Boundary spanning and identity work in the clinical research delivery workforce: a qualitative study of research nurses, midwives and allied health professionals in the National Health Service, United Kingdom.

BACKGROUND: Research nurses, midwives and allied health professionals are members of an important emergent profession delivering clinical research and, in the United Kingdom, have been the focus of considerable investment by the National Institute for Health Research (NIHR). This paper considers the experiences of research nurses, midwives and allied health professionals in relation to professional identity work, recognizing these are coproduced alongside others that they interact with (including patients, clinical staff and other research staff). METHODS: Semi-structured interviews were conducted with 45 nurses, midwives and allied health professionals in the UK about their experiences of working in research delivery. Interviews were transcribed verbatim and thematically coded and analysed. RESULTS: Our analysis highlights how research nurses, midwives and allied health professionals adjust to new roles, shift their professional identities and undertake identity work using uniforms, name badges and job titles as they negotiate complex identities. CONCLUSIONS: Research nurses, midwives and allied health professionals experience considerable challenges as they enter and transition to a research delivery role, with implications for their sense of professional identities. A change in the work that they undertake and how they are (or perceive they are) viewed by others (including clinical non-research colleagues and patients) has implications for their sense of professional and individual identity. The tensions involved extend to their views on symbols of professional identity, such as uniforms, and as they seek to articulate and demonstrate the value of their conjoined role in research and as a healthcare professional, within the unfolding landscape of health research. We embed our study findings in the context of the newly emerging clinical research practitioner workforce, which further exacerbates and complicates the role and identity complexity for nurses, midwives and allied health professionals in research delivery.

Neighbourhood influence on the fourth dose of diphtheria-tetanus-pertussis vaccination.

OBJECTIVES: Using 542,159 vaccination records from children born between April 1, 2007, and March 31, 2012, in the Michigan Care Improvement Registry and data from the American Community Survey, we determine if neighbourhood-level characteristics at the Census tract level and block level are associated with low uptake of the fourth dose of diphtheria-tetanus-acellular pertussis vaccine (DTaP4). STUDY DESIGN: This study was a cross-sectional study. METHODS: We used exploratory factor analysis to determine important socio-economic factors at the Census block level and tract level. We then used generalised estimating equations to test the relationship between block- and tract-level socio-economic factors and DTaP4 uptake. RESULTS: DTaP4 coverage was 88.6% (95% confidence interval [CI]: 88.4%-88.7%) in Michigan. At the Census tract level, two factors surfaced as important for DTaP4 vaccination: 'affluence' (Cronbach's alpha = 0.88) and 'socio-economic disadvantage' (Cronbach's alpha = 0.89). At the Census block level, one factor was important: 'affluence' (Cronbach's alpha = 0.90). Affluence may relate to knowledge about medical exemptions and antivaccination sentiment, while socio-economic disadvantage may indicate limited access to healthcare resources. Children in high-affluence tracts had 1.08% lower vaccination coverage (95% CI: -1.62% to -0.55%) than children in low affluence tracts. Children in low socio-economic disadvantage tracts had 2.92% higher coverage than children in high socio-economic disadvantage tracts (95% CI: 2.58%-3.26%). CONCLUSIONS: This study articulates the need to further understand the contribution of neighbourhood-level characteristics, from both affluent and socioeconomically disadvantaged areas to low vaccination rates. Developing a better understanding of these social environmental factors will help determine useful community-level interventions to improve vaccination rates and reduce disease burden.

An evaluation of immunization services, using the reaching every district criteria, in two districts of Gujarat, India.

