Potential interaction of inflammatory hyperemia and hyperphosphatemia in tumorigenesis.

The present article proposes that the association of inflammation with cancer is potentially mediated by the interaction of inflammatory hyperemia and hyperphosphatemia. Hyperemia increases blood flow rate and blood volume, and hyperphosphatemia is caused by elevated serum levels of dysregulated inorganic phosphate. It is hypothesized that the interaction of inflammatory hyperemia and hyperphosphatemia circulates increased amounts of inorganic phosphate to the tumor microenvironment, where increased uptake of inorganic phosphate through sodium-phosphate cotransporters is sequestered in cells. Elevated levels of intracellular phosphorus increase biosynthesis of ribosomal RNA, leading to increased protein synthesis that supports tumor growth. The present article also proposes that the interaction of inflammatory hyperemia and hyperphosphatemia may help explain a chemopreventive mechanism associated with NSAIDs.

Post-occlusive reactive hyperaemia (POHR) in systemic sclerosis: very early disease (VEDOSS) represents a separate entity compared to established disease.

OBJECTIVES: Vascular involvement is a key feature of systemic sclerosis (SSc). Vascular changes are central to the pathogenesis of the disease and the assessment of vascular involvement has a prognostic value. This assessment therefore has a pivotal role in the management of SSc patients. The aim of our study was to evaluate post-occlusive reactive hyperaemia (PORH) in consecutive SSc patients and to test whether a PORH test might be a useful tool for the early diagnosis of SSc. METHOD: Between April 2011 and April 2015, 60 consecutive SSc patients (mean age 56 ± 15 years, females:males = 18:1) were enrolled in the study. The patients were divided into those with full-blown SSc (n = 50) and those with very early diagnosis of SSc (VEDOSS) (n = 10) according to the literature. Laser speckle contrast analysis (LASCA) was used to assess PORH. RESULTS: A statistically significant difference was detected in the post-ischaemic hyperaemic peak flow between VEDOSS and established SSc (424% vs. 137%, p = 0.0011). PORH peak flow decreased according to the capillaroscopic pattern (early = 419%, active = 163%, late = 145%, p = 0.0027). Moreover, a correlation between capillary density and peak flow was revealed (rho = 0.33, p < 0.01). CONCLUSIONS: These data show a different pattern of vascular involvement in VEDOSS compared to established disease that mirrors capillaroscopic changes. Functional features of very early and established disease seem to be the physiological counterpart of abnormalities detected by capillaroscopy. The POHR test might be a useful aid for further characterization of vascular involvement in SSc. In particular, blunted POHR might prove a tool to separate pre-clinical from full-blown SSc.

A desensitization method to maintain enzyme replacement therapy in mucopolysaccharidosis type VI

No disponible

Digitally Analyzed Conjunctival Redness: Does Repeated Conjunctival Provocation Intrinsically Cause Local Desensitization of the Eye?

BACKGROUND: Allergic reactions in patients with seasonal or perennial rhinoconjunctivitis mediated by airborne allergens can be effectively assessed with the conjunctival provocation test (CPT). The CPT is a fast and easy diagnostic procedure that challenges the ocular mucosa with instillations of allergen solutions into the conjunctival region. This paper aimed to investigate the possible influence of repeated diagnostic CPT procedures on the patient's clinical presentation, i.e. to analyze desensitization effects caused by diagnostic solutions and to show the reproducibility of CPT results. METHODS: Treatment progress in 120 placebo-treated patients from 2 immunotherapeutic dose-finding studies was estimated and documented, as based on the CPT which was applied at 4 visits with intervals of 4, 8 and 16 weeks. High-resolution digital photos collected as part of the CPT documentation were analyzed by an external observer and by digital analysis software to determine conjunctival redness, completely independent of the subjectivity of investigators and patients. RESULTS: Two extremal scenarios of the redness changes were considered after provocation with 10,000 standard quality units/ml. A maximal decrease of about 3% (t test: p = 0.0002; U test: p = 0.001) and a minimal decrease of about 1% (t test: p = 0.254; U test: p = 0.431) were found. CONCLUSIONS: The observed decrease in conjunctival hyperemia can be explained by local desensitization or by placebo effect. Due to the setup of both studies considered, we could not ascertain how these factors influence the decrease in redness. In order to attribute the observed effects to local conjunctival desensitization with certainty, further pilot studies are needed.

Dietary intake of advanced glycation end products did not affect endothelial function and inflammation in healthy adults in a randomized controlled trial.

