Efficacy and safety of low- versus high-dose glucocorticoid regimens for induction of remission of anti-neutrophil cytoplasm antibody-associated vasculitis: a systematic review and meta-analysis.

OBJECTIVE: Glucocorticoids (GCs) remain a cornerstone of the initial management of anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV), but have several dose-dependent side effects, in particular infections. The optimal dosing and tapering of oral GCs for remission induction are unknown. A systematic review and meta-analysis was undertaken to determine the efficacy and safety of low- versus high-dose GC regimens. METHOD: A systematic search of MEDLINE, Embase, and PubMed databases was conducted. Clinical studies using a GC-based induction protocol were selected. A daily dose of 0.5 mg/kg or < 30 mg/day oral prednisolone equivalent by the start of week 4 of the induction tapering schedule marked the threshold between high- and low-dose GCs. Risk ratios (RRs) were calculated by the random effects model for outcomes of remission and infection. Relapse events were summarized using risk differences with 95% confidence intervals (CIs). RESULTS: In total, 1145 participants were included in three randomized controlled trials and two observational studies, of whom 543 were assigned to the low-dose GC group and 602 to the high-dose GC group. A low-dose GC regimen was non-inferior to high-dose GCs with respect to outcomes of remission (RR 0.98, 95% CI 0.95-1.02, p = 0.37; I2 = 0%) and relapse (risk difference 0.03, 95% CI -0.01 to 0.06, p = 0.15; I2 = 12%), while significantly reducing the incidence of infection (RR 0.60, 95% CI 0.39-0.91, p = 0.02; I2 = 65%). CONCLUSION: Studies with low-dose GC regimens in AAV are associated with fewer infections while obtaining equivalent efficacy.

Hexamidine salts - applications in skin health and personal care products.

Hexamidine (HEX) has been used as a preservative in topical preparations since the 1950s. A number of studies also indicate that the molecule plays a beneficial role in skin homoeostasis. In this review, we describe the physicochemical properties of hexamidine diisethionate (HEX D) and the corresponding hydrochloride salt (HEX H). The biocidal and protease inhibition properties of HEX are outlined as well as the effects of HEX on lipid processing enzymes, corneocyte maturity, stratum corneum thickness and transepidermal water loss (TEWL). Skin permeation properties of HEX D and HEX H are summarized, and formulation approaches for effective dermal targeting of HEX are discussed.

Mast cell glycosaminoglycans.

Mast cells contain granules packed with a mixture of proteins that are released on degranulation. The proteoglycan serglycin carries an array of glycosaminoglycan (GAG) side chains, sometimes heparin, sometimes chondroitin or dermatan sulphate. Tight packing of granule proteins is dependent on the presence of serglycin carrying these GAGs. The GAGs of mast cells were most intensively studied in the 1970s and 1980s, and though something is known about the fine structure of chondroitin sulphate and dermatan sulphate in mast cells, little is understood about the composition of the heparin/heparan sulphate chains. Recent emphasis on the analysis of mast cell heparin from different species and tissues, arising from the use of this GAG in medicine, lead to the question of whether variations within heparin structures between mast cell populations are as significant as variations in the mix of chondroitins and heparins.

Increased incidence of nitroimidazole-refractory giardiasis at the Hospital for Tropical Diseases, London: 2008-2013.

Giardia intestinalis is the commonest gastrointestinal protozoal pathogen worldwide, and causes acute and chronic diarrhoea with malabsorption. First-line treatment is with a nitroimidazole, with a reported efficacy rate of 89%. Failure of treatment can occur in patients with hypogammaglobulinaemia or human immunodeficiency virus (HIV), or be due to nitroimidazole-resistant organisms. There is little evidence to guide the clinical management of nitroimidazole-refractory disease. We performed a retrospective audit of nitroimidazole-refractory giardiasis in returned travellers at the Hospital for Tropical Diseases, London between 2011 and 2013. Seventy-three patients with microscopy-proven or PCR-proven giardiasis in whom nitroimidazole treatment had failed were identified, and their management was investigated. In 2008, nitroimidazole treatment failed in 15.1% of patients. This increased to 20.6% in 2011 and to 40.2% in 2013. Patient demographics remained stable during this period, as did routes of referral. Of patients with giardiasis, 39.0% had travelled to India; this rose to 69.9% in patients with nitroimidazole-refractory disease. Of the patients with refractory disease, 44.6% had HIV serological investigations performed and 36.5% had immunoglobulin levels determined. Patients with refractory disease were treated with various agents, including albendazole, nitazoxanide, and mepacrine, alone or in combination. All 20 patients who received a mepacrine-containing regimen were cured. This data shows a worrying increase in refractory disease, predominantly in travellers from India, which is likely to represent increasing nitroimidazole resistance. Improved tools for the diagnosis of resistant G. intestinalis are urgently needed to establish the true prevalence of nitroimidazole-resistant giardiasis, together with clinical trials to establish the most effective second-line agent for empirical treatment regimens.

