Significant Decrease In Sensitivity Research Articles

Taxanes Sensitize Prostate Cancer Cells to TRAIL-Induced Apoptotic Synergy via Endoplasmic Reticulum Stress.

Docetaxel and cabazitaxel are guideline-chemotherapy treatments for metastatic castration-resistant prostate cancer (mCRPC), which comprises the majority of prostate cancer deaths. TNF-related apoptosis inducing ligand (TRAIL) is an anticancer agent that is selectively cytotoxic to cancer cells; however, many human cancers are resistant to TRAIL. In this study, we sensitized androgen-independent and TRAIL-resistant prostate cancer cells to TRAIL-mediated apoptosis via taxane therapy and examined the mechanism of sensitization. DU145 and PC3 cells displayed no significant reduction in cell viability when treated with soluble TRAIL, docetaxel, or cabazitaxel alone indicating that both cell lines are resistant to TRAIL and taxanes individually. Taxane and TRAIL combination synergistically amplified apoptosis strongly suggesting that taxanes sensitize prostate cancer cells to TRAIL. A Jun N-terminal kinases (JNK) inhibitor inhibited apoptosis in treated cells and significantly reduced death receptor expression indicating JNK activation by ER stress sensitizes PCa cells to TRAIL-induced apoptosis by upregulating DR4/DR5 expression. In addition, suppression of C/EBP homologous protein (CHOP) reduced TRAIL sensitization in both cell lines indicating that ER stress-related apoptosis is mediated, in part, by CHOP. Cytochrome c knockdown showed a significant decrease in sensitivity in PC3 cells, but not in Bax-deficient DU145 cells. A computational model was used to simulate apoptosis for cells treated with taxane and TRAIL therapy as demonstrated in in vitro experiments. Pretreatment with taxanes sensitized cells to apoptosis induced by TRAIL-mediated apoptosis, demonstrating that combining TRAIL with ER stress inducers is a promising therapy to reverse TRAIL resistance to treat mCRPC.

Best approach in d-dimer algorithm to exclude pulmonary thromboembolism: a comparative study

Abstract Funding Acknowledgements Type of funding sources: None. Background Ruling out pulmonary embolism (PE) through a combination of clinical assessment and Ddimer is crucial to avoid excessive computed tomography pulmonary angiography (CTPA), and different algorithms should be considered as an alternative to the fixed cutoff to achieve that goal. Purpose To compare sensitivity, specificity, and reduction in CTPA requests of 4 algorithms to rule out PE: fixed Ddimer cutoff, age-adjusted, YEARS and PEGeD. Methods Retrospective study of consecutive outpatients who presented to the emergency department and underwent CTPA for PE suspicion from April 2019 to February 2020. The clinical-decision algorithms were retrospectively applied. In fixed and age-adjusted cutoffs, high probability patients are directly selected for CTPA and the others perform CTPA if Ddimer ≥500µg/L or age x10 µg/L within patients over 50 years, respectively. YEARS includes 3 items (signs of deep vein thrombosis, haemoptysis and whether PE is the most likely diagnosis): patients without any YEARS items and Ddimer ≥1000ng/mL or with ≥1 items and Ddimer 500ng/mL perform CTPA. In the PEGeD, patients with high clinical probability or with intermediate and Ddimers >500µg/L or low probability and Ddimer >1000 µg/L are selected for CTPA. Results We enrolled 409 patients and PE was confirmed by CTPA in 125 patients. Compared with a fixed Ddimer cutoff, age-adjusted was associated with a significant increased of specificity (p < 0.001), correctly avoiding 29 CTPAs, without losing sensitivity. YEARS resulted in a marked increase in specificity, compared to the fixed cutoff, but with an impairment of sensitivity(p = 0.002). PEGeD had the worst sensitivity, associated with 11 more false negatives (FN) than the fixed cutoff. Despite the lack of difference between PEGed and YEARS strategies regarding sensitivity, YEARS had a significantly higher specificity (p < 0.001) and allowed to correctly avoid a higher number of CTPA(55 vs 63), compared to the fixed cutoff. Results are summarized in table 1. Conclusion Compared to fixed d-dimer cutoff, all algorithms were associated with an increased specificity. Age-adjusted cutoff was the only that is not associated with a significant decrease in sensitivity when compared to fixed cutoff, allowing to safely reduce the need to perform CTPA. Sens(%) Spec(%) Correctly avoid CTPAs(n) FN(n) Fixed cutoff 95 29 85 6 Age-adjusted 93 40 114 9 YEARS 87 52 148 16 PEGeD 86 49 140 17

