Adrenomedullin inhibits hypoxic cell death by upregulation of Bcl-2 in endometrial cancer cells: a possible promotion mechanism for tumour growth.

Regions of hypoxia are a common feature of solid tumours. When tumour cells are exposed to hypoxic stress, transcription of a battery of genes is initiated. The angiogenic factor adrenomedullin (ADM) is a hypoxia regulated gene. ADM is thought to act through the G protein-coupled receptor calcitonin receptor-like receptor (CRLR), with specificity being conferred by the receptor associated modifying protein 2 (RAMP2). Here we report for the first time that ADM treated or stably transfected Ishikawa cells overexpressing ADM show increased resistance to hypoxia induced apoptosis. These cells also show an upregulation of the oncoprotein Bcl-2, which is protective against hypoxic cell death when transiently transfected into Ishikawa cells. Since Ishikawa cells express the putative ADM-receptor CRLR-RAMP2 the production and secretion of ADM with the consecutive upregulation of Bcl-2 could establish an autocrine/paracrine mechanism rescuing malignant cells from hypoxic cell death. These results, taken together with our previous findings that ADM is an angiogenic factor which is upregulated by the nonsteroidal antiestrogen tamoxifen (TAM) in endometrial cells, implicate this peptide as a promoter of tumour growth and a possible target for anticancer strategies.

PCR display identifies tamoxifen induction of the novel angiogenic factor adrenomedullin by a non estrogenic mechanism in the human endometrium.

Tamoxifen is currently the most widely used drug for the treatment of breast cancer, but there now exists considerable evidence that tamoxifen can also induce endometrial hyperplasia in pre menopausal women. We have used PCR differential display on primary human endometrial isolates in an attempt to identify genes induced by tamoxifen but not estrogen. Eight such differentially expressed bands were cloned and sequenced, one of which was found to be the peptide adrenomedullin. We have shown that adrenomedullin is a novel growth factor for endothelial cells and is angiogenic in vivo in the chick chorioallantoic membrane assay. Immunohistochemical analysis of endometrial sections have shown that while macrophages in the endometrium express adrenomedullin at a low level, endometrial macrophages of women receiving tamoxifen strongly express adrenomedullin (P=0.008). We postulate that endometrial induction of the angiogenic factor adrenomedullin by tamoxifen is part of the mechanism by which tamoxifen results in endometrial hyperplasia.

Expression of the hypoxically regulated angiogenic factor adrenomedullin correlates with uterine leiomyoma vascular density.

Uterine leiomyomas are the most prevalent benign tumor type in women of reproductive age and are one of the most common indications for hysterectomy. The expression of five angiogenic factors, adrenomedullin (ADM), vascular endothelial growth factor (VEGF), acidic fibroblast growth factor, basic fibroblast growth factor, and platelet-derived endothelial cell growth factor/thymidine phosphorylase, were examined in 91 uteri collected throughout the menstrual cycle; 52 of which contained leiomyomata, and the remainder were normal controls. The microvascular density and endothelial proliferative indices were then determined for each of the uterine sections. ADM and VEGF were the most widely expressed angiogenic factors in the leiomyomas. Furthermore, the expression of ADM and VEGF in the endometrium and myometrium was up-regulated in leiomyoma-bearing uteri compared with controls. Although acidic fibroblast growth factor and basic fibroblast growth factor were expressed in leiomyomas and endometrium in all of the uterine samples examined, they were only expressed in the myometrium of leiomyomata-bearing uteri. Endothelial proliferation in leiomyomas was statistically greater than that of the myometrium and endometrium, both within and between uteri (P < 0.05). The vascular density in the myometrium but not the endometrium was significantly increased in leiomyoma-containing uteri (P < 0.05). Expression of ADM alone correlated directly with vascular density and endothelial cell proliferation index in leiomyomas and myometrium and may account for the high vascularity found in leiomyomas and the myometrium of leiomyoma-bearing uteri. As such, ADM is identified as a novel target for antiangiogenic therapy of these benign, clinically problematic uterine tumors.

Motion detection deficits in infantile esotropia without nystagmus.

