Association between glucocorticoid therapy and incidence of diabetes mellitus in polymyalgia rheumatica and giant cell arteritis: a systematic review and meta-analysis

Background: Polymyalgia rheumatica (PMR) and giant cell arteritis (GCA) are almost always treated with glucocorticoids (GCs), but long-term GC use is associated with diabetes mellitus (DM). The absolute incidence of this complication in this patient group remains unclear. Objective: To quantify the absolute risk of GC-induced DM in PMR and GCA from published literature. Methods: We identified literature from inception to February 2017 reporting diabetes following exposure to oral GC in patients with PMR and/or GCA without pre-existing diabetes. A random-effects meta-analysis was performed to summarise the findings. Results: 25 eligible publications were identified. In studies of patients with GCA, mean cumulative GC dose was almost 1.5 times higher than in studies of PMR (8.2 g vs 5.6 g), with slightly longer treatment duration and longer duration of follow-up (6.4 years vs 4.4 years). The incidence proportion (cumulative incidence) of patients who developed new-onset DM was 6% (95% CI 3% to 9%) for PMR and 13% (95% CI 9% to 17%) for GCA. Based on UK data on incidence rate of DM in the general population, the expected background incidence rate of DM over 4.4 years in patients with PMR and 6.4 years in patients with GCA (follow-up duration) would be 4.8% and 7.0%, respectively. Heterogeneity between studies was high (I2=79.1%), as there were differences in study designs, patient population, geographical locations and treatment. Little information on predictors of DM was found. Conclusion: Our meta-analysis produced plausible estimates of DM incidence in patients with PMR and GCA, but there is insufficient published data to allow precise quantification of DM risk

Whole-body MRI of patients with polymyalgia rheumatica identifies a distinct subset with complete patient-reported response to glucocorticoids

Objectives: To determine whether whole-body MRI defines clinically-relevant subgroups within polymyalgia rheumatica (PMR) including glucocorticoid responsiveness. Methods: 22 patients with PMR and 16 with rheumatoid arthritis, untreated and diagnosed by consultant rheumatologists, underwent whole-body, multiple-joint MRI, scored by two experts. PMR patients reported whether they felt “back to normal” on glucocorticoid therapy and were followed for a median of 2 years. Results: All PMR patients were deemed to respond to glucocorticoids clinically. A characteristic pattern of symmetrical, extracapsular inflammation, adjacent to greater trochanter, acetabulum, ischial tuberosity and/or symphysis pubis, was observed in 14/22 of the PMR cases. In PMR, this pattern was associated with complete glucocorticoid response (p=0.01), higher pre-treatment C-reactive protein (CRP) and serum IL-6, and better post-treatment fatigue and function. Only 1/14 in the extracapsular group could stop glucocorticoids within 1 year, compared to 4/7 of the others. A score derived from the five sites discriminating best between PMR and RA correlated with IL-6 (p<0.002). IL-6 levels ≥16.8 pg/mL had 86% sensitivity and 86% specificity for the extracapsular MRI pattern. Conclusions: A subset of patients with rheumatologist-diagnosed PMR had a characteristic, extracapsular pattern of MRI inflammation, associated with elevated IL-6/CRP and with complete patient-reported glucocorticoid responsiveness

Isolation rearing impairs novel object recognition and attentional set shifting performance in female rats

YesIt has been suggested that the isolation rearing paradigm models certain aspects of schizophrenia symptomatology. This study aimed to investigate whether isolation rearing impairs rats’ performance in two models of cognition: the novel object recognition (NOR) and attentional set-shifting tasks, tests of episodic memory and executive function, respectively. Two cohorts of female Hooded-Lister rats were used in these experiments. Animals were housed in social isolation or in groups of five from weaning, post-natal day 28. The first cohort was tested in the NOR test with inter-trial intervals (ITIs) of 1 min up to 6 h. The second cohort was trained and tested in the attentional set-shifting task. In the NOR test, isolates were only able to discriminate between the novel and familiar objects up to 1-h ITI, whereas socially reared animals remembered the familiar object up to a 4-h ITI. In the attentional set-shifting task, isolates were significantly and selectively impaired in the extra-dimensional shift phase of the task (P < 0.01). Rats reared in isolation show impaired episodic memory in the NOR task and reduced ability to shift attention between stimulus dimensions in the attentional set-shifting task. Because schizophrenic patients show similar deficits in performance in these cognitive domains, these data further support isolation rearing as a putative preclinical model of the cognitive deficits associated with schizophrenia

