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HDL associates with insulin resistance and beta-cell dysfunction in South Asian families at risk of type 2 diabetes
No full textObjective: Dyslipidemia precedes type 2 diabetes (T2D) and worsens with increasing glucose intolerance. First degree relatives of T2D patients have an increased risk to develop dyslipidemia and glucose intolerance. The aim of the present study was to assess the relation between the development of dyslipidemia and glucose intolerance in first-degree relatives of T2D patients. Research design and methods: Fasting lipoprotein profiles were determined by density gradient ultracentrifugation in T2D patients and their first-degree relatives (42 Caucasians and 33 South Asians), and in 29 normoglycemic controls from non-T2D families. Glucose tolerance, insulin sensitivity index (ISI) and insulin disposition index (DI) were assessed by an extended, frequently sampled oral glucose tolerance test (OGTT), and fractional insulin synthesis rate (FSR) was measured by 13C-leucine enrichment in urinary C-peptide during the OGTT. Results: Of the first-degree relatives, 40, 16 and 19 had NGT, prediabetes and T2D, respectively. NGT family members had lower plasma HDL-cholesterol (HDL[sbnd]C) (1.34 ± 0.07 vs 1.58 ± 0.06 mmol/L; p = 0.015), HDL2-C (0.41 ± 0.05 vs 0.57 ± 0.05 mmol/L; p = 0.021) and HDL3-C (0.62 ± 0.03 vs 0.72 ± 0.02 mmol/L; p = 0.043) than controls. HDL2-C levels tended to decrease with increasing glucose intolerance state. In South Asians, buoyant LDL-C levels decreased with increasing glucose intolerance state (p = 0.006). In South Asian families, HDL-C correlated with both ISI and DI (β 0.42; p = 0.04 and β 0.53; p = 0.01, respectively), whereas HDL2-C and HDL3-C levels correlated with DI (β 0.64; p = 0.002 and β 0.57; p = 0.005, respectively). HDL2-C and plasma triglyceride correlated with FSR (β 0.48; p = 0.033 and β −0.50; p = 0.029, respectively). Conclusions: Low HDL2-C and HDL3-C levels are present in NGT first-degree relatives of T2D patients, and HDL2-C tend to decrease further with increasing glucose intolerance. In South Asian families HDL2-C and HDL3-C levels linked predominantly to deteriorating beta cell function.</p
Low prevalence of anti-SSA (anti-Ro) and anti-SSB (anti-La) autoantibodies in female patients with rheumatoid arthritis with a wish to conceive
No full textObjectives Guidelines advise to test for anti-Sjögren's-syndrome-related antigen A (anti-SSA) and anti-Sjögren's-syndrome-related antigen B (anti-SSB) antibodies in all patients with rheumatoid arthritis (RA) who wish to conceive. Our objective was to determine the prevalence and titres of anti-SSA and anti-SSB autoantibodies in patients with RA with a wish to conceive or pregnant. Methods Patients were derived from two large cohorts on RA and pregnancy (PARA cohort and PreCARA cohort). In addition, to determine the clinical relevance of searching for anti-SSA and anti-SSB in patients with RA, we studied the prevalence of the maternal diagnosis of RA in the French national registry of neonatal lupus syndrome (NLS) and congenital heart block (CHB). Results 26 out of 647 patients with RA had detectable anti-SSA and/or anti-SSB. Anti-SSA was detected in 25 out of 647 patients (3.9%) (Ro-52, n=17; Ro-60, n=19), anti-SSB in 7 out of 647 (1.1%). Thirteen women had a titre of >240 units/mL of anti-SSA antibodies. The prevalence of anti-SSA and/or anti-SSB was higher in rheumatoid factor (RF)-positive patients compared with RF-negative patients (5.1% vs 1.6%, p=0.04). No cases of CHB and/or NLS in the offspring were observed. In the French national register, the prevalence of RA in mothers with SSA related CHB was 1.5%. Conclusion Anti-SSA and anti-SSB have a low prevalence in patients with RA who wish to conceive. Especially for RF-negative patients, the current advise to test for anti-SSA and anti-SSB should be reconsidered. </p
Inflammatory bowel disease in primary immunodeficiency disorders is a heterogeneous clinical entity requiring an individualized treatment strategy