BACKGROUND: Immunizations are considered the most successful and cost-effective public health interventions employed today. While immunization coverage in India has improved dramatically in the last decade, areas of very low coverage persist. The University of Michigan School of Public Health and the Indian Institute of Public Health Gandhinagar collaborated to document strengths and weaknesses of immunization service delivery in two districts in India. METHODS: This report describes a qualitative assessment of clinic level immunization service delivery in ten primary health centers (PHCs) located in two districts of Gujarat, India. Assessment criteria were derived from the Reaching Every District (RED) strategy that is intended to provide a framework for delivering childhood immunizations. Staff from the PHCs were interviewed in April 2013. RESULTS: Interviews revealed several barriers to immunization service delivery including: 1) Vaccine and supply stockouts; 2) Hard to reach communities; 3) Unreliable Internet access; 4) Cold chain equipment malfunctions; 5) Inconsistently maintained and utilized immunization records and registries. CONCLUSIONS: Immunization service delivery is a complex process that can encounter barriers at many stages. A RED-based evaluation of the vaccine delivery system in Gujarat, India identified several points where the system was performing sub-optimally and possible solutions to successfully address these challenges.

Factors associated with intentional and unintentional non-adherence to adjuvant endocrine therapy following breast cancer.

Adherence to adjuvant endocrine therapy (AET) following breast cancer is known to be suboptimal despite its known efficacy in reducing recurrence and mortality. This study aims to investigate factors associated with non-adherence and inform the development of interventions to support women and promote adherence. A questionnaire survey to measure level of adherence, side effects experienced, beliefs about medicine, support received and socio-demographic details was sent to 292 women 2-4 years post breast cancer diagnosis. Differences between non-adherers and adherers to AET were explored, and factors associated with intentional and unintentional non-adherence are reported. Approximately one quarter of respondents, 46 (22%), were non-adherers, comprising 29 (14%) intentional non-adherers and 17 (8%) unintentional non-adherers. Factors significantly associated with intentional non-adherence were the presence of side effects (p < .03), greater concerns about AET (p < .001) and a lower perceived necessity to take AET (p < .001). Half of the sample (105/211) reported that side effects had a moderate or high impact on their quality of life. Factors associated with unintentional non-adherence were younger age (<65) (p < .001), post-secondary education (p = .046) and paid employment (p = .031). There are distinct differences between intentional non-adherence and unintentional non-adherence. Differentiation between the two types of non-adherence may help tailor support and advice interventions.

Risk factors for measles among infants in Tianjin, China.

OBJECTIVES: Infants aged <8 months are ineligible for measles vaccination in China but represent a disproportionate number of cases. We examined the risk factors for measles among infants in Tianjin, China. STUDY DESIGN: Case-control study. METHODS: Cases were enrolled from a surveillance system, and IgG-negative controls were sampled from registries at immunization clinics. A logistic regression model assessed for risk factors. RESULTS: Among 82 cases and 485 controls, exposure to a municipal hospital (OR [odds ratio]: 5.21; 95% confidence interval [CI]: 1.19-22.82) or a specialty hospital (OR: 13.22; 95% CI: 6.13-28.51) was associated with the disease, whereas visiting a township or district hospitals was not associated with increased odds of measles. CONCLUSIONS: Hospitals were an important focal point of measles transmission for infants. Hospitals, particularly higher-level municipal and specialty hospitals, should enforce infection control programs to separate infants with highly communicable diseases to prevent transmission.

Syndromic surveillance for influenza in Tianjin, China: 2013-14.

Background: Diverse sources of syndromic surveillance including over-the-counter (OTC) drug sales, hospital and school-based influenza-like illness (ILI) and Baidu search queries estimate influenza activity in Tianjin, China. The purpose of this study was to determine which syndromic surveillance systems had the strongest correlation with laboratory-confirmed influenza activity. Methods: Data were obtained from sentinel hospitals and laboratories; sentinel hospitals also reported percentage of ILI. OTC sales and school-based ILI absentee data were provided by public pharmacies and schools. Baidu search queries for influenza surveillance were analyzed. Spearman correlation analysis examined correlations of syndromic systems with laboratory-confirmed data. Results: Syndromic data for hospital ILI%, OTC sales and school-based ILI correlated well with laboratory data (r = 0.732, 0.490 and 0.693, respectively; P < 0.05). Baidu, the predominant Chinese Internet service, searches for 'influenza', 'cough' and 'fever' correlated best with laboratory-confirmed activity; queries for 'fever' were strongest (r = 0.924, P < 0.001). Correlations between school-based ILI and laboratory-confirmed influenza increased from 0.693 to 0.795 after a 1-week lag (P < 0.05). Conclusions: A Baidu query of 'fever' provided the strongest correlation to laboratory surveillance. School-based ILI absence reporting detected influenza virus activity 1 week earlier than laboratory confirmation. Use of diverse syndromic surveillance systems in conjunction with traditional surveillance systems can improve influenza surveillance.