The role of adhesion and binder stiffness in the impact sensitivity of cast composite energetic materials

The drop weight impact or drop hammer test has been a staple of energetic material small-scale sensitivity testing for over 100 years, but the link between material properties and sensitivity has proven difficult to evaluate, especially for composite materials. In this study, the work of adhesion and elastic modulus of the binder were varied to assess their impact on the sensitivity of a family of plastic bonded explosive composite energetic materials. Drop weight impact tests performed using the German Bundesanstalt für Materialprufung impact test demonstrated significant decreases in sensitivity as the elastic modulus and the work of adhesion decrease. It was determined that the elastic modulus of the binder was the most significant contributor to the corresponding changes in sensitivity.

DDRE-27. LMNA-PRKDC AXIS PROMOTES CHEMORESISTANCE IN RECURRENT GBM BY STABILIZING DNA REPAIR FOCI

Abstract Tumors in patients with recurrent GBM are resistant to standard therapies. Available models for testing experimental therapies to treat GBM are primarily derived from or representative of primary, untreated GBM. We have developed a clinically relevant model of recurrent, therapy-resistant glioblastoma (GBM6R) from a patient-derived xenograft (PDX) of primary glioblastoma (GBM6) that underwent multiple rounds of temozolomide (TMZ) treatment following intracranial engraftment in a host mouse. Initial characterizations of GBM6R revealed a significant decrease in sensitivity to TMZ both in vitro (p< 0.008) and in vivo (p=0.0079). An unbiased screen to identify proteins with altered expression in GBM6R, relative to treatment naïve GBM6, revealed nuclear lamina protein LMNA as highly expressed in GBM6R. From in silico analysis we found that high LMNA expression is associated with poor survival for GBM patients (p=0.0001, Gravendeel; p=0.0078, TCGA_GBM; p< 0.0001, CCGA; GlioVis). GBM5 and GBM43 PDX explant cultures treated with multiple doses of TMZ increased their expression of LMNA. We found that in TMZ treated and TMZ resistant tumors, that LMNA preferentially localizes to the nuclear lamina (p< 0.001), which is not observed in primary, untreated tumors (p< 0.005). Analysis of LMNA by immunoprecipitation revealed that LMNA interacts with DNA-PK and γH2AX. From these results, we hypothesize that LMNA may be acting to stabilize DNA damage foci at the nuclear periphery, which results in enhanced DNA repair. Our observations support the testing of selective DNA-PK inhibitors for treating GBM, which would inhibit TMZ-induced DNA damage repair, and enhance the cytotoxic effects of TMZ.

Refractive index sensitivity of triangular Ag nanoplates in solution and on glass substrate

We report the synthesis of Ag triangular nanoplates and its application for the detection of bulk refractive index change resulting from low molecular weight analyte molecules. Triangular nanoplates of different edge lengths were synthesized using seed mediated approach with small modification in the earlier reported method [Adv. Funct. Mater. 18, 2005–2016 (2008)]. Increase in the edge length of nanoplates was observed with decrease in the volume of seed nanoparticle used. The synthesized nanoplates in colloidal solution were investigated for the refractive index sensing. The nanoplates synthesized with 100 μL seed volume showed maximum sensitivity for glucose and glycerol as 465 and 461 nm/RIU respectively. Triangular nanoplates with highest sensitivity in the solution were immobilized on silanized glass surface using 3-aminopropyl-trimethoxysilane as an adhesion layer. The refractive index sensitivity of immobilized nanoplates was found to be 193 and 204 nm/RIU for glucose and glycerol solutions respectively. The significant decrease in sensitivity could be due to damping of plasmon resonance on substrate or non-availability of all surfaces. The immobilized nanoplates on glass surface can be used as nanoplasmonic sensor chip for chemical and biological analyte detection.

