Angiogenesis

A new prognostic model for survival in second line for metastatic renal cell carcinoma: development and external validation Abstract Background In patients with metastatic renal cell carcinoma (mRCC), the oncologic benefit of second-line treatment for high volume tumors or presence of more than five risk factors remain to be defined. Our aim was to develop and externally validate a new model most likely to correctly predict overall survival (OS) categories in second line. Method mRCC patients treated within clinical trials at Gustave Roussy Cancer Campus (GRCC) formed the discovery set. Patients from two phase III trials from Pfizer database (PFIZERDB), AXIS (NCT00678392), and INTORSECT (NCT00474786), formed the external validation set. New prognostic factors were analyzed using a multivariable Cox model with a backward selection procedure. Performance of the GRCC model and the prognostic classification scheme derived from it, measuring by R2, c-index, and calibration, was evaluated on the validation set and compared to MSKCC and IMDC models. Results Two hundred and twenty-one patients were included in the GRCC cohort and 855 patients in the PFIZERDB. Median OS was similar in the discovery and validation cohorts (16.8 [95% CI 12.9–21.7] and 15.3 [13.6–17.2] months, respectively). Backward selection procedure identified time from first to second-line treatment and tumor burden as new independent prognostic factors significantly associated to OS after adjusting for IMDC prognostic factors (HR 1.68 [1.23–2.31] and 1.43 [1.03–1.99], respectively). Dividing patients into four risk groups, based on the number of factors selected in GRCC model, median OS from the start of second line in the validation cohort was not reached (NE) [95% CI 24.9–NE] in the favorable risk group (n = 20), 21.8 months [18.6–28.2] in the intermediate-risk group (n = 367), 12.7 months [11.0–15.8] in the low poor-risk group (n = 347), and 5.5 months [4.7–6.4] in the high poor-risk group (n = 121). Finally, this model and its prognostic classification scheme provided the better fit, with higher R2 and higher c-index compared to other possible classification schemes. Conclusion A new prognostic model was developed and validated to estimate overall survival of patients with previously treated mRCC. This model is an easy-to-use tool that allows accurate estimation of patient survival to inform decision making and follow-up after first line for mRCC.

Cancer stem cells contribute to angiogenesis and lymphangiogenesis in serous adenocarcinoma of the ovary Abstract The origin of blood and lymphatic vessels in high-grade serous adenocarcinoma of ovary (HGSOC) is uncertain. We evaluated the potential of cancer stem cells (CSCs) in HGSOC to contribute to their formation. Using spheroids as an in vitro model for CSCs, we have evaluated their role in primary malignant cells (PMCs) in ascites from previously untreated patients with HGSOC and cell lines. Spheroids from PMCs grown under specific conditions showed significantly higher expression of endothelial, pericyte and lymphatic endothelial markers. These endothelial and lymphatic cells formed tube-like structures, showed uptake of Dil-ac-LDL and expressed endothelial nitric oxide synthase confirming their endothelial phenotype. Electron microscopy demonstrated classical Weibel–Palade bodies in differentiated cells. Genetically, CSCs and the differentiated cells had a similar identity. Lineage tracking using green fluorescent protein transfected cancer cells in nude mice confirmed that spheroids grown in stem cell conditions can give rise to all three cells. Bevacizumab, a monoclonal antibody that targets vascular endothelial growth factor inhibited the differentiation of spheroids to endothelial cells in vitro. These results suggest that CSCs contribute to angiogenesis and lymphangiogenesis in serous adenocarcinoma of the ovary, which can be inhibited.

Anti-secretogranin III therapy of oxygen-induced retinopathy with optimal safety Abstract Retinopathy of prematurity (ROP) with pathological retinal neovascularization is the most common cause of blindness in children. ROP is currently treated with laser therapy or cryotherapy, both of which may adversely affect the peripheral vision with limited efficacy. Owing to the susceptibility of the developing retina and vasculatures to pharmacological intervention, there is currently no approved drug therapy for ROP in preterm infants. Secretogranin III (Scg3) was recently discovered as a highly disease-restricted angiogenic factor, and a Scg3-neutralizing monoclonal antibody (mAb) was reported with high efficacy to alleviate oxygen-induced retinopathy (OIR) in mice, a surrogate model of ROP. Herein we independently investigated the efficacy of anti-Scg3 mAb in OIR mice and characterized its safety in neonatal mice. We developed a new Scg3-neutralizing mAb recognizing a distinct epitope and independently established the therapeutic activity of anti-Scg3 therapy to alleviate OIR-induced pathological retinal neovascularization in mice. Importantly, anti-Scg3 mAb showed no detectable adverse effects on electroretinography and developing retinal vasculature. Furthermore, systemic anti-Scg3 mAb induced no renal tubular injury or abnormality in kidney vessel development and body weight gain of neonatal mice. In contrast, anti-vascular endothelial growth factor drug aflibercept showed significant side effects in neonatal mice. These results suggest that anti-Scg3 mAb may have the safety and efficacy profiles required for ROP therapy.

The plaque-aortic ring assay: a new method to study human atherosclerosis-induced angiogenesis Abstract Progression of atherosclerotic plaques into life-threatening lesions is associated with angiogenesis which contributes to intraplaque hemorrhages and plaque instability. The lack of adequate models for the study of human plaque-induced angiogenesis has limited progress in this field. We describe here a novel ex vivo model which fills this gap. Plaques obtained from 15 patients who underwent endarterectomy procedures were co-cultured in collagen gels with rat aorta rings which served as read-out of human plaque angiogenic activity. The majority of plaque fragments markedly stimulated angiogenic sprouting from the aortic rings while concurrently promoting the outgrowth of resident macrophages from the aortic adventitia. This stimulatory activity correlated with the presence of intraplaque macrophages. Proteomic analysis of plaque secretomes revealed heterogeneity of macrophage-stimulatory cytokine and angiogenic factor production by different plaques. VEGF was identified in some of the plaque secretomes. Antibody-mediated blockade of VEGF had significant but transient inhibitory effect on angiogenesis, which suggested redundancy of plaque-derived angiogenic stimuli. Pharmacologic ablation of adventitial macrophages permanently impaired the angiogenic response of aortic rings to plaque stimuli. Our results show that human plaque-induced angiogenesis can be reproduced ex vivo using rat aortic rings as read-out of plaque angiogenic activity. This model can be used to identify key cellular and molecular mechanisms responsible for the neovascularization of human plaques.

Cancer-derived exosomal miR-221-3p promotes angiogenesis by targeting THBS2 in cervical squamous cell carcinoma Abstract Aims Recently, cancer-derived exosomes were shown to have pro-metastasis function in cancer, but the mechanism remains unclear. Angiogenesis is essential for tumor progression and is a great promising therapeutic target for advanced cervical cancer. Here, we investigated the role of cervical cancer cell-secreted exosomal miR-221-3p in tumor angiogenesis. Methods and results miR-221-3p was found to be closely correlated with microvascular density in cervical squamous cell carcinoma (CSCC) by evaluating the microvascular density with immunohistochemistry and miR-221-3p expression with in situ hybridization in clinical specimens. Using the groups of CSCC cell lines (SiHa and C33A) with miR-221-3p overexpression and silencing, the CSCC exosomes were characterized by electron microscopy, western blotting, and fluorescence microscopy. The enrichment of miR-221-3p in CSCC exosomes and its transfer into human umbilical vein endothelial cells (HUVECs) were confirmed by qRT-PCR. CSCC exosomal miR-221-3p promoted angiogenesis in vitro in Matrigel tube formation assay, spheroid sprouting assay, migration assay, and wound healing assay. Then, exosome intratumoral injection indicated that CSCC exosomal miR-221-3p promoted tumor growth in vivo. Thrombospondin-2 (THBS2) was bioinformatically predicted to be a direct target of miR-221-3p, and this was verified by using the in vitro and in vivo experiments described above. Additionally, overexpression of THBS2 in HUVECs rescued the angiogenic function of miR-221-3p. Conclusions Our results suggest that CSCC exosomes transport miR-221-3p from cancer cells to vessel endothelial cells and promote angiogenesis by downregulating THBS2. Therefore, CSCC-derived exosomal miR-221-3p could be a possible novel diagnostic biomarker and therapeutic target for CSCC progression.