Streams of data from drops of water: 21st century molecular microbial ecology

Microorganisms are ubiquitous and represent a taxonomically and functionally diverse component of freshwater environments of significant ecological importance. The bacteria, archaea, and microbial eukarya in freshwater systems support a range of ecosystem processes and functions, including mediating all major biogeochemical cycles, and therefore regulate the flow of multiple ecosystem services. Yet relative to conspicuous higher taxa, microbial ecology remains poorly understood. As the anthropocene progresses, the demand for freshwater–ecosystem services is both increasing with growing human population density, and by association, increasingly threatened from multiple and often interacting stressors, such as climate change, eutrophication, and chemical pollution. Thus, it is imperative to understand the ecology of microorganisms and their functional role in freshwater ecosystems if we are to manage the future of these environments effectively. To do this, researchers have developed a vast array of molecular tools that can illuminate the diversity, composition, and activity of microbial communities. Within this primer, we discuss the history of molecular approaches in microbial ecology, and highlight the scope of questions that these methods enable researchers to address. Using some recent case studies, we describe some exemplar research into the microbial ecology of freshwater systems, and emphasize how molecular methods can provide novel ecological insights. Finally, we detail some promising developments within this research field, and how these might shape the future research landscape of freshwater microbial ecology

Relation between Skin Pharmacokinetics and Efficacy in AmBisome Treatment of Murine Cutaneous Leishmaniasis

AmBisome® (LAmB), a liposomal formulation of amphotericin B (AmB), is a second-line treatment for the parasitic skin disease cutaneous leishmaniasis (CL). Little is known about its tissue distribution and pharmacodynamics to inform clinical use in CL. Here, we compared the skin pharmacokinetics of LAmB with Fungizone® (DAmB), the deoxycholate form of AmB, in murine models of Leishmania major CL. Drug levels at the target site (the localized lesion) 48 hours after single intravenous (IV) dosing of the individual AmB formulations (1 mg/kg of body weight) were similar, but were 3-fold higher for LAmB than for DAmB on day 10 after multiple administrations (1 mg/kg on days 0, 2, 4, 6 and 8). After single and multiple dosing, intralesional concentrations were respectively 5- and 20-fold higher compared to those in the healthy control skin of the same infected mice. We then evaluated how drug levels in the lesion after LAmB treatment relate to therapeutic outcomes. After five administrations of the drug at 0, 6.25 or 12.5 mg/kg (IV), there was a clear correlation between dose level, intralesional AmB concentration and relative reduction in parasite load and lesion size (R2 values > 0.9). This study confirms the improved efficacy of the liposomal over the deoxycholate AmB formulation in experimental CL, which is related to higher intralesional drug accumulation

Do you see what I see? Identification of child protection concerns by hospital staff and general dental practitioners

Aim An exploration of the threshold that dentists, doctors and nurses recognise for dental and child protection (CP) actions in sample clinical cases, and any differences between these professional groups. Method We present a cross-sectional survey of dentists, doctors and nurses (50 each), who regularly examine children, utilised five fictitious vignettes, combining an oral examination image and clinical history reflecting dental and CP issues. Demographics were collected, and each participant gave their likely action for the cases presented. Results Dentists were significantly better at answering the dental element than the doctors and nurses, (P <0.0001) with no significant difference between these two; only 8% of the latter had undergone any training in assessment of dental health. Although 90.6% of all professionals had undergone CP training, dentists were significantly less accurate at identifying the CP component than doctors and nurses, (P <0.0001) between whom there were no significant differences. Those with higher levels of CP training were most accurate at identifying correct CP actions. Conclusions CP training is effective at improving recognition of child maltreatment, although there remains a worrying lack of knowledge about thresholds for action among dentists. Doctors and nurses have minimal training in, or knowledge of, dental health in children, thus precluding appropriate onward referrals

The role of the right temporoparietal junction in perceptual conflict: detection or resolution?

The right temporoparietal junction (rTPJ) is a polysensory cortical area that plays a key role in perception and awareness. Neuroimaging evidence shows activation of rTPJ in intersensory and sensorimotor conflict situations, but it remains unclear whether this activity reflects detection or resolution of such conflicts. To address this question, we manipulated the relationship between touch and vision using the so-called mirror-box illusion. Participants' hands lay on either side of a mirror, which occluded their left hand and reflected their right hand, but created the illusion that they were looking directly at their left hand. The experimenter simultaneously touched either the middle (D3) or the ring finger (D4) of each hand. Participants judged, which finger was touched on their occluded left hand. The visual stimulus corresponding to the touch on the right hand was therefore either congruent (same finger as touch) or incongruent (different finger from touch) with the task-relevant touch on the left hand. Single-pulse transcranial magnetic stimulation (TMS) was delivered to the rTPJ immediately after touch. Accuracy in localizing the left touch was worse for D4 than for D3, particularly when visual stimulation was incongruent. However, following TMS, accuracy improved selectively for D4 in incongruent trials, suggesting that the effects of the conflicting visual information were reduced. These findings suggest a role of rTPJ in detecting, rather than resolving, intersensory conflict

