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Objective: Evidence shows that peripheral nervous system (PNS) is involved in systemic sclerosis (SSc), but few morphological studies have assessed the ultrastructural pathological modifications. The aim was to study ultrastructural modifications of skin PNS fibres in SSc according to subsets [limited SSc (lSSc) and diffuse SSc (dSSc)] and phases (early and advanced) of the disease., Methods: Skin biopsies were taken from the forearms of 23 SSc patients (11 lSSc and 12 dSSc) and 10 controls. Each biopsy was processed for transmission electron microscopy (TEM)., Results: At TEM, observation in skin from early lSSc, signs of inflammation were evident, while PNS fibres were not damaged. The microvascular wall showed hypertrophic endothelial cells bulging into the lumen. In advanced lSSc, fibrosis prevailed on inflammation and slight ultrastructural alterations of PNS fibres were evident in the papillary derma. In early dSSc, ultrastructural alterations of PNS fibres, similar to those observed in the advanced phase of lSSc, were found together with signs of inflammation and fibrosis. In advanced dSSc, in the papillary and reticular dermis PNS fibres were reduced and showed relevant ultrastructural alterations., Conclusions: In SSc, PNS ultrastructure damage is linked to the progression and severity of skin involvement. The alterations evolve from the early to the advanced phase mainly in the diffuse subset. In particular, the severe PNS lesions found in advanced lSSc are already present and widely diffuse in early dSSc and the microvascular involvement in early lSSc seems to precede the modification of the PNS in the skin. Thus, an early therapeutic approach can be useful to reduce the progression of PNS and skin damage in SSc patients.

Background: Neutrophils are the predominant phagocytes in the early stages of myocardial ischemia-reperfusion response and are also implicated in the development of tissue damage. This study examined the role of recruited macrophages in the evolution of this tissue injury., Methods: Farm pigs were subjected to 30 minutes of myocardial ischemia followed by 30 minutes of reperfusion. Biopsy samples were taken from the control, ischemic, and ischemic-reperfused left ventricle wall and processed for both morphologic and biochemical analyses. In situ production of tumor necrosis factor-alpha was evaluated by Western blot and immunofluorescence. A full hemodynamic evaluation was also performed., Results: Myocardial ischemia and early reperfusion caused marked neutrophil and macrophage tissue accumulation and tumor necrosis factor-alpha production by the injured tissue. Immunofluorescence studies allowed us to localize tumor necrosis factor-alpha predominantly in tissue-infiltrating macrophages. No depression in the global myocardial contractile function was observed, either during ischemia or after reperfusion., Conclusions: These data suggest that the newly recruited macrophages within the ischemic and early post-ischemic myocardium may play a role in promoting neutrophil tissue infiltration and subsequent neutrophil-induced tissue dysfunction by producing tumor necrosis factor-alpha.

Aim: To investigate the ultrastructural features of the newly hatched larvae of Strongyloides stercoralis in human duodenal mucosa., Methods: Duodenal biopsies from an AIDS patient were studied by transmission electron microscopy to investigate morphology, location, and host-worm relations of newly hatched larvae., Results: Newly hatched larvae were found in the Lieberkuhn crypts within the tunnels formed by migration of parthenogenic females. Delimiting enterocytes were compressed. Release of larvae into the gut lumen was also documented. It was shown that both a thin and a thick membrane surrounded the eggs and larvae, as a tegument derived respectively from parasite and host. Segmentary spike-like waves, caused by contractures of worm body musculature, were observed on the surface of newly hatched larvae, and their intestinal lumen was closed and empty, with no budding microvilli. Immaturity of the cuticle and some degree immaturity of amphidial neurones were found, but there was no evidence of either immaturity or signs of damage to other structures., Conclusions: Newly hatched larvae of S stercoralis appear to be a non-feeding immature stage capable of active movement through the epithelium, causing mechanical damage. The tegument resulting from the thin and the thick membrane may protect the parasite and reduce any disadvantage caused by immaturity.

Aim: To investigate morphological changes in Enterocytozoon bieneusi and the duration of symptomatic relief after combination treatment with furazolidone and albendazole in AIDS patients., Methods: Four severely immunocompromised AIDS patients with symptomatic E bieneusi infection of the gut received an 18 day course of combined furazolidone and albendazole (500 + 800 mg daily). All patients were monitored for parasite shedding in stool by light microscopy at the end of treatment and monthly during follow up. At the end of treatment, duodenal biopsy specimens obtained from three patients were studied by transmission electron microscopy by two pathologists blind to the patients' treatment or clinical outcome. Duodenal biopsy specimens obtained from one of the patients two months after completion of treatment were also studied electronmicroscopically., Results: All patients had long lasting symptomatic relief, with a major decrease--or transient absence--of spore shedding in stools from completion of treatment. After treatment, changes in faecal spores were persistently found by light microscopy in all cases, and there was evidence of both a substantial decrease in the parasite load and ultrastructural damage in the parasite in all biopsy specimens. The treatment was well tolerated, and no patient had clinical or parasitological relapse during follow up (up to 15 months)., Conclusions: The long lasting symptomatic relief observed in all four treated patients correlated with the persistent decrease in parasite load both in tissue and in stool, and with the morphological changes observed in the life cycle of the protozoan. These data suggest that combined treatment with furazolidone and albendazole is active against E bieneusi and may result in lasting remission even in severely immunocompromised patients.

Neuron density and distribution of the NADPH-diaphorase positive neurons were studied in the fundus, corpus and antrum of adult human stomach using cresyl violet staining and NADPH-diaphorase histochemistry. The submucous plexus contained significantly less neurons than the myenteric plexus. Submucous NADPH-d positive neurons were mostly located in ganglia close to the circular muscle layer. Myenteric NADPH-d positive neurons represented 50-60% of the neurons in all the three regions; their density, however, was significantly lower in the fundus. NADPH-d positive fibers formed a rich plexus in the innermost portion of the circular muscle layer of the corpus.

