A phase I dose-escalation study of enzalutamide in combination with the AKT inhibitor AZD5363 (capivasertib) in patients with metastatic castration-resistant prostate cancer.

BACKGROUND: Activation of the PI3K/AKT/mTOR pathway through loss of phosphatase and tensin homolog (PTEN) occurs in approximately 50% of patients with metastatic castration-resistant prostate cancer (mCRPC). Recent evidence suggests that combined inhibition of the androgen receptor (AR) and AKT may be beneficial in mCRPC with PTEN loss. PATIENTS AND METHODS: mCRPC patients who previously failed abiraterone and/or enzalutamide, received escalating doses of AZD5363 (capivasertib) starting at 320 mg twice daily (b.i.d.) given 4 days on and 3 days off, in combination with enzalutamide 160 mg daily. The co-primary endpoints were safety/tolerability and determining the maximum tolerated dose and recommended phase II dose; pharmacokinetics, antitumour activity, and exploratory biomarker analysis were also evaluated. RESULTS: Sixteen patients were enrolled, 15 received study treatment and 13 were assessable for dose-limiting toxicities (DLTs). Patients were treated at 320, 400, and 480 mg b.i.d. dose levels of capivasertib. The recommended phase II dose identified for capivasertib was 400 mg b.i.d. with 1/6 patients experiencing a DLT (maculopapular rash) at this level. The most common grade ≥3 adverse events were hyperglycemia (26.7%) and rash (20%). Concomitant administration of enzalutamide significantly decreased plasma exposure of capivasertib, though this did not appear to impact pharmacodynamics. Three patients met the criteria for response (defined as prostate-specific antigen decline ≥50%, circulating tumour cell conversion, and/or radiological response). Responses were seen in patients with PTEN loss or activating mutations in AKT, low or absent AR-V7 expression, as well as those with an increase in phosphorylated extracellular signal-regulated kinase (pERK) in post-exposure samples. CONCLUSIONS: The combination of capivasertib and enzalutamide is tolerable and has antitumour activity, with all responding patients harbouring aberrations in the PI3K/AKT/mTOR pathway. CLINICAL TRIAL NUMBER: NCT02525068.

Preoperative HBA1c and risk of postoperative complications in patients with gynaecological cancer.

BACKGROUND: HBA1c is used as an indicator for the long-term control of the glycaemic state and outcome predictors in diabetic patients. Diabetic patients have an increased risk of post-operative complications especially those related to infection. The aim of our study is to ascertain the relationship between HBA1c levels and post-operative recovery within the subspecialty of gynaecological oncology. METHOD: Prospective cohort study during the period 1 August 2012 through 31 August 2014. Preoperative measurement of HBA1c on all gynaecological oncology patients that underwent major surgery. Patient variables collected and analysed were BMI (kg/m(2)), length of stay (LOS in days), cancer stage (stage 1 through stage 4), infective complications, non-infective complications and readmission to hospital. RESULTS: A total of 300 patients were included in our study, 34 of them were known to be diabetic while 266 were presumed to be non-diabetic. Of the presumed non-diabetic cohort, 17.3 % (46/266) had impaired glucose tolerance or diabetes. Mean BMI was significantly increased in the pre-existing diabetic group (32.8 vs. 29.3 kg/m(2), p = 0.016). Infective complications were almost double the rate amongst the known diabetic women than those presumed to be non-diabetic (32.4 vs. 18.0 %, p = 0.048). Rate of re-admission to hospital due to complications was 20.6 % in the diabetic group and 4.1 % within the presumed non-diabetic group (p < 0.001). Infective complications occurred in 16.9 % of women with HBA1c <42 mmol/mol, 22.7 % of those with HBA1c of 42-47 mmol/mol, 43.5 % of patients with HBA1c 48-64 mmol/mol and 37.5 % of patients with HBA1c >64 mmol/mol. Non-infective complications were also more frequent in women with elevated HBA1c (11.1, 22.7, 26.1 and 12.5 % in those women with HBA1c <42, 42-47, 48-64 and >64 mmol/mol, respectively). Re-admission to hospital within 30 days for a complication of surgery occurred in 4.4 % of women with HBA1c <42 mmol/mol, 4.5 % of women with HBA1c measured at 42-47 mmol/mol, 30.8 % of those with HBA1c 48-64 mmol/mol and 25 % of women with HBA1c >64 mmol/mol. CONCLUSION: Preoperative measurement of HBA1c may identify patients (both diabetic and non-diabetic women) at higher risk of postoperative complications and could be used as a trigger for modification of the perioperative management of such patients.

