Progressive methylation of POU5F1 regulatory regions during blastocyst development.

The POU5F1 gene encodes one of the 'core' transcription factors necessary to establish and maintain pluripotency in mammals. Its function depends on its precise level of expression, so its transcription has to be tightly regulated. To date, few conserved functional elements have been identified in its 5' regulatory region: a distal and a proximal enhancer, and a minimal promoter, epigenetic modifications of which interfere with POU5F1 expression and function in in vitro-derived cell lines. Also, its permanent inactivation in differentiated cells depends on de novo methylation of its promoter. However, little is known about the epigenetic regulation of POU5F1 expression in the embryo itself. We used the rabbit blastocyst as a model to analyze the methylation dynamics of the POU5F1 5' upstream region, relative to its regulated expression in different compartments of the blastocyst over a 2-day period of development. We evidenced progressive methylation of the 5' regulatory region and the first exon accompanying differentiation and the gradual repression of POU5F1 Methylation started in the early trophectoderm before complete transcriptional inactivation. Interestingly, the distal enhancer, which is known to be active in naïve pluripotent cells only, retained a very low level of methylation in primed pluripotent epiblasts and remained less methylated in differentiated compartments than the proximal enhancer. This detailed study identified CpGs with the greatest variations in methylation, as well as groups of CpGs showing a highly correlated behavior, during differentiation. Moreover, our findings evidenced few CpGs with very specific behavior during this period of development.

How to improve the preoperative staging of presumed early-stage endometrioid endometrial cancer?

PURPOSE OF INVESTIGATION: Accurate preoperative staging of early-stage endometrioid endometrial cancer (EEC) is necessary to avoid under or over surgical treatment. The objective is to determine the rate of understaging and to evaluate the accuracy of different methods: hysteroscopy-curettage versus endometrial biopsy in predicting the final stage. MATERIALS AND METHODS: This retrospective single-centre study led from 2000 to 2010, included women with EEC preoperatively assessed at low- or intermediate-risk. Understaging was defined as a postoperative FIGO Stage > 1 or a determination of high risk after the final histopathologic diagnosis. RESULTS: The study included 101 women (75 low-risk and 26 intermediate-risk). Final diagnosis was upstaged for 26 of them, more frequently in the presumed intermediate-risk group (57.7% vs 14.7%, p < 0.001). The rate of preoperative understaging was higher in the women with endometrial biopsies than those with curettage (34.5% vs 15.2%, p = 0.04). CONCLUSIONS: Hysteroscopy-curettage combined with magnetic resonance imaging (MRI) may improve preoperative staging of early-stage EEC, especially for presumed intermediate-risk disease.

Costs of adverse events among patients with HIV infection treated with nonnucleoside reverse transcriptase inhibitors.

OBJECTIVES: The aim of the study was to assess the incidence and costs of adverse events (AEs) among patients with HIV infection treated with nonnucleoside reverse transcriptase inhibitors (NNRTIs) from the health care system perspective. METHODS: US medical and pharmacy claims during 2004-2009 were examined to select adult new NNRTI users with HIV infection. The incidence of selected AEs and time to occurrence were assessed during the first year. Episodes of care for each AE were identified using claims associated with AE management. For each AE, a propensity score model was used to match patients with an AE to those without (1:4) based on the propensity of having an AE. Mean total health care costs, AE-associated costs and incremental costs per episode, and annual total health care costs per patient were calculated. RESULTS: Of the 2548 NNRTI-treated patients, 29.3% experienced AEs. The incidence ranged from 0.4 episodes/1000 person-years for suicide/self-injury to 14.9 episodes/1000 person-years for dizziness, 49.8 episodes/1000 person-years for depression and 150.3 episodes/1000 person-years for lipid disorder. The mean AE-associated cost (duration) per episode ranged from $586 (88 days) for lipid disorder to $975 (33 days) for rash, $2760 (73 days) for sleep-related symptoms and $4434 (41 days) for nausea/vomiting. The mean incremental cost per episode ranged from $1580 for rash to $2032 for lipid disorder, $8307 for sleep-related symptoms and $12 833 for nausea/vomiting. During the 12 months following NNRTI initiation, the mean annual total health care cost was $27 299 (efavirenz: $26 185; other NNRTIs: $34 993) and AE-associated costs were $608 (efavirenz: $554; other NNRTIs: $979) among all NNRTI users. CONCLUSIONS: With treatment increasing patient survival, comparisons of therapeutic regimens should consider treatment-associated AEs. Findings from this study could be informative for clinicians and payers in managing HIV infection with NNRTIs.

