Dimethyl‐ and monomethylfumarate regulate indoleamine 2,3‐dioxygenase (IDO) activity in human immune cells

Fumaric acid esters (FAEs) are used as an oral treatment for psoriasis. Dimethylfumarate (DMF) and its metabolite monomethylfumarate (MMF) are regarded as the pharmacologically active moieties. Indoleamine 2,3‐dioxygenase (IDO) is the key enzyme for the metabolism of tryptophan. The kynurenine pathway is established as a major regulator of innate and adaptive immunity. Here, we investigated the effect of DMF and MMF on IDO activity and expression in human peripheral blood mononuclear cells (PBMCs). IDO activity was determined by measuring the concentration of kynurenine in the culture medium using a HPLC technique. IDO and kynureninase protein expressions were analysed by Western blot. Our results demonstrated that DMF and MMF dose‐dependently reduced the levels of L‐kynurenine in PBMCs activated by interferon‐γ (IFN‐γ). Furthermore, MMF had an inhibitory effect on IDO activity in vitro with an ED₅₀ of 10 μmol/L, a value within the therapeutic concentration range for this molecule. We also observed that IDO and kynureninase expressions were reduced in PBMCs in a dose‐dependent manner by DMF and MMF. The results of our study show that DMF and MMF (in therapeutic concentrations) inhibited IDO and kynureninase activity and expression in a NF‐κB‐dependent manner in PBMCs while also decreasing the level of L‐kynurenine in these cells. As we found that FAEs inhibit both IDO expression and enzymatic activity leading to a modulation of tryptophan degradation, we believe this effect may contribute to the clinical efficacy of this drug in psoriasis by downregulating pro‐inflammatory mediators generated by the kynurenine pathway.     

Assessment of the Root Canal Similarity in Contralateral Mandibular Incisors

IntroductionThe purpose of this study was to determine the degree of similarity between contralateral mandibular incisors utilising 3-dimensional (3D) models obtained from micro-computed tomographic (micro-CT) scans of extracted human teeth. The null hypothesis was that contralateral mandibular incisors do not exhibit matching symmetry.MethodsSixty pairs (n = 120) of extracted mandibular incisors were obtained from 30 patients and scanned with micro-CT with a voxel size of 15.0 μm. 3D virtual models of the pulpal cavities were rendered. Geometric morphometric deviation analysis was performed after mirroring, automatic alignment, and co-registration of the models of contralateral teeth root mean square (RMS) errors were calculated. The quantitative analysis of the 3D models included 6 different geometric parameters. Data sets were examined with a 2-sample Kolmogorov–Smirnov test. Post hoc retrospective power analysis was performed to find statistical power (α = 0.05).ResultsContralateral pairs had a narrower distribution in deviation than random pairs. Also, contralateral pairs showed a statistically higher similarity coefficient (5 out of 6 geometric parameters) compared to random pairs (P < .001); no difference was found when comparing central to lateral pairs or between Vertucci type I configurations compared to non-type I. RMS errors had significantly lower Contralateral premolars (CPs) values than random pairs (P < .001).ConclusionsA high degree of similarity was demonstrated for pairing contralateral mandibular incisors using 3D models. The similarity between contralateral central and lateral incisors suggests that when screened and matched, these 4 teeth might be used in endodontic research where similar root canal anatomy is crucial.     

Effects of G-CSF treatment on neutrophil mobilization and neurological outcome after transient focal ischemia

Several recent studies demonstrated beneficial effects of G-CSF treatment (granulocyte colony-stimulating factor) in various CNS disease. Possible mechanisms underlying this activity are neuroprotection, anti-apoptosis, angiogenesis and anti-inflammation. Hence, we investigated the efficacy of G-CSF administration in experimental stroke by determining infarct volume and neurological score in wildtype, G-CSF-deficient and G-CSF-treated G-CSF-deficient mice. Besides, cerebral ischemia is followed by an upregulation of endothelial adhesion molecules which promote leukocyte recruitment to the injured area. In combination with G-CSF-induced leukocytosis, increased peripheral neutrophils could aggregate within microvasculature and additionally impair blood perfusion of the ischemic tissue. Therefore, we analyzed the neutrophil counts in both vessel and tissue compartment 2 and 5 days post-stroke by immunohistochemistry.Here we show that G-CSF deficiency leads to increased infarct volumes, whereas G-CSF substitution revokes detrimental effects by reducing lesion size and enhancing neurological outcome compared to untreated animals. Administration of G-CSF is accompanied by significant increase of circulating neutrophils 2 days post-ischemia but leukocytosis is restricted to the vessel compartment and has no deleterious effect on lesion formation and functional recovery. These observations are likely to be important for therapeutic targeting of G-CSF-mediated neuroprotection in stroke.     

