Assessment of Involuntary PFM Contractions in Comparison with Existing Literature and IUGA/ICS Terminology Reports.

INTRODUCTION AND HYPOTHESIS: Involuntary pelvic floor muscle (PFM) contractions are thought to occur during an increase in intra-abdominal pressure (IAP). Although no studies have assessed their presence in women with normal pelvic floor (PF) function, existing literature links the absence of involuntary PFM contractions to various PF dysfunctions. This study rectifies this lacuna by evaluating involuntary PFM contractions during IAP in healthy nulliparous women with no PF dysfunction, using visual observation and vaginal palpation. Results were compared with the literature and the IUGA/ICS Terminology Reports. METHODS: Nulliparous (n=149) women performed three sets of three maximal coughs. Visual observation and vaginal palpation were conducted in the standing and supine positions. The women were not instructed to contract their PFMs. Occurrence rates were calculated for each assessment method and position; differences between positions were analyzed using the Chi-squared test. RESULTS: Rates of occurrence of involuntary PFM contraction were low across both assessments and positions (5-17%). Significant differences were found between standing (5%) and supine (15%) positions for visual observation, but not vaginal palpation (15%, 17% respectively). Occurrence rates also differed compared with the literature and terminology reports. CONCLUSIONS: Contrary to clinical expectations, rates of occurrence of involuntary PFM contraction among our cohort of nulliparous women were extremely low. Digital palpation results showed high agreement with the terminology reports, but only partial agreement was observed for the visual observation results. Our study underscores the need for more research aimed at defining normal involuntary PF functions, a review of our understanding of involuntary PFM contractions, and better standardized guidelines for involuntary PFM assessment methods.

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.

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.

[An International Urogynecological Association (IUGA)/International Continence Society (ICS) joint report on the terminology for the conservative and non-pharmacological management of female pelvic floor dysfunction]. / Traduction française de la terminologie commune de l'International Urogynecological Association (IUGA) et de l'International Continence Society (ICS) relative à la prise en charge conservatrice et non pharmacologique des troubles pelvi-périnéaux de la femme.

INTRODUCTION: There has been an increasing need for the terminology for the conservative management of female pelvic floor dysfunction to be collated in a clinically-based consensus report. METHODS: This report combines the input of members and elected nominees of the Standardization and Terminology Committees of two International Organizations, the International Urogynecological Association (IUGA) and the International Continence Society (ICS), assisted at intervals by many external referees. An extensive process of nine rounds of internal and external review was developed to exhaustively examine each definition, with decision-making by collective opinion (consensus). Before opening up for comments on the webpages of ICS and IUGA, five experts from physiotherapy, neurology, urology, urogynecology and nursing were invited to comment on the paper. RESULTS: A terminology report for the conservative management of female pelvic floor dysfunction, encompassing over 200 separate definitions, has been developed. It is clinically-based with the most common symptoms, signs, assessments, diagnoses and treatments defined. Clarity and user-friendliness have been key aims to make it interpretable by practitioners and trainees in all the different specialty groups involved in female pelvic floor dysfunction. Ongoing review is not only anticipated but will be required to keep the document updated and as widely acceptable as possible. CONCLUSION: A consensus-based terminology report for the conservative management of female pelvic floor dysfunction has been produced aimed at being a significant aid to clinical practice and a stimulus for research.

Evidence for a relationship between Ehlers-Danlos type VII C in humans and bovine dermatosparaxis.

Ehlers-Danlos (ED) syndrome type VII is characterized by the accumulation of collagen precursors in connective tissues. ED VII A and B are caused by mutations in the genes of alpha 1 and alpha 2 collagen I which result in the disruption of the cleavage site of procollagen I N-proteinase. The existence of ED VII C in humans has been hypothesized on the basis of a disorder in cattle and sheep related to the absence of the enzyme. We now present evidence for the existence of this disease in humans, characterized by skin fragility, altered polymers seen as hieroglyphic pictures with electron microscopy, accumulation of p-N-alpha 1 and p-N-alpha 2 collagen type I in the dermis and absence of processing of the p-N-I polypeptides in fibroblast cultures.

Identification of mutations in the alpha 3(IV) and alpha 4(IV) collagen genes in autosomal recessive Alport syndrome.

