The effect of immunomodulators on the immunogenicity of TNF-blocking therapeutic monoclonal antibodies: a review

Therapeutic monoclonal antibodies have revolutionized the treatment of various inflammatory diseases. Immunogenicity against these antibodies has been shown to be clinically important: it is associated with shorter response duration because of diminishing concentrations in the blood and with infusion reactions. Concomitant immunomodulators in the form of methotrexate or azathioprine reduced the immunogenicity of therapeutic antibodies in rheumatoid arthritis, Crohn disease, and juvenile idiopathic arthritis. The occurrence of adverse events does not increase when immunomodulators are added to therapeutic antibodies. The mechanism whereby methotrexate and azathioprine influence immunogenicity remains unclear. Evidence-based consensus on prescribing concomitant immunomodulators is needed

Comparative phylogeography of parasitic Laelaps mites contribute new insights into the specialist-generalist variation hypothesis (SGVH)

BACKGROUND: The specialist-generalist variation hypothesis (SGVH) in parasites suggests that, due to patchiness in habitat (host availability), specialist species will show more subdivided population structure when compared to generalist species. In addition, since specialist species are more prone to local stochastic extinction events with their hosts, they will show lower levels of intraspecific genetic diversity when compared to more generalist. RESULTS: To test the wider applicability of the SGVH we compared 337 cytochrome oxidase I mitochondrial DNA and 268 nuclear tropomyosin DNA sequenced fragments derived from two co-distributed Laelaps mite species and compared the data to 294 COI mtDNA sequences derived from the respective hosts Rhabdomys dilectus, R. bechuanae, Mastomys coucha and M. natalensis. In support of the SGVH, the generalist L. muricola was characterized by a high mtDNA haplotypic diversity of 0.97 (±0.00) and a low level of population differentiation (mtDNA Fst= 0.56, p < 0.05; nuDNA Fst = 0.33, P < 0.05) while the specialist L. giganteus was overall characterized by a lower haplotypic diversity of 0.77 (±0.03) and comparatively higher levels of population differentiation (mtDNA Fst = 0.87, P < 0.05; nuDNA Fst = 0.48, P < 0.05). When the two specialist L. giganteus lineages, which occur on two different Rhabdomys species, are respectively compared to the generalist parasite, L. muricola, the SGVH is not fully supported. One of the specialist L. giganteus species occurring on R. dilectus shows similar low levels of population differentiation (mtDNA Fst= 0.53, P < 0. 05; nuDNA Fst= 0.12, P < 0.05) than that found for the generalist L. muricola. This finding can be correlated to differences in host dispersal: R. bechuanae populations are characterized by a differentiated mtDNA Fst of 0.79 (P < 0.05) while R. dilectus populations are less structured with a mtDNA Fst= 0.18 (P < 0.05). CONCLUSION: These findings suggest that in ectoparasites, host specificity and the vagility of the host are both important drivers for parasite dispersal. It is proposed that the SGHV hypothesis should also incorporate reference to host dispersal since in our case only the specialist species who occur on less mobile hosts showed more subdivided population structure when compared to generalist species

The management of patients with primary chronic anal fissure: a position paper

Anal fissure is one of the most common and painful proctologic diseases. Its treatment has long been discussed and several different therapeutic options have been proposed. In the last decades, the understanding of its pathophysiology has led to a progressive reduction of invasive and potentially invalidating treatments in favor of conservative treatment based on anal sphincter muscle relaxation. Despite some systematic reviews and an American position statement, there is ongoing debate about the best treatment for anal fissure. This review is aimed at identifying the best treatment option drawing on evidence-based medicine and on the expert advice of 6 colorectal surgeons with extensive experience in this field in order to produce an Italian position statement for anal fissures. While there is little chance of a cure with conservative behavioral therapy, medical treatment with calcium channel blockers, diltiazem and nifepidine or glyceryl trinitrate, had a considerable success rate ranging from 50 to 90%. Use of 0.4% glyceryl trinitrate in standardized fashion seems to have the best results despite a higher percentage of headache, while the use of botulinum toxin had inconsistent results. Nonresponding patients should undergo lateral internal sphincterotomy. The risk of incontinence after this procedure seems to have been overemphasized in the past. Only a carefully selected group of patients, without anal hypertonia, could benefit from anoplasty

The protocol of the Oslo Study of Clonidine in Elderly Patients with Delirium; LUCID:a randomised placebo-controlled trial

Background Delirium affects 15% of hospitalised patients and is linked with poor outcomes, yet few pharmacological treatment options exist. One hypothesis is that delirium may in part result from exaggerated and/or prolonged stress responses. Dexmedetomidine, a parenterally-administered alpha2-adrenergic receptor agonist which attenuates sympathetic nervous system activity, shows promise as treatment in ICU delirium. Clonidine exhibits similar pharmacodynamic properties and can be administered orally. We therefore wish to explore possible effects of clonidine upon the duration and severity of delirium in general medical inpatients. Methods/Design The Oslo Study of Clonidine in Elderly Patients with Delirium (LUCID) is a randomised, placebo-controlled, double-blinded, parallel group study with 4-month prospective follow-up. We will recruit 100 older medical inpatients with delirium or subsyndromal delirium in the acute geriatric ward. Participants will be randomised to oral clonidine or placebo until delirium free for 2 days (Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria), or after a maximum of 7 days treatment. Assessment of haemodynamics (blood pressure, heart rate and electrocardiogram) and delirium will be performed daily until discharge or a maximum of 7 days after end of treatment. The primary endpoint is the trajectory of delirium over time (measured by Memorial Delirium Assessment Scale). Secondary endpoints include the duration of delirium, use of rescue medication for delirium, pharmacokinetics and pharmacodynamics of clonidine, cognitive function after 4 months, length of hospital stay and need for institutionalisation. Discussion LUCID will explore the efficacy and safety of clonidine for delirium in older medical inpatients. Trial registration ClinicalTrials.gov NCT01956604 . EudraCT Number: 2013-000815-2

Specific inhibition of nuclear factor-kappa B-dependent inflammatory responses by cell type-specific mechanisms upon A(2A) adenosine receptor gene transfer

Adenosine is a potent inhibitor of inflammatory processes, and the A2A adenosine receptor (A2AAR) plays a key nonredundant role as a suppresser of inflammatory responses in vivo. In this study, we demonstrate that increasing A2AAR gene expression suppressed multiple inflammatory responses in both human umbilical vein endothelial cells (HUVECs) and rat C6 glioma cells in vitro. In particular, the induction of the adhesion mole-cule E-selectin by either tumor necrosis factor (TNF) or Escherichia coli lipopolysaccharide (LPS) was reduced by more than 70 % in HUVECs, whereas inducible nitric-oxide synthase (iNOS) induction was abolished in C6 cells after exposure to interferon- in combination with LPS and TNF, suggesting that the receptor inhibited a common step in the induction of each of these pro-inflammatory genes. Consistent with thi