Enterovirus 71 outbreak in Northern Sydney, 2013: case series and initial response.

AIM: Enteroviruses are a common cause of childhood disease which may manifest in a variety of ways. Enterovirus 71 (EV71) is a subtype of enterovirus which can cause meningoencephalomyelitis resulting in neurological sequelae including lethargy, weakness, ataxia, sleep myoclonus, urinary retention and, in severe cases, cardiorespiratory collapse due to neurogenic pulmonary oedema. EV71 was responsible for outbreaks in South East Asia in 1997-1998, in Western Australia in 1999 and in Sydney in 2000-2001. In 2013, we are experiencing another EV71 outbreak in Sydney. This study describes the discovery of a new outbreak in Sydney's Northern Beaches, the clinical findings as well as the public health response. METHODS: Thirty-seven children in total presented with presumed EV71 to the Northern Beaches Health Service from December 2012 to April 2013. Most children presented with a prodrome lasting 2-7 days prior to seeking medical attention. Sleep myoclonus was a common presenting sign occurring in 65%. Neurological signs were subtle in the majority of children and were at times missed by clinicians on a child's first presentation. Forty-six per cent of children who presented to Northern Beaches Health Service during this outbreak required a transfer to a tertiary paediatric centre for more intensive care. RESULTS: The public health investigation was important in establishing that the disease was widespread throughout the community and not as a result to exposure to a single child care setting. Identification of risk factors enabled more targeted communication to medical practitioners, child care centres and parents within the local community. CONCLUSIONS: EV71 is in Australia and all clinicians seeing children in primary, secondary and tertiary care centres need to be aware of the disease, the subtle nature of initial symptoms and the potentially devastating consequences.

Limb presentations of invasive Group A Streptococci infection in children.

Infections with invasive Group A streptococcus can have a wide range of presentations and be life threatening if not diagnosed and managed rapidly. Limb presentations in children can be especially challenging and we present our experience to help manage such cases. There can be multiple foci of infection with seeding to avascular structures. Therefore, we advocate maintaining a high degree of clinical suspicion when assessing this group of patients, who are often critically unwell, and have varying presentation. Early and aggressive surgical intervention may be key for disease control.

Impact of sampling techniques on measured stormwater quality data for small streams.

Science-based sampling methodologies are needed to enhance water quality characterization for setting appropriate water quality standards, developing Total Maximum Daily Loads, and managing nonpoint source pollution. Storm event sampling, which is vital for adequate assessment of water quality in small (wadeable) streams, is typically conducted by manual grab or integrated sampling or with an automated sampler. Although it is typically assumed that samples from a single point adequately represent mean cross-sectional concentrations, especially for dissolved constituents, this assumption of well-mixed conditions has received limited evaluation. Similarly, the impact of temporal (within-storm) concentration variability is rarely considered. Therefore, this study evaluated differences in stormwater quality measured in small streams with several common sampling techniques, which in essence evaluated within-channel and within-storm concentration variability. Constituent concentrations from manual grab samples and from integrated samples were compared for 31 events, then concentrations were also compared for seven events with automated sample collection. Comparison of sampling techniques indicated varying degrees of concentration variability within channel cross sections for both dissolved and particulate constituents, which is contrary to common assumptions of substantial variability in particulate concentrations and of minimal variability in dissolved concentrations. Results also indicated the potential for substantial within-storm (temporal) concentration variability for both dissolved and particulate constituents. Thus, failing to account for potential cross-sectional and temporal concentration variability in stormwater monitoring projects can introduce additional uncertainty in measured water quality data.