Alport syndrome (AS) is an hereditary disease of basement membranes characterized by progressive renal failure and deafness. Changes in the glomerular basement membrane (GBM) in AS suggest that the type IV collagen matrix, the major structural component of GBM, is disrupted. We recently isolated the genes for two type IV collagens, alpha 3(IV) and alpha 4(IV), that are encoded head-to-head on human chromosome 2. These chains are abundant in normal GBM but are sometimes absent in AS. We screened for mutations in families in which consanguinity suggested autosomal recessive inheritance. Homozygous mutations were found in alpha 3(IV) in two families and in alpha 4(IV) in two others, demonstrating that these chains are important in the structural integrity of the GBM and that there is an autosomal form of AS in addition to the previously-defined X-linked form.

17q21.31 microduplication patients are characterised by behavioural problems and poor social interaction.

BACKGROUND: Microdeletions at 17q21.31 have recently been shown to cause a novel syndrome. Here we identify the reciprocal 17q21.31 duplication syndrome in 4 patients. METHOD: Patients with the 17q21.31 duplication were identified by screening a large cohort of patients (n = 13,070) with mental retardation and congenital malformation by comparative genomic hybridisation microarray. Parental origin was investigated in 3 patients by quantitative polymerase chain reaction and microsatellite genotyping. RESULTS: In three cases it was possible to show that duplication arose de novo. Intellectual skills range from normal to mild mental retardation. Patients are characterised by poor social interaction, with relationship difficulties, reminiscent of autistic spectrum disorders. Other features are rather variable with no striking common phenotypic features. Parental origin was investigated for 3 patients. In all cases duplication was of maternal origin either through interchromosomal (2 cases) or interchromatid (1 case) rearrangement. The 3 mothers are all carriers of the inverted H2 haplotype, emphasising the role of local genomic architecture alteration as a predisposing factor for this duplication. CONCLUSION: Autistic features observed in our patients suggest that genes in the duplicated interval should be considered as candidates for disorders in the autistic spectrum. Other phenotypic observations are rather variable or aspecific. This adds 17q21.31 duplications to a growing group of recently identified genomic disorders with variable penetrance and expressivity.

Hereditary axonal neuropathy related to MME gene mutation in a family with fetomaternal alloimmune glomerulonephritis.

We report a consanguineous family with a homozygous and heterozygous membrane metallo-endopeptidase (MME) mutation (c.467delC) and two clinical conditions: fetomaternal alloimmune membranous glomerulopathy (FMG) and hereditary motor and sensory axonal neuropathy. The penetrance of both phenotypes was variable. Some individuals experienced unusually fast neurological degradation. Pain and vasomotor signs were frequent complaints, possibly due to a loss of the neutral endopeptidase (NEP, the MME gene product) function and its subsequent inability to degrade substance P and vasomotor peptides. Electrophysiological and nerve biopsy findings were consistent with predominantly axonal neuropathy. This specific clinical phenotype was attributed to a c.467delC MME gene mutation. Diagnosis of such a mutation is important but can be challenging, due to allele dropout. Heterozygous subjects who had already reached the expected age of disease onset had peripheral neuropathy, but also suffered from additional diseases. Neurologists should advise women of childbearing age with MME mutations to seek pre-pregnancy genetic advice and nephrologists should search for neuropathy in patients with FMG.

99mTc-HMPAO labelled white blood cell scintigraphy in patients with osteoarticular infection: the value of late images for diagnostic accuracy and interobserver reproducibility.

The objectives of this study were to evaluate the diagnostic value of 99mTc-HMPAO labelled white blood cell scintigraphy (WBCS) in patients with suspected osteomyelitis using late images and to study interobserver reproducibility. This study prospectively included 120 patients, and after a follow-up of one year, only 70 patients (n = 49 with implants, n = 21 without implants) were selected. The final diagnosis of infection was based either on microbiological data (n = 54) or follow-up (n = 16). We performed WBCS with 4 h and 24 h scans. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 77%, 72%, 83%, 64%, and 75% at 4 h, and 74%, 87%, 91%, 59%, and 79% at 24 h, respectively. The interobserver reproducibility shows a 63% prevalence of agreement between results (kappa = 0.5) at 4 h and 80% (kappa = 0.74) at 24 h, respectively. WBCS with 24-h images improves specificity and interobserver reproducibility in patients with suspected osteoarticular sepsis.

Fluorescence in situ hybridization analysis of 110 hematopoietic disorders with chromosome 5 abnormalities: do de novo and therapy-related myelodysplastic syndrome-acute myeloid leukemia actually differ?

