Health-related quality of life after prophylactic cranial irradiation for stage III non-small cell lung cancer patients:Results from the NVALT-11/DLCRG-02 phase III study

BACKGROUND AND PURPOSE: The NVALT-11/DLCRG-02 phase III trial (clinicaltrials.gov identifier: NCT01282437) showed that, after standard curative intent treatment, prophylactic cranial irradiation (PCI) decreased the incidence of symptomatic brain metastases (BM) in stage III non-small cell lung cancer (NSCLC) patients compared to observation. In this study we assessed the impact of PCI on health-related quality of life (HRQoL). In addition, an exploratory analysis was performed to assess the impact of neurocognitive symptoms and symptomatic BM on HRQoL. MATERIALS AND METHODS: Stage III NSCLC patients were randomized between PCI and observation. HRQoL was measured using the EuroQol 5D (EQ-5D-3L), EORTC QLQ-C30 and QLQ-BN20 instruments at completion of standard curative intent treatment and 4 weeks, 3, 6, 12, 24 and 36 months thereafter. Generalized linear mixed effects (GLM) models were used to assess the impact of PCI compared to observation over time on three HRQoL metrics: the EORTC QLQ-C30 global health status and the EQ-5D-3L utility and visual analogue scale (EQ VAS) scores. RESULTS: In total, 86 and 88 patients were included in the PCI and observation arm, with a median follow-up of 48.5 months (95% CI 39-54 months). Baseline mean HRQoL scores were comparable between the PCI and observation arm for the three HRQoL metrics. In the GLM models, none of the HRQoL metrics were clinically relevant or statistically significantly different between the PCI and the observation arm (p-values ranged between 0.641 and 0.914). CONCLUSION: No statistically significant nor a clinically relevant impact of PCI on HRQoL was observed

Foldamers of β-peptides : conformational preference of peptides formed by rigid building blocks : The first MI-IR spectra of a triamide nanosystem

To determine local chirality driven conformational preferences of small aminocyclobutane-1-carboxylic acid derivatives, X-(ACBA) n -Y, their matrix-isolation IR spectra were recorded and analyzed. For the very first time model systems of this kind were deposited in a frozen (~10 K) noble gas matrix to reduce line width and thus, the recorded sharp vibrational lines were analyzed in details. For cis-(S,R)-1 monomer two “zigzag” conformers composed of either a six or an eight-membered H-bonded pseudo ring was identified. For trans-(S,S)-2 stereoisomer a zigzag of an eight-membered pseudo ring and a helical building unit were determined. Both findings are fully consistent with our computational results, even though the relative conformational ratios were found to vary with respect to measurements. For the dimers (S,R,S,S)-3 and (S,S,S,R)-4 as many as four different cis,trans and three different trans,cis conformers were localized in their matrix-isolation IR (MI-IR) spectra. These foldamers not only agree with the previous computational and NMR results, but also unambiguously show for the first time the presence of a structure made of a cis,trans conformer which links a “zigzag” and a helical foldamer via a bifurcated H-bond. The present work underlines the importance of MI-IR spectroscopy, applied for the first time for triamides to analyze the conformational pool of small biomolecules. We have shown that the local chirality of a β-amino acid can fully control its backbone folding preferences. Unlike proteogenic α-peptides, β- and especially (ACBA) n type oligopeptides could thus be used to rationally design and influence foldamer’s structural preferences

Experience of road and other trauma by the opiate dependent patient: a survey report

Background: Trauma plays an important role in the experience of many patients with substance use disorder, but is relatively under-studied particularly in Australia. The present survey examined the lifetime prevalence of various forms of trauma including driving careers in the context of relevant medical conditions. Methods: A survey was undertaken in a family medicine practice with a special interest in addiction medicine in Brisbane, Australia. Results: Of 350 patients surveyed, 220 were substance dependent, and 130 were general medical patients. Addicted patients were younger (mean ± S.D. 33.72 ± 8.14 vs. 44.24 ± 16.91 years, P < 0.0001) and had shorter driving histories (15.96 ± 8.50 vs. 25.54 ± 15.03 years, P < 0.0001). They had less driving related medical problems (vision, spectacle use, diabetes) but more fractures, surgical operations, dental trauma and assaults. Addicted patients also had significantly worse driving histories on most parameters measured including percent with driving suspensions (O.R. = 7.70, C.I. 4.38-13.63), duration of suspensions (1.71 ± 3.60 vs. 0.11 ± 0.31 years, P < 0.0001), number of motor vehicle collisions (2.00 ± 3.30 vs. 1.10 ± 1.32, P = 0.01), numbers of cars repaired (1.73 ± 3.59 vs. 1.08 ± 1.60, P = 0.042), rear end collisions (O.R. = 1.90, CI 1.13-3.25), running away after car crashes (O.R. = 26.37, CI 4.31-1077.48), other people hospitalized (O.R. = 2.00, C.I. 0.93-4.37, P = 0.037) and people killed (17 vs. 0 P = 0.0005). Upon multivariate analysis group membership was shown to be a significant determinant of both cars repaired and cars hit when controlled for length of driving history. Hence use of all types of drugs (O.R. = 10.07, C.I. 8.80-14.72) was more common in addicted patients as were general (O.R. = 3.64, C.I. 2.99-4.80) and road (O.R.= 2.73, C.I. 2.36-3.15) trauma. Conclusion: This study shows that despite shorter driving histories, addicted patients have worse driving careers and general trauma experience than the comparison group which is not explained by associated medical conditions. Trauma is relevant to addiction management at both the patient and policy levels. Substance dependence policies which focus largely on prevention of virus transmission likely have too narrow a public health focus, and tend to engender an unrealistically simplistic and trivialized view of the addiction syndrome. Reduction of drug driving and drug related trauma likely require policies which reduce drug use per se, and are not limited to harm reduction measures alone

