Significant Increase In Frequency Research Articles

HLA C Allele Associations in Mumbai Psoriasis Patients

Psoriasis a common autoimmune disorder characterized by T cell mediated keratinocyte hyperproliferation known to be associated with the presence of certain specific HLA alleles. In this study our aim was to evaluate distribution of HLACw susceptible allele of psoriasis from patients in Western India.The study included 84 Psoriasis patients and 91 normal individuals from same geographical region. HLA-C was typed using high resolution PCR-SSOP (Sequence Specific Oligonucleotide Probes) technique.The study revealed significant increase in frequencies of Cw*0202 (OR-6.508, P<0.0001) and Cw*0604 (OR- 17.710, P=0.0153) when compared to controls while Cw*1502 (OR-0.130, P=0.0490) were significantly decreased in psoriasis patients.Our study shows a strong association of HLA Cw*0202 and Cw*0604 alleles with psoriasis conferring to its susceptibility to psoriasis patients from Western India.

Possible impacts of floods and droughts on water quality

The gradual climate change symptoms in many places on Earth have been observed during the last 20 years. There is a significant increase in frequency and extremity of meteorological and hydrological events (EEA, 2007) that lead to distinct excess or lack of water in landscape. These phenomena affect not only actual quantity of water but also its quality with direct and indirect impacts on aquatic organisms. From the environmental impact point of view, drought events are considered to be more dangerous due to their medium-term to long-term characteristics and large spatial impacts. However, this study presents that the particular flood event had significantly greater impact on water quality than the period of drought even if for only a very short time The paper reviews changes in water quality with all its consequences during selected extreme hydrological situations in the Czech Republic in last 10 years and compares them with the knowledge of impacts of floods and droughts on water quality collected from literature.

Cancer risk with folic acid supplements: a systematic review and meta-analysis

ObjectiveTo explore if there is an increased cancer risk associated with folic acid supplements given orally.DesignSystematic review and meta-analysis of controlled studies of folic acid supplementation in humans reporting cancer...

Crohn’s disease genotypes of patients in remissionvsrelapses after infliximab discontinuation

To investigate genetic differences between Crohn's disease (CD) patients with a sustained remission vs relapsers after discontinuing infliximab while in corticosteroid-free remission. Forty-eight CD patients received infliximab and were in full corticosteroid-free clinical remission but then discontinued infliximab for reasons other than a loss of response, were identified by review of an electronic database and charts. Infliximab-associated remission was defined as corticosteroid-free plus normalization of clinical disease activity [CD activity index (CDAI) < 150] during follow-up visits based on physician global assessments. A CD relapse (loss of infliximab-induced remission) was clinically defined as a physician visit for symptoms of disease activity (CDAI > 220) and a therapeutic intervention with CD medication(s), or a hospitalization with complications related to active CD. Genetic analyses were performed on samples from 14 patients (n = 6 who had a sustained long term remission after stopping infliximab, n = 8 who rapidly relapsed after stopping infliximab). Nucleotide-binding oligomerization domain 2 (NOD2)/caspase activation recruitment domain 15 (CARD15) polymorphisms (R702W, G908R and L1007fs) and the inflammatory bowel disease 5 (IBD5) polymorphisms (IGR2060a1 and IGR3081a1) were analyzed in each group. Five single nucleotide polymorphisms of IBD5 and NOD2/CARD15 genes were successfully analyzed for all 14 subjects. There was no significant increase in frequency of the NOD2/CARD15 polymorphisms (R702W, G908R and L1007fs) and the IBD5 polymorphisms (IGR2060a1 and IGR3081a1) in either group of patients; those whose disease relapsed rapidly or those who remained in sustained long term remission following the discontinuation of infliximab. Nearly a third of patients in full clinical remission who stopped infliximab for reasons other than loss of response remained in sustained clinical remission, while two-thirds relapsed rapidly. There was a marked difference in the duration of clinical remission following discontinuance of infliximab between the two groups. The patients who lost remission did so after 1.0 years ± 0.6 years, while those still in remission were at the time of this study, 8.1 years ± 2.6 years post-discontinuation of infliximab, P < 0.001. The 8 patients who had lost remission after discontinuing infliximab had a mean number of 5 infusions (range 3-7), with a mean treatment time of 7.2 mo (range 1.5 mo-15 mo). The mean duration of time from the last infusion of infliximab to the time of loss of remission was 382 d (range 20 d-701 d). The 6 patients who remained in remission after discontinuing infliximab had a mean number of 6 infusions (range 3-12), with a mean treatment duration of 12 mo (range 3.6 mo-32 mo) (P = 0.45 relative to those who lost remission). There are no IBD5 or NOD2/CARD15 mutations that predict which patients might have sustained remission and which will relapse rapidly after stopping infliximab.

