Gut Microbiome Composition Is Associated With Future Onset of Crohn's Disease in Healthy First-Degree Relatives.

BACKGROUND & AIMS: The cause of Crohn's disease (CD) is unknown, but the current hypothesis is that microbial or environmental factors induce gut inflammation in genetically susceptible individuals, leading to chronic intestinal inflammation. Case-control studies of patients with CD have cataloged alterations in the gut microbiome composition; however, these studies fail to distinguish whether the altered gut microbiome composition is associated with initiation of CD or is the result of inflammation or drug treatment. METHODS: In this prospective cohort study, 3483 healthy first-degree relatives (FDRs) of patients with CD were recruited to identify the gut microbiome composition that precedes the onset of CD and to what extent this composition predicts the risk of developing CD. We applied a machine learning approach to the analysis of the gut microbiome composition (based on 16S ribosomal RNA sequencing) to define a microbial signature that associates with future development of CD. The performance of the model was assessed in an independent validation cohort. RESULTS: In the validation cohort, the microbiome risk score (MRS) model yielded a hazard ratio of 2.24 (95% confidence interval, 1.03-4.84; P = .04), using the median of the MRS from the discovery cohort as the threshold. The MRS demonstrated a temporal validity by capturing individuals that developed CD up to 5 years before disease onset (area under the curve > 0.65). The 5 most important taxa contributing to the MRS included Ruminococcus torques, Blautia, Colidextribacter, an uncultured genus-level group from Oscillospiraceae, and Roseburia. CONCLUSION: This study is the first to demonstrate that gut microbiome composition is associated with future onset of CD and suggests that gut microbiome is a contributor in the pathogenesis of CD.

The Cost-Effectiveness of Early High-Acuity Postoperative Care for Medium-Risk Surgical Patients.

BACKGROUND: Initiatives in perioperative care warrant robust cost-effectiveness analysis in a cost-constrained era when high-value care is a priority. A model of anesthesia-led early high-acuity postoperative care, advanced recovery room care (ARRC), has shown benefit in terms of hospital and patient outcomes, but its cost-effectiveness has not yet been formally determined. METHODS: Data from a previously published single-center prospective cohort study of ARRC in medium-risk patients were used to generate a Markov model, which described patient transition between care locations, each with different characteristics and costs. The incremental cost-effectiveness ratio (ICER), using days at home (DAH) and hospital costs, was calculated for ARRC compared to usual ward care using deterministic and probabilistic sensitivity analysis. RESULTS: The Markov model accurately described patient disposition after surgery. For each patient, ARRC provided 4.3 more DAH within the first 90 days after surgery and decreased overall hospital costs by $1081 per patient. Probabilistic sensitivity analysis revealed that ARRC had a 99.3% probability of increased DAH and a 77.4% probability that ARRC was dominant from the perspective of the hospital, with improved outcomes and decreased costs. CONCLUSIONS: Early high-acuity care for approximately 24 hours after surgery in medium-risk patients provides highly cost-effective improvements in outcomes when compared to usual ward care.

Microutrophin expression in dystrophic mice displays myofiber type differences in therapeutic effects.

Gene therapy approaches for DMD using recombinant adeno-associated viral (rAAV) vectors to deliver miniaturized (or micro) dystrophin genes to striated muscles have shown significant progress. However, concerns remain about the potential for immune responses against dystrophin in some patients. Utrophin, a developmental paralogue of dystrophin, may provide a viable treatment option. Here we examine the functional capacity of an rAAV-mediated microutrophin (µUtrn) therapy in the mdx4cv mouse model of DMD. We found that rAAV-µUtrn led to improvement in dystrophic histopathology & mostly restored the architecture of the neuromuscular and myotendinous junctions. Physiological studies of tibialis anterior muscles indicated peak force maintenance, with partial improvement of specific force. A fundamental question for µUtrn therapeutics is not only can it replace critical functions of dystrophin, but whether full-length utrophin impacts the therapeutic efficacy of the smaller, highly expressed µUtrn. As such, we found that µUtrn significantly reduced the spacing of the costameric lattice relative to full-length utrophin. Further, immunostaining suggested the improvement in dystrophic pathophysiology was largely influenced by favored correction of fast 2b fibers. However, unlike µUtrn, µdystrophin (µDys) expression did not show this fiber type preference. Interestingly, µUtrn was better able to protect 2a and 2d fibers in mdx:utrn-/- mice than in mdx4cv mice where the endogenous full-length utrophin was most prevalent. Altogether, these data are consistent with the role of steric hindrance between full-length utrophin & µUtrn within the sarcolemma. Understanding the stoichiometry of this effect may be important for predicting clinical efficacy.

