Clinical SLEDAI-2K zero may be a pragmatic outcome measure in SLE studies

Objectives: Development of therapies for systemic lupus erythematosus (SLE) has in part been limited by the lack of suitable outcome measures in clinical trials. In the present post-hoc analysis of two clinical trials of belimumab, we investigated two potential outcomes, the Lupus Low Disease Activity State (LLDAS) and clinical SLE disease activity index 2000 (cSLEDAI-2K) zero, in relation to SLE responder index 4 (SRI-4).

Methods: A total of 1684 SLE patients from the BLISS-52 (n = 865) and BLISS-76 (n = 819) trials were surveyed. Physician’s Global Assessment (PGA) scores <0.5 (3-point scale) were used for comparisons. We used the chi-square test for comparisons and the phi coefficient for correlations.

Results: At week 52, LLDAS was achieved by 8.6% of patients, cSLEDAI-2K = 0 by 34.5% and SRI-4 by 45.1%. cSLEDAI-2K = 0 showed the strongest correlation with PGA <0.5 (r_φ = 0.36, P < 0.001). cSLEDAI-2K = 0 unveiled the superiority of belimumab 10 mg/kg over placebo (P = 0.003) with a magnitude which was comparable to that of SRI-4 (P < 0.001). LLDAS displayed a more moderate separation (P = 0.033).

Conclusions: LLDAS was a stringent measure. cSLEDAI-2K = 0 showed the strongest correlation with the clinician-based evaluation. Being based on the SLEDAI-2K only, cSLEDAI-2K = 0 may be considered a more pragmatic outcome measure in SLE studies compared with composite tools.     

A case-control study of paternal and maternal age as risk factors in mood disorders

Objective: Advanced parental age might constitute a risk factor for various disorders. We tested whether this concerns also mood disorder patients.

Methods: The study included 314 subjects (42 bipolar-BD patients; 21 manics and 21 depressives, 68 unipolar-UD, and 204 normal controls-NC). Analysis of Covariance (ANCOVA) and the calculation of the Relative Risk (RR) and the Odds Ratio (OR) were used for the analysis.

Results: Paternal age differed between NC and UD patients (29.42?±?6.07 vs. 32.12?±?5.54; p?=?.01) and manics (29.42?±?6.07 vs. 35.00?±?5.75; p?=?.001) and maternal age between NC and manics (25.46?±?4.52 vs. 31.43?±?4.75; p?<?.001) and manic and UD (31.43?±?4.75 vs. 26.75?±?6.03; p?=?.002). The RR and OR values suggested that advanced parental age constitutes a risk factor for the development of mood disorders.

Conclusions: In a non-dose dependent and gender-independent, advanced parental age constitutes a risk factor for the development of BD with index episode of mania (probably manic predominant polarity); only advanced paternal age constitutes a risk factor for the development of UD and BD with index episode of depression (probably depressive predominant polarity). This is the first study suggesting differential effect of advanced parental age depending on predominant polarity of BD.     

Successful closure of a complicated duodenal ulcer perforation with an expandable esophageal stent

Laparotomy and reoperation remain the standard procedures for patients with suture line disruption after the initial surgical treatment for duodenal ulcer perforation has failed. Recently, endoscopic stents have been employed for dehiscence of the suture line after a surgical repair or even as a primary treatment. We present such a case, the fourth in the literature. In this case, a partially covered stent was placed to cover the duodenal perforation opening after an unsuccessful stitching 6 days earlier. We discuss the difficulties in stent positioning, the choice of sealant, and possible complications. Overall, for older patients with comorbidities, endoscopic stent placement could be considered a promising alternative minimally invasive treatment.     

Exogenous hormone use and cutaneous melanoma risk in women: The European Prospective Investigation into Cancer and Nutrition

Evidence suggests an influence of sex hormones on cutaneous melanoma risk, but epidemiologic findings are conflicting. We examined the associations between use of oral contraceptives (OCs) and menopausal hormone therapy (MHT) and melanoma risk in women participating in the European Prospective Investigation into Cancer and Nutrition (EPIC). EPIC is a prospective cohort study initiated in 1992 in 10 European countries. Information on exogenous hormone use at baseline was derived from country-specific self-administered questionnaires. We used Cox proportional hazards regression models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Over 1992–2015, 1,696 melanoma cases were identified among 334,483 women, whereof 770 cases among 134,758 postmenopausal women. There was a positive, borderline-significant association between OC use and melanoma risk (HR = 1.12, 95% CI = 1.00–1.26), with no detected heterogeneity across countries (p_homogeneity = 0.42). This risk increased linearly with duration of use (p_trend = 0.01). Among postmenopausal women, ever use of MHT was associated with a nonsignificant increase in melanoma risk overall (HR = 1.14, 95% CI = 0.97–1.43), which was heterogeneous across countries (p_homogeneity = 0.05). Our findings do not support a strong and direct association between exogenous hormone use and melanoma risk. In order to better understand these relations, further research should be performed using prospectively collected data including detailed information on types of hormone, and on sun exposure, which may act as an important confounder or effect modifier on these relations.     