The Poultry Red Mite, Dermanyssus gallinae, travels far but not frequently, and takes up permanent residence on farms.

Management of Dermanyssus gallinae, a cosmopolitan hematophagous mite responsible for damage in layer poultry farming, is hampered by a lack of knowledge of its spatio-temporal population dynamics. Previous studies have shown that the circulation of this pest between farms is of strictly anthropogenic origin, that a mitochondrial haplogroup has been expanding on European farms since the beginning of the 21st century and that its local population growth may be particularly rapid. To refine our understanding of how D. gallinae spreads within and among farms, we characterized the genetic structure of mite populations at different spatial scales and sought to identify the main factors interrupting gene flow between poultry houses and between mitochondrial haplogroups. To this end, we selected and validated the first set of nuclear microsatellite markers for D. gallinae and sequenced a region of the CO1-encoding mitochondrial gene in a subsample of microsatellite-genotyped mites. We also tested certain conditions required for effective contamination of a poultry house through field experimentation, and conducted a survey of practices during poultry transfers. Our results confirm the role of poultry transport in the dissemination of mite populations, but the frequency of effective contamination after the introduction of contaminated material into poultry houses seems lower than expected. The high persistence of mites on farms, even during periods when poultry houses are empty and cleaned, and the very large number of nodes in the logistic network (large number of companies supplying pullets or transporting animals) undoubtedly explain the very high prevalence on farms. Substantial genetic diversity was measured in farm populations, probably as a result of the mite's known haplodiploid mode of sexual reproduction, coupled with the dense logistic network. The possibility of the occasional occurrence of asexual reproduction in this sexually reproducing mite was also revealed in our analyses, which could explain the extreme aggressiveness of its demographic dynamics under certain conditions.

[Surgery or not on an atypical breast lesion? Taking anxiety into account in shared decision support from a prospective cohort of 300 patients]. / Opérer ou non une lésion atypique du sein ? Prise en compte de l'anxiété dans l'aide à la décision partagée à partir d'une cohorte prospective de 300 patientes.

INTRODUCTION: Organized and individual breast screening have been accompanied by an increase in the detection of "atypical breast lesions (ABL)". Recently, the NOMAT multicenter study proposed a predictive model of the risk of developing breast cancer after detection of an ABL in order to avoid surgical removal of "low-risk" lesions. It also aimed to provide information on psychological experience, in particularly anxiety, to assist in the shared medical decision process. METHODS: Three hundred women undergoing surgery for ABL were included between 2015 and 2018 at 18 French centers. Women completed questionnaires before and after surgery assessing their level of anxiety (STAI-State, STAI-Trait), their level of tolerance to uncertainty, their perceived risk of developing a breast cancer, and their satisfaction with the management care. RESULTS: One hundred nighty nine patients completed the STAI-Status before and after surgery. Overall, a decrease in anxiety level (35.4 vs 42.7, P<0.001) was observed. Anxious temperament and greater intolerance to uncertainty were significantly associated swith decreased anxiety (33%), whereas younger age was associated with increased anxiety (8%). CONCLUSION: Surgery for ABL seems to be associated with only a few cases with an increase in anxiety and seems to increase the perception of the risk of developing breast cancer. Taking into account the psychological dimension remains in all cases essential in the process of shared therapeutic decision.

Gating of BDNF-induced synaptic potentiation by cAMP.

Neurotrophins have been implicated in activity-dependent synaptic plasticity, but the underlying intracellular mechanisms remain largely unknown. Synaptic potentiation induced by brain-derived neurotrophic factor (BDNF), but not neurotrophin 3, was prevented by blockers of adenosine 3',5'-monophosphate (cAMP) signaling. Activators of cAMP signaling alone were ineffective in modifying synaptic efficacy but greatly enhanced the potentiation effect of BDNF. Blocking cAMP signaling abolished the facilitation of BDNF-induced potentiation by presynaptic activity. Thus synaptic actions of BDNF are gated by cAMP. Activity and other coincident signals that modulate cAMP concentrations may specify the action of secreted neurotrophins on developing nerve terminals.