Time-Restricted Salutary Effects of Blood Flow Restoration on Venous Thrombosis and Vein Wall Injury in Mouse and Human Subjects.

BACKGROUND: Up to 50% of patients with proximal deep vein thrombosis (DVT) will develop the postthrombotic syndrome characterized by limb swelling and discomfort, hyperpigmentation, skin ulcers, and impaired quality of life. Although catheter-based interventions enabling the restoration of blood flow (RBF) have demonstrated little benefit on postthrombotic syndrome, the impact on the acuity of the thrombus and mechanisms underlying this finding remain obscure. In experimental and clinical studies, we examined whether RBF has a restricted time window for improving DVT resolution. METHODS: First, experimental stasis DVT was generated in C57/BL6 mice (n=291) by inferior vena cava ligation. To promote RBF, mice underwent mechanical deligation with or without intravenous recombinant tissue plasminogen activator administered 2 days after deligation. RBF was assessed over time by ultrasonography and intravital microscopy. Resected thrombosed inferior vena cava specimens underwent thrombus and vein wall histological and gene expression assays. Next, in a clinical study, we conducted a post hoc analysis of the ATTRACT (Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis) pharmacomechanical catheter-directed thrombolysis (PCDT) trial (NCT00790335) to assess the effects of PCDT on Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores for specific symptom-onset-to-randomization timeframes. RESULTS: Mice that developed RBF by day 4, but not later, exhibited reduced day 8 thrombus burden parameters and reduced day 8 vein wall fibrosis and inflammation, compared with controls. In mice without RBF, recombinant tissue plasminogen activator administered at day 4, but not later, reduced day 8 thrombus burden and vein wall fibrosis. It is notable that, in mice already exhibiting RBF by day 4, recombinant tissue plasminogen activator administration did not further reduce thrombus burden or vein wall fibrosis. In the ATTRACT trial, patients receiving PCDT in an intermediate symptom-onset-to-randomization timeframe of 4 to 8 days demonstrated maximal benefits in Venous Insufficiency Epidemiological and Economic Study quality-of-life and Villalta scores (between-group difference=8.41 and 1.68, respectively, P<0.001 versus patients not receiving PCDT). PCDT did not improve postthrombotic syndrome scores for patients having a symptom-onset-to-randomization time of <4 days or >8 days. CONCLUSIONS: Taken together, these data illustrate that, within a restricted therapeutic window, RBF improves DVT resolution, and PCDT may improve clinical outcomes. Further studies are warranted to examine the value of time-restricted RBF strategies to reduce postthrombotic syndrome in patients with DVT.

Characterization of a dynamic self-replicating mammalian expression vector based on the circular ssDNA genome of beak and feather disease virus.

In vivo nucleic expression technologies using DNA or mRNA offer several advantages for recombinant gene expression. Their inherent ability to generate natively expressed recombinant proteins and antigens allows these technologies to mimic foreign gene expression without infection. Furthermore, foreign nucleic acid fragments have an inherent ability to act as natural immune adjuvants and stimulate innate pathogen- and DNA damage-associated receptors that are responsible for activating pathogen-associated molecular pattern (PAMP) and DNA damage-associated molecular pattern (DAMP) signalling pathways. This makes nucleic-acid-based expression technologies attractive for a wide range of vaccine and oncolytic immunotherapeutic uses. Recently, RNA vaccines have demonstrated their efficacy in generating strong humoral and cellular immune responses for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). DNA vaccines, which are more stable and easier to manufacture, generate similar immune responses to RNA, but typically exhibit lower immunogenicity. Here we report on a novel method of constructing self-amplifying DNA expression vectors that have the potential to amplify and enhance gene/antigen expression at a cellular level by increasing per cell gene copy numbers, boost genomic adjuvating effects and mitigate through replication many of the problems faced by non-replicating vectors such as degradation, methylation and gene silencing. These vectors employ a viral origin rolling circle replication cycle in mammalian host cells that amplifies the vector and gene of interest (GOI) copy number, maintaining themselves as nuclear episomes. We show that these vectors maintain persistently elevated GOI expression levels at the cellular level and induce morphological cellular alterations synonymous with increased cellular stress.