Prognostic effect of VEGF gene variants in metastatic non-small-cell lung cancer patients Abstract Introduction Clinical and pathological characteristics are still considered prognostic markers in metastatic non-small-cell lung cancer (NSCLC) patients but they cannot explain all interindividual variability. Tumoral angiogenesis mediated by the vascular endothelial growth factor (VEGF) is critical for the progression and metastasis of the disease. We aimed to investigate the prognostic role of genetic variants within the VEGF pathway in patients with metastatic NSCLC. Materials and methods We prospectively included 170 patients with metastatic NSCLC treated with first-line platinum-based chemotherapy. A comprehensive panel of single-nucleotide polymorphisms (SNPs) in genes belonging to the VEGF pathway (VEGFA, VEGFR1/FLT1, VEGFR2/KDR, GRB2, ITGAV, KISS1, KRAS, PRKCE, HIF1α, MAP2K4, MAP2K6, and MAPK11) were genotyped in blood DNA samples. SNPs were evaluated for association with overall survival (OS) and progression-free survival (PFS). Results In multivariate analyses adjusted for patient characteristics, we found that VEGFA rs2010963 and VEGFR2 rs2071559 were significantly associated with OS [Hazard Ratio (HR) 0.7 (0.5–0.9); p = 0.026 and HR 1.5 (1.1–2.3); p = 0.025, respectively]. Additionally, ITGAV rs35251833 and MAPK11 rs2076139 were significantly associated with PFS [HR 2.5 (1.4–4.3; p = 0.002 and HR 0.6 (0.5–0.9); p = 0.013, respectively]. Conclusion Our findings reinforce the potential clinical value of germline variants in VEGFA and VEGFR2 and show for the first time variants in ITGAV and MAPK11 as promising prognostic markers in metastatic NSCLC patients receiving platinum-based chemotherapy.

Monitoring tumour microenvironment changes during anti-angiogenesis therapy using functional MRI Abstract Objective This study aims to explore the feasibility of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and blood oxygen level-dependent magnetic resonance imaging (BOLD-MRI) in assessing vessel function and tumour aggressiveness during anti-angiogenesis treatment. Materials and methods A colon cancer xenograft model was established in BALB/C nude mice with the HCT116 cell line. Sixteen mice were randomly divided into Group A and Group B, which were treated with saline or bevacizumab by intraperitoneal injection on the 1st, 4th, 7th, 10th and 13th days and underwent DCE-MRI and BOLD-MRI examinations before and on the 3rd, 6th, 9th, 12th and 15th days after treatment. Group C was treated with oxaliplatin monotherapy, and Group D was treated with bevacizumab and oxaliplatin as a point of comparison for therapeutic effects. The pathological examinations included HE, HIF-1α, fibronectin and TUNEL staining, as well as α-SMA and CD31 double staining. One-way analysis of variance and correlation analysis were the main methods used for statistical analysis. Results Group D manifested the highest tumour inhibition rate and smallest tumour volume on day 15, followed by Group C, Group B and Group A. Ktrans (F = 81.386, P < 0.001), Kep (F = 45.901, P < 0.001), Ve (F = 384.290, P < 0.001) and R2* values (F = 89.323, P < 0.001) showed meaningful trends with time in Group B but not Group A. The Ktrans values and tumour vessel maturity index (VMI) were higher than baseline values 3–12 days after bevacizumab treatment. The CD31 positive staining rate and VMI had the strongest correlations with Ktrans values, followed by AUC180, Ve and Kep values. The R2* value positively correlated with the positive staining rates of HIF-1α and fibronectin. Conclusion Intermittent application of low-dose anti-angiogenic inhibitor treatment may help improve the effect of chemotherapy by reducing hypoxia-related treatment resistance and improving drug delivery. DCE-MRI is useful for evaluating vessel maturity and vascular normalization, while BOLD-MRI may help to predict tumour hypoxia and metastatic potential after anti-vascular treatment.

Exhaustion of the bone marrow progenitor cell reserve is associated with major events in severe limb ischemia Abstract Lower numbers of progenitor cells (PCs) in peripheral blood (PB) have been associated with cardiovascular events in high-risk populations. Therapies aiming to increase the numbers of PCs in circulation have been developed, but clinical trials did not result in better outcomes. It is currently unknown what causes the reduction in PB PC numbers: whether it is primary depletion of the progenitor cell reserve, or a reduced mobilization of PCs from the bone marrow (BM). In this study, we examine if PB and BM PC numbers predict Amputation-Free Survival (AFS) in patients with Severe Limb Ischemia (SLI). We obtained PB and BM from 160 patients enrolled in a clinical trial investigating BM cell therapy for SLI. Samples were incubated with antibodies against CD34, KDR, CD133, CD184, CD14, CD105, CD140b, and CD31; PC populations were enumerated by flow cytometry. Higher PB CD34+ and CD133+ PC numbers were related to AFS (Both Hazard Ratio [HRevent] = 0.56, p = 0.003 and p = 0.0007, respectively). AFS was not associated with the other cell populations in PB. BM PC numbers correlated with PB PC numbers and showed similar HRs for AFS. A further subdivision based on relative BM and PB PC numbers showed that BM PC numbers, rather than mobilization, associated with AFS. Both PB and BM PC numbers are associated with AFS independently from traditional risk factor and show very similar risk profiles. Our data suggest that depletion of the progenitor cell reserve, rather than decreased PC mobilization, underlies the association between PB PC numbers and cardiovascular risk.

Adgrf5 contributes to patterning of the endothelial deep layer in retina Abstract Neovascularization of the inner retinal space is a major cause of vision loss. In retinal angiomatous proliferation (RAP) syndrome, newly formed vessels originate from the retinal plexus and invade the inner retinal space. However, the molecular pathways preventing subretinal vascularization remain largely unknown. In most murine models of RAP, pathological neovascularization occurs concomitantly with the development of the retinal vasculature. Here, we demonstrate that disturbing the sequence of morphogenetic events that shape the three-layered retinal vascular network leads to subretinal vascularization. Sprouts emerging from the perivenous region after the first postnatal week extended toward the retinal space where they merged into the deep layer. The small GTPase Rac1 was required for the formation of these vascular extensions and the vascular inner plexus is formed coaxially to the overarching veins. The adhesion receptor Adgrf5 was highly expressed in the endothelium of the central nervous system, where it regulates blood–brain barrier formation. The vascular superficial plexus of Adgrf5 mutant mouse retinae exhibited an increased vascular density in the perivenous areas with increased projections toward the inner plexus where they subsequently created hyper-dense endothelial cells (EC) clusters. Disturbing the perivenous pool of EC thus significantly altered the inner plexus formation. These abnormalities culminated in transient vascular protrusions in the inner retinal space. Taken together, these results reveal a previously unobserved vascular morphogenetic defect in Adgrf5 knockout mice, implicating a role for ADGRF5 in the initiation of subretinal vascularization. Our findings also illustrate how vein-derived EC shape the inner retinal layer formation and could control the appearance of angiomatous malformations.

