Understanding psychological outcomes following exposure to potentially morally injurious events in animal care: development of the Moral Distress-Posttraumatic Growth Scale for Veterinary Professionals.

AIMS: To generate a taxonomy of potentially morally injurious events (PMIE) encountered in veterinary care and develop an instrument to measure moral distress and posttraumatic growth following exposure to PMIE in the veterinary population. METHODS: Development and preliminary evaluation of the Moral Distress-Posttraumatic Growth Scale for Veterinary Professionals (MD-PTG-VP) employed data from veterinary professionals (veterinarians, veterinary nurses, veterinary technicians) from Australia and New Zealand across three phases: (1) item generation, (2) content validation, and (3) construct validation. In Phase 1 respondents (n = 46) were asked whether they had experienced any of six PMIE and to identify any PMIE not listed that they had experienced. In Phase 2 a different group of respondents (n = 11) assessed a list of 10 PMIE for relevance, clarity and appropriateness. In Phase 3 the final instrument was tested with a third group of respondents (n = 104) who also completed the Short Post-Traumatic Stress Disorder Rating Interview (SPRINT), a measure of posttraumatic stress, and the Stress-Related Growth Scale-Short Form (SRGS-SF) a measure of perceived posttraumatic growth. Spearman's correlation coefficients were calculated between respondent scores on each of the MD-PTG-VP subscales, the SPRINT, and the SRGS-SF to assess construct validity. RESULTS: A 10-item taxonomy of PMIE encountered in veterinary care was generated in Phase 1. Items were deemed relevant, clear and appropriate by veterinary professionals in Phase 2. These were included in the developed instrument which measures frequency and impact of exposure to 10 PMIE, yielding three subscale scores (exposure frequency, moral distress, and posttraumatic growth). Assessment of construct validity by measuring correlation with SPRINT and SRGS-SF indicated satisfactory validity. CONCLUSIONS: The MD-PTG-VP provides an informative tool that can be employed to examine professionals' mental health and wellbeing following exposure to PMIE frequently encountered in animal care. Further evaluation is required to ascertain population norms and confirm score cut-offs that reflect clinical presentation. CLINICAL RELEVANCE: Once fully validated this instrument may be useful to quantify the frequency and intensity of positive and negative aspects of PMIE exposure on veterinary professionals so that accurate population comparisons can be made and changes measured over time.

Impact of long-term quorum sensing inhibition on uropathogenic Escherichia coli.

BACKGROUND: Quorum sensing is an extracellular bacterial communication system used in the density-dependent regulation of gene expression and development of biofilms. Biofilm formation has been implicated in the establishment of catheter-associated urinary tract infections and therefore quorum sensing inhibitors (QSIs) have been suggested as anti-biofilm catheter coating agents. The long-term effects of QSIs in uropathogens is, however, not clearly understood. OBJECTIVES: We evaluated the effects of repeated exposure to the QSIs cinnamaldehyde, (Z)-4-bromo-5(bromomethylene)-2(5H)-furanone-C30 (furanone-C30) and 4-fluoro-5-hydroxypentane-2,3-dione (F-DPD) on antimicrobial susceptibility, biofilm formation and relative pathogenicity in eight uropathogenic Escherichia coli (UPEC) isolates. METHODS: MICs, MBCs and minimum biofilm eradication concentrations and antibiotic susceptibility were determined. Biofilm formation was quantified using crystal violet. Relative pathogenicity was assessed in a Galleria mellonella model. To correlate changes in phenotype to gene expression, transcriptomic profiles were created through RNA sequencing and variant analysis of genomes was performed in strain EC958. RESULTS: Cinnamaldehyde and furanone-C30 led to increases in susceptibility in planktonic and biofilm-associated UPEC. Relative pathogenicity increased after cinnamaldehyde exposure (4/8 isolates), decreased after furanone-C30 exposure (6/8 isolates) and varied after F-DPD exposure (one increased and one decreased). A total of 9/96 cases of putative antibiotic cross-resistance were generated. Exposure to cinnamaldehyde or F-DPD reduced expression of genes associated with locomotion, whilst cinnamaldehyde caused an increase in genes encoding fimbrial and afimbrial-like adhesins. Furanone-C30 caused a reduction in genes involved in cellular biosynthetic processes, likely though impaired ribonucleoprotein assembly. CONCLUSIONS: The multiple phenotypic adaptations induced during QSI exposure in UPEC should be considered when selecting an anti-infective catheter coating agent.

