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Objective: Dieulafoy's lesions (DLs) are a rare but potentially life-threatening source of gastrointestinal (GI) haemorrhage. They are responsible for roughly 1%-6.5% of all cases of acute non-variceal GI bleeding.Here, we describe retrospectively the clinical and endoscopic features, review the short-term and long-term outcomes of endoscopic management of bleeding DLs and we identify rate and risk factors, of recurrence and mortality in our endoscopic unit., Design: Data were collected from patients presenting with GI haemorrhagic secondary to DLs between January 2018 and August 2023. Patients' medical records as well as endoscopic databases were retrospectively reviewed. Demographic data, risk factors, bleeding site, outcomes of endoscopy techniques, recurrence and mortality rate were taken into account., Results: Among 1170 cases of GI bleeding, we identified only seven cases involving DLs. Median age was 74 years, with a male-to-female ratio of 2.5. 75% of patients had significant comorbidities, mainly cardiovascular diseases. Only anticoagulant and antiplatelet agents were significantly associated with DLs. All patients were presented with GI bleeding as their initial symptom. The initial endoscopy led to a diagnosis in 85% of the cases. Initial haemostasis was obtained in all patients treated endoscopically. Nevertheless, the study revealed early recurrence in two out of three patients treated solely with epinephrine injection or argon plasma coagulation. In contrast, one of three patients who received combined therapy, experienced late recurrence (average follow-up of 1 year). Pathological diagnosis was necessary in one case. One patient (14%) died of haemorrhagic shock. Average length of hospital stay was 3 days., Conclusion: Although rare, DLs may be responsible for active, recurrent and unexplained GI bleeding. Thanks to the emergence of endoscopic therapies, the recurrence rate has decreased and the prognosis has highly improved. Therefore, the endoscopic approach remains the first choice to manage bleeding DLs., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The majority of out-of-hours cases relate to neurological, chest, and gastrointestinal pathologies with acute vascular cases being encountered less commonly. Trainees and exposure of non-vascular/interventional radiology (IR) consultants to angiographic imaging is often limited in working hours and this may lead to reporting on-call cases outside of normal daytime practice. In a recent local review, a number on-call vascular studies were found to contain a number of vascular-related discrepancies. Vascular reporting is a complex subspecialty, which comprises many clear diagnoses (large vessel occlusions, large vessel aneurysms, or dissections); however, also several subtle and complex abnormalities. These more subtle abnormalities, at times, require dedicated vascular specialist review to ensure subtle findings are communicated appropriately to the clinical team. The recent increased complexity of endovascular treatments and their complications has also provided further challenge for the non-specialist reporter. Similarly, improved imaging techniques have allowed for non-obvious but significant findings that may require urgent management, such as small aneurysms and dissection flaps. We will review a range of key vascular findings that demonstrate learning opportunities, particularly within the acute and on-call settings. These will include gastrointestinal haemorrhage, subtle aortic pathologies, head and neck vascular emergencies, small to mid-sized vessel injuries and imaging of post-procedural complications. Educational hints and tips will be provided to enable learning from mistakes encountered by trainees and non-vascular specialist radiologists in the on-call or urgent reporting settings, and these will be reviewed with reference to the literature., (Crown Copyright © 2021. Published by Elsevier Ltd. All rights reserved.)

Non-invasive imaging plays an increasingly important role in assessing the extracranial vasculature. The applications of computed tomography angiography (CTA) and magnetic resonance angiography (MRA) continue to expand with growing demand for stroke imaging and anatomical assessment preceding vascular intervention. Imaging of the neck is performed for a variety of clinical indications with different imaging protocols. Even on non-dedicated vascular imaging, such as soft-tissue studies, the neck vessels and the proximal aortic arch are readily evaluable, providing an opportunity to promptly identify critical vascular abnormalities with significant therapeutic implications. Vascular abnormalities can have non-specific clinical signs and symptoms resulting in delays in both diagnosis and treatment. Understanding the common locations and appearances of vascular pathologies will help the radiologist to develop a systematic search strategy for evaluating neck imaging. Not only is identifying the pathology of paramount importance but also understanding how imaging further prognosticates and determines treatment options. As imaging techniques advance, further vascular radiological features are recognised with therapeutic implications, particularly for stroke. Such features include plaque morphology and vulnerability with imaging helping to identify those at high risk of stroke and recurrent strokes. Using clinical cases from a quaternary care academic medical centre a spectrum of clinically relevant arterial pathologies and associated features that could add further benefit to the radiology report are illustrated. A suggested systematic approach to evaluating the vasculature on neck imaging is also presented., (Copyright © 2021 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Defective pericyte-endothelial cell interaction in tumors leads to a chaotic, poorly organized and dysfunctional vasculature. However, the underlying mechanism behind this is poorly studied. Herein, we develop a method that combines magnetic beads and flow cytometry cell sorting to isolate pericytes from tumors and normal adjacent tissues from patients with non-small cell lung cancer (NSCLC) and hepatocellular carcinoma (HCC). Pericytes from tumors show defective blood vessel supporting functions when comparing to those obtained from normal tissues. Mechanistically, combined proteomics and metabolic flux analysis reveals elevated hexokinase 2(HK2)-driven glycolysis in tumor pericytes, which up-regulates their ROCK2-MLC2 mediated contractility leading to impaired blood vessel supporting function. Clinically, high percentage of HK2 positive pericytes in blood vessels correlates with poor patient overall survival in NSCLC and HCC. Administration of a HK2 inhibitor induces pericyte-MLC2 driven tumor vasculature remodeling leading to enhanced drug delivery and efficacy against tumor growth. Overall, these data suggest that glycolysis in tumor pericytes regulates their blood vessel supporting role., (© 2021. The Author(s).)

Vascular and lymphatic malformations represent a challenge for clinicians. The identification of inherited and somatic mutations in important signaling pathways, including the PI3K (phosphoinositide 3-kinase)/AKT (protein kinase B)/mTOR (mammalian target of rapamycin), RAS (rat sarcoma)/RAF (rapidly accelerated fibrosarcoma)/MEK (mitogen-activated protein kinase kinase)/ERK (extracellular signal-regulated kinases), HGF (hepatocyte growth factor)/c-Met (hepatocyte growth factor receptor), and VEGF (vascular endothelial growth factor) A/VEGFR (vascular endothelial growth factor receptor) 2 cascades has led to the evaluation of tailored strategies with preexisting cancer drugs that interfere with these signaling pathways. The era of theranostics has started for the treatment of vascular anomalies. Registration: URL: https://www.clinicaltrialsregister.eu; Unique identifier: 2015-001703-32.

Vascular malformations, affecting ≈1% to 1.5% of the population, comprise a spectrum of developmental patterning defects of capillaries, arteries, veins, and/or lymphatics. The majority of vascular malformations occur sporadically; however, inherited malformations exist as a part of complex congenital diseases. The malformations, ranging from birthmarks to life-threatening conditions, are present at birth, but may reveal signs and symptoms-including pain, bleeding, disfigurement, and functional defects of vital organs-in infancy, childhood, or adulthood. Vascular malformations often exhibit recurrent patterns at affected sites due to the lack of curative treatments. This review series provides a state-of-the-art assessment of vascular malformation research at basic, clinical, genetic, and translational levels.