Functional requirement for class I MHC in CNS development and plasticity.

Class I major histocompatibility complex (class I MHC) molecules, known to be important for immune responses to antigen, are expressed also by neurons that undergo activity-dependent, long-term structural and synaptic modifications. Here, we show that in mice genetically deficient for cell surface class I MHC or for a class I MHC receptor component, CD3zeta, refinement of connections between retina and central targets during development is incomplete. In the hippocampus of adult mutants, N-methyl-D-aspartate receptor-dependent long-term potentiation (LTP) is enhanced, and long-term depression (LTD) is absent. Specific class I MHC messenger RNAs are expressed by distinct mosaics of neurons, reflecting a potential for diverse neuronal functions. These results demonstrate an important role for these molecules in the activity-dependent remodeling and plasticity of connections in the developing and mature mammalian central nervous system (CNS).

Duloxetine compliance and its association with healthcare costs among patients with diabetic peripheral neuropathic pain.

OBJECTIVE: Duloxetine is approved to treat diabetic peripheral neuropathic pain (DPNP) in the US. The study objective was to examine the predictors of duloxetine compliance, and its association with healthcare costs among DPNP patients. METHODS: The study used administrative claims databases to identify non-depressed DPNP patients with a duloxetine prescription dispensed between October 1, 2004 and December 31, 2006. Two cohorts of patients were constructed based on compliance to duloxetine therapy over 1-year follow-up with high compliance defined as a medication possession ratio (MPR) > or =0.80. All-cause, diabetes-, and DPNP-related healthcare costs during 1-year follow-up were estimated. Logistic regressions were performed to examine how average daily dose (ADD) of duloxetine and other factors may influence compliance. Multivariate regressions were estimated to examine the association between compliance and healthcare costs. RESULTS: The study included 1,380 commercially insured (mean age 55 years) and 974 patients with employer-sponsored Medicare supplemental insurance (mean age 75 years). In both populations, patients with an ADD >30 mg were more likely to be compliant with the therapy compared with those with an ADD of < or =30 mg (odds ratio ranged 1.79-3.38, all p<0.05). Controlling for differences in demographics, clinical and economic characteristics, commercially insured low duloxetine compliance patients had greater all-cause ($5,334, p<0.05) and diabetes-related healthcare costs ($3,414, p<0.05) than high-compliance patients, with the biggest difference from inpatient costs (all-cause: $7,508; diabetes-related: $3,785, all p<0.05). Similar trends were found in the Medicare supplemental insured population; however, differences in all-cause healthcare costs were not significant. CONCLUSIONS: DPNP patients with a higher ADD of duloxetine over a 1-year follow-up period were more compliant with the therapy. Duloxetine patients with high compliance were also associated with lower healthcare costs. Due to the use of a retrospective cohort design on administrative claims database, limitations of this analysis include a lack of formal diagnostic testing of patients, and inability to infer causality or measure factors such as DPNP severity that are not captured in such database.

Development of an animal model to study meshes used in genital prolapse surgery.

OBJECTIVE: The objective was to develop an animal model using bacterial inoculation to evaluate tissue integration and tolerance to meshes used in genital prolapse surgery. STUDY DESIGN: We placed three different meshes under the abdominal skin of 120 Wistar rats: a polypropylene monofilament non-coated mesh (Parietene), a polypropylene monofilament collagen-coated mesh (Ugytex) and a polyethylene terephthalate mesh (Mersuture). We performed bacterial inoculation just after implantation with 1 ml of 10(7) colonies forming unit (CFU) of Staphylococcus epidermidis or Escherichia coli. Rats were sacrificed 7, 14, 60, and 90 days after intervention. We used polarised light microscopy to analyse the collagen deposition and organisation. We quantified the inflammation cells. Bacterial analysis and quantification of the explanted meshes were performed. The exact Fisher's test and Kruskal-Wallis test were used for statistics. RESULTS: We did not find any significant difference between inoculated or non-inoculated meshes in terms of collagen deposition. The scarring process seemed stable at day 90. Tissue integration was best with the polypropylene meshes, which allowed the development of a well-organised, mature connective tissue. Inflammatory reaction was higher in inoculated meshes, but only at day 7. At day 90, we found a high number of macrophages and multinuclear cells around all the meshes. There was no significant difference between prostheses that had been inoculated and those that had not with regard to positive bacterial culture. Quantification of bacterial colonies decreased with time. CONCLUSION: In this animal model, we did not find any clinically related difference in infection and tissue integration between the meshes used in genital prolapse. Such experimental studies must be carried out whenever new prostheses become available before their use is validated in common practice.