PinX1 represses renal cancer angiogenesis via the mir-125a-3p/VEGF signaling pathway Abstract Background PIN2/TRF1-interacting telomerase inhibitor 1 (PinX1) is a tumor suppressor in various tumors. However, the molecular mechanism underlying PinX1's role in cancer development and progression remains unclear. In this study, we aimed to uncover the new molecular mechanism and role of PinX1 in renal cell carcinoma (RCC) progression. Methods We used miRNA microarray to detect the different expressed miRNAs upon PinX1 knockdown. Chromatin immunoprecipitation and Luciferase reporter assays were taken to identify the molecular mechanism of PinX1 in regulating mir-125-3p. In situ hybridization was performed to analyze the expression of mir-125a-3p in RCC using tissue microarray. The correlations between the mir-125a-3p expression level and clinicopathological features were evaluated using the χ2 test. The role and molecular mechanism of PinX1 in RCC angiogenesis were investigated through a series of in vitro and in vivo experiments. Results In this study, we discovered a new molecular mechanism of PinX1, in which PinX1 transcriptionally activated mir-125a-3p expression, thereby inhibiting the expression of vascular endothelial growth factor (VEGF), which is the target gene of mir-125a-3p. PinX1 also repressed tumor angiogenesis by increasing the mir-125a-3p expression in renal cancer. Moreover, the loss of mir-125a-3p expression was manifested in patients with RCC, and low miR-125a-3p levels correlated with poor survival of these patients. Conclusions PinX1 represses renal cancer angiogenesis through mir-125a-3p/VEGF signal pathway. The miR-125a-3p may be a candidate clinical prognostic marker and a novel therapeutic target in RCC.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Musculoskeletal Surgery

Minimally invasive plate osteosynthesis (MIPO) in AO/OTA type B displaced clavicle fractures Abstract Introduction Open reduction and plate fixation is known to reduce chances of malunion and symptomatic nonunion in displaced middle-third clavicle fractures. However, this treatment modality is also associated with several complications, such as hardware irritation, numbness around the surgical scar, infection, nonunion and implant failure. The minimally invasive plate osteosynthesis (MIPO) technique may reduce these complications. Objective To study clinical, radiological and functional outcomes of MIPO in AO/OTA type B displaced clavicle fractures and report any complications. Materials and methods A total of 22 patients underwent internal fixation of acute displaced AO/OTA type B clavicle fractures from Jan 2014 to Dec 2015 by MIPO using locking compression plates. Patients were followed up at a regular interval and assessed clinically and radiologically. The clavicle length difference was measured. Functional assessment was done at the end of 2 year using constant shoulder score (CSS) and disability of the arm, shoulder and hand score (Quick DASH) and complications if any were noted. Results All fractures united at a mean of 12.5 weeks. One (4.5%) patient had numbness around the surgical scar. None of the patients had wound-related complications. In four patients, hardware irritation was noted. The difference in clavicle length was not significant. All patients had excellent CSS and Quick DASH score at the final follow-up. Conclusion Internal fixation of displaced AO/OTA type B clavicle fractures by MIPO showed high fracture union rates and good functional outcomes.

Clinical outcomes in periarticular knee fractures with flexible fixation using far cortical locking screws in locking plate: a prospective study Abstract Purpose Periarticular fractures around the knee joint are treated traditionally by locking plates which provide excellent stability but suppress callus formation. Far cortical locking (FCL) screws allow axial motion and enhance uniform callus formation. Our study aims to evaluate the outcomes of FCL screws in traditional locking plate in periarticular fractures of the knee. Methods Thirty patients with periarticular fractures of the knee joint were operated with locking plate using FCL screws. All patients were evaluated clinically and radiographically using X-rays at 6, 12, 24 weeks, 1 year and with CT scan at 12-weeks follow-up. Results The average time for complete union was 20 weeks in tibial fractures and 24 weeks in femur fractures. Average time to full weight bearing ambulation was 4.8 ± 0.93 weeks. One patient had delayed union in which union was complete after 9 months. Conclusion This study shows that FCL screws in locking plates allow uniform callus formation and fracture union with minimal complication rates.

Surgical strategy in extensive proximal brachial plexus palsies Abstract Purpose To describe and assess an overall surgical strategy addressing extensive proximal brachial plexus injuries (BPI). Methods Forty-five consecutive patients' charts with C5–C6–C7 and C5–C6–C7–C8 BPI were reviewed. Primary procedures were nerve transfers to restore elbow function and grafts to restore shoulder function when a cervical root was available; when nerve surgery was not possible or had failed, tendon transfers were conducted at the elbow while addressing shoulder function with glenohumeral arthrodesis or humeral osteotomy. Tendon transfers were used to restore finger extension. Results Forty-one patients underwent elbow flexion reanimation: thirty-eight had nerve transfers and eight received tendon transfers, including five cases secondary to nerve surgery failure; grade-3 strength or greater was reached in thirty-seven cases (90%). Twenty-nine patients had nerve transfers to restore elbow extension: twenty-five recovered grade-3 or grade-4 strength (86%). Forty-one patients underwent shoulder surgery: fourteen had nerve surgery and thirty-one received palliative procedures, including four cases secondary to nerve surgery failure; thirty patients recovered at least 60° of abduction and rotation (73%). Distal reconstruction was performed in thirty-seven patients, providing finger full extension in all cases but two (95%). Conclusions A standardized strategy may be used in extensive proximal BPI, providing overall satisfactory outcomes.

Passive anterior tibia translation in anterior cruciate ligament-injured, anterior cruciate ligament-reconstructed and healthy knees: a systematic review Abstract Anterior tibia translation (ATT) is mainly prevented by the anterior cruciate ligament. Passive ATT tests are commonly used to diagnose an anterior cruciate ligament (ACL) injury, to select patients for an ACL reconstruction (ACLR), and as an outcome measure after an ACLR. The aim of this review was to present an overview of possible factors determining ATT. A second purpose was to give a summary of the ATT measured in the literature in healthy, ACL-injured and ACLR knees and a comparison between those groups. A literature search was conducted with PubMed. Inclusion criteria were full-text primary studies published in English between January 2006 and October 2016. Studies included reported ATT in explicit data in healthy as well as ACL-injured or ACLR knees or in ACL-injured as well as ACLR knees. Sixty-one articles met inclusion criteria. Two articles measured the ATT in healthy as well as ACL-injured knees, 51 in ACL-injured as well as in ACLR knees, three in ACLR as well as in healthy knees and three in healthy, ACL-injured and ACLR knees. A difference in ATT is found between healthy, contralateral, ACLR and ACL-injured knees and between chronic and acute ACL injury. Graft choices and intra-articular injuries are factors which could affect the ATT. The mean ATT was lowest to highest in ACLR knees using a bone–patella tendon–bone autograft, ACLR knees using a hamstring autograft, contralateral healthy knees, healthy knees, ACLR knees with an allograft and ACL-injured knees. Factors which could affect the ATT are graft choice, ACL injury or reconstruction, intra-articular injuries and whether an ACL injury is chronic or acute. Comparison of ATT between studies should be taken with caution as a high number of different measurement methods are used. To be able to compare studies, more consistency in measuring devices used should be introduced to measuring ATT. The clinical relevance is that an autograft ACLR might give better results than an allograft ACLR as knee laxity is greater when using an allograft tendon. Level of evidence III.

The role of poor oral health in surgical site infection following elective spinal surgery Abstract Study design Cross-sectional study. Objectives To describe oral health and hygiene as a risk factor for surgical site infection (SSI). Methods This cross-sectional study was conducted on patients over 18 years of age who were candidates for elective spinal surgery. The exclusion criteria were immunodeficiency, history of cancer, history of previous infection at the surgical site, cutaneous diseases and long-term use of corticosteroids. Questionnaires were filled out for patients via an interview in order to collect the demographic data of patients. Oral and dental examinations were performed using DMFT (D: decayed, M: missing, F: filled, T: total) and PUFA (P: pulp, U: ulcer, F: fistula, A: abscess) indices. Data were analyzed using Fisher's exact test and Mann–Whitney test. Results A total of 78 patients were evaluated. There were 59 females (75.6%) and 19 males (24.6%). Eight patients were positive for SSI. Teeth caries (P = 0.016) and periodontal disease (P = 0.049) were significantly correlated with SSI. No significant association was noted between PUFA and SSI (P > 0.05). Sixty-five patients (83.3%) had a history of dental infection before surgery. Fifty% of patients being positive for SSI had a history of dental abscess (P = 0.023). Conclusions A significant association exists between SSI and caries, gingivitis/periodontitis and history of dental abscess.

