Hs Scores Research Articles

Therapeutic effect and mechanism of Ento-PB on ulcerative colitis in BALB/c mice induced by sodium dextran sulfate

The traditional Chinese medicine (TCM) formula Ento-PB containing Periplaneta americana (Linnaeus) (Blattidae) and Taraxacum mongolicum Hand.-Mazz. (Compositae) has great potential for treating inflammation. Thus, this study aimed to explore the pharmacodynamic effect of Ento-PB on DSS-induced ulcerative colitis in BALB/c mice, and its effects on immune function, JAK2/STAT3-related signaling pathways and intestinal flora in UC mice. It was identified that the extract Ento-PB mainly contained 20 compounds, accounting for 78.50 % of the total peak area. Compared with the model group, each dose group of Ento-PB could reduce the DAI score, colon index, CMDI score and colon HS score of mice to varying degrees (P < 0.05 or P < 0.01). Ento-PB can reduce the content of IL-1β, TNF-α, IFN-γ in serum and IL-7 and IL-17 in colonic tissue, and increase IL-2, IL-10 in serum and EGF in colonic mucosa, TGF-β1 expression level (P < 0.05 or P < 0.01). In conclusion, Ento-PB has a good therapeutic effect on DSS-induced UC mice. Its mechanism of action may be to up-regulate the levels of IL-2, IL-10, EGF, IL-22 and TGF-β1, and down-regulate the levels of TNF-α,IFN-γ, IL-7 and IL-17 in UC mice. This provides sufficient experimental basis for the clinical treatment of UC with Ento-PB.

Development of a new clinical tool to evaluate the balance abilities of children with bilateral vestibular loss: The Geneva Balance Test.

Vestibular deficits are considered rare in children, but the lack of systematic screening leads to underdiagnosis. It has been demonstrated that chronic vestibular dysfunction impacts the normal psychomotor development of children. Early identification is needed to allow for clinical management, ensuring better global development. For this purpose, our research group has developed the Geneva Balance Test (GBT), aiming to objectively quantify the balance capacity of children over a broad age range, to screen for bilateral vestibulopathy (BV), and to quantify the improvement of balance abilities in children. To determine the capacity of the GBT to quantify the balance capacity of children with BV, we conducted an observational prospective study with three populations: 11 children with BV, and two age-matched control groups composed of (1) 15 healthy subjects without the vestibular or auditory disorder (HS) and (2) 11 pediatric cochlear implant recipients (CIs) without vestibular disorders. Results of the three populations have been compared in three different age sub- groups (3-5, 6-9, and ≥10 years), and with results of a short, modified version of the Bruininks-Oseretsky test of Motor proficiency Ed. 2 (mBOT-2). Statistical analyses demonstrated significant differences in the scores of the GBT between children aged 3-5, 6-9, and ≥10 years with BV and in both control populations (HS and CI). BV scores reflected poorer balance capacities at all ages. Children in the youngest CI sub-group (3-5 years) showed intermediate GBT scores but reached HS scores at 6-9 years, reflecting an improvement in their balance capacities. All the results of the GBT were significantly correlated with mBOT-2 results, although only a few BV completed the entire mBOT-2. In this study, the GBT allowed quantifying balance deficits in children with BV. The BOT-2 test is not validated for children <4.5 years of age, and the GBT seems to be better tolerated in all populations than the mBOT-2. Furthermore, mBOT-2 results saturated, reaching maximum values by 6-9 years whereas the GBT did not, suggesting that the GBT could be a useful tool for monitoring the development of balance capacities with age and could be used in the follow-up of children with severe vestibular disorders.

665 THE UNFORSEEN MECHANISM: A CASE OF DISTRIBUTIVE SHOCK SECONDARY TO REACTIVE HAEMOPHAGOCYTIC SYNDROME LEADING TO SEVERE REVERSIBLE BIVENTRICULAR DYSFUNCTION.