Aims: To investigate changes in morphology of the developmental stages of Enterocytozoon bieneusi and symptomatic relief observed in AIDS patients after treatment with furazolidone., Methods: Six AIDS patients with symptomatic E bieneusi infection of the small intestine were treated with a course of furazolidone. All patients had a weekly monitoring of parasite shedding in stool by light microscopy during and after treatment. At the end of the treatment, duodenal biopsy specimens obtained from three patients were studied by transmission electron microscopy by two pathologists who were unaware of the patients' treatment., Results: All patients showed both clinical and parasitological response with transient clearance or decrease of spore shedding in stool. After treatment, alterations in faecal spores were observed in all patients by light microscopy, and ultrastructural changes in E bieneusi at all stages of the life cycle were demonstrated in biopsy specimens of the three patients who underwent post-treatment endoscopy., Conclusions: The clinical benefit seen after treatment with furazolidone in six AIDS patients with E bieneusi intestinal infection may be due to damage to the developmental stages causing a partial inhibition to reproduction of the parasite.

Purpose: The biochemical and morphological alterations induced in lower limb skeletal muscle by ischemia-reperfusion (I-R) during aortic surgery and the effect of vitamin E pretreatment were investigated., Methods: Two groups of patients undergoing aortic aneurysm resection, one untreated and one treated with vitamin E, were examined. Quadricep muscle biopsies were taken after induction of anesthesia, at the end of ischemia, and after reperfusion. The malondialdehyde (MDA) content and morphology of biopsies were examined to assess peroxidative processes., Results: Ischemia did not induce an increase in MDA content but did increase neutrophil infiltration in muscle fibers of untreated patients. Reperfusion led to a significant increase in MDA content and to intermyofibrillar edema and mitochondrial swelling. The MDA content was not increased during ischemia and neutrophil infiltration was minimal in vitamin E treated patients. At reperfusion, the MDA content, the ultrastructural injuries and neutrophil infiltration were significantly reduced by the treatment., Conclusions: Vitamin E is effective in reducing the oxidative muscle damage occurring after a period of I-R.

A case of chronic intestinal infection due to adenovirus type 40 lasting for 13 months in a patient with AIDS is described. Adenovirus particles were detected by electron microscopy in biopsy samples taken from the duodenum 3 months after the onset of diarrhoea. The virus was identified as adenovirus type 40 in stool samples by ELISA monoclonal antibodies to adenovirus group antigen (MAd-g2) and types 40 and 41 (MA 40-1 and MA 41-1). No other enteropathogens were found. These data support a causal relationship between adenovirus 40 and the gastrointestinal symptoms of the patient. This is the first reported case of intestinal infection caused by adenovirus type 40 in a patient with AIDS.

The lung buds of 15 human fetuses from the 9th to the 14th week of i.u. life were examined by scanning electron microscopy (SEM). SEM allows to clearly evidentiate the branching pattern of the respiratory tree, the development of the vascular network, the differentiation of the layers in the bronchial wall and the maturation of the epithelium. Particularly, as concerns the epithelium, its pattern in the air conducting ways and in the respiratory zone appears to be different from the very start; the presence of vascular spaces and then of well-defined vessels can be already detected starting from the 9th week of development.

Sphincteric anatomy and function are present at the caecocolonic junction in several mammals. In humans, radiologists and endoscopists have respectively reported a circumferential contraction and a prominent ileocaecal fold at the border area between the caecum and the ascending colon. Anatomical findings on necropsy material failed to confirm its presence. Microscopic studies on surgical specimens showed the existence of muscular and innervational patterns different from those of adjacent areas. The aim of this work was to confirm the existence of a specialised fold at the caecocolonic junction in humans and to ascertain its role by carrying out a study of functional anatomy. Pancolonoscopies were performed on 100 patients and ileocaecal fold behaviour was observed before and after mechanical stimulation. Isolated ileocaecocolonic regions, surgically obtained, were filled with a fixative solution to study their macro and microscopic morphology after stimulation. Endoscopically, the ileocaecal fold was semilunar or circular in shape and spontaneous or evoked spasms occurred in 52 patients. A prominent circular fold could be seen in surgical specimens after stimulation. The entire muscle coat deeply penetrated this fold, showing the features characteristic of the ileocaecal junction. In particular, the inner portion of the circular muscle showed a peculiar arrangement and was thicker than elsewhere. These results show that in humans the caecocolonic junction is provided with a sphincter morphology and function. Little is known about its physiological relevance in ileal flow accommodation and caecal filling and emptying but it should not be underestimated with regard to some colonic motility disorders.

The nitric oxide producing neurons of the human colonic myenteric plexus have been studied by using antibodies against cerebellar NO synthase type I (NOS-IR) and NADPH-diaphorase (NAPDH-d) histoenzymatic reaction. The majority of the stained neurons were both NOS-IR and NADPH-d-positive, while a few others were either NADPH-d-positive or NOS-IR only. Among the co-stained neurons, four subpopulations sharing various degrees of staining intensities have been identified. These findings indicate that in the human colon a one-to-one correlation between NOS-IR and NADPH-d positivity does not exist and thus the NADPH-d reaction does not delineate with certainty all NO-producing neurons. The degree of staining intensity might account for different intracellular amounts of these two enzymes.