No full textObjective: To describe the prevalence, clinical presentation and current treatment regimens of inflammatory bowel disease (IBD) in patients with primary immunodeficiency disorders (PIDs). Methods: A systematic review was conducted. The following databases were searched: MEDLINE, Embase, Web of Science, the Cochrane Library and Google Scholar. Results: A total of 838 articles were identified, of which 36 were included in this review. The prevalence of IBD in PIDs ranges between 3.4% and 61.2%, depending on the underlying PID. Diarrhea and abdominal pain were reported in 64.3% and 52.4% of the patients, respectively. Colon ulceration was the most frequent finding on endoscopic evaluation, while cryptitis, granulomas, ulcerations and neutrophilic/lymphocytic infiltrates were the most frequently reported histopathological abnormalities. Described treatment regimens included oral corticosteroids and other oral immunosuppressive agents, including mesalazine, azathioprine and cyclosporin, leading to clinical improvement in the majority of patients. In case of treatment failure, biological therapies including TNF- α blocking agents, are considered. Conclusions: The overall prevalence of IBD in patients with PID is high, but varies between different PIDs. Physicians should be aware of these complications and focus on characteristic symptoms to reduce diagnostic delay and delay in initiation of treatment. Treatment of IBD in PIDs depends on severity of symptoms and may differ between various PIDs based on distinct underlying pathogenesis. An individualized diagnostic and therapeutic approach is therefore warranted.</p
Imputation strategies for missing baseline neurological assessment covariates after traumatic brain injury
No full textStatistical models for outcome prediction are central to traumatic brain injury research and critical to baseline risk adjustment. Glasgow coma score (GCS) and pupil reactivity are crucial covariates in all such models but may be measured at multiple time points between the time of injury and hospital and are subject to a variable degree of unreliability and/or missingness. Imputation of missing data may be undertaken using full multiple imputation or by simple substitution of measurements from other time points. However, it is unknown which strategy is best or which time points are more predictive. We evaluated the pseudo-R2 of logistic regression models (dichotomous survival) and proportional odds models (Glasgow Outcome Score-extended) using different imputation strategies on the The Collaborative European NeuroTrauma Effectiveness Research in Traumatic Brain Injury (CENTER-TBI) study dataset. Substitution strategies were easy to implement, achieved low levels of missingness (<< 10%) and could outperform multiple imputation without the need for computationally costly calculations and pooling multiple final models. While model performance was sensitive to imputation strategy, this effect was small in absolute terms and clinical relevance. A strategy of using the emergency department discharge assessments and working back in time when these were missing generally performed well. Full multiple imputation had the advantage of preserving time-dependence in the models: The pre-hospital assessments were found to be relatively unreliable predictors of survival or outcome. The predictive performance of later assessments was model-dependent. In conclusion, simple substitution strategies for imputing baseline GCS and pupil response can perform well and may be a simple alternative to full multiple imputation in many cases.</p
MEK inhibition ameliorates social behavior phenotypes in a Spred1 knockout mouse model for RASopathy disorders
No full textBackground: RASopathies are a group of disorders that result from mutations in genes coding for proteins involved in regulating the Ras-MAPK signaling pathway, and have an increased incidence of autism spectrum disorder (ASD). Legius syndrome is a rare RASopathy caused by loss-of-function mutations in the SPRED1 gene. The patient phenotype is similar to, but milder than, Neurofibromatosis type 1—another RASopathy caused by loss-of-function mutations in the NF1 gene. RASopathies exhibit increased activation of Ras-MAPK signaling and commonly manifest with cognitive impairments and ASD. Here, we investigated if a Spred1-/- mouse model for Legius syndrome recapitulates ASD-like symptoms, and whether targeting the Ras-MAPK pathway has therapeutic potential in this RASopathy mouse model. Methods: We investigated social and communicative behaviors in Spred1-/- mice and probed therapeutic mechanisms underlying the observed behavioral phenotypes by pharmacological targeting of the Ras-MAPK pathway with the MEK inhibitor PD325901. Results: Spred1-/- mice have robust increases in social dominance in the automated tube test and reduced adult ultrasonic vocalizations during social communication. Neonatal ultrasonic