Cost-Effectiveness in Perioperative Care: Application of Markov Modeling to Pathways of Perioperative Care.

OBJECTIVES: This study aimed to evaluate the application of cost-effectiveness modeling to redesign of perioperative care pathways, from a hospital perspective. METHODS: A Markov cost-effectiveness model of patient transition between care locations, each with different characteristics and cost, was developed. Inputs were derived from clinical trials piloting a preoperative call center and a postoperative medium-acuity care unit. The effect chosen was days at home (DAH) after surgery, reflecting quality of in-hospital care, acknowledged financially by fundholders, and relevant to consumers. Cost was from the hospital's perspective. A model cycle time of 4 hours for 30 days reflected relevant timelines and costs. RESULTS: A Markov model was successfully created, accounting for the care locations in the 2 pathways as model states and accounting for consequences and costs. Cost-effectiveness analysis allowed the calculation of an incremental cost-effectiveness ratio comparing these pathways, providing a mean incremental cost-effectiveness ratio of -$427 per additional DAH, where incremental costs and DAH were -$644 and +1.51, respectively. Probabilistic sensitivity analysis suggested the new pathway had a 61% probability of reduced costs and a 74% probability of increased DAH and a 58% probability this pathway was dominant. Tornado analysis revealed the major contributor to increased costs as intensive care unit stay and the major contributor to decreased costs as ward stay. For the new pathway, the probability of transfer from ward to home and the probability of staying at home had the greatest impact on DAH. CONCLUSIONS: These data suggest Markov modeling may be a useful tool for the cost-effectiveness analysis of initiatives in perioperative care.

Improving safety and outcomes in perioperative care: does implementation matter?

The IMPROVE study describes a large perioperative quality improvement project with reporting of both compliance with improvement activities and patient outcomes. It highlights the importance of such projects, as well as the challenges in implementing change and proving benefit. Challenges identified include the importance of effective training in practice change, selection of trial design and relevant quality measures, and how the context of quality improvement initiatives may influence outcomes. Quality improvement programmes of this nature, despite the difficulties with implementation and trial design, remain a high priority because of their positive influence on improving clinical practice.

Successful Neonatal, Intraoperative Neuromonitoring in the Surgical Correction of a Thoracic Dermal Sinus Tract: Technical Note.

INTRODUCTION: Intraoperative neuromonitoring (IONM) is commonly used during surgery of the spine and spinal cord for early surveillance of iatrogenic injury to the central and peripheral nervous system. However, for infants and young children under 3 years of age, the use of IONM is challenging due to incomplete central and peripheral myelination. CASE PRESENTATION: We report a case of a T4-T6 dermal sinus tract (DST) that was resected on day of life 23, with the successful use of IONM. CONCLUSION: To our knowledge, this is the youngest reported case of the use of IONM in the surgical correction of a DST in a neonatal patient. This case demonstrates the potential efficacy of IONM in neonatal spine surgery and the techniques used to adapt the technology to an immature nervous system.

Advantage of Dimethyl Sulfoxide in the Fabrication of Binder-Free Layered Double Hydroxides Electrodes: Impacts of Physical Parameters on the Crystalline Domain and Electrochemical Performance.