Abstract Distributive shock comprises a variety of processes causing dysregulated vasodilation with consequent life-threatening end-organ dysfunction. While sepsis constitutes by far its most common aetiology, other pathological mechanisms with different therapeutic targets may lead to a similar haemodynamic picture. We hereby present the case of a 35-year-old male with no past cardiological history and a recent diagnosis of stage IVsB Hodgkin's lymphoma relapse 10 years after effective disease eradication with first-line chemotherapy. Shortly after a single cycle of second-line chemotherapy, the patient presented with high fever, acute chest pain and dyspnea associated with marked hypotension and sinus tachycardia. Laboratory tests revealed pancytopenia and raised inflammatory markers as well as evidence of acute kidney injury and hepatocellular damage. Urgent thoracic CT revealed no signs of pneumonia while echocardiography demonstrated severe biventricular dysfunction with 25% left ventricular ejection fraction and severe functional mitral regurgitation. Due to worsening tachypnea and desaturation the patient was intubated and transferred to our Intensive Cardiac Care Unit where urgent instatement of circulatory support with iv fluids, blood transfusions, adrenaline and intra-aortic balloon pump were performed and empirical broad-spectrum antibiotic therapy was started after performing blood cultures from peripheral and central veins. Concurrent right ventricular catheterisation demonstrated high-output cardiac failure (Qs Fick 7.89 Qp/m2, Qs thermodilution 8.0 Qp/m2) with mild increase in biventricular filling pressures and post-capillary pulmonary hypertension. Endomyocardial biopsy in turn revealed only mild subendocardial fibrosis and oedema thus excluding myocarditis as a potential cause for the severe biventricular dysfunction. Due to worsening of renal function with persistent anuria despite circulatory support the patient required continuous veno-venous haemofiltration. Notably, over the coming days no pathogen was isolated from any of the cultures with haemodynamic and respiratory parameters gradually improving, allowing for weaning from circulatory and respiratory support. On further examination of blood tests on admission, hypertriglyceridemia, raised ferritin levels and thrombin consumption were noted. These biochemical features, together with the history of Hodgkin's lymphoma relapse, recent chemotherapy, pancytopenia and splenomegaly, suggestive of natural killer cell dysfunction-related haemophagocytosis, pointed to reactive haemophagocytic syndrome as a potential aetiology of the severe distributive shock (&amp;gt; 99% probability on recently published “HS Score” for Reactive Haemophagocytic Syndrome). This hypothesis was further corroborated by the gradual albeit not complete regression of the severe biventricular dysfunction after haemodynamic support suggesting that this may have represented a byproduct of the patient's high-output state. Unfortunately, due to lymphoma progression with severe multiorgan involvement the patient was admitted shortly after discharge and deceased thereafter. This case provides an example of the diversity of potential disease mechanisms underlying distributive shock where biventricular dysfunction may represent a reversible albeit severe bystander rather than the true driving factor of its life-threatening haemodynamic compromise.

Prognostic factors in patients with bone marrow hemophagocytosis and its association with hematologic malignancies.

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous group of hyperinflammatory statuses that are difficult to diagnose and can be life-threatening. Bone marrow (BM) hemophagocytosis is one of the diagnostic criteria according to HLH 2004 diagnostic criteria and HS score. Limited studies have focused on the prognostic factors of BM hemophagocytosis and its association with hematologic malignancies. We aimed to analyze the clinical significance of BM hemophagocytosis. Patients with BM hemophagocytosis, either by cytology or pathology, were enrolled at Taipei Veterans General Hospital from January 2002 to July 2021. Relevant clinical and laboratory data were extracted from medical records. Of 119 patients with BM hemophagocytosis, 57 were diagnosed with hematologic malignancies. The median age of the patients was 58, ranging from 21 to 90. Splenomegaly (adjusted odds ratio [aOR] 2.96; 95% confidence interval [CI] 1.13-7.79) was a risk factor for hematologic malignancies, while autoimmune disease (aOR 0.07; 95% CI 0.01-0.39) and increased D-dimer (aOR 0.25; 95% CI 0.07-0.92) were protective factors. Risk factors for mortality in patients with BM hemophagocytosis were hematologic malignancies (adjusted hazard ratio [aHR] 2.34; 95% CI 1.24-4.44), Eastern Cooperative Oncology Group score ≥3 (aHR 2.42; 95% CI 1.20-4.89) and thrombocytopenia (aHR 3.09; 95% CI 1.04-9.16). In conclusion, among patients with BM hemophagocytosis, splenomegaly was a predictor of hematologic malignancies. Patients with hematologic malignancies, poor performance status, or thrombocytopenia had a higher mortality risk. Further validation studies are warranted.