vocalization was also altered, with significant differences in spectral properties. Spred1-/- mice also exhibit impaired nesting behavior. Acute MEK inhibitor treatment in adulthood with PD325901 reversed the enhanced social dominance in Spred1-/- mice to normal levels, and improved nesting behavior in adult Spred1-/- mice. Limitations: This study used an acute treatment protocol to administer the drug. It is not known what the effects of longer-term treatment would be on behavior. Further studies titrating the lowest dose of this drug that is required to alter Spred1-/- social behavior are still required. Finally, our findings are in a homozygous mouse model, whereas patients carry heterozygous mutations. These factors should be considered before any translational conclusions are drawn. Conclusions: These results demonstrate for the first time that social behavior phenotypes in a mouse model for RASopathies (Spred1-/-) can be acutely reversed. This highlights a key role for Ras-MAPK dysregulation in mediating social behavior phenotypes in mouse models for ASD, suggesting that proper regulation of Ras-MAPK signaling is important for social behavior.</p
Conspiracy theories as superstition
No full textThe contention in this paper is that the theological-political disputes Spinoza was con-cerned with 350 years ago are similar to the conspiratorial disputes we experience today. The world in Spinoza’s Tractatus theologico-politicus, a political intervention in his time, serves as a “mir-ror image”, that is to say, it deals with the same problem we face today albeit in a different mode. Understanding our contemporary condition under the auspices of a Spinozist perspective, problems in countermeasures to the conspiratorial disputes come to light. Scholarly work and practice focus on the epistemological dimension of conspiracy theories, tying in the extent to which they are problematic to the degree in which they deal in untruth. However, the lesson from Spinoza’s analysis of the theological-political disputes is that such theories do not deal in truth, but, in affect, they do not spring from a lack of education but a lack of certainty. The work of Spinoza opens up a different approach, and if our aim is like that of the TTP, to defend political life against the threat of civil war, such a different approach is in order.</p
Prospective real-world study on the pharmacokinetics of pembrolizumab in patients with solid tumors
No full textBackground Dosing schemes of pembrolizumab (anti-programmed cell death protein 1 monoclonal antibody) are solely based on pharmacokinetic (PK) modelling derived from phase I-III trials. The current study aimed to determine factors affecting PK and its relationship with clinical outcome in the real-world setting. Methods Advanced-stage cancer patients, who were treated with pembrolizumab monotherapy (2 mg/kg Q3W or 200 mg flat Q3W), were prospectively included for serial sampling to obtain trough concentrations. A PK model was generated, covariate effects assessed and internally validated by a bootstrap procedure. PK parameters were related to overall survival (OS) and the occurrence of immune-related adverse events (irAEs). Results 588 serum samples derived from 122 patients with (non-)small-cell lung cancer ([N]SCLC), malignant pleural mesothelioma (MPM), melanoma and urothelial cell cancer (UCC) were analyzed. Median follow-up was 2.2 years. A one-compartment PK model was generated: body surface area (BSA) and serum albumin had a significant effect on drug clearance (CL; covariate estimate 1.46 and -1.43, respectively), and serum lactate dehydrogenase (LDH) on the distribution volume(V d; 0.34). A significant inverse CL-OS relationship was determined for NSCLC (HR:1.69; 95%CI1.07-2.68; p=0.024) and MPM (HR: 3.29; 95% CI 1.08 to 10.09; p=0.037), after correction for prognostic factors, which could not confirmed for melanoma (p=0.22) or UCC (p=0.34). No relationship could be determined between CL and grade >3 irAEs (p=0.70). Conclusions High interpatient variability of pembrolizumab PK is determined by BSA and serum albumin (on CL) and LDH (on V d). A strong inverse CL-OS relationship was demonstrated for NSCLC and MPM, which could not be observed for melanoma and UCC. The findings suggest that personalized dosing should be prospectively explored. </p
The multifaceted role of macrophages in oncolytic virotherapy
