Differentiation between glioblastomas and brain metastases and regarding their primary site of malignancy using dynamic susceptibility contrast MRI at 3T.

BACKGROUND: Differentiation between glioblastoma and brain metastasis may be challenging in conventional contrast-enhanced MRI. PURPOSE: To investigate if perfusion-weighted MRI is able to differentiate glioblastoma from metastasis and, as a second aim was to see if it was possible in the latter group, to predict the primary site of neoplasm. MATERIAL AND METHODS: Hundred and fourteen patients with newly discovered tumor lesion (76 metastases and 38 glioblastomas) underwent conventional contrast-enhanced MRI including dynamic susceptibility contrast perfusion sequence. The calculated relative cerebral blood volumes were analyzed in the solid tumor area, peritumoral area, area adjacent to peritumoral area, and normal appearing white matter in contralateral semioval center. The Student t-test was used to detect statistically significant differences in relative cerebral blood volume between glioblastomas and metastases in the aforementioned areas. Furthermore, the metastasis group was divided in four sub groups (lung-, breast-, melanoma-, and gastrointestinal origin) and using one-way ANOVA test. P-values < 0.05 were considered significant. RESULTS: Relative cerebral blood volume (rCBV) in the peritumoral edema was significantly higher in glioblastomas than in metastases (mean 3.2 ± 1.4 and mean 0.9 ± 0.7), respectively, (P < 0.0001). No significant differences in the solid tumor area or the area adjacent to edema were found, (P = 0.28 and 0.21 respectively). There were no significant differences among metastases in the four groups. CONCLUSION: It is possible to differentiate glioblastomas from metastases by measuring the CBV in the peritumoral edema. It is not possible to differentiate between brain metastases from different primaries (lung-, breast-, melanoma or gastrointestinal) using CBV-measurements in the solid tumor area, peritumoral edema or area adjacent to edema.

Tobacco Abuse and Associated Oral Lesions among Interstate Migrant Construction Workers.

AIM: The present study was conducted to assess the prevalence of tobacco use and associated oral mucosal lesions among construction workers of Cochin, Kerala, India. MATERIALS AND METHODS: A cross-sectional study was carried at various construction sites of Cochin and 2,163 workers were selected using multistage sampling method and were interviewed and examined. Information regarding demographic details, form, type, frequency of tobacco use, earlier attempt to quit, and willingness to quit tobacco use was obtained using predesigned questionnaire. The oral health status was recorded on the World Health Organization oral health assessment form 1997, and the examination was carried out under natural light using mouth mirrors and probe. Data thus collected were analyzed using Statistical Package for the Social Sciences version 17 (Chicago, Illinois, USA) statistical software package. Chi-square test was applied. RESULTS: Among the 2,163 workers, 1,952 were tobacco users and 211 were nonusers. Among the users, 1,021 use smokeless form, 372 use smoked form, and 559 use both. Premalignant lesions/conditions were more commonly seen with tobacco habit, with leukoplakia (14.75%) being the most common followed by oral submucous fibrosis in 201 (9.3%), candidiasis in 123 (5.7%), ulceration in 131 (6.05%), abscess in 59 (2.73%), smokers palate in 58 (2.68%), lichen planus in 21 (0.97%), and malignant tumor in 2 (0.1%). CONCLUSION: Commonness of abusive habits and oral premalig-nant lesions or conditions was considerable among the workers. Control and early diagnosis through workplace screening are the major backbones for the control of oral cancer. CLINICAL SIGNIFICANCE: Building workers are unprotected from various health hazards at workplace. Lack of access to health services makes the situation unsatisfactory. Poor literacy and low socioeconomic status have resulted in practice of tobacco, smoking, and chewing in the majority of them. Hence, it is our responsibility to find and guide them with a proper oral health education.

Beliefs and attitudes of male and female adolescents and the risk of smoking behavior.