Background: Removal of a pontine cavernous malformation requires sufficient exposure since any restriction on surgical freedom may lead to suboptimal visualization of the lesion, injury to the brainstem, and neurological catastrophe., Methods: We describe and demonstrate the subtemporal transtentorial approach to a cavernous malformation of the upper pons, with emphasis on adequate surgical exposure while avoiding the need for extensive bone removal of the skull base., Conclusions: The meticulous technique is paramount to the successful removal of any brainstem cavernous malformation. Along with the surgical exposure, delicate handling of the malformation is demonstrated in the accompanying operative video.

Outflow tract abnormalities are the most frequent congenital heart defects. These are due to the absence or dysfunction of the two main cell types, i.e., neural crest cells and secondary heart field cells that migrate in opposite directions at the same stage of development. These cells directly govern aortic arch patterning and development, ascending aorta dilatation, semi-valvular and coronary artery development, aortopulmonary septation abnormalities, persistence of the ductus arteriosus, trunk and proximal pulmonary arteries, sub-valvular conal ventricular septal/rotational defects, and non-compaction of the left ventricle. In some cases, depending on the functional defects of these cells, additional malformations are found in the expected spatial migratory area of the cells, namely in the pharyngeal arch derivatives and cervico-facial structures. Associated non-cardiovascular anomalies are often underestimated, since the multipotency and functional alteration of these cells can result in the modification of multiple neural, epidermal, and cervical structures at different levels. In most cases, patients do not display the full phenotype of abnormalities, but congenital cardiac defects involving the ventricular outflow tract, ascending aorta, aortic arch and supra-aortic trunks should be considered as markers for possible impaired function of these cells. Neural crest cells should not be considered as a unique cell population but on the basis of their cervical rhombomere origins R3-R5 or R6-R7-R8 and specific migration patterns: R3-R4 towards arch II, R5-R6 arch III and R7-R8 arch IV and VI. A better understanding of their development may lead to the discovery of unknown associated abnormalities, thereby enabling potential improvements to be made to the therapeutic approach.

Background: Off-label drug use is associated with an increased risk of adverse drug reactions. It is common in pediatrics and in rare diseases, which are two characteristics applying to vascular anomalies (VA)., Objectives: The aim of this work was to quantify off-label drug use in VA and assess its safety., Methods: A review was conducted to extract a list of drugs used in VA management. A drug was considered to have significant safety concerns if a black box warning was present or if a serious adverse drug reaction (SADR) was reported in at least 1% of the patients (SADR is defined as a noxious and unintended response to a drug that occurs at any dose and results in hospitalization, prolongation of existing hospitalization, congenital malformation, persistent or significant disability or incapacity, life-threatening condition, or death). The labelling status and safety of each drug was assessed based on the product monograph, Micromedex, and the FDA data., Results: We found that 98.9% of the inventoried drugs were used off-label or unlicensed for VA management. Only the oral solution of propranolol hydrochloride (Hemangeol®) for the treatment of infantile hemangiomas is approved. Significant safety issues concerned 73% of the drugs and were more frequent among systemic than locally delivered drugs., Conclusions: Off-label drug use in VA is the rule and not the exception. Significant safety concerns are common. It is necessary to carefully weigh risk and benefits for every patient when using systemic and local treatments carrying safety concerns. Patients should be openly informed and involved in the decision-making process., (© 2021 S. Karger AG, Basel.)

Aortic aneurysms and vascular malformations are sometimes associated with disseminated intravascular coagulation (DIC). A typical blood coagulation test shows decrease in platelet count and fibrinogen, and increases in fibrin/fibrinogen degradation products (FDP) and D-dimer. The coagulation activation marker thrombin-antithrombin complex (TAT) and the fibrinolysis activation marker plasmin-α 2 plasmin inhibitor (PIC) are significantly increased. α 2 plasmin inhibitor (α 2 PI) is significantly reduced. Since no prolongation of prothrombin time (PT) is noticeable and activated partial thromboplastin time (APTT) is shortened in some cases, DIC cannot be diagnosed or ruled out by PT and APTT alone. The cornerstone of treatment for DIC is to treat the underlying disease. However, surgery is not possible in some cases. Follow-up may be appropriate in patients with abnormal results from coagulation tests and no bleeding. However, pharmacotherapy is often required in cases with bleeding. Unfractionated heparin, low molecular weight heparin, protease inhibitors, recombinant thrombomodulin, direct oral anticoagulants, and factor XIII preparations are effective. If PIC is significantly increased and α 2 PI is significantly decreased, or if the bleeding is severe, tranexamic acid is used as an antifibrinolytic therapy with anticoagulant therapy. In such cases, attention should be paid not only to TAT but also changes in PIC.

Background: /Objectives: This study aimed to elucidate the efficacy of CT findings and perioperative characteristics to predict post-pancreatectomy hemorrhage (PPH): a critical complication after pancreaticoduodenectomy., Methods: The records of 590 consecutive patients who underwent pancreaticoduodenectomy at three institutes between 2012 and 2018 were included. The presence of a vascular wall abnormality or ascites with high density (vascular abnormality) on postoperative day (POD) 5-10 contrast-enhanced CT (early CT), perioperative characteristics, and any PPH or pseudoaneurysm formation (PPH events) were analyzed through a multivariate analysis., Results: PPH events occurred in 48 out of 590 patients (8%). The vascular abnormality on early CT and the C-reactive protein (CRP) value on POD 3 were independent risk factors for PPH events after POD5 (vascular abnormality: odds ratio 6.42, p = 0.001; CRP on POD 3: odds ratio 1.17, p = 0.016). The sensitivity of vascular abnormality for PPH events was 24% (7/29), and the positive predictive value was 30% (7/23). The combination of vascular abnormality and a high CRP value (≥15.5 mg/dL) on postoperative day 3 had a higher positive predictive value of 64% (7/11) than the vascular abnormality alone. None of the seven PPH events that occurred more than one month after surgery were foreseen via early CT., Conclusion: The combination of vascular abnormality and high CRP value was associated with increasing risk of PPH events after pancreaticoduodenectomy, but the low sensitivity of early CT must be noted as an important shortcoming. The normal findings on early CT could not eliminate the risk of late PPH., (Copyright © 2020 IAP and EPC. Published by Elsevier B.V. All rights reserved.)