The electrode fabrication stage is a crucial step in the design of supercapacitors. The latter involves the binder generally for adhesive purposes. The binder is electrochemically dormant and has weak interactions, leading to isolating the active material and conductive additive and then compromising the electrochemical performance. Designing binder-free electrodes is a practical way to improve the electrochemical performance of supercapacitors. However, most of the methods developed for the fabrication of binder-free LDH electrodes do not accommodate LDH materials prepared via the co-precipitation or ions exchange routes. Herein, we developed a novel method to fabricate binder-free LDH electrodes which accommodates LDH materials from other synthesis routes. The induced impacts of various physical parameters such as the temperature and time applied during the fabrication process on the crystalline domain and electrochemical performances of all the binder-free LDH electrodes were studied. The electrochemical analysis showed that the electrode prepared at 200 °C-1 h exhibited the best electrochemical performance compared to its counterparts. A specific capacitance of 3050.95 Fg-1 at 10 mVs-1 was achieved by it, while its Rct value was 0.68 Ω. Moreover, it retained 97% of capacitance after 5000 cycles at 120 mVs-1. The XRD and FTIR studies demonstrated that its excellent electrochemical performance was due to its crystalline domain which had held an important amount of water than other electrodes. The as-developed method proved to be reliable and advantageous due to its simplicity and cost-effectiveness.

[Results of radiofrequency on small renal masses: Complications, effects on renal fonction and oncological outcomes]. / Résultats périopératoires de la radiofréquence sur les petites tumeurs du rein : complications, impact sur la fonction rénale et résultats oncologiques.

INTRODUCTION: Finding of small renal masses and their ablative treatment has increased in patients unfit for surgery. The purpose of this study was to evaluate efficacy of Radiofrequency on those lesions. MATERIAL AND METHOD: A retrospective monocentric study of radiofrequency between 2009 and 2017 on small renal masses was undertaken. Complications, effects on renal function and oncological outcomes, were evaluated. RESULTS: One hundred and three tumors were treated over 96 patients. Two patients (2%) had major complications (Clavien Dindo>=3). Glomerular filtration rate was 66ml/min (±21ml/min) before procedure versus 59ml/min (±21ml/min) after (P<0,001). Ninety-five patients (99%) did not present recurrence with a median follow up of 22,8 months {9,6 ; 37,2}. CONCLUSION: Radiofrequency is a safe technique with low impact on renal function and good oncological outcomes. Selection of patients based on comorbidities, renal status, tumoral data (RENAL score) must be specified to evaluate at long term efficacy of RF.

[Effectiveness of sacral neuromodulation in patients with Parkinson's disease]. / Efficacité de la neuromodulation sacrée chez le patient parkinsonien.

INTRODUCTION: The urinary disorders of the patients with Parkinson's disease are complex and have a negative impact on their quality of life. None of therapy is considered effective ; whether drug or surgical. Sacral neuromodulation, recommended in other neurological pathologies such as multiple sclerosis, has never been studied in the patients with Parkinson's disease. The objective of our study is to assess the efficacy of sacral neuromodulation in the patients with Parkinson's disease. MATERIAL AND METHOD: Multicentric retrospective cohort study, of 22 parkinsonian patients who underwent a sacral neuromodulation test. Epidemiological, clinical and urodynamic data were collected for each patient. A long-term effectiveness telephone survey was conducted. RESULTS: Twenty two patients with Parkinson's disease had a sacral neuromodulation test. 17/22 (77%) had Idiopathic Parkinson's Disease and 5/22 (23%) had Systematized Multi Atrophy. Clinically, the indication for the sacral neuromodulation test was overactive bladder in 68% of the cases. Urodynamically, detrusor hyperactivity is found in 12 patients (8 MPI, 4 AMS). Sacral neuromodulation was effective in only 7 patients (6 MPI and 1 AMS). Rather, the profile of the patient in whom NMS is effective is female, mature, and with PID. The long-term effectiveness of NMS is disappointing. Only 2 permanently implanted patients retained urinary benefit. CONCLUSION: NMS improves urinary symptoms in the patients with Parkinson's disease in 32% of cases. It fluctuates over time and loses its effectiveness in the long term.

[Comparison of systematic, targeted and combined prostate biopsies for the diagnosis of prostate cancer with MRI lesion]. / Comparaison des biopsies de prostate systématiques, ciblées et combinées pour le diagnostic de cancer de prostate en cas de lésion à l'IRM.