BACKGROUND: Adolescent smoking relates to numerous risk factors, of which beliefs and attitudes toward smoking may play a role. The study aimed to investigate the association between beliefs and attitudes and the risk of adolescent smoking. MATERIALS AND METHODS: In a school-based cross-sectional study, 3,400 students were recruited from 34 intermediate and secondary schools in Madinah City, Al Madinah Region, Saudi Arabia. Data about sociodemographics, smoking-related factors, and beliefs and attitudes toward smoking were collected using a valid and reliable self-administered questionnaire. Prevalence of smoking was estimated and the studied beliefs and attitudes were compared by smoking status and sex using appropriate statistical analyses including multivariate logistic regression. RESULTS: Of the 3,322 respondents, 33.02% (38.9% males and 26.4% females) were current smokers. Beliefs and attitudes toward smoking significantly differed between smokers and nonsmokers in the studied male and female students. The adjusted risk of smoking was significantly increased among female adolescents who believed that male smokers were more attractive [odds ratio (OR) = 2.2; 95% confidence interval (CI) = 1.6-2.9] and among male smokers who believed that female smokers are more attractive (OR = 1.7; 95% CI = 1.2-2.2). The risk was also increased among all adolescents who believed that smoking lent comfort in social gatherings. Belief that smoking is harmful, however, was negatively associated with the risk of smoking, particularly among females (OR = 0.55; 95% CI = 0.35-0.91). CONCLUSIONS: The study revealed a considerable high prevalence of smoking among male and female adolescents. Addressing the beliefs and knowledge about smoking during childhood is crucial in any antismoking program.

Express immunochromatographic detection of antibodies against Brucella abortus in cattle sera based on quantitative photometric registration and modulated cut-off level.

An immunochromatographic test system was developed for rapid detection of the levels of specific IgG antibodies to Brucella abortus lipopolysaccharide, as a tool for diagnosis of brucellosis in cattle. The pilot test strips were examined using blood sera from sick (78 samples) and healthy (35 samples) cows. The results obtained by immunochromatographic assay, using a portable optical densitometer for digital video detection, correlate well with the results obtained by immunoenzyme assay and are in agreement with the results of the disease diagnosis. The new test system allows detection of antibodies within 10 min and can be proposed as an alternative to the methods available for serodiagnosis of brucellosis.

EEG-based emotion recognition systems; comprehensive study.

Emotion recognition technology through EEG signal analysis is currently a fundamental concept in artificial intelligence. This recognition has major practical implications in emotional health care, human-computer interaction, and so on. This paper provides a comprehensive study of different methods for extracting electroencephalography (EEG) features for emotion recognition from four different perspectives, including time domain features, frequency domain features, time-frequency features, and nonlinear features. We summarize the current pattern recognition methods adopted in most related works, and with the rapid development of deep learning (DL) attracting the attention of researchers in this field, we pay more attention to deep learning-based studies and analyse the characteristics, advantages, disadvantages, and applicable scenarios. Finally, the current challenges and future development directions in this field were summarized. This paper can help novice researchers in this field gain a systematic understanding of the current status of emotion recognition research based on EEG signals and provide ideas for subsequent related research.

Oral toxicity and pharmacokinetic studies of SHetA2, a new chemopreventive agent, in rats and dogs.

SHetA2 is a heteroarotinoid that has shown selective inhibition of cancer cell growth and an induction of apoptosis without activation of nuclear retinoic acid receptors. In the rat study, SHetA2 was administered in 1% aqueous methylcellulose/0.2% Tween 80 by oral gavage at 0, 100, 500, and 2,000 mg/kg/day for 28 days. The high-dose administration induced decreased activity in male rats, decreased body-weight gains and food consumption, and changes in organ weights. The major metabolite of SHetA2 in rat plasma was monohydroxy SHetA2, which was considerably higher than the parent compound after oral and intravenous administration. Pharmacokinetic analysis showed extremely low (<1%) systemic bioavailability of SHetA2 for all doses tested. The dose of 2,000 mg/kg/day was considered as the lowest observed adverse effect level. The no observed adverse effect level (NOAEL) was 500 mg/kg/day. In the dog study, no toxicity of SHetA2 in 30% aqueous Solutol(®) HS 15 was observed in any tested dose groups (0, 100, 400, and 1,500 mg/kg/day). The major metabolite of SHetA2 in dog plasma was also monohydroxy SHetA2, which was equal to or lower than the parent compound after oral administration. SHetA2 levels in dog plasma were notably higher, when compared to levels in rat plasma. However, exposure was not dose proportional, as exemplified by a lack of proportional increase in maximum concentration or area under the plasma concentration-time curve with increasing dose. The NOAEL was not established and was considered to be above 1,500 mg/kg/day.

