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Results of neuroimaging datasets aggregated from multiple sites may be biased by site-specific profiles in participants' demographic and clinical characteristics, as well as MRI acquisition protocols and scanning platforms. We compared the impact of four different harmonization methods on results obtained from analyses of cortical thickness data: (1) linear mixed-effects model (LME) that models site-specific random intercepts (LMEINT), (2) LME that models both site-specific random intercepts and age-related random slopes (LMEINT+SLP), (3) ComBat, and (4) ComBat with a generalized additive model (ComBat-GAM). Our test case for comparing harmonization methods was cortical thickness data aggregated from 29 sites, which included 1,340 cases with posttraumatic stress disorder (PTSD) (6.2-81.8 years old) and 2,057 trauma-exposed controls without PTSD (6.3-85.2 years old). We found that, compared to the other data harmonization methods, data processed with ComBat-GAM was more sensitive to the detection of significant case-control differences (Χ2(3) = 63.704, p < 0.001) as well as case-control differences in age-related cortical thinning (Χ2(3) = 12.082, p = 0.007). Both ComBat and ComBat-GAM outperformed LME methods in detecting sex differences (Χ2(3) = 9.114, p = 0.028) in regional cortical thickness. ComBat-GAM also led to stronger estimates of age-related declines in cortical thickness (corrected p-values < 0.001), stronger estimates of case-related cortical thickness reduction (corrected p-values < 0.001), weaker estimates of age-related declines in cortical thickness in cases than controls (corrected p-values < 0.001), stronger estimates of cortical thickness reduction in females than males (corrected p-values < 0.001), and stronger estimates of cortical thickness reduction in females relative to males in cases than controls (corrected p-values < 0.001). Our results support the use of ComBat-GAM to minimize confounds and increase statistical power when harmonizing data with non-linear effects, and the use of either ComBat or ComBat-GAM for harmonizing data with linear effects.

Studies of posttraumatic stress disorder (PTSD) report volume abnormalities in multiple regions of the cerebral cortex. However, findings for many regions, particularly regions outside commonly studied emotion-related prefrontal, insular, and limbic regions, are inconsistent and tentative. Also, few studies address the possibility that PTSD abnormalities may be confounded by comorbid depression. A mega-analysis investigating all cortical regions in a large sample of PTSD and control subjects can potentially provide new insight into these issues. Given this perspective, our group aggregated regional volumes data of 68 cortical regions across both hemispheres from 1379 PTSD patients to 2192 controls without PTSD after data were processed by 32 international laboratories using ENIGMA standardized procedures. We examined whether regional cortical volumes were different in PTSD vs. controls, were associated with posttraumatic stress symptom (PTSS) severity, or were affected by comorbid depression. Volumes of left and right lateral orbitofrontal gyri (LOFG), left superior temporal gyrus, and right insular, lingual and superior parietal gyri were significantly smaller, on average, in PTSD patients than controls (standardized coefficients = -0.111 to -0.068, FDR corrected P values

Three new organotin(iv) carboxylate compounds were synthesized and structurally characterized by elemental analysis and FT-IR and multinuclear NMR (1H, 13C, 119Sn) spectroscopy. Single X-ray crystallography reveals that compound C2 has a monoclinic crystal system with space group P21/c having distorted bipyramidal geometry defined by C3SnO2. The synthesized compounds were screened for drug-DNA interactions via UV-Vis spectroscopy and cyclic voltammetry showing good activity with high binding constants. Theoretical investigations also support the reactivity of the compounds as depicted from natural bond orbital (NBO) analysis using Gaussian 09. Synthesized compounds were initially evaluated on two cancer (HeLa and MCF-7) cell lines and cytotoxicity to normal cells was evaluated using a non-cancerous (BHK-21) cell line. All the compounds were found to be active, with IC50 values less than that of the standard drug i.e. cisplatin. The cytotoxic effect of the most potent compound C2 was confirmed by LDH cytotoxicity assay and fluorescence imaging after PI staining. Apoptotic features in compound C2 treated cancer cells were visualized after DAPI staining while regulation of apoptosis was observed by reactive oxygen species generation, binding of C2 with DNA, a change in mitochondrial membrane potential and expression of activated caspase-9 and caspase-3 in cancer cells. Results are indicative of activation of the intrinsic pathway of apoptosis in C2 treated cancer cells.

