With the success that surgical approaches can provide for localization-related epilepsy, accurate seizure localization remains important. Although magnetic resonance (MR) spectroscopy has had success in earlier studies in medial temporal lobe epilepsy, there have been fewer studies evaluating its use in a broader range of localization-related epilepsy. With improvements in signal-to-noise with ultra-high field MR, we report on the use of high resolution 7T MR spectroscopic imaging (MRSI) in 25 surgically treated patients studied over a 3.5-year period.
Patients were included in this analysis if the region of MRSI study included the surgical resection region. Concordance between region of MRSI abnormalities and of surgical resection was classified into three groups (complete, partial, or no agreement) and outcome was dichotomized by International League Against Epilepsy (ILAE) I–III and IV–VI groups. MRSI was performed with repetition time/echo time 1.5 s/40 msec in two-dimensional (2D) or three-dimensional (3D) encoding for robust detection of singlets N-acetyl aspartate (NAA), creatine (Cr), and choline with abnormalities in NAA/Cr determined with correction for tissue content of gray matter.
The concordance between MRSI-determined abnormality and surgical resection region was significantly related to outcome: Outcome was better if the resected tissue was metabolically abnormal. All 14 patients with complete resection of the region with the most severe metabolic abnormality had good outcome, including five requiring intracranial electroencephalography (EEG) analysis, whereas only 3/11 without complete resection of the most severe metabolic abnormality had good outcome (p < 0.001).
This is consistent with the seizure-onset zone being characterized by metabolic dysfunction and suggests that high resolution MRSI can help define these regions for the purposes of outcome prediction.
Localization-related epilepsy; Spectroscopic imaging; Seizure localization; Outcomes
The concept of an epileptic network has long been suggested from both animal and human studies of epilepsy. Based on the common observation that the MR spectroscopic imaging measure of NAA/Cr is sensitive to neuronal function and injury, we use this parameter to assess for the presence of a metabolic network in mesial temporal lobe epilepsy (MTLE) patients.
Materials and methods
A multivariate factor analysis is performed with controls and MTLE patients, using NAA/Cr measures from 12 loci: the bilateral hippocampi, thalami, basal ganglia, and insula. The factor analysis determines which and to what extent these loci are metabolically covarying.
We extract two independent factors that explain the data’s variability in control and MTLE patients. In controls, these factors characterize a ‘thalamic’ and ‘dominant subcortical’ function. The MTLE patients also exhibit a ‘thalamic’ factor, in addition to a second factor involving the ipsilateral insula and bilateral basal ganglia.
These data suggest that MTLE patients demonstrate a metabolic network that involves the thalami, also seen in controls. The MTLE patients also display a second set of metabolically covarying regions that may be a manifestation of the epileptic network that characterizes limbic seizure propagation.
epilepsy; neuroimaging; seizures
While tendons typically undergo primarily tensile loading, the human supraspinatus tendon (SST) experiences substantial amounts of tension, compression, and shear in vivo. As a result, the functional roles of the extracellular matrix components, in particular the proteoglycans (PGs), are likely complex and important. The goal of this study was to determine the PG content in specific regions of the SST that exhibit differing mechanical function. The concentration of aggrecan, biglycan, and decorin were determined in six regions of the human SST using immunochemical techniques. We hypothesized that: aggrecan concentrations would be highest in areas where the tendon likely experiences compression; biglycan levels would be highest in regions likely subjected to injury and/or active remodeling such as the anterior regions; decorin concentrations would be highest in regions of greatest tensile stiffness. Our results generally supported these hypotheses and demonstrated that aggrecan and biglycan share regional variability, with increased concentration in the anterior and posterior regions and smaller concentration in the medial regions. Decorin, however, was in high concentration throughout all regions. The data presented in this study represent the first regional measurements of PG in the SST. Together with our previous regional measurements of mechanical properties, these data can be used to evaluate SST structure-function relationships. With knowledge of the differences in specific PG content, their spatial variations in the SST, and their relationships to tendon mechanics, we can begin to associate defects in PG content with specific pathology, which may provide guidance for new therapeutic interventions.
