Nitric oxide mediates intestinal hyperaemic responses to intraluminal bile-oleate

It has long been recognized that intestinal blood flow increases at mealtimes. Mesenteric hyperaemia is also evoked by activation of sensory peptidergic nerves. Our studies explored the possible role of endogenous nitric oxide (NO) in the rat intestinal vasodilator response to luminal instillation of an oleic acid plus bile mixture before and after acute intrajejunal instillation of capsaicin and after chronic pretreatment with capsaicin. In anaesthetized rats we measured jejunal blood flow (BF) with an ultrasonic Doppler flowmeter and systemic arterial pressure (AP) with a pressure transducer. Intestinal perfusion with 80 mM oleic acid in bile increased BF by 98±12%. Instillation of 4 mg of capsaicin into the jejunal lumen initially increased BF by 42±9% but was followed by vasoconstriction. Inhibition of NO synthase with 25 mg/kg i.v. N-nitro-L-arginine (L-NNA) decreased BF by 27±5% and increased AP by 37±11%. After treatment with L-NNA and after acute and chronic administration of capsaicin, the bile-oleate-induced maximal increases in BF above control levels were 42±7%, 65±12%, and 58±8%, respectively. The observed inhibitory effect of L-NNA on the intestinal hyperaemic response to the bile-oleate mixture was reversed by pretreatment with L-arginine (100 mg/kg i.V.). In capsaicin pretreated rats the subsequent bile-oleate-induced hyperaemia was reduced in magnitude but the inhibitory effects of L-NNA were proportionately the same as in animals not receiving capsaicin. These findings support the hypothesis that NO is involved with bile-oleate-induced mesenteric hyperaemia.     

Grass pollen immunotherapy: symptomatic improvement correlates with reductions in eosinophils and IL-5 mRNA expression in the nasal mucosa during the pollen season

BACKGROUND: Tissue eosinophilia and infiltration by T(H)2-type T cells are characteristic features of allergic rhinitis both after allergen challenge and during natural allergen exposure. Specific immunotherapy inhibits allergen-induced nasal eosinophilia. OBJECTIVES: We sought to assess, in the context of a randomized trial, the relationships between symptomatic improvement after immunotherapy and eosinophil numbers and IL-5 expression in the nasal mucosa during the pollen season. METHODS: Nasal biopsy specimens were taken from 37 adults with severe summer hay fever at baseline (out of season) and at peak season after 2 years of treatment with a depot grass pollen extract or placebo. Biopsy specimens were processed for immunohistochemistry by using mAbs against eosinophils (EG2), T cells (CD3), and IL-2 receptor-positive cells (CD25), as well as for in situ hybridization by using a sulfur 35-labeled antisense riboprobe directed against IL-5. RESULTS: Immunotherapy significantly reduced symptoms (49%, P =.01) and medication requirements (80%, P =.007) compared with placebo. There was a 400% increase (P =.004) in eosinophils during the pollen season in placebo-treated patients, which was inhibited in the immunotherapy group (20% increase, P =.04 between groups). Seasonal increases were also observed for CD25(+) cells (P =.002), CD3(+) cells (P =.02), and IL-5 mRNA-expressing cells (P =.03) in the placebo group but not in the immunotherapy group. A significant correlation was observed between eosinophils and IL-5 expression (r = 0.5, P <.05). Both eosinophils (r = 0.6, P <.02) and IL-5 (r = 0.6, P <.02) correlated with symptoms after immunotherapy. CONCLUSION: Improvement in symptoms after grass pollen immunotherapy may result, at least in part, from inhibition of IL-5-dependent tissue eosinophilia during the pollen season.     

Efficacy response of inhaled beclomethasone dipropionate in asthma is proportional to dose and is improved by formulation with a new propellant

