Effects of a dual CCR3 and H1-antagonist on symptoms and eosinophilic inflammation in allergic rhinitis

<p>Abstract</p> <p>Background</p> <p>The CC-chemokine receptor-3 (CCR3) has emerged as a target molecule for pharmacological intervention in allergic inflammation.</p> <p>Objective</p> <p>To examine whether a dual CCR3 and H₁-receptor antagonist (AZD3778) affects allergic inflammation and symptoms in allergic rhinitis.</p> <p>Methods</p> <p>Patients with seasonal allergic rhinitis were subjected to three seven days' allergen challenge series. Treatment with AZD3778 was given in a placebo and antihistamine-controlled design. Symptoms and nasal peak inspiratory flow (PIF) were monitored in the morning, ten minutes post challenge, and in the evening. Nasal lavages were carried out at the end of each challenge series and α₂-macroglobulin, ECP, and tryptase were monitored as indices of allergic inflammation.</p> <p>Results</p> <p>Plasma levels of AZD3778 were stable throughout the treatment series. AZD3778 and the antihistamine (loratadine) reduced rhinitis symptoms recorded ten minutes post challenge during this period. AZD3778, but not the anti-histamine, also improved nasal PIF ten minutes post challenge. Furthermore, scores for morning and evening nasal symptoms from the last five days of the allergen challenge series showed statistically significant reductions for AZD3778, but not for loratadine. ECP was reduced by AZD3778, but not by loratadine.</p> <p>Conclusions</p> <p>AZD3778 exerts anti-eosinophil and symptom-reducing effects in allergic rhinitis and part of this effect can likely be attributed to CCR3-antagonism. The present data are of interest with regard to the potential use of AZD3778 in allergic rhinitis and to the relative importance of eosinophil actions to the symptomatology of allergic rhinitis.</p> <p>Trial registration</p> <p>EudraCT No: 2005-002805-21.</p

Current strategies for treatment of intervertebral disc degeneration: substitution and regeneration possibilities

Background: Intervertebral disc degeneration has an annual worldwide socioeconomic impact masked as low back pain of over 70 billion euros. This disease has a high prevalence over the working age class, which raises the socioeconomic impact over the years. Acute physical trauma or prolonged intervertebral disc mistreatment triggers a biochemical negative tendency of catabolic-anabolic balance that progress to a chronic degeneration disease. Current biomedical treatments are not only ineffective in the long-run, but can also cause degeneration to spread to adjacent intervertebral discs. Regenerative strategies are desperately needed in the clinics, such as: minimal invasive nucleus pulposus or annulus fibrosus treatments, total disc replacement, and cartilaginous endplates decalcification. Main Body: Herein, it is reviewed the state-of-the-art of intervertebral disc regeneration strategies from the perspective of cells, scaffolds, or constructs, including both popular and unique tissue engineering approaches. The premises for cell type and origin selection or even absence of cells is being explored. Choice of several raw materials and scaffold fabrication methods are evaluated. Extensive studies have been developed for fully regeneration of the annulus fibrosus and nucleus pulposus, together or separately, with a long set of different rationales already reported. Recent works show promising biomaterials and processing methods applied to intervertebral disc substitutive or regenerative strategies. Facing the abundance of studies presented in the literature aiming intervertebral disc regeneration it is interesting to observe how cartilaginous endplates have been extensively neglected, being this a major source of nutrients and water supply for the whole disc. Conclusion: Severalinnovative avenues for tackling intervertebral disc degeneration are being reported â from acellular to cellular approaches, but the cartilaginous endplates regeneration strategies remain unaddressed. Interestingly, patient-specific approaches show great promise in respecting patient anatomy and thus allow quicker translation to the clinics in the near future.The authors would like to acknowledge the support provided by the Portuguese Foundation for Science and Technology (FCT) through the project EPIDisc (UTAP-EXPL/BBBECT/0050/2014), funded in the Framework of the “International Collaboratory for Emerging Technologies, CoLab”, UT Austin|Portugal Program. The FCT distinctions attributed to J. Miguel Oliveira (IF/00423/2012 and IF/01285/ 2015) and J. Silva-Correia (IF/00115/2015) under the Investigator FCT program are also greatly acknowledged.info:eu-repo/semantics/publishedVersio

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

The influence of external ultrasound on the histologic architecture of the organic capsule around smooth silicone implants: Experimental study in rats