When food is heated to high temperatures, the characteristic "browning" generates advanced glycation end products (AGEs). AGEs are associated with an increased risk of cardiovascular disease, diabetes, and other adverse outcomes. Whether dietary AGEs are absorbed and are harmful to human health remains highly controversial. The objective of this study was to compare the effects of a diet high or low in AGEs on endothelial function, circulating AGEs, inflammatory mediators, and circulating receptors for AGEs in healthy adults. A randomized, parallel-arm, controlled dietary intervention was conducted for 6 wk with 24 healthy adults, aged 50-69 y, that compared isocaloric, food-equivalent diets that were prepared at either high or mild temperatures. Peripheral arterial tonometry, serum and urine carboxymethyl-lysine (CML), inflammatory mediators (interleukin-6, C-reactive protein, vascular adhesion molecule-1, and tumor necrosis factor-α receptors I and II), soluble receptor for AGEs, and endogenous secretory receptor for AGEs were measured at baseline and after 6 wk of dietary intervention. In the low-AGE diet group, the following changed from baseline to 6 wk (mean ± SE): serum CML from 763 ± 24 to 679 ± 29 ng/mL (P = 0.03) and urine CML from 1.37 ± 1.47 to 0.77 ± 2.01 µg/mL creatinine (P = 0.02). There were no significant changes in serum and urinary CML concentrations from baseline to follow-up in the high-AGE diet group. A high- or low-AGE diet had no significant impact on peripheral arterial tonometry or any inflammatory mediators after 6 wk of dietary intervention. In healthy middle-aged to older adults, consumption of a diet high or low in AGEs for 6 wk had no impact on endothelial function and inflammatory mediators, 2 precursors of cardiovascular disease.

Image analyses of the kinetic changes of conjunctival hyperemia in histamine-induced conjunctivitis in Guinea pigs.

BACKGROUND: Conjunctival hyperemia is the most common finding in patients with allergic conjunctivitis. Histamine is a typical chemical mediator involved in allergic conjunctivitis and induces hyperemia. Here, we investigated the kinetic changes in bulbar hyperemia induced by histamine in eyedrops. METHODS: Male guinea pigs were challenged with histamine in eyedrops. Bulbar conjunctival images were taken every 10 seconds by a digital camera up to 8 minutes after histamine challenge, and the software program ImageJ was used to analyze the images. Images were binarized, and a region of interest unobscured by corneal and scleral vessels was selected as the evaluation area. Evaluations were carried out before and after histamine challenge by counting the numbers of absolute pixel values, percent changes in pixels, or the fractal dimension in acquired images. RESULTS: After histamine challenge, the conjunctival vessel area continued to increase up to 5 minutes before stabilizing. The various parameters used to evaluate the images (numbers of absolute pixel values, percent change in pixels, or the fractal dimensions) markedly increased 1 minute after histamine challenge, gradually increased up to 5 minutes, and then gradually decreased before reaching a level that remained significantly higher than that before histamine challenge. CONCLUSIONS: This is the first report to quantitatively evaluate bulbar hyperemia induced by histamine using image analysis. The development of software that can automatically yield meaningful values for hyperemia from hyperemia images will be a useful objective tool in clinical trials for evaluation of drug effects in animal models and in humans.

[Endothelial dysfunction development in miners].

The authors studied vascular endothelium state in coal miners. Findings are lower endothelium-dependent and endothelium-independent vasodilatation, dysbalance of humoral markers--that prove endothelial dysfunction development and remodelling of vascular wall.

Protease-activated receptor 2 mediates the proinflammatory effects of synovial mast cells.

OBJECTIVE: Mast cells are hypothesized to play a role in the pathogenesis of rheumatoid arthritis (RA) by mechanisms requiring elucidation. Tryptase released from these cells can activate protease-activated receptor 2 (PAR-2), which was recently shown to have proinflammatory actions. The purpose of this study was to examine the relationship between synovial mast cells and PAR-2. Mast cell proximity to PAR-2-expressing cells was investigated in RA synovium. In murine studies, we assessed the capacity of mast cell tryptase to mediate synovial proinflammatory responses via PAR-2 and whether degranulating mast cells induced synovial hyperemia by PAR-2 activation. METHODS: RA synovial tissue was examined by immunohistochemistry. PAR-2(+/+) and PAR-2(-/-) C57BL/6J mice were used to investigate the PAR-2 dependence of compound 48/80-induced synovial hyperemia, as measured by laser Doppler imaging, and joint swelling and hyperemic responses to recombinant human beta-tryptase. RESULTS: Mast cells and synovial lining cells staining for PAR-2 were colocalized in RA articular tissue. Compound 48/80 administration resulted in vasodilatation in PAR-2(+/+) mice but not in PAR-2(-/-) mice, which showed a vasoconstrictor response. Eliminating the 5-hydroxytryptamine-mediated component of this response with methysergide unveiled an enhanced PAR-2-mediated vasodilatation to compound 48/80 in PAR-2(+/+) mice and ablated the vasoconstrictor response in PAR-2(-/-) mice. Treatment with beta-tryptase resulted in dose-dependent knee joint swelling and synovial vasodilatation in PAR-2(+/+) mice but not PAR-2(-/-) mice. CONCLUSION: This in vivo study is the first to explore the relationship between synovial mast cells and PAR-2. Our results support the hypothesis that mast cells contribute to the pathogenesis of inflammatory arthritis through PAR-2 activation via release of mast cell tryptase.