Assessment of oral toxicity and safety of 9-cis-UAB30, a potential chemopreventive agent, in rat and dog studies.

9-cis-UAB30 is a potential chemopreventative agent that has been shown to be effective on many different types of tumors. The safety and toxicity of 9-cis-UAB30 had not been previously established. These studies were conducted to evaluate the potential toxicity and pharmacokinetics in a rodent and a nonrodent species for the purpose of investigational new drug submission. Oral gavage administration of 9-cis-UAB30 at the doses 0, 3, 15, and 100 mg/kg/day to CD® rats for 28 days showed a dose-dependent (although not dose-proportional) increase in plasma drug levels in week 4. The liver was the target organ for toxicity of 9-cis-UAB30. Hepatomegaly along with increases in serum aspartate-aminotransferase and alkaline-phosphatase levels were seen in rats. Moderate hypoalbuminemia and hyperglobulinemia resulted in a decreased albumin/globulin ratio. Histopathology revealed hepatocellular change consistent with hepatic glycogen deposition. Toxicity studies in dogs did not show treatment-related toxicity at doses as high as 100 mg/kg/day (highest dose tested) administered by capsules for 28 days. No effects on the central nervous system (functional observational battery in rats) or cardiovascular function (safety pharmacology study in telemeterized dogs) were seen. The no observed adverse effect level (NOAEL) in the rat studies was 3 mg/kg/day; however, the adverse effects seen in rats receiving 15 mg/kg/day (the least observed adverse effect level) was a slight, but statistically significant, elevation in fibrinogen and decrease in prothrombin time, which may be a sign of some tendency for increased blood coagulation. The NOAEL in the dog study was at least 100 mg/kg/day.

Hyperdense middle cerebral artery sign is an ominous prognostic marker despite optimal workflow.

OBJECTIVES: To evaluate the association between the hyperdense middle cerebral artery sign (HMCAS) and the functional outcome on one hand, and different predictors such as the National Institutes of Health Stroke Scale (NIHSS), infarct size, ASPECTS Score, intracerebral hemorrhage, and mortality on the other hand. MATERIAL AND METHODS: Retrospective analysis of 120 patients with MCA-stroke treated with intravenous thrombolysis. We tested the association between HMCAS and NIHSS, infarct volume, ASPECTS, outcome, level of consciousness, different recorded time intervals, and the day/time of admission. RESULTS: Seventy-four percentage of patients treated with thrombolysis developed cerebral infarction. All patients with HMCAS (n = 39) sustained infarction and only 31% showed favorable outcome compared with 62% and 60%, respectively among patients without HMCAS (P < 0.001 and P = 0.002). There was statistically significant association between functional outcome and HMCAS (P = 0.002), infarct volume, NIHSS, and ASPECTS (P < 0.001). The time to treatment was 12 min shorter in patients who developed infarction (P = 0.037). Independent predictors for outcome were NIHSS and the occurrence of cerebral infarction on computed tomography for the whole study population, and infarct volume for patients who sustained cerebral infarction. CONCLUSIONS: Despite optimal workflow, patients with HMCAS showed poor outcome after intravenous thrombolysis. The results emphasize the urgent need for more effective revascularization therapies and neuroprotective treatment in this subgroup of stroke patients.

A Novel l-Asparaginase with low l-Glutaminase Coactivity Is Highly Efficacious against Both T- and B-cell Acute Lymphoblastic Leukemias In Vivo.

Acute lymphoblastic leukemia (ALL) is the most common type of pediatric cancer, although about 4 of every 10 cases occur in adults. The enzyme drug l-asparaginase serves as a cornerstone of ALL therapy and exploits the asparagine dependency of ALL cells. In addition to hydrolyzing the amino acid l-asparagine, all FDA-approved l-asparaginases also have significant l-glutaminase coactivity. Since several reports suggest that l-glutamine depletion correlates with many of the side effects of these drugs, enzyme variants with reduced l-glutaminase coactivity might be clinically beneficial if their antileukemic activity would be preserved. Here we show that novel low l-glutaminase variants developed on the backbone of the FDA-approved Erwinia chrysanthemi l-asparaginase were highly efficacious against both T- and B-cell ALL, while displaying reduced acute toxicity features. These results support the development of a new generation of safer l-asparaginases without l-glutaminase activity for the treatment of human ALL.Significance: A new l-asparaginase-based therapy is less toxic compared with FDA-approved high l-glutaminase enzymes Cancer Res; 78(6); 1549-60. ©2018 AACR.

