Magnetic imaging defecography results are comparable to high-resolution manometry and conventional X-ray defecography in the assessment of functional pelvic floor disorders.

BACKGROUND: X-ray defecography or magnetic resonance defecography (MRD) and high-resolution anorectal manometry (HR-ARM) are essential for the diagnosis of pelvic floor disorders (PFD). However, there is only scarce information available about the accuracy of MRD in the functional assessment of the pelvic floor. The aim of this study was to examine the accuracy of MRD in the diagnosis of pelvic floor disorders by examining the intra-test agreement with x-ray defecography and HR-ARM in patients with PFD. METHODS: The study population included adults referred to our institution in January 2018-February 2020 for MRD as part of their evaluation of PFD. The MRD results were compared with X-ray defecography and HR-ARM. RESULTS: Forty-two patients were included in the study (36 female, 86%, mean age 56.9 years ± 15.8, range 19-86 years). When compared to X-ray defecography, the sensitivity of MRD for the evaluation of normal rest and squeeze pressures was high (0.83 and 1, respectively). High sensitivity rates were observed for the detection of pelvic organ prolapse and pelvic floor dyssynergia (0.84-1). When compared to HR-ARM, the sensitivity of MRD for the evaluation of squeeze and dyssynergia was very good (0.92and 1, respectively), and good for the evaluation of rest pressure (0.6). Inter-test agreement was high (0.5, 0.6, 0.6 for rest, squeeze and dyssynergia). Excellent rates of sensitivity as well as almost perfect intra-test agreement was found between abnormal balloon expulsion test and the diagnosis of dyssynergia and pelvic organ prolapse on MRD (1, 0.81). CONCLUSIONS: This study demonstrated substantial diagnostic agreement between HR-ARM and MRD in the diagnosis of pathological etiologies for functional pelvic floor disorders, mainly obstructed defecation syndrome.

The impact of a nationwide hands-on workshop on the diagnostic rates and management of obstetrical anal sphincter Injuries in Israel.

AIM: The aim was to evaluate the influence of a half day, hands-on, workshop on the detection and repair of obstetric anal sphincter injuries (OASIs). METHOD: Starting in February 2011, hands-on workshops for the diagnosis and repair of OASIs were delivered by trained urogynaecologists in departments of tertiary medical centres in Israel. The structure of the hands-on workshop resembles the workshop organized at the International Urogynecological Association annual conferences. Participants included medical staff, midwives and surgical residents from each medical centre. We collected data regarding the rate of OASIs, 1 year before and 1 year following the workshop, in 11 medical centres. The study population was composed of parturients with the following inclusion criteria: singleton pregnancy, vertex presentation and vaginal delivery. Pre-viable preterm gestations (< 24 weeks), birth weight < 500 g, stillborn, and those with major congenital anomalies, multifoetal pregnancies, breech presentations and caesarean deliveries were excluded from the analysis. RESULTS: In the reviewed centres, 70 663 (49.3%) women delivered prior to the workshop (pre-workshop group) and 72 616 (50.7%) women delivered following the workshop (post-workshop group). Third- or fourth-degree perineal tears occurred in 248 women (0.35%) before the workshop, and in 328 (0.45%) following the workshop, a significant increase of 28.7% (P = 0.002). The increase in diagnosis was significant also in women with third-degree tears alone, 226 women (0.32%) before the workshop and 298 (0.41%) following the workshop, an increase of 28.3% (P = 0.005). CONCLUSION: The detection rate of OASIs has significantly increased following the hands-on workshop. The implementation of such programmes is crucial for increasing awareness and detection rates of OASI following vaginal deliveries.

The TEL-AML1 fusion protein of acute lymphoblastic leukemia modulates IRF3 activity during early B-cell differentiation.

