Caring for People with Severe Brain Injuries: Improving Health Care Professional Communication and Practice Through Online Learning.

INTRODUCTION: Severe brain injuries can leave people in prolonged disorder of consciousness resulting in multifaceted medical, nursing, and rehabilitative needs that can be challenging for even the most experienced multidisciplinary team. The complexities of care, communication with families, and best interest decision-making about medical interventions means there is a need for ongoing training in clinical, social, ethical, and legal aspects. METHODS: Using a combination of group discussions, interviews, and questionnaires with learners, this article reports an evaluation of designing and delivering an interprofessional, online work-based course to health care professionals caring for prolonged disorder of consciousness patients. RESULTS: There were challenges for staff uptake because of COVID-19, but engaging with it increased knowledge in defining and diagnosing patients' conditions, understanding multidisciplinary team roles, communicating with families, and navigating legal and ethical issues. Course participation also enhanced critical and reflective thinking skills, provided a sense of connection to other professionals, and generated plans to improve service provision. DISCUSSION: Online learning that enables health care professionals to engage at their own pace and also come together as an interprofessional community can provide invaluable continuing professional development and help to enhance joined up, holistic patient care. However, achieving this requires significant investment in creating research-led, multimedia, learning materials, and courses that include synchronous and asynchronous delivery to combine flexible study with the opportunity for peer networks to form. It also depends on a commitment from organizations to support staff online continuing professional development.

A web-based life-style, exercise and activity intervention for people with progressive multiple sclerosis: Results of a single-arm feasibility study.

BACKGROUND: People with progressive Multiple Sclerosis often struggle to access appropriate and inclusive support for regular physical activity. The Lifestyle, Exercise and Activity Package (LEAP-MS) intervention, is a co-designed web-based physical activity intervention for people with progressive Multiple Sclerosis (MS). It consists of two key components; (1) web-based physical activity coaching with physiotherapists using self-management support strategies and 2) an interactive web-based platform including a physical activity information suite, an activity selection and planning tool and a participant-physiotherapist messaging system. We aimed to evaluate recruitment, retention and uptake, in a single arm feasibility study. METHODS: Participants with primary or secondary progressive MS with an Expanded Disability Status Scale score of 6 to 8 were recruited. Assessments included the MS Impact Scale (MSIS-29) and measures of participation at baseline, three and six months. All participants received the intervention which consisted of up to six web-based physiotherapy- led physical activity coaching sessions alongside access to web-based education and activity suites. Recruitment, retention and uptake data were summarised. Pre-defined progression criteria were used to guide feasibility assessment. Clinical outcome data were analysed descriptively. RESULTS: Fifty-eight percent (21/36) of those submitting expressions of interest were recruited; 76% completed follow-up. Pre-specified progression criteria for retention were met but recruitment did not meet progression criteria. The intervention achieved set fidelity criteria. At three months, 12 participants (75%) reported improvements in routine activities after the intervention. MSIS-29 physical scores improved by an average of eight points (95% CI -12.6 to -3.3). Improvements were also seen in MSIS-29 psychological scores and fatigue. Some improvements were maintained at six months. CONCLUSIONS: The LEAP-MS intervention is feasible and associated with improvements in MSIS-29 scores. The intervention facilitated partnership working between physiotherapists and people with progressive MS. Users developed valuable skills in supported self-management by focussing on enhancing physical activity to support overall wellbeing. This work has laid the foundations for a large-scale evaluation of a co-designed intervention with potential for far reaching impact on the lives of people with progressive MS.

Lifestyle, exercise and activity package for people living with progressive multiple sclerosis (LEAP-MS): protocol for a single-arm feasibility study.