This work was undertaken to assess the role of endothelial E-selectin in the development of neutrophil accumulation into the ischemic and reperfused human skeletal muscle and eventually in the genesis of ischemia-reperfusion syndrome. Twelve patients affected by abdominal aortic aneurysm who were undergoing reconstructive vascular surgery were studied. Muscle biopsies from the right femoral quadriceps were taken (1) immediately after anesthesia, as control samples, (2) before declamping the aorta, as ischemic samples, and (3) 30 minutes after reperfusion and then processed for immunohistochemical and ultrastructural analysis. Immunohistochemistry revealed a strong positive reaction for E-selectin on the venular endothelium during ischemia and reperfusion. Ultrastructural investigation showed that reactivity for E-selectin matched neutrophil accumulation of the skeletal muscle tissue. This phenomenon was dependent upon a complex series of events that included neutrophil adhesion to the inner surface of the postcapillary venules, passage through endothelial intercellular junctions, and migration distally into the interstitial spaces of the skeletal muscle tissue. Neutrophil tissue infiltration was also associated with ultrastructural signs of tissue damage at reperfusion. This is in agreement with accumulating evidence indicating a role for tissue infiltrating neutrophils in the genesis of toxic O2 free radicals. Our data suggest that E-selectin expression on the vascular endothelium of human skeletal muscle may represent a key regulatory point in the process of neutrophil tissue accumulation and indicate an active role for the venular endothelium in the development of human ischemia-reperfusion syndrome.

Objectives: The study aimed to evaluate stiffness and the cross-sectional area (CSA) of the tibial nerve (TN) using shear wave elastography (SWE) and ultrasound (US) and investigate the relationship of these with disease activity, quality of life, and severity of neuropathic pain in patients with systemic sclerosis (SSc). Patients and methods: This cross-sectional study included 28 SSc patients (1 male, 27 females; mean age: 50±11 years; range, 28 to 67 years) and 22 age- and sex-matched healthy controls (4 males, 18 females; mean age: 48±6 years; range, 37 to 66 years) between March and April 2022. US and SWE were performed on the TN, and CSA and nerve stiffness were measured. The TN was examined by a radiologist, 4 cm proximal to the medial malleolus. A few days later, an evaluation was performed in the second session by a second observer to investigate inter-and intraobserver agreement. Interobserver agreement was evaluated using the intraclass correlation coefficient (ICC). The Scleroderma Health Assessment Questionnaire, European League Against Rheumatism European Scleroderma Trial and Research (EUSTAR) group activity index, and Douleur)Neuropathique 4 scores of the patients were evaluated. Correlations between the questionnaires and measurements of nerve stiffness and CSA were assessed. Results: Patients with SSc had significantly higher stiffness and CSA values of the right TN compared to healthy controls (p<0.001 and p=0.015, respectively). The nerve stiffness values of the right TN were positively correlated with the EUSTAR activity index (p=0.004, r=0.552). The CSA of the left TN was larger in patients with SSc (21.3±4.9 mm2 ) than in controls (12.8±3.4 mm2 ), and the nerve elasticity was positively correlated with the EUSTAR activity index (p=0.001, r=0.618). The interobserver agreement was moderate to good for measuring stiffness and CSA of the TN (ICC were 0.660 and 0.818, respectively). There was a good to excellent intraobserver agreement for measuring stiffness and CSA of TN (ICC were 0.843 and 0.940, respectively). Conclusion: The increased disease activity in patients with SSc is associated with TN involvement, which can be demonstrated by US and SWE. [ABSTRACT FROM AUTHOR]

Objective: The epidemiology and treatment of peripheral neuropathy in systemic sclerosis (SSc) is poorly understood. The objectives of this study were to evaluate the incidence, prevalence, risk factors, and treatments of peripheral neuropathy in SSc.Methods: A systematic review of MEDLINE, Embase, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) databases for literature reporting peripheral neuropathy in SSc was performed. Studies evaluating incidence, prevalence, risk factors, and treatments were synthesized. A metaanalysis using a random effects model was used to evaluate the prevalence of peripheral neuropathy.Results: This systematic review identified 113 studies that reported 949 of 2143 subjects with at least 1 type of peripheral neuropathy. The mean age was 48.5 years. The mean time between SSc onset and detection of peripheral neuropathy was 8.85 years. The pooled prevalence of neuropathy was 27.37% (95% CI 22.35-32.70). Risk factors for peripheral neuropathy in SSc included advanced diffuse disease, anticentromere antibodies, calcinosis cutis, ischemia of the vasa nervorum, iron deficiency anemia, metoclopramide, pembrolizumab, silicosis, and uremia. There were 73 subjects with successful treatments (n = 36 restoring sensation, n = 37 restoring motor or sensorimotor function). Treatments included decompression surgery, prednisone, cyclophosphamide, carbamazepine, transcutaneous electrical nerve stimulation, tricyclic antidepressants, and intravenous Ig.Conclusion: All-cause peripheral neuropathy is not uncommon in SSc. Compression neuropathies can be treated with decompression surgery. Observational data reporting immunosuppressives and anticonvulsants to treat peripheral neuropathy in SSc are limited and conflicting. Randomized controlled trials are needed to evaluate the efficacy of these interventions. [ABSTRACT FROM AUTHOR]

Interleukin (IL)‐7 is known to enhance the macrophages cytotoxic activity and that macrophages play a pivotal role in the development and progression of myocardial ischaemia/reperfusion (I/R) injury. However, the effects of IL‐7 on macrophages infiltration and polarization in myocardial I/R injury are currently unclear. This study aimed to evaluate the effects of the IL‐7 expression on myocardial I/R injury and their relationship with macrophages. The data showed that IL‐7 expression in mouse heart tissue increases following I/R injury and that IL‐7 knockout or anti‐IL‐7 antibody treatment significantly improve I/R injury, including reduction in myocardial infarction area, a serum troponin T level decreases and an improvement in cardiac function. On the other hand, recombinant IL‐7 (rIL‐7) supplementation induces opposite effects and the anti‐IL‐7 antibody significantly reduces the cardiomyocyte apoptosis and macrophage infiltration. rIL‐7 cannot directly cause apoptosis, but it can induce cardiomyocyte apoptosis through macrophages, in addition to increase the macrophages migration in vitro. Anti‐IL‐7 antibody affects the cytokine production in T helper (Th) 1 and Th2 cells and also promotes the macrophages differentiation to M2 macrophages. However, anti‐IL‐7 antibody does not reduce the M1 macrophage number, and it only increases the ratio of M2/M1 macrophages in mice heart tissues after I/R injury. Taking together, these data reveal that IL‐7 plays an intensifying role in myocardial I/R injury by promoting cardiomyocyte apoptosis through the regulation of macrophage infiltration and polarization. [ABSTRACT FROM AUTHOR]