The t(12;21) translocation is the most common genetic rearrangement in childhood acute lymphoblastic leukemia (ALL) and gives rise to the TEL-AML1 fusion gene. Many studies on TEL-AML1 describe specific properties of the fusion protein, but a thorough understanding of its function is lacking. We exploited a pluripotent hematopoietic stem/progenitor cell line, EML1, and generated a cell line (EML-TA) stably expressing the TEL-AML1 fusion protein. EML1 cells differentiate to mature B-cells following treatment with IL7; whereas EML-TA display an impaired differentiation capacity and remain blocked at an early stage of maturation. Global gene expression profiling of EML1 cells at different stages of B-lymphoid differentiation, compared with EML-TA, identified the interferon (IFN)α/ß pathway as a primary target of repression by TEL-AML1. In particular, expression and phosphorylation of interferon-regulatory factor 3 (IRF3) was decreased in EML-TA cells; strikingly, stable expression of IRF3 restored the capacity of EML-TA cells to differentiate into mature B-cells. Similarly, IRF3 silencing in EML1 cells by siRNA was sufficient to block B-lymphoid differentiation. The ability of TEL-AML1 to block B-cell differentiation and downregulate the IRF3-IFNα/ß pathway was confirmed in mouse and human primary hematopoietic precursor cells (Lin- and CD34+ cells, respectively), and in a patient-derived cell line expressing TEL-AML1 (REH). Furthermore, treatment of TEL-AML1 expressing cells with IFNα/ß was sufficient to overcome the maturation block. Our data provide new insight on TEL-AML1 function and may offer a new therapeutic opportunity for B-ALL.

Three-dimensional transperineal ultrasound for imaging mesh implants following sacrocolpopexy.

OBJECTIVE: To characterize, using three-dimensional (3D) transperineal ultrasound, the appearance, position and dimensions of mesh implants following minimally invasive abdominal sacrocolpopexy. METHODS: In women who underwent sacrocolpopexy, mesh was evaluated at rest and on maximal Valsalva, on all 3D orthogonal planes and rendered views. Mesh dimensions were obtained by 3D processing in the midsagittal and coronal planes (anterior, posterior and sacral arm) and were analyzed offline, the operator blinded to clinical data. RESULTS: Overall, 62 women, mean age 58.4 (range, 42-79) years were evaluated at a median of 9 (range, 1-26) months following surgery. The anterior arm of the mesh was caudal to the lowermost point of descent of the anterior compartment in 56 (90.3%) women, was equally positioned in five (8.1%) and was cranial in one. The posterior arm was caudal in 44 (71%) women, was equally positioned in 16 (25.8%) and was cranial in two (3.2%). The Y connection and the sacral arm of the mesh could not be adequately seen because of physical limitations of ultrasound (lower resolution at greater depth), large recurrent rectoceles, echogenic stools or folding of mesh remnants. Folding of the mesh was seen in 46 (74.2%) women, folding of the anterior arm in five (8.1%) and folding of the posterior arm in 23 (37.1%). Folding occurred caudally in 26 (41.9%) women, proximally in 11 (17.7%) and in both areas in nine (14.5%). There were no erosions. CONCLUSION: Mesh visualization following minimally invasive abdominal sacrocolpopexy procedures using transperineal 3D/four-dimensional (4D) ultrasound is feasible. Studies are needed to evaluate the correlation between ultrasound measures and prolapse recurrence or mesh erosion.

Use of ultrasound in the clinical evaluation of women following colpocleisis.