Development of an observational measure of healthcare worker hand-hygiene behaviour: the hand-hygiene observation tool (HHOT).

Previous observational measures of healthcare worker (HCW) hand-hygiene behaviour (HHB) fail to provide adequate standard operating procedures (SOPs), accounts of inter-rater agreement testing or evidence of sensitivity to change. This study reports the development of an observational tool in a way that addresses these deficiencies. Observational categories were developed systematically, guided by a clinical guideline, previous measures and pilot hand-hygiene behaviour observations (HHOs). The measure, a simpler version of the Geneva tool, consists of HHOs (before and after low-risk, high-risk or unobserved contact), HHBs (soap, alcohol hand rub, no action, unknown), and type of HCW. Inter-observer agreement for each category was assessed by observation of 298 HHOs and HHBs by two independent observers on acute elderly and intensive care units. Raw agreement (%) and Kappa were 77% and 0.68 for HHB; 83% and 0.77 for HHO; and 90% and 0.77 for HCW. Inter-observer agreement for overall compliance of a group of HCWs was assessed by observation of 1191 HHOs and HHBs by two pairs of independent observers. Overall agreement was good (intraclass correlation coefficient = 0.79). Sensitivity to change was examined by autoregressive time-series modelling of longitudinal observations for 8 months on the intensive therapy unit during an Acinetobacter baumannii outbreak and subsequent strengthening of infection control measures. Sensitivity to change was demonstrated by a rise in compliance from 80 to 98% with an odds ratio of increased compliance of 7.00 (95% confidence interval: 4.02-12.2) P < 0.001.

Apronectomy in combination with major gynaecological procedures.

Removal of excess abdominal fat may be necessary to facilitate major gynaecological surgery for oncology patients. The aim of the study was to assess the feasibility, associated morbidity of such operation when combined with other major gynaecological procedures. This was a retrospective review of cases performed in a tertiary gynaecological oncology centre. All of the patients were diagnosed with gynaecological cancers. The results show a modest increase in operative time; however the procedure was feasible and safe with no other increased risk. This represents time saving for the patients and hospital in having two operations in one session.

The interval from surgery to chemotherapy in the treatment of advanced epithelial ovarian carcinoma.

BACKGROUND: To study the effect of the interval between surgery and the start of chemotherapy in the treatment of patients with advanced ovarian cancer. METHODS: We stratified patients according to the start of platinum-based chemotherapy in group 1 (within 4 weeks from surgery), group 2 (between 4 and 8 weeks) and group 3 (between 8 and 12 weeks). RESULTS: Three hundred and ninty-four stage III ovarian cancer patients were analysed. In the multivariate analysis there were no differences in survival according to the interval between surgery and chemotherapy among the three groups. The independent prognostic variables were type of procedure (p = 0.014), performance status (p = 0.040) and post-chemotherapy CA-125 (p < 0.0001). CONCLUSIONS: The interval between surgery and chemotherapy does not affect outcome.

Molecular population genetics of the southern elephant seal Mirounga leonina.

Southern elephant seals breed on sub-Antarctic islands and have a circumpolar distribution. We assayed mitochondrial DNA (mtDNA) and nuclear DNA (nDNA) variation in the three main populations in the south Atlantic, south Indian, and south Pacific oceans, and a smaller continental population in South America. Population structure of mtDNA was strong and not consistent with isolation by distance. The nDNA loci, although less informative, were consistent with the mtDNA results. Geographic structure appears to be dominated by historical processes, not contemporary gene flow. Uncorrected levels of nucleotide diversity for mtDNA control region I (2.86%) and nDNA (0.09%) were similar to those in humans and mice. Mutation rates for control region I (75 x 10(-9) substitutions per site per year) and nDNA (1.23 x 10(-9)) were similar to those in other mammals. Female effective population size and total effective population size were roughly equal at approximately 4 x 10(4), indicating a twofold greater rate of drift for mtDNA. Effective breeding sex ratio of four to five females per male was estimated from nucleotide diversity and mutation rates for mtDNA and nDNA, and was much less than behavioral observations would suggest. There was no evidence for selection at any of the assayed loci.

