Utility of the blood for gene expression profiling and biomarker discovery in chronic fatigue syndrome

Chronic fatigue syndrome (CFS) is a debilitating illness lacking consistent anatomic lesions and eluding conventional laboratory diagnosis. Demonstration of the utility of the blood for gene expression profiling and biomarker discovery would have implications into the pathophysiology of CFS. The objective of this study was to determine if gene expression profiles of peripheral blood mononuclear cells (PMBCs) could distinguish between subjects with CFS and healthy controls. Total RNA from PBMCs of five CFS cases and seventeen controls was labeled and hybridized to 1764 genes on filter arrays. Gene intensity values were analyzed by various classification algorithms and nonparametric statistical methods. The classification algorithms grouped the majority of the CFS cases together, and distinguished them from the healthy controls. Eight genes were differentially expressed in both an age-matched case-control analysis and when comparing all CFS cases to all controls. Several of the differentially expressed genes are associated with immunologic functions (e.g., CMRF35 antigen, IL-8, HD protein) and implicate immune dysfunction in the pathophysiology of CFS. These results successfully demonstrate the utility of the blood for gene expression profiling to distinguish subjects with CFS from healthy controls and for identifying genes that could serve as CFS biomarkers.     

Sensory and cognitive mechanisms of change detection in the context of speech

The aim of this study was to dissociate the contributions of memory-based (cognitive) and adaptation-based (sensory) mechanisms underlying deviance detection in the context of natural speech. Twenty healthy right-handed native speakers of English participated in an event-related design scan in which natural speech stimuli, /de:/ (“deh”) and /deI/ (“day”); (/te:/ (“teh”) and /teI/ (“tay”) served as standards and deviants within functional magnetic resonance imaging event-related “oddball” paradigm designed to elicit the mismatch negativity component. Thus, “oddball” blocks could involve either a word deviant (“day”) resulting in a “word advantage” effect, or a non-word deviant (“deh” or “tay”). We utilized an experimental protocol controlling for refractoriness similar to that used previously when deviance detection was studied in the context of tones. Results showed that the cognitive and sensory mechanisms of deviance detection were located in the anterior and posterior auditory cortices, respectively, as was previously found in the context of tones. The cognitive effect, that was most robust for the word deviant, diminished in the “oddball” condition. In addition, the results indicated that the lexical status of the speech stimulus interacts with acoustic factors exerting a top-down modulation of the extent to which novel sounds gain access to the subject’s awareness through memory-based processes. Thus, the more salient the deviant stimulus is the more likely it is to be released from the effects of adaptation exerted by the posterior auditory cortex.     

Nasopharyngeal angiofibroma with cavernous sinus involvement — An unusual presentation

Juvenile nasopharyngeal angiofibrama (JNA) is a benign vascular tumour which is locally aggressive and occasionally extends intracranially. It occurs mainly in adolescent males. We report an interesting case of a targe JNA with intracranial extention encroaching on the cavernous sinus which we treated surgically by the conventional lateral rhinotomy and transpalatal approach.     

Variation in orbitofrontal cortex volume: relation to sex, emotion regulation and affect

Sex differences in brain structure have been examined extensively but are not completely understood, especially in relation to possible functional correlates. Our two aims in this study were to investigate sex differences in brain structure, and to investigate a possible relation between orbitofrontal cortex subregions and affective individual differences. We used tensor-based morphometry to estimate local brain volume from MPRAGE images in 117 healthy right-handed adults (58 female), age 18–40 years. We entered estimates of local brain volume as the dependent variable in a GLM, controlling for age, intelligence and whole-brain volume. Men had larger left planum temporale. Women had larger ventromedial prefrontal cortex (vmPFC), right lateral orbitofrontal (rlOFC), cerebellum, and bilateral basal ganglia and nearby white matter. vmPFC but not rlOFC volume covaried with self-reported emotion regulation strategies (reappraisal, suppression), expressivity of positive emotions (but not of negative), strength of emotional impulses, and cognitive but not somatic anxiety. vmPFC volume statistically mediated sex differences in emotion suppression. The results confirm prior reports of sex differences in orbitofrontal cortex structure, and are the first to show that normal variation in vmPFC volume is systematically related to emotion regulation and affective individual differences.     