Protected graft copolymer-formulated fibroblast growth factors mitigate the lethality of partial body irradiation injury.

We evaluated the mitigating effects of fibroblast growth factor 4 and 7 (FGF4 and FGF7, respectively) in comparison with long acting protected graft copolymer (PGC)-formulated FGF4 and 7 (PF4 and PF7, respectively) administered to C57BL/6J mice a day after exposure to LD50/30 (15.7 Gy) partial body irradiation (PBI) which targeted the gastrointestinal (GI) system. The PGC that we developed increased the bioavailability of FGF4 and FGF7 by 5- and 250-fold compared to without PGC, respectively, and also sustained a 24 hr presence in the blood after a single subcutaneous administration. The dose levels tested for mitigating effects on radiation injury were 3 mg/kg for the PF4 and PF7 and 1.5 mg each for their combination (PF4/7). Amifostine administered prior to PBI was used as a positive control. The PF4, PF7, or PF4/7 mitigated the radiation lethality in mice. The mitigating effect of PF4 and PF7 was similar to the positive control and PF7 was better than other mitigators tested. The plasma citrulline levels and hematology parameters were early markers of recovery and survival. GI permeability function appeared to be a late or full recovery indicator. The villus length and crypt number correlated with plasma citrulline level, indicating that it can act as a surrogate marker for these histology evaluations. The IL-18 concentrations in jejunum as early as day 4 and TPO levels in colon on day 10 following PBI showed statistically significant changes in irradiated versus non-irradiated mice which makes them potential biomarkers of radiation exposure. Other colon and jejunum cytokine levels are potentially useful but require larger numbers of samples than in the present study before their full utility can be realized.

Effects of bacterial and presystemic nitroreductase metabolism of 2-chloro-5-nitro-N-phenylbenzamide on its mutagenicity and bioavailability.

2-Chloro-5-nitro-N-phenylbenzamide (GW9662), a potent irreversible PPAR-γ antagonist, has shown promise as a cancer chemopreventive agent and is undergoing preclinical evaluations. Studies were initiated to assess its bacterial mutagenicity and pharmacokinetic profile in two animal species prior to subchronic oral toxicity evaluations and the results are reported here. GW9662 was mutagenic in both TA98 and TA100 bacterial strains with and without metabolic activation but was negative in the nitroreductase-deficient strains (TA98NR and TA100NR) also with and without metabolic activation, indicating that GW9662 mutagenicity is dependent on nitroreduction. The mutagenic activity was predominantly via a base-substitution mechanism. Following oral dosing in rats and dogs, the parent compound, GW9662, was virtually absent from plasma samples, but there was chromatographic evidence for the presence of metabolites in the plasma as a result of oral dosing. Metabolite identification studies showed that an amine metabolite ACPB (5-amino-2-chloro-N-phenylbenzamide), a product of nitro reduction, was the predominant species exhibiting large and persistent plasma levels. Thus systemic circulation of GW9662 has been attained largely in the form of its reduced metabolite, probably a product of gut bacterial metabolism. GW9662 was detectable in plasma of rats and dogs after intravenous dose albeit at low concentrations. Pharmacokinetic analysis following intravenous dosing in rats showed a rapid clearance and an extensive tissue distribution which could have accounted for the very low plasma levels. Of note, the amine metabolite was absent following intravenous dosing in both rats and dogs, confirming it being a product of presystemic metabolism. The potential utility of GW9662 as a chemopreventive agent, especially as an Estrogen Receptor-α (ER-α) inducer in an otherwise ER-α negative breast tissue, is of great interest. However, the results shown here suggest that additional animal toxicological and bioavailability studies are required to establish a role of GW9662 as a chemopreventive agent.

Assessment of oral toxicity and safety of pentamethylchromanol (PMCol), a potential chemopreventative agent, in rats and dogs.

