The role of endothelial dysfunction in the pathogenesis of impaired diabetic wound healing: A novel therapeutic target?

The global burden of diabetes is attributed to its multiple associated complications including impaired wound healing which can ultimately result in amputation. Peripheral vascular disease, infection, neuropathy and abnormal local cellular and cytokine activity are some of the traditionally cited pathological instigators of defective diabetic wound repair. Despite intensive research and subsequent advances in diabetic wound care technology a single treatment with measurable clinical impact has yet to be determined. The phenomenon of endothelial dysfunction as seen in atherosclerosis and recently identified as a characteristic of diabetic vasculature may contribute to impaired cutaneous healing in this group. Indicators of endothelial dysfunction have been demonstrated in diabetic wounds by a number of investigators. Successful results are being obtained with modifiers of endothelial function in the management of cardiovascular disease. We hypothesise that endothelial dysfunction plays a substantial contributory role in the pathogenesis of wound healing impairment of diabetes and holds potential as a target for therapeutic intervention.     

Endothelial progenitor cell dysfunction in type 1 diabetes: another consequence of oxidative stress?

Endothelial progenitor cells (EPC) have been shown to contribute to neovascularization and vascular maintenance and repair in adults. Recently, the concept has evolved that EPC dysfunction, in patients at risk for cardiovascular disease, may contribute to the development of atherosclerosis and ischemic vascular disease. Particularly, patients with diabetes mellitus are likely to be affected by EPC dysfunction as several studies have shown a reduced number and function of EPC in patients, as well as in preclinical models for type 1 diabetes. Here, we review our current understanding of EPC (dys)function in diabetes and discuss some potential mechanisms underlying their altered properties. Moreover, we provide circumstantial evidence indicating that increased oxidative stress could play a role in the development of EPC dysfunction in type 1 diabetes. Finally, we discuss the potential implication of our findings for EPC-based therapies and the potential impact of pharmacological interventions on the vascular regenerative capacity of EPC.     

Acetylcholine and the alpha 7 nicotinic receptor: a potential therapeutic target for the treatment of periodontal disease?

Objectives

The aim of this review is to examine the evidence for a functional cholinergic system operating within the periodontium and determine the evidence for its role in periodontal immunity.

Introduction

Acetylcholine can influence the immune system via the ‘cholinergic anti-inflammatory pathway’. This pathway is mediated by the vagus nerve which releases acetylcholine to interact with the α7 subunit of the nicotinic acetylcholine receptor (α7nAChR) on proximate immuno-regulatory cells. Activation of the α7nAChR on these cells leads to down-regulated expression of pro-inflammatory mediators and thus regulates localised inflammatory responses. The role of the vagus nerve in periodontal pathophysiology is currently unknown. However, non-neuronal cells can also release acetylcholine and express the α7nAChR; these include keratinocytes, fibroblasts, T cells, B cells and macrophages. Therefore, by both autocrine and paracrine methods non-neuronal acetylcholine can also be hypothesised to modulate the localised immune response.

Methods

A Pubmed database search was performed for studies providing evidence for a functional cholinergic system operating in the periodontium. In addition, literature on the role of the ‘cholinergic anti-inflammatory pathway’ in modulating the immune response was extrapolated to hypothesise that similar mechanisms of immune regulation occur within the periodontium.

Conclusion

The evidence suggests a functional non-neuronal ‘cholinergic anti-inflammatory pathway’ may operate in the periodontium and that this may be targeted therapeutically to treat periodontal disease.     

Does the HBZ gene represent a new potential target for the treatment of adult T-cell leukemia?

Links between human T-cell leukemia virus type 1 and adult T-cell leukemia (ATL) were first suspected in 1980. Provirus integration has since been found in all ATL cells. Although the viral Tax protein is involved in the proliferation of the infected cells during the preleukemic stage, Tax expression is not systematically detected in primary leukemic cells. Recent studies found that the viral HBZ gene was always expressed in leukemic cells, suggesting its involvement in the progression of the infected cells toward malignancy. How could this new discovery be translated into possible new avenues for the prevention or treatment of ATL?     

Airway dysfunction in nasal polyposis: a spectrum of asthmatic disease?