Presynaptic depolarization facilitates neurotrophin-induced synaptic potentiation.

Neurotrophins have been proposed to participate in activity-dependent modifications of neuronal connectivity and synaptic efficacy. Preferential strengthening of active inputs requires restriction of putative neurotrophin-mediated synaptic potentiation to active synapses. Here we report that potentiation of synaptic efficacy by brain-derived neurotrophic factor (BDNF) is greatly facilitated by presynaptic depolarization at developing neuromuscular synapses. Brief depolarization in the presence of low-level BDNF results in a marked potentiation of both evoked and spontaneous synaptic transmission, whereas exposure to either BDNF or depolarization alone is without effect. This potentiation depends on the relative timing of depolarization and reflects an enhancement of transmitter secretion from the presynaptic neuron. Thus synapses made by active inputs may be selectively strengthened by secreted neurotrophins as part of activity-dependent refinement of developing connections or of mature synapses.

Nipple sparing mastectomy for breast cancer is associated with high patient satisfaction and safe oncological outcomes.

BACKGROUND: The preservation of the nipple areolar complex (NAC) for cancer treatment is still a matter of debate because of suspected increase of local recurrence and surgery-specific complications. The aim of the study was to investigate both the relapse risk associated with nipple sparing mastectomy (NSM) for breast cancer and women's satisfaction with preservation of the NAC. METHODS: We included retrospectively all patients who had skin-sparing mastectomy (SSM) or NSM from 2007 to 2012 for breast cancer or ductal carcinoma in situ (DCIS). We compared NSM and SSM group for oncological and surgical outcomes. Patients' satisfaction and quality of life has been evaluated by a specifically designed questionnaire. RESULTS: We included 63NSM (41.5%) and 89SM (58.5%). Eighty-nine (58.6%) patients had DCIS, and the other had small invasive disease. Median follow-up was 42 (IQR: 18-58) months. Local recurrence rate was 1.7% (n=1) in the NSM group and 0% in the SSM group without recurrence in the preserved nipple. After NSM, one patient had complete NAC necrosis, and three patients suffered partial necrosis. Satisfaction with the NAC was higher in the NSM group compared to the SSM group with delayed reconstruction of the nipple (75% vs. 59%, P=0.14). Patients with NSM required less psychological support before (P=0.028) and immediately after surgery (P=0.14) than patients in the SSM group. CONCLUSION: NSM can successfully and safely be performed for pre-invasive and small invasive breast cancer. Besides esthetic aspects, preserving the nipple may ease the acceptance of these radical form of surgery.

Neuronal plasticity and cellular immunity: shared molecular mechanisms.

It is becoming evident that neurons express an unusual number of molecules that were originally thought to be specific to immune functions. One such molecule, class I major histocompatibility complex, is required in the activity-dependent refinement and plasticity of connections in the developing and adult central nervous system, demonstrating that molecules can perform critical roles in both systems. Recent studies reveal striking parallels between cellular signaling mechanisms in the immune and nervous systems that may provide unexpected insights into the development, function, and diseases of both systems.

[Abdominal wall endometriosis after caesarean section: report of fifteen cases]. / Endométriose pariétale sur cicatrice de césarienne: à propos de 15 cas.