OBJECTIVE: To assess the role of transperineal ultrasound in the postoperative evaluation of patients undergoing colpocleisis. METHODS: Patients who underwent colpocleisis between July 2009 and January 2011 completed the pelvic floor distress inventory questionnaire (PFDI-20) and underwent pelvic organ prolapse quantification (POP-Q) examination and four-dimensional (4D) transperineal ultrasound. Volumes were analyzed offline for assessment of pelvic organ descent, levator hiatal dimensions, levator avulsion trauma and the location of the colpocleisis scar. RESULTS: The study included 16 women, of mean ± SD age 75.7 ± 2.9 years, median body mass index 28 (range, 21-32) kg/m2 and median parity 2 (range, 0-5); one woman was nulliparous. Nine (56.2%) women were posthysterectomy. The median interval from surgery to ultrasound examination was 6.5 (range, 2-19) months. Most patients did not have symptoms of prolapse. The median pelvic organ prolapse distress inventory (POPDI-6) score was 37.5 (range, 0-75) and the median postoperative clinical POP-Q stage was 1 (range, 0-2). Ultrasound demonstrated clear visualization in all patients. Ten had avulsion defects (six were bilateral). Ultrasound estimated greater prolapse descent for all compartments when compared with the clinical examination. However, this difference was significant for anterior and posterior descent, but not for apical descent. In two women urethral diverticulum was detected on ultrasound; it was neither symptomatic nor clinically apparent. CONCLUSIONS: 4D transperineal ultrasound seems to be a potentially effective tool for the evaluation of vaginal anatomic and functional changes following colpocleisis surgery. Future investigation of the association between ultrasound findings and patients' subjective symptoms in a larger cohort is warranted.

Nucleophosmin and its complex network: a possible therapeutic target in hematological diseases.

Nucleophosmin (NPM, also known as B23, numatrin or NO38) is a ubiquitously expressed phosphoprotein belonging to the nucleoplasmin family of chaperones. NPM is mainly localized in the nucleolus where it exerts many of its functions, but a proportion of the protein continuously shuttles between the nucleus and the cytoplasm. A growing number of cellular proteins have been described as physical interactors of NPM, and consequently, NPM is thought to have a relevant role in diverse cellular functions, including ribosome biogenesis, centrosome duplication, DNA repair and response to stress. NPM has been implicated in the pathogenesis of several human malignancies and intriguingly, it has been described both as an activating oncogene and a tumor suppressor, depending on cell type and protein levels. In fact, increased NPM expression is associated with different types of solid tumors whereas an impairment of NPM function is characteristic of a subgroup of hematolologic malignancies. A large body of experimental evidence links the deregulation of specific NPM functions to cellular transformation, yet the molecular mechanisms through which NPM contributes to tumorigenesis remain elusive. In this review, we have summarized current knowledge concerning NPM functions, and attempted to interpret its multifaceted and sometimes apparently contradictory activities in the context of both normal cellular homeostasis and neoplastic transformation.

Pirin downregulation is a feature of AML and leads to impairment of terminal myeloid differentiation.

Terminal differentiation of blood cells requires the concerted action of a series of transcription factors that are expressed at specific stages of maturation and function in a cell-type and dosage-dependent manner. Leukemogenic oncoproteins block differentiation by subverting the normal transcriptional status of hematopoietic precursor cells. Pirin (PIR) is a putative transcriptional regulator whose expression is silenced in cells bearing the acute myeloid leukemia-1 eight-twenty-one (AML1/ETO) and promyelocytic leukemia/retinoic acid receptor (PML/RAR) leukemogenic fusion proteins. A role for PIR in myeloid differentiation has not to date been reported. In this study we show that PIR expression is significantly repressed in a large proportion of acute myeloid leukemias (AMLs), regardless of subtype or underlying karyotypic abnormalities. We show that PIR expression increases during in vitro myeloid differentiation of primary hematopoietic precursor cells, and that ablation of PIR in the U937 myelomonocytic cell line or in murine primary hematopoietic precursor cells results in impairment of terminal myeloid differentiation. Gene expression profiling of U937 cells after knockdown of PIR revealed increased expression of genes associated with the early phases of hematopoiesis, in particular, homeobox A (HOXA) genes. Our results suggest that PIR is required for terminal myeloid maturation, and its downregulation may contribute to the differentiation arrest associated with AML.

[Muscular complications of hemophilia]. / Complications musculaires de l'hémophilie. Complications musculaires.