Depletion of microglia in developing cortical circuits reveals its critical role in glutamatergic synapse development,functional connectivity,and critical period plasticity

Microglia populate the early developing brain and mediate pruning of the central synapses. Yet, little is known on their functional significance in shaping the developing cortical circuits. We hypothesize that the developing cortical circuits require microglia for proper circuit maturation and connectivity, and as such, ablation of microglia during the cortical critical period may result in a long-lasting circuit abnormality. We administered PLX3397, a colony-stimulating factor 1 receptor inhibitor, to mice starting at postnatal day 14 and through P28, which depletes >75% of microglia in the visual cortex (VC). This treatment largely covers the critical period (P19-32) of VC maturation and plasticity. Patch clamp recording in VC layer 2/3 (L2/3) and L5 neurons revealed increased mEPSC frequency and reduced amplitude, and decreased AMPA/NMDA current ratio, indicative of altered synapse maturation. Increased spine density was observed in these neurons, potentially reflecting impaired synapse pruning. In addition, VC intracortical circuit functional connectivity, assessed by laser scanning photostimulation combined with glutamate uncaging, was dramatically altered. Using two photon longitudinal dendritic spine imaging, we confirmed that spine elimination/pruning was diminished during VC critical period when microglia were depleted. Reduced spine pruning thus may account for increased spine density and disrupted connectivity of VC circuits. Lastly, using single-unit recording combined with monocular deprivation, we found that ocular dominance plasticity in the VC was obliterated during the critical period as a result of microglia depletion. These data establish a critical role of microglia in developmental cortical synapse pruning, maturation, functional connectivity, and critical period plasticity.     

Artificial oocyte activation: physiological,pathophysiological and ethical aspects

Infertile couples with low oocyte yield in combination with abnormal semen parameters may experience intra-cytoplasmic sperm injection (ICSI) failure. An established factor associated with ICSI failure is oocyte activation deficiency (AOD). The latter originates from seminal contributors, such as phospholipase C-zeta (PLCζ) that is not adequate to produce calcium (Ca²⁺) oscillations for oocyte activation. Apart from this natural activator, other stimulants, such as A23187, ionomycin, strontium chloride or even electric pulses, have been used in embryological laboratories to overcome AOD and ICSI failure. The aim of the present narrative review is to discuss the role of Ca⁺² oscillations in oocyte activation and summarize the evidence concerning the use of oocyte activators as agents for artificial oocyte activation (AOA). Studies in humans and animals have emerged many physiological, pathophysiological and ethical aspects of AOA. In conclusion, in mammalian eggs, the cytosolic Ca⁺² oscillations derive from a periodic release of Ca⁺² from intracellular pools. PLCζ, as well as artificial stimulants, have been used to produce Ca⁺² oscillations for AOA. As the latter may increase the risk of epigenetic induced malformations, further studies are required to clarify whether AOA constitutes an effective and safe method to overcome ICSI failure.

Abbreviations: AOA: artificial oocyte activation; AOD: oocyte activation deficiency; Ca⁺²: Calcium; CAMKII: Ca⁺²/calmodulin-dependent protein kinase II; CICR: calcium-induced calcium-release; DAG: diacylglycerol; GM-CSF: granulocyte-macrophage colony-stimulating factor; ICSI: intra-cytoplasmic sperm injection; InsP₃R: inositol-trisphosphate receptor; IP₃: inositol 1,4,5-trisphosphate; IVF: in vitro fertilization; MAP: mitogen-activated protein; MII: metaphase II; NADP: nicotinic acid adenine dinucleotide phosphate; NO: nitric oxide; PAWP: post-acrosomal WW-binding domain protein; PIP₂: phosphatidylinositol 4,5-bisphosphate; PLC: phospholipase C; PLCζ: phospholipase C-zeta; SOAFs: spermatozoon-released oocyte-activating factors; Sr⁺²: strontium; TFF: total fertilization failure