Oscillatory network markers of subcallosal cingulate deep brain stimulation for depression.

Identifying functional biomarkers related to treatment success can aid in expediting therapy optimization, as well as contribute to a better understanding of the neural mechanisms of the treatment-resistant depression (TRD) and subcallosal cingulate deep brain stimulation (SCC-DBS). Magnetoencephalography data were obtained from 16 individuals with SCC-DBS for TRD and 25 healthy subjects. The first objective of the study was to identify region-specific oscillatory modulations that both (i) discriminate individuals with TRD (with SCC-DBS OFF) from healthy controls, and (ii) discriminate TRD treatment responders from non-responders (with SCC-DBS ON). The second objective of this work was to further explore the effects of stimulation intensity and frequency on oscillatory activity in the identified brain regions of interest. Oscillatory power analyses led to the identification of brain regions that differentiated responders from non-responders based on modulations of increased alpha (8-12 Hz) and decreased gamma (32-116 Hz) power within nodes of the default mode, central executive, and somatomotor networks, Broca's area, and lingual gyrus. Within these nodes, it was also found that low stimulation frequency had stronger effects on oscillatory modulation than increased stimulation intensity. The identified functional network biomarkers implicate modulation of TRD-related activity in brain regions involved in emotional control/processing, motor control, and the interaction between speech, vision, and memory, which have all been implicated in depression. These electrophysiological biomarkers have the potential to be used as functional proxies for therapy optimization. Additional stimulation parameter analyses revealed that oscillatory modulations can be strengthened by increasing stimulation intensity or reducing frequency, which may represent potential avenues of direction in non-responders.

New KCNN4 Variants Associated With Anemia: Stomatocytosis Without Erythrocyte Dehydration.

The K+ channel activated by the Ca2+, KCNN4, has been shown to contribute to red blood cell dehydration in the rare hereditary hemolytic anemia, the dehydrated hereditary stomatocytosis. We report two de novo mutations on KCNN4, We reported two de novo mutations on KCNN4, V222L and H340N, characterized at the molecular, cellular and clinical levels. Whereas both mutations were shown to increase the calcium sensitivity of the K+ channel, leading to channel opening for lower calcium concentrations compared to WT KCNN4 channel, there was no obvious red blood cell dehydration in patients carrying one or the other mutation. The clinical phenotype was greatly different between carriers of the mutated gene ranging from severe anemia for one patient to a single episode of anemia for the other patient or no documented sign of anemia for the parents who also carried the mutation. These data compared to already published KCNN4 mutations question the role of KCNN4 gain-of-function mutations in hydration status and viability of red blood cells in bloodstream.

A Deep Learning-Based Approach to Reduce Rescan and Recall Rates in Clinical MRI Examinations.

BACKGROUND AND PURPOSE: MR imaging rescans and recalls can create large hospital revenue loss. The purpose of this study was to develop a fast, automated method for assessing rescan need in motion-corrupted brain series. MATERIALS AND METHODS: A deep learning-based approach was developed, outputting a probability for a series to be clinically useful. Comparison of this per-series probability with a threshold, which can depend on scan indication and reading radiologist, determines whether a series needs to be rescanned. The deep learning classification performance was compared with that of 4 technologists and 5 radiologists in 49 test series with low and moderate motion artifacts. These series were assumed to be scanned for 2 scan indications: screening for multiple sclerosis and stroke. RESULTS: The image-quality rating was found to be scan indication- and reading radiologist-dependent. Of the 49 test datasets, technologists created a mean ratio of rescans/recalls of (4.7 ± 5.1)/(9.5 ± 6.8) for MS and (8.6 ± 7.7)/(1.6 ± 1.9) for stroke. With thresholds adapted for scan indication and reading radiologist, deep learning created a rescan/recall ratio of (7.3 ± 2.2)/(3.2 ± 2.5) for MS, and (3.6 ± 1.5)/(2.8 ± 1.6) for stroke. Due to the large variability in the technologists' assessments, it was only the decrease in the recall rate for MS, for which the deep learning algorithm was trained, that was statistically significant (P = .03). CONCLUSIONS: Fast, automated deep learning-based image-quality rating can decrease rescan and recall rates, while rendering them technologist-independent. It was estimated that decreasing rescans and recalls from the technologists' values to the values of deep learning could save hospitals $24,000/scanner/year.

