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Cyclic adenosine monophosphate (cAMP) is a master regulator of mitochondrial metabolism but its precise mechanism of action yet remains unclear. Here, we found that a dietary saturated fatty acid (FA), palmitate increased intracellular cAMP synthesis through the palmitoylation of soluble adenylyl cyclase in cardiomyocytes. cAMP further induced exchange protein directly activated by cyclic AMP 1 (Epac1) activation, which was upregulated in the myocardium of obese patients. Epac1 enhanced the activity of a key enzyme regulating mitochondrial FA uptake, carnitine palmitoyltransferase 1. Consistently, pharmacological or genetic Epac1 inhibition prevented lipid overload, increased FA oxidation (FAO), and protected against mitochondrial dysfunction in cardiomyocytes. In addition, analysis of Epac1 phosphoproteome led us to identify two key mitochondrial enzymes of the the β-oxidation cycle as targets of Epac1, the long-chain FA acyl-CoA dehydrogenase (ACADL) and the 3-ketoacyl-CoA thiolase (3-KAT). Epac1 formed molecular complexes with the Ca 2+ /calmodulin-dependent protein kinase II (CaMKII), which phosphorylated ACADL and 3-KAT at specific amino acid residues to decrease lipid oxidation. The Epac1-CaMKII axis also interacted with the α subunit of ATP synthase, thereby further impairing mitochondrial energetics. Altogether, these findings indicate that Epac1 disrupts the balance between mitochondrial FA uptake and oxidation leading to lipid accumulation and mitochondrial dysfunction, and ultimately cardiomyocyte death.

Tissue engineering chambers (TECs) bring great hope in regenerative medicine as they allow the growth of adipose tissue for soft tissue reconstruction. To date, a wide range of TEC prototypes are available with different conceptions and volumes. Here, we addressed the influence of TEC design on fat flap growth in vivo as well as the possibility of using bioresorbable polymers for optimum TEC conception. In rats, adipose tissue growth is quicker under perforated TEC printed in polylactic acid than non-perforated ones (growth difference 3 to 5 times greater within 90 days). Histological analysis reveals the presence of viable adipocytes under a moderate (less than 15% of the flap volume) fibrous capsule infiltrated with CD68 + inflammatory cells. CD31-positive vascular cells are more abundant at the peripheral zone than in the central part of the fat flap. Cells in the TEC exhibit a specific metabolic profile of functional adipocytes identified by 1 H-NMR. Regardless of the percentage of TEC porosity, the presence of a flat base allowed the growth of a larger fat volume ( p  < 0.05) as evidenced by MRI images. In pigs, bioresorbable TEC in poly[1,4-dioxane-2,5-dione] (polyglycolic acid) PURASORB PGS allows fat flap growth up to 75 000 mm 3 at day 90, (corresponding to more than a 140% volume increase) while at the same time the TEC is largely resorbed. No systemic inflammatory response was observed. Histologically, the expansion of adipose tissue resulted mainly from an increase in the number of adipocytes rather than cell hypertrophy. Adipose tissue is surrounded by perfused blood vessels and encased in a thin fibrous connective tissue containing patches of CD163 + inflammatory cells. Our large preclinical evaluation defined the appropriate design for 3D-printable bioresorbable TECs and thus opens perspectives for further clinical applications.