DOSE DEPENDENCE OF RADIATION INDUCED DAMAGE IN THE THERMOLUMINESCENT RESPONSE OF LIF:Mg,Ti (TLD-100).

The effect of previous irradiation on the sensitivity of the glow peaks of LiF:Mg,Ti (TLD-100) is investigated up to levels of dose of 400Gy in both slow-cooled and naturally cooled materials following the 400°C/1hour pre-irradiation anneal. It is demonstrated that the naturally cooled samples can be re-used up to accumulated levels of dose of 50Gy without recalibration. At 400Gy a significant decrease in sensitivity of approximately 25% is observed for all the glow peaks (excluding peak 3). In slow-cooled materials even 100Gy does not alter the sensitivity of the material.

Interleukin-8 associated with chemosensitivity and poor chemotherapeutic response to gastric cancer.

Gastric cancer (GC) patients have been found to have developed chemotherapy resistance that has resulted in a lowering of their overall survival rates. Interleukin-6 (IL-6) and interleukin-8 (IL-8) could be responsible as the predictive biomarkers in monitoring drug resistance. We have developed a protocol to monitor drug treatment by testing ex vivo chemosensitivity and cytokine levels of primary gastric cultures obtained from endoscopic biopsies. We studied 49 patients with distal GC who underwent primary surgical resection between June 2014 and December 2016 in the northern endemic region of Thailand. The clinical and pathological data of patients were recorded, and the cancer sub-type was classified. The correlation of cytokine IL-6 and IL-8 protein expression levels and chemotherapy sensitivity in primary gastric cultures was investigated. Endoscopic biopsies were collected before and/or after chemotherapy treatment followed by FOLFOXIV regimen (oxaliplatin + 5-FU/leucovorin). The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed to examine ex vivo chemosensitivity to cisplatin, oxaliplatin, 5-fluorouracil (5-FU) and irinotecan. Enzyme-linked immunosorbent assay (ELISA) was performed to investigate cytokine levels. Ex vivo drug treatment of 49 primary gastric cultures from naive patients revealed a significant correlation between basal levels of IL-8 and chemosensitivity to cisplatin (P=0.001) and oxaliplatin (P=0.001). IL-8 protein expression levels were significantly decreased in the early phase after cisplatin and oxaliplatin treatments leading to an increase in cell sensitivity to drug treatments. Among 49 patients, 11 patients were classified as partial or poor responders after drug interventions, in which case, second endoscopic biopsies were performed for determination of chemosensitivity and cytokine levels. The results demonstrated significant decreases in sensitivity to cisplatin (P=0.049) and oxaliplatin (P=0.014), meanwhile IL-8 protein expression levels were significantly increased by P=0.0423 in both drug treatments. There was no correlation of IL-6 and drug resistance when treatments of the primary gastric cultures involved each of the four chemotherapeutic drugs (P=0.0663). Upregulation of IL-8 after drug intervention might be useful as predictive biomarker in monitoring drug resistance in GC patients; however, this needs to be confirmed among a larger number of patients and with control groups that are properly age-paired. The established primary gastric culture could serve as a valuable tool for chemotherapy screening, while the repeated usage of platinum drugs may result in drug resistance via upregulation of IL-8 levels.

Comprehensive behavioral analysis of heterozygous Syngap1 knockout mice.