OBJECTIVE: The objective of our study is to compare the performance of systematic, targeted and combined biopsies in the same cohort for the detection of clinically significant prostate cancer (csCaP). MATERIAL AND METHOD: We included patients coming for first series of prostate biopsies, from January 2016 to May 2020, with at least one PI-RADS lesion ≥3 on MRI. All patients underwent 12 systematic biopsies, combined with at least 2 biopsies per target lesion, using the MRI/3D ultrasound fusion system Urostation® (Koelis). RESULTS: We included 234 patients. Combined biopsies allowed a better detection rate of csCaP (59.4%) compared to systematic biopsies (55.6%, P=0.01) and targeted biopsies alone (44.4%, P<0.001). The same is true for the overall prostate cancer (CaP) rate: 65.4% for the combined biopsies versus 61.1% for the systematic biopsies (P=0.002) and 49.1% for the targeted biopsies (P<0.001). The detection rates of clinically non-significant prostate cancer (ncsCaP) were similar (6% vs. 5.6% vs. 4.7% for combined, systematic and targeted biopsies respectively). Targeted biopsies found 10 (4.3%) CaP undiagnosed by systematic biopsies including 6 (2.6%) csCaP, and an upgraded ISUP score for 17 (7.3%) patients. Systematic biopsies found 38 (16.2%) CaP undiagnosed by targeted biopsies including 33 (14.1%) csCaP, and allowed an upgraded ISUP score for 19 (8.1%) patients. CONCLUSION: Combined biopsies provide the best detection rate for csCaP in our study.

Venous stasis-induced fibrinolysis prevents thrombosis in mice: role of α2-antiplasmin.

Stasis of venous blood triggers deep vein thrombosis by activating coagulation, yet its effects on the fibrinolytic system are not fully understood. We examined the relationship between stasis, fibrinolysis, and the development of experimental venous thrombosis. Effects of stasis-induced deep vein thrombosis and fibrinolysis on thrombosis were examined by inferior vena cava ligation in congenic mice with and without α2-antiplasmin (α2AP), the primary inhibitor of plasmin. Venous thrombus weights were measured and thrombus composition was determined by Martius scarlet blue and immunofluorescence staining. Venous thrombi from α2AP+/+ mice contained plasminogen activators, plasminogen activator inhibitor-1, plasminogen, and α2AP, which changed with thrombus age. Normal, α2AP+/+ mice developed large, occlusive thrombi within 5 hours after ligation; thrombi were even larger in plasminogen-deficient mice (P < .001). No significant thrombus formation was seen in α2AP-/- mice (P < .0001) or in α2AP+/+ mice treated with an α2AP-inactivating antibody (P < .001). Venous stasis activated fibrinolysis, measured by D-dimer levels, in α2AP-/- mice vs α2AP+/+ mice (P < .05). Inhibition of fibrinolysis by the indirect plasmin inhibitor ε-aminocaproic acid or by α2AP restored thrombosis in α2AP-/- mice. In addition to its effects on acute thrombosis, thrombus formation was also markedly suppressed in α2AP-/- mice vs α2AP+/+ mice (P < .0001) 1, 7, and 14 days after ligation. We conclude that experimental venous stasis activates the fibrinolytic system to block the development of venous thrombosis. Suppression of fibrinolysis by α2AP appears essential for stasis-induced thrombus development, which suggests that targeting α2AP may prove useful for preventing venous thrombosis.

A Low-Sodium Diet Boosts Ang (1-7) Production and NO-cGMP Bioavailability to Reduce Edema and Enhance Survival in Experimental Heart Failure.

Sodium restriction is often recommended in heart failure (HF) to block symptomatic edema, despite limited evidence for benefit. However, a low-sodium diet (LSD) activates the classical renin-angiotensin-aldosterone system (RAAS), which may adversely affect HF progression and mortality in patients with dilated cardiomyopathy (DCM). We performed a randomized, blinded pre-clinical trial to compare the effects of a normal (human-equivalent) sodium diet and a LSD on HF progression in a normotensive model of DCM in mice that has translational relevance to human HF. The LSD reduced HF progression by suppressing the development of pleural effusions (p < 0.01), blocking pathological increases in systemic extracellular water (p < 0.001) and prolonging median survival (15%, p < 0.01). The LSD activated the classical RAAS by increasing plasma renin activity, angiotensin II and aldosterone levels. However, the LSD also significantly up-elevated the counter-regulatory RAAS by boosting plasma angiotensin converting enzyme 2 (ACE2) and angiotensin (1-7) levels, promoting nitric oxide bioavailability and stimulating 3'-5'-cyclic guanosine monophosphate (cGMP) production. Plasma HF biomarkers associated with poor outcomes, such as B-type natriuretic peptide and neprilysin were decreased by a LSD. Cardiac systolic function, blood pressure and renal function were not affected. Although a LSD activates the classical RAAS system, we conclude that the LSD delayed HF progression and mortality in experimental DCM, in part through protective stimulation of the counter-regulatory RAAS to increase plasma ACE2 and angiotensin (1-7) levels, nitric oxide bioavailability and cGMP production.