Plasma calprotectin as a biomarker of ultrasound synovitis in rheumatoid arthritis patients receiving IL-6 antagonists or JAK inhibitors

Objectives:To analyse the accuracy of plasma calprotectin in patients with rheumatoid arthritis (RA) receiving monoclonal antibodies against IL-6 receptors (anti-rIL-6) or JAK inhibitors (JAKis) in detecting ultrasound (US) synovitis and compare it with acute phase reactants [high-sensitivity C-reactive protein (hs-CRP) and ESR].Methods:An observational cross-sectional study of RA patients receiving anti-rIL-6 (tocilizumab or sarilumab) or JAKi, (baricitinib or tofacitinib) was made. Plasma calprotectin for the diagnosis of US synovitis [synovial hypertrophy grade (SH) ⩾ 2 plus power Doppler signal (PD) ⩾ 1] was analysed using receiver operating characteristic curves (ROCs). The performance of ESR and hs-CRP was also studied. The three ROC curves were compared to determine which had the highest discriminatory power. Associations between plasma calprotectin and US scores were made using correlation analysis.Results:Sixty-three RA patients were included. Mean plasma calprotectin levels were significantly higher in patients with US synovitis than in those without (0.89 ± 0.85 vs 0.30 ± 0.12 μg/ml; p = 0.0003). A moderate correlation between calprotectin and all US scores (HS score Rho = 0.479; PD score Rho = 0.492; and global score Rho = 0.495) was found. The discriminatory capacity of plasma calprotectin showed an AUC of 0.795 (95% CI: 0.687–0.904). The AUC of hs-CRP and ESR was 0.721 and 0.564, respectively. hs-CRP serum levels showed a low positive correlation with the three US scores (Rho < 0.40). After analysis according to the drugs administered, the correlation disappeared in patients receiving anti-rIL-6.Conclusion:Plasma calprotectin may be a sensitive biomarker of synovial inflammation in RA patients treated with anti-rIL-6 or JAKi.

Pain as Defining Feature of Health Status and Prominent Therapeutic Target in Patients with Hidradenitis Suppurativa.

Background. Pain is one of the main aspects of hidradenitis suppurativa that strongly affects the quality of life of patients. We explored the relationship between pain and clinical severity as well as its role in defining the health status in patients with HS. Methods. Pain was defined by three measures: (a) question 1 (“my skin hurts”) of the Skindex-17; (b) Bodily Pain (BP) scale of the SF-36; and (c) Visual Analog Scale (VAS). Clinical severity of HS was assessed by the Hurley staging, the Sartorius HS Score, and the International HS Severity Score System. Results. The study population included 341 HS patients with complete data for the VAS pain, 316 for question 1 of the Skindex-17, and 294 for BP. Clinical severity was positively associated with pain. This result was observed for all three severity scores and all three pain evaluation methods. In addition, the number of fistulae, abscesses, and nodules were significantly associated with the three severity measures of pain, while the association with scars was not observed for question 1 of the Skindex-17 and BP. Conclusions. Pain may be a good proxy of clinical severity and efficacy of a treatment in HS and therefore a crucial hallmark of patients’ health status.

Macrophage Activation Syndrome: A case series; From Sepsis to Malignancy: Early diagnosis and treatment

INTRODUCTION: Haemophagocytic lymphohistiocytosis (HLH) or macrophage activation syndrome(MAS) is a syndrome of fulminant cytokine storm leading to multiorgan dysfunction and high mortality rate. HLH may be Familial or Primary(fHLH) and Secondary (sHLH).FHLH is due to mutation in gene coding for perforin or NK cell of CD8 lymphocytes. sHLH may be associated with hematological malignancies, autoimmune disorders like SLE,Still’s diseae, kawasaki disease, infections and sepsis of various etiology starting from bacteria ,viral protozoal ,fungal and zoonotic infection. Main presenting features are fever, hepatospleenomegly, cytopenia,high ferritin level, high serum triglyceride and haemophagocytosis in bone marrow spleen or lymphnode. MATERIAL AND METHOD: In this series we describe Five cases ,(two cases of SLE,one B-Cell lymphoma, one case of scrub typhus,one case of kleibsiella pneumoniae presenting as sepsis ) with their clinical, laboratory investigations, management and outcome with special correlation of ferritin level and HS score with the prognosis. All patients managed with I.V.Methyl prednisolone 30 mg/kg/day for three consecutive days and out come is assessed. CONCLUSION: MAS in SLE and sepsis is a life threatening unrecognised condition, early diagnosis and treatment can increase the survival rate by many folds . a drop of ferritin level by 15% after 48 hrs of treatment is a surrogate marker of good prognosis. From H scoring cut off value 169 corresponds to sensitivity of 93% and specificity of 86%.