Although endocranial abnormal blood vessel impressions (ABVIs) and periosteal appositions (PAs) have been considered as paleopathological diagnostic criteria for tuberculous meningitis (TBM) based on findings of previous studies, they are not pathognomonic for tuberculosis (TB). Therefore, their utilization in the paleopathological practice can be questioned, especially in consideration that most of the previous studies were not performed on identified skeletal collections but on osteoarchaeological material and did not include statistical data analysis. To fill the aforementioned research gap, for the first time, a macroscopic investigation was conducted on identified pre-antibiotic era skeletons from the Terry Collection. A sample set of 234 individuals who died of TB (TB group) and 193 individuals who died of non-tuberculous causes (NTB group) were examined. The frequency of ABVIs and PAs, as well as other probable TB-related lesions was recorded. To determine the significance of difference (if any) in the frequencies of ABVIs and PAs between the two groups, χ2 testing of our data was performed. We found that ABVIs, PAs, and their co-occurrence with each other and with other probable TB-related lesions were more common in the TB group than in the NTB group. In addition, the χ2 comparative frequencies of ABVIs and PAs revealed a statistically significant difference between individuals who died of TB and individuals who died of NTB causes. Our findings strengthen those of previous studies that ABVIs and PAs are not specific to TBM but can be of tuberculous origin. Therefore, they do have a diagnostic value in the identification of TB in human osteoarchaeological material, especially when they simultaneously occur with other probable TB-related lesions. Their prudent utilization provides paleopathologists with a stronger basis for diagnosing TB and consequently, a more sensitive means of assessing TB frequency in past human populations., Competing Interests: The authors have declared that no competing interests exist.

Stroke is one of the leading causes of morbidity and mortality worldwide. Intravenous tissue plasminogen activator and mechanical thrombectomy comprise the two major treatments for acute ischemic stroke. Tissue plasminogen activator has been used for more than two decades and guidelines for hemodynamic management following tissue plasminogen activator administration are well established. However, mechanical thrombectomy is a relatively newer therapy and there is a paucity of evidence regarding hemodynamic management following large vessel occlusion strokes. The important tenets guiding the pathophysiology of large vessel occlusion strokes include understanding of cerebral autoregulation, collateral circulation, and blood pressure variability. In this narrative review, we discuss the current American Heart Association-American Stroke Association guidelines for the early management of acute ischemic stroke during different phases of the illness, encountered at different sections of a hospital including the emergency room, the neuro-interventional suite, and the intensive care unit. There is emerging evidence with regard to post-recanalization blood pressure management following large vessel occlusion strokes. Future research directions will include rea-ltime blood pressure variability assessments, identifying the extent of impaired autoregulation, and providing guidelines related to range and personalized blood pressure trajectories for patients following large vessel occlusion strokes.

Vascular malformations occur during early vascular development resulting in abnormally formed vessels that can manifest as arterial, venous, capillary or lymphatic lesions, or in combination, and include local tissue overdevelopment. Vascular malformations are largely caused by sporadic somatic gene mutations. This article aims to review and discuss current molecular signaling pathways and therapeutic targets for vascular malformations and to classify vascular malformations according to the molecular pathways involved. A literature review was performed using Embase and Medline. Different MeSH terms were combined for the search strategy, with the aim of encompassing all studies describing the classification, pathogenesis, and treatment of vascular malformations. Major pathways involved in the pathogenesis of vascular malformations are vascular endothelial growth factor (VEGF), Ras/Raf/MEK/ERK, angiopoietin-TIE2, transforming growth factor beta (TGF-β), and PI3K/AKT/mTOR. These pathways are involved in controlling cellular growth, apoptosis, differentiation, and proliferation, and play a central role in endothelial cell signaling and angiogenesis. Many vascular malformations share similar aberrant molecular signaling pathways with cancers and inflammatory disorders. Therefore, selective anticancer agents and immunosuppressants may be beneficial in treating vascular malformations of specific mutations. The current classification systems of vascular malformations, including the International Society of the Study of Vascular Anomalies (ISSVA) classification, are primarily observational and clinical, and are not based on the molecular pathways involved in the pathogenesis of the condition. Several molecular pathways with potential therapeutic targets have been demonstrated to contribute to the development of various vascular anomalies. Classifying vascular malformations based on their molecular pathogenesis may improve treatment by determining the underlying nature of the condition and their potential therapeutic target.

Rationale: The incidence of pure arterial malformations is relatively low, and few cases have been reported. Only 2 cases with pure arterial malformation have been reported to receive surgery or endovascular treatment., Patient Concerns: We report 3 cases and review the relevant literatures. The head examinations of the patients suggested the presence of high-density shadows in front of the pons and midbrain, the dilation of the supraclinoid segment of the right internal carotid artery, and moyamoya in the left brain with an aneurysm-like expansion located on the left posterior communicating artery respectively. After admission, head digital subtraction angiography (DSA) was performed., Diagnoses: Digital subtraction angiography (DSA) for these 3 patients showed that the left posterior communicating artery, the supraclinoid segment of the right internal carotid artery, and the left posterior communicating artery appeared dilated, tortuous, and spirally elongated. In addition, the lesions in the latter 2 patients were accompanied with local aneurysmal changes., Interventions: Two patients were given conservative treatment, and another patient was given endovascular treatment. A head DSA was reviewed 6 months after therapy., Outcomes: The prognosis status of the 3 patients was good. Two patients in the conservative treatment group showed no changes in the lesions on head DSA examination. The DSA examination of the third patient indicated that the vascular remodeling of the diseased vessels was good, the blood vessels were unobstructed, and the aneurysms had disappeared., Lessons: Pure arterial malformations mostly occur in young women and may involve any blood vessels in the brain. It can be accompanied with local aneurysms and calcification. The patients are often given conservative treatment but need to be reviewed regularly. However, it is beneficial to give endovascular treatment to the patients with local aneurysms.

Rationale: Noonan syndrome (NS) is one of the most frequent genetic disorders. Bleeding problems are among the most common, yet poorly defined complications associated with NS. A lack of consensus on the management of bleeding complications in patients with NS indicates an urgent need for new therapeutic approaches., Objective: Bleeding disorders have recently been described in patients with NS harboring mutations of LZTR1 (leucine zipper-like transcription regulator 1), an adaptor for CUL3 (CULLIN3) ubiquitin ligase complex. Here, we assessed the pathobiology of LZTR1-mediated bleeding disorders., Methods and Results: Whole-body and vascular specific knockout of Lztr1 results in perinatal lethality due to cardiovascular dysfunction. Lztr1 deletion in blood vessels of adult mice leads to abnormal vascular leakage. We found that defective adherent and tight junctions in Lztr1 -depleted endothelial cells are caused by dysregulation of vesicular trafficking. LZTR1 affects the dynamics of fusion and fission of recycling endosomes by controlling ubiquitination of the ESCRT-III (endosomal sorting complex required for transport III) component CHMP1B (charged multivesicular protein 1B), whereas NS-associated LZTR1 mutations diminish CHMP1B ubiquitination. LZTR1-mediated dysregulation of CHMP1B ubiquitination triggers endosomal accumulation and subsequent activation of VEGFR2 (vascular endothelial growth factor receptor 2) and decreases blood levels of soluble VEGFR2 in Lztr1 haploinsufficient mice. Inhibition of VEGFR2 activity by cediranib rescues vascular abnormalities observed in Lztr1 knockout mice Conclusions: Lztr1 deletion phenotypically overlaps with bleeding diathesis observed in patients with NS. ELISA screening of soluble VEGFR2 in the blood of LZTR1 -mutated patients with NS may predict both the severity of NS phenotypes and potential responders to anti-VEGF therapy. VEGFR inhibitors could be beneficial for the treatment of bleeding disorders in patients with NS.