ELISA; extracellular matrix; shoulder; biomechanics
Impaired consciousness requires altered cortical function. This can occur either directly from disorders that impair widespread bilateral regions of the cortex or indirectly through effects on subcortical arousal systems. It has therefore long been puzzling why focal temporal lobe seizures so often impair consciousness. Early work suggested that altered consciousness may occur with bilateral or dominant temporal lobe seizure involvement. However, other bilateral temporal lobe disorders do not impair consciousness. More recent work supports a ‘network inhibition hypothesis’ in which temporal lobe seizures disrupt brainstem–diencephalic arousal systems, leading indirectly to depressed cortical function and impaired consciousness. Indeed, prior studies show subcortical involvement in temporal lobe seizures and bilateral frontoparietal slow wave activity on intracranial electroencephalography. However, the relationships between frontoparietal slow waves and impaired consciousness and between cortical slowing and fast seizure activity have not been directly investigated. We analysed intracranial electroencephalography recordings during 63 partial seizures in 26 patients with surgically confirmed mesial temporal lobe epilepsy. Behavioural responsiveness was determined based on blinded review of video during seizures and classified as impaired (complex-partial seizures) or unimpaired (simple-partial seizures). We observed significantly increased delta-range 1–2 Hz slow wave activity in the bilateral frontal and parietal neocortices during complex-partial compared with simple-partial seizures. In addition, we confirmed prior work suggesting that propagation of unilateral mesial temporal fast seizure activity to the bilateral temporal lobes was significantly greater in complex-partial than in simple-partial seizures. Interestingly, we found that the signal power of frontoparietal slow wave activity was significantly correlated with the temporal lobe fast seizure activity in each hemisphere. Finally, we observed that complex-partial seizures were somewhat more common with onset in the language-dominant temporal lobe. These findings provide direct evidence for cortical dysfunction in the form of bilateral frontoparietal slow waves associated with impaired consciousness in temporal lobe seizures. We hypothesize that bilateral temporal lobe seizures may exert a powerful inhibitory effect on subcortical arousal systems. Further investigations will be needed to fully determine the role of cortical-subcortical networks in ictal neocortical dysfunction and may reveal treatments to prevent this important negative consequence of temporal lobe epilepsy.
cortex; EEG; seizures; temporal lobe epilepsy; consciousness
Timing abilities are critical to the successful management of everyday activities and personal safety, and timing abnormalities have been argued to be fundamental to impulsiveness, a core symptom of attention-deficit/hyperactivity disorder (ADHD). Despite substantial evidence of timing deficits in ADHD youth, only two studies have explicitly examined timing in ADHD adults, and only at the supra-second time-scale. Also, the neural substrates of these deficits are largely unknown for both youth and adults with ADHD. The present study examined sub-second sensorimotor timing and its neural substrates in ADHD adults.
Using fMRI, we examined paced and unpaced finger tapping in a sample of 20 unmedicated adults with ADHD and 19 controls comparable on age, sex and estimated-IQ. The blood oxygenation level-dependent contrast response was used to estimate task-related neural activity.
Behavioral data showed no between-group differences in mean tapping rates but greater within-subject variability in tap-to-tap intervals for ADHD adults relative to controls. Importantly, ADHD adults had greater clock rather than motor variability, consistent with a central timing locus for the atypical movements. The imaging results demonstrated that, relative to controls, ADHD adults showed less activity in a number of regions associated with sensorimotor timing, including prefrontal and precentral gyri, basal ganglia, cerebellum, inferior parietal lobule, superior temporal gyri and insula.
Our findings show that sub-second timing abnormalities in ADHD youth persist into adulthood and suggest that abnormalities in the temporal structure of behavior observed in ADHD adults result from atypical function of cortico-cerebellar and cortico-striatal timing systems.