Tension band wiring versus locking plate fixation for simple, two-part Mayo 2A olecranon fractures: a comparison of post-operative outcomes, complications, reoperations and economics Abstract Purpose Simple displaced transverse olecranon fractures are traditionally managed operatively with a tension band wire device (TBW). We compared clinical outcomes, morbidity and the cost of treatment of TBW versus pre-countered low-profile locking plates for the treatment of Mayo 2A fractures. Patient and methods All olecranon fractures admitted to our unit between 2008 and 2014 were identified (n = 129). Patient notes and radiographs were studied from presentation to final follow-up. Patient outcomes were recorded using the QuickDASH (Disabilities of Arm, Shoulder and Hand) score. Patient demographics and nature of complications were recorded as were the rate and nature of any repeat operation. Results Eighty-nine patients had Mayo 2A fractures (69%). Sixty-four underwent TBW (n = 48) or locking plate fixation (n = 16). The mean ages of both groups were similar at 57 (15–93) and 60 (22–80), respectively. In the TBW group, the mean post-injury QuickDASH was 12.9, compared with 15.0 for the locking plate group. There was no statistically significant difference between the outcomes for either group. Nineteen of the 48 TBW patients had complications (39.6%). Sixteen of the 48 TBW patients had reoperations (33.3%). In particular, we would highlight that 13 (27.1%) of patients treated with TBW underwent subsequent removal of metalwork for hardware irritation. There were no complications and or reoperations in the 16 patients who received locking plate fixation. Both complication and reoperation rates were statistically significantly different. Despite being initially more expensive, when the cost of reoperation for TBW group was included, locking plates were found to be on average £236.33 less per patient than for TBW. Conclusions We suggest that locking plates are superior to TBW concerning post-operative morbidity, reoperation rate and cost for Mayo 2A fractures in contrast to previous articles. Level of evidence Therapeutic study, III.

Minimally invasive fixation for displaced intra-articular fractures of calcaneum: a short-term prospective study on functional and radiological outcome Abstract Introduction Studies have demonstrated a decrease in the incidence of late consequences and the socio-economic burden of intra-articular fractures of calcaneum when treated by surgical fixation. Operative management of displaced intra-articular calcaneal fractures (DIACF) pose significant challenges such as technical difficulty, wound healing and long-term pain and disability. Materials and methods All patients presenting to the ER with DIACF over a period of 2 years and matching the inclusion criteria were enrolled in the study. Percutaneous fixation with 4 mm CC screw was undertaken with a minimally invasive sinus tarsi approach. All patients were available for a minimum follow-up of 24 months. Six radiological parameters were assessed, and functional outcome was evaluated using AOFAS score. Results Thirty-four patients with 42 calcaneal fractures were included in the study, and all patients were available for minimum follow-up period. All radiological parameters were attained within anatomic normal range and maintained at 24 months of follow-up. AOFAS score showed a mean value of 90.10 which is considered an excellent outcome. Superficial wound infection was seen in two patients, but no patients required a revision surgery. Conclusion Displaced intra-articular fractures pose a treatment dilemma, more so in cases of soft tissue complications like open injury or blisters. Percutaneous screw fixation with limited sinus tarsi incision has shown good functional and radiological outcome with minimal complications and can be undertaken without delay.

Reverdin–Isham procedure for mild or moderate hallux valgus: clinical and radiographic outcomes Abstract Background In the last decade, interests in minimal incision surgery have been growing. Theoretically, this kind of procedure could decrease time to recovery and rehabilitation, with a reduction in morbidity. The present study assessed clinical and radiological outcomes and complications of percutaneous surgery for mild-to-moderate hallux valgus using Reverdin–Isham and Akin osteotomies without fixation after 60 months of follow-up. Methods A series of 48 patients (57 cases) with medium-to-moderate hallux valgus underwent the same percutaneous surgery, between 2003 and 2011. Data collection involved preoperative dorsal flexion, plantar flexion, M1P1, M1M2, DMAA angles, AOFAS scale score, and subjective satisfaction. Results AOFAS scale score rose from a preoperative median of 55.9–89.2/100 postoperatively (p < 0.001); 51 surgical procedures (89.5%) were considered as satisfactory or very satisfactory by patients at the end of follow-up. Hallux valgus and distal metatarsal articular angle (DMAA) were significantly reduced (29.3° and 14.1°–15.4° and 7.7°, p < 0.001, respectively). There was a significant increase in MTPJ 1 stiffness (p < 0.001). Discussion Percutaneous correction by Reverdin–Isham and Akin osteotomies seems to be effective in isolated medium-to-moderate hallux valgus. Stiffness observed is comparable to other percutaneous and open procedures but needs to be compared in a randomized controlled clinical trial to extra-articular percutaneous procedures without capsule detachment in association with an internal fixation which allows an early mobilization. Level of clinical evidence IV.

Surgical treatment of pediatric supracondylar humerus fracture could be safely performed by general orthopedists Abstract Purpose Displaced pediatric supracondylar humerus fracture (SCHF) requires a reduction and instrumentation. The trend is to send the cases to a fellowship-trained pediatric orthopedist. This study reviewed the outcomes and complications of SCHF surgically managed by orthopedic surgeons with different backgrounds of subspecialty training. Methods The medical records of 87 children (87 elbows) with an average age of 5.9 ± 3.1 (range 1.3–14.1) years with SCHF Gartland 2 and 3 who underwent operative fixation were reviewed. The demographics data and operative details were obtained. Radiographically, the Baumann and humerocapitella angles were measured. The lateral rotational percentage of Gordon was calculated. The Griffet index 1 and 2 were retrieved. The parameters were compared among groups of surgeons with a pediatric fellowship-trained background and surgeons with other subspecialty training. A univariate analysis was calculated for the risk of postoperative complications. Results The demographics data were comparable between the two groups. Children who were treated by non-pediatric fellowship-trained orthopedists showed higher but not significant degrees of postoperative Baumann angles; however, the proportion of children with an acceptable range of Baumann angle were similar. The overall complications rate was 17.5% and comparable between the two groups. Only SCHF Gartland 3 was associated with complications (P = 0.01). Conclusions Pediatric SCHF could be efficiently managed by a general orthopedic surgeon because the radiographic outcomes and complications were comparable to pediatric fellowship-trained orthopedists. Extra precautions need to be exercised in SCHF Gartland type 3 because the chance of complications is higher among these types of injuries. Level of evidence Level III.

Goldthwait technique for patellar instability: surgery of the past or here to stay procedure? A systematic review of the literature Abstract Patellar instability is the pathologic condition where the patella is prone to recurrent lateral dislocation. The clinical results on large series of patients and long-term outcome of Goldthwait techniques have not been described in the literature. The aim of this systematic review is: (1) to analyze and summarize the available literature focused on Goldthwait procedure in the treatment of recurrent patellar dislocation and (2) to evaluate the clinical and functional outcomes of patients treated with this surgical procedure. A systematic review of the literature was performed to investigate the results of Goldthwait procedure according to the PRISMA 2009 guidelines. A total of 7 articles published were systematically reviewed. A total of 197 knees (182 patients: 86 males and 96 females) have been treated with Goldthwait procedure. The mean reported follow-up was 6.8 years. The mean age at surgery was 18 years old. The Goldthwait procedure was associated with open lateral retinacular release in 127 (64.5%) knees to arthroscopic lateral retinacular release in 20 (10.1%) knees, and with retinacular plasty and a vastus medialis advancement in 33 (16.7%) knees. Only in 17 (8.6%) knees the Goldthwait procedure was performed as an isolated procedure. Poor standardization of methodological assessment has been observed. Despite the limitations of the available literature, the Goldthwait technique provides satisfying results for the treatment of patellar instability even in pediatric population. More high-quality studies are necessary to evaluate the long-term complications and the real incidence of long-term PF osteoarthritis.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Physiological Sciences

Thyroxin and calcitonin secretion into thyroid venous blood is regulated by pharyngeal mechanical stimulation in anesthetized rats Abstract The effects of the pharyngeal non-noxious mechanical stimulation on the secretion of immunoreactive thyroxin (iT4), immunoreactive calcitonin (iCT), and immunoreactive parathyroid hormone (iPTH) into thyroid venous blood were examined in anesthetized rats. Secretion rates of iT4, iCT, and iPTH were calculated from their concentration in thyroid venous plasma and the plasma flow rate. A mechanical stimulation was delivered to the pharynx by a rubber balloon placed on the tongue that was intermittently pushed into the pharyngeal cavity. Pharyngeal stimulation increased iT4 and iCT secretion, but iPTH secretion was unchanged. The secretion responses were abolished by transecting the superior laryngeal nerves (SLNs) bilaterally. The activities of the thyroid parasympathetic efferent nerves and the afferent nerves in the SLN increased significantly during pharyngeal stimulation. These results indicate that pharyngeal mechanical stimulation promotes thyroxin and calcitonin secretion from the thyroid gland by a reflex increase in SLN parasympathetic efferent activity, triggered by excitation of SLN mechanoreceptive afferents.