Background Soft-tissue reconstruction is crucial in fields such as plastic surgery and oncology to address the repair of damaged tissues. Knitted scaffolds from bioresorbable copolymers, specifically poly(D,L-lactide) (PLA) and polycaprolactone (PCL), offer mechanical and biological properties that are essential for tissue engineering. This study assessed three-dimensional knitted scaffolds fabricated from melt-spun PLA and PCL multifilaments for soft tissue engineering applications. It examined the impact of the PLA/PCL ratio on the knitted scaffold structure, mechanical properties, and biological responses to determine the optimal composition for adipose tissue reconstruction. Results Knitted scaffolds fabricated with the PLA/PCL blends (PLA 70 /PCL 30 and PLA 90 /PCL 10 ) exhibited distinct mechanical and biological profiles. PLA 70 /PCL 30 scaffolds with a higher PCL content showed enhanced elasticity and porosity, whereas PLA 90 /PCL 10 scaffolds maintained better structural integrity and stiffness. Biological assays confirmed the biocompatibility of all scaffolds in vitro, with no cytotoxic effects. The scaffolds supported adipogenic differentiation in vitro, although PLA 70 /PCL 30 exhibited slightly reduced efficacy. Vascularization was evident using chorioallantoic membrane assays, in which blood vessel formation and penetration were observed, regardless of the scaffold composition. In vivo implantation in rat models revealed effective adipocyte integration, structural stability, and minimal inflammatory response, with PLA 90 /PCL 10 scaffolds outperforming PLA 70 /PCL 30 in terms of vascularization and less macrophage infiltration of connective tissue. Conclusion PLA/PCL knitted scaffolds offer a promising solution for enhancing graft volume maintenance and improving long-term outcomes, with tunable mechanical properties and biodegradability. The PLA 90 /PCL 10 scaffold is a superior candidate for adipose tissue reconstruction, balancing the structural stability with biological compatibility. These findings underscore the potential of PLA/PCL scaffolds for reconstructive surgery. Future studies should focus on scalability and long-term biocompatibility to facilitate clinical translation.

AimsThe purpose of the study was to describe the pattern of 99mTc-labeled phosphate agents myocardial uptake by scintigraphy and explore its impact on left ventricular (LV) functions in transthyretin cardiac amyloidosis (TTR-CA).MethodsFifty patients with TTR-CA underwent 99mTc- hydroxymethylene-diphosphonate (99mTc-HMDP) scintigraphy and echocardiography with measure of LV thickness, longitudinal strain (LS), systolic and diastolic functions. Cardiac retention by scintigraphy was assessed by visual scoring and the heart/whole body (H/WB) ratio was calculated by dividing counts in the heart by counts in late whole-body images.ResultsThe mean population age was 79 ± 10 years. Mean H/WB ratio was 12 ± 7. Myocardial 99mTc-HMDP uptake on segments 5, 6, 7, 8, 11, 12, 13, 14, 16, and 17 was correlated with H/WB ratio. Mean LVEF and global LS were 51 ± 10% and − 10 ± 3%, respectively. H/WB ratio was correlated with global LS (R = 0.408, P = .003), Ea (R = − 0.566, P < .001) and mean left ventricular wall thickness (R = 0.476, P < .001) but not with LVEF (R = − 0.109, P = .453). Segmental myocardial uptake was slightly correlated with segmental LS (R = 0.152, P < .001). H/WB ratio was not correlated with NT-proBNP levels (R = 0.219, P = .148) neither E/Ea ratio (R = 0.204, P = .184).ConclusionThese findings show the relationship between bone tracer myocardial uptake and LV functions in patients with TTR cardiac amyloidosis.

Our study aimed to assess the prevalence of post-traumatic stress disorder (PTSD) after childbirth one year after vaginal delivery and to identify characteristics of women and deliveries associated with it. Questionnaires were mailed a year after delivery to 1103 women with prospectively collected delivery and postpartum data, including a question on day 2 assessing their experience of childbirth. PTSD was assessed a year later by the Impact of Event and Traumatic Event Scales; 22 women (4.2%, 95%CI 2.7–6.3%) met the PTSD diagnostic criteria and 30 (5.7%; 95%CI 3.9–8.0%) PTSD profile criteria. Factors associated with higher risk of PTSD profile were previous abortion (aOR 3.6, 95%CI 1.4–9.3), previous postpartum hemorrhage (Aor 5.3, 95%CI 1.3–21.4), and postpartum hemoglobin <9 g/dl (aOR 2.7, 95%CI 1.0–7.5). Among 56 women (10.3%) reporting bad childbirth memories at day 2 postpartum, 11 (21.1%) met PTSD diagnosis and 11 (21.1%) PTSD profile criteria a year later, compared with 11 (2.4%) ( P  < 0.001) and 18 (3.8%) ( P  < 0.001), respectively, of the 489 (87.7%) women with good memories. PTSD is not rare at one year after vaginal delivery in a low-risk population. A simple question at day 2 post partum may identify women most at risk of PTSD and help determine if early intervention is needed.