A retrospective cytogenetic study of acute myeloid leukemias (AML) and myelodysplastic syndromes (MDS) was conducted by the Groupe Francophone de Cytogénétique Hématologique (GFCH) to evaluate the structural abnormalities of chromosome 5 associated with other chromosomal abnormalities, in particular of chromosome 7, in these pathologies. In all, 110 cases of AML/MDS were recruited based on the presence of chromosome 5 abnormalities under conventional cytogenetics and supplemented by a systematic fluorescence in situ hybridization study of chromosomes 5 and 7. The abnormalities of the long arm of chromosome 5 (5q) were deletions of various sizes and sometimes cryptic. The 5q abnormalities were associated with translocations in 54% of cases and were simple deletions in 46%. In 68% of cases, 5q deletions were associated with chromosome 7 abnormalities, and 90% of these presented a complex karyotype. Of the 110 patients, 28 had a hematopoietic disorder secondary to chemotherapy, radiotherapy, or both. Among 82 patients with de novo AML/MDS, 63 were older than 60 years. Chromosomal abnormalities often associated hypodiploidy and chromosome 5 and 7 abnormalities in complex karyotypes, features resembling those of secondary hemopathies. Systematic investigation of the exposure to mutagens and oncogenes is thus essential to specify the factors potentially involved in MDS/AML with 5q abnormalities.

Role of anti-tumour necrosis factor-alpha therapeutic agents in the emergence of infections.

There is increasing interest concerning the possible impact of anti-tumour necrosis factor (TNF)-alpha therapeutic agents on the emergence of infections. However, these agents do not seem to increase the incidence of adverse infectious events significantly. Published observations concern mostly infections of the urinary and upper respiratory tracts that develop in the setting of co-morbidities, such as anterior or concomitant immunosuppressive treatment. Infliximab appears to increase the risk of tuberculosis, but this effect has not been observed with other anti-TNF-alpha agents. To better characterise the adverse infectious effects associated with these agents, physicians should be encouraged to notify the microbiological data relating to all cases.

Pelvic floor muscle training versus no treatment, or inactive control treatments, for urinary incontinence in women.

BACKGROUND: Pelvic floor muscle training is the most commonly used physical therapy treatment for women with stress urinary incontinence. It is sometimes recommended for mixed and less commonly urge urinary incontinence. OBJECTIVES: To determine the effects of pelvic floor muscle training for women with urinary incontinence in comparison to no treatment, placebo or sham treatments, or other inactive control treatments. SEARCH STRATEGY: The Cochrane Incontinence Group Specialised Trials Register was searched. The date of the most recent search was 1 December 2004. SELECTION CRITERIA: Randomised or quasi-randomised trials in women with stress, urge or mixed urinary incontinence (based on symptoms, signs, or urodynamics). One arm of the trial included pelvic floor muscle training (PFMT). Another arm was a no treatment, placebo, sham, or other inactive control treatment arm. DATA COLLECTION AND ANALYSIS: Trials were independently assessed for eligibility and methodological quality. Data were extracted then cross-checked. Disagreements were resolved by discussion. Data were processed as described in the Cochrane Handbook (Higgins 2005). Trials were subgrouped by diagnosis. Formal meta-analysis was not undertaken because of study heterogeneity. MAIN RESULTS: Thirteen trials involving 714 women (375 PFMT, 339 controls) met the inclusion criteria, but only six trials (403 women) contributed data to the analysis. Most studies were at moderate to high risk of bias, based on the trial reports. There was considerable variation in interventions used, study populations, and outcome measures. Women who did PFMT were more likely to report they were cured or improved than women who did not. PFMT women also experienced about one fewer incontinence episodes per day. There were too few data to draw conclusions about effects on other outcomes such as condition specific quality of life. Of the few adverse effects reported, none were serious. The trials in stress urinary incontinent women which suggested greater benefit recruited a younger population and recommended a longer training period than the one trial in women with detrusor overactivity (urge) incontinence. AUTHORS' CONCLUSIONS: Overall, the review provides some support for the widespread recommendation that PFMT be included in first-line conservative management programmes for women with stress, urge, or mixed, urinary incontinence. Statistical heterogeneity reflecting variation in incontinence type, training, and outcome measurement made interpretation difficult. The treatment effect might be greater in younger women (in their 40's and 50's) with stress urinary incontinence alone, who participate in a supervised PFMT programme for at least three months, but these and other uncertainties require testing in further trials.

