Management of Uveitis-Related Choroidal Neovascularization: From the Pathogenesis to the Therapy

Inflammatory choroidal neovascularization is a severe but uncommon complication of uveitis, more frequent in posterior uveitis such as punctate inner choroidopathy, multifocal choroiditis, serpiginous choroiditis, and Vogt-Koyanagi-Harada syndrome. Its pathogenesis is supposed to be similar to the wet age related macular degeneration: hypoxia, release of vascular endothelial growth factor, stromal cell derived factor 1-alpha, and other mediators seem to be involved in the uveitis-related choroidal neovascularization. A review on the factors implicated so far in the pathogenesis of inflammatory choroidal neovascularization was performed. Also we reported the success rate of single studies concerning the therapies of choroidal neovascularization secondary to uveitis during the last decade: photodynamic therapy, intravitreal bevacizumab, and intravitreal ranibizumab, besides steroidal and immunosuppressive therapy. Hereby a standardization of the therapeutic approach is proposed

The moderating role of just-in-time on sociotechnical practices' effect over quality and workers' health

Sociotechnical (ST) theory emphasizes the notion that the design and performance of new systems can be improved, and can only work satisfactorily within an organization if the social and the technical aspects are brought together and treated as interdependent aspects of a work system. The implementation of lean manufacturing (LM) principles and practices has become popular, despite increasing demand on the current and emerging workforce to achieve higher levels of quality and flexibility with lower costs. Exploratory studies that investigate how LM practices influence the effect of ST practices on performance are still scarce, and a holistic view of such a relationship is needed. In this context, this study aims at verifying the moderating effect of just-in-time (JIT) practices on the relationship between ST practices and the performance of quality and workers' health. We carried out a survey with 144 different companies from Southern Brazil that are undergoing a lean implementation. Results indicate that ST practices have a positive significant relationship with such performance, and the concurrent adoption of JIT does not undermine quality and workers' health

Bisphosfonate matrix metalloproteinase inhibitors for the treatment of periodontitis: An in vitro study

Periodontitis is an inflammatory disease caused by anaerobic bacteria, including Porphyromonas gingivalis. Lipopolysaccharide (LPS)-stimulated persistent inflammation is responsible for an increase in matrix metalloproteinase (MMP) expression, resulting in periodontal tissue destruction. The aim of the present study was to investigate synthesized bisphosphonic MMP inhibitors, in an in vitro model consisting of human gingival fibroblasts exposed to LPS, and to compare the biological responses to those induced by zoledronate (ZA), a commercial bisphosphonate. MTT and lactate dehydrogenase (LDH) assays were used to measure cell viability and cytotoxicity, respectively. ELISA was performed to evaluate prostaglandin E2 (PGE2), interleukin (IL)6 and collagen secretion, while western blotting was used to analyze MMP expression. No effect on viability and low cytotoxicity were observed following treatment with bisphosphonate compounds. In the present study, treatment with compound 1 did not increase the release of PGE2and IL6. Increased levels of collagen I secretion were reported when compound 3 and ZA were administered. An increase of MMP8 was observed following ZA treatment, while a decrease of MMP9 and MMP14 following treatment with compounds 1, 2 and ZA were reported. The performance of compound 1 was optimal in terms of cell viability. Compound 1 also did not induce inflammation, and had the ability to counteract LPS-induced increases in MMP expression. These data suggested that compound 1 was the most suitable treatment to progress to an in vivo animal study, with the aim to confirm its use for the treatment of periodontitis

Structural basis for PPAR partial or full activation revealed by a novel ligand binding mode

The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors involved in the regulation of the metabolic homeostasis and therefore represent valuable therapeutic targets for the treatment of metabolic diseases. The development of more balanced drugs interacting with PPARs, devoid of the side-effects showed by the currently marketed PPARλ 3 full agonists, is considered the major challenge for the pharmaceutical companies. Here we present a structure-based virtual screening approach that let us identify a novel PPAR pan-agonist with a very attractive activity profile and its crystal structure in the complex with PPARα and PPARλ 3, respectively. In PPARα this ligand occupies a new pocket whose filling is allowed by the ligand-induced switching of the F273 side chain from a closed to an open conformation. The comparison between this pocket and the corresponding cavity in PPARλ 3 provides a rationale for the different activation of the ligand towards PPARα and PPARλ 3, suggesting a novel basis for ligand design

Bone seeking matrix metalloproteinase-2 inhibitors prevent bone metastatic breast cancer growth