To compare the administration of neuropsychological tests by teleneuropsychology (TeleNP) and face to face (F-F) in order to determine the feasibility and reliability of TeleNP. At the inclusion visit, all participants underwent a traditional F-F neuropsychological assessment as part of their standard care. Four months after inclusion, they were randomized to undergo an additional neuropsychological assessment either by F-F administration or by TeleNP. A total of 150 adults with cognitive complaints, but with no major cognitive or sensorial impairment were included. At 4 months, 69 participants were randomized in the F-F arm and 71 in TeleNP arm (10 lost in the follow-up). The overall satisfaction was high: 87.1% in the TeleNP arm were \"very satisfied\", and 82.9% indicated no preference between F-F and TeleNP. In agreement with previous data from the literature, neuropsychological assessments gave similar results across both administration conditions for a large majority of tests [Mini-Mental State Examination (MMSE), Free and Cued Selective Reminding Test (FCSRT) French version, Mahieux gestural praxis battery, Frontal Assessment Battery (FAB), time of completion of the Trail making Test (TMT) A and B, number of errors of the TMT B, Rey complex figure test, categorical et phonological verbal fluency tests] and minor differences for others [80-picture naming test (DO-80), FAB, Digit Span forward and backward and number of errors in the TMT A]. TeleNP is a promising method to be able to test patients as an alternative to F-F condition. Before this procedure can be generalized, it is now necessary to standardize the adaptation of certain tests and to test them in populations with more significant cognitive disorders.

BackgroundEstimation of left ventricular filling pressures (LVFP) is a determining factor in the follow-up of patients with cardiac amyloidosis (CA). Natriuretic peptides (NPs) and tissue Doppler imaging may be used to monitor LVFP in patients with CA. The aim of this study was to evaluate the value of NPs and Doppler parameters in estimating LVFP in patients with CA.MethodsFifty patients with biopsy-verified light chain (n=31), A protein amyloidosis (AA) (n=1), apoliporotein A2 (n=1) or bone scintigraphy-proven transthyretin (n=17) CA were retrospectively included. All patients underwent right heart catheterisation (RHC). Among them, 48 (96%) and 43 (86%) had assays of NPs (20 brain natriuretic peptide (BNP), 27 N-terminal pro-hormone brain natriuretic peptide (NT-proBNP) and 1 both) and transthoracic echocardiography performed within 24 hours of RHC, respectively.ResultsThe median BNP and NT-proBNP levels were 1000 (243–1477) ng/L and 10 106 (2935–13 348) ng/L, respectively. Echocardiography demonstrated left atrial enlargement with a mean volume of 47±16 mL and low tissue Doppler lateral Ea of 5±2 cm/s. The mean early diastolic mitral inflow velocity on early lateral mitral annular diastolic velocity ratio (E/Ea) ratio was 18±7, and the mean pulmonary capillary wedge pressure (PCWP) by RHC was 18±8 mm Hg. There was no correlation between BNP (r=0.260, p=0.774) or NT-proBNP (r=−0.103, p=0.984) levels and PCWP. There was a slight correlation between E/Ea ratio and PCWP (r=0.337, p=0.029). E/Ea ratio >14 performed poorly in differentiating elevated and low LVFP.ConclusionIn patients with CA, NPs do not accurately estimate PCWP. Tissue Doppler-derived mitral E/Ea ratio is correlated with PCWP, but the slight correlation requires to estimate LVFP in a broad clinical and imaging context to avoid diagnostic errors.