CHADS2-VASc skorunun primer percutan koroner girişim yapılan ST elevasyonlu miyokart enfarktüslü hastalarda ST segment rezolusyonunu öngörmedeki yararlılığı

Background: Rapid supply of coronary blood flow in the occluded coronary artery is the principle aim of early ST-elevation myocardial infarction (STEMI) therapy. Although coronary blood flow has been supplied, insufficient myocardial reperfusion mainly at the level of micro vascular circulation has been assessed a large number of patients. Electrocardiographically by measuring ST-segment resolution (STR) after procedure is an easy and good indicator for the evaluation of reperfusion failure. The CHA2DS2-VASc risk score is used to predict the risk of thromboembolism in non-valvular AF patients. Its usefulness in predicting AF in the development of STR failure in patients presenting with STEMI is unknown. We evaluated the predictive value of the CHA2DS2-VASc score in patients with STR failure following STEMI.Methods: Models including clinical and laboratory parameters were constructed to test the predictive value of CHA2DS2-VASc and CHA2DS2-VASc -HS scores. Patients were divided into two groups: those with STR&amp;gt; 70 % and those without STR&amp;gt; 70. Predictors of STR failure were determined by multivariate regression analysis.Results: Multiple regression analysis showed that CHA2DS2-VASc-HS score, Anterior STEMI, peak CK-MB level and symptom to percutaneous coronary intervention time were associated with development of STR failure in patients presenting with STEMI. ROC curve analyses showed that CHA2DS2-VASc and CHA2DS2-VASc -HS scores were significant predictors for STR failure. Conclusion: CHA2DS2-VASc and CHA2DS2-VASc -HS scores predict STR failure in patients presenting STEMI.

Effects and Mechanism of Constitutive TL1A Expression on Intestinal Mucosal Barrier in DSS-Induced Colitis.

The role of TL1A in the intestinal mucosa barrier in inflammatory bowel disease (IBD) is still unclear. This study was aimed to investigate the expression levels of tight junction protein (TJ), myosin light chain kinase (MLCK), MyD88 and tumor necrosis factor (TNF) receptor-associated factor-6 (TRAF6) and how TL1A influences the intestinal barrier in IBD. The mouse models of IBD were built using FMS-TL1A-GFP-transgenic mice and wild-type mice. The morphological and histopathological changes, bacterial translocation, permeability of colonic mucosa, and LPS level were assessed. Caco-2 cells were used to further investigate the association between TL1A and TNF-α and LPS. The protein level and mRNA changes of TJ proteins including ZO-1, occluding, JAMA, claudin-1, claudin-2, and claudin-3 were investigated using Western blot and real-time PCR. Protein changes of MLCK, MyD88 and TNF receptor-associated factor-6 (TRAF6), and TNF-α mRNA in the mouse colon were further assessed. The IBD models were successfully built. Cooper HS score and histopathological score of the colon were higher in DSS/WT group than in control/WT group (P < 0.05), higher in DSS/Tg group than in control/Tg group (P < 0.05), and higher in DSS/Tg group than in DSS/WT group. PAS, colonic permeability of the colon, and FITC-D examination showed the similar results and trends. Compared with control/WT group, the levels of TL1A and claudin-2 were higher and the levels of ZO-1, occludin, JAMA, claudin-1, and claudin-3 were lower in DSS/WT group (P < 0.05). Compared with control/Tg group, the levels of TL1A and claudin-2 were higher and the levels of ZO-1, occludin, JAMA, claudin-1, and claudin-3 were lower in DSS/Tg group. Compared with Caco-2 + TNF-α group, the expression level of occludin and claudin-1 in Caco-2 + LV-TNFSF15 + TNF-α group was significantly lower (P < 0.05); p-MLC level was significantly higher. Compared with Caco-2 + LPS group, the expression level of occludin and claudin-1 significantly decreased in Caco-2 + LV-TNFSF15 + LPS group; MyD88 and TRAF6 expression level significantly increased. The results suggested that TL1A could impair intestinal epithelial barrier in the mouse model of IBD and might regulate TJ expression via MLCK/p-MLC pathway and LPS-mediated MyD88/TRAF6 pathway.