Human leukocyte antigen (HLA) Cw allele association among psoriasis patients from Western India

Psoriasis a common autoimmune disorder characterized by T cell mediated keratinocyte hyperproliferation known to be associated with the presence of certain specific HLA alleles. In this study our aim was to evaluate distribution of Human leukocyte antigen (HLA-Cw) susceptible allele of psoriasis from patients in Western India. The study included 84 Psoriasis patients and 91 normal individuals from the same geographical region. Human leukocyte antigen HLA-C was typed using high resolution polymerase chain reaction- sequence specific oligonucleotide probes (PCR-SSOP) technique. The study revealed significant increase in frequencies of Cw*0202 (OR-6.508, P<0.0001) and Cw*0604 (OR-17.710, P=0.0153) when compared to controls while Cw*1502 (OR-0.130, P=0.0490) were significantly decreased in psoriasis patients. Our study shows a strong association of HLA Cw*0202 and Cw*0604 alleles with psoriasis conferring to its susceptibility to psoriasis patients from Western India. Key words: HLA Cw alleles, Psoriasis, Mumbai, Western India

Human leukocyte antigen (HLA) Cw allele association among psoriasis patients from Western India

Psoriasis a common autoimmune disorder characterized by T cell mediated keratinocyte hyperproliferation known to be associated with the presence of certain specific HLA alleles. In this study our aim was to evaluate distribution of Human leukocyte antigen (HLA-Cw) susceptible allele of psoriasis from patients in Western India. The study included 84 Psoriasis patients and 91 normal individuals from the same geographical region. Human leukocyte antigen HLA-C was typed using high resolution polymerase chain reaction- sequence specific oligonucleotide probes (PCR-SSOP) technique. The study revealed significant increase in frequencies of Cw*0202 (OR-6.508, P<0.0001) and Cw*0604 (OR-17.710, P=0.0153) when compared to controls while Cw*1502 (OR-0.130, P=0.0490) were significantly decreased in psoriasis patients. Our study shows a strong association of HLA Cw*0202 and Cw*0604 alleles with psoriasis conferring to its susceptibility to psoriasis patients from Western India. Key words: HLA Cw alleles, Psoriasis, Mumbai, Western India

Characteristics of frequent emergency department presenters to an Australian emergency medicine network

BackgroundTo describe the characteristics of emergency department (ED) patients defined as frequent presenters (FP) presenting to an Australian emergency department network and compare these with a cohort of non-frequent presenters (NFP).MethodA retrospective chart review utilising an electronic emergency medicine patient medical record database was performed on patients presenting to Southern Health EDs from March 2009 to March 2010. Non-frequent presenters were defined as patients presenting less than 5 times and frequent presenters as presenting 8 or more times in the study period. Characteristics of both groups were described and compared.ResultsDuring the 12-month study period there were 540 FP patients with 4549 admissions and 73,089 NFP patients with 100,943 admissions. FP patients were slightly older with a significant increase in frequency of patients between the ages of 70 to 79 years and they were more likely to be divorced or separated than NFP patients. Frequent presenters to the emergency department were more likely to utilise the ambulance service to arrive at the hospital, or in the custody of police than NFP patients. FPs were more likely to be admitted to hospital, more likely to have an admission to a mental health bed than NFP patients and more likely to self-discharge from the emergency department while waiting for care.ConclusionsThere are major implications for the utilisation of limited ED resources by frequent presenters. By further understanding the characteristics of FP we may be able to address the specific health care needs of this population in more efficient and cost effective ways. Further research analysing the effectiveness of targeted multidisciplinary interventions aiming to reduce the frequency of ED attendances may be warranted.