EAE-induced upregulation of mitochondrial MnSOD is associated with increases of mitochondrial SGK1 and Tom20 protein in the mouse kidney cortex Abstract Our previous demonstration that severe experimental autoimmune encephalomyelitis (EAE) increases MnSOD protein abundance in the mouse kidney cortex led this study to elucidate the underlying mechanism with monensin-treated HEK293 cells as a model. Severe EAE increases mitochondrial protein abundance of SGK1 kinase and Tom20, a critical subunit of mitochondrial translocase in the renal cortex. In HEK293 cells, catalase inhibits monensin-induced increases of mitochondrial SGK1 and Tom20 protein levels. Further, GSK650394, a specific inhibitor of SGK1 reduces monensin-induced increase of mitochondrial protein abundance of Tom20 and MnSOD. Finally, RNAi of Tom20 reduces the effect of monensin on MnSOD. MnSOD and Tom20 physically associate with each other. In conclusion, in HEK293 cells, mitochondrial reactive oxygen species increase protein abundance of mitochondrial SGK1, which leads to a rise of mitochondrial Tom20, resulting in importing MnSOD protein into the mitochondria. This could be a mechanism by which severe EAE up-regulates mitochondrial MnSOD in the kidney cortex.

Intermittent hyperbaric oxygen exposure mobilizing peroxiredoxin 6 to prevent oxygen toxicity Abstract Intermittent hyperbaric oxygen exposure (IE-HBO) can protect the body against oxygen toxicity, but the underlying mechanisms are not very clear. Peroxiredoxin 6 (Prdx6) is a special endogenous antioxidative protein. We explored if the protective effects of IE-HBO are related to Prdx6. Mice were exposed to 280 kPa O2 for 60 min, followed by 30-min exposure to 20% O2/N2 mixture with equal pressure, repeated for six cycles. The Prdx6 protein level and non-selenium glutathione peroxidase (NSGPx) activity in the brain and lungs were then measured and the injury degree of lung and the oxidation level of brain and lung were evaluated. On this basis, the relationship between Prdx6 and IE-HBO's protection was explored. Generally, both IE-HBO and continuous exposure to HBO (CE-HBO) could increase the protein and mRNA levels of Prdx6, and such increases were more significant 24 h after cessation of exposure; moreover, the Prdx6 level of IE-HBO was higher than that of CE-HBO in both brain and lung, also more significantly 24 h after cessation of exposure. In addition, IE-HBO exposure could more effectively potentiate the activity of NSGPx and increase GSH content in brain and lung tissues. At the same time, it could reduce oxidation products in these tissues. IE-HBO could also provide protection for the lungs against injuries resulting from prolonged HBO exposure. These data showed that IE-HBO can potentiate the production and the activity of Prdx6 and consequently mitigate oxidative damages in brain and lungs. The influences of IE-HBO on Prdx6 may form an important basis for its protection against oxygen toxicity.

Mitofusin-2 regulates inflammation-mediated mouse neuroblastoma N2a cells dysfunction and endoplasmic reticulum stress via the Yap-Hippo pathway Abstract Endoplasmic reticulum (ER) stress is involved in inflammation-induced neurotoxicity. Mitofusin 2 (Mfn2), a member of the GTPase family of proteins, resides in the ER membrane and is known to regulate ER stress. However, the potential role and underlying mechanism of Mfn2 in inflammation-induced neuronal dysfunction is unknown. In our study, we explored the potential of Mfn2 to attenuate inflammation-mediated neuronal dysfunction by inhibiting ER stress. Our data show that Mfn2 overexpression significantly ameliorated tumor necrosis factor alpha (TNFα)-induced ER stress, as indicated by the downregulation of the ER stress proteins PERK, GRP78 and CHOP. Mfn2 overexpression also prevented the TNFα-mediated activation of caspase-3, caspase-12 and cleaved poly (ADP-ribose) polymerase (PARP). Cellular antioxidant dysfunction and reactive oxygen species overproduction were also improved by Mfn2 in the setting of TNFα in mouse neuroblastoma N2a cells in vitro. Similarly, disordered calcium homeostasis, indicated by disturbed levels of calcium-related proteins and calcium overloading, was corrected by Mfn2, as evidenced by the increased expression of store-operated calcium entry (SERCA), decreased levels of inositol trisphosphate receptor (IP3R), and normalized calcium content in TNFα-treated N2a cells. Mfn2 overexpression was found to elevate Yes-associated protein (Yap) expression; knockdown of Yap abolished the regulatory effects of Mfn2 on ER stress, oxidative stress, calcium balance, neural death and inflammatory injury. These results lead us to conclude that re-activation of the Mfn2–Yap signaling pathway alleviates TNFα-induced ER stress and dysfunction of mouse neuroblastoma N2a cells. Our findings provide a better understanding of the regulatory role of Mfn2–Yap–ER stress in neuroinflammation and indicate that the Mfn2–Yap axis may be a focus of research in terms of having therapeutic value for the treatment of neurodegenerative diseases.

Effects of astaxanthin supplementation and electrical stimulation on muscle atrophy and decreased oxidative capacity in soleus muscle during hindlimb unloading in rats Abstract The effects of a combination of the antioxidant astaxanthin (AX) and electrical stimulation (ES) on muscle mass and mitochondrial oxidative capacity were investigated in the soleus muscle of hindlimb unloaded rats. Five groups of male Sprague-Dawley rats were used; control, 1-week hindlimb unloading (HU), HU + AX, HU + ES, and HU + AX + ES. Respective rats in the AX groups received 50-mg/kg AX twice daily during HU. Calf muscles of rats in the ES groups were electrically stimulated for 240 s/day during HU. One-week HU decreased muscle mass along with decreased FoxO3a phosphorylation and increased ubiquitinated proteins expressions, decreased oxidative enzymatic activity accompanied with decline in PGC-1α protein expression, and increased reactive oxygen species production. However, the combination treatment could synergistically attenuate/suppress all HU-related changes, suggesting protective effects on muscle atrophy and decreased muscle oxidative capacity due to chronic neuromuscular inactivity.

Factors inhibiting intestinal calcium absorption: hormones and luminal factors that prevent excessive calcium uptake Abstract Besides the two canonical calciotropic hormones, namely parathyroid hormone and 1,25-dihydroxyvitamin D [1,25(OH)2D3], there are several other endocrine and paracrine factors, such as prolactin, estrogen, and insulin-like growth factor that have been known to directly stimulate intestinal calcium absorption. Generally, to maintain an optimal plasma calcium level, these positive regulators enhance calcium absorption, which is indirectly counterbalanced by a long-loop negative feedback mechanism, i.e., through calcium-sensing receptor in the parathyroid chief cells. However, several lines of recent evidence have revealed the presence of calcium absorption inhibitors present in the intestinal lumen and extracellular fluid in close vicinity to enterocytes, which could also directly compromise calcium absorption. For example, luminal iron, circulating fibroblast growth factor (FGF)-23, and stanniocalcin can decrease calcium absorption, thereby preventing excessive calcium uptake under certain conditions. Interestingly, the intestinal epithelial cells themselves could lower their rate of calcium uptake after exposure to high luminal calcium concentration, suggesting a presence of an ultra-short negative feedback loop independent of systemic hormones. The existence of neural regulation is also plausible but this requires more supporting evidence. In the present review, we elaborate on the physiological significance of these negative feedback regulators of calcium absorption, and provide evidence to show how our body can efficiently restrict a flood of calcium influx in order to maintain calcium homeostasis.