A qualitative study of cancer survivors' responses to information on the long-term and late effects of pelvic radiotherapy 1-11 years post treatment.

As more patients survive cancer for longer term, the long-term and late effects of treatments become increasingly important issues for cancer survivors and providing information to enable survivors to recognise and manage them becomes an increasingly pressing challenge for health care professionals. The aim of this study was to explore the experiences of cancer survivors regarding information given on potential long-term and late effects of pelvic radiotherapy. Semi-structured interviews were conducted with 28 cancer survivors who had had radiotherapy to the pelvic area for a range of cancers 1-11 years previously. Participants were recruited using maximum variation sampling from a larger questionnaire survey of patients treated at one hospital. Interviews were recorded, transcribed and analysed using Framework. Participants recognised the value of information to reassure and to inform action but also its potentially undesirable effects to frighten or raise anxieties about future problems and its inherent limitations in meeting their wider needs. They identified the timing, amount of information and context in which it was given as of particular importance. Information based on personal experience was also valued. These findings highlight the importance of appropriate, individualised information during treatment, at hospital discharge and subsequently in primary care.

The effects of pelvic radiotherapy on cancer survivors: symptom profile, psychological morbidity and quality of life.

AIMS: As cancer survival rates continue to increase, it is important to maximise the quality of life of cancer survivors. Pelvic radiotherapy is a common cancer treatment. Bladder, bowel and sexual dysfunction are recognised side-effects of treatment, and yet relatively little is known of the extent to which they remain problems in the longer term when patients are often managed by primary care, nor of the psychological impact of symptoms and effects on quality of life. Therefore, the aims of this study were to estimate the prevalence of bladder, bowel and sexual dysfunction late effects in a sample of cancer survivors; assess the impact of time since treatment on symptom prevalence; and explore the relationship between symptoms, psychological morbidity and quality of life. MATERIALS AND METHODS: A questionnaire was given to a sample of cancer survivors treated in Oxford who had pelvic radiotherapy 1-11 years previously. The questionnaire measured patient-reported toxicity (Common Toxicity Criteria of Adverse Events/Late Effects of Normal Tissues--Subjective, Objective, Management and Analytic Measure), psychological morbidity (Hospital Anxiety and Depression Scale) and quality of life (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30). RESULTS: In total, 418 (57.1%) completed questionnaires were received. Moderate/severe problems with bowel, urinary and sexual functioning were relatively common: bowel urgency (59% women, 45% men); urine urgency (49% women, 46% men); ability to have a sexual relationship affected (24% women, 53% men). Symptoms were just as frequent in those 6-11 years after treatment as in those 1-5 years after treatment. Symptom severity was significantly associated with poorer overall quality of life and higher levels of depression. CONCLUSIONS: Late effects are common among long-term cancer survivors who have had pelvic radiotherapy, and are associated with reduced quality of life and psychological morbidity. It is imperative due attention is paid to this issue during the follow-up phase--both in secondary and primary care. Health care professionals providing follow-up care need to be aware of the importance of assessing and monitoring symptoms, and need to be adequately informed on the most appropriate management strategies.

Canadian experience with the pipeline embolization device for repair of unruptured intracranial aneurysms.