Dose-dependent expression of claudin-5 is a modifying factor in schizophrenia.

Schizophrenia is a neurodevelopmental disorder that affects up to 1% of the general population. Various genes show associations with schizophrenia and a very weak nominal association with the tight junction protein, claudin-5, has previously been identified. Claudin-5 is expressed in endothelial cells forming part of the blood-brain barrier (BBB). Furthermore, schizophrenia occurs in 30% of individuals with 22q11 deletion syndrome (22q11DS), a population who are haploinsufficient for the claudin-5 gene. Here, we show that a variant in the claudin-5 gene is weakly associated with schizophrenia in 22q11DS, leading to 75% less claudin-5 being expressed in endothelial cells. We also show that targeted adeno-associated virus-mediated suppression of claudin-5 in the mouse brain results in localized BBB disruption and behavioural changes. Using an inducible 'knockdown' mouse model, we further link claudin-5 suppression with psychosis through a distinct behavioural phenotype showing impairments in learning and memory, anxiety-like behaviour and sensorimotor gating. In addition, these animals develop seizures and die after 3-4 weeks of claudin-5 suppression, reinforcing the crucial role of claudin-5 in normal neurological function. Finally, we show that anti-psychotic medications dose-dependently increase claudin-5 expression in vitro and in vivo while aberrant, discontinuous expression of claudin-5 in the brains of schizophrenic patients post mortem was observed compared to age-matched controls. Together, these data suggest that BBB disruption may be a modifying factor in the development of schizophrenia and that drugs directly targeting the BBB may offer new therapeutic opportunities for treating this disorder.

Predictive systems ecology.

Human societies, and their well-being, depend to a significant extent on the state of the ecosystems that surround them. These ecosystems are changing rapidly usually in response to anthropogenic changes in the environment. To determine the likely impact of environmental change on ecosystems and the best ways to manage them, it would be desirable to be able to predict their future states. We present a proposal to develop the paradigm of predictive systems ecology, explicitly to understand and predict the properties and behaviour of ecological systems. We discuss the necessary and desirable features of predictive systems ecology models. There are places where predictive systems ecology is already being practised and we summarize a range of terrestrial and marine examples. Significant challenges remain but we suggest that ecology would benefit both as a scientific discipline and increase its impact in society if it were to embrace the need to become more predictive.

Resilience in animal care professions: does the stress shield model fit?

Animal care professionals can experience adverse psychological outcomes due to their work, therefore research exploring supporting resilience in this population is needed. This study investigated the capacity of the Stress Shield Model (SSM) to explain relationships between individual, interpersonal, and organisational factors with outcomes in resilience (resilience, growth, and job satisfaction) in animal care professionals. Empowerment was hypothesised to mediate these relationships. Australian and New Zealand animal care professionals (N = 393) completed an online survey measuring conscientiousness, coping, team and leader relationships, job demands, organisational resources, empowerment, growth, resilience, and job satisfaction. Results indicated that SSM can partially explain relationships between individual, interpersonal, and organisational factors and outcomes in resilience, and empowerment partially mediated the effect of organisational resources on growth. Problem-approach coping positively predicted resilience and growth; conversely, emotion-avoidant coping negatively predicted these outcomes. Conscientiousness positively predicted resilience and negatively predicted job satisfaction. Team relationships positively predicted growth and resilience, while leader-member relationships positively predicted job satisfaction. Organisational resources positively predicted resilience, growth, and job satisfaction, conversely, job demands predicted reductions across these outcomes. Findings indicate supporting resilience in animal care professionals requires fostering individual, interpersonal, and organisational resources.

A taxonomy of occupational and organisational stressors and protectors of mental health reported by veterinary professionals in Australasia.

AIM: To develop a taxonomy of positive and negative occupational and organisational factors reported that impact the mental health of veterinary professionals. METHODS: Veterinary professionals working in Australasia were surveyed between February and June of 2021. The survey comprised two questions related to participants' perceptions of the positive and negative aspects of their job role that impact their mental health and wellbeing. Reflexive thematic analysis was employed to analyse the responses and generate two taxonomies of occupational and organisation stressors and protectors reported by participants. RESULTS: Fifty-three responses from veterinary professionals were analysed. The final stressor taxonomy generated contained 9 overarching themes and 36 subthemes. The most common of these were negative work conditions, challenging relationships with clients, and adverse events and patient outcomes. The taxonomy of protectors contained 11 overarching themes and 32 subthemes, with the most common including fulfillment and satisfaction, positive work conditions, and relationships with colleagues. CONCLUSION: This study is the first to examine both positive and negative factors in the veterinary industry reported by veterinary professionals in Australasia. The results highlighted stressors that can be addressed on both an individual and organisational level to promote the mental and health well-being of professionals working in the animal care industry.