BACKGROUND: We have co-designed a tailored blended physiotherapy intervention for people with progressive multiple sclerosis (PwPMS) who often struggle to access support for physical activity. Underpinned by self-management principles, the Lifestyle, Exercise and Activity Package for people with Multiple Sclerosis (LEAP-MS) intervention incorporates face-to-face or online physiotherapy coaching sessions with an accompanying online physical activity platform. The LEAP-MS platform is a multi-user system enabling user and physiotherapist to co-create activity plans. The LEAP-MS platform consists of an information and activity suite, interactive components enabling selection of exercises into an activity programme, goal setting and activity logging. The platform also facilitates online remote support from a physiotherapist through an embedded online messaging function. We aim to evaluate the LEAP-MS platform in a feasibility trial. METHODS: LEAP-MS will be evaluated within a single-arm feasibility study with embedded process evaluation. After registration and initial eligible screening, 21 participants will be required to complete baseline self-completion measures. This will be followed by an initial home-based or online coaching session with a physiotherapist (who has received tailored self-management and digital resource training) and access to the online intervention for an initial 3-month period. During this period, participants are given the option to request up to five further home-based or online physiotherapy coaching sessions. Follow-up questionnaires and semi-structured interviews will be administered 3 months after baseline with participants and intervention physiotherapists. The LEAP-MS platform will be available to participants for a further 3 months. Usage of the LEAP-MS platform will be tracked during the full 6-month period and final follow-up will be conducted 6 months after baseline. DISCUSSION: Feasibility outcomes (recruitment, retention, intervention uptake and safety) will be reported. The process evaluation will be undertaken to identify possible mechanisms for any observed effects. The data will inform full-scale evaluations of this co-produced, blended physiotherapy intervention. TRIAL REGISTRATION: ClinicalTrials.gov , NCT03951181 . Registered 15 May 2019.

Lifestyle, Exercise and Activity Package for People living with Progressive Multiple Sclerosis (LEAP-MS): adaptions during the COVID-19 pandemic and remote delivery for improved efficiency.

The LEAP-MS (Lifestyle, Exercise and Activity Package for People living with Progressive Multiple Sclerosis) study has developed an individualised supported self-management approach for physical activity for people with progressive multiple sclerosis (MS) and severe disability. The intervention has been evaluated in a single-arm feasibility study with embedded process evaluation. The feasibility study was due to open to recruitment during the COVID-19 2020-2021 pandemic, 1 month into the first UK-wide lockdown. We worked rapidly to implement adaptions to the trial procedures and intervention delivery that we believe are applicable to randomised controlled trials. Recruitment became predominantly via self-referral. Electronic consent was employed, with consent discussions occurring over the telephone. Registration, consent, eligibility assessment and data collection as well as the intervention (online physical activity tool) were via a secure, encrypted multi-user web-based platform for participants, physiotherapists and researchers accessible via various hardware. Physiotherapy consultations, as well as the process evaluation, were conducted remotely using video conferencing software or the telephone. A remote training package for physiotherapists and site initiations was also developed and electronic site files employed. Our adaptions are extremely topical given the COVID-19 situation, and whilst not what we had originally planned, have enabled successful delivery of the feasibility study and are relevant to conducting randomised controlled trials and meeting the needs of people with MS who are far more isolated than ever before. TRIAL REGISTRATION: ClinicalTrials.gov NCT03951181 . Registered on 15 May 2019.

Web-based physical activity intervention for people with progressive multiple sclerosis: application of consensus-based intervention development guidance.

OBJECTIVES: People with progressive multiple sclerosis (PwPMS) report that they recognise the benefits of activity on their physical and psychological health but need support to achieve their physical activity goals. We aimed to systematically develop a theoretically informed intervention that would enable PwPMS to more readily engage in regular physical activity. DESIGN: We used an intervention mapping approach to inform intervention development. SETTING: We conducted semistructured interviews with PwPMS and their families/carers and physiotherapists recruited from secondary care settings. PARTICIPANTS: Fourteen PwPMS with an Expanded Disability Status Scale score of between 6 and 8 and 7 of their families/carers and 13 physiotherapists and 1 physiotherapy technician participated. RESULTS: Interview data suggested that the development of supportive coaching relationships with physiotherapists could promote the ability of PwPMS to achieve a desirable and achievable physical activity plan. These interview data informed the prototype 'Lifestyle Exercise and Activity Package for Multiple Sclerosis' (LEAP-MS) consisting of a secure multiuser web-based platform (with an education and activity suite, interactive components enabling selection of exercises, goal setting and activity logging), up to six flexible face-to-face or web-based physiotherapy coaching sessions and remote support via an embedded web-based messaging function that all together draw on specific theory-based methods to achieve physical activity behaviour change, namely active learning, reinforcement, modelling, feedback, facilitation, goal setting and guided practice. Implementation is within a multiuser platform accessible to participants, trained physiotherapists and researchers. CONCLUSIONS: We have followed an inclusive, systematic and transparent process to develop the LEAP-MS intervention that enables detailed description of components, context and guiding principles to inform ongoing evaluation. Importantly, PwPMS expressed the need for autonomy in developing physical activity plans. This has been achieved through the embedding of self-management principles in the design and delivery of the LEAP-MS intervention.