Neuroscience drug discovery is challenged by the brain’s structural and cell-type complexity, which is difficult to model in cellular systems compatible with high-throughput screening methods. Calcium oscillation assays, that harness neurons’ intrinsic capability to develop functional neural networks in cell culture, are currently the closest cellular models with a relevant functional endpoint to model human neuronal circuitry in a dish. Here we further developed this useful assay towards scalable drug discovery applications. We show the importance of defined neuron-to-astrocyte ratios for optimal cellular distribution and surface adherence in HTS-compatible cell culture vessels and how the cell type ratios affect network firing patterns. Increasing the neuron density resulted in decreased network spike frequencies, but increased network spike amplitudes. We identified DAPT, a molecule previously shown to promote neuronal maturation and synapse formation, as a negative regulator of astrocyte viability. Furthermore, inclusion of GABAergic neurons in the cocultures increased the network spike frequency while reducing network spike amplitudes. The GABA A receptor antagonist bicuculline did not affect network spike frequency, but increased network spike amplitudes. In order to access local field activity in an automated and scalable calcium imaging environment, we developed a pixel-based analysis for plate reader data. This method revealed that the effect of GABAergic neurons and bicuculline was restricted to local field calcium activity that coincided with synchronized network spikes. Our observations are consistent with previous findings suggesting that the presence of GABAergic neurons decreases synchronization and network spike participation of local neuronal activity, thus potentially echoing aspects of GABA action in vivo , and dysregulation thereof in pathological conditions.

To evaluate the effect of the fetal head station at attempted operative vaginal delivery (aOVD), and specifically midpelvic or low aOVD, on female and male sexual function and symptoms of postpartum depression (PPD) at 6 months. Prospective population-based cohort study. 1,941 women with singleton term fetuses in vertex presentation with midpelvic or low aOVD between 2008 and 2013 in a tertiary care university hospital. Symptoms of female sexual dysfunction using the Pelvic Organ Prolapse/Urinary Incontinence/Sexual Function Short Form Questionnaire (PISQ-12), symptoms of PPD using the Edinburgh Postnatal Depression Scale (EPDS) score, symptoms of male sexual dysfunction using the International Index of Erectile Function (IIEF-15) and perineal pain were assessed 6 months after aOVD. We measured the association between midpelvic or low aOVD and symptoms of female and male sexual function and symptoms of PPD at 6 months using multiple regression and adjusting for demographics, and risk factors of sexual dysfunction, symptoms of PPD and perineal pain with adjusted odds ratios (aORs) and 95% confidence intervals (95% CI). The study included 907 women (46.7%) who responded to the questionnaire; 18.4% (167/907) had midpelvic aOVD, and 81.6% (740/907) low. Most women (873/907 [96.3%]) of those with partners reported sexual activity at 6 months. No significant difference was observed for PISQ-12, EPDS, IIEF-15 scores and perineal pain between mid and low pelvic groups. Compared with low pelvic aOVD, midpelvic aOVD was not significantly associated with either female or male sexual dysfunction (p = 0.89 and p = 0.76, respectively), or maternal symptoms of PPD (p = 0.83). Perineal pain significantly increased the risk of male and female sexual dysfunction and maternal symptoms of PPD at 6 months (p = 0.02, p = 0.006, and p = 0.02, respectively). Midpelvic compared with low pelvic aOVD was not associated with an increase in sexual dysfunction, nor with symptoms of PPD at 6 months.

This research examines levels of objective and perceived control held by incumbents and successors in 100 Canadian family businesses approaching succession. Although results suggest that control remains largely with incumbents, indicators of succession readiness were more reliably correlated with the successors' levels of control. Generational differences in the association between succession indicators and actual levels of control are highlighted. Implications of these generational differences and the association between succession readiness indicators and control outcomes are discussed.