Effects of testosterone on circadian rhythmicity in old mice Abstract Serum testosterone concentration decreases with age in humans and rodents. Accordingly, old male mice show changes in locomotor activity rhythms: a lengthened free-running period and decreased activity levels among others. To investigate whether testosterone replacement improves the age-related decline in circadian rhythmicity, we examined the effects of testosterone on the circadian rhythms of wheel running activity in old male mice. Intact male C57BL/6J mice (18–22 months old) were subcutaneously implanted with silicone tubes packed with testosterone propionate (TP) or cholesterol. TP treatment significantly decreased the daily wheel running revolutions in a normal light/dark (LD) cycle and in constant darkness (DD), but did not affect the free-running period. The same experiment performed on young male gonadectomized mice (3–5 months old) demonstrated that TP treatment significantly increased activity levels in both LD and DD. These results suggest that testosterone replacement exacerbates the age-related decline in circadian rhythmicity.

Phorbol 12-myristate 13-acetate (PMA) suppresses high Ca 2+ -enhanced adipogenesis in bone marrow stromal cells Abstract We have previously reported that increased extracellular and intracellular Ca2+ lead to adipocyte accumulation in bone marrow stromal cells (BMSCs). However, strategies to suppress high Ca2+-enhanced adipocyte accumulation have not been reported. We examined the effects of the diacylglycerol analog phorbol 12-myristate 13-acetate (PMA) on proliferation and adipogenesis of mouse primary BMSCs. We used 9 mM CaCl2 and 100 nM ionomycin to increase extracellular Ca2+ and intracellular Ca2+, respectively. PMA suppressed the expression of both C/EBPα and PPARγ under normal adipogenesis, adipogenesis + CaCl2, and adipogenesis + ionomycin conditions. PMA enhanced proliferation under normal adipogenesis conditions but suppressed proliferation under adipogenesis + CaCl2 and adipogenesis + ionomycin conditions. PMA did not affect the accumulation of adipocytes under normal adipogenesis conditions but suppressed adipocyte accumulation under adipogenesis + CaCl2 and adipogenesis + ionomycin conditions. These results suggest that the PMA-dependent pathway is an important signaling pathway to suppress high Ca2+-enhanced adipocyte accumulation.

Anxiety-like behaviors and hippocampal nNOS in response to diet-induced obesity combined with exercise Abstract A high-fat diet (HFD) and overweight status can induce hippocampal dysfunction, leading to depression and anxiety. Exercise has beneficial effects on emotional behaviors. We previously reported that exercise training rescues HFD-induced excess hippocampal neuronal nitric oxide synthase (nNOS) expression, which is a key regulator of anxiety. Here, we investigated anxiety-like behaviors and hippocampal nNOS expression in response to HFD combined with exercise. Mice were assigned to standard diet, HFD, or HFD with exercise groups for 12 weeks. We found that exercise during the final 6 weeks of the HFD regime improved 12 weeks of HFD-induced defecation, accompanied by rescue of excess nNOS expression. However, anxiety indicators in the elevated plus maze were unchanged. These effects were not apparent after only 1 week of exercise. In conclusion, 6 weeks of exercise training reduced HFD-related anxiety according to one of our measures (defecation), and reversed changes in the hippocampal nNOS/NO pathway.

Peripheral nerve injury in rats induces alternations in choice behavior associated with food reinforcement Abstract Operant methods that allow animals to avoid painful stimuli are interpreted to assess the aversive quality of pain; however, such measurements require investigator-initiated stimuli to animals. Here we developed a shuttle maze test to repeatedly assess activity associated nociception without forced stimulation. Rats ambulate back and forth between two treat feeders by taking either a short route with a prickly surfaced arch or a longer route with a smooth floor. L5–L6 spinal nerve ligation (SNL) reduced the preference for the short route with the arch, correlated with hypersensitivity in the hind paw. Oral gabapentin restored the short route preference and reduced hypersensitivity in SNL rats, and blockade of spinal α2-adrenoceptors reduced gabapentin's effects on hypersensitivity but not on preference index. These results suggest that SNL injury alters behavior in the shuttle maze test and that the shuttle maze test shows comparable results to reflexive hypersensitivity after SNL in magnitude and response to gabapentin.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Cardiology

Electrical Storm: Current Evidence, Clinical Implications, and Future Perspectives Abstract Purpose of Review Electrical storm (ES) is a life-threatening medical emergency of repetitive episodes of sustained ventricular arrhythmias within a short period. Its occurrence is associated with poor short- and long-term survival, even in patients with implantable cardioverter defibrillators (ICD). Management of ES is challenging and mainly based on retrospective studies. This article reviews the existing literature on ES, presents the available data regarding its management, and proposes a new algorithm based on current evidence. Recent Findings Recent research could modify the management of ES supporting the role of non-selective β1 and β2 blockade and the early intervention with catheter ablation as well as strengthening the role of cardiac sympathetic denervation. Summary A multipronged approach should be considered for the management of ES including identification and correction of reversible causes, ICD reprogramming, drug therapy (beta-blockers—especially non-selective ones—and other anti-arrhythmic drugs) and non-pharmacologic therapies such as catheter ablation and techniques of neuroaxial modulation. Although current data suggest early aggressive management, further research is required to clarify the optimal order and combination of therapies for the prevention of future events.

Do Thiazide Diuretics Increase the Risk of Skin Cancer? A Critical Review of the Scientific Evidence and Updated Meta-Analysis Abstract Purpose of Review We reviewed the hypothesised mechanisms of skin cancerogenesis for thiazide diuretics; conducted an updated meta-analysis of studies focusing on their association with skin cancer risk; critically appraised the quality of available studies and identified knowledge gaps; and discussed implications for health professionals and patients. Recent Findings Thiazide diuretics possess well-described photosensitizing properties and a causal association with skin cancer is biologically plausible. The epidemiological evidence is stronger for squamous cell cancer; however, diversity in design among studies, methodological concerns potentially affecting the validity of results, and scarcity of data on dose-relation relationship suggest caution in drawing conclusions. Only few, unbalanced, and/or heterogeneous data exist to date for melanoma and basal cell cancer. Summary Patients effectively treated with thiazide diuretics are currently not advised to stop treatment, but encouraged to limit exposure to sunlight and regularly check their skin. While endorsing these recommendations, we believe that well-designed studies are urgently needed to overcome persistent knowledge gaps.

Current Role of the CardioMEMS Device for Management of Patients with Heart Failure Abstract Purpose of Review Heart failure (HF) remains a significant burden to our healthcare system and a leading cause of hospitalizations. Current reactive strategies to treat and manage HF have failed to reduce hospitalizations and improve survival. The CardioMEMS device has recently been demonstrated to improve quality of life in HF and reduce HF-related hospitalizations. Current HF management strategies are reviewed with a particular emphasis on the current role of the CardioMEMS device. Recent Findings The CHAMPION trial is the only randomized trial looking at the CardioMEMS device. Patients managed with targeted pulmonary artery pressures resulted in 28% reduction in the primary end-point of HF-related hospitalization at 6 months (HR 0.72, 95% CI 0.60–0.85, p = 0.0002) and 37% reduction during the entire follow-up period, which averaged 15 months (HR 0.63, 95% CI 0.52–0.77, p < 0.0001). The prospective open-label post-approval study recently presented a 58% reduction in HF hospitalizations per patient year (HR 0.42, 95% CI 0.38–0.47, p < 0.0001). Summary Management of HF using the CardioMEMS device has been shown to reduce HF hospitalizations and improve quality of life regardless of ejection fraction. Patients best suited for this device are those with recurrent congestive symptoms despite optimal medical therapy.

Strategies for Appropriate Selection of SGLT2-i vs. GLP1-RA in Persons with Diabetes and Cardiovascular Disease Abstract Purpose of Review This review will serve to highlight the clinical rationale used in the selection of sodium-glucose cotransporter 2 inhibitors (SGLT2-i) or glucagon-like peptide 1 receptor agonists (GLP1-ra). Recent Findings SGLT2-i and GLP1-ra are the first anti-hyperglycemics to demonstrate significant cardiovascular benefit in multiple cardiovascular outcomes trials (CVOTs), with benefits that are consistent across class of medication. Summary Diabetes is a major risk factor for morbidity and mortality from cardiovascular disease. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) and glucagon-like peptide 1 receptor agonists (GLP1-ra) are the first anti-hyperglycemics to demonstrate significant cardiovascular benefit. Given the unique side effect and benefit profiles, appropriate consideration of these agents with a focus on cardiovascular risk reduction requires an individualized approach.