ADHD; fMRI; timing; cerebellum; frontal cortex; basal ganglia
Several large and meta-analytic studies have failed to support a consistent relationship between visual or “nonverbal” memory deficits and right mesial temporal lobe changes. However, the Brown Location Test (BLT) is a recently developed dot location learning and memory test that uses a nonsymmetrical array and provides control over many of the confounding variables (e.g., verbal influence and drawing requirements) inherent in other measures of visual memory. In the present investigation, we evaluated the clinical utility of the BLT in patients who had undergone left or right anterior mesial temporal lobectomies. We also provide adult normative data of 298 healthy adults in order to provide standardized scores. Results revealed significantly worse performance on the BLT in the right as compared to left lobectomy group and the healthy adult normative sample. The present findings support a role for the right anterior-mesial temporal lobe in dot location learning and memory.
spatial; visuospatial; lateralization; memory; location; epilepsy
EEG power and high frequency activity in the seizure onset zone has been increasingly considered for its relationship with seizures in animal and human studies of epilepsy. We examine the relationship between quantitative EEG measures and metabolic imaging in epilepsy patients undergoing intracranial EEG (icEEG) analysis for seizure localization. Patients with mesial temporal lobe epilepsy (MTLE) and neocortical epilepsy (NE) were studied. Metabolic imaging was performed with MR spectroscopic imaging using N-acetyl aspartate (NAA) and creatine (Cr). All data were acquired from the mesial temporal lobe such that a direct comparison of the same anatomical regions between the two groups could be performed. While no difference was seen in the total power recorded from the mesial temporal lobe, the MTLE group had significantly greater power in the high frequency bands. There was a significant positive exponential relationship between total icEEG power with NAA/Cr in MTLE, R= +0.84 p<0.001, which was not seen in NE. There was also a significant negative relationship between fractional gamma power with NAA/Cr in MTLE R= −0.66 p<0.02, also not seen in NE. These data argue that within the seizure onset zone, the tight correlation between total power and NAA/Cr suggests that total electrical output is powered by available mitochondrial function. These data are also consistent with the hypothesis that high frequency activity is an abnormal manifestation of tissue injury.
intracranial EEG; gamma power; N-acetyl aspartate; human
Studies of working memory load effects on human EEG power have indicated divergent effects in different frequency bands. Although gamma power typically increases with load, the load dependency of the lower frequency theta and alpha bands is uncertain. We obtained intracranial electroencephalography measurements from 1453 electrode sites in 14 epilepsy patients performing a Sternberg task, in order to characterize the anatomical distribution of load-related changes across the frequency spectrum. Gamma power increases occurred throughout the brain, but were most common in the occipital lobe. In the theta and alpha bands, both increases and decreases were observed, but with different anatomical distributions. Increases in theta and alpha power were most prevalent in frontal midline cortex. Decreases were most commonly observed in occipital cortex, colocalized with increases in the gamma range, but were also detected in lateral frontal and parietal regions. Spatial overlap with group functional magnetic resonance imaging results was minimal except in the precentral gyrus. These findings suggest that power in any given frequency band is not a unitary phenomenon; rather, reactivity in the same frequency band varies in different brain regions, and may relate to the engagement or inhibition of a given area in a cognitive task.
alpha; BOLD; ECoG; fMRI; gamma; Sternberg; theta
Patients with temporal lobe epilepsy (TLE) often have a shrunken hippocampus that is known to be the location in which seizures originate. The role of the sclerotic hippocampus in the causation and maintenance of seizures in temporal lobe epilepsy (TLE) has remained incompletely understood despite extensive neuropathological investigations of this substrate. To gain new insights and develop new testable hypotheses on the role of sclerosis in the pathophysiology of TLE, the differential gene expression profile was studied. To this end, DNA microarray analysis was used to compare gene expression profiles in sclerotic and non-sclerotic hippocampi surgically removed from TLE patients. Sclerotic hippocampi had transcriptional signatures that were different from non-sclerotic hippocampi. The differentially expressed gene set in sclerotic hippocampi revealed changes in several molecular signaling pathways, which included the increased expression of genes associated with astrocyte structure (glial fibrillary acidic protein, ezrin-moesin-radixin, palladin), calcium regulation (S100 calcium binding protein beta, chemokine (C-X-C motif) receptor 4) and blood-brain barrier function (Aquaaporin 4, Chemokine (C-C- motif) ligand 2, Chemokine (C-C- motif) ligand 3, Plectin 1, intermediate filament binding protein 55kDa) and inflammatory responses. Immunohistochemical localization studies show that there is altered distribution of the gene-associated proteins in astrocytes from sclerotic foci compared with non-sclerotic foci. It is hypothesized that the astrocytes in sclerotic tissue have activated molecular pathways that could lead to enhanced release of glutamate by these cells. Such glutamate release may excite surrounding neurons and elicit seizure activity.