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Inactivation of the Hippo pathway protects the myocardium from cardiac ischemic injury. MicroRNAs (miRs) have been reported to play pivotal roles in the progression of myocardial infarction (MI). The present study examined whether miR-93 could promote angiogenesis and attenuate remodeling after MI via inactivation of the Hippo/Yes-associated protein (Yap) pathway, by targeting large tumor suppressor kinase 2 (Lats2). It was identified that transfection of human umbilical vein endothelial cells with miR-93 mimic significantly decreased Lats2 expression and Yap phosphorylation, increased cell viability and migration, and attenuated cell apoptosis following hypoxia/reoxygenation injury. Moreover, increased expression of miR-93 resulted in an improvement of cardiac function, promotion of angiogenesis and attenuation of remodeling after MI. Additionally, miR-93 overexpression significantly decreased intracellular adhesion molecule 1 and vascular cell adhesion protein 1 expression levels, as well as attenuated the infiltration of neutrophils and macrophages into the myocardium after MI. Furthermore, it was found that miR-93 overexpression significantly suppressed Lats2 expression and decreased the levels of phosphorylated Yap in the myocardium after MI. Collectively, the present results suggested that miR-93 may exert a protective effect against MI via inactivation of the Hippo/Yap pathway by targeting Lats2. [ABSTRACT FROM AUTHOR]

Objective To investigate the relationship between intestinal inflammation and the central and peripheral innate immune system in the pathogenesis of HLA-B27-associated spondyloarthritis using an HLA-B27-transgenic (B27-Tg) rat model. Methods The myeloid compartment of the blood and bone marrow (BM) of B27-Tg rats, as well as HLA-B7-Tg and non-Tg rats as controls, was evaluated by flow cytometry. Plasma from rats was assessed by enzyme-linked immunosorbent assay for levels of CCL2 and interleukin-1α (IL-1α). Rats were treated with antibiotics for 4 weeks, and the myeloid compartment of the blood and BM was evaluated by flow cytometry. The osteoclastogenic potential of BM-derived cells from antibiotic-treated rats, in the presence or absence of tumor necrosis factor (TNF), was evaluated in vitro. Results B27-Tg rats had substantially higher numbers of circulating Lin−CD172a+CD43low monocytes as compared to control animals, and this was significantly correlated with higher levels of plasma CCL2. Antibiotic treatment of B27-Tg rats markedly reduced the severity of ileitis, plasma levels of CCL2 and IL-1α, and number of BM and blood Lin−CD172a+CD43low monocytes, a cell subset shown in the present study to have the greatest in vitro osteoclastogenic potential. Antibiotic treatment also prevented the TNF-dependent enhancement of osteoclastogenesis in B27-Tg rats. Conclusion Microbiota-dependent intestinal inflammation in B27-Tg rats directly drives the systemic inflammatory and bone-erosive potential of the monocyte compartment. [ABSTRACT FROM AUTHOR]

Peripheral artery disease (PAD) is a common circulatory disorder of the lower limb arteries that reduces functional capacity and quality of life of patients. Despite relatively effective available treatments, PAD is a serious public health issue associated with significant morbidity and mortality. Ischemia-reperfusion (I/R) cycles during PAD are responsible for insufficient oxygen supply, mitochondriopathy, free radical production, and inflammation and lead to events that contribute to myocyte death and remote organ failure. However, the chronology of mitochondrial and cellular events during the ischemic period and at the moment of reperfusion in skeletal muscle fibers has been poorly reviewed. Thus, after a review of the basal myocyte state and normal mitochondrial biology, we discuss the physiopathology of ischemia and reperfusion at the mitochondrial and cellular levels. First we describe the chronology of the deleterious biochemical and mitochondrial mechanisms activated by I/R. Then we discuss skeletal muscle I/R injury in the muscle environment, mitochondrial dynamics, and inflammation. A better understanding of the chronology of the events underlying I/R will allow us to identify key factors in the development of this pathology and point to suitable new therapies. Emerging data on mitochondrial dynamics should help identify new molecular and therapeutic targets and develop protective strategies against PAD. [ABSTRACT FROM AUTHOR]

Aim A tension-free anastomosis is required to minimize anastomotic leakage after an extended left colectomy when the residual transverse colon is too short to spontaneously reach the pelvis. To resolve this problem, colonic rotation with a right colonic transposition ( RCT) or even with a complete intestinal derotation ( CID) is mandatory. This study compared these two techniques. Method Between January 2001 and December 2011, 39 patients had undergone right colonic transposition ( n = 29) or complete intestinal derotation ( n = 10) after an extended left colectomy. All anastomotic complications had been recorded during the follow up. Results No differences were found between right colonic transposition and complete intestinal derotation in terms of patient characteristics, surgical indications, therapeutic features and risk factors for anastomotic leakage (sex, American Society of Anesthesiology ( ASA) score, diabetes, bevacizumab use, colorectal anastomotic level or protective stoma use). Ligature of the middle colic artery was significantly more frequent with right colonic transposition than with complete intestinal derotation (82.7% vs 50%; P = 0.04). An additional colonic resection tended to be required more often in the right colonic transposition group than in the complete intestinal derotation group (55.1% vs 20%; P = 0.054). The anastomotic complication rate was 10.2% and was not significantly different between right colonic transposition and complete intestinal derotation (6.9% vs 20%, P = 0.24). Conclusion Both colonic rotation techniques are feasible and safe. The right colonic transposition and complete intestinal derotation techniques yielded similar results in terms of colorectal anastomotic complications, but right colonic transposition required ligature of the middle colic artery and additional colonic resection tended to be required more frequently. [ABSTRACT FROM AUTHOR]