Secular trends of macrosomia in southeast China, 1994-2005

BackgroundThe rate of macrosomia (birth weight≥4, 000 g) increased over the past four decades in many parts of the world. Macrosomia is associated not only with higher risks of maternal and neonatal complications but also with health risks in adulthood. We examined trends in neonatal macrosomia and large-for-gestational-age (LGA) births among singleton, live, term and postterm births (≥37 complete weeks' gestation) in southeast China from 1994 to 2005 and explored possible causes of the temporal trends.MethodsData from Perinatal Health Care Surveillance System in 12 cities and counties in southeast China were analyzed for trends in birth weight, neonatal macrosomia and LGA from 1994 to 2005. A total of 594, 472 singleton live births were included. We conducted multiple logistic regression analyses to relate these trends to changes in maternal and pregnancy characteristics.ResultsThe rate of macrosomia rose from 6.00% in 1994 to 8.49% in 2000 and then levelled off to 7.83% in 2005. Similar trends were observed in mean birth weight. The incidence of LGA births increased continuously from 13.72% in 1994 to 18.08% in 2000, but the LGA rate remained relatively stable from 2002 to 2005. There was a decrease in gestational age and a significant increase in frequency of prelabor caesarean delivery from 1994 to 2005. In an adjusted multivariable model, the increase in LGA rate from 1994 to 2000 was associated with increasing net gestational weight gain, maternal age, maternal height and maternal education. But they didn't fully explain the increase. The trends of 2002-2005 LGA declined after adjusted for maternal and neonatal characteristics.ConclusionsIn southeast China, the incidence of macrosomia increased from 1994 to 2000 was mainly related to increasing net gestational weight gain. The incidence of macrosomia has levelled off in recent years partly due to increasing use of prelabor caesarean delivery and earlier delivery and partly due to moderation of gestational weight gain.

Alfaxalone anaesthesia in the green iguana (Iguana iguana)

ObjectiveTo characterise the anaesthetic effects of alfaxalone administered intramuscularly (IM) at 10, 20, and 30 mg kg−1. Study designProspective, randomized cross-over study. AnimalsTen juvenile green iguanas (Iguana iguana) of mean body weight (±SD) 480 ± 134 g. MethodsAlfaxalone was administered IM in the triceps of both thoracic limbs. Times for anaesthetic induction, plateau and recovery periods were recorded. Skeletal muscle tone of the jaw, neck, thoracic limbs, pelvic limbs, and tail was scored. The palpebral, corneal and righting reflexes, and the response to painful stimuli were also assessed. Pulse rate and respiratory rate were recorded. Comparisons between different dosages and over time were made using anova. ResultsTimes are given for 10, 20 and 30 mg kg−1 dosages respectively: mean time to maximal effect was 7.7 ± 2.2, 5.4 ± 1.7 and 3.9 ± 1.2 minutes; duration of the plateau phase was 11.3 ± 3.8, 22.1 ± 6.5 and 39.1 ± 11.5 minutes; recovery time was 10 ± 2.4, 17.5 ± 8.6 and 25 ± 7.1 minutes; and total anaesthetic duration was 29 ± 35.7, 45 ± 8.2 and 68 ± 9.8 minutes. Endotracheal intubation was possible in 40% of the subjects given 10 mg kg−1 and in 100% subjects given both 20 and 30 mg kg−1. Loss of response to a painful stimulus was seen in 0/10, 8/10 and 9/10 animals at 10, 20, and 30 mg kg−1 respectively. There was an initial dose-dependent depression of respiration followed by a significant increase in frequency over time. In contrast, pulse rates decreased by 20% over the duration of the anaesthetic events. Conclusions and clinical relevanceIntramuscular administration of alfaxalone is a simple, rapid and reliable means of achieving relatively brief sedation or anaesthesia in healthy green iguanas. A dosage of 10 mg kg−1 provides light sedation, appropriate for examination and venipuncture; 20 mg kg−1 provides a level suitable for minor procedures or for endotracheal intubation and supplementation with inhalational anaesthesia; 30 mg kg−1 produces an anaesthetic plane suitable for surgical procedures of limited duration (up to 40 minutes).

