Malignant gliomas: Current perspectives in diagnosis, treatment, and early response assessment using advanced quantitative imaging methods

Malignant gliomas consist of glioblastomas, anaplastic astrocytomas, anaplastic oligodendrogliomas and anaplastic oligoastrocytomas, and some less common tumors such as anaplastic ependymomas and anaplastic gangliogliomas. Malignant gliomas have high morbidity and mortality. Even with optimal treatment, median survival is only 12-15 months for glioblastomas and 2-5 years for anaplastic gliomas. However, recent advances in imaging and quantitative analysis of image data have led to earlier diagnosis of tumors and tumor response to therapy, providing oncologists with a greater time window for therapy management. In addition, improved understanding of tumor biology, genetics, and resistance mechanisms has enhanced surgical techniques, chemotherapy methods, and radiotherapy administration. After proper diagnosis and institution of appropriate therapy, there is now a vital need for quantitative methods that can sensitively detect malignant glioma response to therapy at early follow-up times, when changes in management of nonresponders can have its greatest effect. Currently, response is largely evaluated by measuring magnetic resonance contrast and size change, but this approach does not take into account the key biologic steps that precede tumor size reduction. Molecular imaging is ideally suited to measuring early response by quantifying cellular metabolism, proliferation, and apoptosis, activities altered early in treatment. We expect that successful integration of quantitative imaging biomarker assessment into the early phase of clinical trials could provide a novel approach for testing new therapies, and importantly, for facilitating patient management, sparing patients from weeks or months of toxicity and ineffective treatment. This review will present an overview of epidemiology, molecular pathogenesis and current advances in diagnoses, and management of malignant gliomas. © 2014 Ahmed et al

T Cells Recognizing a Peptide Contaminant Undetectable by Mass Spectrometry

Synthetic peptides are widely used in immunological research as epitopes to stimulate their cognate T cells. These preparations are never completely pure, but trace contaminants are commonly revealed by mass spectrometry quality controls. In an effort to characterize novel major histocompatibility complex (MHC) Class I-restricted β-cell epitopes in non-obese diabetic (NOD) mice, we identified islet-infiltrating CD8+ T cells recognizing a contaminating peptide. The amount of this contaminant was so small to be undetectable by direct mass spectrometry. Only after concentration by liquid chromatography, we observed a mass peak corresponding to an immunodominant islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)206-214 epitope described in the literature. Generation of CD8+ T-cell clones recognizing IGRP206-214 using a novel method confirmed the identity of the contaminant, further underlining the immunodominance of IGRP206-214. If left undetected, minute impurities in synthetic peptide preparations may thus give spurious results

Knee arthroplasty: are patients' expectations fulfilled?: A prospective study of pain and function in 102 patients with 5-year follow-up

Background and purpose With an aging population expecting an active life after retirement, patients’ expectations of improvement after surgery are also increasing. We analyzed the relationship between preoperative expectations and postoperative satisfaction and self-reported outcomes with regard to pain and physical function after knee arthroplasty

Reliability and concurrent validity of the Dutch hip and knee replacement expectations surveys

Background: Preoperative expectations of outcome of total hip and knee arthroplasty are important determinants of patients' satisfaction and functional outcome. Aims of the study were (1) to translate the Hospital for Special Surgery Hip Replacement Expectations Survey and Knee Replacement Expectations Survey into Dutch and (2) to study test-retest reliability and concurrent validity. Methods: Patients scheduled for total hip (N = 112) or knee replacement (N = 101) were sent the Dutch Expectations Surveys twice with a 2 week interval to determine test-retest reliability. To determine concurrent validity, the Expectation WOMAC was sent. Results: The results for the Dutch Hip Replacement Expectations Survey revealed good test-retest reliability (ICC 0.87), no bias and good internal consistency (alpha 0.86) (N = 72). The correlation between the Hip Expectations Score and the Expectation WOMAC score was 0.59 (N = 86). The results for the Dutch Knee Replacement Expectations Survey revealed good test-retest reliability (ICC 0.79), no bias and good internal consistency (alpha 0.91) (N = 46). The correlation with the Expectation WOMAC score was 0.52 (N = 57). Conclusions: Both Dutch Expectations Surveys are reliable instruments to determine patients' expectations before total hip or knee arthroplasty. As for concurrent validity, the correlation between both surveys and the Expectation WOMAC was moderate confirming that the same construct was determined. However, patients scored systematically lower on the Expectation WOMAC compared to the Dutch Expectation Surveys. Research on patients' expectations before total hip and knee replacement has only been performed in a limited amount of countries. With the Dutch Expectations Surveys it is now possible to determine patients' expectations in another culture and healthcare setting

Isolation and purification of Cu-free methanobactin from Methylosinus trichosporium OB3b

<p>Abstract</p> <p>Background</p> <p>The isolation of highly pure copper-free methanobactin is a prerequisite for the investigation of the biogeochemical functions of this chalkophore molecule produced by methane oxidizing bacteria. Here, we report a purification method for methanobactin from <it>Methylosinus trichosporium </it>OB3b cultures based on reversed-phase HPLC fractionation used in combination with a previously reported resin extraction. HPLC eluent fractions of the resin extracted product were collected and characterized with UV-vis, FT-IR, and C-1s NEXAFS spectroscopy, as well as with elemental analysis and ESI-MS.</p> <p>Results</p> <p>The results showed that numerous compounds other than methanobactin were present in the isolate obtained with resin extraction. Molar C/N ratios, mass spectrometry measurements, and UV-vis spectra indicated that methanobactin was only present in one of the HPLC fractions. On a mass basis, methanobactin carbon contributed only 32% to the total organic carbon isolated with resin extraction. Our spectroscopic results implied that besides methanobactin, the organic compounds in the resin extract comprised breakdown products of methanobactin as well as polysaccharide-like substances.</p> <p>Conclusion</p> <p>Our results demonstrate that a purification step is indispensable in addition to resin extraction in order to obtain pure methanobactin. The proposed HPLC purification procedure is suitable for semi-preparative work and provides copper-free methanobactin.</p