AimsSynaptic Ras GTPase‐activating protein 1 (SYNGAP1) regulates synaptic plasticity through AMPA receptor trafficking. SYNGAP1 mutations have been found in human patients with intellectual disability (ID) and autism spectrum disorder (ASD). Almost every individual with SYNGAP1‐related ID develops epilepsy, and approximately 50% have ASD. SYNGAP1‐related ID is estimated to account for at least 1% of ID cases. In mouse models with Syngap1 mutations, strong cognitive and affective dysfunctions have been reported, yet some findings are inconsistent across studies. To further understand the behavioral significance of the SYNGAP1 gene, we assessed various domains of behavior in Syngap1 heterozygous mutant mice using a behavioral test battery.MethodsMale mice with a heterozygous mutation in the Syngap1 gene (Syngap1 −/+ mice) created by Seth Grant's group were subjected to a battery of comprehensive behavioral tests, which examined general health, and neurological screens, rotarod, hot plate, open field, light/dark transition, elevated plus maze, social interaction, prepulse inhibition, Porsolt forced swim, tail suspension, gait analysis, T‐maze, Y‐maze, Barnes maze, contextual and cued fear conditioning, and home cage locomotor activity. To control for type I errors due to multiple‐hypothesis testing, P‐values below the false discovery rate calculated by the Benjamini‐Hochberg method were considered as study‐wide statistically significant.Results Syngap1 −/+ mice showed increased locomotor activity, decreased prepulse inhibition, and impaired working and reference spatial memory, consistent with preceding studies. Impairment of context fear memory and increased startle reflex in Syngap1 mutant mice could not be reproduced. Significant decreases in sensitivity to painful stimuli and impaired motor function were observed in Syngap1 −/+ mice. Decreased anxiety‐like behavior and depression‐like behavior were noted, although increased locomotor activity is a potential confounding factor of these phenotypes. Increased home cage locomotor activity indicated hyperlocomotor activity not only in specific behavioral test conditions but also in familiar environments.ConclusionIn Syngap1 −/+ mice, we could reproduce most of the previously reported cognitive and emotional deficits. The decreased sensitivity to painful stimuli and impaired motor function that we found in Syngap1 −/+ mice are consistent with the common characteristics of patients with SYNGAP‐related ID. We further confirmed that the Syngap1 heterozygote mouse recapitulates the symptoms of ID and ASD patients.

Molecular and Biochemical Characterization of Carbendazim-Resistant Botryodiplodia theobromae Field Isolates.

Stem-end rot caused by Botryodiplodia theobromae is a destructive disease of mango. B. theobromae field isolates resistant to carbendazim (MBC) were collected in Hainan Province, China. In this study, the characteristics of these field isolates with resistance to MBC were investigated. The resistance of B. theobromae isolates to MBC was stably inherited. Both the MBC-resistant and MBC-sensitive isolates had similar mycelial growth rates, pathogenicity, sensitivity to high glucose, glycerol content, and peroxidase activity. Compared with MBC-sensitive isolates, MBC-resistant isolates were more sensitive to low temperature and had a significant decrease in sensitivity to high NaCl and a significant increase in catalase (CAT) and glutathione S-transferase (GST) activities. After MBC treatment, the cell membrane permeability of the sensitive isolates was markedly increased compared with that of the resistant isolates. Analysis of the β-tubulin gene sequence revealed point mutations resulting in substitutions at codon 198 from glutamic acid (GAG) to alanine (GCG) in moderately resistant isolates, and at codon 200 from phenylalanine (TTC) to tyrosine (TAC) in highly resistant isolates. These β-tubulin gene mutations were consistently associated with MBC resistance. Overall, we infer that the altered cell membrane permeability and the increase in CAT and GST activities of the resistant isolates are linked to MBC resistance.

The mechanistic basis for photobiomodulation therapy of neuropathic pain by near infrared laser light.