Impacto da hipertensão arterial no remodelamento ventricular, em pacientes com estenose aórtica

Left ventricular hypertrophy (LVH) is a marker of increased cardiovascular risk and is frequently associated with both arterial hypertension (AH) and aortic stenosis (AoS). Also, these two maladies may co-exit in a same patient. However, in these cases, it is not clear the impact of each one in LVH. To evaluate LVH and ventricular geometry in patients with AS associated or not with arterial hypertension. This was a retrospective, observational and transversal study, including 298 consecutive patients with echocardiographic diagnosis of AoS. LVH was defined as myocardial mass > 224 g for men and > 162 g for women. Patients were classified as having mild (peak gradient < 30 mmHg), moderate (between 30 and 50 mmHg) or severe (> 50 mmHg) AoS and separated into two subgroups: with and without hypertension. AH was associated with increased ventricular mass in all three levels of aortic stenosis (mild AS: 172 ± 45 g vs 223 ± 73 g, p < 0.0001 moderate AoS: 189 ± 77 g vs 245 ± 81 g, p = 0.0313 severe AoS: 200 ± 62 g vs 252 ± 88 g, p = 0.0372), and increased risk of LVH (OR = 2.1 CI95%:1.2-3.6 p = 0.012). Regarding to geometric remodeling, hypertensive patients with severe AS presented a significant increase in frequency of concentric hypertrophy, when compared with those without hypertension (p = 0.013). Hypertension is an additional factor of increased left ventricular mass in patients with AS. Also, hypertension was influential in ventricular geometry.

Polymorphisms of DNA repair genes and sun exposure as predisposing factors for age related cataract

Age-related cataract is a leading cause of blindness throughout the world. Regular exposure to sunlight increases the risk of cataract development. Ultraviolet light causes oxidative stress which induces DNA damage in the lens epithelium and the development of opacities. The existence of DNA repair in lens epithelial cells has been reported, and polymorphisms of DNA repair genes may affect repair efficiency. This work aims to study the frequency of polymorphisms of two DNA repair genes, xeroderma pigmentosum complementation group D (XPD) codon751 and X-ray cross-complementing group 1 (XRCC1) codon399, in cataract in the sunny weather of Egypt. Forty-two Egyptian patients with maturity onset cataract were compared to 41 control subjects using polymerase chain reaction and restriction fragment length polymorphism. There was a significant increase in frequency of XRCC1-399 Arg/Arg genotype in cataract patients (42.8%) compared to healthy controls (22%) (p = 0.042).This increase remained significant after redistribution according to occupational exposure. No significant difference was found for the genotypic and allelic distributions of the polymorphisms in XPD-751 gene (p > 0.05) between groups. There was a significant increase in cataract development in subjects with high exposure risk to sunlight more than those with low risk, either due to their occupation (p = 0.034) or to residence in sunny areas of upper Egypt (p = 0.037). Findings suggest that polymorphism in XRCC1 codon399 may predispose to the development of maturity-onset cataract and support the hypothesis that sun exposure is a leading factor for cataract development.

Evaluation of genotoxic and oxidative effects in workers exposed to jet propulsion fuel

Jet fuel is a common occupational exposure risk among military and civilian populations. The purpose of this study was to evaluate genotoxic and oxidative effects in workers occupational exposure to jet propulsion fuel (JP-8). In this study, sister-chromatid exchange (SCE), high frequency of SCE cells (HFCs), and micronuclei (MN) were determined for 43 workers exposed to JP-8 and 38 control subjects. We measured the antioxidant enzyme activities including that of superoxide dismutase (SOD), glutathione peroxidase (GPX), and catalase (CAT). The levels of thiobarbituric acid-reactive substances (TBARS) were also studied. Urinary 1- and 2-naphthol excretion was used as a biomarker of occupational exposure to JP-8. The results obtained from cytogenetic analysis show a statistically significant increase in frequency of SCE in the exposed workers when compared to controls (P<0.05). Interestingly, the mean value of the frequency (%o) of MN and HFCs for workers and controls did not show any statistical differences (P>0.05). Oxidative stress parameters were not statistically different between exposed and control groups except for TBARS levels. Urinary 1-and 2-naphthol levels of exposed workers were found to be significantly higher than those of control subjects. Occupational exposure to JP-8 resulted in no significant genotoxic and oxidative effects, while smoking is the principal confounding factor for the some parameters. To understand the genotoxic and oxidative effects of JP-8 exposure, further studies should be planned to find out whether human populations may be at increased risk for cancer because of the exposures related to occupation and lifestyle.

