Natural History of Tuberculosis: Duration and Fatality of Untreated Pulmonary Tuberculosis in HIV Negative Patients: A Systematic Review

Background The prognosis, specifically the case fatality and duration, of untreated tuberculosis is important as many patients are not correctly diagnosed and therefore receive inadequate or no treatment. Furthermore, duration and case fatality of tuberculosis are key parameters in interpreting epidemiological data. Methodology and Principal Findings To estimate the duration and case fatality of untreated pulmonary tuberculosis in HIV negative patients we reviewed studies from the pre-chemotherapy era. Untreated smear-positive tuberculosis among HIV negative individuals has a 10-year case fatality variously reported between 53% and 86%, with a weighted mean of 70%. Ten-year case fatality of culture-positive smear-negative tuberculosis was nowhere reported directly but can be indirectly estimated to be approximately 20%. The duration of tuberculosis from onset to cure or death is approximately 3 years and appears to be similar for smear-positive and smear-negative tuberculosis. Conclusions Current models of untreated tuberculosis that assume a total duration of 2 years until self-cure or death underestimate the duration of disease by about one year, but their case fatality estimates of 70% for smear-positive and 20% for culture-positive smear-negative tuberculosis appear to be satisfactory

Excitation/inhibition balance in the aMCC influences resting state activity in the CEN

Introduction: Excitation/inhibition balance can be used as a predictor not only for the functional regional response in the task-based functional magnetic resonance imaging (fMRI) but also for functional connectivity (FC) strength measured within and between networks [1]. Previous studies reported that both Glutamate (Glu) and γ-Aminobutyric acid (GABA) levels can predict within network connectivity patterns [2,3]. However, the results were inconsistent and they were mainly focused on the default mode network confirming that there is a need for more robust and extensive measurements. Therefore, we investigated whole brain associations between the main excitatory – Glu – and inhibitory neurotransmitter – GABA – with the FC of the anterior mid cingulate cortex (aMCC), a node of the salience network (SN), with a particular focus on regions of the central executive network (CEN). We additionally explored how these metabolites influence basic neuronal measurements such as fractional amplitude of low frequency fluctuations (fALFF). Methods: 106 subjects (age = 27.09 ± 6.72, 44 females) completed a research paradigm that included a resting-state fMRI and a magnetic resonance spectroscopy (MRS) session in 7T. An MRS voxel was placed in the aMCC, and Glu, GABA and Creatine (Cr) levels were acquired using a stimulated-echo acquisition mode (STEAM) sequence. A regression analysis was conducted in SPM8 between metabolites and aMCC voxel–seed FC maps with age, sex and grey matter ratio as covariates of nuisance. Additionally, the same regression analysis was performed for fALFF. Results are reported on FWE < 0.05 cluster level significance with an initial threshold of p < 0.001, uncorrected. Results: Glu/Cr and aMCC voxel FC showed a strong negative association in the left posterior frontal gyrus and several nodes of the visual cortex. A regionally converging positive correlation was found between fALFF and GABA/Cr in the left posterior frontal gyrus. Conclusions: Both GABA and Glu levels measured in the aMCC predict the strength and the basal activity of the posterior frontal gyrus, which is a node of the CEN

Excitation/inhibition balance in the aMCC influences resting state activity in the CEN

Background: Excitation/inhibition balance can be used as a predictor not only for the functional regional response in the task-based functional magnetic resonance imaging (fMRI) but also for functional connectivity (FC) strength measured within and between networks. Previous studies reported that both Glutamate (Glu) and γ-Aminobutyric acid (GABA) levels can predict within network connectivity patterns. However, the results were inconsistent and they were mainly focused on the default mode network confirming that there is a need for more robust and extensive measurements. Therefore, we investigated whole brain associations between the main excitatory - Glu - and inhibitory neurotransmitter - GABA - with the FC of the anterior mid cingulate cortex (aMCC), a node of the salience network (SN), with a particular focus on regions of the central executive network (CEN). We additionally explored how these metabolites influence basic neuronal measurements such as fractional amplitude of low frequency fluctuation (fALFF). Methods: 78 healthy subjects (39 females, age = 26.97 ± 6.53) completed a research paradigm that included a resting-state fMRI and a magnetic resonance spectroscopy (MRS) session in 7T. An MRS voxel was placed in the aMCC, and Glu, GABA and Creatine (Cr) levels were acquired using a stimulated-echo acquisition mode (STEAM) sequence. A regression analysis was conducted in SPM8 between metabolites and aMCC voxel-seed FC maps with age, sex and grey matter ratio as covariates of nuisance. Additionally, the same regression analysis was performed for fALFF. Results are reported on FWE < 0.05 cluster level significance with an initial threshold of p < 0.001, uncorrected. Results: Glu/Cr and aMCC voxel FC showed a strong negative association in the left posterior frontal gyrus and several nodes of the visual cortex. A regionally converging positive correlation was found between fALFF and GABA/Cr in the left posterior frontal gyrus. Conclusion: Both GABA and Glu levels measured in the aMCC predict the strength and the basal activity of the posterior frontal gyrus, which is a node of the CEN