Various irradiances have been reported to be beneficial for the treatment of neuropathic pain with near infrared light. However, the mechanistic basis for the beneficial outcomes may vary based on the level of irradiance or fluence rate used. Using in vivo and in vitro experimental models, this study determined the mechanistic basis of photobiomodulation therapy (PBMT) for the treatment of neuropathic pain using a high irradiance. In vitro experiments: Cultured, rat DRG were randomly assigned to control or laser treatment (LT) groups with different irradiation times (2, 5, 30, 60, or 120 seconds). The laser parameters were: output power = 960 mW, irradiance = 300 mW/cm2 , 808 nm wavelength, and spot size = 3 cm diameter/area = 7.07cm2 , with different fluences according to irradiation times. Mitochondrial metabolic activity was measured with the MTS assay. The DRG neurons were immunostained using a primary antibody to β-Tubulin III. In vivo experiments: spared nerve injury surgery (SNI), an animal model of persistent peripheral neuropathic pain, was used. The injured rats were randomly divided into three groups (n = 5). (i) Control: SNI without LT; (ii) Short term: SNI with LT on day 7 and euthanized on day 7; (iii) Long term: SNI with LT on day 7 and euthanized on day 22. An 808 nm wavelength laser was used for all treatment groups. Treatment was performed once on day 7 post-surgery. The transcutaneous treatment parameters were: output power: 10 W, fluence rate: 270 mW/cm2 , treatment time: 120 seconds. The laser probe was moved along the course of the sciatic/sural nerve during the treatment. Within 1 hour of irradiation, behavior tests were performed to assess its immediate effect on sensory allodynia and hyperalgesia caused by SNI. In vitro experiments: Mitochondrial metabolism was significantly lower compared to controls for all LT groups. Varicosities and undulations formed in neurites of DRG neurons with a cell body diameter 30 µm or less. In neurites of DRG neurons with a cell body diameter of greater than 30 µm, varicosities formed only in the 120 seconds group. In vivo experiments: For heat hyperalgesia, there was a statistically significant reduction in sensitivity to the heat stimulus compared to the measurements done on day 7 prior to LT. A decrease in the sensitivity to the heat stimulus was found in the LT groups compared to the control group on days 15 and 21. For cold allodynia and mechanical hyperalgesia, a significant decrease in sensitivity to cold and pin prick was found within 1 hour after LT. Sensitivity to these stimuli returned to the control levels after 5 days post-LT. No significant difference was found in mechanical allodynia between control and LT groups for all time points examined. These in vitro and in vivo studies indicate that treatment with an irradiance/fluence rate at 270 mW/cm2 or higher at the level of the nerve can rapidly block pain transmission. A combination therapy is proposed to treat neuropathic pain with initial high irradiance/fluence rates for fast pain relief, followed by low irradiance/fluence rates for prolonged pain relief by altering chronic inflammation. Lasers Surg. Med. 49:516-524, 2017. © 2017 Wiley Periodicals, Inc.

Resistance to 6-Methylpurine is Conferred by Defective Adenine Phosphoribosyltransferase in Tetrahymena.

6-methylpurine (6mp) is a toxic analog of adenine that inhibits RNA and protein synthesis and interferes with adenine salvage mediated by adenine phosphoribosyltransferase (APRTase). Mutants of the ciliated protist Tetrahymena thermophila that are resistant to 6mp were isolated in 1974, but the mechanism of resistance has remained unknown. To investigate 6mp resistance in T. thermophila, we created 6mp-resistant strains and identified a mutation in the APRTase genomic locus (APRT1) that is responsible for 6mp resistance. While overexpression of the mutated APRT1 allele in 6mp-sensitive cells did not confer resistance to 6mp, reduced wild-type APRT1 expression resulted in a significant decrease in sensitivity to 6mp. Knocking out or reducing the expression of APRT1 by RNA interference (RNAi) did not affect robust cell growth, which indicates that adenine salvage is redundant or that de novo synthesis pathways provide sufficient adenosine monophosphate for viability. We also explored whether 6mp resistance could be used as a novel inducible selection marker by generating 6mp- and paromomycin-resistant double mutants. While 6mp- and paromomycin-resistant double mutants did express fluorescent proteins in an RNAi-based system, the system requires optimization before 6mp resistance can be used as an effective inducible selection marker.

Safety and acceptability of human papillomavirus testing of self-collected specimens: A methodologic study of the impact of collection devices and HPV assays on sensitivity for cervical cancer and high-grade lesions

BackgroundComparative data on different self-collection methods is limited. ObjectivesTo assess the impact of hrHPV testing of two self-collection devices for detection of cervical carcinoma and high-grade lesions. Study designThree hundred ten patients collected two cervicovaginal specimens using a brush (Evalyn®Brush) and a swab (FLOQSwabs™), and filled a questionnaire at home. Then, a physician at the clinic took a cervical specimen into PreservCyt® buffer for hrHPV testing and cytology. All specimens were tested using Anyplex™ II HPV28, Cobas® 4800 HPV Test and Xpert®HPV. ResultsPerformance comparison included 45 cervical carcinomas and 187 patients with premalignant lesions. Compared to the physician-specimen, hrHPV testing of Evalyn®Brush showed non-inferior sensitivity for CIN3+ (relative sensitivity of Anyplex™ 0.99; Cobas® 0.96; Xpert®HPV 0.97) while hrHPV testing of FLOQSwabs™ showed inferior sensitivity (relative sensitivity of Anyplex™ 0.91; Cobas® 0.92; Xpert®HPV 0.93). Similar results were observed for invasive carcinomas albeit that FLOQSwabs™ was statistically non-inferior to the physician-specimen. Self-collection by either Evalyn®Brush or FLOQSwabs™ was more sensitive for CIN3+ than LSIL or worse cytology. Significant decrease in sensitivity for CIN3+ were observed for FLOQSwabs™ when specimens were preprocessed for hrHPV testing after 28 days. Both devices were well accepted, but patients considered Evalyn®Brush easier and more comfortable than FLOQSwabs™. ConclusionsSelf-collection is comparable to current screening practice for detecting cervical carcinoma and CIN3+ but device and specimen processing effects exist. Only validated procedure including collection device, hrHPV assay and specimen preparation should be used.