Idiopathic intestinal varicosis is a developmental disorder defined by dilated and convoluted submucosal veins in the colon or small bowel. A limited number of families with idiopathic intestinal varices has been reported, but the genetic cause has not yet been identified. We performed whole-exome and targeted Sanger sequencing of candidate genes in five intestinal varicosis families. In four families, mutations in the RPSA gene were found, a gene previously linked to congenital asplenia. Individuals in these pedigrees had intestinal varicose veins and angiodysplasia, often in combination with asplenia. In a further four-generation pedigree that only showed intestinal varicosities, the RPSA gene was normal. Instead, a nonsense mutation in the homeobox gene NKX2-3 was detected which cosegregated with the disease in this large family with a LOD (logarithm of the odds) score of 3.3. NKX2-3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Our results provide a molecular basis for familial idiopathic intestinal varices. We provide evidence for a relationship between the molecular pathways underlying the development of the spleen and intestinal mucosal vasculature that is conserved between humans and mice. We propose that clinical management of intestinal varices, should include assessment of a functional spleen., (© 2019 The Authors. Human Mutation Published by Wiley Periodicals, Inc.)

Rationale: Aberrant formation of blood vessels precedes a broad spectrum of vascular complications; however, the cellular and molecular events governing vascular malformations are not yet fully understood., Objective: Here, we investigated the role of CDC42 (cell division cycle 42) during vascular morphogenesis and its relative importance for the development of cerebrovascular malformations., Methods and Results: To avoid secondary systemic effects often associated with embryonic gene deletion, we generated an endothelial-specific and inducible knockout approach to study postnatal vascularization of the mouse brain. Postnatal endothelial-specific deletion of Cdc42 elicits cerebrovascular malformations reminiscent of cerebral cavernous malformations (CCMs). At the cellular level, loss of CDC42 function in brain endothelial cells (ECs) impairs their sprouting, branching morphogenesis, axial polarity, and normal dispersion within the brain tissue. Disruption of CDC42 does not alter EC proliferation, but malformations occur where EC proliferation is the most pronounced during brain development-the postnatal cerebellum-indicating that a high, naturally occurring EC proliferation provides a permissive state for the appearance of these malformations. Mechanistically, CDC42 depletion in ECs elicited increased MEKK3 (mitogen-activated protein kinase kinase kinase 3)-MEK5 (mitogen-activated protein kinase kinase 5)-ERK5 (extracellular signal-regulated kinase 5) signaling and consequent detrimental overexpression of KLF (Kruppel-like factor) 2 and KLF4, recapitulating the hallmark mechanism for CCM pathogenesis. Through genetic approaches, we demonstrate that the coinactivation of Klf4 reduces the severity of vascular malformations in Cdc42 mutant mice. Moreover, we show that CDC42 interacts with CCMs and that CCM3 promotes CDC42 activity in ECs., Conclusions: We show that endothelial-specific deletion of Cdc42 elicits CCM-like cerebrovascular malformations and that CDC42 is engaged in the CCM signaling network to restrain the MEKK3-MEK5-ERK5-KLF2/4 pathway.

Proper nomenclature is a major obstacle in understanding and managing vascular anomalies. Often the same term is used for totally different types of lesions or, conversely, the same lesion may be labeled with different terms. Although in recent times there has been a greater understanding of the problems concerning vascular anomalies, episodes of improper use of terminology still remain. The aim of this article, starting from the most recent classification of vascular anomalies, is to provide a clinical and instrumental approach to identifying these lesions and to converge towards a clear and unambiguous terminology that must become univocal among the various operators to avoid diagnostic misunderstandings and therapeutic errors.

Current methods to detect placental vascular pathologies that monitor Doppler ultrasound changes in umbilical artery (UA) pulsatility have only moderate diagnostic utility, particularly in late gestation. In fetal mice, we recently demonstrated that reflected pressure waves propagate counter to the direction of flow in the UA and proposed the measurement of these reflections as a means to detect abnormalities in the placental circulation. In the present study, we used this approach in combination with microcomputed tomography to investigate the relationship between altered placental vascular architecture and changes in UA wave reflection metrics. Fetuses were assessed at embryonic day (E) 15.5 and E17.5 in control C57BL6/J mice and dams treated with combination antiretroviral therapy (cART), a known model of fetal growth restriction. Whereas the reflection coefficient was not different between groups at E15.5, it was 27% higher at E17.5 in cART-treated mice compared with control mice. This increase in reflection coefficient corresponded to a 36% increase in the total number of vessel segments, a measure of overall architectural complexity. Interestingly, there was no difference in UA pulsatility index between groups, suggesting that the wave reflections convey information about vascular architecture that is not captured by conventional ultrasound metrics. The wave reflection parameters were found to be associated with the morphology of the fetoplacental arterial tree, with the area ratio between the UA and first branch points correlating with the reflection coefficient. This study highlights the potential for wave reflection to aid in the noninvasive clinical assessment of placental vascular pathology. NEW & NOTEWORTHY We used a novel ultrasound methodology based on detecting pulse pressure waves that propagate along the umbilical artery to investigate the relationship between changes in wave reflection metrics and altered placental vascular architecture visualized by microcomputed tomography. Using pregnant mice treated with combination antiretroviral therapy, a model of fetal growth restriction, we demonstrated that reflections in the umbilical artery are sensitive to placental vascular abnormalities and associated with the geometry of the fetoplacental tree.

Purpose: Situs inversus totalis is mirror transposition of thoracic and abdominal organs. Very few reports have been published on anatomic dissections of cadavers with this condition., Methods: This work describes a case of situs inversus totalis identified during the anatomical dissection of a 91-year-old woman., Results: Thoracic and abdominal viscera were inverted, but otherwise normal. The aorta originated from the right ventricle, which exhibited characteristics of the systemic ventricle. The pulmonary artery originated from the left ventricle, which had a tricuspid valve, three papillary muscles, thick trabeculae, a supraventricular crest, and septomarginal trabecula. The atrial situs was concordant with ventricular morphology. Lungs and paranasal sinuses were not suggestive of Kartagener's syndrome. Only the right adrenal gland was present, and variations in vascular anatomy were observed. The latter included: the celiac trunk branching into a phrenic artery, the splenic artery and a right gastric artery; the common hepatic artery originating from the superior mesenteric artery; and, on the left side, two inferior thyroid arteries, both originating from thyrocervical trunk. The occurrence of a double inferior thyroid artery and agenesis of adrenal gland was never communicated in situs inversus. Embryonic origin of celiac trunk and superior mesenteric artery variations could be explained by the separation at higher levels of the longitudinal anastomoses formed between the four roots of omphalomesenteric artery., Conclusion: It can be hypothesized that this phenomenon could occur more frequently in situs inversus than in situs solitus. However, the number of cases investigated in such detail is too small to draw firm conclusions.

