Apelin signaling modulates splanchnic angiogenesis and portosystemic collateral vessel formation in rats with portal hypertension

BACKGROUND/AIMS: Angiogenesis is a pathological hallmark of portal hypertension. Although VEGF is considered to be the most important proangiogenic factor in neoangiogenesis, this process requires the coordinated action of a variety of factors. Identification of novel molecules involved in angiogenesis is highly relevant, since they may represent potential new targets to suppress pathological neovascularization in angiogenesis-related diseases like portal hypertension. The apelin/APJ signaling pathway plays a crucial role in angiogenesis. Therefore, we determined whether the apelin system modulates angiogenesis-driven processes in portal hypertension. METHODS: Partial portal vein-ligated rats were treated with the APJ antagonist F13A for seven days. Splanchnic neovascularization and expression of angiogenesis mediators (Western blotting) was determined. Portosystemic collateral formation (microspheres), and hemodynamic parameters (flowmetry) were also assessed. RESULTS: Apelin and its receptor APJ were overexpressed in the splanchnic vasculature of portal hypertensive rats. F13A effectively decreased, by 52%, splanchnic neovascularization and expression of proangiogenic factors VEGF, PDGF and angiopoietin-2 in portal hypertensive rats. F13A also reduced, by 35%, the formation of portosystemic collateral vessels. CONCLUSIONS: This study provides the first experimental evidence showing that the apelin/APJ system contributes to portosystemic collateralization and splanchnic neovascularization in portal hypertensive rats, presenting a potential novel therapeutic target for portal hypertension.

Hemoglobin vesicles improve wound healing and tissue survival in critically ischemic skin in mice

Local hypoxia, as due to trauma, surgery, or arterial occlusive disease, may severely jeopardize the survival of the affected tissue and its wound-healing capacity. Initially developed to replace blood transfusions, artificial oxygen carriers have emerged as oxygen therapeutics in such conditions. The aim of this study was to target primary wound healing and survival in critically ischemic skin by the systemic application of left-shifted liposomal hemoglobin vesicles (HbVs). This was tested in bilateral, cranially based dorsal skin flaps in mice treated with a HbV solution with an oxygen affinity that was increased to a P(50) (partial oxygen tension at which the hemoglobin becomes 50% saturated with oxygen) of 9 mmHg. Twenty percent of the total blood volume of the HbV solution was injected immediately and 24 h after surgery. On the first postoperative day, oxygen saturation in the critically ischemic middle flap portions was increased from 23% (untreated control) to 39% in the HbV-treated animals (P < 0.05). Six days postoperatively, flap tissue survival was increased from 33% (control) to 57% (P < 0.01) and primary healing of the ischemic wound margins from 6.6 to 12.7 mm (P < 0.05) after HbV injection. In addition, higher capillary counts and endothelial nitric oxide synthase expression (both P < 0.01) were found in the immunostained flap tissue. We conclude that left-shifted HbVs may ameliorate the survival and primary wound healing in critically ischemic skin, possibly mediated by endothelial nitric oxide synthase-induced neovascularization.

Mechanistic and therapeutic implications of angiogenesis in endometriosis

Like tumor metastases, endometriotic implants require neovascularization to proliferate and invade into ectopic sites within the host. Endometrial tissue, with its robust stem cell populations and remarkable regenerative capabilities, is a rich source of proangiogenic factors. Among the most potent and extensively studied of these proteins, vascular endothelial growth factor has emerged as a critical vasculogenic regulator in endometriosis. Accordingly, angiogenesis of the nascent endometriotic lesion has become an attractive target for novel medical therapeutics and strategies to inhibit vascular endothelial growth factor action. Vascular endothelial growth factor gene regulation in endometrial and endometriosis cells by nuclear receptors, other transcription factors, and also by infiltrating immune cells is emphasized. New data showing that oxidative and endoplasmic reticulum stress increase vascular endothelial growth factor expression are provided. Finally, we review the clinical implications of angiogenesis in this condition and propose potential antiangiogenic therapies that may become useful in the control or eradication of endometriotic lesions.