No full textOne of the cancer hallmarks is immune evasion mediated by the tumour microenvironment (TME). Oncolytic virotherapy is a form of immunotherapy based on the application of oncolytic viruses (OVs) that selectively replicate in and induce the death of tumour cells. Virotherapy confers reciprocal interaction with the host’s immune system. The aim of this review is to explore the role of macrophage-mediated responses in oncolytic virotherapy efficacy. The approach was to study current scientific literature in this field in order to give a comprehensive overview of the interactions of OVs and macrophages and their effects on the TME. The innate immune system has a central influence on the TME; tumour-associated macrophages (TAMs) generally have immunosuppressive, tumour-supportive properties. In the context of oncolytic virotherapy, macrophages were initially thought to predominantly contribute to anti-viral responses, impeding viral spread. However, macrophages have now also been found to mediate transport of OV particles and, after TME infiltration, to be subjected to a phenotypic shift that renders them pro-inflammatory and tumour-suppressive. These TAMs can present tumour antigens leading to a systemic, durable, adaptive anti-tumour immune response. After phagocytosis, they can recirculate carrying tissue-derived proteins, which potentially enables the monitoring of OV replication in the TME. Their role in therapeutic efficacy is therefore multifaceted, but based on research applying relevant, immunocompetent tumour models, macrophages are considered to have a central function in anti-cancer activity. These novel insights hold important clinical implications. When optimised, oncolytic virotherapy, mediating multifactorial inhibition of cancer immune evasion, could contribute to improved patient survival.</p
Phospholipid-coated targeted microbubbles for ultrasound molecular imaging and therapy
No full textPhospholipid-coated microbubbles are ultrasound contrast agents that, when functionalized, adhere to specific biomarkers on cells. In this concise review, we highlight recent developments in strategies for targeting the microbubbles and their use for ultrasound molecular imaging (UMI) and therapy. Recently developed novel targeting strategies include magnetic functionalization, triple targeting, and the use of several new ligands. UMI is a powerful technique for studying disease progression, diagnostic imaging, and monitoring of therapeutic responses. Targeted microbubbles (tMBs) have been used for the treatment of cardiovascular diseases and cancer, with therapeutics either coadministered or loaded onto the tMBs. Regardless of which disease was treated, the use of tMBs always resulted in a better therapeutic outcome than non-tMBs when compared in vitro or in vivo.</p
Treatment-related risk factors for inhibitor development in non-severe hemophilia A after 50 cumulative exposure days
No full textBackground: Non-severe hemophilia A patients have a life-long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs). Objectives: This case-control study investigated treatment-related risk factors for inhibitor development in non-severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development. Patients/Methods: Non-severe hemophilia A patients (FVIII:C 2%–40%) were selected from the INSIGHT study. Inhibitor-positive patients were defined as early (<50 EDs) or late (>50EDs) cases and matched to 1–4 inhibitor-negative controls by year of birth, cumulative number of EDs, and center/country. We investigated treatment intensity during the last 10 EDs prior to inhibitor development. Intensive treatment was defined as: surgery, peak treatment (10 consecutive EDs), and high mean FVIII dose (>45 IU/kg/ED). Odds ratios (OR) were calculated by logistic regression. Results: Of 2709 patients, we analyzed 63 early and 26 late cases and 195 and 71 respectively matched controls. Peak treatment was associated with early and late inhibitor risk (crude OR 1.8, 95% confidence interval [CI] 1.0–3.4; 4.0, 95%CI 1.1–14.3). This association was slightly less pronounced after adjustment for mean FVIII dose. High mean FVIII dose was also associated with early and late inhibitor risk (crude OR 2.8, 95%CI 1.5–5.1; 4.5, 95%CI 1.2–16.6). Surgery increased inhibitor risk for early cases. This was less pronounced for late cases. Conclusions: Our findings suggest that intensive FVIII treatment remains a risk factor for inhibitor development in non-severe hemophilia A after more than 50 EDs. Therefore, persistent caution is required throughout the life-time treatment course.</p