Balloon Cell Urethral Melanoma: Differential Diagnosis and Management.

Introduction. Primary malignant melanoma of the urethra is a rare tumour (0.2% of all melanomas) that most commonly affects the meatus and distal urethra and is three times more common in women than men. Case. A 76-year-old lady presented with vaginal pain and discharge. On examination, a 4 cm mass was noted in the vagina and biopsy confirmed melanoma of a balloon type. Preoperative CT showed no distant metastases and an MRI scan of the pelvis demonstrated no associated lymphadenopathy. She underwent anterior exenterative surgery and vaginectomy also. Histology confirmed a urethral nodular malignant melanoma. Discussion. First-line treatment of melanoma is often surgical. Adjuvant treatment including chemotherapy, radiotherapy, or immunotherapy has also been reported. Even with aggressive management, malignant melanoma of the urogenital tract generally has a poor prognosis. Recurrence rates are high and the mean period between diagnosis and recurrence is 12.5 months. A 5-year survival rate of less than 20% has been reported in balloon cell melanomas along with nearly 20% developing local recurrence. Conclusion. To the best of our knowledge, this case is the first report of balloon cell melanoma arising in the urethra. The presentation and surgical management has been described and a literature review provided.

p53 and related proteins in epithelial ovarian cancer.

We conducted a retrospective immunohistochemical evaluation of the prognostic significance of the expression of p53 and the related proteins Bax, Bcl-2, growth arrest and DNA damage (Gadd45), murine double minute 2 (Mdm2) and p21(WAF1/CIP1) in chemonaive tumours taken from 66 patients with ovarian cancer. Ki-67 expression (a marker of cell proliferation) was also evaluated immunohistochemically, while apoptosis within malignant cells was determined with the terminal deoxynucleotidyltransferase-mediated dUTP nick-end labelling (TUNEL) assay. The expression of each of the following proteins was significantly associated in the tumours (P < 0.05 unless otherwise stated): Bax with Bcl-2 (P < 0.01); Bax with Mdm2; p21(WAF1/CIP1) with Gadd45 (P < 0.01); p21(WAF1/CIP1) with p53; p53 with Mdm2. Univariate analysis showed that expression of p53, Bax, bulk residual disease and International Federation of Gynecology and Obstetricians (FIGO) stage were all strongly correlated with response to chemotherapy (P < 0.01). Similarly, the FIGO stage and Ki-67 expression (P < 0.01), as well as pathological subtype and bulk residual disease (P < 0.05), were prognostic factors for disease progression. The FIGO stage and Ki-67 expression were significant prognostic factors for overall survival (P < 0.01), with Gadd45 expression and pathological subtype also significant (P < 0.05) in a univariate analysis. Multivariate analysis for response to chemotherapy showed that expression of p53, Bax and FIGO stage were all independent prognostic factors (P < 0.01). The FIGO stage was the most important independent prognostic factor for progression and survival on multivariate analysis (P < 0.01). However, Ki-67 expression was also an independent prognostic factor for disease progression (P < 0.05) and approached significance for survival (P = 0.055). Taken together, these data suggest that determination of Ki-67 expression could supplement established prognostic factors.

Plasmodium vivax synonymous substitution frequencies, evolution and population structure deduced from diversity in AMA 1 and MSP 1 genes.