This paper describes a powerful programming tool that should be considered as an alternative to the more conventional programming languages now in use for developing medical computer systems. Forth provides instantaneous response to user commands, rapid program execution and tremendous programming versatility. An operating system and a language in one carefully designed unit, Forth is well suited for developing data acquisition systems and for interfacing computers to other instruments. We present some of the general features of Forth and describe its use in implementing a data collection system for a Respiratory Intensive Care Unit (RICU).
Low socioeconomic status (SES) influences the risk of acquiring human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and thus should be considered when analyzing HIV/AIDS surveillance data. Most surveillance systems do not collect individual level SES data but do collect residential ZIP code. We developed SES deprivation indices at the ZIP code tabulation area and assessed their predictive validity for AIDS incidence relative to individual neighborhood-level indicators in Florida using reliabililty analysis, factor analysis with principal component factorization, and structural equation modeling. For urban areas an index of poverty performed best, although the single factor poverty also performed well. For rural areas no index performed well, but the individual indicators of no access to a car and crowding performed well. In rural areas poverty was not associated with increased AIDS incidence. Users of HIV/AIDS surveillance data should consider urban and rural areas separately when assessing the impact of SES on AIDS incidence.
Socioeconomic status; Deprivation; Urban/rural neighborhood; Poverty index; Acquired immunodeficiency syndrome
Death adders (genus Acanthophis) differ from most other elapid snakes, and resemble many viperid snakes, in their thickset morphology and ambush foraging mode. Although these snakes are widely distributed through Australia and Papua New Guinea, their basic biology remains poorly known. We report morphological and ecological data based upon dissection of >750 museum specimens drawn from most of the range of the genus. Female death adders grow larger than conspecific males, to about the same extent in all taxa (20% in mean adult snout-vent length, = SVL). Most museum specimens were adult rather than juvenile animals, and adult males outnumbered females in all taxa except A. pyrrhus. Females have shorter tails (relative to SVL) than males, and longer narrower heads (relative to head length) in some but not all species. The southern A. antarcticus is wider-bodied (relative to SVL) than the other Australian species. Fecundity of these viviparous snakes was similar among taxa (mean litter sizes 8 to 14). Death adders encompass a broad range of ecological attributes, taking a wide variety of vertebrate prey, mostly lizards (55%), frogs and mammals (each 21%; based on 217 records). Dietary composition differed among species (e.g. frogs were more common in tropical than temperate-zone species), and shifted with snake body size (endotherms were taken by larger snakes) and sex (male death adders took more lizards than did females). Overall, death adders take a broader array of prey types, including active fast-moving taxa such as endotherms and large diurnal skinks, than do most other Australian elapids of similar body sizes. Ambush foraging is the key to capturing such elusive prey.
Dendrobium huoshanense is a valuable and versatile Chinese herbal medicine with the anecdotal claims of cancer prevention and anti-inflammation. However, its immunological activities are limited to in vitro studies on a few cytokines and immune cell functions. First, we investigated the effects of polysaccharides isolated from DH (DH-PS) on inducing a panel of cytokines/chemokines in mice in vivo and human in vitro. We found that DH polysaccharides (DH-PS) induced TH1, TH2, inflammatory cytokines and chemokines in mouse in vivo and human cells in vitro. Secondly, we demonstrated that DH-PS expanded mouse splenocytes in vivo including CD4+ T cells, CD8+ T cells, B cells, NK cells, NKT cells, monocytes/macrophages, granulocytes and regulatory T cells. Notably, DH-PS induced an anti-inflammatory molecule, IL-1ra, in mouse and human immune cells, especially monocytes. The serum level of IL-1ra elicited by the injection of DH-PS was over 10 folds of IL-1β, suggesting that DH-PS-induced anti-inflammatory activities might over-ride the inflammatory ones mediated by IL-1β. The signaling pathways of DH-PS-induced IL-1ra production was shown to involve ERK/ELK, p38 MAPK, PI3K and NFκB. Finally, we observed that IL-1ra level induced by DH-PS was significantly higher than that by F3, a polysaccharide extract isolated from another popular Chinese herbal medicine, Ganoderma lucidum. These results indicated that DH-PS might have potential applications for ameliorating IL-1-induced pathogenic conditions.