Celecoxib is a non-steroidal anti-inflammatory drug that selectively inhibits cyclooxygenase-2 and is prescribed for severe pain and inflammation. The excellent therapeutic effects of celecoxib mean that it is frequently used clinically, including for women of child-bearing age. However, the prenatal effects of this compound have not been studied extensively in vertebrates. The present study examined the developmental toxicity of celecoxib using a frog embryo teratogenic assay-Xenopus (FETAX). In addition, we examined its effects on cell migration using co-cultures of human umbilical vein endothelial cells and 10T1/2 cells. These studies revealed that celecoxib induced concentration-dependent mortality and various malformations of the Xenopus internal organs, including gut miscoiling, haemorrhage, and oedema. Celecoxib also downregulated the expression of vascular wall markers (Msr and alpha smooth muscle actin) and other organ-specific markers (Nkx2.5, Cyl104 and IFABP). In vitro co-culture studies revealed that celecoxib inhibited pericyte migration and differentiation into vascular smooth muscle cells. In conclusion, celecoxib was both toxic and teratogenic in Xenopus embryos, where it produced serious heart and vessel malformation by inhibiting vascular wall maturation and vascular network formation., (Copyright © 2018. Published by Elsevier Inc.)

Leishmaniasis is one of the diverse and neglected tropical diseases. Embryo-toxicity of drugs has always been a major concern. Chick embryo is a preclinical model relevant in the assessment of adverse effects of drugs. The current study aimed to assess embryonic histopathological disorders and amniotic fluid biochemical changes following meglumine antimoniate treatment. The alteration of vascular branching pattern in the chick's extra-embryonic membrane and exploration of molecular cues to early embryonic vasculogenesis and angiogenesis were also quantified. Embryonated chicken eggs were treated with 75 or 150 mg/kg of meglumine antimoniate. Embryo malformations, growth retardation and haemorrhages on the external body surfaces were accompanied by histopathological lesions in the brain, kidney, liver and heart in a dose-dependent manner. Significant rise occurred in the biochemical indices of alkaline phosphatase, aspartate aminotransferase, alanine aminotransferase and amylase in the amniotic fluid. Quantification of the extra-embryonic membrane vasculature showed that the anti-angiogenic and anti-vasculogenic effects of the drug were revealed by a significant decrease in fractal dimension value and mean capillary area. The relative expression levels of vascular endothelial growth factor A and vascular endothelial growth factor receptor 2 mRNA also significantly reduced. Concerns of a probable teratogenicity of meglumine antimoniate were established by data presented in this study. It is concluded that tissue lesions, amniotic fluid disturbance, altered early extra-embryonic vascular development and gene expression as well as the consecutive cascade of events, might eventually lead to developmental defects in embryo following meglumine antimoniate treatment. Therefore, the use of meglumine antimoniate during pregnancy should be considered as potentially embryo-toxic. Hence, physicians should be aware of such teratogenic effects and limit the use of this drug during the growing period of the fetus, particularly in rural communities. Further pharmaceutical investigations are crucial for planning future strategies., Competing Interests: The authors have declared that no competing interests exist.

High-grade glioma (HGG) is highly angiogenic, but antiangiogenic therapy has transient clinical benefit in only a fraction of patients. Vascular regulators of these heterogeneous responses remain undetermined. We found up-regulation of Sox7 and down-regulation of Sox17 in tumor endothelial cells (tECs) in mouse HGG. Sox7 deletion suppressed VEGFR2 expression, vascular abnormality, hypoxia-driven invasion, regulatory T cell infiltration, and tumor growth. Conversely, Sox17 deletion exacerbated these phenotypes by up-regulating Sox7 in tECs. Anti-VEGFR2 antibody treatment delayed tumor growth by normalizing Sox17 -deficient abnormal vessels with high Sox7 levels but promoted it by regressing Sox7 -deficient vessels, recapitulating variable therapeutic responses to antiangiogenic therapy in HGG patients. Our findings establish that Sox7 promotes tumor growth via vessel abnormalization, and its level determines the therapeutic outcome of VEGFR2 inhibition in HGG. In 189 HGG patients, Sox7 expression was heterogeneous in tumor vessels, and high Sox7 levels correlated with poor survival, early recurrence, and impaired vascular function, emphasizing the clinical relevance of Sox7 in HGG., (© 2018 Kim et al.)

Background: Although sclerotherapy is a common treatment for benign oral vascular lesions, there is no well-standardized protocol for this purpose. The aim of the present study was to describe the clinical characteristics of patients treated by sclerotherapy with ethanolamine oleate (EO), in order to contribute to a better understanding of this technique., Material and Methods: Medical records and images of 90 patients treated by the same sclerotherapy protocol were retrieved and analysed. Thus, 43 cases with complete information were selected and described., Results: The most affected age group was 41-70 years, with a female predominance and 86% of patients being Caucasian. Lips were the most affect site (70%) followed by the tongue (16%). Regarding clinical appearance, approximately 90% of lesions were classified as nodules, and 90% of patients reported no pain. Approximately 40% of lesions were 0.5-1.0 cm in size. In 58% of the patients, only one application of ethanolamine oleate was necessary. The application doses varied according to the lesion size and number of applications. Complete clinical regression occurred in 91% of cases, whereas 9% showed partial regression., Conclusions: Sclerotherapy with EO is an acceptable, effective and affordable treatment for benign oral vascular lesions.

This article presents an overview of the literature publications concerning pathological changes in the cerebral blood vessels and the factors underlying the development of hemorrhagic complications leading to sudden death of young people. The special emphasis is placed on the most important causes behind the changes in the vascular wall (including the congenital ones) responsible for the high risk of rupture of the intracerebral vessels associated with the development of hemorrhagic complications.

Glioma growth and progression are characterized by abundant development of blood vessels that are highly aberrant and poorly functional, with detrimental consequences for drug delivery efficacy. The mechanisms driving this vessel dysmorphia during tumor progression are poorly understood. Using longitudinal intravital imaging in a mouse glioma model, we identify that dynamic sprouting and functional morphogenesis of a highly branched vessel network characterize the initial tumor growth, dramatically changing to vessel expansion, leakage, and loss of branching complexity in the later stages. This vascular phenotype transition was accompanied by recruitment of predominantly pro-inflammatory M1-like macrophages in the early stages, followed by in situ repolarization to M2-like macrophages, which produced VEGF-A and relocate to perivascular areas. A similar enrichment and perivascular accumulation of M2 versus M1 macrophages correlated with vessel dilation and malignancy in human glioma samples of different WHO malignancy grade. Targeting macrophages using anti-CSF1 treatment restored normal blood vessel patterning and function. Combination treatment with chemotherapy showed survival benefit, suggesting that targeting macrophages as the key driver of blood vessel dysmorphia in glioma progression presents opportunities to improve efficacy of chemotherapeutic agents. We propose that vessel dysfunction is not simply a general feature of tumor vessel formation, but rather an emergent property resulting from a dynamic and functional reorganization of the tumor stroma and its angiogenic influences., (© 2017 The Authors. Published under the terms of the CC BY 4.0 license.)