Joint Hypermobility among Female Patients Presenting with Chronic Myofascial Pelvic Pain.

BACKGROUND: Female chronic pelvic pain is estimated to affect up to 24% of adult women, many of whom have a component of myofascial pelvic pain. Although an association of joint hypermobility and pelvic pain has been hypothesized, limited data are available that estimate the prevalence of joint hypermobility in this population. OBJECTIVE: To estimate the prevalence of generalized hypermobility spectrum disorder (G-HSD) among female patients with chronic myofascial pelvic pain and examine the association between G-HSD and other frequent pelvic pain-associated complaints. STUDY DESIGN: Retrospective case control. SETTING: Tertiary referral center within a university-affiliated public health system. PATIENTS: Adult women who were diagnosed with myofascial pelvic pain during a 1-year period (n = 77 with G-HSD and n = 241 without G-HSD). METHODS: Data were abstracted via chart review of patients meeting inclusion criteria. OUTCOMES: The primary outcome of this study was the prevalence of G-HSD among patients with persistent myofascial pelvic pain. Secondary outcomes included the prevalence of dyspareunia, provoked vestibulodynia, stress urinary incontinence, irritable bowel syndrome, hip pain, low back pain, and fibromyalgia in patients with persistent myofascial pelvic pain with and without G-HSD. RESULTS: Twenty-four percent (N = 77; 95% CI: 19.6, 29.4) of myofascial pelvic pain patients also met criteria for G-HSD. After adjusting for confounders, the odds in favor of having G-HSD was 3.55 higher (95% CI: 1.50, 8.40) (P = .004) in females with dyspareunia; 7.46 higher (95% CI: 2.41, 23.1) (P < .001) with low back pain; 3.76 higher (95% CI: 1.35, 10.5) (P = .02) with stress urinary incontinence; 4.72 higher (95% CI: 2.00, 11.2) (P < .001) with irritable bowel syndrome; and 3.12 higher (95% CI: 1.36, 7.13) (P = .007) with hip pain. There was no significant association identified between provoked vestibulodynia or fibromyalgia and G-HSD. CONCLUSION: The estimated prevalence of G-HSD is higher in chronic myofascial pelvic pain patients than in the general population with statistically significant associations with several comorbid conditions. Characterizing these associations is the first step in developing effective, evidence-based screening recommendations. LEVEL OF EVIDENCE: III.

RUMOURS, RIOTS AND THE REJECTION OF MASS DRUG ADMINISTRATION FOR THE TREATMENT OF SCHISTOSOMIASIS IN MOROGORO, TANZANIA.

In 2008 in Morogoro region, Tanzania, mass drug administration (MDA) to school-aged children to treat two neglected tropical diseases (NTDs) - urinary schistosomiasis and soil-transmitted helminths - was suspended by the Ministry of Health and Social Welfare after riots broke out in schools where drugs were being administered. This article discusses why this biomedical intervention was so vehemently rejected, including an eyewitness account. As the protest spread to the village where I was conducting fieldwork, villagers accused me of bringing medicine into the village with which to 'poison' the children and it was necessary for me to leave immediately under the protection of the Tanzanian police. The article examines the considerable differences between biomedical and local understandings of one of these diseases, urinary schistosomiasis. Such a disjuncture was fuelled further by the apparent rapidity of rolling out MDA and subsequent failures in communication between programme staff and local people. Rumours of child fatalities as well as children's fainting episodes and illnesses following treatment brought about considerable conjecture both locally and nationally that the drugs had been either faulty, counterfeit, hitherto untested on humans or part of a covert sterilization campaign. The compelling arguments by advocates of MDA for the treatment of NTDs rest on the assumption that people suffering from these diseases will be willing to swallow the medicine. However, as this article documents, this is not always the case. For treatment of NTDs to be successful it is not enough for programmes to focus on economic and biomedical aspects of treatment, rolling out 'one size fits all' programmes in resource-poor settings. It is imperative to develop a biosocial approach: to consider the local social, biological, historical, economic and political contexts in which these programmes are taking place and in which the intended recipients of treatment live their lives. If this is not done, the world's poor will continue to be neglected.

Changes in eutopic endometrial gene expression during the progression of experimental endometriosis in the baboon, Papio anubis.