Polymorphic regions of the genes encoding Plasmodium vivax apical membrane antigen 1 (PvAMA1) and P. vivax merozoite surface protein 1 (PvMSP1) were sequenced to examine population diversity both within and between geographical areas. Sequences were obtained for 219 isolates for PvAMA1 and for 175 isolates for PvMSP1 from Africa, China, India, Indonesia, Philippines, Papua New Guinea, Solomon Islands and Thailand. Over half of the isolates were obtained from different regions within the Philippines, and this was used to look at the diversity within a country. Sixty nine haplotypes and 22 polymorphic sites in a 414-bp region of PvAMA1 and 41 haplotypes and 34 polymorphic sites in a 249-bp fragment of PvMSP1 were detected. For both PvAMA1 and PvMSP1, four previously unreported polymorphic nucleotide positions were identified. Population analysis indicated that there were significant differences in allele frequencies between different regions but these differences were small compared to the diversity within populations (Fixation index, F(ST), of 0.126 and 0.078 for PvAMA1 and PvMSP1, respectively). PvAMA1 and PvMSP1 had similar nonsynonymous substitution frequencies but surprisingly, the synonymous substitution frequency for PvMSP1 was eight times the frequency for PvAMA1 suggesting that synonymous substitutions in at least PvAMA1 are not neutral.

Limited MHC polymorphism in the southern elephant seal: implications for MHC evolution and marine mammal population biology.

Genes of the major histocompatibility complex (MHC) are highly polymorphic in most terrestrial mammal populations so far studied. Exceptions to this are typically populations that lack genome-wide diversity. Here I show that two populations of the southern elephant seal (Mirounga leonina) have low DNA restriction fragment length polymorphism at MHC loci when compared with terrestrial mammals. Limited studies on MHC polymorphism in two cetacean species suggest this is a feature of marine mammal populations in general. MHC polymorphism is thought to be maintained by balancing selection, and several types of disease-based and reproductive-based mechanisms have been proposed. For the three marine mammal species examined, the low MHC polymorphism cannot be explained by low genome-wide diversity, or by any reproductive-based selection pressure. It can, however, be explained by diminished exposure to pathogenic selection pressure compared with terrestrial mammals. Reduced exposure to pathogens would also mean that marine mammal populations may be susceptible to occasional pathogen-induced mass mortalities.

Phylogeography of Bufo marinus from its natural and introduced ranges.

The marine toad, Bufo marinus, has a broad natural distribution extending from the south-west of the USA to southern Peru and the central Amazon. It was introduced to several localities in the Caribbean and Pacific Oceans to control sugar cane pests. We sequenced 468 bp of mitochondrial DNA (mtDNA) containing the ND3 gene, and flanking tRNA genes from toads spanning the broad natural and introduced ranges. Consistent with the known history of introductions and expected effects of serial bottlenecks, mtDNA within introduced populations in Hawaii and Australia was uniform and most closely related to samples from eastern Venezuela and French Guiana. However, mtDNA nucleotide diversity in the geographic region spanning the source areas is also relative low (0.18-0.46%) and the absence of variation in the introduced populations precludes quantitative assessment of the reduction in genetic diversity. Unexpectedly, there was a large phylogeographic break (5.4% sequence divergence) within the natural range separating populations east and west of the Venezuelan Andes. We hypothesize that the two major lineages of B. marinus were isolated by the uplift of the eastern Andean cordillera which was completed approximately 2.7 Ma. Another species of the marinus group, B. paracnemis, had mtDNA paraphyletic, with marinus, being nested within the eastern lineage. Thus, at least one speciation event within the marinus group postdates the split within marinus. These findings suggest that the taxonomy of B. marinus should be re-evaluated and that the search for pathogens to control Australian populations should be conducted in populations from both lineages in the natural range.

Spontaneous graft-versus-host disease following autologous peripheral blood progenitor cell transplantation in chronic myeloid leukaemia.