Bone metastasis is common during breast cancer progression. Matrix metalloproteinase-2 (MMP-2) is significantly associated with aggressive breast cancer and poorer overall survival. In bone, tumor or host derived MMP-2 contributes to breast cancer growth and does so by processing substrates including type I collagen and transforming growth factorβ (TGFβ) latency proteins. These data provide strong rationale for the application of MMP-2 inhibitors to treat the disease. However, in vivo, MMP-2 is systemically expressed. Therefore, to overcome potential toxicities noted with previous broad-spectrum MMP inhibitors (MMPIs), we used highly selective bisphosphonic based MMP-2 inhibitors (BMMPIs) that allowed for specific bone targeting. In vitro, BMMPIs impacted the viability of breast cancer cell lines and osteoclast precursors but not osteoblasts. In vivo, we demonstrated using two bone metastatic models (PyMT-R221A and 4T1) that BMMPI treatment significantly reduced tumor growth and tumor associated bone destruction. Additionally, BMMPIs are superior in promoting tumor apoptosis compared to the standard of care bisphosphonate, zoledronate. We demonstrated MMP-2 selective inhibition in the bone microenvironment using specific and broad spectrum MMP probes. Further, compared to zoledronate, BMMPI treated mice had significantly lower levels of TGFβ signaling and MMP generated type I collagen carboxy-terminal (ICTP) fragments. Taken together, our data show the feasibility of selective inhibition of MMPs in the bone metastatic breast cancer microenvironment. We posit that BMMPIs could be easily translated to the clinical setting for the treatment of bone metastases given the well-tolerated nature of bisphosphonates

Molecular determinants for the activating/blocking actions of the 2H-1,4-benzoxazine derivatives, a class of potassium channel modulators targeting the skeletal muscle KATP channels

The 2H-1,4-benzoxazine derivatives are modulators of the skeletal muscle ATP-sensitive-K+ channels (KATP), activating it in the presence of ATP but inhibiting it in the absence of nucleotide. To investigate the molecular determinants for the activating/blocking actions of these compounds, novel molecules with different alkyl or aryl-alkyl substitutes at position 2 of the 1,4-benzoxazine ring were prepared. The effects of the lengthening of the alkyl chain and of branched substitutes, as well as of the introduction of aliphatic/aromatic rings on the activity of the molecules, were investigated on the skeletal muscle KATP channels of the rat, in excised-patch experiments, in the presence or absence of internal ATP (10 -4 M). In the presence of ATP, the 2-n-hexyl analog was the most potent activator (DE50 = 1.08 × 10-10 M), whereas the 2-phenylethyl was not effective. The rank order of efficacy of the openers was 2-n-hexyl ≥2-cyclohexylmethyl >2-isopropyl = 2-n-butyl = 2-phenyl ≥ 2-benzyl = 2-isobutyl analogs. In the absence of ATP, the 2-phenyl analog was the most potent inhibitor (IC50 = 2.5 × 10-11 M); the rank order of efficacy of the blockers was 2-phenyl ≥ 2-n-hexyl > 2-n-butyl > 2-cyclohexylmethyl, whereas the 2-phenylethyl, 2-benzyl, and 2-isobutyl 1,4-benzoxazine analogs were not effective; the 2-isopropyl analog activated the KATP channel even in the absence of nucleotide. Therefore, distinct molecular determinants for the activating or blocking actions for these compounds can be found. For example, the replacement of the linear with the branched alkyl substitutes at the position 2 of the 1,4-benzoxazine nucleus determines the molecular switch from blockers to openers. These compounds were 100-fold more potent and effective as openers than other KCO against the muscle KATP channels. Copyright © 2008 The American Society for Pharmacology and Experimental Therapeutics

A systematic literature review on the stochastic analysis of value streams

Value stream analysis is a very useful approach in the identification of non-value adding wastes and developing a systemic plan for achieving process improvement. However, traditional value stream mapping fails in considering the inherent variability of processes, hence reinforcing improvements that might not lead to significant results. In this sense, the uncertainties associated with value streams become an issue that can be curbed with the integration of stochastic methods. By conducting a systematic literature review, this research evaluates the level of integration of stochastic methods into value stream analysis and identifies those stochastic methods that are widely adopted to address uncertainties in the value stream analysis. Results from the review indicate that the application of the existing stochastic methods into value stream analysis is still at its infancy and is not systematically integrated. In addition, the few studies that consider stochasticity of value streams weakly examines the effect that uncertainty sources entail on each other

Patient expression of emotions and neurologist responses in first multiple sclerosis consultations

