Multifaceted impairments in impulsivity and brain structural abnormalities in opioid dependence and abstinence

This study was part funded by an unrestricted educational grant provided by Schering-Plough, a grant by an anonymous trust and the Scottish Mental Health Research Network.Background: Chronic opioid exposure, as a treatment for a variety of disorders or as drug of misuse, is common worldwide, but behavioural and brain abnormalities remain under-investigated. Only a small percentage of patients who receive methadone maintenance treatment (MMT) for previous heroin misuse eventually achieve abstinence and studies on such patients are rare. Method: The Cambridge Neuropsychological Test Automated Battery and T1 weighted magnetic resonance imaging (MRI) were used to study a cohort of 122 male individuals: a clinically stable opioid-dependent patient group receiving MMT (n = 48), an abstinent previously MMT maintained group (ABS) (n = 24) and healthy controls (n = 50). Results: Stable MMT participants deliberated longer and placed higher bets earlier in the Cambridge Gambling Task (CGT) and showed impaired strategic planning compared with healthy controls. In contrast, ABS participants showed impairment in choosing the least likely outcome, delay aversion and risk adjustment on the CGT, and exhibited non-planning impulsivity compared with controls. MMT patients had widespread grey matter reductions in the orbitomedial prefrontal cortex, caudate, putamen and globus pallidus. In contrast, ABS participants showed midbrain–thalamic grey matter reductions. A higher methadone dose at the time of scanning was associated with a smaller globus pallidus in the MMT group. Conclusions: Our findings support an interpretation of heightened impulsivity in patients receiving MMT. Widespread structural brain abnormalities in the MMT group and reduced brain structural abnormality with abstinence suggest benefit of cessation of methadone intake. We suggest that a longitudinal study is required to determine whether abstinence improves abnormalities, or patients who achieve abstinence have reduced abnormalities before methadone cessation.Publisher PDFPeer reviewe

Chemical exchange saturation transfer MRI shows low cerebral 2-deoxy-D-glucose uptake in a model of Alzheimer's Disease

Glucose is the central nervous system's only energy source. Imaging techniques capable to detect pathological alterations of the brain metabolism are useful in different diagnostic processes. Such techniques are also beneficial for assessing the evaluation efficacy of therapies in pre-clinical and clinical stages of diseases. Chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI) is a possible alternative to positron emission tomography (PET) imaging that has been widely explored in cancer research in humans and animal models. We propose that pathological alterations in brain 2-deoxy-D-glucose (2DG) uptake, typical of neurodegenerative diseases, can be detected with CEST MRI. Transgenic mice overexpressing a mutated form of amyloid precusrsor protein (APP23), a model of Alzheimer's disease, analyzed with CEST MRI showed a clear reduction of 2DG uptake in different brain regions. This was reminiscent of the cerebral condition observed in Alzheimer's patients. The results indicate the feasibility of CEST for analyzing the brain metabolic state, with better image resolution than PET in experimental models

Chronic tobacco smoking and neuropsychological impairments:A systematic review and meta-analysis

The link between neuropsychological impairments and chronic tobacco smoking is not clear and in the current literature there is a lack of robust analyses investigating this association. A systematic review of the literature was conducted in order to identify relevant longitudinal and cross-sectional studies conducted from 1946 to 2017. A meta-analysis was performed from 24 studies testing the performance of chronic tobacco smokers compared with non-smokers on neuropsychological tests related to eight different neuropsychological domains. The results revealed a cross-sectional association between neuropsychological impairments and chronic tobacco smoking in cognitive impulsivity, non-planning impulsivity, attention, intelligence, short term memory, long term memory, and cognitive flexibility, with the largest effect size being related to cognitive impulsivity (SDM = 0.881, p <0.005), and the smallest effect size being related to intelligence (SDM = 0.164, p < 0.05) according to Cohen’s benchmark criteria. No association was found between chronic smoking and motor impulsivity (SDM = 0.105, p = 0.248). Future research is needed to investigate further this association by focusing on better methodologies and alternative methods for nicotine administration.PostprintPeer reviewe

Enteric Absorption of Ciprofloxacin During Tube Feeding in the Critically Ill

To determine the pharmacokinetic properties of ciprofloxacin in the critically ill, we studied seven mechanically ventilated patients with pneumonia during entcral feedings. Subjects received ciprofloxacin 750 mg every 12 h via nasogastric tube and serial serum drug concentrations were measured after the first and fourth dose. After the initial dose, the maximum serum concentration ranged from 1.24–3.06 mg/L, and the area under the time curve from 0–12 h ranged from 3.2–19.65 mg.h/L. Similar levels were noted after dose four. Gastrointestinal absorption of ciprofloxacin in tube fed critically ill patients was decreased, but well above MIC values for many pathogenic bacteria

Evaluation of chromosome microarray analysis in a large cohort of females with autism spectrum disorders: A single center Italian study

Autism spectrum disorders (ASD) encompass a heterogeneous group of neurodevelopmental disorders resulting from the complex interaction between genetic and environmental factors. Thanks to the chromosome microarray analysis (CMA) in clinical practice, the accurate identification and characterization of submicroscopic deletions/duplications (copy number variants, CNVs) associated with ASD was made possible. However, the widely acknowledged excess of males on the autism spectrum reflects on a paucity of CMA studies specifically focused on females with ASD (f-ASD). In this framework, we aim to evaluate the frequency of causative CNVs in a single-center cohort of idiopathic f-ASD. Among the 90 f-ASD analyzed, we found 20 patients with one or two potentially pathogenic CNVs, including those previously associated with ASD (located at 16p13.2 16p11.2, 15q11.2, and 22q11.21 regions). An exploratory genotype/phenotype analysis revealed that the f-ASD with causative CNVs had statistically significantly lower restrictive and repetitive behaviors than those without CNVs or with non-causative CNVs. Future work should focus on further understanding of f-ASD genetic underpinnings, taking advantage of next-generation sequencing technologies, with the ultimate goal of contributing to precision medicine in ASD

Structure and mechanics of supporting cells in the guinea pig organ of Corti.