Relationship between BDNF expression in major striatal afferents, striatum morphology and motor behavior in the R6/2 mouse model of Huntington's disease.

Patients with Huntington's disease (HD) and transgenic mouse models of HD show neuronal loss in the striatum as a major feature, which contributes to cognitive and motor manifestations. Reduced expression of the neurotrophin brain-derived neurotrophic factor (BDNF) in striatal afferents may play a role in neuronal loss. How progressive loss of BDNF expression in different cortical or subcortical afferents contributes to striatal atrophy and behavioral dysfunction in HD is not known, and may best be determined in animal models. We compared age-dependent alterations of BDNF mRNA expression in major striatal afferents from the cerebral cortex, thalamus and midbrain in the R6/2 transgenic mouse model of HD. Corresponding changes in striatal morphology were quantified using unbiased stereology. Changes in motor behavior were measured using an open field, grip strength monitor, limb clasping and a rotarod apparatus. BDNF expression in cortical limbic and midbrain striatal afferents is reduced by age 4 weeks, prior to onset of motor abnormalities. BDNF expression in motor cortex and thalamic afferents is reduced by 6 weeks, coinciding with early motor dysfunction and reduced striatum volume. BDNF loss in afferents progresses until death at 13-15 weeks, correlating with progressive striatal neuronal loss and motor abnormalities. Mutant huntingtin protein expression in R6/2 mice results in progressive loss of BDNF in both cortical and subcortical striatal afferents. BDNF loss in limbic and dopaminergic striatal inputs may contribute to cognitive/psychiatric dysfunction in HD. Subsequent BDNF loss in cortical motor and thalamic afferents may accelerate striatal degeneration, resulting in progressive involuntary movements.

Comparison of three real-time PCR methods with blood smears and rapid diagnostic test in Plasmodium sp. infection.

In cases of malaria, rapid and accurate diagnosis of Plasmodium sp. is essential. In this study three different quantitative, real-time PCR methods were compared with routine methods used for malaria diagnosis. A comparative study was conducted prospectively in the laboratories of Montpellier and Nîmes University Hospitals. The methods used for routine diagnostic malaria testing consisted of microscopic examination of Giemsa-stained blood smears and rapid diagnostic tests. Three quantitative real-time PCR methods (qRT-PCR) were tested: qRT-PCR1 amplified a specific sequence on the P. falciparum Cox1 gene, qRT-PCR2 amplified a species-specific region of the multicopy 18S rDNA, and qRT-PCR3 amplified a mitochondrial DNA sequence. Among the 196 blood samples collected, 73 samples were positive in at least one of the five tests. Compared with the routine method, there were no false negatives for P. falciparum diagnosis in either qRT-PCR1 or qRT-PCR3. In all P. ovale, P. vivax and P. malariae infections diagnosed from blood smears, qRT-PCR1 was negative, as expected, whereas qRT-PCR2 and qRT-PCR3 were positive and concordant (simple kappa coefficient = 1). One negative sample from microscopy was positive with both qRT-PCR2 and qRT-PCR3. Together, qRT-PCR3 and the combined qRT-PCR1 and qRT-PCR2 were concordant with routine methods for malaria diagnosis (99% and 99.5%, respectively). These three rapid, molecular qRT-PCR methods, used alone or in association, showed excellent results, with high concordance, accuracy and reliability in malaria diagnosis.

Preparing public participation at the catchment level: comparison of three methodologies applied to the Hérault river basin.

Public participation in water resources management has increasingly been recommended to increase the effectiveness and the acceptability of proposed water management projects and plans. Different levels of public participation are possible depending on the governance context. This paper reports on the practical implementation of three different methodologies in the Hérault river catchment (France). The analysis of public view points, carried out using a quantitative opinion survey and focus groups, reveals important information needs which have to be fulfilled for any further consultation to be efficient. A complementary analysis of stakeholders' opinions, carried out through semi-structured interviews also highlights the need to construct a common knowledge base between stakeholders, expert and scientists. This is seen as a prerequisite to implementing more elaborated forms of participation.

Cellular expression of functional chemokine receptor CCR5 and CXCR4 in human embryonic neurons.