Exendin-4 reverses biochemical and behavioral deficits in a pre-motor rodent model of Parkinson's disease with combined noradrenergic and serotonergic lesions.

Research on Parkinson's disease (PD) has mainly focused on the degeneration of the dopaminergic neurons of nigro-striatal pathway; however, post-mortem studies have demonstrated that other brain regions such as the locus coeruleus (LC) and raphe nuclei (RN) are significantly affected as well. Degeneration of these crucial neuronal cell bodies may be responsible for depressive behavior and cognitive decline present in the pre-motor stage of PD. We have thus set out to create a pre-motor rodent model of PD which mimics the early stages of the condition. N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a selective noradrenergic neurotoxin, and parachloroampetamine (pCA), a selective serotonergic neurotoxin, were utilized concomitantly with bilateral 6-hydroxydopamine (6-OHDA) injections into the striatum to produce a pre-motor rodent model of PD with partial deficits in the dopaminergic, noradrenergic, and serotonergic systems. Our model exhibited a depressive/anhedonic condition as assessed using sucrose preference testing and the forced swim test. Our model also demonstrated deficits in object memory. These behavioral impairments were accompanied by a decline in both tissue and extracellular levels of all three neurotransmitters in both the frontal cortex and striatum. Immunohistochemistry also revealed a decrease in TH+ cells in the LC and substantia nigra. Exendin-4 (EX-4), a glucagon-like peptide-1 receptor (GLP-1R) agonist, promoted recovery of both the biochemical and behavioral dysfunction exhibited by our model. EX-4 was able to preserve the functional integrity of the dopaminergic, noradrenergic, and serotonergic systems. In conclusion, we have generated a novel animal model of PD that recapitulates certain pre-motor symptomology. These symptoms and causative physiology are ameliorated upon treatment with EX-4 and thus it could be used as a possible therapy for the non-motor symptoms prominent in the early stages of PD.

Exendin-4 reverts behavioural and neurochemical dysfunction in a pre-motor rodent model of Parkinson's disease with noradrenergic deficit.

BACKGROUND AND PURPOSE Parkinson's disease (PD) is characterized by progressive dopaminergic cell loss; however, the noradrenergic system exhibits degeneration as well. Noradrenergic deficit in PD may be responsible for certain non-motor symptoms of the pathology, including psychiatric disorders and cognitive decline. The aim of this study was to generate a pre-motor rodent model of PD with noradrenergic denervation, and to assess whether treatment with exendin-4 (EX-4), a glucagon-like peptide 1 receptor agonist, could reverse impairment exhibited by our model. EXPERIMENTAL APPROACH We generated a model of PD utilizing N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine and 6-hydroxydopamine to create partial lesions of both the noradrenergic and dopaminergic systems respectively. We then assessed the validity of our model using an array of behavioural paradigms and biochemical techniques. Finally, we administered EX-4 over a 1 week period to determine therapeutic efficacy. KEY RESULTS Our model exhibits anhedonia and decreased object recognition as indicated by a decrease in sucrose preference, increased immobility in the forced swim test and reduced novel object exploration. Tissue and extracellular dopamine and noradrenaline were reduced in the frontal cortex and striatum. TH+ cell counts decreased in the locus coeruleus and substantia nigra. Treatment with EX-4 reversed behavioural impairment and restored extracellular/tissue levels of both dopamine and noradrenaline and TH+ cell counts. CONCLUSION AND IMPLICATIONS We conclude that early treatment with EX-4 may reverse certain neuropsychiatric dysfunction and restore dopamine and noradrenaline content.

