Abstract Background Toll-like receptor 2 (TLR2) molecules play a pivotal role in innate immune responses by their ability to recognize and sense a wide repertoire of infectious and endogenous ...cellular structural elements. Here we evaluated whether genetic variants in TLR2 influence the age of the disease onset in bipolar disorder (BD). Methods DNAs from 571 BD patients 229 early-onset (EO-BD) and 342 late-onset (LO-BD) and 199 healthy controls (HC) were analyzed for the following TLR2 polymorphisms: the 5′-UTR −196 to −174 insertion/deletion (ins/del), the intron 1 rs 4696480 A/T, and the exon 3 rs 3804099 C/T and rs 3804100 C/T. PHASE software was used for haplotype reconstruction. Genetic associations were examined using a chi-square test. Results We found that the TLR2 rs 3804099 TT was significantly more prevalent in EO-BD than in LO-BD patients (corrected p ( pc )=0.024). After excluding family history of psychiatric disorders, we also found that the TLR2 rs 4696480 TT genotype was significantly more prevalent in EO-BD as compared to LO-BD and controls ( pc =0.002 and 0.002). Homozygous state for the ins TTT haplotype, carrying the above mentioned risk genotypes, was significantly more frequent in EO-BD than in LO-BD patients ( pc =0.007) and in EO-BD without family history of psychiatric disorders as compared to (i) those with positive history ( pc =0.03), (ii) with LO-BD without family history ( pc =0.001) and (iii) with HC ( pc =0.009). Limitations Confirmation by replication in independent BD cohorts is warranted. Conclusions Our data suggest the potential role of TLR2 genetic variants in the pathogen-mediated susceptibility to BD.
Purpose
To compare different extractions routes for robot-assisted living donor nephrectomy in terms of post-operative pain and renal function recovery.
Methods
Live donor kidney transplantation data ...from our institution were reviewed from November 2011 to March 2017. Postoperative pain was estimated using cumulative painkillers consumption. Variables were compared between the 3 groups with ANOVA for continuous data,
χ
2
test for categorial data. A survival analysis with Kaplan–Meier curve assessing time to transplant recipient nadir was performed to compare the renal function recovery.
Results
Sixty-three RLDN were performed (23 iliac, 23 vaginal and 17 umbilical extractions). There was no significant difference between the three groups in terms of operative time, blood lost, warm ischemia time, cumulative painkiller consumption and renal function recovery time. Postoperative complications for Umbilical, Vaginal and Iliac were, respectively, of 0, 3 and 1. No major difference was found between the 3 groups beside a slightly longer hospital stay in the iliac group.
Conclusion
Iliac incision might impact post-operative pain with a moderate but significant longer hospital stay. Vaginal extraction is an option when cosmetic outcomes present a real demand. The three options appeared to be safe and should be discussed with the patient in regard of the surgeon experience.
Abstract Background Strategies to reduce prostate-specific antigen (PSA)–driven prostate cancer (PCa) overdiagnosis and overtreatment seem to be necessary. Objective To test the accuracy of serum ...isoform −2proPSA (p2PSA) and its derivatives, percentage of p2PSA to free PSA (fPSA; %p2PSA) and the Prostate Health Index (PHI)—called index tests —in discriminating between patients with and without PCa. Design, setting, and participants This was an observational, prospective cohort study of patients from five European urologic centers with a total PSA (tPSA) range of 2–10 ng/ml who were subjected to initial prostate biopsy for suspected PCa. Outcome measurements and statistical analysis The primary end point was to evaluate the specificity, sensitivity, and diagnostic accuracy of index tests in determining the presence of PCa at prostate biopsy in comparison to tPSA, fPSA, and percentage of fPSA to tPSA (%fPSA) (standard tests) and the number of prostate biopsies that could be spared using these tests. Multivariable logistic regression models were complemented by predictive accuracy analysis and decision curve analysis. Results and limitations Of >646 patients, PCa was diagnosed in 264 (40.1%). Median tPSA (5.7 vs 5.8 ng/ml; p = 0.942) and p2PSA (15.0 vs 14.7 pg/ml) did not differ between groups; conversely, median fPSA (0.7 vs 1 ng/ml; p < 0.001), %fPSA (0.14 vs 0.17; p < 0.001), %p2PSA (2.1 vs 1.6; p < 0.001), and PHI (48.2 vs 38; p < 0.001) did differ significantly between men with and without PCa. In multivariable logistic regression models, p2PSA, %p2PSA, and PHI significantly increased the accuracy of the base multivariable model by 6.4%, 5.6%, and 6.4%, respectively (all p < 0.001). At a PHI cut-off of 27.6, a total of 100 (15.5%) biopsies could have been avoided. The main limitation is that cases were selected on the basis of their initial tPSA values. Conclusions In patients with a tPSA range of 2–10 ng/ml, %p2PSA and PHI are the strongest predictors of PCa at initial biopsy and are significantly more accurate than tPSA and %fPSA. Trial registration The study is registered at http://www.controlled-trials.com , ref. ISRCTN04707454.