Myeloablation followed by haemopoietic reconstitution using autologous peripheral blood progenitor cells (PBPC) is applicable to some patients with CML, particularly where there is no allogeneic stem cell donor available, and interferon alpha has failed to achieve a significant cytogenetic response. Cells lacking the Philadelphia (Ph) chromosome can be collected at the early phase of myeloid recovery after intensive chemotherapy, and reconstitution after autografting can be associated with prolonged suppression of the Ph positive clone. It is possible that mechanisms other than this "in vivo purge' may contribute to disease control, for example an autologous graft-versus-leukaemia effect. We report two patients in whom significant autologous graft-versus-host disease (auto-GVHD) has occurred, which has not previously been described as a spontaneous event after PBPC autograft for CML. We postulate that mononuclear cells collected in an early phase of recovery after intense myelosuppression have the capacity to produce self-reactivity after autografting. These cells, which may include autoreactive T lymphocytes or antigen-presenting dendritic cells, might mediate a useful graft-versus-leukaemia effect.

Ozone toxicity in the mouse: comparison and modeling of responses in susceptible and resistant strains.

Previous studies from this laboratory have demonstrated a concentration-related hypothermia and increases in bronchoalveolar lavage (BAL) fluid indexes of toxicity in the rat after exposure to environmentally relevant levels of ozone (O3). In similar studies with C57BL/6J (B6) and C3H/HeJ (C3) mice, other investigators have reported differential effects on BAL toxicity indexes between the two strains after O3 exposure. The present study investigated the relationship between the reported strain differences in BAL parameters in B6 and C3 mice exposed to O3 and the induced hypothermic response. Male 80-day-old mice (n = 94, 47/strain) were used for these studies. Subsets (n = 8/strain) of these animals were surgically implanted with radiotelemetry transmitters that permitted continuous monitoring of core body temperature and activity. All telemetry animals and an equal number of nontelemetry animals (n = 8/strain) were exposed to filtered air for 24 h followed by a 2-h exposure to 2 parts/million 16O3. With use of a similar protocol, groups of nontelemetry mice (n = 12/strain) were exposed to either filtered air or 2 parts/million 16O3 for 2 h. At 0 or 22 h postexposure, mice were anesthetized with halothane and intubated, and their lungs were lavaged with 37 degrees C saline. Although both strains of mice exhibited significant abrupt decreases in core body temperature on exposure to O3 and both recovered rapidly after cessation of the O3 exposure, the response of the C3 mice was more dynamic than that of the B6 mice. Similarly, both strains showed characteristic changes in biomarkers of O3 toxicity; however, the increases in BAL fluid protein and cells at 22 h postexposure were significantly greater and the percentage of neutrophils was significantly less in B6 mice than in C3 mice. It is possible that the strain differences in BAL constituents may be related to the differences in the hypothermic response.

Oxidative stress in female B6C3F1 mice following acute and subchronic exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is a highly persistent trace environmental contaminant and is one of the most potent toxicants known to man. Hassoun et al. (1998, Toxicol. Sci. 42, 23-27) reported an increase in the production of reactive oxygen species (ROS) in the brain of female B6C3F1 mice following subchronic exposure to TCDD at doses as low as 0.45 ng/kg/day. In the present study, oxidative stress was characterized in liver, spleen, lung, and kidney following subchronic (0.15-150 ng/kg; 5 days/week for 13 weeks, po) or acute exposure (0.001-100 microg/kg, po) to TCDD in order to investigate the interaction between tissue concentration and time for production of ROS. Seven days following acute administration of TCDD, mice were sacrificed; they demonstrated increases in liver superoxide anion production (SOAP) and thiobarbituric acid reactive substances (TBARS) at doses of 10 and 100 microg/kg, associated with hepatic TCDD concentrations of 55 and 321 ng/g, respectively. Liver obtained from mice following subchronic TCDD exposure demonstrated an increase in SOAP and TBARS above controls at doses of 150 ng/kg/day with liver TCDD concentration of only 12 ng/g. Interestingly, glutathione (GSH) levels in lung and kidney following sub-chronic TCDD exposure were decreased at the low dose of 0.15 ng/kg/day. This effect disappeared at higher TCDD doses. The data suggest that higher tissue TCDD concentrations are required to elicit oxidative stress following acute dosing than with subchronic TCDD exposure. Therefore, the mechanism of ROS production following TCDD exposure does not appear to be solely dependent upon the concentration of TCDD within the tissue. In addition, very low doses of TCDD that result in tissue concentrations similar to the background levels found in the human population produced an effect on an oxidative stress endogenous defense system. The role of this effect in TCDD-mediated toxicity is not known and warrants further investigation.