Orofacial clefting: update on the role of genetics.

INTRODUCTION: Cleft lip with or without cleft palate (CL/P) is one of the most common birth defects in the world. Prevalence varies between populations, with an average of 1/700. CL/P has a major clinical impact, requiring surgical, dental, orthodontic, speech, hearing and psychological management throughout childhood. The aetiology of CL/P is mostly unknown, and it is thought that both genetic and environmental factors play a role. Several causative genes for inherited syndromic forms of CL/P have been identified, and some recent studies have shown that these genes also contribute to the occurrence of isolated forms. Van der Woude syndrome (VWS) is one of the best models for non-syndromic CLP. It is an autosomal dominant disorder characterised by the presence of pits on the lower lip in addition to CL/P. Pits are the only feature distinguishing VWS from isolated clefts. Interestingly, in numerous VWS patients, the lip pits are very small and not readily diagnosed, thus mimicking isolated CL/P. Mutations in the IRF6 gene were shown to be the major genetic cause of VWS.' RESULTS: We performed direct sequence analysis of IRF6 on samples from a large European cohort and identified mutations in 27 (80%) families. This shows that IRF6 is the major causative gene of VWS in Europe also. Moreover, it is the gene to study when a seemingly isolated CL/P patient has minor signs, such as lip pits, since the identification of a mutation in IRF6 is associated with an increase in the risk of having a child with CL/P from 4-6%, the risk of transmission of an isolated cleft, to 50%, the risk of transmission of a dominant Mendelian disorder like VWS. Moreover, we studied the association of isolated CL/P with the IRF6 locus using two variants in a set of 195 patients from Belgium. As in an American study, a clear association was observed. This suggests that IRF6 also contributes to the occurrence of sporadic, isolated CL/P, even if no mutation in the gene can be identified in such patients. CONCLUSION: In conclusion, genes that are mutated in familial syndromic forms of CL/P may be predisposing genetic factors to sporadic isolated CL/P. Due to technological advances and the availability of the human genome sequence, we have now the opportunity to try and unravel the genetic factors behind the various forms of CL/P.

Effectiveness and safety profile of leflunomide in rheumatoid arthritis: actual practice compared with clinical trials.

OBJECTIVE: Leflunomide, an immunosuppressant agent for treating rheumatoid arthritis, was first marketed in France in 2000. Three years after its launch, we sought to assess its prescription patterns in the real world of prescription and use, and to see if its efficacy and safety profiles observed during clinical trials were confirmed. METHODS: All patients treated with leflunomide from May 2000 to April 2003 in the Department of Rheumatology of the Bordeaux University Hospital were identified, and their treatment patterns and outcome ascertained. This was compared to data from clinical trials. RESULTS: 116 were included (mean age = 55 years, 70% women). Almost 21.7% stopped treatment for lack of efficacy (after a mean delay of 3.6 months), 16% for secondary loss of efficacy (median = 7 months), and 32% for the occurrence of an adverse event (half within 4 months). Over a similar time frame in clinical trials, in patients of about the same age and sex but with less severe disease, the corresponding figures were 7-17% for lack or loss of efficacy, and 14-22% for adverse effects. At one year of follow-up, the discontinuation rate was 70% in the cohort compared to 28-47% in clinical trials. DISCUSSION: The differences between the two populations confirm the need to conduct post-marketing studies in order to obtain better knowledge on the effectiveness and safety of a new drug. In many cases, a simple drug utilization study can provide relevant information on the degree of shift between populations included in clinical trials and those treated in real life.

Hematological malignancies with a deletion of 11q23: cytogenetic and clinical aspects. European 11q23 Workshop participants.

Balanced translocations of 11q23 are associated with specific clinical features and a poor outcome, but the relevance of deletions involving 11q23 is not clear. Fifty-seven patients with this deletion were collected by the Workshop, 30 had terminal and 27 had interstitial deletions. Twenty-seven patients had acute lymphoblastic leukemia (ALL), 16 had acute myeloid leukemia (AML), one had acute biphenotypic leukemia, one had acute undifferentiated leukemia and 12 had myelodysplastic syndrome (MDS). ALL patients had a median age of 7 years, median white blood cell count (WBC) of 15 x 10(9)/l, and 10/24 had common ALL. AML patients had a median age of 23 years, a median WBC of 49 x 10(9)/l, and 9/16 had M4 or M5. MDS patients were all adult, median age of 69 years, median WBC of 3 x 10(9)/l, and 7/12 had refractory anemia. The clinical outcome depended on diagnosis: children with ALL had a better prognosis (4/16 relapsed, one died) than AML patients; all adults and children with AML and 5/12 MDS patients died. Fluorescence in situ hybridization (FISH) identified 3 del(11q23) as translocations or insertions. Molecular studies revealed a MLL rearrangement in 8/10 patients. Because the involvement of MLL might be of prognostic relevance, identification of a del(11q23) should be an indication for FISH and molecular studies.

