Pelvic floor muscle rehabilitation for genitourinary syndrome of menopause: why, how and when?

Genitourinary syndrome of menopause (GSM) is caused by chronic deprivation of estrogen and other sex steroids during the postmenopausal period, which leads to changes in the vulvovaginal tissues. These changes cause bothersome symptoms, such as vaginal dryness, pruritus, dyspareunia, increased daytime urinary frequency, urgency and urinary incontinence, which have considerable negative effects on women's quality of life and sexual function. Recent studies have investigated a novel treatment approach for GSM. Pelvic floor muscle (PFM) rehabilitation, a low-cost conservative management with no side-effects, has been studied alone or in combination with other treatment modalities to reduce the signs and symptoms of GSM. The aim of this article is to discuss why PFM rehabilitation could be useful for women with GSM, how it may help improve signs and symptoms of GSM and when this treatment should be recommended.

[COVID-19 in children: SARS-CoV-2-related inflammatory multisystem syndrome mimicking Kawasaki disease]. / COVID-19 chez l'enfant : syndrome inflammatoire multi-systémique lié à SARS-CoV-2 mimant un syndrome de Kawasaki.

SARS-CoV-2 pandemics is characterized by a high level of infectivity and a high mortality among adults at risk (older than 65 years, obesity, diabetes, systemic hypertension). Following a common viral pneumonia, a multisystem inflammatory syndrome sometimes occurs, including an Acute Respiratory Distress Syndrome (ARDS) carrying a high mortality. Unlike most common respiratory viruses, children seem less susceptible to SARS-CoV-2 infection and generally develop a mild disease with low mortality. However, clusters of severe shock associated with high levels of cardiac biomarkers and unusual vasoplegia requiring inotropes, vasopressors and volume loading have been recently described. Both clinical symptoms (i.e., high and persistent fever, gastrointestinal disorders, skin rash, conjunctivitis and dry cracked lips) and biological signs (e.g., elevated CRP/PCT, hyperferritinemia) resembled Kawasaki disease. In most instances, intravenous immunoglobin therapy improved the cardiac function and led to full recovery within a few days. However, adjunctive steroid therapy and sometimes biotherapy (e.g., anti-IL-1Ra, anti-IL-6 monoclonal antibodies) were often necessary. Although almost all children fully recovered within a week, some of them developed coronary artery dilation or aneurysm. Thus, a new 'Multisystem Inflammatory Syndrome associated with SARS-CoV-2' has been recently described in children and helps to better understand Kawasaki disease pathophysiology.

Pelvic floor muscle training: mechanisms of action for the improvement of genitourinary syndrome of menopause.

Objective: This study aims to investigate the mechanism of action of pelvic floor muscle training (PFMT) for the improvement of the signs and symptoms of genitourinary syndrome of menopause (GSM) in postmenopausal women with GSM and urinary incontinence (UI).Methods: Twenty-nine women were included in the secondary analysis of a single-arm feasibility study. Using color Doppler ultrasound, the peak systolic velocity, time-averaged maximum velocity, and pulsatility index of the internal pudendal and dorsal clitoral arteries were measured at rest and after a pelvic floor muscle (PFM) contraction task. PFM function was assessed by dynamometry, and vulvovaginal tissue elasticity was measured using the Vaginal Atrophy Index.Results: PFMT significantly improved blood flow parameters in both arteries (p < 0.05) and significantly increased the speed of PFM relaxation after a contraction (p = 0.003). After the intervention, a marginally significant decrease in PFM tone was observed, as well as an increase in PFM strength (p = 0.060 and p = 0.051, respectively). Finally, improvements in skin elasticity and introitus width were observed as measured by the Vaginal Atrophy Index (p < 0.007).Conclusion: Our findings suggest that PFMT improves blood flow in vulvovaginal tissues, PFM relaxation capacity, and vulvovaginal tissue elasticity in postmenopausal women with GSM and UI.

Keeping the pelvic floor healthy.