Tenomodulin is necessary for tenocyte proliferation and tendon maturation

Tenomodulin (Tnmd) is a member of a new family of type II transmembrane glycoproteins. It is predominantly expressed in tendons, ligaments, and eyes, whereas the only other family member, chondromodulin I (ChM-I), is highly expressed in cartilage and at lower levels in the eye and thymus. The C-terminal extracellular domains of both proteins were shown to modulate endothelial-cell proliferation and tube formation in vitro and in vivo. We analyzed Tnmd function in vivo and provide evidence that Tnmd is processed in vivo and that the proteolytically cleaved C-terminal domain can be found in tendon extracts. Loss of Tnmd expression in gene targeted mice abated tenocyte proliferation and led to a reduced tenocyte density. The deposited amounts of extracellular matrix proteins, including collagen types I, II, III, and VI and decorin, lumican, aggrecan, and matrilin-2, were not affected, but the calibers of collagen fibrils varied significantly and exhibited increased maximal diameters. Tnmd-deficient mice did not have changes in tendon vessel density, and mice lacking both Tnmd and ChM-I had normal retinal vascularization and neovascularization after oxygen-induced retinopathy. These results suggest that Tnmd is a regulator of tenocyte proliferation and is involved in collagen fibril maturation but do not confirm an in vivo involvement of Tnmd in angiogenesis.

Switching of vascular phenotypes within a murine breast cancer model induced by angiopoietin-2

Sustained growth of solid tumours can rely on both the formation of new and the co-option of existing blood vessels. Current models suggest that binding of angiopoietin-2 (Ang-2) to its endothelial Tie2 receptor prevents receptor phosphorylation, destabilizes blood vessels, and promotes vascular permeability. In contrast, binding of angiopoietin-1 (Ang-1) induces Tie2 receptor activation and supports the formation of mature blood vessels covered by pericytes. Despite the intense research to decipher the role of angiopoietins during physiological neovascularization and tumour angiogenesis, a mechanistic understanding of angiopoietin function on vascular integrity and remodelling is still incomplete. We therefore assessed the vascular morphology of two mouse mammary carcinoma xenotransplants (M6378 and M6363) which differ in their natural angiopoietin expression. M6378 displayed Ang-1 in tumour cells but no Ang-2 in tumour endothelial cells in vivo. In contrast, M6363 tumours expressed Ang-2 in the tumour vasculature, whereas no Ang-1 expression was present in tumour cells. We stably transfected M6378 mouse mammary carcinoma cells with human Ang-1 or Ang-2 and investigated the consequences on the host vasculature, including ultrastructural morphology. Interestingly, M6378/Ang-2 and M6363 tumours displayed a similar vascular morphology, with intratumoural haemorrhage and non-functional and abnormal blood vessels. Pericyte loss was prominent in these tumours and was accompanied by increased endothelial cell apoptosis. Thus, overexpression of Ang-2 converted the vascular phenotype of M6378 tumours into a phenotype similar to M6363 tumours. Our results support the hypothesis that Ang-1/Tie2 signalling is essential for vessel stabilization and endothelial cell/pericyte interaction, and suggest that Ang-2 is able to induce a switch of vascular phenotypes within tumours.

The impact of lymphadenectomy and lymph node metastasis on the outcomes of radical cystectomy for bladder cancer

CONTEXT: The presence of lymph node metastases and the extent of lymphadenectomy have both been shown to influence the outcome of patients with muscle-invasive bladder cancer. OBJECTIVE: Current standards for detection of lymph node metastases, lymph-node mapping studies, histopathologic techniques, and risk factors in relation to lymph node involvement are discussed. The impact of lymph node metastases and the extent of lymphadenectomy on the outcome of patients treated with radical cystectomy are analyzed. EVIDENCE ACQUISITION: A systematic literature review of bladder cancer and lymph nodes was performed searching the electronic databases Pubmed/Medline, Cochrane, and Embase. Articles were selected based on title, abstract, study format, and content by a consensus of all participating authors. EVIDENCE SYNTHESIS: Lymph node status is highly consequential in bladder cancer patients because the presence of lymph node metastases is predictive of poor outcome. Knowledge of primary landing sites of lymph node metastases is important for optimum therapeutic management. Accurate pathologic work-ups of resected lymph node tissue are mandatory. Molecular markers could potentially guide therapeutic decisions in the future because they may enable the detection of micrometastatic disease. In current series, radical cystectomy with an extended lymphadenectomy seems to provide a clinically meaningful therapeutic benefit compared with a limited approach. However, the anatomic boundaries of lymph node dissection are still under debate. Therefore, large prospective multicenter trials are needed to validate the influence of extended lymph node dissection on disease-specific survival. CONCLUSIONS: An extended pelvic lymph node dissection (encompassing the external iliac vessels, the obturator fossa, the lateral and medial aspects of the internal iliac vessels, and at least the distal half of the common iliac vessels together with its bifurcation) can be curative in patients with metastasis or micrometastasis to a few nodes. Therefore, the procedure may be offered to all patients undergoing radical cystectomy for invasive bladder cancer.