Telocytes, a peculiar type of stromal cells, have been recently identified in a variety of tissues and organs, including human skin. Systemic sclerosis ( SSc, scleroderma) is a complex connective tissue disease characterized by fibrosis of the skin and internal organs. We presently investigated telocyte distribution and features in the skin of SSc patients compared with normal skin. By an integrated immunohistochemical and transmission electron microscopy approach, we confirmed that telocytes were present in human dermis, where they were mainly recognizable by their typical ultrastructural features and were immunophenotypically characterized by CD34 expression. Our findings also showed that dermal telocytes were immunophenotypically negative for CD31/ PECAM-1 (endothelial cells), α- SMA (myofibroblasts, pericytes, vascular smooth muscle cells), CD11c (dendritic cells, macrophages), CD90/Thy-1 (fibroblasts) and c-kit/ CD117 (mast cells). In normal skin, telocytes were organized to form three-dimensional networks distributed among collagen bundles and elastic fibres, and surrounded microvessels, nerves and skin adnexa (hair follicles, sebaceous and sweat glands). Telocytes displayed severe ultrastructural damages (swollen mitochondria, cytoplasmic vacuolization, lipofuscinic bodies) suggestive of ischaemia-induced cell degeneration and were progressively lost from the clinically affected skin of SSc patients. Telocyte damage and loss evolved differently according to SSc subsets and stages, being more rapid and severe in diffuse SSc. Briefly, in human skin telocytes are a distinct stromal cell population. In SSc skin, the progressive loss of telocytes might (i) contribute to the altered three-dimensional organization of the extracellular matrix, (ii) reduce the control of fibroblast, myofibroblast and mast cell activity, and (iii) impair skin regeneration and/or repair. [ABSTRACT FROM AUTHOR]

Gastric adaptive relaxation (GAR) is impaired in ~40% of functional dyspepsia (FD) patients, and nitric oxide (NO) released from inhibitory motor neurons plays an important role in this relaxation. Although the underlying molecular mechanism of GAR is poorly understood, transient receptor potential channel vanilloid 2 (TRPV2) mechano- and chemoreceptors are expressed in mouse intestinal inhibitory motor neurons and are involved in intestinal relaxation. The aim of this study was to evaluate the distribution of TRPV2 in inhibitory motor neurons throughout the mouse gastrointestinal tract and the contribution of TRPV2 to GAR. RT-PCR and immunohistochemical analyses were used to detect TRPV2 mRNA and protein, respectively. Intragastric pressure was determined with an isolated mouse stomach. Gastric emptying (GE) in vivo was determined using a test meal. TRPV2 mRNA was detected throughout the mouse gastrointestinal tract, and TRPV2 immunoreactivity was detected in 84.3% of neuronal nitric oxide synthaseexpressing myenteric neurons in the stomach. GAR, which was expressed as the rate of decline of intragastric pressure in response to volume stimuli, was significantly enhanced by the TRPV2 activator probenecid, and the enhancement was inhibited by the TRPV2 inhibitor tranilast. GE was significantly accelerated by TRPV2 agonist applications, and the probenecid-induced enhancement was significantly inhibited by tranilast coapplication. Mechanosensitive TRPV2 was expressed in inhibitory motor neurons in the mouse stomach and contributed to GAR and GE. TRPV2 may be a promising target for FD patients with impaired GAR. [ABSTRACT FROM AUTHOR]

Background Scleroderma is a connective tissue disease that includes localized and systemic forms. Our recent encounter with a morphea case exhibiting prominent perineural inflammation microscopically prompted us to assess the features of all patients diagnosed with morphea/scleroderma at our institution. Objective/methods To describe the clinicopathological features of all patients diagnosed with morphea/scleroderma at American University of Beirut Medical Center (AUB-MC) between 1999 and 2010, and compare our findings with those published in the literature. Results A total of 81 cases (63 women and 18 men) were identified, of which 73 were localized (morphea) and eight were systemic scleroderma. Clinically, plaque type morphea was the most common variant both in adults and children, and seven (9%) cases of morphea were associated with lichen sclerosis et atrophicus (LSA). Histopathologically, perineural inflammation was observed in 49% of cases, and may serve, in addition to other features including lichen sclerosis-like changes (observed in exclusively nine cases of morphea), more diffuse dermal and less subcutaneous sclerosis, and intense inflammation, as clues favouring diagnosis of morphea over systemic sclerosis. Conclusion The features of morphea/scleroderma patients in this study are generally comparable to those published in the literature, with few differences. Clinically, plaque type morphea was the most common variant both in adults and children and LSA was a frequent association. Histopathologically, perineural inflammation was commonly observed and may serve in addition to lichen sclerosis-like changes and intense inflammation as clues favouring diagnosis of morphea over systemic sclerosis. [ABSTRACT FROM AUTHOR]

Ischemia/reperfusion injury (IRI) is crucial in the pathology of major cardiovascular diseases, such as stroke and myocardial infarction. Paradoxically, both the lack of oxygen during ischemia and the replenishment of oxygen during reperfusion can cause tissue injury. Clinical outcome is also determined by a third, post-reperfusion phase characterized by tissue remodeling and adaptation. Increased levels of reactive oxygen species (ROS) have been suggested to be key players in all three phases. As a second paradox, ROS seem to play a double-edged role in IRI, with both detrimental and beneficial effects. These Janus-faced effects of ROS may be linked to the different sources of ROS or to the different types of ROS that exist and may also depend on the phase of IRI. With respect to therapeutic implications, an untargeted application of antioxidants may not differentiate between detrimental and beneficial ROS, which might explain why this approach is clinically ineffective in lowering cardiovascular mortality. Under some conditions, antioxidants even appear to be harmful. In this review, we discuss recent breakthroughs regarding a more targeted and promising approach to therapeutically modulate ROS in IRI. We will focus on NADPH oxidases and their catalytic subunits, NOX, as they represent the only known enzyme family with the sole function to produce ROS. Similar to ROS, NADPH oxidases may play a dual role as different NOX isoforms may mediate detrimental or protective processes. Unraveling the precise sequence of events, i.e., determining which role the individual NOX isoforms play in the various phases of IRI, may provide the crucial molecular and mechanistic understanding to finally effectively target oxidative stress. [ABSTRACT FROM AUTHOR]