Female pelvic floor muscles form a diaphragm that spans the entire pelvic cavity. They consist of the fibers of the coccygeus and the levator ani muscles, the latter of which is composed of five parts. Together with their fascia, the pelvic floor muscles provide support for the urethra, the vagina, and the rectum and constrict the urethral, vaginal, and anal orifices. Alterations in the composition of the pelvic floor muscles at menopause appear to affect their properties and, thereby, their ability to function adequately. This can lead to an increased prevalence in urinary incontinence and other lower urinary tract dysfunction, pelvic organ prolapse, and genitourinary syndrome of menopause. This article aims to define the pelvic floor muscles and functions and to summarize the direct and indirect changes to women's pelvic floor muscles during and after menopause and through aging. A particular focus is also given to the evidence-based literature on how to keep pelvic floor muscles healthy during menopause and in postmenopause using conservative management therapy.

Enhanced resonance of sparse arrays of Helmholtz resonators-Application to perfect absorption.

The influence of the spacing on the resonance of a periodic arrangement of Helmholtz resonators is inspected. An effective problem is used which accurately captures the properties of the resonant array within a large range of frequencies, and whose simplified version leaves an impedance condition. It is shown that the strength of the resonance is enhanced when the array becomes sparser. This degree of freedom on the radiative damping is of particular interest since it does not affect the resonance frequency nor the damping due to losses within each resonator; in addition, it does not affect the total thickness of the array. It is shown that it can be used for the design of a perfect absorbing wall.

Two weeks of high-fat feeding disturb lipid and cholesterol molecular markers.

Metabolic disorders are often associated with liver steatosis and increased plasma cholesterol levels. However, the link between excessive lipid accumulation and impairments in cholesterol metabolism remains uninvestigated in the liver. Short term of high-fat diet (HFD) was previously shown to promote excessive lipid accumulation prior to the development of metabolic disorders. The present study intended to characterize how increases in liver fat alter the expression of several key regulators of hepatic cholesterol metabolism in response to a short-term HFD. Wistar rats were randomly submitted either to HFD (n = 8) or a regular chow diet (n = 8) for 14 days. Increases in triglycerides were highly significant (P < 0.01) in the liver but marginal in the plasma of HFD rats. In contrast, the HFD resulted in higher (P < 0.01) cholesterol levels in plasma but not in liver samples. Gene expression of key markers involved in cholesterol uptake (LDL particles) including low-density lipoprotein receptor-related protein-1 (LRP-1) and protein convertase subtilisin/kexin type 9 (PCSK9) along with ATP-binding cassette, superfamily G, member 5 (ABCG5) involved in cholesterol exportation via bile ducts was found to be higher (P < 0.05) in response to the HFD. In contrast, expression of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR), involved in cholesterol synthesis, was downregulated in the liver. The data support the concept that excessive accumulation of lipids promptly alters the expression of key genes regulating cholesterol metabolism in the liver. On a clinical point of view, this indicates that increases in plasma cholesterol occur after a short-term HFD.

Combining balneotherapy and health promotion to promote active and healthy ageing: the Balaruc-MACVIA-LR® approach.

Scaling up and replication of successful innovative integrated care models for chronic diseases is one of the targets of the European Innovation Partnership on Active and Healthy Ageing (EIP on AHA). MACVIA-LR® (MAladies Chroniques pour un VIeillissement Actif en Languedoc-Roussillon) is a Reference Site of the EIP on AHA. The main objective of MACVIA-LR® is to develop innovative solutions in order to (1) improve the care of patients affected by chronic diseases, (2) reduce avoidable hospitalization and (3) scale up the innovation to regions of Europe. The MACVIA-LR® project also aims to assess all possible aspects of medicine-including non-pharmacologic approaches-in order to maintain health and prevent chronic diseases. These approaches include hydrotherapy and balneotherapy which can be of great importance if health promotion strategies are considered. Balneotherapy at Balaruc-les-Bains focusses on musculoskeletal diseases and chronic venous insufficiency of the lower limbs. Each year, over 46,000 people attend an 18-day course related to a new falls prevention initiative combining balneotherapy and education. On arrival, each person receives a flyer providing information on the risk of fall and, depending on this risk, a course is proposed combining education and physical activity. A pilot study assesses the impact of the course 6 and 12 months later. This health promotion strategy for active and healthy ageing follows the FEMTEC (World Federation of Hydrotherapy and Climatotherapy) concept.