2,2,5,7,8-Pentamethyl-6-chromanol (PMCol) was administered by gavage in rats for 28 days at dose levels of 0, 100, 500, and 2000mg/kg/day. PMCol administration induced decreases in body weight gains and food consumption, hepatotoxicity (increased TBILI, ALB, ALT, TP; increased relative liver weights; increased T4 and TSH), nephrotoxicity (increased BUN and BUN/CREAT, histopathology lesions), effect on lipid metabolism (increased CHOL), anemia, increase in WBC counts (total and differential), coagulation (FBGN upward arrow and PT downward arrow) and hyperkeratosis of the nonglandular stomach in the 2000mg/kg/day dose group (in one or both sexes). In the 500mg/kg/day dose group, toxicity was seen to a lesser extent. In the 100mg/kg/day dose group, only increased CHOL (females) was observed. To assess the toxicity of PMCol in male dogs it was administered orally by capsule administration for 28 days at dose levels of 0, 50, 200 and 800mg/kg/day (four male dogs/dose group). PMCol treatment at 800mg/kg/day resulted in pronounced toxicity to the male dogs. Target organs of toxicity were liver and thymus. Treatment at 200mg/kg/day resulted in toxicity consistent with slight adverse effect on the liver only. The results of the safety pharmacology study indicate that doses of 0, 50, 200 and 800mg/kg administered orally did not have an effect on the QT interval, blood pressures and body temperatures following dosing over a 24-h recording period. Under the conditions of this study, the no-observed-adverse effect level (NOAEL) for daily oral administration of PMCol by gavage for 28 days to male rats was 100mg/kg/day and 50mg/kg in male dogs. In female rats, the NOAEL was not established due to statistically significant and biologically meaningful increases in CHOL level seen in the 100mg/kg/day dose group. The results of these studies indicated that administration of PMCol at higher dose levels resulted in severe toxicity in dogs and moderate toxicity in rats, however, administration at lower levels is considered to be less likely to result in toxicity following 28 days of exposure. Sex-related differences were seen in rats. Male rats appeared to have greater sensitivity to nephrotoxicity, while female animals had a greater incidence of hepatoxicity and changes in hematological parameters evaluated, especially at a dose of 500mg/kg/day, which correlated to the higher plasma drug levels in female rats. It appeared that dogs were generally more sensitive than rats to oral administration of PMCol. Further examination of the potential toxic effects of PMCol in longer term studies is required prior to understanding the full risks of PMCol administration as a chemopreventative agent.

In vitro assessment of P450 induction potential of novel chemopreventive agents SR13668, 9-cis-UAB30, and pentamethychromanol in primary cultures of human hepatocytes.

Several compounds, including 2,10-dicarbethoxy-6-methoxy-5,7-dihydroindolo[2,3-b]carbazole (SR13668), (2E,4E,6Z,8E)-8-(3',4'-dihydro-1'(2'H)-napthalen-1'-ylidene)-3,7-dimethyl-2,4,6-octatrienoic acid (9-cis-UAB30), and 2,2,5,7,8-pentamethyl-6-chromanol (PMCol), were selected as promising chemopreventive agents and have entered preclinical trials for cancer prevention. The potential for adverse drug events resulting from interactions with other administered drugs, food components, or food additives presents an important question. Among the most important drug-drug interactions (DDI) is the potential of a new chemical entity (NCE) to induce cytochrome P450 enzymes (P450). Drug induction of P450 enzymes can lead to adverse drug interactions by increasing the metabolism of other drugs that are substrates for the induced isoform. Currently, sandwich cultured primary human hepatocytes are the standard for predicting human P450 enzyme induction in vitro as these cells retain the ability to respond to prototypical P450 inducers with the same specificity and potency exhibited in vivo. Therefore, a select panel of inducible P450 target genes (CYP1A2, CYP2B6, and CYP3A4) and their induction activity (measured by LC-MS/MS of respective marker substrate metabolites) were monitored in cultured hepatocytes following treatment with SR13668, 9-cis-UAB30, or PMCol to predict clinically significant drug-induced expression. The concentration ranges of the NCE used were selected to maximize the clinical relevance of these results. All responses were evaluated according to major prototypical P450 inducers (i.e., 3-methylcholanthrene, 3-MC; phenobarbital, PB; rifampicin, RIF) and increases > or = 40% of the respective positive control(s) were considered an indication of demonstrable induction. Herein, we report that there is low potential for DDI with SR13668 and PMCol due to enzyme induction of CYP1A2, CYP2B6, and CYP3A4 expression at the concentrations examined. Similarly, the study results suggested that 9-cis-UAB30 has low potential to induce CYP1A2 and CYP3A4 expression at the concentrations examined. However, 9-cis-UAB30 was shown to significantly induce CYP2B6 enzyme activity at 10 microM suggesting the potential for DDI as a result.