Background: Congenital heart defects are the most common birth defects worldwide. Although defective Notch signaling is the major cause of mouse embryonic death from cardiovascular defects, how Notch signaling is regulated during embryonic vasculogenesis and heart development is poorly understood., Methods and Results: Regulator of G protein signaling 6 (RGS6) -/- /Ca 2+ /calmodulin-dependent protein kinase II (CaMKII) VV double mutant mice were developed by crossing RGS6 -/- mice with mice expressing an oxidation-resistant CaMKIIδ (CaMKII VV ), and the resulting embryonic defects/lethality were investigated using E7.5 to E15.5 embryos. While loss of either RGS6 or oxidized CaMKIIδ does not alter embryogenesis, their combined loss causes defective Notch signaling, severe cardiovascular defects, and embryonic lethality (≈E10.5-11.5). Embryos lacking RGS6 and expressing oxidation-resistant CaMKIIδ exhibit reduced myocardial wall thickness, abnormal trabeculation, and arterial specification defects. Double mutants show vascular remodeling defects, including reduced neurovascularization, delayed neural tube maturation, and small dorsal aortae. These striking cardiovascular defects were accompanied by placental and yolk sac defects in angiogenesis, hematopoiesis, and vascular remodeling similar to what is seen with defective Notch1 signaling. Double mutant hearts, embryos, and yolk sacs exhibit profound downregulation of Notch1, Jagged 1, and Notch downstream target genes Hey1, Hey2, and Hey1L as well as impaired Notch1 signaling in embryos/hearts., Conclusions: RGS6 and oxidized CaMKIIδ together function as novel critical upstream modulators of Notch signaling required for normal cardiovascular development and embryo survival. Their combined need indicates that they function in parallel pathways needed for Notch1 signaling in yolk sac, placenta and embryos. Thus, dysregulated embryonic RGS6 expression and oxidative activation of CaMKII may potentially contribute to congenital heart defects., (© 2017 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley.)

Correct organization of the vascular tree requires the balanced activities of several signaling pathways that regulate tubulogenesis and vascular branching, elongation, and pruning. When this balance is lost, the vessels can be malformed and fragile, and they can lose arteriovenous differentiation. In this review, we concentrate on the transforming growth factor (TGF)-β/bone morphogenetic protein (BMP) pathway, which is one of the most important and complex signaling systems in vascular development. Inactivation of these pathways can lead to altered vascular organization in the embryo. In addition, many vascular malformations are related to deregulation of TGF-β/BMP signaling. Here, we focus on two of the most studied vascular malformations that are induced by deregulation of TGF-β/BMP signaling: hereditary hemorrhagic telangiectasia (HHT) and cerebral cavernous malformation (CCM). The first of these is related to loss-of-function mutation of the TGF-β/BMP receptor complex and the second to increased signaling sensitivity to TGF-β/BMP. In this review, we discuss the potential therapeutic targets against these vascular malformations identified so far, as well as their basis in general mechanisms of vascular development and stability., (© 2017 American Heart Association, Inc.)

Anomalies affecting the capillary and venous channels form the bulk of the spectrum of vascular anomalies. As per International Society for the Study of Vascular Anomalies (ISSVA) classification, these are referred to as hemangiomas and venous malformations respectively. The present article is a descriptive note of their management and outcomes. Retrospective records of patients over 17 y (January 2000 through December 2016) were reviewed for presentation, management and outcomes. Outcomes were graded into 3 subgroups based on subjective assessment of clinical images: Group A = near-total response (>90%); Group B = 50-90% and Group C = <50% reduction. Among 90 cases of hemangioma, majority were located in head and neck (86.7%). Outcomes recorded in children who received steroids (n = 36) were: Group A = 61.1%, B = 25% and C = 13.9%; steroids and beta-blockers (n = 8): Group A = 62.5%, B = 25% and C = 12.5%; only beta-blockers (n = 4): Group A = 75% and B = 25%; intralesional sclerotherapy (n = 32): Group A = 55.2% and B = 44.8%; steroids followed by sclerotherapy (n = 7): Group A = 28.6% and B = 71.4%; excision (n = 3): Group A = 100%. Among 171 cases of venous malformation, majority were located in head and neck (49.6%). Outcomes recorded in children who received sclerotherapy (n = 165) were Group A = 20.7%, B = 51% and C = 28.3%; steroids (n = 3): Group A = 100%; beta-blockers (n = 1): Group C = 100%; excision (n = 2): Group A = 100%. Better outcome was noted in smaller-sized lesions and those who required lesser volume of sodium tetradecyl sulfate (STS) injection. Thus, to conclude, the decision regarding the choice and timing of each therapeutic modality should be individualized based on location, size and type of the lesion. The goal of management in these lesions should be to improve the quality of life rather than elimination of the lesion.

Background: Sirolimus has recently been shown to be efficacious and tolerable in pediatric patients with complicated vascular anomalies. Nevertheless, dosing information remains very limited especially for neonates and infants. The purpose of this study was to develop an age-appropriate sirolimus starting dosing regimen based on the developmental changes in drug elimination capacity using data collected in neonates and infants., Procedure: A recently developed sirolimus maturation model [Emoto et al. CPT Pharmacometrics Syst Pharmacol, 2016] was used to simulate clearance estimates using realistic age and weight covariates for age cohorts aged 0-24 months. Next, predose concentrations at steady state were generated for each age cohort of neonates and infants. Dose requirements to attain predefined target trough concentration ranges (10-15 and 5-10 ng/ml) were simulated across the different age groups. Starting doses were chosen to maximize the likelihood of achieving sirolimus-targeted concentrations., Results: The trajectory of simulated sirolimus clearances increased with age and was in agreement with the previous findings in the Phase 2 study. The proposed dosing regimens covered eight age cohorts and resulted in target attainment of more than 75-95% across selected regimens., Conclusions: This study identified age-appropriate sirolimus dosing regimens for neonates and infants. The algorithm in combination with therapeutic drug management will facilitate sirolimus precision dosing in young children with vascular anomalies. A prospective evaluation is being planned., (© 2017 Wiley Periodicals, Inc.)

Introduction: Raynaud's phenomenon (RP) can be either primary (idiopathic) or secondary to a number of different diseases/conditions, when vasopasm can be superimposed upon structural vascular abnormality or a hyperviscosity state and may then lead to severe ischaemia with tissue damage. Treatment must be tailored to the individual. Areas covered: This review discusses how increased understanding of the pathogenesis of RP has driven and is driving new approaches to therapy, and how we are now better able to predict which patients presenting with RP are likely to have an underlying disease requiring specific intervention. Medline searches (1946 to August 2016) were conducted for 'Raynaud's' in combination with relevant terms including different drugs. All papers identified were English language, with abstracts. Expert commentary: Randomised controlled trials of RP present particular challenges. The major aim must continue to be development of safe, effective treatments for patients across the spectrum of RP.