BACKGROUND AND PURPOSE: Flow-diverting stents, such as the PED, have emerged as a novel means of treating complex intracranial aneurysms. This retrospective analysis of the initial Canadian experience provides insight into technical challenges, clinical and radiographic outcomes, and complication rates after the use of flow-diverting stents for unruptured aneurysms. MATERIALS AND METHODS: Cases were compiled from 7 Canadian centers between July 2008 and December 2010. Each center prospectively tracked their initial experience; these data were retrospectively updated and pooled for analysis. RESULTS: During the defined study period, 97 cases of unruptured aneurysm were treated with the PED, with successful stent deployment in 94 cases. The overall complete or near-complete occlusion rate was 83%, with a median follow-up at 1.25 years (range 0.25-2.5 years). Progressive occlusion was witnessed over time, with complete or near-complete occlusion in 65% of aneurysms followed through 6 months, and 90% of aneurysms followed through 1 year. Multivariate analysis found previous aneurysm treatment and female sex predictive of persistent aneurysm filling. Most patients were stable or improved (88%), with the most favorable outcomes observed in patients with cavernous carotid aneurysms. The overall mortality rate was 6%. Postprocedural aneurysm hemorrhage occurred in 3 patients (3%), while ipsilateral distal territory hemorrhage was observed in 4 patients (3.4%). CONCLUSIONS: Flow-diverting stents represent an important tool in the treatment of complex intracranial aneurysms. The relative efficacy and morbidity of this treatment must be considered in the context of available alternate interventions.

Human rabies in Tianjin, China.

BACKGROUND: Human rabies has recently re-emerged as a significant public health threat in Tianjin, China. METHODS: Using surveillance data compiled by the Tianjin Centers for Disease Control and Prevention, we describe 60 cases of human rabies reported from 2005 to 2011 in the municipality of Tianjin, China. RESULTS: All 60 cases of human rabies resulted in death. Cases were primarily male (80%), middle aged (mean 40.6 years), and exposed to rabies in a rural setting (82%). Most exposures were associated with dog bites (93%) and no animal had a history of rabies vaccination; no cases were laboratory confirmed. Fifteen percent of patients sought medical attention for their wound, and none received a complete regimen of WHO-recommended post-exposure prophylaxis (PEP). CONCLUSIONS: These findings suggest the need for China's public health authority to improve animal rabies surveillance and control strategies through laboratory case confirmation, more rapid response to potential exposures with provision of appropriate PEP, and education to the public and to health care providers on identifying and reducing rabies risk.

The 'Green Revolution' dwarfing genes play a role in disease resistance in Triticum aestivum and Hordeum vulgare.

The Green Revolution dwarfing genes, Rht-B1b and Rht-D1b, encode mutant forms of DELLA proteins and are present in most modern wheat varieties. DELLA proteins have been implicated in the response to biotic stress in the model plant, Arabidopsis thaliana. Using defined wheat Rht near-isogenic lines and barley Sln1 gain of function (GoF) and loss of function (LoF) lines, the role of DELLA in response to biotic stress was investigated in pathosystems representing contrasting trophic styles (biotrophic, hemibiotrophic, and necrotrophic). GoF mutant alleles in wheat and barley confer a resistance trade-off with increased susceptibility to biotrophic pathogens and increased resistance to necrotrophic pathogens whilst the converse was conferred by a LoF mutant allele. The polyploid nature of the wheat genome buffered the effect of single Rht GoF mutations relative to barley (diploid), particularly in respect of increased susceptibility to biotrophic pathogens. A role for DELLA in controlling cell death responses is proposed. Similar to Arabidopsis, a resistance trade-off to pathogens with contrasting pathogenic lifestyles has been identified in monocotyledonous cereal species. Appreciation of the pleiotropic role of DELLA in biotic stress responses in cereals has implications for plant breeding.

Proteomic profiling of human retinal pigment epithelium exposed to an advanced glycation-modified substrate.