Hydrogen sulfide (H2S) has recently been proposed as an endogenous mediator of inflammation and is present in human synovial fluid. This study determined whether primary human articular chondrocytes (HACs) and mesenchymal progenitor cells (MPCs) could synthesize H2S in response to pro-inflammatory cytokines relevant to human arthropathies, and to determine the cellular responses to endogenous and pharmacological H2S. HACs and MPCs were exposed to IL-1β, IL-6, TNF-α and lipopolysaccharide (LPS). The expression and enzymatic activity of the H2S synthesizing enzymes cystathionine-β-synthase (CBS) and cystathionine-γ-lyase (CSE) were determined by Western blot and zinc-trap spectrophotometry, respectively. Cellular oxidative stress was induced by H2O2, the peroxynitrite donor SIN-1 and 4-hydroxynonenal (4-HNE). Cell death was assessed by 3-(4,5-dimethyl-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and lactate dehydrogenase (LDH) assays. Mitochondrial membrane potential (ΔΨm) was determined in situ by flow cytometry. Endogenous H2S synthesis was inhibited by siRNA-mediated knockdown of CSE and CBS and pharmacological inhibitors D,L-propargylglycine and aminoxyacetate, respectively. Exogenous H2S was generated using GYY4137. Under basal conditions HACs and MPCs expressed CBS and CSE and synthesized H2S in a CBS-dependent manner, whereas CSE expression and activity was induced by treatment of cells with IL-1β, TNF-α, IL-6 or LPS. Oxidative stress-induced cell death was significantly inhibited by GYY4137 treatment but increased by pharmacological inhibition of H2S synthesis or by CBS/CSE-siRNA treatment. These data suggest CSE is an inducible source of H2S in cultured HACs and MPCs. H2S may represent a novel endogenous mechanism of cytoprotection in the inflamed joint, suggesting a potential opportunity for therapeutic intervention.
arthritis; cystathionine-γ-lyase; cystathionine-β-synthase; GYY4137; apoptosis; oxidative stress
It was hypothesized that affect-amplifying individuals would be more reactive to affective events in daily life. Affect amplification was quantified in terms of overestimating the font size of positive and negative, relative to neutral, words in a basic perception task. Subsequently, the same (N = 70) individuals completed a daily diary protocol in which they reported on levels of daily stressors, provocations, and social support as well as six emotion-related outcomes for 14 consecutive days. Individual differences in affect amplification moderated reactivity to daily affective events in all such analyses. For example, daily stressor levels predicted cognitive failures at high, but not low, levels of affect amplification. Affect amplification, then, appears to have widespread utility in understanding individual differences in emotional reactivity.
Individual Differences; Affect; Perception; Reactivity; Daily Life
Background & Aims
Studies investigating insulin resistance (IR) in chronic hepatitis C virus (HCV) infection have used surrogate measures of IR that have limited reliability. We aimed to describe the distribution and risk factors associated with IR and its change over time in HCV using direct measurement.
One hundred and two non-cirrhotic, non-diabetic, HCV-infected subjects underwent clinical, histologic, and metabolic evaluation, and 27 completed repeat evaluation at 6 months. Insulin-mediated glucose uptake was measured by steady-state plasma glucose (SSPG) concentration during the insulin suppression test.
Three subjects with diabetes were excluded and 95 completed all testing. SSPG ranged from 39 to 328 mg/dL (mean 135 mg/dL) and was stable over time (mean SSPG change -0.3 mg/dL). SSPG was associated with Latino ethnicity (Coef 67, 95%CI 37-96), BMI (Coef 19 per 5 kg/m2, 95%CI 5-32), ferritin (Coef 1.4 per 10 ng/ml, 95%CI 0.2-2.5), male gender (Coef -48, 95%CI -80 to -16), and HDL (Coef -16, 95%CI -28 to -5 mg/dL). Current tobacco use (Coef 55, 95%CI 19-90), steatosis (Coef -44, 95%CI -86 to -3), and increases in BMI (Coef 30 per 5 kg/m2, 95%CI 6-53) and triglyceride (Coef 3.5 per 10 mg/dL, 95%CI 0.3-6.7) predicted change in SSPG.