PurposeMost myeloablative regimens before stem cell transplant involved total body irradiation (TBI). Pulmonary complications from TBI contribute to treatment-related mortality and toxicity. We report the rate of acute respiratory complications after TBI at our institution. In an exploratory analysis, we investigated differences in dosimetry between patients who did and did not experience respiratory complications.Methods and materialsIn this single institution retrospective study, 49 patients received TBI from 2016 to 2018 and had dosimetry data available for analysis. Patients were prescribed 1200 cGy to be delivered over 6 fractions. Lung doses were limited using custom lung blocks. Clinical lung complications (eg, coughing and shortness of breath) were reviewed for the hospitalization period during transplant, at 4 months after transplant, and at 1 year after transplant. Supplemental oxygen use during the hospitalization period was also reported. Median anterior-posterior diameter at the umbilicus, body mass index, and lung doses were compared between patients with and without respiratory complications using a Mann-Whitney U test.ResultsDuring the hospitalization period, 14% (n = 7) of patients used supplemental oxygen administered by nasal canula and 16% (n = 8) experienced respiratory symptoms. At the 4-month follow-up, 16% (n = 8) of patients had documented respiratory symptoms. Respiratory symptoms were grade 1 to 2 except for one grade 3 attributed to infection during the hospitalization period and another grade 3 due to infection during the 4-month follow-up. At 1-year post-TBI, 4% (n = 2) of patients reported grade 1 to 2 chronic cough. Patients with respiratory complications at the 4-month follow-up had a larger umbilical anterior-posterior diameter (31.5 cm vs 26.5 cm, P = .01) and body mass index (34.5 kg/m2 vs 29.7 kg/m2, P = .02) than patients without respiratory complication. Respiratory complications were not associated with higher lung doses.ConclusionsThere was no respiratory-related mortality using the individualized planning technique described here. Acute and chronic respiratory complications were minor, with the most significant intervention requiring antibiotics for respiratory infection.

Traumatic brain injury can cause extensive damage to the white matter (WM) of the brain. These disruptions can be especially damaging in children, whose brains are still maturing. Diffusion magnetic resonance imaging (dMRI) is the most commonly used method to assess WM organization, but it has limited resolution to differentiate causes of WM disruption. Magnetic resonance spectroscopy (MRS) yields spectra showing the levels of neurometabolites that can indicate neuronal/axonal health, inflammation, membrane proliferation/turnover, and other cellular processes that are on-going post-injury. Previous analyses on this dataset revealed a significant division within the msTBI patient group, based on interhemispheric transfer time (IHTT); one subgroup of patients (TBI-normal) showed evidence of recovery over time, while the other showed continuing degeneration (TBI-slow). We combined dMRI with MRS to better understand WM disruptions in children with moderate-severe traumatic brain injury (msTBI). Tracts with poorer WM organization, as shown by lower FA and higher MD and RD, also showed lower N-acetylaspartate (NAA), a marker of neuronal and axonal health and myelination. We did not find lower NAA in tracts with normal WM organization. Choline, a marker of inflammation, membrane turnover, or gliosis, did not show such associations. We further show that multi-modal imaging can improve outcome prediction over a single modality, as well as over earlier cognitive function measures. Our results suggest that demyelination plays an important role in WM disruption post-injury in a subgroup of msTBI children and indicate the utility of multi-modal imaging.

ObjectiveTo examine longitudinal trajectories of white matter organization in pediatric moderate/severe traumatic brain injury (msTBI) over a 12-month period.MethodsWe studied 21 children (16 M/5 F) with msTBI, assessed 2-5 months postinjury and again 13-19 months postinjury, as well as 20 well-matched healthy control children. We assessed corpus callosum function through interhemispheric transfer time (IHTT), measured using event-related potentials, and related this to diffusion-weighted MRI measures of white matter (WM) microstructure. At the first time point, half of the patients with TBI had significantly slower IHTT (TBI-slow-IHTT, n = 11) and half were in the normal range (TBI-normal-IHTT, n = 10).ResultsThe TBI-normal-IHTT group did not differ significantly from healthy controls, either in WM organization in the chronic phase or in the longitudinal trajectory of WM organization between the 2 evaluations. In contrast, the WM organization of the TBI-slow-IHTT group was significantly lower than in healthy controls across a large portion of the WM. Longitudinal analyses showed that the TBI-slow-IHTT group experienced a progressive decline between the 2 evaluations in WM organization throughout the brain.ConclusionsWe present preliminary evidence suggesting a potential biomarker that identifies a subset of patients with impaired callosal organization in the first months postinjury who subsequently experience widespread continuing and progressive degeneration in the first year postinjury.