Endometriosis is associated with aberrant gene expression in the eutopic endometrium of women with disease. To determine if the development of endometriotic lesions directly impacts eutopic endometrial gene expression, we sequentially analyzed the eutopic endometrium across the time course of disease progression in a baboon model of induced disease. Endometriosis was induced in baboons (n = 4) by intraperitoneal inoculation of autologous menstrual endometrium. Eutopic endometria were collected during the midsecretory phase (Days 9-11 postovulation) at 1, 3, 6-7, 10-12, and 15-16 mo after disease induction and compared with tissue from disease-free baboons. RNA was hybridized to Human Genome U133 Plus 2.0 Arrays, and data were extracted using Gene-Chip Operating Software. Subsequently, both Gene Set Enrichment Analysis and Ingenuity Pathways Analysis were used to find biological states that have a statistically significant enrichment concomitant with pairwise comparison of human endometriosis arrays. Within 1 mo of induction of the disease, 4331 genes were differentially expressed (P < 0.05). Hierarchical clustering revealed self-segregation into two groups-a) 1, 3, and 10-12 mo and b) 6-7 and 15-16 mo-together with controls. Clustering analysis at each stage of disease validated dysregulation of several signaling pathways, including Nodal-like receptor, EGF, ERK/MAPK, and PI3/AKT. Sequential analysis of the same animals during disease progression demonstrated an early disease insult and a transitory dominance of an estrogenic phenotype; however, as the disease progressed, a progesterone-resistant phenotype became evident. Furthermore, we demonstrate a 38.6% differential gene expression overlap with endometrial samples in the midsecretory phase from women with endometriosis, concomitant with similar dysregulation in human disease candidate genes Fos, Nodal, Suclg2, and Kras, among others. Molecular changes in the eutopic endometrium, associated with endometriosis, are directly impacted by endometriotic lesions, providing strong evidence that it is the disease rather than inherent defective endometrium that results in aberrant gene expression in the eutopic endometrium. Furthermore, this baboon model provides a powerful means whereby the early events associated with the pathology of disease and the resulting infertility may be elucidated.

Inhibition of delta-like ligand 4 induces luteal hypervascularization followed by functional and structural luteolysis in the primate ovary.

Using specific inhibitors established that angiogenesis in the ovarian follicle and corpus luteum is driven by vascular endothelial growth factor. Recently, it has been demonstrated that the Notch ligand, delta-like ligand 4 (Dll4) negatively regulates vascular endothelial growth factor-mediated vessel sprouting and branching. To investigate the role of Dll4 in regulation of the ovarian vasculature, we administered a neutralizing antibody to Dll4 to marmosets at the periovulatory period. The vasculature was examined on luteal d 3 or d 10: angiogenesis was determined by incorporation of bromodeoxyuridine, staining for CD31 and cell death by staining for activated caspase-3. Ovulatory progesterone rises were monitored to determine effects of treatment on luteal function and time to recover normal cycles in a separate group of animals. Additionally, animals were treated in the follicular or midluteal phase to determine effects of Dll4 inhibition on follicular development and luteal function. Controls were treated with human IgG (Fc). Corpora lutea from marmosets treated during the periovulatory period exhibited increased angiogenesis and increased vascular density on luteal d 3, but plasma progesterone was significantly suppressed. By luteal d 10, corpora lutea in treated ovaries were significantly reduced in size, with involution of luteal cells, increased cell death, and suppressed plasma progesterone concentrations. In contrast, initiation of anti-Dll4 treatment during the midluteal phase produced only a slight suppression of progesterone for the remainder of the cycle. Moreover, Dll4 inhibition had no appreciable effect on follicular development. These results show that Dll4 has a specific and critical role in the development of the normal luteal vasculature.

Resisting control of neglected tropical diseases: dilemmas in the mass treatment of schistosomiasis and soil-transmitted helminths in north-west Uganda.

A strong case has recently been made by academics and policymakers to develop national programmes for the integrated control of Africa's 'neglected tropical diseases'. Uganda was the first country to develop a programme for the integrated control of two of these diseases: schistosomiasis and soil-transmitted helminths. This paper discusses social responses to the programme in Panyimur, north-west Uganda. It shows that adults are increasingly rejecting free treatment. Resistance is attributed to a subjective fear of side-effects; divergence between biomedical and local understandings of schistosomiasis/bilharzia; as well as inappropriate and inadequate health education. In addition, the current procedures for distributing drugs at a district level are problematic. Additional research was carried out in neighbouring areas to explore the generalizability of findings. Comparable problems have arisen. It is concluded that the national programme will not fulfil its stated objectives of establishing a local demand for mass treatment unless it can establish more effective delivery strategies and promote behavioural change in socially appropriate ways. To do so will require new approaches to social, economic and political aspects of distribution. There are reasons why populations infected with the 'neglected tropical diseases' are themselves neglected. Those reasons cannot just be wished away.