Size-fractionated heparins have differential effects on human neutrophil function in vitro.

BACKGROUND AND PURPOSE: Heparin is known to possess a range of activities, other than effects on blood coagulation, many of which are anti-inflammatory. Effects with potential anti-inflammatory applications include the inhibition of elastase release from neutrophils, as well as the adhesion of these cells to vascular endothelium. In the present study we aimed to investigate whether fractionation of heparin may yield molecules with enhanced or specific effects on human neutrophil function. EXPERIMENTAL APPROACH: Fractions of defined molecular size were obtained from heparin by different methods and assessed for their effects on elastase release induced by formyl Met-Leu-Phe (fMLP), from neutrophils, in some cases following the priming of these cells with tumour necrosis factor-alpha (TNF-alpha). Effects of the fractions on neutrophil adhesion to interleukin-1beta (IL-beta)-stimulated human umbilical vein endothelial cells (HUVECs) were also examined. KEY RESULTS: Elastase release was inhibited by very low molecular weight fractions of heparin, with an apparent minimum chain length of 10 saccharides required for full effect. In contrast, neutrophil-endothelial adhesion was unaffected by these fractionated heparins, suggesting that certain non-anticoagulant actions of heparin may be lost by such an approach. CONCLUSIONS AND IMPLICATIONS: These data suggest that an optimum chain length of heparin possibly exists for certain non-anticoagulant actions of heparin, which may prove to be useful in the design of novel drugs with specific anti-inflammatory actions.

Effect of tecastemizole on pulmonary and cutaneous allergic inflammatory responses.

BACKGROUND: Tecastemizole, a major metabolite of astemizole, is a potent and selective H1 receptor antagonist. Evidence suggests that this and certain other H1 receptor antagonists may possess anti-inflammatory effects that are, in some cases, independent of H1 receptor antagonism. Objective The aim of this study was to investigate the anti-inflammatory effects of tectastemizole in models of allergic inflammation. METHODS: Effects of tecastemizole were assessed in a murine model of allergic lung inflammation, in passive cutaneous anaphylaxis (PCA) responses in guinea-pig skin and in in vitro assays measuring endothelial adhesion molecule expression and leucocyte-endothelial adhesion. RESULTS: Tecastemizole inhibited antigen-induced eosinophil recruitment to the lungs of allergic mice in a dose-dependent manner. Furthermore, combination of a sub-effective dose of tecastemizole, combined with a sub-effective dose of dexamethasone inhibited eosinophil accumulation in this model. Plasma extravasation in PCA reactions was inhibited by tecastemizole, although by a mechanism that would appear to be H1 receptor-dependent. Cytokine-induced endothelial intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 expression, as well as mononuclear cell adhesion to human umbilical vein endothelial cells was inhibited by tecastemazole in a manner independent of H1 receptor antagonism. CONCLUSION: These data suggest that tecastemizole may have H1 receptor-independent effects in inhibiting late-phase inflammatory responses, while acute responses appear to be inhibited in a H1 receptor-dependent manner. Furthermore, our data suggest an important potential steroid-sparing role for such drugs in the treatment of allergic inflammatory conditions.

Narrowband ultraviolet B (UVB) phototherapy in children.

BACKGROUND: While narrowband ultraviolet B (UVB) phototherapy is a well-established treatment for a range of skin conditions in adults, there is little in the literature about its use in children and data regarding its long-term carcinogenic potential are lacking. AIM: We undertook a retrospective review of the use of narrowband UVB phototherapy in a paediatric population attending two Glasgow Hospitals. METHODS: Phototherapy case notes for all children aged 16 years and under at time of treatment were reviewed at two hospital sites between 1996 and 2002. RESULTS: In total, 77 children had been treated (median age 12 years, range 4-16). The conditions treated most frequently were psoriasis (45%) and atopic eczema (32%). Other dermatoses treated included alopecia areata, acne, hydroa vacciniforme and polymorphic light eruption. Treatment courses for atopic conditions were longer than those required for psoriatic conditions: median number of treatments 24 for atopic eczema (range 3-46), and 17.5 for psoriasis (range 9-35). By the end of treatment, 68% of the atopic patients and 63% of the patients with psoriasis had cleared. The adverse event profile was similar to that in adults, with erythema, herpes simplex reactivation and PLE all recorded. Anxiety was a problem for five patients. CONCLUSION: We conclude that narrowband UVB phototherapy is a useful and well-tolerated treatment for children with severe or intractable inflammatory skin disease, but concerns remain regarding long-term side-effects.