The role of the cerebrovascular network and its acute response to TBI is poorly defined and emerging evidence suggests that cerebrovascular reactivity is altered. We explored how cortical vessels are physically altered following TBI using a newly developed technique, vessel painting. We tested our hypothesis that a focal moderate TBI results in global decrements to structural aspects of the vasculature. Rats (naïve, sham-operated, TBI) underwent a moderate controlled cortical impact. Animals underwent vessel painting perfusion to label the entire cortex at 1 day post TBI followed by whole brain axial and coronal images using a wide-field fluorescence microscope. Cortical vessel network characteristics were analyzed for classical angiographic features (junctions, lengths) wherein we observed significant global (both hemispheres) reductions in vessel junctions and vessel lengths of 33% and 22%, respectively. Biological complexity can be quantified using fractal geometric features where we observed that fractal measures were also reduced significantly by 33%, 16% and 13% for kurtosis, peak value frequency and skewness, respectively. Acutely after TBI there is a reduction in vascular network and vascular complexity that are exacerbated at the lesion site and provide structural evidence for the bilateral hemodynamic alterations that have been reported in patients after TBI.

Traumatic brain injury (TBI) is a significant public health concern, and can be especially disruptive in children, derailing on-going neuronal maturation in periods critical for cognitive development. There is considerable heterogeneity in post-injury outcomes, only partially explained by injury severity. Understanding the time course of recovery, and what factors may delay or promote recovery, will aid clinicians in decision-making and provide avenues for future mechanism-based therapeutics. We examined regional changes in brain volume in a pediatric/adolescent moderate-severe TBI (msTBI) cohort, assessed at two time points. Children were first assessed 2-5 months post-injury, and again 12 months later. We used tensor-based morphometry (TBM) to localize longitudinal volume expansion and reduction. We studied 21 msTBI patients (5 F, 8-18 years old) and 26 well-matched healthy control children, also assessed twice over the same interval. In a prior paper, we identified a subgroup of msTBI patients, based on interhemispheric transfer time (IHTT), with significant structural disruption of the white matter (WM) at 2-5 months post injury. We investigated how this subgroup (TBI-slow, N = 11) differed in longitudinal regional volume changes from msTBI patients (TBI-normal, N = 10) with normal WM structure and function. The TBI-slow group had longitudinal decreases in brain volume in several WM clusters, including the corpus callosum and hypothalamus, while the TBI-normal group showed increased volume in WM areas. Our results show prolonged atrophy of the WM over the first 18 months post-injury in the TBI-slow group. The TBI-normal group shows a different pattern that could indicate a return to a healthy trajectory.

Traumatic brain injury (TBI) is the leading cause of death and disability in children, and can lead to long lasting functional impairment. Many factors influence outcome, but imaging studies examining effects of individual variables are limited by sample size. Roughly 20-40% of hospitalized TBI patients experience seizures, but not all of these patients go on to develop a recurrent seizure disorder. Here we examined differences in structural network connectivity in pediatric patients who had sustained a moderate-severe TBI (msTBI). We compared those who experienced early post-traumatic seizures to those who did not; we found network differences months after seizure activity stopped. We also examined correlations between network measures and a common measure of injury severity, the Glasgow Coma Scale (GCS). The global GCS score did not have a detectable relationship to brain integrity, but sub-scores of the GCS (eyes, motor, verbal) were more closely related to imaging measures.

Memory and related cognitive functions are progressively impaired in a subgroup of individuals experiencing childhood adversity and stress. However, it is not possible to identify vulnerable individuals early, a crucial step for intervention. In this study, high-resolution magnetic resonance imaging (MRI) and intra-hippocampal diffusion tensor imaging (DTI) were employed to examine for structural signatures of cognitive adolescent vulnerabilities in a rodent model of early-life adversity. These methods were complemented by neuroanatomical and functional assessments of hippocampal network integrity during adolescence, adulthood and middle-age. The high-resolution MRI identified selective loss of dorsal hippocampal volume, and intra-hippocampal DTI uncovered disruption of dendritic structure, consistent with disrupted local connectivity, already during late adolescence in adversity-experiencing rats. Memory deteriorated over time, and stunting of hippocampal dendritic trees was apparent on neuroanatomical analyses. Thus, disrupted hippocampal neuronal structure and connectivity, associated with cognitive impairments, are detectable via non-invasive imaging modalities in rats experiencing early-life adversity. These high-resolution imaging approaches may constitute promising tools for prediction and assessment of at-risk individuals in the clinic. © 2016 Wiley Periodicals, Inc.