BACKGROUND: This study tested the hypothesis that there would be improved asthma control with increasing doses of beclomethasone dipropionate (BDP) formulated in hydrofluoroalkane-134a (HFA-BDP) and the standard chlorofluorocarbon propellants (CFC-BDP). Because HFA-BDP has improved lung deposition compared with CFC-BDP, this study also tested the hypothesis that HFA-BDP would provide more effective control of asthma than CFC-BDP. METHODS: In this multicenter, randomized, parallel-group blinded study, asthmatic subjects who had deterioration in asthma control after discontinuation of inhaled corticosteroids were randomized to receive one of 6 possible treatments: 100 microg/d, 400 microg/d, or 800 microg/d of HFA-BDP or 100 microg/d, 400 microg/d, or 800 microg/d of CFC-BDP for 6 weeks. Changes in spirometry, daytime asthma symptom and nighttime asthma-related sleep disturbance scores, morning and evening peak expiratory flows, and daily use of inhaled beta-agonist for symptom control on diary cards were assessed over 6 weeks of treatment. RESULTS: Three hundred twenty-three patients were randomized to the 6 treatment groups, which had similar demographics and baseline lung function. There were significantly larger changes from baseline at week 6 in FEV(1) percent predicted with increasing doses of both HFA-BDP and CFC-BDP. The FEV(1) percent predicted dose-response curve for HFA-BDP was shifted to the left compared with the dose-response curve for CFC-BDP. By using the Finney bioassay method, it was calculated that 2.6 times as much CFC-BDP would be required to achieve the same improvement in FEV(1) percent predicted as HFA-BDP (95% confidence interval, 1.1-11.6). All treatment groups except the 100 microg/d CFC-BDP group tolerated study drug well. Ten (17%) of 59 patients in this group reported an acute asthma episode, increased asthma symptoms (6 of the 8 reports of increased asthma symptoms were classified as severe), or both, and 8 patients withdrew from the study (3 for adverse events related to asthma). CONCLUSIONS: Increasing doses of inhaled corticosteroids lead to improved lung function and asthma control. Moreover, the reformulation of BDP in HFA enables effective asthma control at much lower doses than CFC-BDP.     

Frequency of measles virus-specific CD4+ and CD8+ T cells in subjects seronegative or highly seropositive for measles vaccine

The protective effect of measles immunization is due to humoral and cell-mediated immune responses. Little is known about cell-mediated immunity (CMI) to measles vaccine virus, the relative contribution of CD4(+) and CD8(+) T cells to variability in such immune responses, and the immunologic longevity of the CMI after measles vaccination in humans. Our study characterizes cellular immune response in subjects seronegative or highly seropositive for measles vaccine immunoglobulin G-specific antibody, aged 15 to 25 years, previously immunized with two doses of measles-mumps-rubella II vaccine. We evaluated the ability of subjects to respond to measles vaccine virus by measuring measles virus-specific T-cell proliferation. We examined the frequencies of measles virus-specific memory Th1 and Th2 cells by an ELISPOT assay. Our results demonstrated that proliferation of T cells in seronegative subjects was significantly lower than that for highly seropositive subjects (P = 0.003). Gamma interferon (IFN-gamma) secretion predominated over interleukin 4 (IL-4) secretion in response to measles virus in both groups. The median frequency of measles virus-reactive CD8(+) T cells secreting IFN-gamma was 0.09% in seronegative subjects and 0.43% in highly seropositive subjects (P = 0.04). The median frequency of CD4(+) T cells secreting IL-4 in response to measles virus was 0.03% in seronegative subjects and 0.09% in highly seropositive subjects (P = 0.005). These data confirm the presence of measles virus-specific cellular immune responses post-measles vaccine immunization in humans. The detection of measles virus-induced IFN-gamma and IL-4 production by ELISPOT can be used to identify measles virus-specific low-frequency memory T cells in subjects immunized with measles vaccine. These differences agree in directionality with the observed antibody response phenotype.     

Leishmaniasis in the Jordan Valley: differential attraction of dispersing and breeding site populations of Phlebotomus papatasi (Diptera: Psychodidae) to manure and water

The response of Phlebotomus papatasi Scopoli to traps baited with manure or water was used to compare the behavior of flies near rodent burrows (breeding sites) and dispersing flies in fallow fields. The degree of response in each biotype was defined for each bait by the difference between catches in baited and unbaited traps. Manure bait attracted twice as many flies near the burrows and 2.7 times more flies in the field compared with unbaited traps. In both locations, the manure bait increased the capture of males and nongravid females, whereas gravid females were attracted only near burrows and not in the fields. The catch in the fields with water bait was similar to the unbaited control. However, near burrows, water bait captured more males and gravid females, but not nongravid females. These results demonstrate specific behavioral patterns of the dispersing P. papatasi population.     

Nuclear receptor NR2E3 gene mutations distort human retinal laminar architecture and cause an unusual degeneration

Mutations in the nuclear receptor gene, NR2E3, cause a disorder of human retinal photoreceptor development characterized by hyperfunction and excess of the minority S (short wavelength or blue) cone photoreceptor type, but near absence of function of the majority rod receptor. NR2E3 disease can also progress to blindness. How the human retina accommodates mis-specified types and numbers of neurons and advances to retinal degeneration are unknown. We studied the retinal organization in vivo of patients with NR2E3 mutations. Early human NR2E3 disease with S cone hyperfunction showed thickened retinal layers within an otherwise normally structured retina. With visual loss, however, lamination was coarse and there was a strikingly thick and bulging appearance to the retina, localized to an annulus encircling the central fovea. This pattern was not found in other retinal degenerations. The abnormal laminar retinal architecture of early NR2E3 disease may be due in part to larger cells with an S cone phenotype in place of rods that failed to differentiate. The later-stage dysplastic appearance suggests a previously unrecognized proliferative response in human retinal degeneration.     

