE antibodies in healthy tissue. IgE-bearing basophils are recruited to inflamed skin via CXCL12 and thymic stromal lymphopoietin (TSLP)/IL-3-dependent upregulation of CXCR4. In the inflamed skin, IgE/FcεRI-signalling in basophils promotes epithelial cell growth and differentiation, partly through histamine engagement of H1R and H4R. Furthermore, this IgE response strongly drives tumour outgrowth of epithelial cells harbouring oncogenic mutation. These findings indicate that natural IgE antibodies support skin barrier defences, but that during chronic tissue inflammation this role may be subverted to promote tumour growth.

Hiperplasia linfoide de intestino delgado en escolar inmunodeprimido / Lymphoid hyperplasia of small intestine in immune-depressed student

Fundamento: la afección intestinal es signo clave del cuadro de inmunodeficiencia. Suele presentarse un desorden de malabsorción y diarrea, con hiperplasia nodular linfoide intestinal. La importancia del estudio de esta enfermedad radica en que debe ser detectada en etapas precoces pues estos pacientes son más susceptibles a presentar neoplasias de intestino delgado. Objetivo: presentar el caso de un escolar con diarreas crónicas, desnutrición proteico energética e inmunodeficiencia como manifestaciones de hiperplasia nodular linfoide de intestino delgado. Presentación del caso: paciente de nueve años, masculino, con historia de diarreas crónicas y desnutrición. Por esta sintomatología es remitido a consulta de Gastroenterología. Conclusiones: se debe sospechar la hiperplasia nodular linfoide de intestino delgado en pacientes pediátricos con síndrome de malabsorción intestinal. Se observó mejoría clínica de las manifestaciones digestivas, del estado de inmunidad y recuperación nutricional (AU)

Background: the intestinal affection is key sign of the immunodeficiency. It usually presents a mal-absorption disorder and diarrhea, with intestinal lymphoid nodular hyperplasia. The importance of the study of this entity resides in that it should be detected in precocious stages because these patients are more susceptible to present neoplasias of small bowel. Objective: to present the case of a student with chronic diarrheas, energy protein malnutrition and immunodeficiency like manifestations of nodular lymphoid hyperplasia of small intestine. Case report: patient of nine years, masculine, with history of chronic diarrheas and malnutrition. For these clinical symptoms he is remitted to Gastroenterology consultation. Conclusions: the nodular lymphoid hyperplasia of small bowel should be suspected in pediatric patients with syndrome of intestinal mal-absorption. Clinical improvement of the digestive manifestations, of the state of immunity, and nutritional recovery was observed (AU)

Systematic review with network meta-analysis: endoscopic techniques for dysplasia surveillance in inflammatory bowel disease.

BACKGROUND: International guidelines recommend dysplasia surveillance in IBD. AIM: To compare endoscopic techniques for dysplasia surveillance METHODS: We searched MEDLINE, Embase, CENTRAL for randomised trials through May 2019. We estimated odds ratios (ORs) for binary and mean differences (MDs) for continuous outcomes, using frequentist random-effects network meta-analysis. We assessed study risk of bias and appraised evidence certainty using GRADE. RESULTS: Eighteen trials (2638 participants) were included. Standard definition white-light endoscopy (OR 0.44, 95% CI 0.26-0.73; high certainty) and i-SCAN (OR 0.47, 95% CI 0.25-0.90; moderate certainty) had lower odds of detecting neoplasia than chromoendoscopy. Fujinon intelligent colour enhancement (FICE), standard definition white-light endoscopy and i-SCAN had lower odds for this outcome than full spectrum high definition white-light endoscopy (ORs 0.02 to 0.15; low certainty). Standard definition white-light endoscopy had lower odds of detecting nonpolypoid neoplasia than full spectrum high definition white-light endoscopy, narrow band imaging, chromoendoscopy and high definition white-light endoscopy (ORs 0.01-0.14; moderate certainty). Full spectrum high definition white-light endoscopy ranked as the best technique for both outcomes (moderate certainty). Standard definition white-light endoscopy had lower odds of detecting neoplasia by target biopsy (OR 0.27, 95% CI 0.08-0.91) and had shorter procedure time (MD -14.81 minutes, 95% CI -25.03, -4.06) than chromoendoscopy (moderate certainty). CONCLUSIONS: Chromoendoscopy, high definition white-light endoscopy, narrow band imaging, autofluorescence, FICE and full spectrum high definition white-light endoscopy may be comparable for dysplasia surveillance. Standard definition white-light endoscopy and i-SCAN probably provide lower yields for neoplasia identification. Full spectrum high definition white-light endoscopy may represent the first-line approach.

Hypothyroidism induces uterine hyperplasia and inflammation related to sex hormone receptors expression in virgin rabbits.

