Selective progesterone receptor modulators: current applications and perspectives.

Selective progesterone receptor modulators (SPRMs) are steroid progesterone receptor ligands able to induce agonistic or antagonistic activities. Mifepristone, the class leader, was primarily used for pregnancy termination from the 1980s. Emergency contraception with extended activity was the second major development 30 years later, with mifepristone in some countries and ulipristal acetate world-wide.

Efficacy of Continuous Interleukin 1 Blockade in Mevalonate Kinase Deficiency: A Multicenter Retrospective Study in 13 Adult Patients and Literature Review.

Objective: To report efficacy and tolerance of interleukin 1 blockade in adult patients with mevalonate kinase deficiency (MKD).

Methods: We retrospectively collected data on 13 patients with MKD who had received anakinra (n = 10) and canakinumab (n = 7).

Results: Anakinra resulted in complete or partial remission in 3/10 and 5/10 patients, respectively, and no efficacy in 2/10, but a switch to canakinumab led to partial remission.

Emerging Issues in AAV-Mediated Gene Therapy.

In recent years, the number of clinical trials in which adeno-associated virus (AAV) vectors have been used for gene transfer has steadily increased. The excellent safety profile, together with the high efficiency of transduction of a broad range of target tissues, has established AAV vectors as the platform of choice for gene therapy. Successful application of the AAV technology has also been achieved in the clinic for a variety of conditions, including coagulation disorders, inherited blindness, and neurodegenerative diseases, among others.

Dual function of thalamic low-vigilance state oscillations: rhythm-regulation and plasticity.

During inattentive wakefulness and non-rapid eye movement (NREM) sleep, the neocortex and thalamus cooperatively engage in rhythmic activities that are exquisitely reflected in the electroencephalogram as distinctive rhythms spanning a range of frequencies from <1 Hz slow waves to 13 Hz alpha waves. In the thalamus, these diverse activities emerge through the interaction of cell-intrinsic mechanisms and local and long-range synaptic inputs. One crucial feature, however, unifies thalamic oscillations of different frequencies: repetitive burst firing driven by voltage-dependent Ca spikes.

Expanded neurochemical profile in the early stage of Huntington disease using proton magnetic resonance spectroscopy.

The striatum is a well-known region affected in Huntington disease (HD). However, other regions, including the visual cortex, are implicated. We have identified previously an abnormal energy response in the visual cortex of patients at an early stage of HD using P magnetic resonance spectroscopy ( P MRS).

Fertility outcomes in women experiencing severe complications after surgery for colorectal endometriosis.

Study Question: What are the fertility outcomes in women wishing to conceive after experiencing a severe complication from surgical removal of colorectal endometriosis?

Summary Answer: The pregnancy rate (PR) among women who wished to conceive after a severe complication of surgery for colorectal endometriosis was 41.2% (spontaneously for 80%, after ART procedure for 20%).

What Is Known Already: While the long-term benefit of surgery on pain and quality of life is well documented for women with colorectal endometriosis, it exposes women to the risk of severe complications.

Srf controls satellite cell fusion through the maintenance of actin architecture.

Satellite cells (SCs) are adult muscle stem cells that are mobilized when muscle homeostasis is perturbed. Here, we show that serum response factor (Srf) is needed for optimal SC-mediated hypertrophic growth. We identified Srf as a master regulator of SC fusion required in both fusion partners, whereas it was dispensable for SC proliferation and differentiation.

Prevention and management of adverse events of Novel agents in multiple myeloma: A consensus of the european myeloma network.

During the last few years, several new drugs have been introduced for treatment of patients with multiple myeloma, which have significantly improved treatment outcome. All of these novel substances differ at least in part in their mode of action from similar drugs of the same drug class, or are representatives of new drugs classes, and as such present with very specific side effect profiles. In this review, we summarize these adverse events, provide information on their prevention, and give practical guidance for monitoring of patients and for management of adverse events.

Plasma oxysterols: biomarkers for diagnosis and treatment in spastic paraplegia type 5.

The hereditary spastic paraplegias are an expanding and heterogeneous group of disorders characterized by spasticity in the lower limbs. Plasma biomarkers are needed to guide the genetic testing of spastic paraplegia. Spastic paraplegia type 5 (SPG5) is an autosomal recessive spastic paraplegia due to mutations in CYP7B1, which encodes a cytochrome P450 7α-hydroxylase implicated in cholesterol and bile acids metabolism.

Rescue of Pompe disease in mice by AAV-mediated liver delivery of secretable acid α-glucosidase.

Glycogen storage disease type II or Pompe disease is a severe neuromuscular disorder caused by mutations in the lysosomal enzyme, acid α-glucosidase (GAA), which result in pathological accumulation of glycogen throughout the body. Enzyme replacement therapy is available for Pompe disease; however, it has limited efficacy, has high immunogenicity, and fails to correct pathological glycogen accumulation in nervous tissue and skeletal muscle. Using bioinformatics analysis and protein engineering, we developed transgenes encoding GAA that could be expressed and secreted by hepatocytes.