Allelic heterogeneity of SMARD1 at the IGHMBP2 locus.

Spinal Muscular Atrophy with Respiratory Distress (SMARD) is an autosomal recessive disorder characterized by neurogenic muscular atrophy due to progressive anterior horn cell degeneration and early life-threatening respiratory failure ascribed to diaphragmatic dysfunction. SMARD is clinically and genetically heterogeneous. SMARD type 1 is characterized by onset of respiratory failure within the first weeks of life and has been ascribed to mutations in the immunoglobulin mu-binding protein 2 (IGHMBP2) gene on chromosome 11q13-q21. We report here the identification of nine novel IGHMBP2 mutations in five SMARD1 patients, including seven missense [ c.587A>G (p.Gln196Arg), c.647C>T (p.Pro216Leu), c.752T>C (p.Leu251Pro), c.1693G>A (p.Asp565Asn), c.1730T>C (p.Leu577Pro), c.1807C>T (p.Arg603Cys), c.1909C>T (p.Arg637Cys)] and two nonsense mutations [ c.1488C>A (p.Cys496X), c.2368C>T (p.Arg790X)]. Interestingly, 7 of 9 mutations occurred at highly conserved residues of the putative DNA helicase domain. The identification of novel IGHMBP2 variants will hopefully help diagnosing SMARD1 and contribute to a better functional characterization of IGHMBP2 gene product.

Clinical evaluation of stenosis of the carotid bifurcation with magnetic resonance angiographic techniques.

We evaluated the images of 60 carotid artery bifurcations in 31 patients suspected to have carotid artery disease who underwent invasive carotid angiography and combined two-dimensional, phase-sensitive and a gradient-echo magnetic resonance angiography. The phase scans consisted of seven serial projections that were obtained at 20 degrees intervals (11.0 minutes) around the carotid bifurcation; the gradient-echo (GRASS) scans were composed of 11 axial images (2.4 minutes) acquired through the bifurcation. The two magnetic resonance angiographic techniques yielded complementary pieces of information and were used together to compare magnetic resonance angiography with invasive angiography. Comparison of magnetic resonance and invasive angiograms of the 60 carotid arteries shows that the sensitivity (86%) and specificity (92%) of the magnetic resonance angiographic techniques we used to diagnose clinically significant carotid stenosis approach but do not reach those of invasive angiography.

Congenital muscular dystrophy with central and peripheral nervous system involvement in a Belgian patient.

We report a patient with congenital muscular dystrophy (CMD), developmental brain defects, and peripheral neuropathy. Marked hypotonia and plagiocephaly were noted at birth. Failure to thrive, generalized muscle weakness and wasting, absent deep tendon reflexes, partial seizures, and secondary microcephaly developed. Brain MRI showed a large area of cortical dysplasia, a thin but complete corpus callosum, and diffuse ventriculomegaly. Nerve conduction velocities were slow and creatine kinase levels only mildly elevated. Muscle biopsy showed dystrophic features with normal merosin, sarcoglycan, and dystrophin immunostaining. The Japanese Fukuyama CMD founder mutation was not detected. This is the first report of a patient with merosin-positive CMD, cobblestone lissencephaly, and demyelinating peripheral neuropathy.

Oral-facial-digital syndrome type I in a newborn male.

We report on a newborn male, born at term with clinical manifestations of oral-facial-digital (OFD) syndrome type I. This syndrome is generally assumed to be inherited in an X-linked dominant fashion with lethality in males. Therefore, liveborn males are exceptional. This liveborn male also had Dandy-Walker malformation and polycystic kidneys. From a general point of view, distinction between the 8 types of OFD syndromes described so far appears subtle and considerable overlap exists between them. In this regard, it should be noted that polycystic kidneys different from adult polycystic kidney disease both macroscopically and microscopically are a frequent manifestation of OFD I.