Hypovitaminosis D, neighborhood poverty, and progression of chronic kidney disease in disadvantaged populations.

In the United States, there are significant racial disparities in the incidence and prevalence of end-stage renal disease. The disparities are greatest for the Blacks and the magnitude of disparity is significantly greater than is evident from the incidence and prevalence data of end-stage renal disease - early stage chronic kidney disease is less common in Blacks and during that stage, mortality rate is significantly higher for that racial group. Recent studies have identified a genetic predisposition for non-diabetic renal disease among Blacks. However, genetic factors explain only part of the higher risk and the racial disparities are a result of a complex interplay of biology and sociology. Herein we focus on two factors and their role in explaining the higher risk for progression of chronic kidney disease among Blacks - one biologic (vitamin D deficiency) and one sociologic (neighborhood poverty). A greater Understanding of these factors is important in order to reduce the racial disparities in the United States.

Cardiovascular risk modification in participants with coronary disease screened by the Kidney Early Evaluation Program.

BACKGROUND: Coronary artery disease (CAD) identifies the need for intensive treatment of risk factors among individuals with chronic kidney disease (CKD), a high-risk, complex cardiovascular risk state. METHODS: An estimated glomerular filtration rate<60 mL/min/1.73 m2 or a urine albumin:creatinine ratio (ACR)≥30 mg/g (3.4 mg/mmol) defined CKD. RESULTS: Of 70,454 volunteers screened the mean age was 53.5±15.7 years and 68.3% were female. A total of 5410 (7.7%) had a self-reported history of CAD; 1295 (1.8%) had a history of prior percutaneous coronary intervention (PCI); and 1124 (1.6%) had a prior history of coronary artery bypass surgery (CABG). Multivariate analysis for the outcome of suboptimal CAD risk management (composite of systolic blood pressure≥130 mmHg, glucose≥125 mg/dL (6.9 mmol/L) for diabetics, total cholesterol≥200 mg/dL (5.2 mmol/L), or current smoking; n=38,746/53,403, 72.5%) revealed older age (per year) (odds ratio (OR)=1.04, 95% confidence interval (CI) 1.03-1.04, P<0.0001), male gender (OR=1.40, 95% CI 1.34-1.47, P<0.0001), ACR≥30 mg/g (3.4 mg/mmol) (OR=1.66, 95% CI 1.55-1.79, P<0.0001), body mass index (per kg/m2) (OR=1.06, 95% CI 1.06-1.06, P<0.0001), CAD without a history of revascularization (OR=1.14, 95% CI 1.02-1.28, P=0.02) and care received by a nephrologist (OR=1.49, 95% CI 1.22-1.83, P<0.0001) were associated with worse risk factor control. Prior coronary revascularization and being under the care of a cardiologist were not associated with either improved or suboptimal risk factor control. CONCLUSIONS: Chronic kidney disease is associated with overall poor rates of CAD risk factor control.

Indirect population dynamic benefits of altered life-history trade-offs in response to egg harvesting.

Variations in demographic rates due to differential resource allocation between individuals are important considerations in the development of accurate population dynamic models. Systematic harvesting can alter age structure and/or reduce population density, conferring indirect positive benefits on the source population as a result of a consequent redistribution of resources between the remaining individuals. Independently of effects mediated through changes in density and competition, demographic rates can also be influenced by within-individual competition for resources. Harvesting dependent life stages can reduce an individual's current reproductive costs, allowing increased investment in its future fecundity and survival. Although such changes in demographic rates are well known, there has been little exploration of the potential impact on population dynamics. We use empirical data collected from a successfully reintroduced population of the Mauritius kestrel Falco punctatus to explore the population consequences of manipulating reproductive effort through harvesting. Consequent increases in an individual's future fecundity and survival allow source populations to withstand longer and more intensive harvesting regimes without being exposed to an increase in extinction risk, increasing maximum sustainable yields. These effects may also buffer populations against the impacts of stochastic events, but directional shifts in environmental conditions that increase reproductive costs may have detrimental population-level effects.