PURPOSE: The retinal pigment epithelium (RPE) and underlying Bruch's membrane undergo significant modulation during ageing. Progressive, age-related modifications of lipids and proteins by advanced glycation end products (AGEs) at this cell-substrate interface have been implicated in RPE dysfunction and the progression to age-related macular degeneration (AMD). The pathogenic nature of these adducts in Bruch's membrane and their influence on the overlying RPE remains unclear. This study aimed to identify alterations in RPE protein expression in cells exposed to AGE-modified basement membrane (AGE-BM), to determine how this "aged" substrate impacts RPE function and to map the localisation of identified proteins in ageing retina. METHODS: Confluent ARPE-19 monolayers were cultured on AGE-BM and native, non-modified BM (BM). Following 28-day incubation, the proteome was profiled using 2-dimensional gel electrophoresis (2D), densitometry and image analysis was employed to map proteins of interest that were identified by electrospray ionisation mass spectrometry (ESI MS/MS). Immunocytochemistry was employed to localise identified proteins in ARPE-19 monolayers cultured on unmodified and AGE-BM and to analyze aged human retina. RESULTS: Image analysis detected altered protein spot densities between treatment groups, and proteins of interest were identified by LC ESI MS/MS which included heat-shock proteins, cytoskeletal and metabolic regulators. Immunocytochemistry revealed deubiquitinating enzyme ubiquitin carboxyterminal hydrolase-1 (UCH-L1), which was upregulated in AGE-exposed RPE and was also localised to RPE in human retinal sections. CONCLUSIONS: This study has demonstrated that AGE-modification of basement membrane alters the RPE proteome. Many proteins are changed in this ageing model, including UCHL-1, which could impact upon RPE degradative capacity. Accumulation of AGEs at Bruch"s membrane could play a significant role in age-related dysfunction of the RPE.

Transretinal degeneration in ageing human retina: a multiphoton microscopy analysis.

AIM: Retinal cell remodelling has been reported as a consistent feature of ageing. However, the degree to which this results in transretinal degeneration is unclear. To address this, the authors used multiphoton microscopy to quantify retinal degeneration in post-mortem human eyes of two age groups. METHODS: Retinas from six young subjects (18-33 years old) and six older subjects (74-90 years old) were prepared as wholemount preparations. All retinas were stained with 4,6-diamidino-2-phenylindole and imaged by multiphoton confocal microscopy to quantify neuron densities in the retinal ganglion cell layer (RGCL), inner nuclear layer (INL) and outer nuclear layer (ONL). Neurons were counted using automated cell identification algorithms. All retinas were imaged hydrated to minimise tissue artefacts. RESULTS: In both groups, 56% of the area within the central 4 mm eccentricity and 27% of the area with eccentricity between 4 mm and 7 mm were imaged. Compared with young subjects, the peak RGCL neuron loss in the aged subjects (25.5%) was at 1 mm eccentricity. INL and ONL neuron densities significantly decreased at 1-2 mm eccentricity (8.7%) and 0.5-4 mm eccentricity (15.6%) respectively (P <0.05). The reduction in neuron density in the INL corresponded, spatially, to the region with the greatest neuron loss in the RGCL and ONL. CONCLUSIONS: This is the first study to correlate neurodegeneration in different populations of cells in the ageing retinas. These data confirm that the greatest neuronal loss occurs in the RGCL and ONL in human ageing retinas, whereas the INL is relatively preserved.

Tear film volume and protein analysis in full-term newborn infants.

PURPOSE: To investigate infant tear film secretion and protein profile, and to compare major tear proteins, such as immunoglobulin A, lactoferrin, and lysozyme, with those of adult controls. METHODS: Tears were collected, with a cellulose rod, from 40 healthy infants (19 female infants and 21 male infants, gestational duration: 39.71 ± 1.27 weeks) within 48 hours of birth and 22 adults (10 female infants and 12 male infants, mean age: 24.95 ± 3.63 years). A second collection was obtained from 14 of the infants (8 female infants and 6 male infants, postnatal age: 7.76 ± 6.14 weeks). The tear volume was measured, and protein in the samples was analyzed by Bradford assay and gel electrophoresis. RESULTS: Median tear volume (interquartile range) was 0.5 µL (0.6-2 µL) for newborn infants, 2.5 µL (1.4-7.75 µL) for these infants at an older age, and 6 µL (2.73-12.75 µL) in adults (P < 0.001, Kruskall-Wallis test). Immunoglobulin A concentration was significantly lower in newborns (P < 0.001, analysis of variance). Lipocalin was present in 36% of the newborn tear samples, whereas serum albumin was found in 86%. Mean protein concentration (µg/µL ± SD) was 10.95 ± 5.51 in the newborns, 12.93 ± 3.99 in the older infants, and 13.04 ± 3.46 in the adults (P > 0.5, analysis of variance). CONCLUSIONS: This is the first study reporting an investigation of unstimulated infant tears, using a noninvasive collection method. Tear protein content demonstrated that the infant tear film is different to that in adults.