Extended Abstract: Utilizing Event Rate As a Manipulation of Task Difficulty in Vigilance

Vigilance refers to the ability of an observer to maintain attention over extended periods of time, and to respond to critical signals that occur (Davies & Parasuraman, 1982). Vigilance has been ex...

Comparative clinical evaluation of two different techniques of local anaesthesia in the posterior mandible using 4% articaine with 1:100,000 adrenaline

Background/Aim. Local infiltration anaesthesia (LIA) is significantly simpler compared to the inferior alveolar nerve block (IAB) and less unpleasant for patients. However, it is not efficient if used in posterior region of the mandible, at least with traditional local anaesthetics. The aim of this study was to compare anaesthetic efficacy of two techniques the LIA in the posterior segment of the mandible, and the IAB, using 4% articaine with 1 : 100,000 adrenaline and to note possible changes in haemodynamic parameters caused by these two techniques. Methods. Sixty pre-informed patients were divided into two study groups. Both groups received 1.8 mL of the same anaesthetic solution, 4% articaine with adrenaline 1 : 100,000, with two different techniques of local anaesthesia. The first group received the LIA in projection of root apex of the first lower molar; the second group received the IAB. The examined parameters were: changes in tooth sensitivity after 5 and 30 minutes in relation to the value recorded before administering the anaes-thetics, onset of anaesthesia, width of anaesthetic field, and duration of anaesthesia. Also, the impact of the applied techniques on cardiovascular parameters was noticed. Results. The LIA group had a statistically significant decrease in sensitivity 5 minutes after application of the local anaesthetic. The decreasing trend continued between 5 and 30 minutes, although without statistical significance. There was no statistically significant difference in sensitivity changes between two groups for the first molar and the first and second premolars. However, there was a statistically significant difference in duration of local anaesthesia in favour of the IAB, while the width of anaesthetic fields was significantly higher after the LIA. Significant changes in hemodynamic parameters were not recorded within the two groups. Conclusion. The effect of the LIA on tooth sensitivity of premolars and first molar is quite satisfactory. The IAB was more effective for canine and second molar. None of the tested techniques had any significant effect on the cardio-vascular parameters.

Long–term Drifts in Sensitivity Caused by Biofouling of an Amperometric Oxygen Sensor

AbstractChanges in oxygen sensitivity of an poly(o‐phenylenediamine) (PoPD) coated gold electrode was determined by constructing calibration curves in vitro. Oxygen sensitivities recorded in the presence of biofoulants were significantly different from those recorded in buffer; however, PoPD demonstrated its effectiveness in providing some resistance to changes in oxygen sensitivity over time compared to a bare electrode. Three sets of PoPD‐coated electrodes were calibrated in simple electrolyte of phosphate buffered saline; each set yielding an average oxygen sensitivity of 0.58±0.03 μA/ppm, 0.68±0.01 μA/ppm, and 0.48±0.01 μA/ppm (n=4), which shows the electrode to electrode variation in the PoPD‐coating/electrode. These sets were correspondingly exposed to bovine serum albumin, fibrinogen, rat brain homogenate. Exposure to these biofoulants resulted in decreases in sensitivity ranging from 26–35 % after immediate exposure. Furthermore, long‐term exposure to some biofoulants causes significant decreases in sensitivity over a time period of 14 days. We also estimated through in vitro exposure to rat brain homogenate the errors that might be associated with current methods of calibration. Sensitivities to oxygen determined by precalibration resulted in a 50 % error from the sensitivity found in vitro; the error from postcalibration after rinsing resulted in 25 % error.