Interactive educational DVD on hoof protection, horseshoeing and diseases of the hoof

Good cooperation between farrier, veterinarian and horse owner is an important prerequisite for optimal support of the horse with regards to shoeing and hoof health. The introduction of a joint educational aid aims to improve the level of education of both veterinarians and farriers. The interactive, multimedia approach represents an innovative new dimension in instruction techniques, predominantly provided through images and videos. The contents of the new teaching aid will focus on detailed anatomy of the foot and distal limb, as well as currently accepted shoeing practices and techniques and pathologic conditions of the hoof and foot.

Alterations of white matter integrity related to the season of birth in schizophrenia: a DTI study

In schizophrenia there is a consistent epidemiological finding of a birth excess in winter and spring. Season of birth is thought to act as a proxy indicator for harmful environmental factors during foetal maturation. There is evidence that prenatal exposure to harmful environmental factors may trigger pathologic processes in the neurodevelopment, which subsequently increase the risk of schizophrenia. Since brain white matter alterations have repeatedly been found in schizophrenia, the objective of this study was to investigate whether white matter integrity was related to the season of birth in patients with schizophrenia. Thirty-four patients with schizophrenia and 33 healthy controls underwent diffusion tensor imaging. Differences in the fractional anisotropy maps of schizophrenia patients and healthy controls born in different seasons were analysed with tract-based spatial statistics. A significant main effect of season of birth and an interaction of group and season of birth showed that patients born in summer had significantly lower fractional anisotropy in widespread white matter regions than those born in the remainder of the year. Additionally, later age of schizophrenia onset was found in patients born in winter months. The current findings indicate a relationship of season of birth and white matter alterations in schizophrenia and consequently support the neurodevelopmental hypothesis of early pathological mechanisms in schizophrenia.

Characteristics and dimensions of the sinus membrane in patients referred for single-implant treatment in the posterior maxilla: a cone beam computed tomographic analysis

PURPOSE The purpose of the present study was to evaluate the thickness and anatomic characteristics of the sinus membrane using cone beam computed tomography (CBCT) in patients evaluated for implant surgery in the posterior maxilla. MATERIALS AND METHODS The study included 131 consecutive patients referred for dental implant placement in the posterior maxilla. A total of 138 CBCT images was obtained using fields of view of 4 × 4 cm, 6 × 6 cm, or 8 × 8 cm. Reformatted sagittal CBCT slices were analyzed with regard to the thickness and characteristics of the sinus membrane at single-tooth gaps in the posterior maxilla. Factors that might influence the dimensions of the sinus membrane, such as age, sex, endodontic status, and the season, were analyzed. RESULTS The mean thickness of the maxillary sinus mucosa varied between 2.1 and 2.69 mm in the three locations analyzed. Fewer than half of the evaluated sinuses exhibited a healthy mucosa (49 of 138, or 35.51%). Most of the pathologic findings were flat, shallow thickenings (63 of 138, or 45.65%). Sex did not influence the thickness of the sinus membrane at the root tips of the premolars or at single-tooth gaps, but there was a statistically significant correlation in the region of the maxillary molars. No other evaluated factors had a statistically significant effect on the dimensions of the antral mucosa. CONCLUSIONS In the present study, sex was the only factor influencing the dimension of the sinus membrane, whereas patient age, season, and the endodontic status of neighboring teeth had no significant effect on the thickness of the antral mucosa. Future studies should address which types of mucosal thickening require interdisciplinary therapy.