Topography of neuron loss in the retinal ganglion cell layer in human glaucoma.

AIM: To determine if retinal ganglion cell (RGC) loss influences the loss of surrounding RGCs to generate clustered patterns of cell death in human glaucoma. It is hypothesised that retinal ganglion cell loss accelerates the loss of surrounding cells to generate, at a local, cellular scale, clustered patterns of retinal of RGC death. The absence of these interactions would result in a diffuse pattern RGC loss. METHOD: Six glaucomatous retinas (67-83 years old) and six age-matched control retinas (61-89 years old) were prepared as wholemounts and stained by 4',6-diamidino-2-phenylindole (DAPI) solution (3 microg/ml in PBS). An area corresponding to central 14 degrees of the visual field was imaged. The nearest-neighbour distribution was determined for cells in both normal and glaucomatous RGCL. RESULTS: Clustered RGC loss in human glaucoma was observed on a background of diffuse loss. The mean nearest-neighbour distance (NND) of the glaucomatous retinas was significantly higher than with controls (p<0.001). The distribution of NND in glaucomatous retinas was skewed to the higher values with a higher positive kurtosis relative to controls. The quantitative analysis of the pattern of cell loss is supported by the visual inspection of the patterns of cell loss. DISCUSSION: The nearest-neighbour analysis is consistent with the presence of two patterns of cell loss in the RGCL in glaucoma. While the diffuse of cell loss can account for an overall reduction in the RGC population, an additional non-random pattern is consistent with the hypothesis that RGC loss has a local influence on the viability of surrounding cells.

Surveillance of trend and distribution of stroke mortality by subtype, age, gender, and geographic areas in Tianjin, China, 1999-2006.

BACKGROUND: The purpose of this study was to analyze the epidemiological trend and distribution of stroke mortality in the city of Tianjin, China, in order to provide evidence for the prevention and control of stroke. METHODS: The study was based on 102 718 cases of stroke mortality in Tianjin between 1999 and 2006. The cause of death was coded according to the International Classification of Diseases into stroke subtypes. Standardized mortality rates were calculated for stroke and its subtypes, adjusted for age and gender using the year 2000 world standard population. The age, gender, and geographic distribution of stroke and subtype mortality were analyzed. chi2-tests were used to determine the statistical significance of differences in mortality trends. RESULTS: The stroke mortality rate in Tianjin declined from 133.52/100 000/year in 1999 to 102.52/100 000/year in 2006. The stroke mortality rate for males was higher than that for females. Stroke mortality rates increased with increasing age. The subtypes of stroke have changed considerably in Tianjin. Hemorrhagic was major in 1999-2001, while cerebral infarction attained the first rank and accounted for more than 50% of stroke mortality in 2002-2006. The most pronounced finding was that the proportion of ischemic stroke was 66.65% in the urban population and over 20% higher than that in the rural area. Stroke in the suburban area was mainly hemorrhagic stroke, up to 62.67%. CONCLUSIONS: There are significant differences in the distribution of stroke mortality by subtype, age, gender, and geographic areas in Tianjin, China. Various subtypes of stroke are associated with different risk factors and therefore require different public health prevention and control measures. This study provides pertinent information for formulation of measures for the prevention and control of stroke.

Veterinarian injuries associated with bovine TB testing livestock in Michigan, 2001.