Background Chronic rhinosinusitis with nasal polyposis (CRSwNP) represents an interesting model to investigate the existence of a non‐allergic unified airway. The factors associated with airway dysfunction in CRSwNP are not fully understood. Objective To assess the impact of nasal disease on lower airway dysfunction in CRSwNP. Methods Fifty‐seven patients with CRSwNP underwent spirometry, nasal endoscopy, exhaled nitric oxide, methacholine bronchial challenge, blood sampling for total IgE, eosinophil count and radioallergosorbent testing (NCT00788749). Three phenotypic groups were identified: ‘asthma group’ (asthma diagnosis); ‘inflammatory group’ [no asthma diagnosis, but elevated fractionated exhaled nitric oxide (FE_NO) and/or bronchial‐hyperreactivity (BHR)]; and ‘non‐inflammatory group’ (no asthma diagnosis, no BHR and normal FE_NO). Group comparisons, univariate and multivariate analyses were performed to examine associations with airway dysfunction. Results FEV₁ and FEF_25?75% were reduced in asthma, but there was no difference between the non‐asthmatic groups. Total IgE and eosinophils were elevated in asthma vs. the non‐inflammatory group, but there was no difference for asthma vs. inflammatory groups. BHR was the only significant predictor of FEV₁ (P<0.001). For FEF_25?75, BHR and eosinophil count were independent predictors (P<0.001 and P=0.04). Nasal outcomes were not predictors of spirometry. Conclusion and Clinical Relevance In CRSwNP there is asymptomatic airway dysfunction suggestive of an asthmatic phenotype. Impairment of lung function is significantly associated with BHR and eosinophilia but not parameters of nasal disease suggesting that severity of airway dysfunction relates to the spectrum of asthma rather than rhinosinusitis. Lower airway dysfunction is common in CRSwNP but does not correlate to the severity of nasal disease. Signs and symptoms of asthma should be sought and treated in CRSwNP. Cite this as: P. A. Williamson, S. Vaidyanathan, K. Clearie, M. Barnes and B. J. Lipworth, Clinical & Experimental Allergy, 2011 (41) 1379–1385.     

Endometriosis: the consequence of neurological dysfunction?

Endometriosis describes endometrium found outside the uterine cavity and is frequently associated with clinical presentations of chronic pelvic pain, dysmenorrhoea, dyspareunia and subfertility. It was originally attributed to retrograde menstruation with endometrium passing in a reverse direction along the Fallopian tubes into the peritoneal cavity though this theory does not account for the spectrum of intrapelvic findings. Denervation followed by reinnervation in the uterine isthmus is proposed as the primary source of clinical symptoms, and, retrograde menstruation with adhesion of endometrium to injured tissue surfaces the variable laparoscopic findings. Primary sources of denervation are difficult intrapartum episodes (parous women) and persistent straining to achieve defaecation (nulliparous women). Progressive reinnervation including stromal nerve fibre proliferation, microneuroma formation and periarterial nerve fibre proliferation, takes place over five to ten years. Damage to uterine innervation interrupts normal patterns of uterine contractility, causing loss of fundocervical polarity which promotes retrograde menstruation. Ectopic endometrium may be a marker for prior tissue damage and does not contribute to the clinical symptoms--the disease may have been largely defined by an epiphenomenon.     

Simvastatin treatment in the SLO syndrome: a safe approach?

Soon after the discovery of reduced cholesterol synthesis in the Smith-Lemli-Opitz syndrome (SLOS), several trials with dietary supplementation were initiated with the aim of increasing cholesterol and reducing the de novo synthesis and accumulation of 7- and 8-dehydrocholesterol (DHC). Dietary cholesterol raises cholesterol levels in the circulation with only marginal effects on levels of DHC. Photosensitivity and polyneuropathy have been reported to be improved by the treatment, but other effects have been difficult to evaluate. In order to see whether inhibition of hydroxymethylglutaryl CoA reductase is of benefit, two of our patients have been treated with simvastatin in addition to the long-term treatment with cholesterol and bile acids. Absolute as well as relative levels of DHC were reduced. In one patient, creatine kinase increased moderately after 2 months of treatment. In the other patient, the treatment had to be interrupted because of hepatotoxic side effects with a marked increase in alanine aminotransferase and aggravation of the hypocholesterolemia and photosensitivity. We conclude that even if the levels of accumulated intermediates can be reduced, treatment with a statin may be harmful in some patients with SLOS.     

Is there a role for palmitoylethanolamide in the treatment of depression?