Developmental determinants in non-communicable chronic diseases and ageing.

Prenatal and peri-natal events play a fundamental role in health, development of diseases and ageing (Developmental Origins of Health and Disease (DOHaD)). Research on the determinants of active and healthy ageing is a priority to: (i) inform strategies for reducing societal and individual costs of an ageing population and (ii) develop effective novel prevention strategies. It is important to compare the trajectories of respiratory diseases with those of other chronic diseases.

Generalized method for retrieving effective parameters of anisotropic metamaterials.

Electromagnetic or acoustic metamaterials can be described in terms of equivalent effective, in general anisotropic, media and several techniques exist to determine the effective permeability and permittivity (or effective mass density and bulk modulus in the context of acoustics). Among these techniques, retrieval methods use the measured reflection and transmission coefficients (or scattering coefficients) for waves incident on a metamaterial slab containing few unit cells. Until now, anisotropic effective slabs have been considered in the literature but they are limited to the case where one of the axes of anisotropy is aligned with the slab interface. We propose an extension to arbitrary orientations of the principal axes of anisotropy and oblique incidence. The retrieval method is illustrated in the electromagnetic case for layered media, and in the acoustic case for array of tilted elliptical particles.

Early inhaled nitric oxide at high dose enhances rat lung development after birth.

RATIONAL: Inhaled nitric oxide (NO) is frequently administered to full term and preterm newborns in various clinical settings in order to alleviate pulmonary hypertension whilst improving oxygenation. However, the physiological effect of NO on early postnatal lung development has not yet been clearly described. We therefore investigated whether NO administered by inhalation affects lung development at early postnatal life. METHODS: Pregnant rats were placed in a chamber containing 5 ppm (iNO-5 ppm group) and 20 ppm NO (iNO-20 ppm group), started from the last day of their pregnancy in order to keep rat pups under ambient NO from birth to 7 days postnatal. Control animals were kept at room air and all rat pups were sacrificed at postnatal day 7 and day 14. RESULTS: Lung-to-body weight and wet-to-dry lung weight ratios did not significantly differ among 3 groups at postnatal day 7 and day 14. Vascular volume densities (Vv) in both NO groups (5 and 20 ppm) were higher than controls (P<0.05; P<0.001). Pulmonary vessel number was significantly increased in iNO-20 ppm group. Radial alveolar counts (RAC) and mean linear intercepts (MLI) markedly increased (consistent with increased alveolarization) in iNO-20 ppm group. This was associated with upregulation of VEGF/VEGFR-2, MT1-MMP/MMP2 and HO-1 protein expression in iNO-20 ppm group. CONCLUSIONS: We concluded that inhaled NO at 20 ppm enhanced lung development possibly through increased expression of HO-1, VEGF/VEGFR-2, and MMP2 at early stage of postnatal rat life.

First Report of Podosphaera xanthii Race 1W Causing Powdery Mildew of Watermelon in California.

