Effects of antidepressant treatment on mice lacking brain‐derived neurotrophic factor expression through promoter IV

Brain‐derived neurotrophic factor (BDNF) is implicated in the pathophysiology of major depression; mice lacking BDNF expression through promoter IV (BDNF‐KIV) exhibit a depression‐like phenotype. We tested our hypothesis that deficits caused by promoter IV deficiency (depression‐like behavior, decreased levels of BDNF, and neurogenesis in the hippocampus) could be rescued by a 3‐week treatment with different types of antidepressants: fluoxetine, phenelzine, duloxetine, or imipramine. Each antidepressant reduced immobility time in the tail suspension test without affecting locomotor activity in the open field test in both BDNF‐KIV and control wild type mice, except that phenelzine increased locomotor activity in wild type mice and anxiety‐like behavior in BDNF‐KIV mice. The antidepressant treatments were insufficient to reverse decreased BDNF levels caused by promoter IV deficiency. No antidepressant treatment increased the hippocampal progenitors of either genotype, whereas phenelzine decreased the surviving progenitors in both genotypes. The antidepressant treatments differently affected the dendritic extension of hippocampal immature neurons: fluoxetine and imipramine increased extension in both genotypes, duloxetine increased it only in BDNF‐KIV mice, and phenelzine decreased it only in wild type mice. Interestingly, a saline‐only injection increased neurogenesis and dendrite extensions in both genotypes. Our results indicate that the behavioral effects in the tail suspension test by antidepressants do not require promoter IV‐driven BDNF expression and occur without a detectable increase in hippocampal BDNF levels and neurogenesis but may involve increased dendritic reorganisation of immature neurons. In conclusion, the antidepressant treatment demonstrated limited efficacy; it partially reversed the defective phenotypes caused by promoter IV deficiency but not hippocampal BDNF levels.     

Outcome after decompressive craniectomy in patients with dominant middle cerebral artery infarction: A preliminary report

Introduction:

Life-threatening, space occupying, infarction develops in 10-15% of patients after middle cerebral artery infarction (MCAI). Though decompressive craniectomy (DC) is now standard of care in patients with non-dominant stroke, its role in dominant MCAI (DMCAI) is largely undefined. This may reflect the ethical dilemma of saving life of a patient who may then remain hemiplegic and dysphasic. This study specifically addresses this issue.

Materials and Methods:

This retrospective analysis studied patients with DMCAI undergoing DC. Patient records, operation notes, radiology, and out-patient files were scrutinized to collate data. Glasgow outcome scale (GOS), Barthel index (BI) and improvement in language and motor function were evaluated to determine functional outcome.

Results:

Eighteen patients between 22 years and 72 years of age were included. 6 week, 3 month, 6 month and overall survival rates were 66.6% (12/18), 64% (11/17), 62.5% (10/16) and 62.5% (10/16) respectively. Amongst ten surviving patients with long-term follow-up, 60% showed improvement in GOS, 70% achieved BI score >60 while 30% achieved full functional independence. In this group, motor power and language function improved in 9 and 8 patients respectively. At last follow-up, 8 of 10 surviving patients were ambulatory with (3/8) or without (5/8) support. Age <50 years corresponded with better functional outcome amongst survivors (P value –0.0068).

Conclusion:

Language and motor outcomes after DC in patients with DMCAI are not as dismal as commonly perceived. Perhaps young patients (<50 years) with DMCAI should be treated with the same aggressiveness that non-DMCAI is currently dealt with.Key Words: Craniectomy, dominant, middle cerebral artery, outcome, stroke     

Moiréless correlations in ABCA graphene

Atomically thin van der Waals materials stacked with an interlayer twist have proven to be an excellent platform toward achieving gate-tunable correlated phenomena linked to the formation of flat electronic bands. In this work we demonstrate the formation of emergent correlated phases in multilayer rhombohedral graphene––a simple material that also exhibits a flat electronic band edge but without the need of having a moiré superlattice induced by twisted van der Waals layers. We show that two layers of bilayer graphene that are twisted by an arbitrary tiny angle host large (micrometer-scale) regions of uniform rhombohedral four-layer (ABCA) graphene that can be independently studied. Scanning tunneling spectroscopy reveals that ABCA graphene hosts an unprecedentedly sharp van Hove singularity of 3–5-meV half-width. We demonstrate that when this van Hove singularity straddles the Fermi level, a correlated many-body gap emerges with peak-to-peak value of 9.5 meV at charge neutrality. Mean-field theoretical calculations for model with short-ranged interactions indicate that two primary candidates for the appearance of this broken symmetry state are a charge-transfer excitonic insulator and a ferrimagnet. Finally, we show that ABCA graphene hosts surface topological helical edge states at natural interfaces with ABAB graphene which can be turned on and off with gate voltage, implying that small-angle twisted double-bilayer graphene is an ideal programmable topological quantum material.