There was a wide spectrum of insulin resistance in our HCV population. Host factors, rather than viral factors, appeared to more greatly influence insulin action and its change in HCV.
Diabetes; HCV; Insulin Resistance; Oral Glucose Tolerance Test
We described the racial/ethnic disparities in survival among people diagnosed with AIDS in Florida from 1993 to 2004, as the availability of highly active antiretroviral therapy (HAART) became widespread. We determined whether these disparities decreased after controlling for measures of community-level socioeconomic status.
We compared survival from all causes between non-Hispanic Blacks and non-Hispanic Whites vis-a-vis survival curves and Cox proportional hazards models controlling for demographic, clinical, and area-level poverty factors.
Racial/ethnic disparities in survival peaked for those diagnosed during the early implementation of HAART (1996–1998) with a Black-to-White hazard ratio (HR) of 1.72 (95% confidence interval [CI] = 1.62, 1.83) for males and 1.40 (95% CI = 1.24, 1.59) for females. These HRs declined significantly to 1.48 (95% CI = 1.35, 1.64) for males and nonsignificantly to 1.25 (95% CI = 1.05, 1.48) for females in the 2002 to 2004 diagnosis cohort. Disparities decreased significantly for males but not females when controlling for baseline demographic factors and CD4 count and percentage, and became nonsignificant in the 2002 to 2004 cohort after controlling for area poverty.
Area poverty appears to play a role in racial/ethnic disparities even after controlling for demographic factors and CD4 count and percentage.
The literature on development has focused on the concept of transition in understanding the emergent challenges facing poor but rapidly developing countries. Scholars have focused extensively on the health and urban transitions associated with this change and, in particular, its use for understanding emerging infectious diseases. However, few have developed explicit empirical measures to quantify the extent to which a transitions focus is useful for theory, policy, and practice. Using open source data on avian influenza in 2004 and 2005 and the Vietnam Census of Population and Housing, this paper introduces the Kuznets curve as a tool for empirically estimating transition and disease. Findings suggest that the Kuznets curve is a viable tool for empirically assessing the role of transitional dynamics in the emergence of new infectious diseases.
Avian influenza; Vietnam; Emerging infectious disease; Urban transition; Health transition
This study investigated the development of tense markers (e.g., past tense –ed) in children with cochlear implants (CIs) over a 3-year span. Nine children who received CIs before 30 months of age participated in this study at three, four, and five years postimplantation. Nine typical 3-, 4-, and 5-year- olds served as control groups. All children participated in a story-retell task. Percent correct of tense marking in the task was computed. Within the groups, percent correct of tense marking changed significantly in children with CIs and in typical children who had more hearing experience. Across the groups, children with CIs were significantly less accurate in tense marking than typical children at four and five years postimplantation. In addition, the performance of tense marking in children with CIs was correlated with their speech perception skills at earlier time points. Errors of tense marking tended to be omission rather than commission errors in typical children as well as in children with CIs. The findings suggested that despite the perceptual and processing constraints, children who received CIs may learn tense marking albeit with a delayed pattern.
Few studies have examined differences in long-term mortality between coronary artery bypass graft surgery and stenting with drug-eluting stents (DES) for multivessel disease without left main coronary artery stenosis. This study compares the risks of long-term mortality between these 2 procedures during a follow-up of up to 5 years.
Patients who underwent isolated bypass surgery (n=13,212) and stenting with DES (n=20,161) between October 2003 and December 2005 in New York State were followed for their vital status through 2008. To control for treatment selection bias, bypass and stenting patients were matched on age, number of diseased coronary vessels, presence of proximal or nonproximal left anterior descending (LAD) artery disease, and propensity of undergoing bypass surgery. Five-year survival rates for the 2 procedures were compared and hazard ratios for death of bypass surgery compared to stenting were obtained.
The respective 5-year survival rates in the 8,121 pairs of matched bypass and stenting patients were 80.4%and 73.6% (P<0.001), and the risk of death following bypass surgery was 29% lower than for stenting (hazard ratio=0.71, 95% confidence interval: 0.67-0.77, P<0.001). Significantly lower risks of death for bypass surgery were observed in patients with LAD artery disease but not in patients without LAD artery disease. Significantly lower risks of death for bypass surgery were also found in all patient subgroups defined by the presence of selected baseline risk factors.