The mechanical properties of the mammalian organ of Corti determine its sensitivity to sound frequency and intensity, and the structure of supporting cells changes progressively with frequency along the cochlea. From the apex (low frequency) to the base (high frequency) of the guinea pig cochlea inner pillar cells decrease in length incrementally from 75-55 µm whilst the number of axial microtubules increases from 1,300-2,100. The respective values for outer pillar cells are 120-65 µm and 1,500-3,000. This correlates with a progressive decrease in the length of the outer hair cells from >100 µm to 20 µm. Deiters'cell bodies vary from 60-50 µm long with relatively little change in microtubule number. Their phalangeal processes reflect the lengths of outer hair cells but their microtubule numbers do not change systematically. Correlations between cell length, microtubule number and cochlear location are poor below 1 kHz. Cell stiffness was estimated from direct mechanical measurements made previously from isolated inner and outer pillar cells. We estimate that between 200 Hz and 20 kHz axial stiffness, bending stiffness and buckling limits increase, respectively,~3, 6 and 4 fold for outer pillar cells, ~2, 3 and 2.5 fold for inner pillar cells and ~7, 20 and 24 fold for the phalangeal processes of Deiters'cells. There was little change in the Deiters'cell bodies for any parameter. Compensating for effective cell length the pillar cells are likely to be considerably stiffer than Deiters'cells with buckling limits 10-40 times greater. These data show a clear relationship between cell mechanics and frequency. However, measurements from single cells alone are insufficient and they must be combined with more accurate details of how the multicellular architecture influences the mechanical properties of the whole organ

Statistical Mechanics of Semiflexible Bundles of Wormlike Polymer Chains

We demonstrate that a semiflexible bundle of wormlike chains exhibits a state-dependent bending stiffness that alters fundamentally its scaling behavior with respect to the standard wormlike chain. We explore the equilibrium conformational and mechanical behavior of wormlike bundles in isolation, in crosslinked networks, and in solution.Comment: 4 pages, 3 figures, final version as publishe

t(15;21) translocations leading to the concurrent downregulation of RUNX1 and its transcription factor partner genes SIN3A and TCF12 in myeloid disorders.

Through a combined approach integrating RNA-Seq, SNP-array, FISH and PCR techniques, we identified two novel t(15;21) translocations leading to the inactivation of RUNX1 and its partners SIN3A and TCF12. One is a complex t(15;21)(q24;q22), with both breakpoints mapped at the nucleotide level, joining RUNX1 to SIN3A and UBL7-AS1 in a patient with myelodysplasia. The other is a recurrent t(15;21)(q21;q22), juxtaposing RUNX1 and TCF12, with an opposite transcriptional orientation, in three myeloid leukemia cases. Since our transcriptome analysis indicated a significant number of differentially expressed genes associated with both translocations, we speculate an important pathogenetic role for these alterations involving RUNX1

Synthesis, antiproliferative activity, and mechanism of action of a series of 2-{[2E]-3-phenylprop-2-enoylamino}benzamides

Several new 2-{[2E]-3-phenylprop-2-enoylamino}benzamides 12a-s and 17t-v were synthesized by stirring in pyridine the (E)-3-(2-R1-3-R2-4-R3-phenyl)acrylic acid chlorides 11c-k and 11t-v with the appropriate anthranilamide derivatives 10a-c or the 5-iodo anthranilic acid 13. Some of synthesized compounds were evaluated for their in vitro antiproliferative activity against the full NCI tumor cell line panel derived from nine clinically isolated cancer types (leukemia, non-small cell lung, colon, CNS, melanoma, ovarian, renal, prostate and breast). COMPARE analysis, effects on tubulin polymerization in cells and with purified tubulin, and effects on cell cycle distribution for 17t, the most active of the series, indicate that these new antiproliferative compounds act as antitubulin agent

Efficacy of acute administration of inhaled argon on traumatic brain injury in mice

BACKGROUND: Whilst there has been progress in supportive treatment for traumatic brain injury (TBI), specific neuroprotective interventions are lacking. Models of ischaemic heart and brain injury show the therapeutic potential of argon gas, but it is still not known whether inhaled argon (iAr) is protective in TBI. We tested the effects of acute administration of iAr on brain oedema, tissue micro-environmental changes, neurological functions, and structural outcome in a mouse model of TBI. METHODS: Anaesthetised adult C57BL/6J mice were subjected to severe TBI by controlled cortical impact. Ten minutes after TBI, the mice were randomised to 24 h treatments with iAr 70%/O2 30% or air (iCtr). Sensorimotor deficits were evaluated up to 6 weeks post-TBI by three independent tests. Cognitive function was evaluated by Barnes maze test at 4 weeks. MRI was done to examine brain oedema at 3 days and white matter damage at 5 weeks. Microglia/macrophages activation and functional commitment were evaluated at 1 week after TBI by immunohistochemistry. RESULTS: iAr significantly accelerated sensorimotor recovery and improved cognitive deficits 1 month after TBI, with less white matter damage in the ipsilateral fimbria and body of the corpus callosum. Early changes underpinning protection included a reduction of pericontusional vasogenic oedema and of the inflammatory response. iAr significantly reduced microglial activation with increases in ramified cells and the M2-like marker YM1. CONCLUSIONS: iAr accelerates recovery of sensorimotor function and improves cognitive and structural outcome 1 month after severe TBI in adult mice. Early effects include a reduction of brain oedema and neuroinflammation in the contused tissue