Clinical and pathological analysis of epidural inflammation in intervertebral disk extrusion in dogs

BACKGROUND Little is known about the pathologic changes in the epidural space after intervertebral disk (IVD) extrusion in the dog. OBJECTIVES To analyze the pathology of the epidural inflammatory response, and to search for correlations between this process and clinical findings. METHODS Clinical data from 105 chondrodystrophic (CD) and nonchondrodystrophic (NCD) dogs with IVD extrusion were recorded. Epidural material from these dogs was examined histopathologically and immunohistochemically. Using statistical analysis, we searched for correlations between severity of epidural inflammation and various clinical and pathologic variables. RESULTS Most dogs exhibited an epidural inflammatory response, ranging from acute invasion of neutrophils to formation of chronic granulation tissue. The mononuclear inflammatory infiltrates consisted mostly of monocytes and macrophages and only few T and B cells. Surprisingly, chronic inflammatory patterns also were found in animals with an acute clinical history. Severity of the epidural inflammation correlated with degree of the epidural hemorrhage and nucleus pulposus calcification (P = .003 and .040), but not with age, chondrodystrophic phenotype, neurologic grade, back pain, pretreatment, or duration. The degree of inflammation was statistically (P = .021) inversely correlated with the ability to regain ambulation. CONCLUSION AND CLINICAL IMPORTANCE Epidural inflammation occurs in the majority of dogs with IVD extrusion and may develop long before the onset of clinical signs. Presence of calcified IVD material and hemorrhage in the epidural space may be the triggers of this lesion rather than an adaptive immune response to the nucleus pulposus as suggested in previous studies. Because epidural inflammation may affect outcome, further research is warranted.

Assessment of bone channels other than the nasopalatine canal in the anterior maxilla using limited cone beam computed tomography

PURPOSE The anterior maxilla, sometimes also called premaxilla, is an area frequently requiring surgical interventions. The objective of this observational study was to identify and assess accessory bone channels other than the nasopalatine canal in the anterior maxilla using limited cone beam computed tomography (CBCT). METHODS A total of 176 cases fulfilled the inclusion criteria comprising region of interest, quality of CBCT image, and absence of pathologic lesions or retained teeth. Any bone canal with a minimum diameter of 1.00 mm other than the nasopalatine canal was analyzed regarding size, location, and course, as well as patient gender and age. RESULTS A total of 67 accessory canals ≥1.00 mm were found in 49 patients (27.8%). A higher frequency of accessory canals was observed in males (33.0%) than in females (22.7%) (p = 0.130). Accessory canals occurred more frequently in older rather than younger patients (p = 0.115). The mean diameter of accessory canals was 1.31 ± 0.26 mm (range 1.01-2.13 mm). Gender and age did not significantly influence the diameter. Accessory canals were found palatal to all anterior teeth, but most frequently palatal to the central incisors. In 56.7%, the accessory canals curved superolaterally and communicated with the ipsilateral alveolar extension of the canalis sinuosus. CONCLUSIONS The study confirms the presence of bone channels within the anterior maxilla other than the nasopalatine canal. More than half of these accessory bone canals communicated with the canalis sinuosus. From a clinical perspective, studies are needed to determine the content of these accessory canals.

Emergence of Canine Distemper Virus Strains With Modified Molecular Signature and Enhanced Neuronal Tropism Leading to High Mortality in Wild Carnivores

An ongoing canine distemper epidemic was first detected in Switzerland in the spring of 2009. Compared to previous local canine distemper outbreaks, it was characterized by unusually high morbidity and mortality, rapid spread over the country, and susceptibility of several wild carnivore species. Here, the authors describe the associated pathologic changes and phylogenetic and biological features of a multiple highly virulent canine distemper virus (CDV) strain detected in and/or isolated from red foxes (Vulpes vulpes), Eurasian badgers (Meles meles), stone (Martes foina) and pine (Martes martes) martens, from a Eurasian lynx (Lynx lynx), and a domestic dog. The main lesions included interstitial to bronchointerstitial pneumonia and meningopolioencephalitis, whereas demyelination-the classic presentation of CDV infection-was observed in few cases only. In the brain lesions, viral inclusions were mainly in the nuclei of the neurons. Some significant differences in brain and lung lesions were observed between foxes and mustelids. Swiss CDV isolates shared together with a Hungarian CDV strain detected in 2004. In vitro analysis of the hemagglutinin protein from one of the Swiss CDV strains revealed functional and structural differences from that of the reference strain A75/17, with the Swiss strain showing increased surface expression and binding efficiency to the signaling lymphocyte activation molecule (SLAM). These features might be part of a novel molecular signature, which might have contributed to an increase in virus pathogenicity, partially explaining the high morbidity and mortality, the rapid spread, and the large host spectrum observed in this outbreak.