AIMS: In women, uterine alterations have been associated with sex steroid hormones. Sex hormones regulate the expression of thyroid hormone receptors (TRs) in the uterus, but an inverse link is unknown. We analyzed the impact of hypothyroidism on histological characteristics, vascular endothelial growth factor (VEGF-A), progesterone receptors (PR), estrogen receptors (ER), thyroid hormone receptors (TRs), perilipin (PLIN-A), and lipid content in the uterus of virgin rabbits. MAIN METHODS: Twelve Chinchilla-breed adult female rabbits were grouped into control (n = 6) and hypothyroid (n = 6; 0.02% of methimazole for 30 days). The thickness of endometrium and myometrium, number of uterine glands, and infiltration of immune cells were analyzed. The expression of VEGF-A, PR, ERα, and PLIN-A was determined by RT-PCR and western blot. The uterine content of triglycerides (TAG), total cholesterol (TC), and malondialdehyde (MDA) was quantified. KEY FINDINGS: Hypothyroidism promoted uterine hyperplasia and a high infiltration of immune cells into the endometrium, including macrophages CD163+. It also increased the expression of VEGF-A, TRA, and ERα-66 but reduced that of PR and ERα-46. The uterine content of PLIN-A, TAG, and TC was reduced, but that of MDA was augmented in hypothyroid rabbits. SIGNIFICANCE: Our results suggest that uterine hyperplasia and inflammation promoted by hypothyroidism should be related to changes in the VEGF-A, PR, ER, and TRs expression, as well as to modifications in the PLIN-A expression, lipid content, and oxidative status. These results suggest that hypothyroidism should affect the fertility of females.

Intimal Hyperplasia After Aneurysm Treatment by Flow Diversion.

BACKGROUND: Flow diverter stents have become a useful tool for treatment of complex intracranial aneurysms. A serious complication is incomplete wall apposition after flow diverter placement. The aim of this study was to present a comprehensive investigation of hemodynamic changes induced by incomplete expansion of a flow diverter. METHODS: A case of a patient treated for an internal carotid artery aneurysm by flow diversion with incomplete wall apposition was virtually investigated. The effect of incomplete flow diverter expansion was studied using image-based blood flow simulations under physiologically relevant flow conditions based on patient-specific clinical data. RESULTS: The numerical results revealed that incomplete expansion at the proximal end of the stent had minimal impact on the intra-aneurysmal blood flow alteration. A region of nonphysiologically high wall shear stress was observed near the contact area between the incompletely expanded proximal end of the flow diverter and the parent artery, which caused an intimal hyperplasia in this region. These simulation results were consistent with the real-life clinical course and outcome. CONCLUSIONS: The results of this study can be considered during treatment planning of complex cases where the risk of incomplete flow diverter expansion exists. Further studies are required before results can also be used to support the decision process about antiplatelet therapy and additional interventions to improve wall apposition.

Carotid Geometry as a Predictor of In-Stent Neointimal Hyperplasia　- A Computational Fluid Dynamics Study.

BACKGROUND: Carotid angioplasty and stenting (CAS) is emerging as an alternative treatment for carotid stenosis, but neointimal hyperplasia (NIH) remains a drawback of this treatment strategy. This study aimed to evaluate the effect of variations of carotid bifurcation geometry on local hemodynamics and NIH.Methods and Results:Hemodynamic and geometric effects on NIH were compared between 2 groups, by performing computational fluid dynamics (CFD) simulations both on synthetic models and patient-specific models. In the idealized models, multiple regression analysis revealed a significant negative relationship between internal carotid artery (ICA) angle and the local hemodynamics. In the patient-derived models, which were reconstructed from digital subtraction angiography (DSA) of 25 patients with bilateral CAS, a low time-average wall shear stress (TAWSS) and a high oscillatory shear index (OSI) were often found at the location of NIH. Larger difference values of the OSI percentage area (10.56±20.798% vs. -5.87±18.259%, P=0.048) and ECA/CCA diameter ratio (5.64±12.751% vs. -3.59±8.697%, P=0.047) were detected in the NIH-asymmetric group than in the NIH-symmetric group. CONCLUSIONS: Changes in carotid bifurcation geometry can make apparent differences in hemodynamic distribution and lead to bilateral NIH asymmetry. It may therefore be reasonable to consider certain geometric variations as potential local risk factors for NIH.

Common variable immunodeficiency syndrome with chronic diarrhoea.

Common variable immunodeficiency syndrome (CVID) is a heterogeneous disorder characterised by diminished levels of IgG, IgA and/or IgM, and recurrent bacterial infections. Sinopulmonary infections are most commonly reported followed by gastrointestinal (GI) infections. GI tract represents the largest immune organ with abundance of lymphoid cells, its involvement can manifest variably ranging from asymptomatic involvement to florid symptoms and signs. Diffuse nodular lymphoid hyperplasia (DNLH) of the GI tract is characterised by numerous small polypoid nodules of variable size in the small intestine, large intestine or both. It is commonly seen in association to immunodeficiency states such as CVID, IgA deficiency and chronic infections due to Giardia lamblia and Helicobacter pylori and cryptosporidiosis. Repetitive antigenic stimulation leads to lymphoid hyperplasia. We herein describe a case of DNLH of the intestine and another case of duodenal cytomegalovirus (CMV) infection associated with CVID.