The effect of selective phosphodiesterase isoenzyme inhibition on neutrophil function in vitro.

Neutrophil-derived proteases such as neutrophil elastase (NE) and matrix metalloproteinase (MMP) are implicated in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). In this study, the effects of selective phosphodiesterase (PDE) inhibition on NE and MMP-9 release, as well as Myeloperoxidase (MPO) activity and integrin-mediated neutrophil adhesion to human umbilical vein endothelial cells (HUVECs), were investigated. Human neutrophils were treated with PDE inhibitors (10(-11)-10(-4)M) in the absence and presence of TNF-alpha (tumour necrosis factor) (100 U ml(-1)) for 30 min, prior to fMLP activation. After 45 min, the cells were removed and NE, MPO and MMP-9 release assessed. In the adhesion studies, the neutrophils were radio-labelled with 51Cr, stimulated and immediately transferred to cultured HUVEC monolayers for 30 min, prior to assessment of adhesion. TNF-alpha (100 U ml(-1)) acted synergistically with fMLP in stimulating azurophil degranulation with respect to both MPO activity (P<0.01) and NE release (P<0.01). In contrast, an additive effect was observed with TNF-alpha and fMLP with regard to MMP-9 release and neutrophil adhesion to HUVECs. The PDE4 inhibitors, roflumilast, roflumilast N-oxide, cilomilast and rolipram significantly suppressed MPO, NE and MMP-9 release in both the presence and absence of TNF-alpha (P<0.05; n=6-10) and also reduced neutrophil adhesion to HUVECs. In contrast, milrinone, a PDE3 inhibitor and the non-selective PDE inhibitor, theophylline did not inhibit azurophil degranulation under any of the experimental conditions. These data provide further evidence that selective PDE4 isoenzyme inhibitors can inhibit neutrophil degranulation, effects not shared by PDE3 inhibitors or theophylline.

The effects of heparin on the adhesion of human peripheral blood mononuclear cells to human stimulated umbilical vein endothelial cells.

1. The effects of unfractionated heparin (UH) and a selectively O-desulphated derivative of heparin (ODSH), lacking anticoagulant activity, on the adhesion of human peripheral blood mononuclear cells (HPBMNC) to human stimulated umbilical vein endothelial cells (HUVECs), were investigated. 2. For comparison, the effects of poly-L-glutamic acid (PGA), a large polyanionic molecule without sulphate groups and two different molecular weight sulphated dextrans (DS 5 k and DS 10 k) were studied. 3. UH (50 - 1000 u ml(-1)) significantly (P<0.05) inhibited the adhesion of HPBMNC to HUVECs, stimulated with IL-1beta (100 u ml(-1)), TNF-alpha (1000 u ml(-1)) or LPS (100 microg ml(-1)), when the drugs were added together with stimuli to HUVECs and coincubated for 6 h. Such effects on adhesion occurred with limited influence on expression of relevant endothelial adhesion molecules (ICAM-1 and VCAM-1). 4. UH (100 - 1000 u ml(-1)), when added to prestimulated HUVECs, significantly (P<0.05) increased adhesion of mononuclear cells to endothelium at the higher concentrations tested, without any effect on adhesion molecule expression. In contrast, the opposite effect was observed when human polymorphonuclear leucocyte adhesion was examined, under the same experimental conditions, suggesting that the observed potentiation of HPBMNC adhesion is cell specific. 5. The effects of UH on HPBMNC adhesion were shared by the non-anticoagulant ODSH (600 - 6000 microg ml(-1)) but not by sulphated dextrans or PGA (300 - 6000 microg ml(-1)). 6. Heparin affects the adhesion of HPBMNC to stimulated endothelium, in both an inhibitory and potentiating manner, effects which are unrelated to its anticoagulant activity and not solely dependent on molecular charge characteristics.