The Challenges of Redo Aortic Coarctation Repair in Adults Abstract Purpose of Review Aortic coarctation is a common congenital abnormality causing significant morbidity and mortality if not corrected. Re-coarctation or restenosis of the aorta following treatment is a relatively common long-term problem and the optimal therapy has not been elucidated. In this review, we identify the challenges associated with and the optimal management for recurrent aortic coarctation and the most appropriate therapy for different patient cohorts. Recent Findings Open surgery provides a durable long-term aortic repair, however, given the complex nature of the procedure, has a somewhat higher rate of serious complications. Endovascular repair, although less invasive and relatively safe, has limitations in treated complex anatomy and is more likely to require repeat intervention. Summary Open surgical repair is more appropriate for infants that have not been intervened on and endovascular therapy should be reserved for older children and adults and those that require repeat intervention.

Imaging Strategies for Evaluating Low-Flow, Low-Gradient Aortic Stenosis with Reduced and Preserved Left Ventricular Ejection Fraction Abstract Purpose of Review Aortic stenosis (AS) is one of the most common valvular heart diseases, and aortic valve replacement (AVR) provides both symptomatic and survival benefit in symptomatic severe AS patients. The purpose of this review is to discuss low-flow low-gradient AS which is still a challenging diagnostic entity. Recent Findings Thirty–forty percent of patients with AS have low flow which makes it difficult to differentiate truly severe AS that benefits from AVR compared to pseudo-severe AS which is currently managed conservatively. Patients with low-flow low-gradient AS (LF-LG AS) include those with reduced left ventricular systolic function (classical LF-LG AS) and those with preserved left ventricular systolic function (paradoxical LF-LG AS). Low-dose dobutamine stress echocardiography (DSE) helps to identify truly severe stenosis in patients with classical LF-LG AS. Aortic valve calcium scoring with multidetector computed tomography plays a major role in patients with paradoxical LF-LG AS and also among classical LF-LG AS patients who have reduced contractile reserve on DSE. Summary This article will provide an overview of imaging strategies for evaluating LF-LG AS with reduced and preserved left ventricular ejection fraction.

Stroke Risk in Atrial Fibrillation: Beyond the CHA 2 DS 2 -VASc Score Abstract Purpose of Review Stroke prevention is the cornerstone of atrial fibrillation (AF) management and the anticoagulation decision is currently based on CHA2DS2-VASc risk score. We discuss several novel risk factors besides those included in CHA2DS2-VASc score and alternative models for stroke prediction. Recent Findings Several clinical markers including obstructive sleep apnea and renal failure, laboratory markers like brain natriuretic peptide, imaging criteria including left atrial appendage morphology, spontaneous echo contrast, and coronary artery calcium score may predict stroke in AF patients. Addition of African American ethnicity to CHA2DS2-VASc score also improves stroke prediction in AF. Finally, novel models including TIMI-AF score, ATRIA score, and GARFIELD-AF scores have potential roles in risk stratification for stroke. Summary While CHA2DS2-VASc score is the currently recommended risk stratification model for stroke prediction in AF, use of additional clinical, laboratory, imaging markers, ethnicity, and novel stroke prediction models may further assist in decision to anticoagulate the AF patient for stroke prevention.

Effectiveness of Changes in Diet Composition on Reducing the Incidence of Cardiovascular Disease Abstract Purpose of Review To highlight dietary changes shown to be associated with a lower risk of cardiovascular events in epidemiological studies and that have been proven to be effective in preventing cardiovascular diseases in clinical trials Recent Findings Since dietary changes always involve multiple variables, recent observational and intervention studies on dietary prevention of cardiovascular disease focus not only to the limitation of a single nutrient/food intake but also to the other dietary changes implemented to replace it. Summary The available evidence supports three major dietary strategies for cardiovascular disease prevention: (1) the replacement of saturated fat with unsaturated fat and/or fiber-rich carbohydrate foods; (2) the reduction of salt intake; (3) the implementation of dietary patterns resembling the traditional Mediterranean diet. This support derives not only from RCTs but also from the combination of large observational cohort studies and relatively short-term randomized trials on cardiovascular risk factors.

Cardiac Magnetic Resonance Fingerprinting: Technical Developments and Initial Clinical Validation Abstract Purpose of Review Magnetic resonance imaging (MRI) has enabled non-invasive myocardial tissue characterization in a wide range of cardiovascular diseases by quantifying several tissue specific parameters such as T1, T2, and T2* relaxation times. Simultaneous assessment of these parameters has recently gained interest to potentially improve diagnostic accuracy and enable further understanding of the underlying disease. However, these quantitative maps are usually acquired sequentially and are not necessarily co-registered, making multi-parametric analysis challenging. Magnetic resonance fingerprinting (MRF) has been recently introduced to unify and streamline parametric mapping into a single simultaneous, multi-parametric, fully co-registered, and efficient scan. Feasibility of cardiac MRF has been demonstrated and initial clinical validation studies are ongoing. Provide an overview of the cardiac MRF framework, recent technical developments and initial undergoing clinical validation. Recent Findings Cardiac MRF has enabled the acquisition of co-registered T1 and T2 maps in a single, efficient scan. Initial results demonstrate feasibility of cardiac MRF in healthy subjects and small patient cohorts. Current in vivo results show a small bias and comparable precision in T1 and T2 with respect to conventional clinical parametric mapping approaches. This bias may be explained by several confounding factors such as magnetization transfer and field inhomogeneities, which are currently not included in the cardiac MRF model. Initial clinical validation for cardiac MRF has demonstrated good reproducibility in healthy subjects and heart transplant patients, reduced artifacts in inflammatory cardiomyopathy patients and good differentiation between hypertrophic cardiomyopathy and healthy controls. Summary Cardiac MRF has emerged as a novel technique for simultaneous, multi-parametric, and co-registered mapping of different tissue parameters. Initial efforts have focused on enabling T1, T2, and fat quantification; however this approach has the potential of enabling quantification of several other parameters (such as T2*, diffusion, perfusion, and flow) from a single scan. Initial results in healthy subjects and patients are promising, thus further clinical validation is now warranted.

Contributions of Interactions Between Lifestyle and Genetics on Coronary Artery Disease Risk Abstract Purpose of the Review To summarize current knowledge on interactions between genetic variants and lifestyle factors (G×L) associated with the development of coronary artery disease (CAD) and prioritize future research. Recent Findings Genetic risk and combined lifestyle factors and behaviors have a log-additive effect on the risk of developing CAD. Summary First, we describe genetic and lifestyle factors associated with CAD and then focus on G×L interactions. The majority of G×L interaction studies are small-scale candidate gene studies that lack replication and therefore provide spurious results. Only a few studies, of which most use genetic risk scores or genome-wide approaches to test interactions, are robust in number and analysis strategy. These studies provide evidence for the existence of G×L interactions in the development of CAD. Further G×L interactions studies are important as they contribute to our understanding of disease pathophysiology and possibly provide insights for improving interventions or personalized recommendations.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Gastroenterology

Recurrence of hepatocellular carcinoma at the porta-hepatis following liver transplantation diagnosed on EUS-FNA Abstract Hepatocellular carcinoma (HCC) is a potentially fatal complication of chronic liver disease. Liver transplantation is now the preferred treatment due to good outcomes. We present a unique case of recurrence of HCC at the porta hepatis four years after orthotopic liver transplantation diagnosed via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA). Our report also highlights that intrahepatic recurrence of HCC can be surgically treated. However, further studies are needed to develop treatment algorithms for intra-hepatic recurrence of HCC post liver transplantation.