Pro-inflammatory cytokines and endothelium-dependent vasodilation in the forearm. Serial assessment in patients with congestive heart failure.

BACKGROUND: In patients with heart failure endothelium-dependent vasodilation of the forearm conduit vessels is impaired possibly because of elevated plasma levels of pro-inflammatory cytokines. The effect of elevated plasma cytokines on endothelium-dependent vasodilation of forearm conduit vessels was therefore serially investigated in 16 patients with congestive heart failure during an episode of acute failure and at the time of recompensation. METHODS AND RESULTS: Pro-inflammatory cytokine levels and hyperaemic brachial artery diameters were obtained shortly after admission for an episode of acute heart failure and 11 +/- 3 days later at the time of recompensation, which was obtained using diuretic therapy without changing other cardiovascular medications. Serum concentrations (Mean +/- SD) of tumour necrosis factor alpha (TNF-alpha) (decompensation vs recompensation: 25 +/- 23 pg.ml-1 vs 26 +/- 17 pg.ml-1) and interleukine 6 (IL-6) (decompensation vs recompensation: 27 +/- 24 pg.ml-1 vs 20 +/- 18 pg.ml-1), determined in venous blood using immunoradiometric assays were elevated but remained unaltered following recompensation. Brachial artery diameter, derived from high-resolution ultrasound scans at rest and during reactive hyperaemia, 90 s after forearm cuff deflation, increased significantly during reactive hyperaemia at the time of admission (3.4 +/- 0.7 mm vs 4.0 +/- 0.5 mm; P = 0.014) and following recompensation (3.4 +/- 0.5 mm vs 3.8 +/- 0.2 mm; P = 0.032). The brachial artery diameter during recompensation expressed as a percentage of the baseline value was similar at both intervals (decompensation vs recompensation: 117 +/- 14% vs 116 +/- 10%; P = ns). At the time of decompensation, the correlation between TNF-alpha and the percentage change in brachial artery diameter following reactive hyperaemia was absent (r = 0.098; P = 0.719). The same correlation became significant at the time of recompensation (r = 0.750; P = 0.001). CONCLUSIONS: In patients with congestive heart failure, plasma levels of pro-inflammatory cytokines correlate with endothelium-dependent vasodilation of the brachial artery following recompensation, but not during an acute episode of heart failure.

Human in vivo cutaneous microdialysis: estimation of histamine release in cold urticaria.

A novel bioanalytical in vivo sampling technique, cutaneous microdialysis, was used to follow the chronology of skin histamine release in 3 patients with cold urticaria and in 2 healthy volunteers. Laser Doppler perfusion imaging was used simultaneously to monitor the skin circulatory response. Microdialysis samples were collected at 10-min intervals and analysed by radioimmunoassay technique. Fifty minutes after probe insertion, the ventral forearm skin in the area of the dialysis membrane was provoked for 5-15 min with a 25 x 40 mm ice cube covered with plastic foil. In the cold urticaria patients, an up to 80-fold increase of histamine was observed, with peak levels 20-30 min after challenge. Histamine levels then fell to reach "baseline" levels within 50 min. In the healthy subjects, the histamine increase was earlier, less pronounced and of shorter duration. Cutaneous microdialysis and laser Doppler imaging offer new possibilities for the chronological multiparameter assessment of inflammatory skin disorders in vivo.

Immunoglobulin and haematocrit values of dental pulp showing hyperaemia and acute serious pulpitis.

In this study, we examined how the pulpal immune systems differ in children who suffer from hyperaemia and acute serous pulpitis. The Radial Immune Diffusion (RID) method was used to measure the IgA, IgG and IgM levels in pulpal blood in hyperaemia and acute serous pulpitis cases. The patient's own peripheral blood was used as the control group. The peripheral blood was taken with a capillary tube from the finger tip. The immunoglobulins and the Htc values of the blood were measured by the radial immune diffusion method. In our research, the immunoglobulin and hematocrit values of the blood (pulpal and peripheral) of 39 patients between the ages 6 to 13 years were measured. No significant difference was found between the IgA, IgG and IgM levels of pulpal and peripheral blood in hyperaemia and acute serous pulpitis cases. In the same patients, a significant difference was noted between the Htc values of the pulpal and peripheral blood.

[Stimulation of the transient endogenous spleen colony formation in normal mice and in plethoric mice infected with Mycoplasma arthritidis]. / Stimuliatsiia obrazovaniia tranzitornykh éndogennykh kolonii v selezenke normal'nykh i pletoricheskikh myshei, infitsirovannykh Mycoplasma arthritidis.