Genetic and pharmacological inhibition of microRNA-92a maintains podocyte cell cycle quiescence and limits crescentic glomerulonephritis.

Crescentic rapidly progressive glomerulonephritis (RPGN) represents the most aggressive form of acquired glomerular disease. While most therapeutic approaches involve potentially toxic immunosuppressive strategies, the pathophysiology remains incompletely understood. Podocytes are glomerular epithelial cells that are normally growth-arrested because of the expression of cyclin-dependent kinase (CDK) inhibitors.

Urinary Disorders and Marfan Syndrome: A Series of 4 Cases.

Marfan syndrome is a genetic disease responsible for causing cardiovascular, eye and musculoskeletal damages. Urinary disorders are not common. We present 4 cases of chronic urinary tract symptoms, with 2 different pathophysiological processes.

Hospital-acquired pneumonia in ICU.

The French Society of Anesthesia and Intensive Care Medicine and the French Society of Intensive Care edited guidelines focused on hospital-acquired pneumonia (HAP) in intensive care unit (ICU). The goal of 16 French-speaking experts was to produce a framework enabling an easier decision-making process for intensivists. The guidelines were related to 3 specific areas related to HAP (prevention, diagnosis and treatment) in 4 identified patient populations (COPD, neutropenia, postoperative and pediatric).

Lomustine and Bevacizumab in Progressive Glioblastoma.

Background: Bevacizumab is approved for the treatment of patients with progressive glioblastoma on the basis of uncontrolled data. Data from a phase 2 trial suggested that the addition of bevacizumab to lomustine might improve overall survival as compared with monotherapies. We sought to determine whether the combination would result in longer overall survival than lomustine alone among patients at first progression of glioblastoma.

A double-blind, placebo-controlled trial of triheptanoin in adult polyglucosan body disease and open-label, long-term outcome.

Background: Adult polyglucosan body disease (APBD) is a progressive neurometabolic disorder caused by a deficiency of glycogen branching enzyme. We tested the efficacy of triheptanoin as a therapy for patients with APBD based on the hypothesis that decreased glycogen degradation leads to brain energy deficit.

Methods And Results: This was a two-site, randomized crossover trial of 23 patients (age 35-73 years; 63% men) who received triheptanoin or vegetable oil as placebo.

A strategy for multimodal data integration: application to biomarkers identification in spinocerebellar ataxia.

The growing number of modalities (e.g. multi-omics, imaging and clinical data) characterizing a given disease provides physicians and statisticians with complementary facets reflecting the disease process but emphasizes the need for novel statistical methods of data analysis able to unify these views.

Arctic Climate Change, Economy and Society (ACCESS): Integrated perspectives.

This introduction to the special issue presents an overview of the wide range of results produced during the European Union project Arctic Climate Change, Economy and Society (ACCESS). This project assessed the main impacts of climate change on Arctic Ocean's geophysical variables and how these impending changes could be expected to impact directly and indirectly on socio-economic activities like transportation, marine sea food production and resource exploitation. Related governance issues were examined.

Impact of hospital and surgeon case volume on morbidity in colorectal endometriosis management: a plea to define criteria for expert centers.

Unlabelled: National and international guidelines recommend referring patients with severe forms of endometriosis to expert centers. However, there is a lack of clear criteria to define an expert center. We examined the roles of surgeon and hospital procedure volumes as determinants of morbidity in deep infiltrating endometriosis of the rectum and sigmoid colon (DIERS).

Predicting Response to Intravesical Bacillus Calmette-Guérin Immunotherapy: Are We There Yet? A Systematic Review.

Context: Bacillus Calmette-Guérin (BCG) is currently the most effective intravesical therapy for nonmuscle invasive bladder cancer, reducing not only recurrence rates but also preventing progression and reducing deaths. However, response rates to BCG vary widely and are dependent on a multitude of factors.

Objective: To review existing data on clinical, pathologic, immune, and molecular markers that allow prediction of BCG response.

Bioengineered AAV Capsids with Combined High Human Liver Transduction In Vivo and Unique Humoral Seroreactivity.

Existing recombinant adeno-associated virus (rAAV) serotypes for delivering in vivo gene therapy treatments for human liver diseases have not yielded combined high-level human hepatocyte transduction and favorable humoral neutralization properties in diverse patient groups. Yet, these combined properties are important for therapeutic efficacy. To bioengineer capsids that exhibit both unique seroreactivity profiles and functionally transduce human hepatocytes at therapeutically relevant levels, we performed multiplexed sequential directed evolution screens using diverse capsid libraries in both primary human hepatocytes in vivo and with pooled human sera from thousands of patients.

Overcoming the Host Immune Response to Adeno-Associated Virus Gene Delivery Vectors: The Race Between Clearance, Tolerance, Neutralization, and Escape.

Immune responses in gene therapy with adeno-associated virus (AAV) vectors have been the object of almost two decades of study. Although preclinical models helped to define and predict certain aspects of interactions between the vector and the host immune system, most of our current knowledge has come from clinical trials. These studies have allowed development of effective interventions for modulating immunotoxicities associated with vector administration, resulting in therapeutic advances.