Obstructive pancreatitis secondary to a pancreatic metastasis from lung cancer treated with nasopancreatic drainage Abstract A 44- and a 66-year-old woman underwent nasopancreatic drainage (NPD) to treat obstructive pancreatitis secondary to a pancreatic metastasis from lung cancer. Both patients were diagnosed with stage IV lung cancer and underwent chemotherapy for 17 and 15 months, respectively. Abdominal ultrasonography and computed tomography revealed a solid pancreatic tail tumor measuring 2.5 cm and 1.3 cm in diameter, respectively. Additionally, we observed dilatation of the upstream main pancreatic duct (MPD) and edematous parenchyma with peripancreatic inflammatory changes limited to the pancreatic tail. Both patients were diagnosed with moderately severe acute pancreatitis and received fluid resuscitation, an opioid analgesic, antibiotics, and a protease inhibitor. However, owing to unrelenting pain, we performed endoscopic retrograde cholangiopancreatography (ERCP) for pancreatic duct drainage in both patients. ERCP showed a stricture in the MPD in the pancreatic tail with upstream dilatation. A 5-Fr NPD tube was inserted to drain the dilated MPD, and cloudy pancreatic juice was drained. NPD tube placement led to pain relief in both patients. Pancreatic juice cultures grew Enterococcus faecium and Enterobacter cloacae, respectively. The NPD tube was later cut in both cases using a pair of scissor forceps.

Hepatic portal venous gas associated with Klebsiella oxytoca infection in the absence of preceding antibiotic treatment Abstract Klebsiella oxytoca (K. oxytoca) is a causative organism for hemorrhagic antibiotic-associated colitis. K. oxytoca infection is a typical example of microbial substitution diseases caused by exposure to antibiotics prior to the onset of diarrhea. Here, we repot a case with ileitis associated with K. oxytoca infection in the absence of preceding antibiotic treatment. Interestingly, abdominal computed tomography revealed wall thickening of the ileum and hepatic portal venous gas (HPVG). K. oxytoca was isolated from the stool. This very elderly patient had been treated with azathioprine for long-standing history of ulcerative colitis. Immuno-compromised state of this patient was considered to allow overgrowth of K. oxytoca in the small bowel to cause not only ileitis but also HPVG.

Acute pancreatitis associated with massive bleeding due to a duodenal ulcer Abstract A 74-year-old man presented to the emergency department with acute abdominal pain in addition to anemia and melena, which were suspected to be due to gastrointestinal bleeding. Computed tomography (CT) revealed a blood-filled duodenum and acute pancreatitis. We prioritized treatments for pancreatitis, as the vital signs were stable, and temporary hemostasis was achieved. Two days later, esophagogastroduodenoscopy revealed a duodenal ulcer with an exposed vessel, and endoscopic hemostasis was performed. We urge clinicians to consider the possibility of pancreatitis associated with massive bleeding due to a duodenal ulcer.

Esophageal intramural pseudodiverticulosis complicated with severe stricture requiring surgical resection Abstract Esophageal intramural pseudodiverticulosis (EIPD) is an uncommon benign disorder leading to esophageal strictures. The etiology remains unknown; however, anti-fungal treatments or endoscopic balloon dilation can improve early esophageal strictures and these rarely require surgical treatment. We report a case of a 46-year-old male with a 6 cm-long esophageal stricture due to EIPD, which did not improve following treatment with an anti-fungal agent, eventually causing aspiration pneumonia. Therefore, we performed a thoraco-laparoscopic esophagectomy, and his symptoms were improved after surgery. This case suggests that a surgical treatment should be considered in patients with extensive, severe strictures attributable to EIPD.

Early gastric cancer with ball valve syndrome treated by endoscopic submucosal dissection Abstract An 84-year-old woman with pneumonia, congestive heart failure and chronic renal failure presented for iron-deficiency anemia and appetite loss. Esophagogastroduodenoscopy revealed a 60-mm sub-pedunculated tumor arising from the antrum of the stomach. The tumor was friable, with bleeding, and prolapsed into the duodenal bulb, the ball valve syndrome. The tumor was considered the cause of the anemia and appetite loss. Attempted endoscopic reduction of the prolapsing tumor was unsuccessful, but the base of its stalk could be identified through the transparent hood; thus, we removed the tumor with endoscopic submucosal dissection. The tumor was retrieved successfully, and pathohistological examination revealed the tumor to be a well-differentiated adenocarcinoma. This case suggests that endoscopic submucosal dissection is useful as an alternative to surgery for removal of gastric tumors that have prolapsed into the duodenal bulb when polypectomy was difficult, but provided the tumor's attachment site can be identified endoscopically.

Curative endoscopic treatment of intussusception due to a giant colonic lipoma using a wedged balloon and ligation with detachable snares Abstract A 67-year-old woman presented with symptoms of bowel obstruction. Radiographic and ultrasonographic findings suggested colo-colonic intussusception caused by a colonic lipoma. Colonoscopy with an endoscope tip balloon was performed for reduction. The intussusception was partially reduced by injecting dilute contrast media with a wedged inflated balloon at the endoscope tip. For definitive treatment of the polyp, ischemia was induced using a detachable snare. The abdominal pain well improved after endoscopic treatment. However, ultrasonography suggested a residual lesion. Another detachable snare was applied to the stalk on day 6. A large amount of dark-red necrotic tissue was passed per anus the following day. One month later, complete scarring of the site was confirmed colonoscopically. This is the first report of curative endoscopic treatment of an intussusception due to a giant colonic lipoma with detachable snares after the reduction with a wedged balloon of colonoscope tip.

A case of esophagogastroduodenoscopy induced Takotsubo cardiomyopathy with complete heart block Abstract Takotsubo cardiomyopathy (TC) describes a reversible left ventricular dysfunction characterized by apical ballooning and basal hyperkinesis, commonly triggered by emotional or physical distress. TC associated with an esophagogastroduodenoscopy (EGD) has rarely been reported. We report a case of TC with complete heart block (CHB) in a patient receiving an EGD, who had no underlying cardiac disease, had previously tolerated both local and general anesthesia, and who had previously undergone similar endoscopic procedures without complications. The concurrence of both TC and CHB is unique in this case pertaining to a patient with no significant risk factors. The incidence, mechanism and prognosis of TC-associated arrhythmias are also reviewed.

Asymptomatic giant cell hepatitis: a subtype of post-infantile giant cell hepatitis? Abstract Giant cell hepatitis in adults is considered a rapidly progressive and life-threatening disease, but there are few descriptions of a prolonged disease course. A 36-year-old Japanese man was referred to our hospital for further evaluation of abnormal liver function test results. Although asymptomatic, he had undergone follow-up for 9 years with these abnormalities. Because the cause of liver injury was not identified despite extensive noninvasive examinations, the patient underwent needle biopsy. He was finally diagnosed with post-infantile giant cell hepatitis (PIGCH) based on the presence of small numbers of giant multinucleated hepatocytes scattered primarily around the portal area. Necroinflammatory changes were very mild in the portal tracts and hepatic parenchyma. According to the histological findings as well as the accepted international diagnostic scoring system for autoimmune hepatitis (AIH), which is closely related to PIGCH, AIH was unlikely, although antinuclear antibody was positive at a titer of 1:160. The present case may describe an unknown subtype of PIGCH, characterized by insidious disease onset and progression with concurrent, mildly active underlying hepatitis, which is in contrast with the well-documented aggressive nature of PIGCH.

Hepatic angiomyolipoma with early drainage veins into the hepatic and portal vein Abstract Hepatic angiomyolipoma (AML) is a rare stromal tumor composed of variable admixtures of thick-walled vessels, smooth muscles and adipose tissue. One of the specific radiological findings of hepatic AML is an early drainage vein noted via enhanced computed tomography (CT). We report a case of hepatic AML showing early drainage veins into both the hepatic and portal vein. The case involved a 46-year-old woman who was referred to our hospital because of a giant hepatic tumor. CT revealed well-enhanced 14 cm and 1 cm tumors in the left and right lobes, respectively. Magnetic resonance imaging demonstrated the existence of adipose tissues in the larger tumor. Hepatic arteriography revealed early drainage veins draining into both the hepatic and portal vein. Based on a diagnosis of hepatic AML, left hepatectomy and partial hepatectomy were performed. Pathology revealed both tumors as hepatic AML based on human melanoma black-45 immuno-positivity. Hepatic AML with early drainage veins into both the hepatic and portal vein is rare. The dilated and retrogressive vein drains the abundant arterial blood flow of the tumor. The finding of early drainage veins into not only the hepatic vein but also the portal vein should be helpful for diagnosing hepatic AMLs.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com