The number of transient endogenous spleen colonies (TEC) formed on days 4-6 postirradiation was found to be greatly increased in mice inoculated with M. arthritidis 1 day prior to sublethal irradiation. In irradiated plethoric mice, TEC formation was reduced (about 10-fold), but preinfection with M. arthritidis reversed the effect of plethora, and TEC formation in infected plethoric mice was almost as high as in infected normal mice. An abortive wave of 59Fe uptake was revealed as early as 5-6 days postirradiation in the spleen of control and infected mice. At day 6 a similar transient peak of erythropoiesis was observed in the marrow of mice infected with M. arthritidis. The data attest to the possible existence of the erythropoietin-independent mechanisms of the mycoplasma-induced activation of transient endogenous colony-forming units. The latter may play a major role in the development of various impairments of hematopoiesis and immune reactivity, which were often observed in mice infected either with mycoplasma or dually infected with mycoplasma and virus species.

Pathways to inflammation induced by immune complexes: development of the Arthus reaction.

The changes associated with inflammation induced by immune complexes (reversed passive Arthus reaction induced with egg albumin-anti-egg albumin) were quantitated and the kinetics of the various vascular phenomena were ascertained. Hyperemia, increase in vascular permeability, platelet accumulation, and polymorphonuclear (PMN) leukocyte accumulation occurred relatively early after induction of the inflammatory lesions, and peaked in 2-4 h. Hemorrhage peaked in 6-h-old lesions. Morphological studies confirmed that almost all infiltrating cells were PMN leukocytes and immunofluorescent tracer studies showed immune complexes in vessel walls as early as 15 min after i.v. injection of the fluoresceinated antigen and the intradermal injection of antibody. By 8 h the progression of the lesions had subsided and by 24 h there were signs of resolution. A pathway for the development of the inflammatory lesions induced with immune complexes is proposed.

The appearance and significance of phospholipase A2 in lymph draining tuberculin reactions.

Popliteal and prefemoral lymphatics of sheep were cannulated, and lymph was collected before and during the course of responses to PPD and concanavalin A. Hyperemia-inducing activity (HIA) and phospholipase A2 (PLA2) were released into lymph in response to antigenic stimulation, whereas lymph plasma draining unstimulated lymph nodes had consistently little or no detectable HIA and PLA2 activity. HIA appeared in the lymph efferent to the stimulated node at a time when blood flow to the responding node was enhanced. While the appearance of HIA did not directly correlate with changes in lymphocyte output, lymph protein concentration, or lymph flow rates, there was, however, a statistically significant correlation between HIA and PLA2 levels in lymph plasma, suggesting that extracellular PLA2 may contribute to the vasoactivity in lymph and thereby modulate blood flow to areas of antigenic stimulation. Vasoactive lymph, injected into rabbits, induced hyperemia via an indomethacin-sensitive pathway, since the induction of hyperemia was abrogated by pretreatment of injection sites with indomethacin. The extracellular release of PLA2 in response to inflammatory stimuli may represent an amplification mechanism for the generation of high levels of prostaglandins found in lymph draining stimulated nodes.

The role of hyperemia in cellular hypersensitivity reactions.

The three physiological processes vascular permeability, blood flow and lymphocyte migration were all enhanced in tuberculin reactions induced in guinea pigs and sheep and also in normal lymphocyte transfer reactions in sheep. Microspheres labelled with 85Sr were used to measure blood flow to dermal sites and it was found that cellular hypersensitivity reactions had blood flows 7-25 times that of normal skin at the reaction peak. Vascular permeability was measured as an increase in the flow rate of afferent lymph or, in guinea pigs, as the enhanced leakage of intravascular 125I-albumin. When the permeability-inducing peptide bradykinin was injected directly into tuberculin reaction, the resulting permeability was greater than the sum of the tuberculin and bradykinin permeability taken individually and it was concluded that the hyperemia enhanced the permeability-inducing capacity of bradykinin. When the traffic of lymphocytes through hypersensitivity lesions was measured in sheep by cannulating the regional afferent lymph vessels and continuously collecting the lymph, the increase in lymphocyte traffic was of the same order of magnitude as the increase in blood flow. It is suggested than the antigen-induced enhancement of blood flow caused the increase in lymphocyte traffic and that the mechanism was similar to that occurring within lymph nodes during the immune response to all antigens.

Rubeosis iridis generated by insulin hypersensitivity.

There are important similarities between human and experimental monkey rubeosis iridis. We believe that we have developed a useful primate model to study iris neovascularization and that the possible role of immunity to insulin in the pathogenesis of human diabetic rubeosis iridis warrants further detailed consideration.