Haemophilia causes principally bleedings in muscles and joints. Therapy is purely palliative, based on injections of antihemophilic factor. Muscular hematomas represent the most precocious complication and generally happen after a trauma. Though they scarcely threaten the life of the patients, they often may generate an important functional disability if not treated quickly, and vigorously. Treatment should associate injections of the defective clotting factor to physiotherapy and contractions of the involved muscle. When hematomas involve lower limbs, standing up and walking should not be authorized before the end of the flessum or recovering of the statu quo ante.

Cytoplasmic localization of NPM in myeloid leukemias is dictated by gain-of-function mutations that create a functional nuclear export signal.

Nucleophosmin (NPM) is a nucleus-cytoplasmic shuttling protein that is implicated in centrosome duplication, cell cycle progression and stress response. At the steady state, NPM localizes mainly in the nucleolus, where it forms a complex with different cellular proteins. One-third of acute myeloid leukemias (AML) are characterized by aberrant cytoplasmic localization of NPM, due to mutations within its last coding exon (exon 12) that cause a frameshift and the formation of novel C-termini. We report here our investigations on the molecular basis for the aberrant localization of mutated NPM. Alignment of the C-terminus of the various NPM mutants revealed the obligatory presence of four amino-acid residues that match a CRM1-dependent nuclear export signal (NES). Single alanine-substitutions at these sites provoked nuclear re-localization, while fusion of the mutated C-terminus to a heterologous nuclear protein induced CRM1-dependent cytoplasmic localization. Molecular characterization of one exceptional AML carrying cytoplasmic NPM and germ line exon 12 revealed a somatic mutation in the splicing donor site of exon 9 that caused the formation of a functional NES. It appears, therefore, that AMLs are frequently characterized by gain-of-function mutations of NPM that create functional NES, suggesting that alterations of nuclear export might represent a general mechanism of leukemogenesis and a novel target for therapeutic intervention.

Bone density, parathyroid hormone, calcium and vitamin D nutritional status of institutionalized elderly subjects.

INTRODUCTION: Osteoporosis is characterized by a decrease in bone mass and a change in bone microarchitecture. This causes skeletal fragility and may result in fractures. Fractures of the femur neck (FM) are frequent and have major consequences in terms of morbidity and mortality in elderly subjects. We carried out a cross-sectional study to evaluate bone and nutritional status in an elderly population from a same geriatrics department. AIMS OF THE STUDY: We aimed to screen for nutritional deficiencies and to measure bone mineral density (BMD) in the femur neck by dual-energy X-ray absorptiometry (DEXA). RESULTS: The study included 64 white Caucasian subjects, 44 of whom were women. The mean age of the subjects was 80.6 +/- 7.1 years. The mean time since the menopause was 31.45 +/- 7.8 years and 31 subjects presented previous fractures, 12 of which concerned the FM. Mean body mass index (BMI) was 25.8 +/- 4.4 and mean calcium intake was 670 +/- 258.3 mg/d. Mean PTH level was 48.5 +/- 30.34. Thirty-five subjects presented vitamin D deficiencies (mean concentration 8.56 +/- 5.2 microg/L), and 11 of these patients had associated secondary hyperparathyroidism. Fifty-four subjects had osteoporosis (T score <-2.5 standard deviation). Mean bone mineral density (BMD) was 0.596 +/- 0.157 g/cm2 for the femur neck (T score = -3.15 +/- 1.39 standard deviation) and 0.501 +/- 0.169 g/cm2 for the trochanter (T score = - 2.55 +/- 1.68 standard deviation). CONCLUSIONS: Vitamin D deficiency and low calcium intake were observed in a large number of elderly subjects. The patients with the lowest BMD values had secondary hyperparathyroidism.

GAAS: gene array analyzer software for management, analysis and visualization of gene expression data.

SUMMARY: GAAS, Gene Array Analyzer Software supports multi-user efficient management and suitable analyses of large amounts of gene expression data across replicated experiments. Its management framework handles input data generated by different technologies. A multi-user environment allows each user to store his/her own data visualization scheme, analysis parameters used, values and formats of the output data. The analysis engine performs: background and spot quality evaluation, data normalization, differential gene expression analyses in single and multiple replica experiments. Results of expression profiles can be interactively navigated through graphical interfaces and stored into output databases.