In September and October 2012, powdery mildew was detected on watermelon (Citrullus lanatus var. lanatus) plants of various breeding lines growing in field plots in Davis, California. Plants had partially necrotic leaves, yellowing to brown in color, with white surface mycelium and faint sporulation. No teleomorph was observed. Infected leaves were collected for examination and a spore suspension of the field isolate was made in water with 0.01% Tween 20 to spray inoculate watermelon seedlings of cultivar Dixie Lee with two true leaves. Plants were incubated in a growth chamber (22 to 26°C, 12-h photoperiod) for approximately 10 days, until sporulation was apparent. Microscopic observation of conidial chains showed that they had clearly crenate edges indicative of Podosphaera xanthii (4). To confirm the identity of the pathogen, we used Podosphaera-specific primers PFITS-F (5'-CCAACTCGTGCTGAGTGT-3') and PF5.8-R (5'-TGTTGGTTTCTTTTCCTCCG-3') to amplify and sequence the internal transcribed spacer regions of the nuclear rDNA. The 326-bp sequence had 98% homology to the GenBank sequence (accessions JQ340082.1 and AB774158.1) for P. xanthii. Infected 'Dixie Lee' leaves were used to make a spore suspension (approximately 5 × 104 conidia/ml) as described above to inoculate watermelon, melon, and squash seedlings (2 to 3 plants per cultivar) in a greenhouse. It caused severe symptoms on all watermelon plants cv. Charleston 76, P8, and Sugar Baby in the form of a powdery mildew with surface mycelium and chains of conidia, with leaves becoming gradually more necrotic and eventually dying, with the appearance of a melting down. Non-inoculated plants did not develop symptoms. The isolate also infected all squash plants 'Zucchini Elite' and melon powdery mildew differentials Iran H and 'Védrantais.' On these plants, the pathogen produced a powdery mildew (white surface mycelium with sporulation) but did not cause extensive necrosis. All other melon powdery mildew differentials ('PMR5,' 'PMR45,' WMR29, MR1, PI 124112, and PI 313970) did not develop any powdery mildew. A follow-up test in a growth chamber (22 to 26°C, 12-h photoperiod) with the same set of species and cultivars gave the same results. Based on these results, we conclude that this isolate belongs to race 1W (1,2). The presence of race 1W could have implications in disease management for this crop in the Central Valley of California as most cultivars are not resistant to it and the disease has been shown to cause severe damage in other states (1,3). References: (1) A. R. Davis et al. J. Am. Soc. Hort. Sci. 132:790, 2007. (2) J. D. McCreight. Amer. Soc. Hort. Sci. 131:59, 2006. (3) A. Y. Tetteh et al. Crop Sci. 50:933, 2010. (4) T. A. Zitter. Page 28 in: Compendium of Cucurbit Diseases, The American Phytopathological Society, St. Paul, MN, 1996.

Disturbance in uniformly 13C-labelled DHA metabolism in elderly human subjects carrying the apoE ε4 allele.

Carrying the apoE ε4 allele (E4+ ) is the most important genetic risk for Alzheimer's disease. Unlike non-carriers (E4- ), E4+ seem not to be protected against Alzheimer's disease when consuming fish. We hypothesised that this may be linked to a disturbance in n-3 DHA metabolism in E4+. The aim of the present study was to evaluate [13C]DHA metabolism over 28 d in E4+ v. E4-. A total of forty participants (twenty-six women and fourteen men) received a single oral dose of 40 mg [13C]DHA, and its metabolism was monitored in blood and breath over 28 d. Of the participants, six were E4+ and thirty-four were E4-. In E4+, mean plasma [13C]DHA was 31% lower than that in E4-, and cumulative b-oxidation of [13C]DHA was higher than that in E4- 1­28 d post-dose (P ≤0·05). A genotype x time interaction was detected for cumulative b-oxidation of [13C]DHA (P ≤ 0·01). The whole-body half-life of [13C]DHA was 77% lower in E4+ compared with E4- (P ≤0·01). In E4+ and E4-, the percentage dose of [13C]DHA recovered/h as 13CO2 correlated with [13C]DHA concentration in plasma, but the slope of linear regression was 117% steeper in E4+ compared with E4- (P ≤ 0·05). These results indicate that DHA metabolism is disturbed in E4+, and may help explain why there is no association between DHA levels in plasma and cognition in E4+. However, whether E4+ disturbs the metabolism of 13C-labelled fatty acids other than DHA cannot be deduced from the present study.

Diversity of ARSACS mutations in French-Canadians.

BACKGROUND: The growing number of spastic ataxia of Charlevoix-Saguenay (SACS) gene mutations reported worldwide has broadened the clinical phenotype of autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). The identification of Quebec ARSACS cases without two known SACS mutation led to the development of a multi-modal genomic strategy to uncover mutations in this large gene and explore phenotype variability. METHODS: Search for SACS mutations by combining various methods on 20 cases with a classical French-Canadian ARSACS phenotype without two mutations and a group of 104 sporadic or recessive spastic ataxia cases of unknown cause. Western blot on lymphoblast protein from cases with different genotypes was probed to establish if they still expressed sacsin. RESULTS: A total of 12 mutations, including 7 novels, were uncovered in Quebec ARSACS cases. The screening of 104 spastic ataxia cases of unknown cause for 98 SACS mutations did not uncover carriers of two mutations. Compounds heterozygotes for one missense SACS mutation were found to minimally express sacsin. CONCLUSIONS: The large number of SACS mutations present even in Quebec suggests that the size of the gene alone may explain the great genotypic diversity. This study does not support an expanding ARSACS phenotype in the French-Canadian population. Most mutations lead to loss of function, though phenotypic variability in other populations may reflect partial loss of function with preservation of some sacsin expression. Our results also highlight the challenge of SACS mutation screening and the necessity to develop new generation sequencing methods to ensure low cost complete gene sequencing.