[Penile prosthesis for erectile dysfunction in the neurological patient, indication, complications and satisfaction: Retrospective study on 27 patients]. / Implant pénien pour dysfonction érectile chez le patient neurologique, indication, complications et satisfaction : étude rétrospective sur 27 patients.

INTRODUCTION: Penile prosthesis for erectile dysfunction in patients with spinal cord injury or multiple sclerosis is sometimes discussed after failure of drug or instrumental treatments (vacuum). The objective of this study was to evaluate the complications, evolution and patient satisfaction after the implantation of a penile prosthesis in the neurological patient. MATERIALS AND METHODS: Multi-center retrospective study of 27 consecutive patients including 18 spinal cord injured patients and 9 patients with multiple sclerosis benefiting from the implantation of a penile prosthesis for erectile dysfunction purposes in two French centers between 2009 and 2019. Post-implantation complications, evolution of the use of the prosthesis and global patient satisfaction were evaluated using the standardized questionnaire Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) during a telephone call between March and May 2020. RESULTS: The average age of implantation was 46.4 years (±12.74). The length of follow-up to date of call was 6.05 years (±2.86). 8/27 patients (29.6 %) had at least one complication of any Clavien-Dindo grade included 2 infection. 2/27 (7,4 %) patients had a mechanical prosthesis injury during follow-up. The patient's dexterity with inflation of the prosthesis was perfect in 85 % of cases, and 75 % for deflation. The satisfaction rate for prosthesis use at the time of the call was 75.36/100pts for the patient and 66.88/100pts for the partner. CONCLUSION: This study found an increased rate of prothesis infection compared to the general population in the neurologic patient, but patient and partner satisfaction remain sustainable after more than 5 years of implantation. Dexterity was maintained over the long term, demonstrating a good selection of indications. These data invite to favorably consider the installation of a penile prosthesis in neurological patients who have failed first-line treatments. LEVEL OF EVIDENCE: 4.

Syntrophin binds directly to multiple spectrin-like repeats in dystrophin and mediates binding of nNOS to repeats 16-17.

Mutation of the gene encoding dystrophin leads to Duchenne and Becker muscular dystrophy (DMD and BMD). Currently, dystrophin is thought to function primarily as a structural protein, connecting the muscle cell actin cytoskeleton to the extra-cellular matrix. In addition to this structural role, dystrophin also plays an important role as a scaffold that organizes an array of signaling proteins including sodium, potassium, and calcium channels, kinases, and nitric oxide synthase (nNOS). Many of these signaling proteins are linked to dystrophin via syntrophin, an adapter protein that is known to bind directly to two sites in the carboxyl terminal region of dystrophin. A search of the dystrophin sequence revealed three additional potential syntrophin binding sites (SBSs) within the spectrin-like repeat (SLR) region of dystrophin. Binding assays revealed that the site at SLR 17 bound specifically to the α isoform of syntrophin while the site at SLR 22 bound specifically to the ß-syntrophins. The SLR 17 α-SBS contained the core sequence known to be required for nNOS-dystrophin interaction. In vitro and in vivo assays indicate that α-syntrophin facilitates the nNOS-dystrophin interaction at this site rather than nNOS binding directly to dystrophin as previously reported. The identification of multiple SBSs within the SLR region of dystrophin demonstrates that this region functions as a signaling scaffold. The signaling role of the SLR region of dystrophin will need to be considered for effective gene replacement or exon skipping based DMD/BMD therapies.

In Experimental Dilated Cardiomyopathy Heart Failure and Survival Are Adversely Affected by a Lack of Sexual Interactions.