OBJECTIVE: Parietal endometriosis is an uncommon pathology. It can occur on all the scars, most often after a surgical procedure with hysterotomy. Surgical scar endometriosis following caesarean section has an incidence of 0.03 to 0.4%. PATIENTS AND METHODS: This retrospective study reviewed all the cases of parietal endometriosis seen during a 7-year period in the department of visceral surgery of the Armentière's hospital center. A pathological analysis has confirmed each lesion retained. RESULTS: 15 women were treated during this period. The mean age is 32 years. All the women have one or two antecedents of caesarean with Pfannenstiel's laparotomy. The interval between the caesarean and the appearance of the first symptoms is on average of 5 years and 11 months. Only 66.6% of cases presented the classical symptoms with cyclic pain. For 66.6% of patients, the diagnosis of parietal endometriosis was suspected before the treatment. The treatment is a surgical one with exeresis for all the women. In 13.3% of the cases, the lesion is pre aponeurotic. In 46.6% of the cases, it overgrows the rectus abdominis muscle, in 33.3% of the cases the external abdominal oblique and at last a lesion overgrows the transversus abdominis and one is in an inguinal localization. The mean size of lesions is 2.48 cm. We have not notified complications and no recurrence was noted. DISCUSSION AND CONCLUSION: The local endometrial cell transplant is the most likely mechanism to explain the physiopathology of parietal endometriosis. The classical symptoms associate a painful swelling and cyclic pain related to the menstrual period, but all of these symptoms are not always associated. The contribution to the diagnosis of the imaging studies is weak. The surgical treatment has to be sufficiently wide to avoid all recurrence. No means of prevention has proved its efficiency. In 26.6% of cases the parietal endometriosis is associated to pelvic endometriosis. This localization is more often asymptomatic. Then the realization of a laparoscopic exploration is not indicated immediately.

[Transvaginal surgery for genital prolapse in women aged over 80 years: Results in 48 procedures]. / Traitement chirurgical du prolapsus génital chez les femmes âgées de plus de 80 ans: à propos de 48 patientes opérées par voie vaginale.

OBJECTIVES: The aim of this study was to assess the morbidity and the effectiveness of the vaginal surgical treatment for women over 80 years of age with genital prolapse. MATERIALS AND METHODS: All the women over 80 years operated in our institution between 1996 and 2003 were reviewed retrospectively. We examined the risk and the effectiveness of this surgery. RESULTS: Forty-eight women underwent surgery during this period. No colpocleisis was performed. The most frequent surgery was a combination of vaginal patch plastron, Richter's spinous fixation and posterior perineorrhaphy. No major intra- or post-operative complication occurred. One woman required blood transfusion. The most frequent postoperative complication was voiding difficulties (12%), which had disappeared 3 months later. A partial stenosis of a left ureter with ureterohydronephrosis occurred, requiring endoscopic dilatation. At 3 months, anatomic and functional outcome was good in 92% of women. The number of patients lost to follow-up at one year was to large to draw any conclusion. CONCLUSION: Complete transvaginal surgical treatment is a safe procedure for elderly women which provides good short-term effectiveness.

Cellular distribution of growth hormone-releasing hormone receptor in human reproductive system and breast and prostate cancers.

Growth hormone releasing hormone receptor (GHRH-R) mRNA and protein was first localized to the anterior pituitary gland, consequent with the action of its ligand on GH synthesis and release. Subsequent studies found GHRH-R also expressed in the hypothalamus and in systemic tissues including those of the reproductive system. In the present work, we studied the distribution of GHRH-R in human reproductive system of males and females by immunohistochemical method. GHRH-R immunostaining was localized in male reproductive system: Leydig cells, Sertoli and basal germ cells of the seminiferous tubules and prostate secretory cells. GHRH-R immunostaining was also demonstrated in the ovary: oocytes, follicular cells, granulosa, thecal and corpus luteum cells. Endometrial glands, placenta and normal mammary glands also showed GHRH-R immunostaining. Our results demonstrate the localization of GHRH-R in the reproductive system, which may mediate the direct action of GHRH in these tissues. Moreover, GHRH-R was demonstrated in prostate and breast carcinomas, opening a variety of possibilities for the use of GHRH antagonists in the treatment of prostatic and mammary tumors.

Potential short-term economic benefits of improved glycemic control: a managed care perspective.