Importance of First and Second Authorship in Assessing Citation-Based Scholarly Activity of United States Radiation Oncology Residents and Subsequent Choice of Academic versus Private Practice Career

The Hirsch index (h-index) has become increasingly popular in assessing citation-based scholarly activity of physicians, and has been shown to correlate with Radiation Oncology residents having a first job in academics versus private practice. A limitation of the h-index methodology is its inability to distinguish between the differing significance of co-author roles in manuscripts (i.e. first author versus fifth author). This study was performed to assess the role of first and second author publications and their association with resident pursuit of academic versus private practice career. A list of 2016 radiation oncology resident graduates (163 residents from 76 Accreditation Council for Graduate Medical Education-certified programs) and their post-residency career choice (academic versus private practice) was compiled as previously described (McClelland et al., Practical Radiation Oncology 2017). The SCOPUS bibliometric citation database was then searched to collect h-index data for manuscripts limited to first-author only (hf) and first or second-author only (hs) for each resident. Demographics included in analyses were gender and PhD degree status. The mean hf was 2.06 for all resident graduates; mean hs was 2.77. Residents with a PhD had significantly higher hf (3.11 versus 1.76; p<0.01) and hs (4.50 versus 2.28; p<0.01). There was no statistically significant difference between male and female residents fpr hf (2.19 versus 1.61; p=0.11) or hs (2.91 versus 2.25; p=0.15). With regard to career choice, residents going on to academic jobs had higher hf (2.72 versus 1.44; p<0.01) and hs (3.57 versus 2.01; p<0.01) than those choosing private practice. Less than 20% of graduates with hf of zero chose academic careers, and only 10% of graduates with hs of zero went on to academic jobs. The average radiation oncology resident graduate has published a minimum of two first and/or second-author manuscripts cited at least twice. As with the traditional h-index, graduates with a PhD and/or choosing academic careers are more likely to have higher hf and hs scores, and there is no significant difference in scores between male and female residents. Noteworthy is that only 10% of graduates without any first and/or second-author manuscripts cited at least once went on to academic jobs. These findings indicate that stratifying publications by first or second authorship when developing benchmarks for evaluating both radiation oncology resident productivity and post-residency career choices may be useful. This work represents the first demonstration of these assessment measures in radiation oncology, and show that they are well associated with post-residency career type. Consequently, these measures deserve further study.

Relationship between clinical severity of "new" bronchopulmonary dysplasia and HRCT abnormalities in VLBW infants.

To assess the relationship between HRCT abnormalities and the clinical severity of "new" bronchopulmonary dysplasia (BPD) and respiratory assistance in <1500 g preterm infants. HRCT was performed at the time of discharge in 109 preterm infants with BPD who were born between 2008 and 2014. BPD severity was defined as mild, moderate, or severe according to the NIH diagnostic criteria. Total HRCT scores for each infant were obtained from the sum of the number of BPD lobes assessed by two radiologists: a hyperaeration score (Hs) composed of decreased attenuation, mosaic attenuation, and bulla/bleb, and a parenchyma score (Ps) composed of linear lesions, consolidation, bronchial wall thickening, and bronchiectasis. We compared HRCT scores based on BPD severity and respiratory modes, such as invasive mechanical ventilation (IMV), non-invasive MV (NIMV), and oxygen therapy. Among the group of included infants (n = 101), mild BPD was found in 46.5%, moderate BPD in 45.5%, and severe BPD in 7.9%. When partial correlation was adjusted by gestational age (GA) and birth weight, the duration of NIMV was correlated with Ps (r = 0.382, P < 0.001), Hs (r = 0.223, P = 0.027), and total score (r = 0.384, P < 0.001). The duration of oxygen therapy was correlated with Ps (r = 0.374, P < 0.001) and Hs (r = 0.227, P = 0.023). Ps showed a correlation with BPD severity (r = 0.381, P = 0.007) in infants born at ≤26 weeks (GA) and those born at >27 weeks GA (r = 0.298, P = 0.042). Parenchymal changes showed a greater correlation with the clinical severity of "new" BPD cases, especially in infants born at ≤26 weeks GA. The use of NIMV showed a greater correlation with Ps than Hs.