The altered distribution of the steroid hormone receptors and the chaperone immunophilin FKBP52 in a baboon model of endometriosis is associated with progesterone resistance during the window of uterine receptivity.

This study examines the distribution of estrogen receptors (ESR), progesterone receptors (Pgr), and the chaperone immunophilin FKBP52 in the eutopic endometrium in a baboon model of endometriosis during the window of receptivity to determine if their aberrant distribution contributes to reduced fecundity. Endometriosis was induced by inoculation of menstrual endometrium into the peritoneal cavity. Eutopic endometrium was collected at 3, 6, 9, 12, and 15 months postinoculation. Western blot (WB) and immunohistochemical analyses were performed. Isolated endometrial stromal cells were cultured in the presence or absence of steroid hormones. In animals with endometriosis, ESR-1 (ER-alpha) decreased in endometrial stromal cells, while ESR-2 (ER-beta) was reduced in both glandular epithelial (GE) and stromal cells. Immunoreactive total Pgr was markedly diminished in the GE, which was confirmed by WB analysis. Furthermore, treatment of isolated stromal cells from baboons with endometriosis with hormones did not increase levels of PRA or PRB as in control baboons. FKBP52 was also reduced in the eutopic endometrium of baboons with endometriosis. Endometriosis results in an aberrant distribution of ESR-1, ESR-2, Pgr, and FKBP52 in the eutopic endometrium. The authors propose that a dysregulation in the paracrine signaling between the endometrial stromal and GE cells reduces the responsiveness of Pgr, creating an endometrial environment that is unsuitable for implantation.

A baboon model for endometriosis: implications for fertility.

Endometriosis is one of the most common causes of chronic pelvic pain and infertility in women in the reproductive age group. Although the existence of this disease has been known for over 100 years our current knowledge of its pathogenesis and the pathophysiology of its related infertility remains unclear. Several reasons contribute to our lack of knowledge, the most critical being the difficulty in carrying out objective long-term studies in women. Thus, we and others have developed a model of this disease in the non-human primate, the baboon (Papio anubis). Intraperitoneal inoculation of autologous menstrual endometrium results in the development of endometriotic lesions with gross morphological characteristics similar to those seen in the human. Multiple factors have been implicated in endometriosis-associated infertility. We have described aberrant levels of factors involved in multiple pathways important in the establishment of pregnancy, in the endometrium of baboons induced with endometriosis. Specifically, we have observed dysregulation of proteins involved in invasion, angiogenesis, methylation, cell growth, immunomodulation, and steroid hormone action. These data suggest that, in an induced model of endometriosis in the baboon, an increased angiogenic capacity, decreased apoptotic potential, progesterone resistance, estrogen hyper-responsiveness, and an inability to respond appropriately to embryonic signals contribute to the reduced fecundity associated with this disease.

The estrogen early response gene FOS is altered in a baboon model of endometriosis.

Endometriosis, the presence of a functional endometrium outside of the uterine cavity, is associated with infertility. In our simulated model of pregnancy in baboons with experimental endometriosis, hCG infusion fails to induce expression of the immunoregulatory protein glycodelin. To test the hypothesis that the development of endometriosis is associated with an aberrant endometrial immunological environment, we examined the expression of a series of immunoregulatory genes in endometrium from baboons with and without endometriosis. Six months following intraperitoneal inoculation with menstrual endometrium, eutopic endometrium was surgically collected between Days 9 and 11 postovulation. Control endometrium was similarly collected from disease-free animals. Total RNA was extracted, and biotinylated cDNA probes were hybridized to the SuperArray GEArray Q series Th1/Th2/Th3 cDNA array, representing 96 genes. Gene expression levels were determined using ScanAlyze and GEArray Analyzer software. Seven genes were upregulated, including JUND, FOS, CCL11, NFKB1 and others, in the endometrium from baboons with endometriosis compared with the endometrium from disease-free animals; one gene, IL1R1, was downregulated. Quantitative RT-PCR confirmed upregulation of FOS and CCL11 in endometriotic eutopic endometrium. Immunohistochemical analysis revealed altered levels and distribution of FOS protein in the eutopic endometrium of baboons with induced endometriosis. These data suggest that in an induced model of endometriosis an aberrant eutopic immunological environment results in a decreased apoptotic potential and in rapid alterations in endometrial gene expression. We propose that the reduced fecundity associated with endometriosis has a multifold etiology in spontaneous and induced disease.