Dedifferentiation of Human Primary Thyrocytes into Multilineage Progenitor Cells without Gene Introduction

While identification and isolation of adult stem cells have potentially important implications, recent reports regarding dedifferentiation/reprogramming from differentiated cells have provided another clue to gain insight into source of tissue stem/progenitor cells. In this study, we developed a novel culture system to obtain dedifferentiated progenitor cells from normal human thyroid tissues. After enzymatic digestion, primary thyrocytes, expressing thyroglobulin, vimentin and cytokeratin-18, were cultured in a serum-free medium called SAGM. Although the vast majority of cells died, a small proportion (∼0.5%) survived and proliferated. During initial cell expansion, thyroglobulin/cytokeratin-18 expression was gradually declined in the proliferating cells. Moreover, sorted cells expressing thyroid peroxidase gave rise to proliferating clones in SAGM. These data suggest that those cells are derived from thyroid follicular cells or at least thyroid-committed cells. The SAGM-grown cells did not express any thyroid-specific genes. However, after four-week incubation with FBS and TSH, cytokeratin-18, thyroglobulin, TSH receptor, PAX8 and TTF1 expressions re-emerged. Moreover, surprisingly, the cells were capable of differentiating into neuronal or adipogenic lineage depending on differentiating conditions. In summary, we have developed a novel system to generate multilineage progenitor cells from normal human thyroid tissues. This seems to be achieved by dedifferentiation of thyroid follicular cells. The presently described culture system may be useful for regenerative medicine, but the primary importance will be as a tool to elucidate the mechanisms of thyroid diseases

Internal representations of smell in the Drosophila brain

Recent advances in sensory neuroscience using Drosophila olfaction as a model system have revealed brain maps representing the external world. Once we understand how the brain's built-in capability generates the internal olfactory maps, we can then elaborate how the brain computes and makes decision to elicit complex behaviors. Here, we review current progress in mapping Drosophila olfactory circuits and discuss their relationships with innate olfactory behaviors

Modulation of the endocannabinoids N-Arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) on Executive Functions in Humans

Animal studies point to an implication of the endocannabinoid system on executive functions. In humans, several studies have suggested an association between acute or chronic use of exogenous cannabinoids (Δ9-tetrahydrocannabinol) and executive impairments. However, to date, no published reports establish the relationship between endocannabinoids, as biomarkers of the cannabinoid neurotransmission system, and executive functioning in humans. The aim of the present study was to explore the association between circulating levels of plasma endocannabinoids N-arachidonoylethanolamine (AEA) and 2-Arachidonoylglycerol (2-AG) and executive functions (decision making, response inhibition and cognitive flexibility) in healthy subjects. One hundred and fifty seven subjects were included and assessed with the Wisconsin Card Sorting Test; Stroop Color and Word Test; and Iowa Gambling Task. All participants were female, aged between 18 and 60 years and spoke Spanish as their first language. Results showed a negative correlation between 2-AG and cognitive flexibility performance (r = −.37; p<.05). A positive correlation was found between AEA concentrations and both cognitive flexibility (r = .59; p<.05) and decision making performance (r = .23; P<.05). There was no significant correlation between either 2-AG (r = −.17) or AEA (r = −.08) concentrations and inhibition response. These results show, in humans, a relevant modulation of the endocannabinoid system on prefrontal-dependent cognitive functioning. The present study might have significant implications for the underlying executive alterations described in some psychiatric disorders currently associated with endocannabinoids deregulation (namely drug abuse/dependence, depression, obesity and eating disorders). Understanding the neurobiology of their dysexecutive profile might certainly contribute to the development of new treatments and pharmacological approaches