Importance of First and Second Authorship in Assessing Citation-Based Scholarly Activity of US Radiation Oncology Residents and Subsequent Choice of Academic Versus Private Practice Career

PurposeThe Hirsch index (h-index) has been shown to correlate with radiation oncology residents’ having a first job in academics versus private practice, but it is limited by its inability to distinguish between the differing significance of coauthor roles in articles. MethodsA list of 2016 radiation oncology resident graduates and their postresidency career choices was compiled. The Scopus bibliometric citation database was then searched to collect h-index data for articles limited to first author only (hf) and first or second-author only (hs) for each resident. ResultsMean hf was 2.06 for all resident graduates, and mean hs was 2.77. Residents with PhDs had significantly higher hf (3.11 versus 1.76, P < .01) and hs (4.50 versus 2.28, P < .01). There was no statistically significant difference between male and female residents for hf (2.19 versus 1.61, P = .11) or hs (2.91 versus 2.25, P = .15). Residents choosing academia had higher hf (2.72 versus 1.44, P < .01) and hs (3.57 versus 2.01, P < 0.01) than those in private practice. Fewer than 20% of graduates with hf = 0 and only 10% of graduates with hs = 0 secured academic jobs. ConclusionThe average radiation oncology resident graduate has published a minimum of two first- and/or second-author articles cited at least twice. Graduates with PhDs and/or choosing academic careers were more likely to have higher hf and hs scores; there was no significant score difference by gender. Only 10% of graduates without any first- and/or second-author articles cited at least once secured academic jobs. These findings indicate that stratifying publications by first or second authorship when developing benchmarks for evaluating resident productivity and postresidency career type may be useful.

Frontal Electroencephalogram Alpha Asymmetry Relates to Implicit Achievement Motives: A Pilot Study

ABSTRACTThe achievement motive is one of the core motives of human behavior and can be divided into two motives: an approach motive (i.e., hope for success [HS]), and an avoidance motive (i.e., fear of failure [FF]). Research has demonstrated that frontal electroencephalogram (EEG) asymmetry in the alpha frequency band is an important marker for differences in motivational processes. The present study investigated the relationship between resting state alpha asymmetry and the achievement motive. Resting state EEG was recorded, and implicit and explicit achievement motives, divided in HS and FF, assessed. Alpha activation asymmetries were calculated by subtracting the average left ln power from the average right ln power at frontal sites and at parietal sites as control position. Our results suggest a positive relationship between stronger left‐sided activation and higher implicit HS scores; no other significant correlations where found. Possible explanations for these findings are discussed.

Combination of oral zinc gluconate and topical triclosan: An anti-inflammatory treatment modality for initial hidradenitis suppurativa

BackgroundHidradenitis suppurativa (HS) is often a therapeutic challenge with relapses and chronicity which can severely impact patients’ quality of life. ObjectiveTo evaluate the efficacy of anti-inflammatory oral zinc gluconate, 90mg/day, combined with topical triclosan, 2% twice daily. MethodsWe retrospectively evaluated the medical records of HS patients in our HS Center of the Department of Dermatology, Venereology, and Allergology, Ruhr-University Bochum, regarding change of disease severity and quality of life. Secondary outcome measures were the number of nodules and fistulas, the number of boils or flair-ups, and the intensity of pain. ResultsSixty-six patients in Hurley stage I and II were included. After 3 months of combination therapy, the modified HS Score and the Dermatology Life Quality Index improved significantly (p<0.0001 and p=0.0386, respectively). The number of inflammatory nodules, new boils or flare-ups, and erythema scores decreased significantly. Fistula count and the visual analogue scale score showed no significant difference. Side-effects (mostly abdominal pain and nausea) were reported by 12 (22.2%) patients. ConclusionThe combination therapy of zinc gluconate and topical triclosan can be considered as an anti-inflammatory treatment for HS patients in Hurley stage I and initial Hurley stage II.

Prospective technical validation and assessment of intra-tumour heterogeneity of a low density array hypoxia gene profile in head and neck squamous cell carcinoma