Alterations in neural connectivity in preterm children at school age

Converging data suggest recovery from injury in the preterm brain. We used functional magnetic resonance imaging (fMRI) to test the hypothesis that cerebral connectivity involving Wernicke's area and other important cortical language regions would differ between preterm (PT) and term (T) control school age children during performance of an auditory language task. Fifty-four PT children (600–1250 g birth weight) and 24 T controls were evaluated using an fMRI passive language task and neurodevelopmental assessments including: the Wechsler Intelligence Scale for Children — III (WISC-III), the Peabody Individual Achievement Test — Revised (PIAT-R) and the Peabody Picture Vocabulary Test — Revised (PPVT-R) at 8 years of age. Neural activity was assessed for language processing and the data were evaluated for connectivity and correlations to cognitive outcomes. We found that PT subjects scored significantly lower on all components of the WISC-III (p < 0.009), the PIAT-R Reading Comprehension test (p = 0.013), and the PPVT-R (p = 0.001) compared to term subjects. Connectivity analyses revealed significantly stronger neural circuits in PT children between Wernicke's area and the right inferior frontal gyrus (R IFG, Broca's area homologue) and both the left and the right supramarginal gyri (SMG) components of the inferior parietal lobules (p ≤ 0.02 for all). We conclude that PT subjects employ neural systems for auditory language function at school age differently than T controls; these alterations may represent a delay in maturation of neural networks or the engagement of alternate circuits for language processing.     

Increasing the reference populations for the 55 AISNP panel: the need and benefits

Ancestry inference for an individual can only be as good as the reference populations with allele frequency data on the SNPs being used. If the most relevant ancestral population(s) does not have data available for the SNPs studied, then analyses based on DNA evidence may indicate a quite distantly related population, albeit one among the more closely related of the existing reference populations. We have added reference population allele frequencies for 14 additional population samples (with >1100 individuals studied) to the 125 population samples previously published for the Kidd Lab 55 AISNP panel. Allele frequencies are now publicly available for all 55 SNPs in ALFRED and FROG-kb for a total of 139 population samples. This Kidd Lab panel of 55 ancestry informative SNPs has been incorporated in commercial kits by both ThermoFisher Scientific and Illumina for massively parallel sequencing. Researchers employing those kits will find the enhanced set of reference populations useful.

     

Gene expression profile of empirically delineated classes of unexplained chronic fatigue

OBJECTIVES: To identify the underlying gene expression profiles of unexplained chronic fatigue subjects classified into five or six class solutions by principal component (PCA) and latent class analyses (LCA). METHODS: Microarray expression data were available for 15,315 genes and 111 female subjects enrolled from a population-based study on chronic fatigue syndrome. Algorithms were developed to assign gene scores and threshold values that signified the contribution of each gene to discriminate the multiclasses in each LCA solution. Unsupervised dimensionality reduction was first used to remove noise or otherwise uninformative gene combinations, followed by supervised dimensionality reduction to isolate gene combinations that best separate the classes. RESULTS: The authors' gene score and threshold algorithms identified 32 and 26 genes capable of discriminating the five and six multiclass solutions, respectively. Pair-wise comparisons suggested that some genes (zinc finger protein 350 [ZNF350], solute carrier family 1, member 6 [SLC1A6], F-box protein 7 [FBX07] and vacuole 14 protein homolog [VAC14]) distinguished most classes of fatigued subjects from healthy subjects, whereas others (patched homolog 2 [PTCH2] and T-cell leukemia/lymphoma [TCL1A]) differentiated specific fatigue classes. CONCLUSION: A computational approach was developed for general use to identify discriminatory genes in any multiclass problem. Using this approach, differences in gene expression were found to discriminate some classes of unexplained chronic fatigue, particularly one termed interoception.