Background: Anxiety and depression are common in people with multiple sclerosis (MS), but data on emotional communication during MS consultations are lacking. We assessed patient expressions of emotion and neurologist responses during first-ever MS consultations using the Verona Coding Definitions of Emotional Sequences (VR-CoDES). Methods: We applied VR-CoDES to recordings/transcripts of 88 outpatient consultations (10 neurologists, four MS Italian centers). Before consultation, patients completed the Hospital Anxiety and Depression Scale (HADS). Multilevel sequential analysis was performed on the number of cues/concerns expressed by patients, and the proportion of reduce space responses by neurologists. Results: Patients expressed 492 cues and 45 concerns (median 4 cues and 1 concern per consultation). The commonest cues were verbal hints of hidden worries (cue type b, 41%) and references to stressful life events (type d, 26%). Variables independently associated with number of cues/concerns were: anxiety (HADS-Anxiety score >8) (incidence risk ratio, IRR 1.08, 95% CI 1.06-1.09; p <0.001); patient age (IRR 0.98, 95% CI 0.98-0.99; p <0.001); neurologist age (IRR 0.94, 95% CI 0.92-0.96; p=0.03); and second opinion consultation (IRR 0.72, 95% CI 0.60-0.86; p=0.007). Neurologists reacted to patient emotions by reducing space (changing subject, taking no notice, giving medical advice) for 58% of cues and 76% of concerns. Anxiety was the only variable significantly associated with ‘reduce space’ responses (odds ratio 2.17, 95% CI 1.32-3.57; p=0.003). Conclusions: Patient emotional expressions varied widely, but VR-CoDES cues b and d were expressed most often. Patient anxiety was directly associated with emotional expressions; older age of patients and neurologists, and second opinion consultations were inversely associated with patient emotional expression. In over 50% of instances, neurologists responded to these expressions by reducing space, more so in anxious patients. These findings suggest that neurologists need to improve their skills in dealing with patient emotions

Structural nucleotide analogs are potent activators/inhibitors of pancreatic beta-cell KATP channels: an emerging mechanism supporting their use as anti-diabetic drugs.

The 2H-1,4-benzoxazine derivatives are novel drugs structurally similar to nucleotides; however, their actions on the pancreatic beta-cell ATP-sensitive-K(+)(KATP) channel and on glucose disposal are unknown. Therefore, the effects of the linear/branched alkyl substituents and the aliphatic/aromatic rings at position 2 of the 2H-1,4-benzoxazine nucleus on the activity of these molecules against the pancreatic beta-cell KATP channel and the Kir6.2C36 subunit were investigated using a patch-clamp technique. The effects of these compounds on glucose disposal that followed glucose loading by i.p. GTT and on fasted glycemia were investigated in normal mice. The 2-n-hexyl analog blocked the KATP(IC50=10.1x10(-9)M) and Kir6.2C36(IC50=9.6x10(-9)M) channels which induced depolarization. In contrast, the 2-phenyl analog was a potent opener(DE50=0.04x10(-9)M), which induced hyperpolarization. The ranked order of the potency/efficacy of the analog openers was 2-phenyl>2-benzyl>2-cyclohexylmethyl. The 2-phenylethyl and 2-isopropyl analogs were not effective as blockers/openers. The 2-n-hexyl (2-10 mg kg(-1)) and 2-phenyl analogs (2-30 mg kg(-1)) reduced and enhanced the glucose AUC curves, respectively, following the glucose loading in mice. These compounds did not affect the fasted glycemia as is observed with glibenclamide. The linear alkyl chain and the aromatic ring at position 2 of the 1,4-benzoxazine nucleus are the determinants, which respectively confer the KATP channel blocking action with glucose lowering effects and the opening action with increased glucose levels. The opening/blocking actions of these compounds mimic those that were observed with ATP and ADP. The results support the use of these compounds as novel anti-diabetic drugs

In vitro comparison of new bisphosphonic acids and zoledronate effects on human gingival fibroblasts viability, inflammation and matrix turnover

Bisphosphonates (BPs) are well known clinically used drugs, commonly applied to treat osteoclast-mediated bone resorption. Some clinically used BPs were demonstrated to be able to inhibit the activity of matrix metalloproteinases (MMPs) (1), a protease family required to fully degrade all the components of the extracellular matrix during connective tissue remodelling (2). Combining the arylsulfonamide function with the bisphosphonic group, several compounds were synthesized to obtain selective inhibitors of MMPs. The aim of the present work is to compare the effects on cell adhesion, cytotoxicity, inflammatory response occurrence and matrix turnover process in an in vitro model of primary human gingival fibroblasts (HGFs) treated with newly synthesized sulfonamide BPs and with zoledronic acid (ZA), a clinically used drug. Western blot was used to measure Procollagen I, β1 integrin MMP-8 and MMP-9, phase contrast and MTT for cell viability, LDH was performed for toxicity evaluation, ELISA for Prostaglandin E2 (PGE2) secretion assessment. When compared with ZA, the treatment with the newly synthetized compounds shows increasing viability, Procollagen I expression and decreased expression of β1 integrin in HGFs. Higher levels of released LDH, PGE2 and MMP-9 expression are recorded in ZA-treated HGFs. Increased levels of MMP-8 are recorded in newly synthetized compounds-treated samples.These findings imply that new BPs could accelerate the physiological matrix turnover, they are more able to preserve the soft tissue surrounding bone as they have neither inflammatory effects nor toxicity, along with reduced effects on the cell viability, which are instead typical side effects of ZA administration. We can conclude that the newly synthesized compounds are better tolerated, leading to the hypothesis that their use leads to connective tissues side effects reduction compared to clinically used drugs, even though several studies are required to deeply investigate the signaling cascades involved in the mechanism of action of these new BPs