Testing all the cattle in an entire state with a uniform procedure for each animal affords an opportunity to relate human injury data to a known number of animals handled while carrying out a standardized procedure. Our objective was to describe the type and incidence density of injuries associated with TB-testing a large number of cattle herds, and to delineate the various factors associated with the risk of injury. A survey was mailed to all veterinarians (N = 259) who had completed at least five official bovine TB (bTB) herd tests in Michigan in 2001. We collected data regarding basic demographics and health status, work experience, veterinary specialty, and practice information. Each veterinarian was also requested to complete a separate injury questionnaire for each injury received while TB testing livestock in 2001. Accurate addresses were found for 247 eligible veterinarians, 175 (71%) of whom returned the survey. Thirty-six veterinarians reported a total of 53 injuries (10 major, 12 minor and 31 self-treated). Hands (29%) and legs (21%) were the anatomic locations most frequently injured, with sprains/strains (30%) and abrasion/contusion (30%) the most common types of injuries sustained. The overall incidence density of injuries was 1.9 per 10,000 animals tested. Female gender (RR = 3.3), being employed by the government (RR = 4.5), and smoking (RR = 6.0) were significantly associated with a higher rate of injury. Significant colliniearities were found between some risk factors associated with an increased rate of injury and participants thought 81% of their injuries could have been prevented. These results are explained by the administrative structure of the bTB testing program in Michigan, and the changing demographics of the veterinary workforce.

Retinal and choroidal microangiopathies: therapeutic opportunities.

Pathological angiogenesis in the retina and underlying choroid is a major cause of visual impairment in all age groups. The last decade has seen an explosion in the clinical availability of antiangiogenic compounds. Emphasis has been placed on inhibitors of the VEGF signaling pathway and considerable success has been achieved with aptamers and antibodies that bind VEGF. However, regression of neovascularization is rarely permanent and the regrowth of new vessels, often within a few months, requires multiple applications of drug. A number of antiangiogenic factors such as IGFBP3, SDF-1 blockers, PEDF, gamma-secretase, Delta-like ligand 4, and integrin antagonists have been identified, which act either indirectly on the VEGF system or independent of it. The importance of other candidates such as HIF-1alpha and protein kinase CK2, which act as "master" regulators of angiogenesis, offer realistic alternative targets for pharmacological intervention. The concept of combination therapy is rapidly gaining interest in the eye field and co-administration of two angiogenic agents (e.g., a CK2 inhibitor with a somatostatin analog, octreotide) are often significantly more effective at inhibiting retinal angiogenesis than either drug alone. The following review will discuss the current therapies available for aberrant ocular angiogenesis, consider new candidate targets for development of antiangiogenic compounds and emphasize the importance of combinatorial pharmacological agents in the treatment of such a dynamic cellular event as angiogenesis.

VEGF-A regulates the expression of VEGF-C in human retinal pigment epithelial cells.

AIM: To determine the expression and regulation of vascular endothelial growth factor C (VEGF-C), and its receptor VEGFR-3, in human retinal pigment epithelial (RPE) cells and to consider their angiogenic role in choroidal neovascularisation (CNV). METHOD: The expression of VEGF-C and VEGFR-3 in cultured human RPE was confirmed by immunostaining, PCR, western blotting, and ELISA. Cultured RPE cells were exposed to VEGF-A and glucose and VEGF-C and VEGFR-3 changes in gene expression determined by RT-PCR. Secreted VEGF-C protein in conditioned media from RPE was examined by western blotting and ELISA analysis. The ability of VEGF-C to elicit tube formation in choroidal endothelial cells was assayed by an in vitro Matrigel model. RESULT: VEGF-A and glucose upregulated VEGF-C mRNA expression and increased the secretion of VEGF-C protein into the culture medium. VEGF-A, but not glucose alone, stimulated VEGFR-3 mRNA expression. VEGF-C acted synergistically with VEGF-A to promote in vitro tube formation by choroidal endothelial cells. CONCLUSION: VEGF-A has a critical role in the orchestration of VEGF-C expression in RPE cells and the synergistic action of VEGF-C with VEGF-A may play an important part in the aetiology of CNV.