Swimming speed of a Pacific bottlenose porpoise.

Four kinds of speed runs showed a Pacific bottlenose porpoise (Tursiops gilli) to have a top speed of 29.9 kilometers per hour (16.1 knots) for 7.5 seconds and a top speed of 21.9 kilometers per hour (11.8 knots) for 50 seconds. These results compare closely with highest predictions based upon rigid body drag calculations, the same power output per unit body weight as for athletes, and a propulsive efficiency of 85 percent.

Lizard reflectivity change and its effect on light transmission through body wall.

Light transmission through the body wall of living, color-labile desert iguanas (Dipsosaurus dorsalis) was measured by spectrophotometry. In the dark phase, the body wall's absorption of ultraviolet light and visible light was approximately twice that of the body wall in the light phase. The shorter wavelengths of ultraviolet could penetrate the body wall in the light phase but not in the dark phase. The intensity and wavelengths of light which could penetrate the body wall without pigments are potentially mutagenic when judged by bacterial standards.

Sequence diversity of the Trypanosoma cruzi complement regulatory protein family.

As a central component of innate immunity, complement activation is a critical mechanism of containment and clearance of microbial pathogens in advance of the development of acquired immunity. Several pathogens restrict complement activation through the acquisition of host proteins that regulate complement activation or through the production of their own complement regulatory molecules (M. K. Liszewski, M. K. Leung, R. Hauhart, R. M. Buller, P. Bertram, X. Wang, A. M. Rosengard, G. J. Kotwal, and J. P. Atkinson, J. Immunol. 176:3725-3734, 2006; J. Lubinski, L. Wang, D. Mastellos, A. Sahu, J. D. Lambris, and H. M. Friedman, J. Exp. Med. 190:1637-1646, 1999). The infectious stage of the protozoan parasite Trypanosoma cruzi produces a surface-anchored complement regulatory protein (CRP) that functions to inhibit alternative and classical pathway complement activation (K. A. Norris, B. Bradt, N. R. Cooper, and M. So, J. Immunol. 147:2240-2247, 1991). This study addresses the genomic complexity of the T. cruzi CRP and its relationship to the T. cruzi supergene family comprising active trans-sialidase (TS) and TS-like proteins. The TS superfamily consists of several functionally distinct subfamilies that share a characteristic sialidase domain at their amino termini. These TS families include active TS, adhesions, CRPs, and proteins of unknown functions (G. A. Cross and G. B. Takle, Annu. Rev. Microbiol. 47:385-411, 1993). A sequence comparison search of GenBank using BLASTP revealed several full-length paralogs of CRP. These proteins share significant homology at their amino termini and a strong spatial conservation of cysteine residues. Alternative pathway complement regulation was confirmed for CRP paralogs with 58% (low) and 83% (high) identity to AAB49414. CRPs are functionally similar to the microbial and mammalian proteins that regulate complement activation. Sequence alignment of mammalian complement control proteins to CRP showed that these sequences are distinct, supporting a convergent evolutionary pathway. Finally, we show that a clonal line of T. cruzi expresses multiple unique copies of CRP that are differentially recognized by patient sera.

Low birth weight is associated with chronic kidney disease only in men.

The association of low birth weight and chronic kidney disease was examined in a screened volunteer population by the National Kidney Foundation's Kidney Early Evaluation Program. This is a free, community-based health program enrolling individuals aged 18 years or older with diabetes, hypertension, or a family history of kidney disease, diabetes, or hypertension. Self-reported birth weight was categorized and chronic kidney disease defined as an estimated glomerular filtration rate less than 60 ml per min per 1.73 m(2) or a urine albumin/creatinine ratio >or=30 mg/g. Among 12 364 participants, 15% reported a birth weight less than 2500 g. In men, significant corresponding odds ratios were found after adjustment for demographic characteristics and health conditions to this low birth weight and chronic kidney disease, but there was no association among women. There was no significant interaction between birth weight and race for either gender. Efforts to clinically understand the etiology of this association and potential means of prevention are essential to improving public health.

Effects of dietary salt on intrarenal angiotensin system, NAD(P)H oxidase, COX-2, MCP-1 and PAI-1 expressions and NF-kappaB activity in salt-sensitive and -resistant rat kidneys.