Background and purposeTumour hypoxia is associated with a poor prognosis in head and neck squamous cell carcinoma (HNSCC), however there is no accepted method for assessing hypoxia clinically. We aimed to conduct a technical validation of a hypoxia gene expression signature using the TaqMan Low Density Array (TLDA) platform to investigate if this approach reliably identified hypoxic tumours. Materials and methodsTumour samples (n=201) from 80 HNSCC patients were collected prospectively from two centres. Fifty-three patients received pimonidazole prior to surgery. TaqMan Low Density Array-Hypoxia Scores (TLDA-HS) were obtained by quantitative real-time PCR (qPCR) using a 25-gene signature and customised TLDA cards. Assay performance was assessed as coefficient of variation (CoV). ResultsThe assay was sensitive with linear reaction efficiencies across a 4log10 range of inputted cDNA (0.001–10ng/μl). Intra- (CoV=6.9%) and inter- (CoV=2.0%) assay reproducibility were excellent. Intra-tumour heterogeneity was lower for TLDA-HS (23.2%) than for pimonidazole (67.2%) or single gene measurements of CA9 (62.2%), VEGFA (45.0%) or HIG2 (39.4%). TLDA-HS in HNSCC cell lines increased with decreasing pO2. TLDA-HS correlated with Affymetrix U133 Plus 2.0 microarray HS (p<0.01) and positive pimonidazole scores (p=0.005). ConclusionsGene expression measurements of hypoxia using a 25-gene signature and TLDA cards are sensitive, reproducible and associated with lower intra-tumour heterogeneity than assaying individual genes or pimonidazole binding. The approach is suitable for further assessment of prognostic and predictive capability in clinical trial material.

Abstract LB-440: Low density array profiling of head and neck squamous cell carcinoma utilizing a 25-gene signature can reliably identify hypoxic tumors

Abstract Purpose: Administering hypoxia modifying therapy to patients with head and neck squamous cell carcinoma (HNSCC) improves outcomes in those with identified hypoxic tumors. As no method for measuring tumor hypoxia has demonstrated clinical utility, this study aimed to validate use of a gene expression signature with a TaqMan Low Density Array (TLDA) platform. Experimental design: Tumor samples (n=201) from 80 HNSCC patients were collected prospectively from two centers. Fifty-three patients received pimonidazole prior to surgery. Hypoxia scores (TLDA HS) were obtained by quantitative real-time PCR (qPCR) using a 25-gene signature and customized TLDA cards. Assay performance was assessed as coefficient of variation (CoV). Relationships with outcome were determined by log-rank analysis. Results: The assay was sensitive with linear reaction efficiencies across a 4log10 range of inputted cDNA (0.001-10 ng/µl). Intra- (CoV=0.5%) and inter- (CoV=0.1%) assay reproducibility were excellent. Intra-tumor heterogeneity was lower for TLDA HS (23.2%) than for pimonidazole (67.2%) or single gene measurements of CA9 (62.2%), VEGFA (45.0%) or HIG2 (39.4%). TLDA HS in HNSCC cell lines increased with decreasing pO2 and was reduced but not completely abrogated in HIF1A silenced cells. TLDA HS correlated with Affymetrix U133 Plus 2.0 microarray HS (p&amp;lt;0.01) and pimonidazole scores (p=0.021). High TLDA HS was associated with worse overall (p=0.037) and recurrence free (p=0.036) survival. Conclusions: Gene expression measurements of hypoxia using a 25-gene signature and TLDA cards are sensitive, reproducible and associated with lower intra-tumor heterogeneity than assaying individual genes or pimonidazole binding. The approach is suitable for application in clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-440. doi:1538-7445.AM2012-LB-440

Hepatic Steatosis and Disease Activity in Subjects with Psoriatic Arthritis Receiving Tumor Necrosis Factor-α Blockers

Little is known about tumor necrosis factor-α (TNF-α) blockers, disease activity, and liver steatosis (hepatic steatosis; HS) in subjects with psoriatic arthritis (PsA). We prospectively evaluated changes in HS during treatment with TNF-α blockers. In 48 patients with PsA who had evidence of HS before the beginning of TNF-α blocker treatment, an ultrasound followup examination was performed after a 12-month treatment period with TNF-α blockers. All subjects were stratified according to minimal disease activity (MDA) or not (n-MDA), during treatment with TNF-α blockers. Changes in grade of HS were evaluated in parallel in 42 controls with HS and without PsA. At baseline, no significant difference in HS score was found between PsA subjects and controls (HS scores 1.46 ± 0.65 vs 1.62 ± 0.66, respectively; p = 0.249). At 12-month followup, a worsening HS score was found in 20 (41.7%) patients with PsA and in 6 (14.3%) controls (p = 0.005). Overall, the grade of HS worsening was higher in patients with PsA (0.37 ± 0.70) than in controls (0.09 ± 0.43; p = 0.028). A significantly lower prevalence of worsening HS was found among patients with PsA with MDA, compared with n-MDA subjects (16.7% vs 66.7%, respectively; p = 0.001). Laboratory measures of liver function behaved similarly. The risk of worsening HS in patients with PsA who had MDA was similar to that in controls (HR 1.20, 95% CI 0.34-4.33, p = 0.77), and higher in patients who did not have MDA (HR 4.46, 95% CI 1.73-11.47, p = 0.001, regression analysis). Compared with patients with MDA, those with active disease after 12-month treatment with TNF-α blockers exhibited significantly higher incidence of worsening liver steatosis.