Candidate Glutamatergic Neurons in the Visual System of Drosophila

The visual system of Drosophila contains approximately 60,000 neurons that are organized in parallel, retinotopically arranged columns. A large number of these neurons have been characterized in great anatomical detail. However, studies providing direct evidence for synaptic signaling and the neurotransmitter used by individual neurons are relatively sparse. Here we present a first layout of neurons in the Drosophila visual system that likely release glutamate as their major neurotransmitter. We identified 33 different types of neurons of the lamina, medulla, lobula and lobula plate. Based on the previous Golgi-staining analysis, the identified neurons are further classified into 16 major subgroups representing lamina monopolar (L), transmedullary (Tm), transmedullary Y (TmY), Y, medulla intrinsic (Mi, Mt, Pm, Dm, Mi Am), bushy T (T), translobula plate (Tlp), lobula intrinsic (Lcn, Lt, Li), lobula plate tangential (LPTCs) and lobula plate intrinsic (LPi) cell types. In addition, we found 11 cell types that were not described by the previous Golgi analysis. This classification of candidate glutamatergic neurons fosters the future neurogenetic dissection of information processing in circuits of the fly visual system

On the Zwitterionic Nature of Gas-Phase Peptides and Protein Ions

Determining the total number of charged residues corresponding to a given value of net charge for peptides and proteins in gas phase is crucial for the interpretation of mass-spectrometry data, yet it is far from being understood. Here we show that a novel computational protocol based on force field and massive density functional calculations is able to reproduce the experimental facets of well investigated systems, such as angiotensin II, bradykinin, and tryptophan-cage. The protocol takes into account all of the possible protomers compatible with a given charge state. Our calculations predict that the low charge states are zwitterions, because the stabilization due to intramolecular hydrogen bonding and salt-bridges can compensate for the thermodynamic penalty deriving from deprotonation of acid residues. In contrast, high charge states may or may not be zwitterions because internal solvation might not compensate for the energy cost of charge separation

Decision making as a predictor of first ecstasy use: a prospective study

Ecstasy (+/- 3,4-methylenedioxymethamphetamine) is a widely used recreational drug that may damage the serotonin system and may entail neuropsychological dysfunctions. Few studies investigated predictors for ecstasy use. Self-reported impulsivity does not predict the initiation of ecstasy use; the question is if neuropsychological indicators of impulsivity can predict first ecstasy use. This study tested the hypothesis that a neuropsychological indicator of impulsivity predicts initiation of ecstasy use. Decision-making strategy and decision-making reaction times were examined with the Iowa Gambling Task in 149 ecstasy-naive subjects. The performance of 59 subjects who initiated ecstasy use during a mean follow-up period of 18 months (range, 11-26) was compared with the performance of 90 subjects that remained ecstasy-naive. Significant differences in decision-making strategy between female future ecstasy users and female persistent ecstasy-naive subjects were found. In addition, the gap between decision-making reaction time after advantageous choices and reaction time after disadvantageous choices was smaller in future ecstasy users than in persistent ecstasy-naives. Decision-making strategy on a gambling task was predictive for future use of ecstasy in female subjects. Differences in decision-making time between future ecstasy users and persistent ecstasy-naives may point to lower punishment sensitivity or higher impulsivity in future ecstasy users. Because differences were small, the clinical relevance is questionabl

The human keratins: biology and pathology

The keratins are the typical intermediate filament proteins of epithelia, showing an outstanding degree of molecular diversity. Heteropolymeric filaments are formed by pairing of type I and type II molecules. In humans 54 functional keratin genes exist. They are expressed in highly specific patterns related to the epithelial type and stage of cellular differentiation. About half of all keratins—including numerous keratins characterized only recently—are restricted to the various compartments of hair follicles. As part of the epithelial cytoskeleton, keratins are important for the mechanical stability and integrity of epithelial cells and tissues. Moreover, some keratins also have regulatory functions and are involved in intracellular signaling pathways, e.g. protection from stress, wound healing, and apoptosis. Applying the new consensus nomenclature, this article summarizes, for all human keratins, their cell type and tissue distribution and their functional significance in relation to transgenic mouse models and human hereditary keratin diseases. Furthermore, since keratins also exhibit characteristic expression patterns in human tumors, several of them (notably K5, K7, K8/K18, K19, and K20) have great importance in immunohistochemical tumor diagnosis of carcinomas, in particular of unclear metastases and in precise classification and subtyping. Future research might open further fields of clinical application for this remarkable protein family