Exercise induces cardioprotection against myocardial infarction, despite obesity, by restoring pro-survival pathways and increasing resistance of mitochondrial permeability transition pore (mPTP) ...opening at reperfusion. Among the mechanisms involved in the inactivation of these pathways, oxysterols appear interesting. Thus, we investigated the influence of regular exercise on the reperfusion injury salvage kinase (RISK) pathway, oxysterols, and mitochondria, in the absence of ischemia-reperfusion. We also studied 7β-hydroxycholesterol (7βOH) concentration (mass spectrometry) in human lean and obese subjects. Wild-type (WT) and obese (ob/ob) mice were assigned to sedentary conditions or regular treadmill exercise. Exercise significantly increased Akt phosphorylation, whereas 7βOH concentration was reduced. Moreover, exercise induced the translocation of PKCε from the cytosol to mitochondria. However, exercise did not affect the calcium concentration required to open mPTP in the mitochondria, neither in WT nor in ob/ob animals. Finally, human plasma 7βOH concentration was consistent with observations made in mice. In conclusion, regular exercise enhanced the RISK pathway by increasing kinase phosphorylation and PKCε translocation and decreasing 7βOH concentration. This activation needs the combination with stress conditions, i.e., ischemia-reperfusion, in order to inhibit mPTP opening at the onset of reperfusion. The human findings suggest 7βOH as a candidate marker for evaluating cardiovascular risk factors in obesity.
Abstract Background Childhood trauma (CT) is a major risk factor for psychiatric conditions. It is hypothesized that CT effects are mediated by the limbic system. Few multimodal neuroimaging studies ...allow an integrated perspective of this impact. Our goal was thus to study the effects of CT on the limbic network. Methods We acquired multimodal MRI (T1, diffusion weighted, and resting state fMRI) data from 79 subjects (47 healthy controls and 32 patients with bipolar disorder, BD). We performed correlational analyses between Childhood Trauma Questionnaire (sub)scores (physical and emotional abuse/neglect and sexual abuse) and anatomo-functional measurements of the limbic network (hippocampal and amygdala volumes, prefronto-limbic functional connectivity, uncinate fractional anisotropy). Results We found CTQ total scores to be negatively correlated with amygdala volume, prefronto-limbic functional connectivity (FC) and uncinate fractional anisotropy in our sample. Considering subscores, neglects (physical and emotional) were the only to affect neural parameters. The patients with BD drove most of the results. Limitations small sample size and low level of trauma in controls. Conclusions: Our multimodal approach enabled an integrated view of the long-term effects of CT on the limbic system.
Background: Pulmonary artery remodeling triggered by alveolar hypoxia is considered the main mechanism of pulmonary hypertension (PH)
in COPD patients. We hypothesized that the risk for PH in COPD is ...increased by an elevation in the proinflammatory cytokines
interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1), and IL-1β, as well as by specific genetic polymorphisms of
these cytokines.
Methods: We assessed cytokine plasma levels and the polymorphisms G(â174)C IL-6, C(â511)T IL-1β, and A(â2518)G MCP-1 in 148 COPD patients
(recruited at two centers) with right heart catheterization data and 180 control subjects including smokers and nonsmokers.
Human pulmonary artery smooth muscle cells (PA-SMCs) were cultured for IL-6 messenger RNA assays under normoxic and hypoxic
conditions.
Results: Patients with PH (mean pulmonary artery pressure PAP, ⥠25 mm Hg) had lower Pa o 2 and higher plasma IL-6 values than those without PH; there were no differences in terms of pulmonary function test results
or CT scan emphysema scores. Plasma IL-6 correlated with mean PAP ( r = 0.39; p < 0.001) and was included in a multiple stepwise regression analysis, with mean PAP as the dependent variable.
In patients with the IL-6 GG genotype, the mean PAP value was significantly higher and PH was more common than in CG or CC patients (adjusted odds
ratio, 4.32; 95% confidence interval, 1.96 to 9.54). Exposure to 4 h of hypoxia led to an about twofold increase in IL-6 messenger
RNA in cultured human PA-SMCs.
Conclusions: Inflammation, most likely involving IL-6, may contribute substantially to PH complicating COPD.
Aims
Same‐day discharge (SDD) after percutaneous coronary intervention (PCI) was safe and cost‐effective in randomized and observational studies but faces limited acceptance due to concerns about ...early adverse events. Our aim was to evaluate early outcomes after SDD PCI in a high‐volume urban PCI center over 10 years.