OBJECTIVE: There are limited data relating glycemic control to medical costs among patients with diabetes. The goal of this study was to examine the potential impact of improved glycemic control on selected short-term complications of diabetes and associated costs in a managed care setting. RESEARCH DESIGN AND METHODS: Using a retrospective cohort design and automated databases from January 1994 to 30 June 1998, adult members of the Fallon Clinic who were diagnosed with diabetes were identified and assigned to one of three study groups based on each patient's mean HbA1c level: good control (<8%), fair control (8-10%), and poor control (> 10%) groups. Inpatient (hospital or skilled nursing facility) admissions for selected acute (short-term) complications, represented by selected infections, hyperglycemia, hypoglycemia, and electrolyte disturbances, and the associated medical charges were evaluated across the three HbA1c groups. Multivariate analyses were used to control for differences in several potential confounding factors among the study groups. All findings were expressed on a 3-year basis. RESULTS: Of 2,394 patients with diabetes, approximately 10% (251) had at least one inpatient stay for a short-term complication, accounting for 447 admissions. Over 3 years, the adjusted rate of inpatient treatment ranged from 13 per 100 patients with good glycemic control to 16 per 100 patients with fair glycemic control and 31 per 100 patients with poor glycemic control (P < 0.05). The corresponding mean adjusted charges were approximately $970, $1,380, and $3,040, respectively Among the 30% of the study population with long-term diabetic complications, the results were more marked; the adjusted admissions per 100 patients (mean charges) were estimated to be 30 ($2,610), 38 ($3,810), and 74 ($8,320) over 3 years for patients with an HbA1c of <8, 8-10, and > 10%, respectively. CONCLUSIONS: In typical practice, better glycemic control is associated with a reduced rate of admission for selected short-term complications and, therefore, reduced medical charges for these complications over a 3-year period. The potential short-term economic benefits are important to consider when making decisions regarding the adoption and use of new interventions for the management of diabetes.

[How to explore breast skin lesion?: Guidelines]. / Comment explorer une lésion cutanée mammaire?: recommandations.

A change in the shape or appearance of the nipple-areola complex, especially if it is unilateral and recent appearance, is a sign of underlying breast tumor. Breast imaging is then required (grade C). Any erythematous lesion of the nipple or nipple-areola can be a Paget's disease, an adenoma of the nipple or a nipple eczema. Clinical course and pattern can point to a diagnosis without sufficient specificity (LE4). If nipple eczema is suspected, it is recommended to perform a test treatment with topical corticosteroids. In case of failure or if a Paget's disease of the breast is suspected, a biopsy must be done. When indicated, it is not possible to recommend a biopsy modality (scrape cytology, punch biopsy, nipple core biopsy and surgical excision) compared to another. When imaging exploration of the nipple-areola complex is necessary, ultrasound and mammography are recommended as first-line. In the absence of signal, an MRI is recommended as second-line (grade C).

[Oncoplastic breast surgery for the management of ductal carcinoma in situ]. / Place de l'oncoplastie dans la prise en charge des carcinomes canalaires in situ.

DCIS (Ductal carcinoma in situ) constitutes 15,2% of breast cancers. Conservative surgery coupled with adjuvant radiotherapy is often recommended. The rate of revision surgery is high, from 30 to 60%. The concern is a high quality resection within clear margins with a satisfactory aesthetic result. The objective of this review is to precise the place of oncoplastic surgery in DCIS care. Among risk factors of recurrence, tumoral invasion of surgical margins is capital. In histology, clear margins usually adopted for DCIS are 2mm, even though there is no international consensus. Recent studies show that a 10mm limit would be better. Aesthetic damage caused by surgery, often increased by radiotherapy, has a negative impact on women quality of life: oncoplastic surgery may minimize it. Techniques of plastic surgery, arranged into level 1 and 2, allow pushing back conservative treatment limits by removing a larger tumor with clear margins. Often used in invasive cancers, few data exist regarding oncoplastic surgery and DCIS. It allows to increase the dimensions of surgical resection by 20% and to decrease positive margins significantly therefore the rate of revision surgeries. Patients are satisfied with it. Specific indications need to be clarified according to age, size and "comedonecrosis" presence. Oncoplastic surgery should be developed in DCIS specific care.