Neutrophil activation in anti-proteinase 3-positive vasculitis--a prospective study

In vitro studies have demonstrated that antineutrophil cytoplasmic antibodies (ANCA) have the capacity to activate neutrophils. Whether circulating neutrophils in patients with vasculitis are activated is under debate. Eight consecutive patients with antiproteinase 3 (PR3) positive acute vasculitis were included in this prospective study. Neutrophil expression of adhesion molecules, Fc-receptors and the ANCA-antigen PR3 was analysed and clinical characteristics were documented at inclusion and after 1, 3, 6 and 9 months in the same individuals. As additional markers of inflammation and endothelial activation interleukin-8 and soluble vascular cell adhesion molecule-1 in serum were analysed at the same time points. The expression of adhesion molecules on circulating neutrophils, CD62L and CD11b after in vitro N-formyl-methionyl-leucyl-phenylalanine stimulation was significantly decreased at diagnosis and after 1 month but returned to normal levels after 3-9 months. The neutrophil expression of Fc-receptor IIIb (CD 16) was decreased at diagnosis but normalized after 1-9 months. The main finding was an activated neutrophil adhesion phenotype at diagnosis and after 1 month, with normalized expression of adhesion molecules at 3-9 months. A pathological regulation of adhesion molecules may have implications on the endothelial damage seen in vasculitis.     

Mantle cell lymphoma disguised as marginal zone lymphoma

We report a case of mantle cell lymphoma histologically indistinguishable from marginal zone lymphoma. An 83-year-old man presented with a 9.0-cm, slowly enlarging axillary mass. Microscopically, the neoplastic process was largely interfollicular, surrounding residual follicular centers, some of which had discernible small lymphocyte mantles. Overall, the morphologic pattern was highly suggestive of marginal zone lymphoma. However, flow cytometric and immunohistochemical results, including cyclin D1 positivity, revealed an immunophenotype that fit with mantle cell lymphoma. The differential diagnosis of mantle cell lymphoma is broad, and it is well known that mantle cell lymphoma can assume a number of histologic appearances, including, infrequently, that of more indolent B-cell non-Hodgkin lymphomas. Although not pathognomonic, cyclin D1 positivity is highly specific for mantle cell lymphoma and is key in distinguishing these clinically dissimilar malignant lymphomas. In recent years, detection of cyclin D1 has expanded the recognizable histologic spectrum of mantle cell lymphoma.     

Response suppression by extending sine-wave gratings within the receptive fields of neurons in visual cortical area V3A of the macaque monkey

Even though there are many more cycles of the "optimal" grating extending across the receptive fields of cells in V3A than of cells in V1 and V2, the spatial frequency bandwidths in V3A are no narrower than in V1 or V2. Thus, the inputs to V3A cells are not combined in a phase coherent manner across the entire receptive field. Moreover, the defined receptive fields of cells in V3A are generally surrounded by suppressive regions which are, on average, much stronger than those found for neurons in V1 and V2. Even within the classical receptive field, most neurons in V3A respond far more vigorously to a limited patch of a few cycles of a grating at the preferred spatial frequency than to wider grating stimuli. This intra-receptive field suppression demonstrates a new level of response complexity, and suggests that V3A cells may antagonistically combine nonlinear mechanisms that themselves encode stimulus energy over a restricted region of space and spatial-frequency.     

Validation of low-cost models for minimal invasive surgery training of congenital diaphragmatic hernia and esophageal atresia

BackgroundMinimal invasive surgery (MIS) is increasingly used for the correction of congenital diaphragmatic hernia (CDH) and esophageal atresia (EA). It is important to master these complex procedures, preferably preclinically, to avoid complications. The aim of this study was to validate recently developed models to train these MIS procedures preclinically.MethodsTwo low cost, reproducible models (one for CDH and one for EA) were validated during several pediatric surgical conferences and training sessions (January 2017–December 2018), used in either the LaparoscopyBoxx or EoSim simulator. Participants used one or both models and completed a questionnaire regarding their opinion on realism (face validity) and didactic value (content validity), rated on a five-point-Likert scale.ResultsOf all 60 participants enrolled, 44 evaluated the EA model. All items were evaluated as significantly better than neutral, with means ranging from 3.7 to 4.1 (p < 0.001). The CDH model was evaluated by 48 participants. All items scored significantly better than neutral (means 3.5–3.9, p < 0.001), with exception of the haptics of the simulated diaphragm (mean 3.3, p = 0.054). Both models were considered a potent training tool (means 3.9).ConclusionThese readily available and low budget models are considered a valid and potent training tool by both experts and target group participants.Type of studyProspective study.Level of evidenceLevel II.