ARSACS, a spastic ataxia common in northeastern Québec, is caused by mutations in a new gene encoding an 11.5-kb ORF.

Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS or SACS) is an early onset neurodegenerative disease with high prevalence (carrier frequency 1/22) in the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region of Quebec. We previously mapped the gene responsible for ARSACS to chromosome 13q11 and identified two ancestral haplotypes. Here we report the cloning of this gene, SACS, which encodes the protein sacsin. The ORF of SACS is 11,487 bp and is encoded by a single gigantic exon spanning 12,794 bp. This exon is the largest to be identified in any vertebrate organism. The ORF is conserved in human and mouse. The putative protein contains three large segments with sequence similarity to each other and to the predicted protein of an Arabidopsis thaliana ORF. The presence of heat-shock domains suggests a function for sacsin in chaperone-mediated protein folding. SACS is expressed in a variety of tissues, including the central nervous system. We identified two SACSmutations in ARSACS families that lead to protein truncation, consistent with haplotype analysis.

CFTR pharmacological modulators: A great advance in cystic fibrosis management.

Cystic fibrosis is a severe monogenic disease that affects around 7400 patients in France. More than 2100 mutations in the cystic fibrosis conductance transmembrane regulator (CFTR), the gene encoding for an epithelial ion channel that normally transports chloride and bicarbonate, lead to mucus dehydration and impaired bronchial clearance. Systematic neonatal screening in France since 2002 has enabled early diagnosis of cystic fibrosis. Although highly demanding, supportive treatments including daily chest physiotherapy, inhaled aerosol therapy, frequent antibiotic courses, nutritional and pancreatic extracts have improved the prognosis. Median age at death is now beyond 30 years. Ivacaftor was the first CFTR modulator found to both reduce sweat chloride concentration and improve pulmonary function in the rare CFTR gating mutations. Combinations of modulators such as lumacaftor + ivacaftor or tezacaftor + ivacaftor were found to improve pulmonary function both in patients homozygous for the F508del mutation characterized by the lack of CFTR protein and those heterozygous for F508del with minimal CFTR activity. The triple combination of ivacaftor + tezacaftor + elexacaftor was recently shown to significantly improve pulmonary function and quality of life, to normalize sweat chloride concentration, and to reduce the need for antibiotic therapy in patients with at least one F508del mutation (83% in France). These impressive data, however, need to be confirmed in the long term. Nevertheless, it is encouraging to hear treated patients testify about their markedly improved quality of life and to observe that the number of lung transplants for cystic fibrosis decreased dramatically in France after 2020, despite the COVID pandemic, with no increase in deaths without lung transplant.

Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins.

The most common and problematic side effect of statins is myopathy. To date, the patho-physiological mechanisms of statin myotoxicity are still not clearly understood. In previous studies, we showed that acute application in vitro of simvastatin caused impairment of mitochondrial function and dysfunction of calcium homeostasis in human and rat healthy muscle samples. We thus evaluated in the present study, mitochondrial function and calcium signaling in muscles of patients treated with statins, who present or not muscle symptoms, by oxygraphy and recording of calcium sparks, respectively. Patients treated with statins showed impairment of mitochondrial respiration that involved mainly the complex I of the respiratory chain and altered frequency and amplitude of calcium sparks. The muscle problems observed in statin-treated patients appear thus to be related to impairment of mitochondrial function and muscle calcium homeostasis, confirming the results we previously reported in vitro.

Effect of a high dose of simvastatin on muscle mitochondrial metabolism and calcium signaling in healthy volunteers.