PURPOSE: To investigate whether adults with infantile strabismus but without latent nystagmus have abnormalities of horizontal motion detection. METHODS: Eleven adult subjects with infantile esotropia but without latent nystagmus and 15 control subjects were required to detect the onset of motion and drift direction of a sinusoidal, spatial frequency grating that moved with linearly increasing velocity. The grating was presented monocularly in paracentral vision at an eccentricity of 16.5 degrees with a field size of 18 degrees. The contrast of the grating was just above contrast threshold for visibility. RESULTS: The mean velocity threshold for detection of motion was raised significantly in the patient group compared with the control group. Nine of the 11 subjects with infantile esotropia demonstrated directional asymmetry for the detection of motion. Thresholds were elevated more often when the grating was moving nasally in the squinting eye and temporally in the nonsquinting eye, and raised thresholds were more prevalent in the squinting eye. CONCLUSIONS: The findings indicate that in infantile esotropia, the presence of motion perception deficits are not always associated with the development of latent nystagmus. The predominance of nasally directed motion deficits in the squinting eye and temporally directed motion deficits in the nonsquinting eye was unexpected and may have been caused by abnormal development of cortical motion processing.

Multifocal choroiditis: clinicopathologic correlation.

Many of the white dot syndromes are considered to have a granulomatous pathogenesis. The histopathologic characteristics of this case of multifocal choroiditis seen within 15 months of apparent clinical onset show that the white dot lesions were nongranulomatous perivascular choroidal infiltrates, consisting mainly of B lymphocytes. Early choroidal neovascularization was also seen.

Postural changes in perfusion pressure and retinal arteriolar calibre.

Ophthalmic artery perfusion pressures and retinal arteriolar calibres were studied in 10 human subjects when sitting, standing, and lying. Differing responses in perfusion pressure were found; autoregulatory responses were found in 13 of the 18 significant calibre changes on moving from sitting to standing and 13 of 22 significant calibre changes on moving from standing to lying. The remaining significant calibre changes were non-autoregulatory, the arterioles dilating with perfusion pressure increase and constricting with decrease.

Ocular quinine toxicity.

A case of ocular quinine toxicity is described which showed the typical acute visual loss and subsequent recovery. Vermiform motion of the pupil was noted 48 hours after overdose. This acute effect has not been reported before. Although acute systemic intoxication may respond to removal of quinine from the gut and circulation, there is no evidence that any treatment affects the visual prognosis. The action of quinine on the retina is unknown. We suggest it may block cholinergic neurotransmission in the inner synaptic layer.

Morphological changes in the human corneal epithelium associated with surgical corneal clouding.

Light microscopy and electron microscopy were used to define morphological changes occurring in human corneal epithelium during surgery. No correlation was established between preoperative medication or peroperative fluids and corneal epithelial clouding. It is suggested that the changes we observed in relation to epithelial clouding were the direct result of disturbance to endothelial pump functions.

Assessment of angiogenic factors the chick chorioallantoic membrane assay.

Angiogenesis is the growth of new vessels from existing vessels. It is important in the physiological processes of wound healing, embryogenesis, and the female menstrual cycle and involved in pathologies such as diabetic retinopathy and rheumatoid arthritis (1). There is now abundant evidence that tumors are angiogenesis dependent. Unless tumors can stimulate angiogenesis, and generate their own blood supply, they fail to grow larger than 2-3 mm(3). The angiogenic status of a tumor can be assessed directly using immunohistochem istry on pathology sections (see Chapter 13 by Kilic and Ergün in this volume and Chapter 7 by Ranieri and Gasparini and Chapter 8 by Turner and Harris in the companion volume) to count the number of blood vessels within a given area (microvessel density [MVD]). MVD is a prognostic indicator in a number of tumors including breast, bladder, and prostate (2). Angiogenic capacity can also be measured by assaying the various stimulatory and inhibitory factors that regulate angiogenesis. This can be done either by determining the mRNA level using ribonuclease protection (see Chapter 16 by Jones et al. in the companion volume) or the protein by either Western blotting (see Chapter 11 by Blancher and Jones in the companion volume) or with one of the commercially available enzyme-linked immunosorbent assay (ELISA) kits. Again, levels of these factors have been shown to be prognostic in a number of tumors.

A study of the public's knowledge regarding advance directives.