Orexinergic Input to Dopaminergic Neurons of the Human Ventral Tegmental Area

The mesolimbic reward pathway arising from dopaminergic (DA) neurons of the ventral tegmental area (VTA) has been strongly implicated in reward processing and drug abuse. In rodents, behaviors associated with this projection are profoundly influenced by an orexinergic input from the lateral hypothalamus to the VTA. Because the existence and significance of an analogous orexigenic regulatory mechanism acting in the human VTA have been elusive, here we addressed the possibility that orexinergic neurons provide direct input to DA neurons of the human VTA. Dual-label immunohistochemistry was used and orexinergic projections to the VTA and to DA neurons of the neighboring substantia nigra (SN) were analyzed comparatively in adult male humans and rats. Orexin B-immunoreactive (IR) axons apposed to tyrosine hydroxylase (TH)-IR DA and to non-DA neurons were scarce in the VTA and SN of both species. In the VTA, 15.062.8% of TH-IR perikarya in humans and 3.260.3% in rats received orexin B-IR afferent contacts. On average, 0.2460.05 and 0.0560.005 orexinergic appositions per TH-IR perikaryon were detected in humans and rats, respectively. The majority(86–88%) of randomly encountered orexinergic contacts targeted the dendritic compartment of DA neurons. Finally, DA neurons of the SN also received orexinergic innervation in both species. Based on the observation of five times heavierorexinergic input to TH-IR neurons of the human, compared with the rat, VTA, we propose that orexinergic mechanism acting in the VTA may play just as important roles in reward processing and drug abuse in humans, as already established well in rodents

The role of the helper lipid on the DNA transfection efficiency of lipopolyplex formulations.

Multifunctional, lipopolyplex formulations comprising a mixture of cationic liposomes and cationic, receptor-targeting peptides have potential use in gene therapy applications. Lipopolyplex formulations described here are typically far more efficient transfection agents than binary lipoplex or polyplex formulations. It has been shown previously that the peptide component mediates both DNA packaging and targeting of the nanoparticle while in this report we investigate the contribution of the lipid component. We hypothesised that the lipid components synergise with the peptides in the transfection process by promoting endosomal escape after lipid bilayer fusion. Lipopolyplexes were prepared with cationic liposomes comprising DOTAP with either neutral lipid DOPE or DOPC. DOPE promotes fusogenic, inverted hexagonal lipid structures while DOPC promotes more stable laminar structures. Lipopolyplexes containing DOPE showed substantially higher transfection efficiency than those formulated with DOPC, both in vitro and in vivo. DOPE-containing lipopolyplexes showed rapid endosomal trafficking and nuclear accumulation of DNA while DOPC-containing formulations remained within the late endo-lysosomal compartments. These findings are consistent with previous finding for the role of DOPE in lipoplexes and support the hypothesis regarding the function of the lipid components in lipopolyplexes. These findings will help to inform future lipopolyplex design, strategies and clinical development processes

Synthesis and structural characterization of a mimetic membrane-anchored prion protein

During pathogenesis of transmissible spongiform encephalopathies (TSEs) an abnormal form (PrPSc) of the host encoded prion protein (PrPC) accumulates in insoluble fibrils and plaques. The two forms of PrP appear to have identical covalent structures, but differ in secondary and tertiary structure. Both PrPC and PrPSc have glycosylphospatidylinositol (GPI) anchors through which the protein is tethered to cell membranes. Membrane attachment has been suggested to play a role in the conversion of PrPC to PrPSc, but the majority of in vitro studies of the function, structure, folding and stability of PrP use recombinant protein lacking the GPI anchor. In order to study the effects of membranes on the structure of PrP, we synthesized a GPI anchor mimetic (GPIm), which we have covalently coupled to a genetically engineered cysteine residue at the C-terminus of recombinant PrP. The lipid anchor places the protein at the same distance from the membrane as does the naturally occurring GPI anchor. We demonstrate that PrP coupled to GPIm (PrP-GPIm) inserts into model lipid membranes and that structural information can be obtained from this membrane-anchored PrP. We show that the structure of PrP-GPIm reconstituted in phosphatidylcholine and raft membranes resembles that of PrP, without a GPI anchor, in solution. The results provide experimental evidence in support of previous suggestions that NMR structures of soluble, anchor-free forms of PrP represent the structure of cellular, membrane-anchored PrP. The availability of a lipid-anchored construct of PrP provides a unique model to investigate the effects of different lipid environments on the structure and conversion mechanisms of PrP