In the present study we analysed expression of the chemokine receptors CCR5 and CXCR4 in human embryonic neurons. Both receptors were detected in neurons from primary cultures by immunofluorescence and confocal laser microscopy analysis. Both CCR5 and CXCR4 were mainly located inside the cell in the neuronal cell body and processes. In addition, neurons synthesised CCR5 and CXCR4 transcripts, as demonstrated by reverse transcription-polymerase chain reaction. Stimulation with the CCR5 and the CXCR4 agonists increased [Ca(2+)](i) in embryonic neurons, indicating that CXCR4 and CCR5 were functional at the neuronal surface. The inhibitory effect of pertussis toxin demonstrated that G(i)alpha protein is involved in chemokine receptor activation. The fact that chemokine receptors are expressed at embryonic stage in neurons reinforces the idea that chemokines might be cues for neuron pathfinding during brain ontogeny.

Isolated human astrocytes are not susceptible to infection by M- and T-tropic HIV-1 strains despite functional expression of the chemokine receptors CCR5 and CXCR4.

Within the brain, HIV-1 targets the microglia and astrocytes. Previous studies have reported that viral entry into astrocytes is independent of CD4, in contrast to microglia. We aimed to determine whether chemokine receptors play a role in mediating CD4-independent HIV-1 entry into astrocytes. We found that embryonic astrocytes and microglial cells express CCR5, CCR3, and CXCR4 transcripts. Intracellular calcium levels in astrocytes were found to increase following application of RANTES, MIP-1beta (CCR5-agonist), SDF-1alpha (CXCR4-agonist), but not eotaxin (CCR3-agonist). In microglial cells, eotaxin was also able to modulate internal calcium homeostasis. CD4 was not present at the cell surface of purified astrocytes but CD4 mRNA could be detected by RT-PCR. Neither HIV-1(9533) (R5 isolate) nor HIV-1(LAI) (X4 isolate) penetrated into purified astrocytes. In contrast, mixed CNS cell cultures were infected by HIV-1(9533) and this was inhibited by anti-CD4 mAb in 4/4 tested cultures and by anti-CCR5 mAb in 2/4. Thus, the HIV-1 R5 strain requires CD4 to penetrate into brain cells, suggesting that CCR5 cannot be used as the primary receptor for M-tropic HIV-1 strains in astrocytes. Moreover, inconstant inhibition of HIV-1 entry by anti-CCR5 mAb supports the existence of alternative coreceptors for penetration of M-tropic isolates into brain cells.

Direct role of plasma membrane-expressed gp120/41 in toxicity to human astrocytes induced by HIV-1-infected macrophages.

OBJECTIVE: To compare astrocyte toxicity induced by plasma membrane-expressed gp120/41 and soluble gp120. DESIGN: Analysis of morphological alterations and lactate dehydrogenase (LDH) release from astrocytes in culture with monocytes infected with HIV-1, microglia expressing Env of a macrophage-tropic HIV-1 isolate or soluble Env. METHODS: Primary human embryonic astrocytes were cultured with: monocytes infected with two M-tropic HIV-1 isolates (HIV-1(9533), HIV-1(BX08)); human microglia infected with the defective Semliki Forest virus (SFV) vector coding for the env gene of HIV-1(BX08) isolate (SFVenvBX08); and soluble gp140 purified from baby hamster kidney cells transfected with the env gene of HIV-1(BX08) lacking the intracytoplasmic region of gp41 (SFVdelta envBX08). Gp120 mRNA levels were assessed by quantitative reverse transcriptase-polymerase chain reaction and the protein was detected by immunofluorescence in infected monocytes or microglia. RESULTS: Contact of HIV-infected monocytes induced morphological changes in astrocytes and a 137% increase in LDH release at day 2 of co-culture compared with controls (uninfected monocytes). Gp120/41(BX08)-expressing microglia induced a 170% increase in LDH release (relative to SFVLacZ-infected microglia). Pretreatment of co-cultures with an anti-gp120 monoclonal antibody (mAb; NEA-9305) directed against the V3 loop inhibited LDH release. Soluble purified gp140 from BX08 isolate induced only a weak LDH release (104%). Finally, cytotoxicity was not blocked by treatment of the co-culture with Bordetella pertussis toxin, an inhibitor of Gi alpha protein-dependent receptors. CONCLUSION: HIV envelope glycoprotein expressed at the plasma membrane induced astrocyte damage more efficiently than its soluble counterpart. The V3 loop was involved in toxicity induction through a pathway independent of the Gi alpha protein-coupled receptor.