BACKGROUND: Chronic consumption of a high-salt diet causes hypertension (HTN) and renal injury in Dahl salt-sensitive (SSR) but not salt-resistant rats (SRR). These events are, in part, mediated by oxidative stress and inflammation in the kidney and vascular tissues. Activation of the angiotensin II type 1 (AT(1)) receptor plays an important role in the pathogenesis of oxidative stress and inflammation in many hypertensive disorders. However, the systemic renin-angiotensin system (RAS) is typically suppressed in salt-sensitive HTN. This study was designed to test the hypothesis that differential response to a high-salt diet in SSR versus SRR may be related to upregulation of tissue RAS and pathways involved in inflammation and reactive oxygen species (ROS) production. METHODS AND RESULTS: SSR and SRR were studied 3 weeks after consumption of high- (8%) or low-salt (0.07%) diets. The SSR consuming a low-salt diet exhibited significant increases in AT(1) receptor, cyclooxygenase (COX) 2, plasminogen activator inhibitor (PAI) and phospho-I kappaB in the kidney as compared to those found in SRR. The high-salt diet resulted in severe HTN and proteinuria (in SSR but not SRR) and marked elevations of renal tissue monocyte chemoattractant protein 1, p22(phox), NADPH oxidase subunit 4, angiotensin-II-positive cell count, infiltrating T cells and macrophages and further increases in AT(1) receptor, COX-2, PAI-1 and phospho-I kappaB in the SSR group. The high-salt diet significantly lowered plasma renin activity (PRA) in SRR but not in the SSR. COX-1 abundance was similar on the low-salt diet and rose equally with the high-salt diet in both groups. Among subgroups of animals fed the low-salt diet, kidney glutathione peroxidase (GPX) abundance was significantly lower in the SSR than SRR. The high-salt diet raised GPX and mitochondrial superoxide dismutase (SOD) abundance in the SRR kidneys but failed to do so in SSR. Cu/Zn-SOD abundance was similar in the subgroups of SSR and SRR fed the low-salt diet. The high-salt diet resulted in downregulation of Cu/Zn-SOD in SSR but not SRR. CONCLUSIONS: Salt sensitivity in the SSR is associated with upregulations of the intrarenal angiotensin system, ROS-generating and proinflammatory/profibrotic proteins and an inability to raise antioxidant enzymes and maximally suppress PRA in response to high salt intake. These events can contribute to renal injury with high salt intake in SSR.

Race is a major determinant of secondary hyperparathyroidism in uremic patients: comparative study of Blacks and Hispanics.

BACKGROUND: Racial differences in bone and mineral metabolism are characterized by higher circulating intact parathyroid hormone levels (iPTH) in Black vs. White patients with end-stage renal disease (ESRD). The susceptibility of Hispanic patients to secondary hyperparathyroidism is not known. METHOD: This is a cross-sectional study that compares bone and mineral parameters of 48 Black and 61 Hispanic ESRD patients attending a single outpatient hemodialysis center. RESULT: The mean iPTH level was significantly higher in Blacks vs. Hispanics, despite similar levels of serum bone-specific alkaline phosphatase (BSAP), calcium, phosphorus and similar dosages of vitamin D analogs. After adjusting for independent variables including age, diabetic status and plasma levels of C-reactive protein, phosphorus and albumin significant predictors of iPTH were race (p < 0.01), gender (p < 0.05), serum calcium (p < 0.05), BSAP (p < 0.0001) and doses of vitamin D analogs (p < 0.001). Adjusted predictors of serum BSAP were PTH (p < 0.0001), gender (p = 0.01) and serum albumin (p < 0.005), but not race. There was no significant difference in serum BSAP between Blacks and Hispanics despite 60% higher iPTH levels in Blacks. CONCLUSIONS: Amongst ESRD patients, Blacks have higher iPTH levels compared with Hispanics despite similar BSAP levels, these finding support the emerging evidence of racial/ethnic differences in response of bone to PTH action.

Surveillance of CKD epidemiology in the US - a joint analysis of NHANES and KEEP.