Statin use may be limited by muscle side effects. Although incompletely understood to date, their pathophysiology may involve oxidative stress and impairments of mitochondrial function and of muscle Ca(2+) homeostasis. In order to simultaneously assess these mechanisms, 24 male healthy volunteers were randomized to receive either simvastatin for 80 mg daily or placebo for 8 weeks. Blood and urine samples and a stress test were performed at baseline and at follow-up, and mitochondrial respiration and Ca(2+) spark properties were evaluated on a muscle biopsy 4 days before the second stress test. Simvastatin-treated subjects were separated according to their median creatine kinase (CK) increase. Simvastatin treatment induced a significant elevation of aspartate amino transferase (3.38±5.68 vs -1.15±4.32 UI/L, P<0.001) and CK (-24.3±99.1±189.3 vs 48.3 UI/L, P=0.01) and a trend to an elevation of isoprostanes (193±408 vs 12±53 pmol/mmol creatinine, P=0.09) with no global change in mitochondrial respiration, lactate/pyruvate ratio or Ca(2+) sparks. However, among statin-treated subjects, those with the highest CK increase displayed a significantly lower Vmax rotenone succinate and an increase in Ca(2+) spark amplitude vs both subjects with the lowest CK increase and placebo-treated subjects. Moreover, Ca(2+) spark amplitude was positively correlated with treatment-induced CK increase in the whole group (r=0.71, P=0.0045). In conclusion, this study further supports that statin induced muscular toxicity may be related to alterations in mitochondrial respiration and muscle calcium homeostasis independently of underlying disease or concomitant medication.

Impact of implementing French antibiotic guidelines for acute respiratory-tract infections in a paediatric emergency department, 2005-2009.

Acute respiratory tract infections (ARTIs) are the main reason for antibiotic prescription in children. In 2005, the French Drug Agency published guidelines to minimise inappropriate use of antibiotics for ARTI. The purpose of this study was to assess the impact of implementing these guidelines in a paediatric emergency department. We retrospectively analysed data collected prospectively in a French paediatric emergency department from November 2005 (date of guideline implementation) to October 2009. For each child diagnosed with ARTI, we collected age, diagnosis, and prescribed antibiotics. We computed antibiotic prescription rates in the study population. During the study period, 53,055 children were diagnosed with ARTI and 59% of the 22,198 antibiotic prescriptions given at discharge were related to ARTI. The proportion of ARTI patients given antibiotic prescriptions fell from 32.1% during the first year to 21% in year 4 (p<10(-4), Cochran-Armitage test). Amoxicillin-clavulanic acid and amoxicillin accounted for 50% and 34% of antibiotic prescriptions for ARTI, respectively. French antibiotic guidelines led to significant decreases in antibiotic prescription for ARTI in our paediatric emergency department.

Interaction between maternal obesity and post-natal over-nutrition on skeletal muscle metabolism.

BACKGROUND AND AIMS: Maternal obesity and post-natal over-nutrition play an important role in programming glucose and lipid metabolism later in life. The aim of this study was to decipher the contributions of maternal obesity and post-natal over-nutrition on glucose and lipid metabolism in skeletal muscle. METHOD AND RESULTS: Male offspring of Sprague Dawley rat mothers fed either chow or high fat diet (HFD) for 5 weeks prior to mating were subsequently fed either chow or HFD until 18 weeks of age. Collection of plasma and skeletal muscle was performed at weaning (20 days) and 18 weeks. At weaning, offspring from obese mothers showed increased body weight, plasma insulin and lactate concentrations associated with reduced skeletal muscle glucose transporter 4 (GLUT4) and increased monocarboxylate transporter 1 (MCT1) protein. In 18-week old offspring, post-weaning HFD further exacerbated the elevated body weight caused by maternal obesity. Surprisingly this additive effect on body weight was not reflected in plasma glucose, insulin, lactate and MCT1; these markers were only increased by post-weaning HFD consumption. However, an additive effect of maternal obesity and post-weaning HFD led to decreased muscle GLUT4 levels, as well as mRNA levels of carnitine palmitoyl transferase-1, myogenic differentiation protein and myogenin. CONCLUSION: Post-weaning HFD exerted an additive effect to that of maternal obesity on body weight and skeletal muscle markers of glucose and lipid metabolism but not on plasma glucose and insulin levels, suggesting that maternal obesity and post-natal over-nutrition impair skeletal muscle function via different mechanisms.