The article focuses on various skin conditions which may exhibit cutaneous perineural inflammation which can help dermatopathologists and pathologists in their diagnosis. It relates that perineural inflammation has been described in association with skin tuberculosis and is evidenced by decreased sensation and the enlargement of peripheral nerves. It mentions various skin conditions which can lead to perineural inflammation which include leprosy, secondary syphilis, and leishmaniasis.

Human adenovirus 40 (Ad40) is an interesting candidate for vector construction because of its tropism for the gastrointestinal tract. Although effective preparation of the vector is necessary for its in vivo application, amplification of Ad40 has been very difficult. Ad40 E1 deletion mutants were detected by PCR in the viral DNA from Ad40 Dugan amplified by Ad5 E1-expressing human embryonic kidney (293) cells and in Ad40 Dugan plaques observed with Ad5 E1-expressing human retinoblastic cells. For the purpose of generating a single wild-type Ad40 clone, the entire Ad40 DNA was cloned into a plasmid by homologous recombination. A pure Ad40 was successfully generated by plasmid transfection and subsequently amplified with Ad5 E4orf6-inducible 293 (2V6.11) cells. 2V6.11 is an apposite cell line for effective Ad40 amplification and for future vector construction because Ad40 genetic integrity was maintained with this Ad5 E1 and E4orf6 trans-complementing cell line. [ABSTRACT FROM AUTHOR]

• Neuronal diversity in the adult enteric nervous system (ENS) • Developmental appearance and birthdating of enteric neuron subtypes and glial cells - Developmental appearance of pan-neuronal markers and enteric neuron subtypes - Time of exit from cell cycle of different neuron types • Morphological development of enteric neurons • Axon guidance in the developing ENS • Development of connectivity • Mechanisms controlling enteric neuronal differentiation and the generation of neuron diversity - Transcriptional control of enteric neuronal differentiation and the generation of neuron diversity - Role of glial cell line-derived neurotrophic factor (GDNF) family members in enteric neuronal differentiation and the generation of neuron diversity - Role of endothelin-3/Ednrb signalling - Role of other signalling pathways - Neurotrophin-3 (NT-3) - Bone morphogenetic proteins (BMPs) - L1 - Sonic hedgehog - Role of electrical activity • Development of enteric glia • Development of neurons and neuronal subtypes in the human ENS and clinical relevance - Hirschsprung's disease - Is the ganglionic segment of Hirschsprung's patients ‘normal’? - Other paediatric motility disorders - Defects in the development of subtypes of enteric neurons - Defects in the number of enteric neurons • Conclusions The mature enteric nervous system (ENS) is composed of many different neuron subtypes and enteric glia, which all arise from the neural crest. How this diversity is generated from neural crest-derived cells is a central question in neurogastroenterology, as defects in these processes are likely to underlie some paediatric motility disorders. Here we review the developmental appearance (the earliest age at which expression of specific markers can be localized) and birthdates (the age at which precursors exit the cell cycle) of different enteric neuron subtypes, and their projections to some targets. We then focus on what is known about the mechanisms underlying the generation of enteric neuron diversity and axon pathfinding. Finally, we review the development of the ENS in humans and the etiologies of a number of paediatric motility disorders. [ABSTRACT FROM AUTHOR]

Acute ischaemia–reperfusion disrupts capillary fine structure and increases leukocyte adhesion in postcapillary venules. We determined whether chronic muscle ischaemia has similar consequences, and whether it is possible to ameliorate its effect on muscle performance. Following ischaemia (unilateral ligation, common iliac artery) rat hindlimb muscles were examined without other intervention or following treatment with an xanthine oxidase inhibitor (allopurinol), a Na+/H+ exchange blocker (amiloride), or an oxygen free radical scavenger (vitamin E). No significant leukocyte adhesion or rolling, nor changes in capillary fine structure were observed 3 days postsurgery, when limb use was limited. However, leukocyte rolling and adhesion almost trebled by 7 days ( P < 0.001), when normal gait was largely restored. Capillary fine structure was disturbed over a similar time course, e.g. relative endothelial volume (control 46%, 7 days 61%; P < 0.05), that resolved by 5 weeks. Where activity was increased by mild electrical stimulation 3 days after ligation muscles showed enhanced capillary swelling (endothelial volume 66% versus 50%, P < 0.005), but improved fatigue index (52% versus 16%, P < 0.001) as a result of greater blood flow. Muscle fatigue after ligation was related to the extent of contraction-induced hyperaemia ( R2= 0.725), but not capillary swelling. Amiloride, and to a lesser extent allopurinol but not vitamin E, significantly decreased leukocyte rolling and adhesion, as well as capillary endothelial swelling. We conclude that increased activity of ischaemic muscles on recovery is likely to accentuate acidosis accompanying changes in microcirculation and contribute to enhanced muscle fatigue, whereas formation of oxygen free radicals may be attenuated by endogenous protective mechanisms. [ABSTRACT FROM AUTHOR]