Background Capsular contracture is the main complication related to breast silicone implants, and its prevention remains a medical challenge. The authors present experimental research examining the effect of external ultrasound on the formation and contracture of peri-implant capsules.Methods In this study, 42 male Wistar rats had a 2-mm smooth surface implant placed in a dorsal submuscular pocket. They then were separated into ultrasound'' and control'' groups that received repeated external applications either with or without the ultrasound power on. Ultrasound applications were given three times a week for a period of 90 days. After that, both groups were housed under the same conditions with no application scheduled. Five animals of each group, killed at 30, 60, 90, and 180 days, had their implants removed along with the capsule, which received a special histologic preparation via annular sectioning that provided wide circumferential observation of the capsular tissue. Sections were stained with hematoxylin/eosin stain, Masson's trichrome stain, and Pricrosirius Red stain for regular microscopic evaluation under normal and polarized light.Results Histologic data showed that capsules from the ultrasound and control groups had statistically significant differences. Ultrasound application developed a capsular architecture similar to that shown within textured silicone implants, and its effect had an early definition with subsequent stabilization.Conclusion The authors conclude that early and repeated external ultrasound application enhances the thickness, cellular count, and vascularity of smooth silicone capsular tissue, whereas it diminishes the pattern of parallel orientation of collagen fibers

The proliferating cell nuclear antigen index in breast carcinomas does not correlate with mitotic index and estrogen receptor immunoreactivity

To investigate the expression of a marker of cell proliferation (PCNA/Cyclin) and its putative relationship with histological grading, mitotic index and estrogen receptor immunoreactivity, we studied twenty-seven cases of invasive breast carcinoma in formalin-fixed, paraffin-embedded tissue sections. The PCNA and estrogen receptor were detected by the PC10 and H222 monoclonal antibodies respectively, using an avidin-biotin-pernxidase method. The median value of PCNA index was 20.9% with a range from 1.4 to 84.2%. We did not find any significant relationship between PCNA index anti the histological grading, mitotic index and estrogen receptor immunoreactivity. We conclude that PCNA detected by the monoclonal antibody PC10 in formalin-fixed material looks at present unrealiable as a proliferation marker in breast carcinoma

In vitro detection of neutralizing antibodies to Chlamydia suis in pig sera.

In this study the in vitro neutralizing activity of 71 swine sera resulted positive by microimmunofluorescence (MIF) test against Chlamydia suis was evaluated. These sera were collected from swine with clinical signs of conjunctivitis or reproductive disorders, reared in different farms in Emilia Romagna (Northern Italy). Neutralizing antibodies specific for C. suis were present in 57 out of the 71 swine sera tested (80.3%), positive by MIF with titres ranging between 32 and 2048. The 82.8% of the 71 swine sera tested presented by MIF titres &#8805; 128. The presence of neutralizing antibodies was significantly correlated (p &lt; 0.001) with MIF titres. All sera (11/11) positive by MIF with titres ranging from 512 and 2048 presented neutralizing antibodies and the 79.2% (42/53) of sera with MIF titres to C. suis ranging from 128 and 256 were neutralizing. Most of the sera presented a complement-dependent neutralizing activity even at a final dilution of 1:40

Increasing effect of high dose of PG-1 peptide on the infectivity of different animal species of Chlamydia.

The modification of infectivity of different animal chlamydial species after their in vitro treatment with 10 and 80 \ub5g/ml of PG-1 peptide, was studied. PG-1 at 10 \ub5g/ml concentration had neither inhibitory nor increasing effects on the infectivity of all Chlamydia tested, whereas the incubation of 80 \ub5g/ml of PG-1 with C. suis and Cp. pecorum isolates resulted in a twofold increase in the number of inclusions; a five- to tenfold increase in chlamydial infectivity was observed when Cp. psittaci and Cp. abortus strains were tested with the concentration of 80 \ub5g/ml of PG-1 peptide. On the contrary, C. muridarum strain and Cp.felis isolates did not show any increase in the number of inclusions when incubated with PG-1 at a 80 \ub5g/ml concentration. The different effect of PG-1 on the animals strains of chlamydiae could be due to the unique characteristics in the membrane structure of each strain

Antibody-neutralizing activity against all urogenital Chlamydia trachomatis serovars in Chlamydia suis-infected pigs.

It is known that neutralizing species-specific or serovar-specific antibodies are produced in response to chlamydial infection in humans and in some animal species. In a previous study, a strong in vitro neutralizing activity to Chlamydia suis in 80% of sera from C. suis-infected pigs had been observed. In view of the close relationship between C. suis and Chlamydia trachomatis, in the present study, the neutralizing activity against D-K C. trachomatis and C. suis purified elementary bodies (EBs) in sera collected from C. trachomatis-infected patients and C. suis infected pigs was evaluated. A neutralizing activity of 50\u201370% was observed in the human sera against the homologous serovar and one to five heterologous C. trachomatis serovars. These sera were also able to neutralize C. suis EBs. The pig sera showed a strong neutralizing activity (70\u2013100%) against C. suis EBs and all eight urogenital C. trachomatis serovars. These results suggested the presence of common immunogenic antigens in C. trachomatis and C. suis. Immunoblot analysis, performed to elucidate the target of this neutralizing activity, showed a clear reactivity in human and pig sera against two proteins of 150 and 40 kDaMW, when tested either with C. trachomatis or with C. suis EBs