Chronic Kidney Disease (CKD), is highly prevalent in the United States. Epidemiological systems for surveillance of CKD rely on data that are based solely on the NHANES survey, which does not include many patients with the most severe and less frequent forms of CKD. We investigated the feasibility of estimating CKD prevalence from the large-scale community disease detection Kidney Early Evaluation and Program (KEEP, n = 127,149). We adopted methodologies from the field of web surveys to address the self-selection bias inherent in KEEP. Primary outcomes studied were CKD Stage 3-5 (estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2, and CKD Stage 4-5 (eGFR <30 mL/min/1.73 m2). The unweighted prevalence of Stage 4-5 CKD was higher in KEEP (1.00%, 95%CI: 0.94-1.05%) than in NHANES (0.51%, 95% CI: 0.43-0.59%). Application of a selection model that used  variables related to demographics, recruitment and socio-economic factors resulted in estimates similar to NHANES (0.55%, 95% CI: 0.50-0.60%). Weighted prevalence of Stages 3-5 CKD in KEEP was 6.45% (95% CI: 5.70-7.28%) compared to 6.73% (95% CI: 6.30-7.19%) for NHANES. Application of methodologies that address the self-selection bias in the KEEP program may allow the use of this large, geographically diverse dataset for CKD surveillance.

Genetic and environmental factors that regulate cytosolic epoxide hydrolase activity in normal human lymphocytes.

To determine whether genetic mechanisms control large variations in cytosolic epoxide hydrolase (cEH) activity of unstimulated lymphocytes from normal human subjects, cEH activity was measured in (a) 6 sets of monozygotic (MZ) twins and 6 sets of dizygotic (DZ) twins; (b) 100 unrelated male subjects; and (c) 6 families. The twin study revealed predominantly genetic control (H2(1) = 0.95). Variability was markedly less within MZ (intrapair variance = 0.25) than DZ twins (intrapair variance = 6.33). In 100 unrelated male subjects the extent of interindividual variation was 11-fold. Unimodal distribution of values among 99 subjects encompassed a sixfold range. One outlier with very high activity clearly stood apart. Using the whole distribution curve we phenotyped members of six families. In the outlier's family, analysis of three generations suggested autosomal dominant transmission of high cEH activity. Analysis of the other 5 families and of 12 sets of twins, all from the large unimodal distribution, was consistent with either monogenic or polygenic control of variations within this mode. Several temporal host factors, including fever, the menstrual cycle, a 24-h fast, and diurnal variations, were investigated. Fever and fasting elevated cEH activity. Diurnal variations produced no observable alteration. During the menstrual cycle irregular fluctuations occurred.

Evidence that epithelial glycoprotein 330/megalin mediates uptake of polybasic drugs.

Glycoprotein 330 (gp330) is an endocytic receptor expressed in the renal proximal tubules and some other absorptive epithelia, e.g., in the inner ear. The present study shows that the antifibrinolytic polypeptide, aprotinin, and the nephro- and ototoxic antibiotics, aminoglycosides, and polymyxin B compete for binding of 125I-urokinase-plasminogen activator inhibitor type-1 complexes to purified rabbit gp330. Half maximal inhibition was measured at 4 microM for aprotinin, 50 microM for gentamicin, and 0.5 microM for polymyxin B. Drug binding to gp330 was validated by equilibrium dialysis of [3H] gentamicin-gp330 incubations and binding/uptake studies in rat proximal tubules and gp330-expressing L2 carcinoma cells. Analyses of mutant aprotinins expressed in Saccharomyces cerevisiae revealed that basic residues are essential for the binding to gp330 and renal uptake. The polybasic drugs also antagonized ligand binding to the human alpha 2-macroglobulin receptor. However, the rapid glomerular filtration of the drugs suggests kidney gp330 to be the quantitatively most important target. In conclusion, a novel role of gp330 as a drug receptor is demonstrated. The new insight into the mechanism of epithelial uptake of polybasic drugs might provide a basis for future design of drugs with reduced toxicity.

Combined therapeutic use of AdGFPFasL and small molecule inhibitors of ceramide metabolism in prostate and head and neck cancers: a status report.

As of January 2005, there were 1020 gene therapy clinical trials ongoing worldwide with 675 or 66.2% devoted to cancer gene therapy. The majority are occurring in the US and Europe (http://www.wiley.co.uk/genetherapy/clinical/). At the present time, to our knowledge there are no trials that employ gene delivery of Fas Ligand (FasL). As an important note, and in contrast to somatic cell therapy trials, there are no reported deaths due to therapeutic vector administration in any cancer gene therapy trial. That said, from our studies and from the published literature, the issue of gene delivery remains the major obstacle to successfully employing gene therapy for cancer treatment. Numerous laboratories are studying this with many different approaches. My co-workers and I have focused on the delivery issue by using various approaches that address tumor targeting and transgene expression. In addition, we are focusing on enhancing tumor cell killing via the bystander effect and through use of small molecules to enhance bystander activity.