Depression is a common brain disorder affecting about 350 million people worldwide. Although the pharmacological treatment currently available can produce benefits in the majority of cases, residual depressive symptoms, cognitive deficits, functional impairment, and increase in frequency of relapses are frequently present in unipolar and bipolar depressed patients correctly treated. In the last years, numerous evidences have demonstrated the involvement of endocannabinoid system in the pathophysiology of mood disorders. Considering the recent findings about the antidepressant effect of palmitoylethanolamide in animal model, we have hypothesized the potential antidepressant effect of this fatty acid amide in unipolar and bipolar depressed patients.     

What influences a patient's desire to participate in the management of their hypertension?

There are potential benefits to giving the patient a more active role in the management of his or her care. This study explored the characteristics which influence a preference for participation and the extent to which hypertensive patients wish to participate in the management of their condition. A cross-sectional study with in-depth, face-to-face interviews was conducted with 49 hypertensive patients from one health centre. Interview themes were identified using content analysis. Characteristics predictive of participation desire were detected via quantitative analyses. Half of those interviewed were interested in participating in hypertension management. Those who had been hypertensive longer were less inclined to favour participation. Those with negative views of their 'disease' status and with higher blood pressure were more likely to want to participate. Patients needed further information and advice before decisions about future level of participation could be properly considered.     

Cost-effectiveness of biologic treatment for rheumatoid arthritis in clinical practice: An achievable target?

The burden of illness of rheumatoid arthritis (RA) falls on patients, families and society through the direct costs, indirect costs, and intangible costs. A large number of RA cost-of-illness studies have been performed in recent decades with discrepant results due to patient heterogeneity, and different health-care organization, employment rate or social support, job opportunities, and methodologies used to calculate the costs. The greatest burden of RA is the indirect and the intangible costs, but how to estimate them remains controversial. The systematic use of traditional disease modifying anti rheumatic drugs has changed the evolution of the disease. However, a considerable improvement in the management of RA has been obtained since the advent of biologic response modifiers. The use of these drugs, which have demonstrated greater efficacy than conventional therapies, have tripled the direct costs of RA, which rose from about € 4000 to roughly € 12,000, in a period of five years, from 2000 to 2005. The present paper is aimed to examine the effects of this change in therapeutic strategy.     

Idiopathic intracranial hypertension: priapism of the brain?

It has long been recognized that a clinical syndrome similar to idiopathic intracranial hypertension can occur secondary to venous sinus obstruction with the elevation in sinus pressure causing a reversal in the pressure gradient across the arachnoid granulations and therefore elevated CSF pressure. There remains, however, a group of predominantly obese female patients with elevated CSF pressures who have either no apparent abnormality of venous outflow or a tapering, apparently extrinsic compression, of their dominant transverse sinuses on catheter venography. This suggests that venous collapse may be associated in some way with the cause of the elevated pressure but clearly something else must be initiating the pressure rise or a circular argument ensues. Elevated CSF pressure compresses the veins, which then elevates CSF pressure. However, collapse of the venous sinuses secondary to the elevated CSF pressure once initiated may exacerbate the condition. It has been suggested that the initiating event leading to the elevated pressures in the idiopathic group of patients may be caused by cerebral hyperaemia and cerebral dysautoregulation. Priapism is a condition of pathological elevation of venous pressure of the male genitalia in which there are two forms: (1) venous out flow obstruction and (2) hyperaemia due to a to loss of regulation of blood flow and secondary venous out flow compression. Review of the literature suggests the pathophysiology of idiopathic intracranial hypertension may be analogous to that of priapism.     

The role of the brain renin–angiotensin system in hypertension: Implications for new treatment

Hypertension affects 26% of adults and is in constant progress related to increased incidence of obesity and diabetes. One-third of hypertensive patients may be successfully treated with one antihypertensive agent, one-third may require two agents and in the remaining patients will need three agents for effective blood pressure (BP) control. The development of new classes of antihypertensive agents with different mechanisms of action therefore remains an important goal. Brain renin–angiotensin system (RAS) hyperactivity has been implicated in hypertension development and maintenance in several types of experimental and genetic hypertension animal models. Among the main bioactive peptides of the brain RAS, angiotensin (Ang) II and Ang III have similar affinities for type 1 (AT1) and type 2 (AT2) Ang II receptors. Following intracerebroventricular (i.c.v.) injection, Ang II and Ang III similarly increase arginine–vasopressin (AVP) release and BP. Blocking the brain RAS may be advantageous as it simultaneously (1) decreases sympathetic tone and consequently vascular resistance, (2) decreases AVP release, reducing blood volume and vascular resistance and (3) blocks angiotensin-induced baroreflex inhibition, decreasing both vascular resistance and cardiac output. However, as Ang II is converted to Ang III in vivo, the exact nature of the active peptide is not precisely determined. We summarize here the main findings identifying AngIII as one of the major effector peptides of the brain RAS in the control of AVP release and BP. Brain AngIII exerts a tonic stimulatory effect on BP in hypertensive rats, identifying brain aminopeptidase A (APA), the enzyme generating brain Ang III, as a potentially candidate target for hypertension treatment. This has led to the development of potent orally active APA inhibitors, such as RB150 — the prototype of a new class of centrally acting antihypertensive agents.     