Methods and results
From 2007 to 2016, 1,635 unselected patients had PCI at our ambulatory cardiac care unit, mainly for stable ischemic heart disease (SIHD). Among them, 1,073 (65.6%), most of whom underwent ad hoc PCI, were discharged on the same day and 562 (34.4%) were admitted, for adverse events during PCI (n = 60) or within the next 4–6 hr (n = 52) or chiefly due to physician preference (n = 450). In the SDD group, radial access was used in 98.5% of patients; 36% and 15% of patients had two‐ and three‐vessel disease, respectively; and two‐vessel PCI was performed in 11% of patients. No MACCEs (death, myocardial infarction, stroke, urgent repeat PCI/CABG, and major vascular complications) occurred within 24 hr post‐discharge. Two patients were readmitted on the next day for chest pain but did not require repeat PCI.
Conclusion
SDD after successful PCI without complications within the next 4–6 hr is safe and feasible in most patients with SIHD. Among 1,035 SDD patients treated over 10 years, only two required readmission, and none experienced major cardiac adverse events such as death or stent thrombosis. SDD is safe for the patient and cost‐effective for the healthcare system and should be implemented more widely.
Whether the systemic manifestations observed in Chronic Obstructive Pulmonary Disease (COPD) are ascribable to lung dysfunction or direct effects of smoking is in debate. Structural Equations ...Modeling (SEM), a causal-oriented statistical approach, could help unraveling the pathways involved, by enabling estimation of direct and indirect associations between variables. The objectives of the study was to investigate the relative impact of smoking and COPD on systemic manifestations, inflammation and telomere length. In 292 individuals (103 women; 97 smokers with COPD, 96 smokers without COPD, 99 non-smokers), we used SEM to explore the pathways between smoking (pack-years), lung disease (FEV
, K
), and the following parameters: arterial stiffness (aortic pulse wave velocity, PWV), bone mineral density (BMD), appendicular skeletal muscle mass (ASMM), grip strength, insulin resistance (HOMA-IR), creatinine clearance (eGFR), blood leukocyte telomere length and inflammatory markers (Luminex assay). All models were adjusted on age and gender. Latent variables were created for systemic inflammation (inflammatory markers) and musculoskeletal parameters (ASMM, grip strength, BMD). SEM showed that most effects of smoking were indirectly mediated by lung dysfunction: e.g. via FEV
on musculoskeletal factor, eGFR, HOMA-IR, PWV, telomere length, CRP, white blood cells count (WBC) and inflammation factor, and via K
on musculoskeletal factor, eGFR and PWV. Direct effects of smoking were limited to CRP and WBC. Models had excellent fit. In conclusion, SEM highlighted the major role of COPD in the occurrence of systemic manifestations while smoking effects were mostly mediated by lung function.
Background
Multiple devices are available for noninvasive oxygenation support, including non-rebreather oxygen mask (O
2
-mask), high-flow oxygen through nasal cannula (HFNC), continuous positive ...airway pressure (CPAP), mask noninvasive ventilation (Mask-NIV) and helmet NIV (Helmet-NIV). As tidal volume is a key determinant of efficacy and safety during ventilatory support, we assessed whether it was influenced by the type of noninvasive oxygenation device.
Methods
A bench study using a manikin with a realistic face connected to a lung simulator was performed. Six conditions were assessed: no device, O
2
-mask, HFNC, CPAP, Mask-NIV and Helmet-NIV. Three respiratory mechanics were simulated (normal, obstructive, restrictive), at three simulated efforts (low, moderate, respiratory distress). Flow was recorded at the lung simulator inlet and mouth pressure into the manikin mouth. The same devices were evaluated on healthy volunteers with tidal volume assessed by electrical impedance tomography (EIT).
Results
Tidal volume was significantly influenced by oxygenation devices in bench model. As compared to O
2
-mask, HFNC and CPAP delivered significantly lower tidal volumes (440 ± 352 mL, 414 ± 333 mL and 377 ± 297 mL, respectively), while Mask-NIV or Helmet-NIV were associated with significantly higher tidal volumes (690 ± 321 mL and 652 ± 366 mL, respectively). Tidal volume was strongly correlated with the specific effect of each device on mouth pressure during inspiration: HFNC and CPAP were characterized by a negative PTPmouth (− 0.3 − 0.8 to − 0.2 and − 0.7 − 2.2 to − 0.5 cmH
2
O.sec/cycle, respectively), while Helmet-NIV and Mask-NIV were associated with a positive PTPmouth (4.5 4.1–4.6 and 6.1 5.9–7.1 cmH
2
O.sec/cycle, respectively). Tidal volume was also significantly influenced by oxygenation devices in healthy volunteers, with similar tidal volumes between O
2
-mask and CPAP (644 571–764 and 648 586–770 mL) but higher with HFNC, Mask-NIV and Helmet-NIV (819 609–918, 1110 661–1305 and 1086 833–1243 mL).
Conclusions
Tidal volume is significantly influenced by noninvasive oxygenation support devices, with a strong correlation with the pressure variation generated into the mouth during inspiration. NIV was associated with the highest tidal volumes and CPAP with the lowest ones. Clinical studies are needed to clarify the clinical implications of these effects.
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