Limb malformations are amongst the most common and visible birth effects. Causes have been purported to include genetic aberrations as well as teratogens, such as thalidomide. Here we review the evidence for vascular disruption in the genesis of limb malformations through abnormal arterial transitioning and from events such as amniocentesis, uterine constriction, and through teratogen exposure. We use several clinical and experimental examples and highlight the need to understand more about the role the vascular system plays in the molecular mechanisms underpinning normal limb development., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Collagen IV is a major component of basement membranes (BMs). The α1(IV) chain, encoded by the COL4A1 gene, is expressed ubiquitously and associates with the α2(IV) chain to form the α1α1α2(IV) heterotrimer. Several COL4A1 mutations affecting a conformational domain containing integrin-binding sites are responsible for the systemic syndrome of hereditary angiopathy, nephropathy, aneurysms, and cramps (HANAC). To analyze the pathophysiology of HANAC, Col4a1 mutant mice bearing the p.Gly498Val mutation were generated. Analysis of the skeletal muscles of Col4a1 G498V mutant animals showed morphologic characteristics of a muscular dystrophy phenotype with myofiber atrophy, centronucleation, focal inflammatory infiltrates, and fibrosis. Abnormal ultrastructural aspects of muscle BMs was associated with reduced extracellular secretion of the mutant α1α1α2(IV) trimer. In addition to muscular dystrophic features, endothelial cell defects of the muscle capillaries were observed, with intracytoplasmic accumulation of the mutant α1α1α2(IV) molecules, endoplasmic reticulum cisternae dilation, and up-regulation of endoplasmic reticulum stress markers. Induction of the unfolded protein response in Col4a1 mutant muscle tissue resulted in an excess of apoptosis in endothelial cells. HANAC mutant animals also presented with a muscular functional impairment and increased serum creatine kinase levels reflecting altered muscle fiber sarcolemma. This extensive description of the muscular phenotype of the Col4a1 HANAC murine model suggests a potential contribution of primary endothelial cell defects, together with muscle BM alterations, to the development of COL4A1-related myopathy., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

PAGOD Syndrome is an acronym for lung and pulmonary arteries hypoplasia, agonadism, omphalocele / diaphragmatic defect and dextrocardia. A series of 21 patients is described, where 90.5% had a 46,XY karyotype and only two cases 46,XX; 66.6% exhibited a female phenotype and 28.6% ambiguous genitalia. The occurrence of two patients 46,XX excludes the Y chromosome as a carrier of the genetic defect and raises the possibility of a recessive X-linked inheritance, without ruling out that the observed cases in siblings may be due to mutations in other genes as Stra6, VEGFA, VEGFB, VEGFC, and alternative splicing of transcripts VEGFA, HIF1, HIF2, among others. Congenital malformations were observed in patients’ genitals and gonads 85.7%, 66.6% in diaphragm and abdominal wall , heart 80.9%, 71.4% lungs, blood vessels 80.9% and 42.8% in abdomen. The review of patients has demonstrated a high degree of variability in the expression of malformations of organs and organ systems. Vascular malformations represent an important and characteristic component of PAGOD syndrome and whose base morphogenetic syndrome may be due to a defect in early embryonic angiogenesis with impact on organogenesis and system development. Among genes related to vascular remodeling during embryogenesis, tissue regeneration and carcinogenesis, the Endothelial Growth Factor D Vascular (VEGFD), located in the Xp22.31 region, with expression in lung, heart, small intestine, uterus, breast, neuroblastoma and neural tissue, represents a strong candidate for molecular analysis as a cause of the syndrome.

The vertebrate circulatory system is composed of closely related blood and lymphatic vessels. It has been shown that lymphatic vascular patterning is regulated by blood vessels during development, but its molecular mechanisms have not been fully elucidated. Here, we show that the artery-derived ligand semaphorin 3G (Sema3G) and the endothelial cell receptor PlexinD1 play a role in lymphatic vascular patterning. In mouse embryonic back skin, genetic inactivation of Sema3G or PlexinD1 results in abnormal artery-lymph alignment and reduced lymphatic vascular branching. Conditional ablation in mice demonstrates that PlexinD1 is primarily required in lymphatic endothelial cells (LECs). In vitro analyses show that Sema3G binds to neuropilin-2 (Nrp2), which forms a receptor complex with PlexinD1. Sema3G induces cell collapse in an Nrp2/PlexinD1-dependent manner. Our findings shed light on a molecular mechanism by which LECs are distributed away from arteries and form a branching network during lymphatic vascular development., (Copyright © 2016 The Author(s). Published by Elsevier Inc. All rights reserved.)

We report the case of a young girl who was presented with complex clinical symptoms caused by the deletion of contiguous genes: RASA1 and MEF2C, located on chromosome 5q14.3. Specifically, the diagnosis of her skin disorder and vascular malformations involving central nervous system is consistent with a RASopathy. The child's neurological manifestations are observed in most patients suffering from 5q14.3 by deletion or mutation of the MEF2C gene. A review of the literature allowed us to conclude that the contiguous deletion of genes RASA1 and MEF2C fulfills the criteria for the diagnosis of a Neurocutaneous syndrome as proposed by Carr et al. [2011]. We also assessed the penetrance of RASA1 and clinical manifestations of MEF2C according to the type of deletion. This child described presents the complete symptomatology of both deleted genes. We would also like to highlight the progression of the disorder., (© 2016 Wiley Periodicals, Inc.)