Diagnostic accuracy of static CT perfusion for the detection of myocardial ischemia. A systematic review and meta-analysis

ObjectivesThe aim of this study is to provide a meta-analysis of all published studies assessing the diagnostic accuracy of stress CT myocardial perfusion imaging (CTP) in patients suspected of or with known coronary artery disease. This analysis is limited to static stress CTP. MethodsSystematic literature review and meta-analysis of studies examining the diagnostic accuracy of static CTP imaging alone or combined with coronary CT angiography (CTA) in comparison to single photon emission computed tomography (SPECT), magnetic resonance perfusion (MRP), and/or invasive coronary angiography with and without fractional flow reserve (FFR). ResultsThe search revealed 19 eligible studies including 1188 patients. Pooled results showed that CTP had a good agreement with SPECT and MRP. On a per-patient level, sensitivity, specificity and AUC were 0.85 (95% CI: 0.70–0.93), 0.81 (95% CI: 0.59–0.93), 0.90 (95% CI: 0.87–0.92). On a per-artery level, sensitivity, specificity and AUC were 0.80 (95% CI: 0.67–0.88), 0.81 (95% CI: 0.72–0.88) and 0.87 (95% CI: 0.84–0.90). When invasive coronary angiography was used as reference standard, combined coronary CTA and CTP compared to coronary CTA alone significantly improved the specificity from 0.62 (95% CI: 0.52–0.70) to 0.84 (95% CI: 0.74–0.91) on a per-patient level (p = 0.008) and from 0.72 (95% CI: 0.63–0.79) to 0.90 (95% CI: 0.85–0.93) on a per-artery level (p = 0.0001) without significant decrease in sensitivity (p = 0.59 and p = 0.23, respectively). ConclusionIn selected patients, static CT myocardial perfusion has high diagnostic accuracy to detecting myocardial ischemia. Specificity increases significantly when CT myocardial perfusion is combined with coronary CTA.

Peripheral contrast sensitivity and attention in myopia

Disruption of normal visual experience or changes in the normal interaction between central and peripheral retinal input may lead to the development of myopia. In order to examine the relationship between peripheral contrast sensitivity and myopia, we manipulated attentional load for foveal vision in emmetropes and myopes while observers detected targets with peripheral vision. Peripheral contrast detection thresholds were measured binocularly using vertical Gabor stimuli presented at three eccentricities (±8°, 17°, 30°) in a spatial 2 alternative forced choice task. Contrast thresholds were measured in young adult (mean age 24.5±2.6years) emmetropes (n=17; group SE: +0.19±0.32D) and myopes (n=25; group SE: −3.74±1.99D). Attention at central fixation was manipulated with: (1) a low attention task, requiring simple fixation; or (2) a high attention task, which required subjects to perform a mathematical task. We found that at 30° all subjects exhibited lower contrast sensitivity (higher thresholds). In addition, myopes (Wilcoxon, p<0.01), but not emmetropes (Wilcoxon, p=0.1), had a significant decrease in sensitivity at 30° during the high attention task. However, the attention dependent threshold increase for myopes was not significantly greater than for emmetropes (Wilcoxon, p=0.27). Attentional load did not increase thresholds at 8° or 17° for either refractive group. These data indicate that myopes experience a greater decrease in contrast sensitivity in the far periphery than emmetropes when attention is deployed in central vision.

Value of Quantitative Sensory Testing in the Evaluation of Genital Sensation: Its Application to Female Sexual Dysfunction