Excitation/inhibition balance in the aMCC influences resting state activity in the CEN

Introduction: Excitation/inhibition balance can be used as a predictor not only for the functional regional response in the task-based functional magnetic resonance imaging (fMRI) but also for functional connectivity (FC) strength measured within and between networks [1]. Previous studies reported that both Glutamate (Glu) and γ-Aminobutyric acid (GABA) levels can predict within network connectivity patterns [2,3]. However, the results were inconsistent and they were mainly focused on the default mode network confirming that there is a need for more robust and extensive measurements. Therefore, we investigated whole brain associations between the main excitatory – Glu – and inhibitory neurotransmitter – GABA – with the FC of the anterior mid cingulate cortex (aMCC), a node of the salience network (SN), with a particular focus on regions of the central executive network (CEN). We additionally explored how these metabolites influence basic neuronal measurements such as fractional amplitude of low frequency fluctuations (fALFF). Methods: 106 subjects (age = 27.09 ± 6.72, 44 females) completed a research paradigm that included a resting-state fMRI and a magnetic resonance spectroscopy (MRS) session in 7T. An MRS voxel was placed in the aMCC, and Glu, GABA and Creatine (Cr) levels were acquired using a stimulated-echo acquisition mode (STEAM) sequence. A regression analysis was conducted in SPM8 between metabolites and aMCC voxel–seed FC maps with age, sex and grey matter ratio as covariates of nuisance. Additionally, the same regression analysis was performed for fALFF. Results are reported on FWE < 0.05 cluster level significance with an initial threshold of p < 0.001, uncorrected. Results: Glu/Cr and aMCC voxel FC showed a strong negative association in the left posterior frontal gyrus and several nodes of the visual cortex. A regionally converging positive correlation was found between fALFF and GABA/Cr in the left posterior frontal gyrus. Conclusions: Both GABA and Glu levels measured in the aMCC predict the strength and the basal activity of the posterior frontal gyrus, which is a node of the CEN

Sequence of Multiple Slope Failures in the Headwall Area of the Giant Sahara Slide Complex at the NW African Continental Margin

Abstract Submarine mega‐slides involving hundreds of cubic kilometers of slope material pose a major threat due to their potential to destroy offshore infrastructure and trigger devastating tsunamis. The Sahara Slide Complex affected about 50,000 km2 of the northwestern (NW) African continental margin. Previous studies focused either on its distal depositional zone or the uppermost headwall area, but failed in reconstructing the succession of individual slide events within the entire headwall area. New hydroacoustic data reveal a complex slide morphology including three main acoustic facies, large scale slide blocks, linear troughs, multiple glide planes and three major headwall scarps (the upper, southern and lower headwall). The evacuated slide scar hosts chaotic slide deposits that cover stratified sediments in the upper and southern headwall area, but are vertically stacked onto older slide deposits in the lower headwall area. Based on these observations, and dating of recently collected sediment samples, we reconstructed the history of slope failures that led to the formation of the structurally and morphologically complex headwall area of the Sahara Slide. Slope instability initiated when the lower headwall failed at ∼60 kyr, followed by the failure of the northeastern upper headwall at ∼14 kyr. Around 6 kyr, a major slide within the upper headwall area took place, followed by a series of smaller events within the southern and most‐proximal upper headwall area. The youngest of these slides occurred around 2 kyr. This scenario suggests a long‐lasting history of successive slope failures for the Sahara Slide Complex along the NW African continental slope

Glutamate in salience network predicts BOLD response in default mode network during salience processing