Effect of ammonium glycyrrhizinate on haloperidol- and reserpine- induced neurobehavioral alterations in experimental paradigms

The present work was aimed to assess the effect of ammonium glycyrrhizinate, AG (50, 100, and 150 mg/kg, i.p.) on haloperidol induced catalepsy in mice; reserpine induced orofacial dyskinesia in rats; and reserpine antagonism in mice. Additionally the effect of AG on lipid peroxidation (LP) in cataleptic mice brain and monoamine oxidase-B (MAO-B) levels in normal mice brain was assessed. Administration of AG 100 and 150 mg/kg showed significant reduction in the duration of cataleptic behavior at 60 to 180 min and dose dependent decrease in LP induced by haloperidol. AG showed significant decrease in frequency of vacuous chewing movements at 150 mg/kg and frequency of tongue protrusion at 100 and 150 mg/kg in reserpine induced orofacial dyskinesia test. AG showed significant increase in frequency of horizontal movement and rearing behavior at 150 mg/kg and increase in grooming behavior at 100 and 150 mg/kg in reserpine antagonism test. AG showed dose dependent inhibition of MAO-B in the normal mice brain. These results suggested that AG prevented the haloperidol- and reserpine- induced neurobehavioral alterations possibly by acting as free radical scavenger or inhibiting MAO-B thereby increasing dopaminergic transmition consequently decreasing dopamine metabolites and ultimately preventing the generation of free radicals.

In vitro evaluation of the genotoxic and cytotoxic effects of artesunate, an antimalarial drug, in human lymphocytes

Artesunate is one of the main antimalarial drugs used in several countries. It is a semisynthetic compound derived from artemisinin, a substance extracted from the Chinese plant, Artemisia annua L. Despite the widespread use of artesunate as an antimalarial drug, there is a lack of data regarding its genotoxic effects in human lymphocytes. Therefore, in this study, we used the comet assay and micronucleus test to evaluate the possible genotoxic effects of artesunate in cultured human lymphocytes. In addition, cell death by necrosis and apoptosis was also assessed. Cells exposed to different concentrations of artesunate showed a significant concentration-dependent increase (P < 0.05) in DNA damage index and micronuclei frequency. A significant increase in the frequency of apoptotic and necrotic cells was also observed. Our results showed that artesunate is a genotoxic and cytotoxic compound in cultured human lymphocytes.

Effect of nickel and chromium exposure on buccal cells of electroplaters

The electroplating industry commonly involves the use of nickel and chromium. An assessment of the genotoxic effects of these metals can be carried out by micronucleus (MN) test in buccal cells. Other nuclear anomalies (NA) observed in buccal cells viz., karyorrhexis, pyknosis and karyolysis are also the indicators of genotoxicity. The current study aims at determining the extent of genotoxic damage in relation to the duration of exposure to nickel and hexavalent chromium via micronuclei induction and other nuclear anomalies. The present investigation included 150 subjects of which 50 individuals with no history of nickel/chromium exposure (Group I) were taken as control, 50 electroplaters exposed to nickel and hexavalent chromium for duration of less than 10 years (Group II) and 50 electroplaters exposed for ≥10 years (Group III) were included. Slides of buccal cells were prepared and the frequency of MN (‰) and NA (‰) were calculated. ANOVA was applied to test significance. Results were considered significant at p < 0.05 and p < 0.001. Group III showed the highest MN frequency (1.08 ± 0.54‰, p < 0.05), karyorrhexis (20.75 ± 6.29, p < 0.05), karyolysis (3.50 ± 1.91, p < 0.001), binucleate (4.75 ± 2.75, p < 0.05) and enucleated cells (5.75 ± 1.70, p < 0.05). Significant increase in frequencies between Group II and III was found as duration of exposure increased. Plasma nickel and chromium levels were also determined which showed a positive correlation with frequency MN and other nuclear abnormalities (p < 0.01).