Nearly one in three people in the U.S. will develop heart failure (HF), characterized by fluid retention (edema) in the lungs and elsewhere. This leads to difficult breathing, deterioration of physical capacity, restriction of normal activities and death. There is little data about the safety and effects of sexual interactions in patients with HF. We tested whether a lack of sexual interactions affected pathophysiological outcomes in a pre-clinical mouse model of dilated cardiomyopathy that recapitulates the progressive stages of human HF. Male mice were randomly given access to, or deprived from, sexual interactions with female mice, which were confirmed by videography and generation of offspring. Cohousing with access to sexual interactions markedly prolonged survival, while cohousing without access to sexual activity did not. Sexual interactions improved systolic function, reduced HF-associated edema, altered transcription of heart contractile protein genes and decreased plasma testosterone levels. To determine whether testosterone levels contributed to survival, testosterone levels were experimentally reduced. Reduction of testosterone levels significantly prolonged survival. Taken together, in mice with dilated cardiomyopathy, sexual activity altered cardiac contractile gene transcription, improved systolic function, reduced edema and prolonged survival which may be in part due to lower testosterone levels.

Corin Overexpression Reduces Myocardial Infarct Size and Modulates Cardiomyocyte Apoptotic Cell Death.

Altered expression of corin, a cardiac transmembrane serine protease, has been linked to dilated and ischemic cardiomyopathy. However, the potential role of corin in myocardial infarction (MI) is lacking. This study examined the outcomes of MI in wild-type vs. cardiac-specific overexpressed corin transgenic (Corin-Tg) mice during pre-MI, early phase (3, 24, 72 h), and late phase (1, 4 weeks) post-MI. Corin overexpression significantly reduced cardiac cell apoptosis (p < 0.001), infarct size (p < 0.001), and inhibited cleavage of procaspases 3, 9, and 8 (p < 0.05 to p < 0.01), as well as altered the expression of Bcl2 family proteins, Bcl-xl, Bcl2 and Bak (p < 0.05 to p < 0.001) at 24 h post-MI. Overexpressed cardiac corin also significantly modulated heart function (ejection fraction, p < 0.0001), lung congestion (lung weight to body weight ratio, p < 0.0001), and systemic extracellular water (edema, p < 0.05) during late phase post-MI. Overall, cardiac corin overexpression significantly reduced apoptosis, infarct size, and modulated cardiac expression of key members of the apoptotic pathway in early phase post-MI; and led to significant improvement in heart function and reduced congestion in late phase post-MI. These findings suggest that corin may be a useful target to protect the heart from ischemic injury and subsequent post-infarction remodeling.

[Cystocele repair by a light tension-free vaginal mesh: results after 6 years of follow-up]. / Cure de cystocèle par prothèse vaginale libre de faible grammage : résultats à 6 ans.

INTRODUCTION: The objective of this study was to evaluate the long-term anatomical and functional efficacy, but also the safety of tension-free vaginal mesh in cystocele repair. METHODS: This retrospective and monocentric study included 90 women who underwent a prolapse repair between June 2006 and November 2008. A light-weight polypropylene vaginal mesh (22g/m2, Novasilk COLOPLAST®) was used without any fixation. Females were followed at 1 month, 1 year, 3 years and 6 years. Only long-term results are presented in this study. The anatomical result was assessed by the POP-Q classification and the functional results by standardized symptoms (PFDI-20), sexuality (PISQ-12) and quality of life (PFIQ-7) questionnaires. RESULTS: 6 years after surgery, the follow-up rate was 74%. Anatomically, the prolapse recurrence rate (Ba≥0) was 17% (n=8). Functionally, the overall patient satisfaction rate was 89%. Quality of life and symptoms scores (4,11±8.45 vs. 17.5±14.4 and 35.8±15.9 vs 94±23.4 respectively) were significantly improved (p<0.001). Concerning the prevalence of the complication, the retraction and exposition rate was 1.7% (n=1) and a re-intervention rate was 6.7% (n=4). The rate of de novo dyspareunia was 1.7% (n=1). CONCLUSION: In this short retrospective series of vaginal mesh interposition for cystocele repair, the prevalence of medium-term patient satisfaction was high.