Common themes in the pathogenesis of acute myeloid leukemia.

The pathogenesis of acute myeloid leukemia is associated with the appearance of oncogenic fusion proteins generated as a consequence of specific chromosome translocations. Of the two components of each fusion protein, one is generally a transcription factor, whereas the other partner is more variable in function, but often involved in the control of cell survival and apoptosis. As a consequence, AML-associated fusion proteins function as aberrant transcriptional regulators that interfere with the process of myeloid differentiation, determine a stage-specific arrest of maturation and enhance cell survival in a cell-type specific manner. The abnormal regulation of transcriptional networks occurs through common mechanisms that include recruitment of aberrant co-repressor complexes, alterations in chromatin remodeling, and disruption of specific subnuclear compartments. The identification and analysis of common and specific target genes regulated by AML fusion proteins will be of fundamental importance for the full understanding of acute myeloid leukemogenesis and for the implementation of disease-specific drug design.

Proposed technique for evaluation of endotracheal tube fixation and comparison of four fixation methods.

BACKGROUND: The fixation of an endotracheal tube must be rapid in conditions involving numerous casualties, such as a chemical warfare (CW) situation. The tube also should be fixed and strong to prevent unplanned extubations. METHODS: We developed a technique for the evaluation of fixation methods. This technique was used to evaluate four methods. Three commercial fixators were compared with the fixation method used today in the Israeli Defense Forces (IDF) and commonly used in different out-of-hospital settings. The exercises were performed on adult intubation mannequins with and without CW protective gear. The fixations were timed, and their quality was evaluated by the participants and inspectors. RESULTS: The time score for the method used today in the IDF was significantly higher compared with the commercial fixation methods. The quality scores for the Thomas fixator and the IDF method were significantly higher than for the fixators by VBM and Rusch. The CW protective gear significantly prolonged the time but did not affect the quality of the fixation. CONCLUSIONS: With this technique, a good estimation of the time and quality of fixation can be achieved.

Bretazenil, a benzodiazepine receptor partial agonist, as an adjunct in the prophylactic treatment of OP poisoning.

Benzodiazepines, mainly diazepam, are commonly used as anticonvulsants in the treatment of organophosphate casualties. Although very effective, diazepam usually is not used in prophylactic treatments because of its adverse effects on task performance and its abuse liability. Benzodiazepine (BZ) partial agonists are unique in that they are able to occupy all the population of a given receptor without eliciting the maximal physiological response. The BZ receptor agonistic occupancy was found to differ among the various physiological responses in the following order: antipanic > anticonvulsion > sedation > muscle relaxation. Thus, partial agonists, by the use of which controlled levels of agonistic activity can be achieved, might serve as effective anticonvulsants, with fewer side-effects. Bretazenil, a partial agonist, was found to counteract metrazol-induced convulsions in rats. At the anticonvulsive doses (125-250 microg x kg(-1), i.p.) bretazenil, in combination with pyridostigmine (100 microg x kg(-1), i.m.) and aprophen (4 mg x kg(-1), i.m.), conferred prophylactic protection against sarin and soman poisoning (protective ratios 2.6 and 2.1, respectively). Relevant doses of bretazenil (50-400 microg x kg(-1), i.p.) also were tested for general behavioural effects in the open field and for its anti-anxiety properties in the plus maze. The incapacitation was much lower compared with diazepam. Bretazenil should be considered as a candidate for incorporating into a prophylactic mixture as a central nervous system protectant, with significant advantages concerning incapacitation.

Ball urethroplasty combined with Marshall-Marchetti-Krantz urethropexy versus suburethral sling in patients with intrinsic sphincter deficiency and urethral hypermobility.