Background and Aim: The oral manifestations of familial adenomatous polyposis (FAP) have been reported in the recent literature. Therefore, there has been growing interest in the characterization of the dento-osseous anomalies because they may precede colorectal cancer and may be used as a diagnostic marker. This systematic review and meta-analysis was performed to evaluate the published evidence for what are the oral manifestations of FAP and their frequency in affected individuals., Methods: The search was performed at Cochrane Library, EMBASE, LILACS, PubMed, Scopus, and Web of Science for articles published up to March 2015. A grey literature search was conducted through Google Scholar. Reference lists of the included articles and additional studies identified by expert were screened for potential relevant studies. The methodology of selected studies was evaluated using the risk of bias checklist of the Agency for Healthcare Research and Quality., Results: Twenty observational studies totalizing 1635 individuals affected by FAP met the inclusion criteria. Osseous, dental, and oral mucosa alterations were observed in FAP patients. The meta-analysis showed the frequency of osseous jaw lesions, and the dental anomalies were 65.35% and 30.48%, respectively, and two studies suggested that oral mucosa vascular density is a phenotypic manifestation in patients with FAP. Most of the studies were evaluated as moderate risk of bias., Conclusion: The most frequent oral manifestation on FAP patients is osseous jaw alterations. In the future, well-designed studies are necessary to classify osseous and dental anomalies in order to demonstrate the true prevalence of each alteration separately., (© 2015 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Purpose: We report the results of laparoscopic vascular hitching (LVH) in a series of children with ureteropelvic junction obstruction (UPJO) owing to aberrant lower polar crossing vessels (CV). Our aim is to confirm if LVH associated with intraoperative diuretic test (DT) represents a good procedure to treat extrinsic-UPJO by CV. In order to confirm the relief of the obstruction we suggest performing an intraoperative DT., Materials and Methods: In our department from 2006 to 2014, 120 patients were treated for both extrinsic and intrinsic-UPJO. 85 (30 females, 55 males) presented an intrinsic obstruction and underwent dismembered pyeloplasty (AHDP), 61 open, 16 laparoscopic, 8 retroperitoneoscopic. 35 (23 males, 12 females) were studied for a suspected extrinsic-UPJO: 30 were treated with LVH (modified Hellström vascular hitch). Intraoperative-DT was performed in all patients before and after vessel transpositions confirming the UPJO and eventual relief after the procedure. We included in the study only patients with suspicion of vascular extrinsic-UPJO. Average age at surgery was 7.5years. Symptoms of presentation were recurrent abdominal/flank pain and hematuria. All patients presented ultrasound (US) detection of hydronephrosis. Preoperative diagnostic studies include: US/doppler scan, MAG3 renogram, urography, functional magnetic resonance urography (fMRU) and CT scan., Results: 28 out 35 patients had a correct preoperative diagnosis, and the remaining needed an intraoperative diagnosis confirmation. All 35 patients had an intraoperative-DT: 30 patients underwent LVH (positive-DT); 3 patients (negative-DT) underwent laparoscopic-AHDP for intrinsic-UPJO; two with positive-DT and nonobstructive CV, had no surgical treatment. Median operating time was 95min; mean hospital stay was 4days. At 12-84months follow-up 29 patients remained symptoms-free, one needed after two years a laparoscopic-AHDP., Conclusions: According our experience, LVH associated with intraoperative-DT may be considered a safe procedure to treat extrinsic-UPJO by CV in carefully selected patients. In particular, the very low incidence of relapse suggest that in suspicion of extrinsic-UPJO, performing intraoperative-DT after CV transposition allows to exclude intrinsic-UPJO confirming that the LVH-procedure has relieved the pelvic obstruction, precluding the need for AHDP., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: To report a series of children with pelviureteric junction obstruction (PUJO) due to lower polar crossing vessels who underwent laparoscopic vascular transposition. In order to confirm the relief of the obstruction and avoid unnecessary additional procedures, we suggest performing an intraoperative measure of the ureteral opening pressure., Patients and Methods: From January 2007 and January 2014, 11 children underwent laparoscopy to treat well-documented PUJO by polar vessels. In the first 7 cases, children underwent a careful dissection of the polar vessels that were transposed cranially in the pelvis. In the last 4 cases, a percutaneous needle was inserted into the renal pelvis, and the ureteral opening pressure was obtained intraoperatively, before and after the vascular hitch procedure, in 3 cases. No vascular relocation was necessary except in 1 case with a polar vessel unrelated to the obstruction., Results: The laparoscopic procedure was feasible in all cases. Median operative time was 90 minutes without intraoperative complications. In the last 3 cases, a decrease in the renal pelvic pressure was demonstrated just after releasing the ureter from the polar vessels, confirming the extrinsic obstruction. In 1 case, the intraoperative pelvic pressure measurement showed that there was no vascular compression but that obstruction was due to renal rotation. During follow-up (range, 12-96 months) all patients reported resolution of their symptoms, nine children showed a decrease in the hydronephrosis grade, and all but one with poor function had improved drainage on diuretic renography., Conclusions: Intraoperative measurement of ureteral opening pressure may help to confirm that the vascular hitch procedure has relieved the pelvic obstruction, precluding the need for dismembered procedures. We believe that in some doubtful cases, with the addition of intraoperative pelvic pressure measurement, vascular hitch may be considered a safe procedure to treat selected cases of PUJO in children.

Fibulin-4 is an extracellular matrix protein essential for elastic fiber formation. Frameshift and missense mutations in the fibulin-4 gene (EFEMP2/FBLN4) cause autosomal recessive cutis laxa (ARCL) 1B, characterized by loose skin, aortic aneurysm, arterial tortuosity, lung emphysema, and skeletal abnormalities. Homozygous missense mutations in FBLN4 are a prevalent cause of ARCL 1B. Here we generated a knock-in mouse strain bearing a recurrent fibulin-4 E57K homozygous missense mutation. The mutant mice survived into adulthood and displayed abnormalities in multiple organ systems, including loose skin, bent forelimb, aortic aneurysm, tortuous artery, and pulmonary emphysema. Biochemical studies of dermal fibroblasts showed that fibulin-4 E57K mutant protein was produced but was prone to dimer formation and inefficiently secreted, thereby triggering an endoplasmic reticulum stress response. Immunohistochemistry detected a low level of fibulin-4 E57K protein in the knock-in skin along with altered expression of selected elastic fiber components. Processing of a precursor to mature lysyl oxidase, an enzyme involved in cross-linking of elastin and collagen, was compromised. The knock-in skin had a reduced level of desmosine, an elastin-specific cross-link compound, and ultrastructurally abnormal elastic fibers. Surprisingly, structurally aberrant collagen fibrils and altered organization into fibers were characteristics of the knock-in dermis and forelimb tendons. Type I collagen extracted from the knock-in skin had decreased amounts of covalent intermolecular cross-links, which could contribute to the collagen fibril abnormalities. Our studies provide the first evidence that fibulin-4 plays a role in regulating collagen fibril assembly and offer a preclinical platform for developing treatments for ARCL 1B., (© 2015 by The American Society for Biochemistry and Molecular Biology, Inc.)

Autotaxin (ATX) is a secretory protein, which converts lysophospholipids to lysophosphatidic acid (LPA), and is essential for embryonic vascular formation. ATX is abundantly detected in various biological fluids and its level is elevated in some pathophysiological conditions. However, the roles of elevated ATX levels remain to be elucidated. In this study, we generated conditional transgenic (Tg) mice overexpressing ATX and examined the effects of excess LPA signalling. We found that ATX overexpression in the embryonic period caused severe vascular defects and was lethal around E9.5. ATX was conditionally overexpressed in the neonatal period using the Cre/loxP system, which resulted in a marked increase in the plasma LPA level. This resulted in retinal vascular defects including abnormal vascular plexus and increased vascular regression. Our findings indicate that the ATX level must be carefully regulated to ensure coordinated vascular formation.

Background: Collagen type IV alpha1 (COL4A1) and alpha2 (COL4A2) form heterotrimers critical for vascular basement membrane stability and function. Patients with COL4A1 or COL4A2 mutations suffer from diverse cerebrovascular diseases, including cerebral microbleeds, porencephaly, and fatal intracerebral hemorrhage (ICH). However, the pathogenic mechanisms remain unknown, and there is a lack of effective treatment., Methods and Results: Using Col4a1 and Col4a2 mutant mouse models, we investigated the genetic complexity and cellular mechanisms underlying the disease. We found that Col4a1 mutations cause abnormal vascular development, which triggers small-vessel disease, recurrent hemorrhagic strokes, and age-related macroangiopathy. We showed that allelic heterogeneity, genetic context, and environmental factors such as intense exercise or anticoagulant medication modulated disease severity and contributed to phenotypic heterogeneity. We found that intracellular accumulation of mutant collagen in vascular endothelial cells and pericytes was a key triggering factor of ICH. Finally, we showed that treatment of mutant mice with a US Food and Drug Administration-approved chemical chaperone resulted in a decreased collagen intracellular accumulation and a significant reduction in ICH severity., Conclusions: Our data are the first to show therapeutic prevention in vivo of ICH resulting from Col4a1 mutation and imply that a mechanism-based therapy promoting protein folding might also prevent ICH in patients with COL4A1 and COL4A2 mutations., (© 2015 American Heart Association, Inc.)