Cerebrovascular mental stress reactivity is impaired in hypertension

<p>Abstract</p> <p>Background</p> <p>Brachial artery reactivity in response to shear stress is altered in subjects with hypertension. Since endothelial dysfunction is generalized, we hypothesized that carotid artery (CA) reactivity would also be altered in hypertension.</p> <p>Purpose</p> <p>To compare (CA endothelium-dependent vasodilation in response to mental stress in normal and hypertensive subjects.</p> <p>Methods</p> <p>We evaluated CA reactivity to mental stress in 10 young healthy human volunteers (aged 23 ± 4 years), 20 older healthy volunteers (aged 49 ± 11 years) and in 28 patients with essential hypertension (aged 51 ± 13 years). In 10 healthy volunteers and 12 hypertensive subjects, middle cerebral artery (MCA) PW transcranial Doppler was performed before and 3 minutes after mental stress.</p> <p>Results</p> <p>Mental stress by Stroop color word conflict, math or anger recall tests caused CA vasodilation in young healthy subjects (0.61 ± 0.06 to 0.65 ± 0.07 cm, p < 0.05) and in older healthy subjects (0.63 ± 0.06 to 0.66 ± 0.07 cm, p < 0.05), whereas no CA vasodilation occurred in hypertensive subjects (0.69 ± 0.06 to 0.68 ± 0.07 cm; p, NS). CA blood flow in response to mental stress increased in young healthy subjects (419 ± 134 to 541 ± 209 ml, p < 0.01 vs. baseline) and in older healthy subjects (351 ± 114 to 454 ± 136 ml, p < 0.01 vs. baseline) whereas no change in blood flow (444 ± 143 vs. 458 ± 195 ml; p, 0.59) occurred in hypertensive subjects. There was no difference in the CA response to nitroglycerin in healthy and hypertensive subjects. Mental stress caused a significant increase in baseline to peak MCA systolic (84 ± 22 to 95 ± 22 cm/s, p < 0.05), diastolic (42 ± 12 to 49 ± 14 cm/s, p < 0.05) as well as mean (30 ± 13 to 39 ± 13 cm/s, p < 0.05) PW Doppler velocities in normal subjects, whereas no change in systolic (70 ± 18 to 73 ± 22 cm/s, p < 0.05), diastolic (34 ± 14 to 37 ± 14 cm/s, p = ns) or mean velocities (25 ± 9 to 26 ± 9 cm/s, p = ns) occurred in hypertensive subjects, despite a similar increase in heart rate and blood pressure in response to mental stress in both groups.</p> <p>Conclusion</p> <p>Mental stress produces CA vasodilation and is accompanied by an increase in CA and MCA blood flow in healthy subjects. This mental stress induced CA vasodilation and flow reserve is attenuated in subjects with hypertension and may reflect cerebral vascular endothelial dysfunction. Assessment of mental stress induced CA reactivity by ultrasound is a novel method for assessing the impact of hypertension on cerebrovascular endothelial function and blood flow reserve.</p

Exceptionally Preserved Jellyfishes from the Middle Cambrian

Cnidarians represent an early diverging animal group and thus insight into their origin and diversification is key to understanding metazoan evolution. Further, cnidarian jellyfish comprise an important component of modern marine planktonic ecosystems. Here we report on exceptionally preserved cnidarian jellyfish fossils from the Middle Cambrian (∼505 million years old) Marjum Formation of Utah. These are the first described Cambrian jellyfish fossils to display exquisite preservation of soft part anatomy including detailed features of structures interpreted as trailing tentacles and subumbrellar and exumbrellar surfaces. If the interpretation of these preserved characters is correct, their presence is diagnostic of modern jellyfish taxa. These new discoveries may provide insight into the scope of cnidarian diversity shortly after the Cambrian radiation, and would reinforce the notion that important taxonomic components of the modern planktonic realm were in place by the Cambrian period

Comparative Therapeutic Effects of Velaglucerase Alfa and Imiglucerase in a Gaucher Disease Mouse Model

Gaucher disease type 1 is caused by the defective activity of the lysosomal enzyme, acid β-glucosidase (GCase). Regular infusions of purified recombinant GCase are the standard of care for reversing hematologic, hepatic, splenic, and bony manifestations. Here, similar in vitro enzymatic properties, and in vivo pharmacokinetics and pharmacodynamics (PK/PD) and therapeutic efficacy of GCase were found with two human GCases, recombinant GCase (CHO cell, imiglucerase, Imig) and gene-activated GCase (human fibrosarcoma cells, velaglucerase alfa, Vela), in a Gaucher mouse, D409V/null. About 80+% of either enzyme localized to the liver interstitial cells and <5% was recovered in spleens and lungs after bolus i.v. injections. Glucosylceramide (GC) levels and storage cell numbers were reduced in a dose (5, 15 or 60 U/kg/wk) dependent manner in livers (60–95%) and in spleens (∼10–30%). Compared to Vela, Imig (60 U/kg/wk) had lesser effects at reducing hepatic GC (p = 0.0199) by 4 wks; this difference disappeared by 8 wks when nearly WT levels were achieved by Imig. Anti-GCase IgG was detected in GCase treated mice at 60 U/kg/wk, and IgE mediated acute hypersensitivity and death occurred after several injections of 60 U/kg/wk (21% with Vela and 34% with Imig). The responses of GC levels and storage cell numbers in Vela- and Imig-treated Gaucher mice at various doses provide a backdrop for clinical applications and decisions