Sun-induced migraine attacks in an Arctic population

The main purpose of the study was to evaluate the impact of weather, and especially sun exposure, on migraine. Data from a previous prospective 12-month diary study was compared with meteorological data. We retrospectively evaluated 1250 migraine attacks recorded by a group of 40 women with a mean age of 37.1 years who fulfilled the IHS criteria for migraine with and without aura. The patients reported more sun-induced migraine attacks on sunny days, but the total distribution of migraine attacks was constant throughout the year. Also, no seasonal variation of migraine, nor any relationships between weather parameters and onset of migraine attacks, were found. An analysis of a subgroup of patients with 'sun-induced' migraine showed a significant increase in frequency of migraine attacks in the summer compared to the winter (p = 0.04). This study confirms that sunlight might be a trigger for migraine, but a risk for increased impact of light on the total ailment of migraine headache should be searched for in a subgroup of sensitive migraineurs.

Attention Deficit Hyperactivity Disorder and Enuresis in Children and Adolescents

Frequency of comorbid disorders and neuropsychological state, executive functions (EF), were studied in two groups of patients aged from 5 to 14 years: 53 patients with attention-deficit hyperactivity disorder (ADHD) in the association with enuresis and 71 patients with ADHD without enuresis. The most cases of enuresis (50 out of 53 patients) were represented by primary nocturnal enuresis. The significant increase of total number of ADHD cases with comorbidity for oppositional-defiant disorder, anxiety disorder, tics or encopresis (77.7%) was found in the first group compared to the second one (60.6%). The presence of enuresis in ADHD was associated with the significant increase of frequency of anxiety disorders (54.7% versus 39.4%). Moreover, in the group of patients with ADHD and enuresis, the frequency of oppositional-defiant disorder and encopresis was higher in the age of 5-9 years while the frequency of obsessive-compulsive disorder and tics increased in the period of 10-14 years as compared to patients without enuresis. The assessment of executive functions with the Wisconsin Card Sorting Test did not reveal any differences between patients of two groups.

Flow Cytometric Analysis of TCR Vβ Repertoire in Patients with 22q11.2 Deletion Syndrome

In 22q11.2 deletion patients, the normal decrease in T lymphocyte counts after 1-2 years is blunted such that relatively T lymphocyte numbers increase over early childhood, probably via post-thymic expansion of peripheral lymphocytes. This may leave less T lymphocyte receptor (TCR) diversity than when derived from naive thymic emigrants. We analysed TCR Vβ repertoire on 27 22q11.2 chromosome deletion patients. No patient had infection at sampling. CD3(+) CD4(+) recent thymic emigrants (RTEs) were identified by CD45RA and CD31 expression. TCR Vβ repertoire was determined using four-colour flow cytometry. Patients and controls showed significant TCR Vβ family usage differences between CD3(+) CD4(+) and CD3(+) CD4(-) T lymphocyte subpopulations. Vβ family abnormalities (±3 SD of controls) were identified in 18/27 (67%) patients and 12/47 (25%) controls. In patients, the magnitude of expansions was increased, with some Vβ families representing 37% of the cells present in the subpopulations. There was a significant increase in frequency of abnormalities in CD3(+) CD4(+) (P < 0.001) and CD3(+) CD4(-) T lymphocytes (P < 0.05) in patients. A total of 11/16 patients had an abnormal CD4(+) CD25(Bright) TCR Vβ repertoire. There was no difference in expansions/contractions between CD4(+) CD25(Bright) and CD4(+) T lymphocyte repertoires (P = 0.575) for individual patients but significant differences in expansions/contractions between CD4(+) CD25(Bright) and CD8(+) T lymphocytes repertoires (P = 0.011). There was bias in Vβ usage between CD3(+) CD4(+) and CD3(+) CD4(-) T lymphocyte subsets. A total of 67% patients had TCR Vβ repertoire abnormalities, with a trend towards increased repertoire abnormalities with fewer RTEs, suggesting thymic output plays an important role in TCR repertoire diversity. There was no correlation between skewed repertoire and symptoms of infection or autoimmunity.