Presence of Novel, Potentially Homoacetogenic Bacteria in the Rumen as Determined by Analysis of Formyltetrahydrofolate Synthetase Sequences from Ruminants

Homoacetogens produce acetate from H(2) and CO(2) via the Wood-Ljungdahl pathway. Some homoacetogens have been isolated from the rumen, but these organisms are expected to be only part of the full diversity present. To survey the presence of rumen homoacetogens, we analyzed sequences of formyltetrahydrofolate synthetase (FTHFS), a key enzyme of the Wood-Ljungdahl pathway. A total of 275 partial sequences of genes encoding FTHFS were PCR amplified from rumen contents of a cow, two sheep, and a deer. Phylogenetic trees were constructed using these FTHFS gene sequences and the translated amino acid sequences, together with other sequences from public databases and from novel nonhomoacetogenic bacteria isolated from the rumen. Over 90% of the FTHFS sequences fell into 34 clusters defined with good bootstrap support. Few rumen-derived FTHFS sequences clustered with sequences of known homoacetogens. Conserved residues were identified in the deduced FTHFS amino acid sequences from known homoacetogens, and their presence in the other sequences was used to determine a "homoacetogen similarity" (HS) score. A homoacetogen FTHFS profile hidden Markov model (HoF-HMM) was used to assess the homology of rumen and homoacetogen FTHFS sequences. Many clusters had low HS scores and HoF-HMM matches, raising doubts about whether the sequences originated from homoacetogens. In keeping with these findings, FTHFS sequences from nonhomoacetogenic bacterial isolates grouped in these clusters with low scores. However, sequences that formed 10 clusters containing no known isolates but representing 15% of our FTHFS sequences from rumen samples had high HS scores and HoF-HMM matches and so could represent novel homoacetogens.

MMPI-2 profiles: Fibromyalgia Patients Compared to Epileptic and Non-Epileptic Seizure Patients

We compared MMPI-2 profiles of Gulf War veterans with fibromyalgia (FM) to epileptic seizure (ES) patients, psychogenic non-epileptic seizure (PNES) patients, and Gulf War veteran healthy controls. Both PNES and FM are medically unexplained conditions. In previous MMPI-2 research PNES patients were shown to have significantly higher Hs and Hy clinical scales than ES patients. In the present research the FM group had significantly higher Hs and Hy scale scores than both the ES group and the healthy control group. There was no significant difference between the FM and PNES Hs scale scores; however, the FM Hy scale score was significantly lower than the PNES Hy scale score. Present findings indicate a high level of psychological distress in the FM group.

Best Friendship Qualities and Mental Health Symptomatology Among Young Adults

Studies have shown the potential value of social support in altering the progression of various forms of psychopathology. While best friendships represent an important element of social support, their development and associations with mental health status in young adulthood is not well understood. The present study provided unique data regarding MMPI-2 that correlates with the closeness, maintenance difficulty, and rewards of the best friendships described by 398 young adult men and women. The finding of 57 (31%) significant (p < .05) correlations suggested extensive covariation (Cohen d effect sizes ranging from .28 to .72) between MMPI-2 scale indicators of mental health concerns and the best friendship qualities measured by the Acquaintance Description Form (Wright in (Duck, Perlman (eds.) The acquaintance description form, 1985). Four of the ADF-F2 scales (security, social regulation, personal, and situational maintenance difficulty) were found strongly related to selected MMPI-2 (F, Sc and K) features. D, Pt, and Hs scores predicted lower levels of best friendship security along with higher situational maintenance difficulty. The MMPI-2 personality disorder scales (Pd and Hy) provided weak predictors of best friendship qualities. Gender differences in the nature of these relationships were minimal. Empirical relationships between friendship qualities and mental health status in childhood and young adulthood appear to warrant closer systematic attention in the psychological literature.