A cDNA encoding a pepsinogen-like, aspartic protease from the human roundworm parasite Strongyloides stercoralis.

Using degenerate oligonucleotide primers based on conserved active site residues, we have isolated a cDNA encoding an aspartic protease from the nematode parasite Strongyloides stercoralis, an important, enteric pathogen of humans. cDNAs encoding the aspartic protease were isolated from the infective, third stage larvae of the parasite as well as from free-living, rhabditiform larvae. Based on comparisons of other aspartic proteases, the cDNA encoded a short signal peptide, an enzyme pro-segment of 35 amino acid residues, and mature enzyme of 337 residues. Homology alignments using the proenzyme sequence showed that the novel S. stercoralis zymogen was 36% identical to human pepsinogen A and 36% identical to pepsinogen C (progastricin) from humans and macaques. Phylogenetic analyses using the Phylip program and analysis of Glx/Asx and Leu/Ile ratios indicated that the proenzyme was closely related to pepsinogen A-like enzymes from the free-living nematode Caenorhabditis elegans and Haemonchous contortus, a nematode parasite of the gastro-intestinal tract of sheep. We have termed this novel enzyme strongyloidespepsin.

The effect of a vitamin A acetate diet on ultraviolet radiation-induced immune suppression as measured by contact hypersensitivity in mice.

The adverse health effects caused by increased exposure to ultraviolet radiation (UVR) due to deterioration of stratospheric ozone are of major concern. These health effects include sunburn, skin cancer, cataracts and immune suppression. Immune suppression has been associated with the release of cytokines, a defect in antigen presentation, induction of suppressor T cells and suppression of contact hypersensitivity (CH). CH is typically assessed by the mouse ear swelling test (MEST). Previous studies have demonstrated enhanced CH responses with vitamin A acetate (VAA) dietary supplementation assessed by MEST and the local lymph node assay (LLNA). To determine the effect that VAA has on UVR-induced immune suppression, we examined both the induction and elicitation phases of CH using murine models. The MEST was used to evaluate the interaction of UVR and VAA on CH elicitation. However, a positive MEST response requires that the induction phase as well as the elicitation phase of CH be functional. The LLNA was used to evaluate the interaction of UVR and VAA only on CH induction. We tested the hypothesis that mice maintained on a VAA-enriched diet are more resistant to UVR-induced immune suppression (CH) than those maintained on a control diet. Mice were maintained on a VAA-enriched or the control diet for 3 weeks and then exposed to UVR 3 days prior to sensitization with 2,4-dinitrofluorobenzene (DNFB). VAA enhanced the MEST response in both UVR-exposed and non-UVR-exposed mice. The VAA-enriched diet did not significantly alter the LLNA response in either UVR- or non-UVR-exposed mice. However, there was significant suppression in CH by UVR as measured by the LLNA. These results indicate that (1) the VAA-enriched diet does not restore the number of proliferating cells in the CH induction phase of UVR-induced immunosuppression; (2) the immunosuppressive effects of UVR affect the induction phase of CH; and (3) the LLNA should be examined as an alternative to the MEST for measurement of UVR-induced immunosuppression. The data indicate that the VAA-enriched diet enhanced the elicitation response (MEST) but not the earlier induction phase (LLNA). Further studies are necessary to define mechanisms of action, but modulation of cytokines and effects of specific lymphocyte subsets, as well as systemic effects and local modulation at the site of elicitation are possible. Additionally, future studies to evaluate the effect of the VAA-enriched diet when multiple doses of both UVR and DNFB are used would be of interest for both the LLNA and MEST end-points.