We have previously shown oxidative stress and oedema, caused by both xanthine oxidase-derived oxidants and infiltrating neutrophils, within skeletal muscle after contractile-induced claudication. The purpose of this study was to determine whether supplementation with antioxidant vitamins attenuates the oxidative stress, neutrophil infiltration and oedema associated with an acute bout of contractile-induced claudication. Rats received vehicle, vitamin C, vitamin E or vitamin C + E for 5 days prior to contractile-induced claudication. Force production was significantly reduced in the claudicant limbs of all groups compared with the control (sham) limb of control animals. Contractile-induced claudication caused a significant increase in protein oxidation, lipid peroxidation, neutrophil infiltration and oedema compared with sham muscles. Supplementation with vitamin C, E or C + E prevented the increases in each of these, and there were no differences between groups. These findings suggest that, in an animal model of exercise-induced claudication, neutrophil chemotaxis is caused by oxidizing species and that antioxidant supplementation can prevent oxidative damage, neutrophil infiltration and oedema following an acute bout of contractile-induced claudication. [ABSTRACT FROM AUTHOR]

Examines whether the legs or gastrointestinal tract provide the greater contribution to the inflammatory response during abdominal aortic aneurysm repair. Measurement of interleukin 6 using a commercially available enzyme-linked immunosorbent assay kit.

This article focuses on the management of infectious diarrhoea, which is the most common cause of diarrhoea worldwide and is responsible for more deaths than gastrointestinal cancers, peptic ulcer or inflammatory bowel disease. A vast numbers of bacteria, viruses and parasites can cause diarrhoeal disease. Infectious diarrhoea occurs as a result of two major disturbances in normal intestinal physiology: increased intestinal secretion of fluid and electrolytes and decreased absorption of fluid, electrolytes, and sometimes nutrients that can involve the small and large intestine.

The major functions of the stomach are under the control of the enteric nervous system (ENS), but the neuronal circuits involved in this control are largely unknown in humans. Enteric neurones can be characterized by their neuromediator or marker content, i.e. by neurochemical coding. The purpose of this study was to characterize the presence and co-localization of neurotransmitters in myenteric neurones of the human gastric fundus. Choline acetyltransferase (ChAT), neurone-specific enolase (NSE), vasoactive intestinal polypeptide (VIP), nitric oxide synthase (NOS), substance P (SP) were detected by immunohistochemical methods in whole mounts of gastric fundus myenteric plexus (seven patients). Antibodies against ChAT and NOS labelled the majority of myenteric neurones identified by NSE (57.2 ± 5.6% and 40.8 ± 4.5%, respectively; mean ± SD). The proportions of VIP- and SP-immunoreactive neurones were significantly smaller, constituting 19.6 ± 6.9% and 16.0 ± 3.7%, respectively. Co-localization studies revealed five major populations representing over 75% of the myenteric neurones: ChAT/-, 30.1 ± 6.1%; NOS/-, 24.2 ± 4.4%; ChAT/SP/-, 8.3 ± 3.1%; NOS/VIP/-, 7.2 ± 6.0%; ChAT/VIP/-, 4.9 ± 2.6. Some similarities are apparent in the neurochemical coding of myenteric neurones in the stomach and intestine of humans, and between the stomach of humans and animals, but striking differences exist. The precise functional role of the neurochemically identified classes of neurones remains to be determined. [ABSTRACT FROM AUTHOR]

Background: The object of this study was to develop an animal model in which changes in microvascular haemodynamics and leucocyte–vessel wall interactions due to acute limb ischaemia–reperfusion (I/R) can be measured in the skin. Furthermore, it was investigated whether these changes are related to local muscle injury. Methods: Male Lewis rats were subjected to unilateral limb ischaemia for 1 h (n = 8) or 2 h (n = 8) by cuff inflation, or to a sham protocol (n = 6). Intravital video microscopic measurements of leucocyte–vessel wall interactions, venular diameter, red blood cell velocity and reduced velocity (which is proportional to wall shear rate) were performed in skin venules before ischaemia and at 0·5, 1, 2, 3 and 4 h after the start of reperfusion. Oedema and leucocyte infiltration of ischaemic/reperfused skeletal muscle were quantified histologically. Results: In skin venules, both 1 and 2 h of ischaemia induced a significant increase in leucocyte rolling (six and five times baseline, respectively; P < 0·05) and adherence during reperfusion (eight and four times baseline; P < 0·05). No significant increase in muscular leucocyte infiltration was detected. After an initial hyperaemic response of 180 per cent of baseline values (P < 0·05), blood flow decreased to about 60 per cent after 4 h of reperfusion in skin venules of both experimental groups. I/R induced tibial muscle oedema, the severity of which depended on the ischaemic interval (wet to dry ratio: control, 4·0; 1 h, 4·5 (P not significant); 2 h, 5·8 (P < 0·05)). Conclusion: A non-invasive animal model was developed that enables investigation of the consequences of acute limb I/R. [ABSTRACT FROM AUTHOR]

Entamoeba histolytica trophozoites were inoculated into the liver of hamsters and serum nitrate/nitrite levels [expressed as nitric oxide (NO) production] were determined at different times during amebic liver abscess (ALA) development. We also tested the effects of NO synthase (NOS) inhibitors such as N G-nitro- L-arginine methyl ester (L-NAME), aminoguanidine, and dexamethasone during ALA production. Since NOS activity has been correlated with expression of reduced nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd) in tissues, we performed histochemistry studies to determine the activity of the latter in livers infected with E. histolytica trophozoites. Production of NO in serum was directly proportional to the size of ALAs, and NOS inhibitors caused low levels of NO and smaller ALAs. Our data suggest that NO does not have any lytic effect on E. histolytica trophozoites and is therefore incapable of providing protection against the amebic liver infection. In addition, NADPHd activity was detected histochemically in hepatocytes and inflammatory cells associated with focal necrosis containing trophozoites. The positive reactivity observed in these parasites may be attributable to a close biochemical similarity of NADPHd to the NADPH:flavin oxidoreductase described in E. histolytica by other investigators. [ABSTRACT FROM AUTHOR]