Failure to deactivate in the prefrontal cortex in schizophrenia: dysfunction of the default mode network?

BACKGROUND: Functional imaging studies using working memory tasks have documented both prefrontal cortex (PFC) hypo- and hyperactivation in schizophrenia. However, these studies have often failed to consider the potential role of task-related deactivation. METHOD: Thirty-two patients with chronic schizophrenia and 32 age- and sex-matched normal controls underwent functional magnetic resonance imaging (fMRI) scanning while performing baseline, 1-back and 2-back versions of the n-back task. Linear models were used to obtain maps of activations and deactivations in the groups. RESULTS: The controls showed activation in the expected frontal regions. There were also clusters of deactivation, particularly in the anterior cingulate/ventromedial PFC and the posterior cingulate cortex/precuneus. Compared to the controls, the schizophrenic patients showed reduced activation in the right dorsolateral prefrontal cortex (DLPFC) and other frontal areas. There was also an area in the anterior cingulate/ventromedial PFC where the patients showed apparently greater activation than the controls. This represented a failure of deactivation in the schizophrenic patients. Failure to activate was a function of the patients' impaired performance on the n-back task, whereas the failure to deactivate was less performance dependent. CONCLUSIONS: Patients with schizophrenia show both failure to activate and failure to deactivate during performance of a working memory task. The area of failure of deactivation is in the anterior prefrontal/anterior cingulate cortex and corresponds to one of the two midline components of the 'default mode network' implicated in functions related to maintaining one's sense of self.     

Genetic and pharmacological targeting of TPL-2 kinase ameliorates experimental colitis: a potential target for the treatment of Crohn's disease?

Inflammatory bowel disease is characterized by dysregulated immune responses against intestinal microflora leading to marked activation of nuclear factor-κB (NF-κB) with subsequent production of pro-inflammatory cytokines. Besides NF-κB, the tumor progression locus 2 (TPL-2)/extracellular signal-regulated kinase (ERK) pathway also regulates inflammatory cytokines such as interleukin-1β and tumor necrosis factor-α, but its role during intestinal inflammation is incompletely understood. We analyzed the impact of TPL-2 in the dextran sulfate sodium-induced experimental colitis model. Despite normal activation of NF-κB, animals lacking TPL-2 developed only mild colitis with reduced synthesis of inflammatory cytokines. Further, pharmacological inhibition of the TPL-2 kinase was similarly effective in ameliorating colitis as TPL-2 deficiency without obvious side effects. Because increased TPL-2/ERK activation was seen in patients with Crohn's disease (CD) but not ulcerative colitis, our findings encourage further investigation of TPL-2 kinase as potential target for the treatment of CD patients.     

Prevalence of hypertension in a hemodialysis population

INTRODUCTION　　 Cardiovascular and cerebrovascular diseases remain the lead cause of death indialysis patients.Most studies have shown that hypertension has a close relationwith morbidity and mortality in hemodialysis population.There are a few papers de…     

Notch signaling in glioblastoma: a developmental drug target?

Malignant gliomas are among the most devastating tumors for which conventional therapies have not significantly improved patient outcome. Despite advances in imaging, surgery, chemotherapy and radiotherapy, survival is still less than 2 years from diagnosis and more targeted therapies are urgently needed. Notch signaling is central to the normal and neoplastic development of the central nervous system, playing important roles in proliferation, differentiation, apoptosis and cancer stem cell regulation. Notch is also involved in the regulation response to hypoxia and angiogenesis, which are typical tumor and more specifically glioblastoma multiforme (GBM) features. Targeting Notch signaling is therefore a promising strategy for developing future therapies for the treatment of GBM. In this review we give an overview of the mechanisms of Notch signaling, its networking pathways in gliomas, and discuss its potential for designing novel therapeutic approaches.