Bypass surgery is associated with lower risk of death than stenting with DES for multivessel disease without left main stenosis.
CABG; stents; outcomes
It is generally assumed that the MHC class I antigen (Ag)-processing (CAP) machinery —which supplies peptides for presentation by class I molecules— plays no role in class II-restricted presentation of cytoplasmic Ags. In striking contrast to this assumption, we previously reported that proteasome inhibition or TAP- or ERAAP-deficiency led to dramatically altered T helper (Th) cell responses to allograft (HY) and microbial (Listeria monocytogenes) Ags. Herein, we tested whether altered Ag processing and presentation, altered CD4+ T cell repertoire, or both underlay the above finding. We found that TAP- and ERAAP-deficiency dramatically altered the quality of class II-associated self peptides suggesting that the CAP machinery impacts class II-restricted Ag processing and presentation. Consistent with altered self peptidomes, the CD4+ T cell receptor repertoire of mice deficient in the CAP machinery substantially differed from that of wildtype animals resulting in altered CD4+ T cell Ag recognition patterns. These data suggest that TAP and ERAAP sculpt the class II-restricted peptidome, impacting the CD4+ T cell repertoire, and ultimately altering Th cell responses. Together with our previous findings, these data suggest multiple CAP machinery components sequester or degrade MHC class II-restricted epitopes that would otherwise be capable of eliciting functional Th cell responses.
antigen presentation; mass spectrometry; T helper cells; self peptidome; MHC
Understanding the factors governing host species barriers to virus transmission has added significantly to our appreciation of virus pathogenesis. Jaagsiekte sheep retrovirus (JSRV) is the causative agent of ovine pulmonary adenocarcinoma (OPA), a transmissible lung cancer of sheep that has rarely been found in goats. In this study, in order to further clarify the pathogenesis of OPA, we investigated whether goats are resistant to JSRV replication and carcinogenesis. We found that JSRV induces lung tumors in goats with macroscopic and histopathological features that dramatically differ from those in sheep. However, the origins of the tumor cells in the two species are identical. Interestingly, in experimentally infected lambs and goat kids, we revealed major differences in the number of virus-infected cells at early stages of infection. These differences were not related to the number of available target cells for virus infection and cell transformation or the presence of a host-specific immune response toward JSRV. Indeed, we also found that goats possess transcriptionally active endogenous retroviruses (enJSRVs) that likely influence the host immune response toward the exogenous JSRV. Overall, these results suggest that goat cells, or at least those cells targeted for viral carcinogenesis, are not permissive to virus replication but can be transformed by JSRV.
The field of microbiome research is growing rapidly. We developed a method for self-collection of fecal specimens that can be used in population-based studies of the gut microbiome. We conducted a pilot study to test the feasibility of our methods among a random sample of healthy, postmenopausal women who are members of Kaiser Permanente Colorado (KPCO). We aimed to collect questionnaire data, fecal and urine specimens from 60 women, aged 55–69, who recently had a normal screening mammogram. We designed the study such that all questionnaire data and specimens could be collected at home.
We mailed an invitation packet, consent form and opt-out postcard to 300 women, then recruited by telephone women who did not opt-out. Verbally consented women were mailed an enrollment package including a risk factor questionnaire, link to an online diet questionnaire, specimen collection kit, and instructions for collecting stool and urine. Specimens were shipped overnight to the biorepository. Of the 300 women mailed an invitation packet, 58 (19%) returned the opt-out postcard. Up to 3 attempts were made to telephone the remaining women, of whom 130 (43%) could not be contacted, 23 (8%) refused, and 12 (4%) were ineligible. Enrollment packages were mailed to 77 women, of whom 59 returned the risk factor questionnaire and specimens. We found no statistically significant differences between enrolled women and those who refused participation or could not be contacted.
We demonstrated that a representative sample of women can be successfully recruited for a gut microbiome study; however, significant personal contact and carefully timed follow-up from the study personnel are required. The methods employed by our study could successfully be applied to analytic studies of a wide range of clinical conditions that have been postulated to be influenced by the gut microbial population.
Study design; Microbiome; Breast cancer