Why women douche and why they may or may not stop

BACKGROUND: Although douching is common, it is a potentially harmful habit. GOAL: We studied attitudes and knowledge around the behavior of douching. STUDY DESIGN: Of 1,200 women enrolled in this multisite study, 532 douched and answered questions on a structured interview regarding douching behaviors. RESULTS: Over half had douched for 5 or more years. Douching was most often initiated on the recommendation of female relatives and practiced for reasons of hygiene. Half of women considered douching to be healthy. Those who considered douching to be unhealthy reported that douching may disrupt vaginal flora but did not cite more serious risks. Nonetheless, women who had been advised by a health professional to stop douching were less likely to consider douching healthful and were more likely to have tried to stop. CONCLUSION: Women had a limited understanding of potential adverse health consequences associated with douching. Targeted health messages may influence women to initiate douching cessation.     

Inhibition of iNOS with S-methylisothiourea was impaired in wound healing in caustic esophageal burn

OBJECTIVE: Stricture formation is a late complication of caustic esophageal burn, which is a common problem in childhood. For this reason, this experimental study was designed to observe the possible effect of nitric oxide on healing and fibrosis formation in caustic esophageal burns. MATERIALS AND METHODS: The rats were divided into five groups. Group A (n=12) received sham burn and treatment with saline injection. Group B (n=34) received caustic burn. Rats in group C (n=31), were given water supplement with 10 g/L L-arginine that was started 24 h preoperatively and continued until postoperative day 4. In group D (n=21), S-methylisothiourea (SMT, specific inducible nitric oxide synthase (iNOS) inhibitor), was injected at a dose of 3 mg/kg i.p. at 30 min before caustic burn, and similar dose was reinjected immediately after caustic burn. SMT 6 mg/kg/day injections continued for 4 days long. In group E (n=22), Nomega-nitro-L-arginine (L-NNA, nonspecific nitric oxide synthase (NOS) inhibitor) was injected at a dose of 15 mg/kg i.p. at 30 min before caustic burn, and similar dose was reinjected immediately after caustic burn. L-NNA 30 mg/kg/day continues for 4 days. RESULTS: Dead rates were significantly higher in group E than in groups A-D. The mean hydroxyproline levels in esophageal tissue were significantly lower in groups A and B than in group D. Histopathologically, tissue damage scores in the esophageal tissue were higher in group D than in groups A-C. CONCLUSIONS: Inhibition of iNOS with SMT was impaired in wound healing due to caustic esophageal burn and provoked collagen accumulation at a later period. Those effects may due to inhibition of antioxidant, immunomodulatory and antifibrotic effects of NO.     

Lack of Chlamydophila pneumoniae and predominance of Alloiococcus otitidis in middle ear fluids of children with otitis media with effusion

Objective

To investigate the presence of Chlamydophila pneumoniae and other bacterial pathogens in middle ear effusion samples obtained from children with otitis media with effusion (OME).

Materials and methods

Twenty-eight children (mean age 7.03; standard deviation 2.18) with OME unresponsive to medical therapy were included in the study. All of the children underwent ventilation tube insertion under general anesthesia. Eighteen patients were bilaterally affected whereas 10 children had unilateral disease. The middle ear fluids (46 samples in total) were collected during ventilation tube insertion, and were evaluated subsequently for the presence of C. pneumoniae and other bacterial pathogens using polymerase chain reaction (PCR).

Results

Although all samples were negative for C. pneumoniae, bacterial DNA was detected in 21 of 46 samples. Overall 40% of the patients (4/10) with unilateral involvement, and 61% of the patients (11/18) with bilateral involvement were positive for bacterial DNA. In 6 patients with bilateral OME bilateral samples were positive, whereas 5 patients with bilateral OME showed only unilateral positivity. According to the results of DNA sequencing analysis, all of the positive samples harbored only one bacterial species. In 12 of 46 samples Alloiococcus otitidis DNA (26%), in 7 Haemophilus influenzae DNA (15%), in one Streptoccoccus pneumoniae DNA (2%) and in one Moraxella catarrhalis DNA (2%) were present.

Conclusions

Our findings support that C. pneumoniae does not seem to have a role in OME in children whereas A. otitidis was found to be more frequent than the other common pathogens. Further studies are required to elucidate the exact pathogenetic role of these microorganisms in OME.     

Determinants and consequences of sexual networks as they affect the spread of sexually transmitted infections

Because pathogens spread only within the unique context of a sexual union between people when one person is infectious, the other is susceptible to new infection, and condoms are not used to prevent transmission, the epidemiological study of sexually transmitted infections (STIs) is particularly challenging. Social network analysis entails the study of ties among people and how the structure and quality of such ties affect individuals and overall group dynamics. Although ascertaining complete sexual networks is difficult, application of this approach has provided unique insights into the spread of STIs that traditional individual-based epidemiological methods do not capture. This article provides a brief background on the design and assessments of studies of social networks, to illustrate how these methods have been applied to understanding the distribution of STIs, to inform the development of interventions for STI control.