Induced endometriosis in the baboon (Papio anubis) increases the expression of the proangiogenic factor CYR61 (CCN1) in eutopic and ectopic endometria.

The expression of human CYR61 (cysteine-rich, angiogenic inducer, 61; CCN1) mRNA has been previously shown to be deregulated in the endometrium of women with endometriosis. We have chosen the baboon model (Papio anubis) of induced endometriosis to clarify whether CYR61 mRNA upregulation is predisposed to an inappropriately differentiated endometrium or is deregulated as a response to the presence of ectopic lesions. In the baboon, endometrial CYR61 mRNA expression underwent moderate cyclical variation, with a significant 7.3-fold increase detected at Day 2 postmenses when compared to endometrium from the proliferative and secretory phases. The CYR61 transcript was extensively upregulated in the eutopic endometrium from all baboons with induced endometriosis, as early as 1 mo postinoculation of menstrual tissue into the peritoneal cavity. CYR61 mRNA expression then decreased throughout progression of the disease, but remained higher compared to control tissues. Ectopic endometriotic lesions showed a further increase in CYR61 mRNA, with highest expression found in red lesions. Moreover, the expression levels of CYR61 transcripts correlated significantly with those of VEGF. Immunohistochemistry revealed the presence of CYR61 protein in glandular and luminal epithelial cells as well as in blood vessels of eutopic and ectopic endometrium. As in humans, increased levels of CYR61 mRNA correlated with the development of endometriosis in baboons. The increase of CYR61 mRNA in eutopic endometrium of baboons following peritoneal inoculation with menstrual endometrium provides evidence for a feedback mechanism from resulting lesions to induce a shift in gene expression patterns in the eutopic endometrium.

In vivo infusion of interleukin-1beta and chorionic gonadotropin induces endometrial changes that mimic early pregnancy events in the baboon.

Both human chorionic gonadotropin (hCG) and IL-1beta induce changes in the endometrium that are associated with the establishment of pregnancy. We investigated the synergistic effect of these two embryonic signals on endometrial function using a baboon model of simulated pregnancy. Recombinant hCG (30 IU/d) was infused between d 6 and 10 post ovulation (PO) to mimic blastocyst transit. On the expected day of implantation (d 10 PO), IL-1beta (12 ng/d) or IL-1 receptor antagonist (IL-1Ra; 12 ng/d) was infused for an additional 5 d. Endometria were harvested on d 15 PO. Both hCG and hCG plus IL-1beta induced marked differences in the distribution of alpha-smooth muscle actin, proliferation marker Ki67, decidualization marker IGF-binding protein-1, and cyclooxygenase-1. The most marked effect of IL-1beta was the induction of IGF-binding protein-1 protein in stromal cells close to the apical surface, whereas cyclooxygenase-1 was down-regulated in the glandular epithelium. Protein arrays of uterine flushings showed significant suppression of death receptors, Fas and TNF receptor 1, in the hCG- with or without IL-1beta-treated groups, suggesting an inhibition of apoptosis. Additionally, cytotoxic T lymphocyte antigen-4, matrix metalloproteinase-3, and IL-4 were suppressed in treated animals compared with controls. However, no differences were observed in cytokine profile between hCG-treated and hCG- plus IL-1beta-treated baboons. This study confirms that in preparation for pregnancy, the primate endometrium undergoes both morphological and functional changes, which are modulated by hCG and IL-1beta, that lead to the inhibition of apoptosis and the development of an immunotolerant environment. These changes suggest that infusion of IL-1beta at the time of implantation into the nonpregnant baboon treated with hCG synergizes with hCG and mimics the early endometrial events associated with the presence of an embryo.

Future directions in endometriosis research.