Abstract 5512: Immune correlates of clinical response and survival in castration-resistant prostate cancer patients treated with prostate GVAX and anti-CTLA4 immunotherapy

Abstract The effects of Prostate GVAX and the anti-CTLA4 antibody Ipilimumab were investigated in a Phase I dose escalation/expansion trial of patients with castration resistant prostate cancer. Results showed that the GVAX/Ipilimumab combination was clinically active with PSA declines of more than 50% (Partial Response, PR) in 6 and PSA stabilizations (Stable Disease, SD) in 11 of 28 patients. Immune response monitoring was performed to identify changes that might predict or correlate with clinical efficacy. Upon administration of high Ipilimumab dosages (3 or 5 mg/kg), significant increases in frequencies of activated CD4+ and/or CD8+ T cells were observed by HLA-DR, PD-1, FoxP3 and ICOS expression. Monitoring over the course of treatment, revealed these markers to be differentially associatied with survival, as were levels of effector/memory T cells or Tregs. Early HLA-DR upregulation appeared useful as a marker for response prediction, since it was observed to significant levels in PR or SD, but not in PD patients. In addition, GVAX/Ipilimumab administration was found to induce Th2/Th17 cytokine profiles, as determined ex vivo by intracellular staining of peripheral T cells. Significantly increased levels of IL-4 in both CD4+ and CD8+ T cells were observed in patients with PR or SD, but not in patients with PD and, importantly, profound up-regulation of CD4+IL-5+ T cell frequencies was associated with improved overall survival (p=0.03). Similarly, significantly increased Th17 rates were only observed in patients with PR and SD (p&amp;lt;0.05). Of particular interest, the increased Th17 frequencies coincided with onset of hypophysitis and/or adrenal insufficiencies, as well as of PSA declines in PR patients. As an indication of tumor-specific responsiveness, IgG antibody responses against 11 (prostate) tumor-associated antigens were determined by western blot and ELISA. Increased seroreactivity to prostate-specific membrane antigen (PSMA), pyridoxamine 5′-phosphate oxidase (PNPO) and/or Neuropilin-2 (NRP2) was significantly correlated with improved overall survival (p&amp;lt;0.03). Our data indicate that changes in frequencies of activated memory/effector T cells and Tregs, Th2 and Th17 rates and seroconversion to multiple tumor antigens may define a predictive immune profile for patients with potential benefit from Prostate GVAX and/or anti-CTLA4 immunotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5512. doi:10.1158/1538-7445.AM2011-5512

Characterization of HCV-Specific CD4+Th17 Immunity in Recurrent Hepatitis C–Induced Liver Allograft Fibrosis

Hepatitis C virus (HCV) recurrence with accelerated fibrosis following orthotopic liver transplantation (OLT) is a universal phenomenon. To evaluate mechanisms contributing to HCV induced allograft fibrosis/cirrhosis, we investigated HCV-specific CD4+Th17 cells and their induction in OLT recipients with recurrence utilizing 51 HCV+ OLT recipients, 15 healthy controls and 9 HCV- OLT recipients. Frequency of HCV specific CD4+ Tcells secreting IFN-γ, IL-17 and IL-10 was analyzed by ELISpot. Serum cytokines and chemokines were analyzed by LUMINEX. Recipients with recurrent HCV induced allograft inflammation and fibrosis/cirrhosis demonstrated a significant increase in frequency of HCV specific CD4+Th17 cells. Increased pro-inflammatory mediators (IL-17, IL-1β, IL-6, IL-8 and MCP-1), decreased IFN-γ, and increased IL-4, IL-5 and IL-10 levels were identified. OLT recipients with allograft inflammation and fibrosis/cirrhosis demonstrated increased frequency of Foxp3+ regulatory T cells (Tregs) that inhibited HCV specific CD4+Th1 but not Th17 cells. This suggests that recurrent HCV infection in OLT recipients induces an inflammatory milieu characterized by increased IL-6, IL-1β and decreased IFN-γ which facilitates induction of HCV specific CD4+Th17 cells. These cells are resistant to suppression by Tregs and may mediate an inflammatory cascade leading to cirrhosis in OLT recipients following HCV recurrence.