Advance directives are legal documents used to indicate individuals' wishes concerning medical care and treatment in the event that they are no longer able to do so. This study assessed the level of knowledge of 157 adults concerning advance directives and other medical terminology related to end-of-life events. Results indicated that 57% to 79% of respondents demonstrated an understanding of four to five major elements related to advance directives. There were no significant differences in level of understanding among groups of differing ethnicity, religion, and gender. Nor were there significant correlations found between level of understanding and the respondents' age and years of education.

Collaborative research: benefits and guidelines.

Several benefits of collaborative research and guidelines for strengthening collaborative mechanisms have been described here, but the impetus for research and development of competent research teams must come from health professionals themselves. The literature makes it apparent that allied health professionals need to devote a considerable amount of energy and resources to develop a knowledge base for the health-related professions, similar to those in medicine and the biological sciences. Research projects, particularly collaborative ones, can make significant contributions to the body of professional knowledge, the knowledge-generation process, the health care practitioner, and the patient. The results of research should not be judged successful until its ultimate goal (ie, impact on patients and practice) has been measured. In collaborative research, relationships should be based on systems thinking, making networking into a scientific approach--a true partnership approach--which is crucial in dealing with the problems of health care today.

Neurodegenerative disorders: Parkinson's disease and Huntington's disease.

Parkinson's disease and Huntington's disease are both model diseases. Parkinson's disease is the most common of several akinetic-rigid syndromes and Huntington's disease is only one of an ever growing number of trinucleotide repeat disorders. Molecular genetic studies and subsequent molecular biological studies have provided fascinating new insights into the pathogenesis of both disorders and there is now real hope for disease modifying treatment in the not too distant future for patients with Parkinson's disease or Huntington's disease.

Blepharoplasty and ptosis.

Recent advances in local anesthetic techniques have led to suggestions that buffered solutions for infiltration increase patient comfort. The use of an eutectic mixture of local anesthetics cream has however proved to be disappointing. The use of monopolar electrocautery, carbon dioxide lasers, and high-frequency radio wave electrosection provide the surgeon with new modes of cutting and coagulation. Lower lid blepharoplasty via a conjunctival approach may avoid many of the complications of the anterior approach. Such complications may also be minimized by careful preoperative planning and frequently the inclusion of a lateral canthopexy in the surgical procedure. The lid height after anterior and posterior levator resection can now be set more accurately with adjustable suture techniques. A new technique combining a superior tarsectomy with levator resection is described. A range of materials for brow suspension are now available. Autogenous fascia lata remains the material of choice when available.

Children presenting to an ophthalmic casualty department.

A five month prospective survey of all children (0-14 years) attending an ophthalmic accident and emergency department was carried out to determine the disease profile and the primary ophthalmic health care provided. A data base was used to collect and analyse all cases. Seventy three per cent of 475 children attending had non-traumatic ophthalmic diagnoses, less than half being referred from their general practitioners. The remaining children had minor ophthalmic injuries of which less than one quarter were referred from their general practitioners. Four of the minor ophthalmic injuries were suspected of being non-accidental injury. The management of such cases is discussed. The ophthalmologist in an ophthalmic casualty department has an important role in the provision of primary ophthalmic care for children. In the management of minor ophthalmic injuries, the alerting factors for non-accidental injury should be sought, although the apparent incidence is low.

The calibre changes of retinal vessels subject to prolonged hyperoxia.

The constriction of retinal vessels occurring in response to breathing 100% oxygen was studied in 10 normal subjects over a period of 30 min. Brachial blood pressure, radial pulse and end tidal CO2 were recorded throughout. The mean arteriolar constriction was 15.3% +/- 4.6 and venous constriction 21.8% +/- 4.3. Time constants (the time for 95% of the maximal response to have occurred) were 2.25 min +/- 0.75 and 2.37 min +/- 0.57 for arterioles and veins respectively. A highly variable late vascular response was recorded. A small proportion of arterial vessels showing a response were nonuniform while a larger proportion of veins showed a significant dilatation.

Regulation of endometrial angiogenesis.

Bleeding problems are the most common reason for discontinuation of hormone replacement therapy. Human endometrium undergoes the unique process of benign angiogenesis under the control of ovarian steroids during reproductive life and it is presumed that similar processes occur when women take hormone replacement therapy. The key players in endometrial growth and angiogenesis are vascular endothelial growth factor, thymidine phosphorylase and adrenomedullin. Regulation of these angiogenic factors is described.