Endometriosis is an estrogen-dependent condition that affects 5 million American women; however, its etiology is not fully understood. The development of the baboon model of endometriosis provides an extremely powerful tool to investigate the development and progression of endometriosis from the early invasive phase to the advanced established disease. The inflammatory reaction that occurs in the peritoneal cavity at the site of endometriotic lesions does not clear the refluxed endometrial fragments. Moreover, this reaction appears to promote the survival of the tissue and the development of the disease. Exploration of the interactions between peritoneal macrophages and cytotoxic T cells and endometrial cells will determine whether their ability to scavenge and induce apoptosis is altered. Determining the mechanism(s) that induces the expression of estrogen and its receptor (ERbeta) is crucial to our understanding of the progression of the disease. The effects of ERbeta activation in endometriotic lesions should be investigated. It is important to determine the effects of estrogen on the function of the immune cells, either directly or indirectly. Finally, determining the effect of events at sites of ectopic endometrium on the eutopic endometrium may elucidate the mechanism(s) of infertility associated with endometriosis.

Expression of vascular endothelial growth factor (VEGF)-D and its receptor, VEGF receptor 3, as a prognostic factor in endometrial carcinoma.

PURPOSE: To evaluate the prognostic value of vascular endothelial growth factor (VEGF)-D and VEGF receptor (VEGFR)-3 in endometrial carcinoma. EXPERIMENTAL DESIGN: We assessed the levels of immunoreactivity for VEGF-D and VEGFR-3 in 71 endometrial carcinomas, 14 complex atypical endometrial hyperplasias, and 16 normal endometria by immunohistochemistry. RESULTS: VEGF-D was stained in both tumor cells and adjacent stromal cells. VEGFR-3 was stained in both tumor cells and adjacent endothelial cells. Immunoreactivity for VEGF-D in tumor cells and adjacent stromal cells became significantly stronger as lesions progressed from normal endometrium to advanced carcinoma. Similarly, immunoreactivity for VEGFR-3 in tumor cells and adjacent endothelial cells was significantly greater as lesions progressed from normal endometrium to advanced carcinoma. A strong correlation was found between high levels of VEGF-D immunoreactivity in carcinoma cells and VEGFR-3 in both carcinoma cells and adjacent endothelial cells. Similarly, high levels of VEGF-D immunoreactivity in stromal cells were significantly correlated with those of VEGFR-3 in both carcinoma cells and endothelial cells. High levels of VEGF-D in carcinoma cells and stromal cells, as well as those of VEGFR-3 in carcinoma cells and endothelial cells, were significantly related to myometrial invasion and lymph node metastasis. A strong correlation was found between poor survival and high levels of VEGF-D in both carcinoma cells and stromal cells and between poor survival and high levels of VEGFR-3 in carcinoma cells. Moreover, the high levels of VEGF-D in stromal cells and VEGFR-3 in carcinoma cells were independent prognostic factors in endometrial carcinoma. CONCLUSIONS: The presence of VEGF-D and VEGFR-3 in endometrial carcinoma may predict myometrial invasion and lymph node metastasis and may prospectively identify patients who are at increased risk for poor outcome. In addition, VEGF-D and VEGFR-3 may be promising targets for new therapeutic strategies in endometrial carcinoma.

Soluble vascular endothelial growth factor receptor 1 inhibits edema and epithelial proliferation induced by 17beta-estradiol in the mouse uterus.

The uterine response to 17beta-estradiol (E2) includes increased water retention, enhanced vascular permeability, DNA and RNA synthesis, and increased cellular mitosis. We have used the natural antagonist of vascular endothelial growth factor A (VEGF-A), sflt-1 (soluble form of flt-1), to determine whether the edematous and proliferative effects of E2 in the uterus are mediated by VEGF-A. Female BALB/c mice were ovariectomized and treated with E2 (10 micro g/kg) in the absence or presence of sflt-1 (0.8 and 4.0 mg/kg) for 24 h. E2 induced increases in uterine mass from 25.3 to 36.8 mg, in total cross-sectional uterine area from 771 to 1133 micro m(2), in cross-sectional endometrial area from 268 to 569 micro m(2), and in the mitotic index of lumenal epithelial cells from 0% to 53%. Antagonism with sflt-1 reduced the E2-induced increases in total uterine area to 779 micro m(2), endometrial area to 398 micro m(2) and the mitotic index of lumenal epithelial cells to 25%, but the E2-induced increase in uterine mass was not significantly reduced. From these data we conclude that the edematous response and proliferation of lumenal epithelial cells in the murine uterus are mediated in part through VEGF-A. These data suggest that sflt-1 could be a useful anti-VEGF-A agent and may be effective in modifying uterine biology.