Glycosaminoglycans, airways inflammation and bronchial hyperresponsiveness.

Glycosaminoglycans (GAGs) are large, polyanionic molecules expressed throughout the body. The GAG heparin, co-released with histamine, is synthesised by and stored exclusively in mast cells, whereas the closely related molecule heparan sulphate is expressed, as part of a proteoglycan, on cell surfaces and throughout tissue matrices. These molecules are increasingly thought to play a role in regulation of the inflammatory response and heparin, for many years, has been considered to hold potential in the treatment of diseases such as asthma. Heparin and related molecules have been found to exert antiinflammatory effects in a wide range of in vitro assays, animal models and, indeed, human patients. Moreover, the results of studies carried out to date indicate that the antiinflammatory activities of heparin are dissociable from its well-established anticoagulant nature, suggesting that the separation of these characteristics could yield novel antiinflammatory drugs which may be useful in the future treatment of diseases such as asthma

The effects of heparin and related molecules upon the adhesion of human polymorphonuclear leucocytes to vascular endothelium in vitro.

1. The effects of an unfractionated heparin preparation (Multiparin), a low molecular weight heparin preparation (Fragmin) and a selectively O-desulphated derivative of heparin lacking anticoagulant activity, have been investigated for their effects on the adhesion of human polymorphonuclear leucocytes (PMNs) to cultured human umbilical vein endothelial cells (HUVECs) in vitro. The effect of poly-L-glutamic acid, a large, polyanionic molecule was also studied. 2. Unfractionated heparin (50-1000 U ml-1), the O-desulphated derivative (0.3-6 mg ml-1) and the low molecular weight heparin (50 U-1000 U ml-1) all inhibited significantly the adhesion of 51Cr labelled PMNs to HUVECs stimulated with interleukin-1 beta (IL-1 beta; 10 U ml-1), bacterial lipopolysaccharide (LPS; 2.5 micrograms ml-1) or tumour necrosis factor-alpha (TNF-alpha; 125 U ml-1) for 6 h, whereas poly-L-glutamic acid had no effect. In addition, the three heparin preparations in the same concentration range inhibited significantly the adhesion of f-met-leu-phe-stimulated PMNs to resting HUVECs. 3. The effects of unfractionated heparin upon the expression of adhesion molecules intercellular adhesion molecule-1 (ICAM-1) and E-selection were also investigated, as were the effects of unfractionated heparin upon adhesion of human PMNs to previously stimulated HUVECs. Heparin had little effect upon levels of expression of these adhesion molecules on stimulated HUVECs. However, a profound effect upon PMN adhesion to previously stimulated HUVECs was demonstrated using the same preparation, suggesting that inhibition of adhesion molecule expression is not a major component of the described inhibitory effects of heparin. 4. Pre-incubation of PMNs with heparin followed by washing inhibited their adhesion to HUVECs, under different conditions of cellular activation, implying that heparin can bind to these cells and exert its anti-adhesive effects even when not directly present in the system. 5. These observations would suggest that both heparin and a low molecular weight heparin are capable of inhibiting adhesion of human PMNs to endothelial cells, an effect not dependent solely upon the polyanionic nature of these molecules, nor dependent upon their ability to act as anticoagulants.

Latex allergy in atopic children.

The incidence of positive circulating specific immunoglobulin E (IgE) antibodies to latex and evidence of clinical latex sensitivity appears to be increasing since its first description in 1979. Although heightened medical awareness may be a factor, exposure to latex products, particularly rubber gloves, has increased since the discovery of the human immunodeficiency virus (HIV). Atopic individuals are at greater risk of developing latex sensitivity. We identified seven children with atopic eczema who were known to have clinically significant latex allergy and examined the relationship of prior exposure to latex gloves. All children had significant serum levels of specific IgE to latex. Before developing clinical symptoms of latex allergy, all had been exposed to latex in the form of gloves during either inpatient or outpatient treatments of their skin. Exposure of atopic individuals to latex gloves could be a major risk factor for sensitization and could increase the incidence of serious reactions.