Female sexual dysfunction (FSD) is multifactorial, with psychological and organic elements. Genital sensation, an important component of sexual response, has until recently not been subjected to adequate clinical appraisal. During the past 15 years we have performed Quantitative Sensory Testing (QST) to assess genital sensation in healthy women and women with FSD. To review available evidence of QST in the investigation of genital sensation in women with FSD. We examined data obtained from assessment of genital sensation in normal women and those with different conditions, including multiple sclerosis, pelvic floor disorders, effect of hysterectomy, and vulvar vestibulitis. Use of QST for assessment of FSD. Normograms for healthy women were used to measure parameters during arousal, orgasm, and the refractory phase. Using QST, genital sensation was found to be impaired in women with multiple sclerosis. Clitoral vibratory sensation most significantly correlated with FSD parameters. Women with greater deficit in vibratory sensation encountered more sexual dysfunction. Women with urinary incontinence had a significant decrease in sensitivity to warm, cold, and vibratory thresholds in the anterior vaginal wall and clitoral area. A study comparing women with andwithout pelvic organ prolapse showed mean thresholds for vibratory and warm stimuli to be significantly higher and mean thresholds for cold stimuli to be significantly lower in the group with prolapse. QST of women undergoing hysterectomy showed a significant decrease in sensation to cold, warm, and vibratory stimuli at the anterior andposterior vaginal wall; clitoral thermal and vibratory sensation thresholds remained unchanged after surgery. In astudy of vulvar vestibulitis, patients reported significantly lower heat pain thresholds compared with controls. QST appears useful for evaluating various gynecologic disorders associated with disturbed sexual function and with multiple sclerosis, which might be accompanied by disturbed genital sensation.

Chronic Oxidative Stress Increases Resistance to Doxorubicin-Induced Cytotoxicity in Renal Carcinoma Cells Potentially Through Epigenetic Mechanism.

Renal cell carcinoma is the most common form of kidney cancer and is highly resistant to chemotherapy. Although the role of oxidative stress in kidney cancer is known, the chemotherapeutic response of cancer cells adapted to chronic oxidative stress is not clear. Hence, the effect of oxidative stress on sensitivity to doxorubicin-induced cytotoxicity was evaluated using an in vitro model of human kidney cancer cells adapted to chronic oxidative stress. Results of MTT- and anchorage-independent growth assays and cell cycle analysis revealed significant decrease in sensitivity to doxorubicin in Caki-1 cells adapted to oxidative stress. Changes in the expression of genes involved in drug transport, cell survival, and DNA repair-dependent apoptosis further confirmed increased resistance to doxorubicin-induced cytotoxicity in these cells. Decreased expression of mismatch repair (MMR) gene MSH2 in cells exposed to oxidative stress suggests that loss of MMR-dependent apoptosis could be a potential mechanism for increased resistance to doxorubicin-induced cytotoxicity. Additionally, downregulation of HDAC1, an increase in the level of histone H3 acetylation, and hypermethylation of MSH2 promoter were also observed in Caki-1 cells adapted to chronic oxidative stress. DNA-demethylating agent 5-Aza-2dC significantly restored the expression of MSH2 and doxorubicin-induced cytotoxicity in Caki-1 cells adapted to chronic oxidative stress, suggesting the role of DNA hypermethylation in inactivation of MSH2 expression and consequently MMR-dependent apoptosis in these cells. In summary, this study for the first time provides direct evidence for the role of oxidative stress in chemotherapeutic resistance in renal carcinoma cells potentially through epigenetic mechanism.

The nature of the salt error in the Sn(II)-reduced molybdenum blue reaction for determination of dissolved reactive phosphorus in saline waters

Sn(II) is a well-known reductant used in the formation of phosphomolybdenum blue for the determination of dissolved reactive phosphorus (DRP) in waters because it provides rapid and quantitative reduction. However, in saline waters, this method suffers from a salt error which causes a significant decrease in sensitivity. This phenomenon has never been adequately explained in the literature. The Murphy and Riley method, which uses Sb(III) and ascorbic acid for the reduction step, is preferred for DRP determination in saline waters because it is unaffected by salinity, but it exhibits a sensitivity approximately 30% lower than that when Sn(II) is used as the reductant without Cl− interference. This study investigates the processes causing the salt error and possible ways of minimizing it, so that the benefits of Sn(II) reduction on the molybdenum blue reaction rate and sensitivity may be exploited in the determination of low levels of DRP in marine and estuarine waters. It has been established that the salt error is caused by the formation of Sn(IV) chloro-complexes which compete with the formation of Sn(IV)-substituted phosphomolybdenum blue, forcing the reaction to proceed via the much slower, less favourable process of direct reduction that occurs in methods using organic reductants such as ascorbic acid.