We studied the pharmacology of the neural pathways mediating the responses of ileo- and coloileo-colonic junction (ICJ) to regional distension in ten anaesthetized pigs. Using manometric pullthroughs and a sleeve sensor, we found the ICJ demonstrated sustained tone that was resistant to tetrodotoxin. Ileal distension decreased ICJ pressure by 22.2 ± 10.1% (11.9 ± 2.7–10.1 ± 2.6 mmHg; P=0.002) and colonic distension augmented ICJ pressure by 23.5 ± 8.6% (12.8 ± 1.5–15.6 ± 2.1 mmHg; P=0.02). Bethanecol and Nω-nitro-L-arginine methyl ester (L-NAME) increased ICJ pressure (P=0.002, P=0.01, respectively). Sodium nitroprusside and isoproterenol reduced ICJ pressure (P=0.004, P=0.02, respectively). In the presence of L-NAME, the early inhibitory ileo-ICJ response was abolished, while early and late inhibitory responses were abolished by further addition of propranolol but not by the addition of hexamethonium, atropine, prazosin or yohimbine. The excitatory colo-ICJ response was replaced by inhibition in the presence of L-NAME. We concluded that: 1 the porcine ICJ displays myogenic tone which is influenced by excitatory muscarinic and inhibitory nitrergic and beta adrenergic pathways 2 an inhibitory ileo-sphincteric reflex mediated by nitrergic and beta adrenergic postganglionic neural pathways 3 both excitatory and inhibitory neurogenic colo-sphincteric reflexes exist, and the excitatory pathway involves nitrergic neurotransmission. [ABSTRACT FROM AUTHOR]

Intestinal parasites colonize patients worldwide. Due to modern travel, emigration, and exotic cuisines, parasitic infections can present in any locale. Some cause severe disease, while others are usually self-limited or asymptomatic. Patients with diarrhea should have at least three stool specimens, gathered on separate days, checked for ova and parasites. The medical laboratory must be alerted for specific concerns, because the method of assay differs among various parasites. Stool antigen and blood serology tests increase diagnostic sensitivity. Physicians need to consider, recognize, and know how to treat intestinal parasitosis. [ABSTRACT FROM AUTHOR]

The effect of age on the proportion of nicotinamide adenine dinucleotide phosphate diaphorase (NADPHd)-positive neurons was investigated in the myenteric plexus of five different gastric areas of 1-day-, 1-week-, 2-week-, 1-month- and 2-month-old rats. Protein gene product 9.5 immunocytochemistry was used as a marker for the total enteric neuron population in order to establish the percentage of gastric nitrergic neurons in relation to age. The percentage of NADPHd-positive neurons in the proximal parts of the rat stomach (34–38%) is significantly higher than in the antral part (29%). This difference persists in all the age groups investigated. No significant relative increase with age of NADPHd-positive neurons could be observed in any of the areas studied. These findings imply that the increased nitrergic response in the rat proximal stomach as seen in pharmacological studies cannot be explained by an increased relative number of nitrergic neurons. [ABSTRACT FROM AUTHOR]

Aim:To review the physiology of colonic motility and sensation in healthy humans and the pathophysiological changes associated with constipation and diarrhoea. Source:Medline Search from 1965 using the index terms: human, colonic motility, sensation, pharmacology, neurohormonal control, gastrointestinal transit, constipation, diarrhoea and combinations of these. Results:In health, the ascending and transverse regions of colon function as reservoirs to accommodate ileal chyme and the descending colon acts as a conduit; the neuromuscular functions and transmitters control colonic motility and sensation and play pivotal roles in disorders associated with constipation and/or diarrhoea. Disorders of proximal colonic transit contribute to symptoms in idiopathic constipation, diarrhoea-predominant irritable bowel syndrome and carcinoid diarrhoea. Colonic function in patients presenting with constipation is best assessed clinically by colonic transit time using radiopaque markers ingested orally. Measurements of colonic contractility are less useful clinically but they can help identify motor abnormalities including colonic inertia; in some patients with irritable bowel syndrome, abdominal pain, urgency and diarrhoea are temporally associated with high amplitude contractions, which originate in the proximal colon and traverse the distal conduit at very high propagation velocities. Visceral hypersensitivity contributes to the urgency and tenesmus in irritable bowel syndrome and inflammatory bowel disease. Colonic motility and sensation can be reduced by anticholinergic agents, somatostatin analogues and 5HT3 antagonists. Conclusion:Physiological and pharmacological studies of the human colon have provided new insights into the pathophysiology of colonic disorders, and offer possibilities of novel therapeutic approaches for constipation or diarrhoea associated with colonic motor or sensory dysfunction. [ABSTRACT FROM AUTHOR]

Ischemia-reperfusion injury is caused by a period of ischemia followed by massive blood flow into a tissue that had experienced restricted blood flow. The severity of the injury is dependent on the time the tissue was restricted from blood flow, becoming more severe after longer ischemia times. This can lead to many complications such as tissue necrosis, cellular apoptosis, inflammation, metabolic and mitochondrial dysfunction, and even organ failure. One of the emerging therapies to combat ischemic reperfusion injury complications is hydrogen sulfide, which is a gasotransmitter that diffuses across cell membranes to exert effects on various signaling pathways regulating cell survival such as Akt, mitochondrial activity, and apoptosis. Although commonly thought of as a toxic gas, low concentrations of hydrogen sulfide have been shown to be beneficial in promoting tissue survival post-ischemia, and modulate a wide variety of cellular responses. This review will detail the mechanisms of hydrogen sulfide in affecting the Akt signaling pathway, mitochondrial function, and apoptosis, particularly in regards to ischemic reperfusion injury in muscle tissue. It will conclude with potential clinical applications of hydrogen sulfide, combinations with other therapies, and perspectives for future studies. [ABSTRACT FROM AUTHOR]