The value of contrast administration in the MRI evaluation of scoliosis in the pediatric population.

The aim of this study was to analyze the added utility of contrast administration for spine MRI in children with scoliosis. A retrospective review of 663 consecutive contrast-enhanced spine MRI performed in 319 patients as part of the work up of scoliosis in children 2-18 years with clinically suspected or known scoliosis over a seven year period. Those patients with known tumors (13 patients) being evaluated for scoliosis were excluded from the study. In 306 patients with scoliosis and no history of tumor pathologic contrast enhancement was seen in seven (2%) patients. Lack of enhancement helped to characterize benign lesions in 31 (10%) of the patients. Although MRI is often recommended to exclude intraspinal pathology in pediatric patients with scoliosis, the need for contrast enhanced imaging is very limited and contrast medium should not be administered unless questionable pathology is detected on noncontrast MR spine imaging.

Radiation Dose Optimization in CT Planning of Corrective Scoliosis Surgery. A Phantom Study.

The aim of the study was to explore the possibility of obtaining a helical CT scan of a long segment of vertebral column, optimally reduce the radiation dose, compare the radiation dose of the low dose helical CT with that of some of the CT protocols used in clinical practice and finally assess the impact of such a dose reduction on the image quality. A chest phantom was examined with a 16-slice CT scanner. Six scans were performed with different radiation doses. The lowest radiation dose which had no impact on image quality with regard to the information required for surgical planning of patients with scoliosis, was 20 times lower than that of routinely used protocol for CT examination of the spine in children (0.38 mSv vs 7.76 mSv). Patients with scoliosis planned for corrective spinal surgery can be examined with low dose helical CT scan. The dose reduction systems (DRS) available in modern CT scanners contribute to dose reduction and should be used.

Perfusion Weighted MR Imaging may Differentiate Primary CNS Lymphoma from other Homogeneously Enhancing Brain Tumors.

Primary central nervous system lymphoma (PCNSL), glioblastoma multiforme (GBM) and metastases may be difficult to differentiate based on conventional imaging alone. The aim of this study was to investigate the value of perfusion weighted imaging (PWI) in differentiating homogeneously enhancing PCNSL from homogeneously enhancing GBM and metastases. Seven consecutive patients presenting with homogeneously enhancing intraaxial tumors on MRI were retrospectively analyzed. All seven patients (three immunocompetent patients with PCNSL, three with GBM, and one with cerebral metastases) were examined with identical MR-sequences including PWI. The relative regional Cerebral Blood Volume (rrCBV) and the rrCBV ratio (rrCBVratio) were calculated. In lymphomas rrCBVratio was 0.93 ± 0.42 (mean ± SD) compared with 7.93 ± 1.44 in GBM and metastases. All lymphomas had rrCBVratio < 1.43 while all GBM and metastases had rrCBVratio > 1.43 (Fischer exact test; p < 0.001). PWI may be a valuable method in differentiating homogenously enhancing PCNSL from GBM and metastases.

MRI findings in spinal MRI of 306 children with scoliosis.

The aim of this study was to analyze the MRI findings and assess the prevalence of different associated structural abnormalities in children with scoliosis and to determine if the age of onset is a possible indicator of intraspinal pathology. This is a retrospective analysis of 663 consecutive MR examinations (319 patients). Thirteen patients with known intraspinal tumors were excluded and a total of 306 patients aged 2-18 years with scoliosis were subjected for analysis. The scoliosis was regarded as idiopathic in 62% of patients. Among the remaining 38% the most commonly seen abnormality was syrinx and Chiari malformations. There was no statistically significant difference in the occurrence of syrinx only or syrinx associated with Chiari I malformation in patients younger than ten years and those older than ten years. MRI examination is an essential part of the work up of scoliosis in the pediatric population especially before any corrective surgery. This study and a review of the current literature suggest there is no clinical marker that would definitely serve as an indicator of the presence of intraspinal pathology in these patients.