Traumatic brain injury (TBI) can disrupt the white matter (WM) integrity in the brain, leading to functional and cognitive disruptions that may persist for years. There is considerable heterogeneity within the patient group, which complicates group analyses. Here we present improvements to a tract identification workflow, automated multi-atlas tract extraction (autoMATE), evaluating the effects of improved registration. Use of study-specific template improved group classification accuracy over the standard workflow. The addition of a multi-modal registration that includes information from diffusion weighted imaging (DWI), T1-weighted, and Fluid-Attenuated Inversion Recovery (FLAIR) further improved classification accuracy. We also examined whether particular tracts contribute more to group classification than others. Parts of the corpus callosum contributed most, and there were unexpected asymmetries between bilateral tracts.

Epilepsy is a common neurological disorder with many causes. For temporal lobe epilepsy, antecedent insults are typically found. These risk factors include trauma or history of long fever-associated seizures (febrile status epilepticus) in childhood. Whereas the mechanisms by which such insults promote temporal lobe epilepsy are unknown, an extensive body of work has implicated inflammation and inflammatory mediators in both human and animal models of the disorder. However, direct evidence for an epileptogenic role for inflammation is lacking. Here we capitalized on a model where only a subgroup of insult-experiencing rodents develops epilepsy. We reasoned that if inflammation was important for generating epilepsy, then early inflammation should be more prominent in individuals destined to become epileptic compared with those that will not become epileptic. In addition, the molecular and temporal profile of inflammatory mediators would provide insights into which inflammatory pathways might be involved in the disease process. We examined inflammatory profiles in hippocampus and amygdala of individual rats and correlated them with a concurrent noninvasive, amygdalar magnetic resonance imaging epilepsy-predictive marker. We found significant individual variability in the expression of several important inflammatory mediators, but not in others. Of interest, a higher expression of a subset of hippocampal and amygdalar inflammatory markers within the first few hours following an insult correlated with the epilepsy-predictive signal. These findings suggest that some components of the inflammatory gene network might contribute to the process by which insults promote the development of temporal lobe epilepsy.

The present study is aimed at designing bilayer-floating tablets to improve the drug concentration in the stomach for enhanced therapeutic efficacy. The tablets are comprised of an upper layer of levofloxacin (466.5 mg) and a lower layer of famotidine (133.5 mg). Five formulations (F1-F5) were developed by using hydroxypropyl methylcellulose grades (K4M, K15M, and K100M) along with Carbopol 934. In the case of the effervescent system (F1-F3), sodium bicarbonate was added to impart buoyancy to the tablets; while in the case of noneffervescent formulations (F4 & F5), guar gum and xanthan gum were incorporated to induce flotation and swelling and retard the release of a drug. The precompression characteristics of tablets depict the suitability of all formulation powder for direct compression. The ATR-FTIR analyses have shown that the components of both effervescent and noneffervescent tablets are compatible with each other. The total weight of each tablet was 600 mg, with a weight variation of about ≤10 mg. Both the layers were smooth and flat with a thickness ranging from 3.16 ± 0.04 to 3.54 ± 0.01 mm. The diameters of prepared floating tablets were about 15 mm, optimum for oral administration. After adjusting the tablet's hardness to 6-7 kg/cm2, its friability was found to be <0.35 percent. The mean drug content of the formulations was above 90%. The floating lag time of all formulations (F2-F5) was below 25 seconds, except F1 which took almost 50 seconds to start floating on the surface of gastric content due to its higher density. The total floating time of effervescent (F1-F3) and noneffervescent formulations was in the range of 15-25 hours, thereby providing sufficient time to complete drug release and absorption in the gastric area. The total floating time of noneffervescent formulations was higher (p ≤ 0.05) than effervescent formulations due to efficient wettability and swelling characteristics. The release of drugs from both layers of noneffervescent tablets was significantly controlled when compared to the effervescent system, and an anomalous non-Fickian diffusion was found for the drug release. The stability study of the optimized formulation proved the integrity and stability of the developed formulation. Thus, developed formulations are deemed suitable for controlled codelivery of active pharmaceutical ingredients for the effective treatment of H. pylori. [ABSTRACT FROM AUTHOR]