OBJECTIVE: It was our goal to compare the efficacy of a suburethral fascial sling with that of a combination of Marshall-Marchetti-Krantz urethropexy and Ball urethroplasty in patients with intrinsic sphincter deficiency and urethral hypermobility. STUDY DESIGN: This study consisted of a retrospective observational evaluation of patients from 2 separate practice sites. Preoperative and postoperative data were collected from patients' medical records. The long-term results were based on a mailed questionnaire addressing bladder symptoms and quality-of-life issues. RESULTS: Among a total of 48 patients, 37 (77. 1%) responded in the group undergoing Marshall-Marchetti-Krantz urethropexy combined with Ball urethroplasty, and 30 out of 35 (85.7%) patients replied in the suburethral fascial sling group. The mean length of follow-up was 2. 7 years (range, 1-5 years). The patients were similar in age, hormonal status, parity, and previous bladder neck surgery. Similar cure and improvement were demonstrated in both groups (86.6% in the suburethral fascia group and 89.2% in the group with the Marshall-Marchetti-Krantz procedure combined with Ball urethroplasty). No significant differences were found in urinary incontinence types, irritable bladder symptoms, voiding difficulties, or quality-of-life measures. CONCLUSIONS: The suburethral fascial sling and a procedure consisting of Marshall-Marchetti-Krantz urethropexy combined with Ball urethroplasty have similar results in patients with intrinsic sphincter and urethral hypermobility.

Femoral neuropathy secondary to ossification of the ligamentum flavum.

Radiculopathy resulting from ossification of the ligamentum flavum (OLF) is extremely rare and concerns only intercostal neuralgias. We describe a 37-year-old Caucasian woman with a lumbar radiculopathy revealing an OLF. Her symptoms were completely and definitively relieved by surgery.

Evaluation of a novel protective gas mask during medical unit activity.

Evaluation of a battalion medical unit drill in a chemical warfare environment was carried out by comparing two respiratory protective devices: a new protective device (the Chemical Team Respirator) and the mask currently used in the Israel Defense Forces (the M-15). After a medical deployment drill conducted with 24 participants and 14 inspectors, comfort, communication, and various aspects of activity were evaluated by structured questionnaires. The new device, consisting of a hood, nose cup, and air blower system, was found to be preferable to the M-15 mask for physical and respiratory comfort, quality of visual field, and performance. The communication capabilities of the unit members, on the other hand, were severely limited by the hearing reduction caused by the hood of the new protective device. We conclude that the new device proved superior to the current mask by facilitating better performance of the team at the drill. Interference with hearing must be dealt with technically or bypassed by modifications in the unit's mode of communication.

Expression and role of PML gene in normal adult hematopoiesis: functional interaction between PML and Rb proteins in erythropoiesis.

The expression of the PML gene was investigated in purified early hematopoietic progenitor cells (HPCs) induced to unilineage erythroid or granulocytic differentiation. PML mRNA and protein, while barely detectable in quiescent HPCs, are consistently induced by growth factor stimulation through the erythroid or granulocytic lineage. Thereafter, PML is downmodulated in late granulocytic maturation, whereas it is sustainably expressed through the erythroid pathway. In functional studies, PML expression was inhibited by addition of antisense oligomers targeting PML mRNA (alpha-PML). Interestingly, early treatment (day 0 HPCs) with alpha-PML reduced the number of both erythroid and granulocytic colonies, whereas late treatment (day 5 culture) reduced erythroid, but not granulocytic, clonogenesis. These findings suggest that PML is required for early hematopoiesis and erythroid, but not granulocytic maturation. The pattern of PML expression in normal hematopoiesis mimics that of retinoblastoma pRb 105. Combined treatment of HPCs with alpha-PML and alpha-Rb oligomers inhibited both PML and Rb protein expression and completely blocked erythroid colony development. Furthermore, PML and pRb 105 were co-immunoprecipitated in cellular lysates derived from erythroid precursors indicating that this functional interaction may have a biochemical basis. These results suggest a key functional role of PML in early hematopoiesis and late erythropoiesis: the latter phenomenon may be related to the molecular and functional interaction of PML with pRb 105.