Background: Brain investigations identified salience network (SN) comprising the dorsal Anterior Cingulate Cortex (dACC) and the Anterior Insula (AI). Magnetic resonance spectroscopy (MRS) studies revealed the link between the glutamate concentration in the ACC and alterations in attentional scope. Hence, we investigated whether glutamate concentration in the dACC modulates brain response during salience processing. Methods: Twenty-seven healthy subjects (12♀, 15♁) provided both STEAM MRS at 7T measuring glutamate concentrations in the dACC as well as a functional magnetic resonance imaging (fMRI) task to study the influence on content-related salience processing and expectedness. Salience was modulated for both sexual and non-sexual emotional photos in either expected or unexpected situations. Correlation between MRS and task fMRI was investigated by performing regression analyses controlling for age, gender, and gray matter partial volume. Results/Conclusion: During picture processing, the extent of deactivation in the Posterior Cingulate Cortex (PCC) was attenuated by two different salience attributions: sexual content and unexpectedness of emotional content. Our results indicate that stimulus inherent salience induces an attenuation of the deactivation in PCC, which is in turn balanced by higher level of glutamate in the dACC

Ketamine influences the locus coeruleus norepinephrine network, with a dependency on norepinephrine transporter genotype: a placebo controlled fMRI study

Background Ketamine is receiving increasing attention as a rapid-onset antidepressant in patients suffering from major depressive disorder (MDD) with treatment resistance or severe suicidal ideation. Ketamine modulates several neurotransmitter systems, including norepinephrine via the norepinephrine transporter (NET), both peripherally and centrally. The locus coeruleus (LC), which has high NET concentration, has been attributed to brain networks involved in depression. Thus we investigated the effects of single-dose of racemic ketamine on the LC using resting state functional MRI. Methods Fifty-nine healthy participants (mean age 25.57 ± 4.72) were examined in a double-blind, randomized, placebo-controlled study with 7 Tesla MRI. We investigated the resting state functional connectivity (rs-fc) of the LC before and one hour after subanesthetic ketamine injection (0.5 mg/kg), as well as associations between its rs-fc and a common polymorphism in the NET gene (rs28386840). Results A significant interaction of drug and time was revealed, and post hoc testing showed decreased rs-fc between LC and the thalamus after ketamine administration compared with baseline levels, including the mediodorsal, ventral anterior, ventral lateral, ventral posterolateral and centromedian nuclei. The rs-fc reduction was more pronounced in NET rs28386840 [AA] homozygous subjects than in [T] carriers. Conclusions We demonstrated acute rs-fc changes after ketamine administration in the central node of the norepinephrine pathway. These findings may contribute to understanding the antidepressant effect of ketamine at the system level, supporting modes of action on networks subserving aberrant arousal regulation in depression

Rostral Anterior Cingulate Glutamine/Glutamate Disbalance in Major Depressive Disorder Depends on Symptom Severity

Background Patients with major depressive disorder (MDD) show glutamatergic deficits in the ventral anterior cingulate cortex. The glutamine/glutamate (Gln/Glu) ratio was proposed to be connected to glutamatergic cycling, which is hypothesized to be dysregulated in MDD. As an indicator of regional metabolite status, this ratio might be a robust state marker sensitive to clinical heterogeneity. Methods Thirty-two MDD patients (mean age 40.88 ± 13.66 years, 19 women) and control subjects (mean age 33.09 ± 8.24 years, 19 women) were compared for pregenual anterior cingulate cortex levels of Gln/Glu, Gln/total creatine (tCr), Glu/tCr, and gamma-aminobutyric acid/tCr as determined by high-field magnetic resonance spectroscopy. We tested if symptom severity (Hamilton Depression Rating Scale) and anhedonia (Snaith-Hamilton Pleasure Scale) influence the relation of metabolites to clinical symptoms. Results MDD patients showed higher Gln/Glu. This was driven by marginally higher Gln/tCr and nonsignificantly lower Glu/tCr. Groups defined by severity moderated relationship between Gln/Glu and the Hamilton Depression Rating Scale. Moreover, severe cases differed from both control subjects and moderate cases. Groups defined by the Snaith-Hamilton Pleasure Scale also displayed differential relationship between Gln/Glu and levels of anhedonia, predominantly driven by Gln/tCr. Conclusions We elaborate previous accounts of metabolite deficits in the anterior cingulate cortex toward increased Gln/Glu. There is a moderated relationship between severity and the ratio, which suggests consideration of different mechanisms or disease state for the respective subgroups in future studies