Bovine Respiratory Syncytial Virus Infection in McNay Farm Calves

Clinical respiratory disease occurs almost every year in fall calves in the McNay Farm herd. Diagnostic procedures have implicated Haemophilus somnus (H. somnus) and bovine respiratory syncyial virus (BRSV) as the infectious agents primarily associated with this disease. Therefore, the 1995 calves were closely monitored after weaning and during the course of a respiratory disease. Serologic evidence indicated the involvement of the same two agents in the pathogenesis of the disease. Also, experimental evidence suggested a role for a preexisting immediate hypersensitivity to H. somnus and the development of this type of response to BRSV. We theorize that the pathogenesis of the clinical disease involved infection with H. somnus, establishment of immediate hypersensitivity in the lungs, viral infection with associated pathologic lesions, and viral exacerbation of the immediate hypersensitivity reaction with resultant clinical signs and tissue damage.

Impact of the CTLA-4/CD28 axis on the processes of joint inflammation in rheumatoid arthritis

OBJECTIVE: The importance of the costimulatory molecules CD28 and CTLA-4 in the pathologic mechanism of rheumatoid arthritis (RA) has been demonstrated by genetic associations and the successful clinical application of CTLA-4Ig for the treatment of RA. This study was undertaken to investigate the role of the CTLA-4/CD28 axis in the local application of CTLA-4Ig in the synovial fluid (SF) of RA patients. METHODS: Quantitative polymerase chain reaction was used to analyze the expression of proinflammatory and antiinflammatory cytokines in ex vivo fluorescence-activated cell sorted CTLA-4+ and CTLA-4- T helper cells from the peripheral blood and SF of RA patients. T helper cells were also analyzed for cytokine expression in vitro after the blockade of CTLA-4 by anti-CTLA-4 Fab fragments or of B7 (CD80/CD86) molecules by CTLA-4Ig. RESULTS: CTLA-4+ T helper cells were unambiguously present in the SF of all RA patients examined, and they expressed increased amounts of interferon-γ (IFNγ), interleukin-17 (IL-17), and IL-10 as compared to CTLA-4- T helper cells. The selective blockade of CTLA-4 in T helper cells from the SF in vitro led to increased levels of IFNγ, IL-2, and IL-17. The concomitant blockade of CD28 and CTLA-4 in T helper cells from RA SF by CTLA-4Ig in vitro resulted in reduced levels of the proinflammatory cytokines IFNγ and IL-2 and increased levels of the antiinflammatory cytokines IL-10 and transforming growth factor β. CONCLUSION: Our ex vivo and in vitro results demonstrate that the CTLA-4/CD28 axis constitutes a drug target for not only the systemic, but potentially also the local, application of the costimulation blocking agent CTLA-4Ig for the treatment of RA.

Characteristics of visual hallucinations in Parkinson disease dementia and dementia with Lewy bodies

OBJECTIVE Parkinson disease dementia (PDD) and dementia with Lewy bodies (DLB) have overlapping clinical and pathologic features. Recurrent visual hallucinations (RVH) are common in both disorders. The authors have compared details of hallucination characteristics and associated neuropsychiatric features in DLB and PDD. METHODS This is a descriptive, cross-sectional study using the Institute of Psychiatry Visual Hallucinations Interview (IP-VHI) to explore self-reported frequency, duration, and phenomenology of RVH in PDD and DLB. The caregivers' ratings of hallucinations and other neuropsychiatric features were elicited with the Neuropsychiatric Inventory (NPI). RESULTS Fifty-six patients (35 PDD; 21 DLB) with RVH were assessed. Hallucination characteristics were similar in both disorders. Simple hallucinations were rare. Most patients experienced complex hallucinations daily, normally lasting minutes. They commonly saw people or animals and the experiences were usually perceived as unpleasant. NPI anxiety scores were higher in PDD. Neuropsychiatric symptoms coexisting with hallucinations were apathy, sleep disturbance, and anxiety. CONCLUSIONS Patients with mild to moderate dementia can provide detailed information about their hallucinations. Characteristics of RVH were similar in PDD and DLB, and phenomenology suggests the involvement of dorsal and ventral visual pathways in their generation. The coexistence of RVH with anxiety, apathy, and sleep disturbance is likely to impair patients' quality of life and may have treatment implications.