Two-dimensional (2D) van der Waals heterostructures with an interlayer twist have provided a new avenue for observing emergent tunable many-body electron phenomena. Recent experimental realizations include twisted bilayer graphene (tBG) near the so-called “magic angle” of 1.1° (1–3), twisted double-bilayer graphene (tDBG) (4–6), ABC trilayer graphene on near-perfectly aligned hexagonal boron nitride (hBN) (ABC-tLG/hBN) (7, 8) and transition-metal dichalcogenide heterostructures (9–12) [with predictions on a variety of other systems (13, 14)]. All of these systems host an interplay of two phenomena––the presence of one or more van Hove singularities (which we colloquially refer to as “flat bands” henceforth) at low energy where the density of states is sharply peaked, and the existence of a moiré pattern that creates a unit cell that is about a hundred times larger than the carbon–carbon nearest-neighbor distance in graphene. The large number of electrons with quenched kinetic energy make the flat bands conducive to interaction-driven phases (15). The enlarged moiré unit cell is thought to reduce both the flat-band bandwidth and the interaction energy scales, and also introduces easily accessible integer fillings that create Mott-like insulating states (1–12), the relation of which to nearby superconductivity is debated. A natural question that arises from all of these works is whether the moiré pattern is a necessary condition for the observation of correlated many-body phases, or whether it is simply sufficient to further reduce the flat-band bandwidth and hence the kinetic energy in the heterostructure.In this regard, multilayer rhombohedral (ABC) graphene offers a different perspective toward achieving a flat-band edge without the use of a moiré potential (16). Indeed, in a seminal work (17), it was theoretically shown that the low-energy band structure of multilayer rhombohedral graphene has a sharply peaked density of state (DOS), with the band structure E(k)∝kN (where N is the number of layers) at low energy in the nearest-neighbor hopping approximation. This implies a peak in the DOS at charge neutrality in this material for N>2, with an appreciable fraction of the entire band within this peak (18). Indeed, this physics is already at play in ABC-tLG/hBN (7, 8), where some of the flatness of the bands comes from the intrinsic band structure of ABC graphene, which is then further flattened and isolated by the moiré pattern from the hBN alignment. A facile alternative to flatten the bandwidth without introducing a moiré potential is to simply increase the number of layers of the rhombohedral stacked graphene. Unfortunately, isolating rhombohedral stacked graphene of any thickness is extremely difficult as it is less energetically favorable than the multilayer counterpart, Bernal stacked graphene. Since the difference between rhombohedral and Bernal graphene is simply a lattice shift, and the interlayer van der Waals forces are weak, it is well known that rhombohedral graphene reverts to the Bernal form when samples are processed with heat, pressure, or while performing lithography (19). In this work, we show that twisting two sheets of tDBG by a tiny (<0.1°) angle is a simple and robust method to create large area (up to micrometer-scale) rhombohedral graphene of four-layer thickness (ABCA graphene). We present gate-tunable scanning tunneling microscopy and spectroscopy (STM/STS) measurements at 5.7 K on these regions. We show that correlated phases can be achieved without the need for a moiré pattern and that rhombohedral graphene has unique topological properties.     

Normative MDCT Cross-Sectional Data Estimation of Superior Vena Cava and Innominate Vein in Growing Children Using Age as a Predictor

This retrospective study aimed to determine the superior vena cava (SVC) and left innominate vein (INV) normative cross-sectional area in children noninvasively using age as a predictor and also to compare the correlation of the area measured with the diameter on multidetector computed tomography (MDCT). Analysis of the SVC-INV cross-sectional area was performed for 73 consecutive patients. The cross-sectional area of the SVC-INV was manually estimated. A regression analysis was performed for the cross-sectional area and age separately, and regression equations were compared. One-way analysis of variance (ANOVA) was performed to evaluate significant differences in the area means according to age groups. Regression analysis showed that age can be a predictor for the area of the SVC (50.6 mm² + 1.01 × age), te INV (48.3 mm² + 0.93 × age), and the left SVC-INV junction (47.2 mm² + 0.92 × age), with respective R ² values of 93, 88 and 94 %. The comparative evaluation of the cross-sectional area and the diameter measurement of SVC showed that the cross-sectional area was more closely associated with the increasing age of the cohort (R ² of 68 vs. 61 %) than the measured diameter. For a cohort of patients without congenital or acquired heart disease, MDCT can be used as a complementary test for a normative cross-sectional normogram area database of SVC-INV using age as a predictor.     

Phase I dose-escalation trial of the oral AKT inhibitor uprosertib in combination with the oral MEK1/MEK2 inhibitor trametinib in patients with solid tumors

This study aimed to determine the safety, tolerability, and recommended phase II doses of trametinib plus uprosertib (GSK2141795) in patients with solid tumors likely to be sensitive to MEK and/or AKT inhibition. This was a phase I, open-label, dose-escalation, and dose-expansion study in patients with triple-negative breast cancer or BRAF-wild type advanced melanoma. The primary outcome of the expansion study was investigator-assessed response. Among 126 enrolled patients, 63 received continuous oral daily dosing of trametinib and uprosertib, 29 received various alternative dosing schedules, and 34 were enrolled into expansion cohorts. Doses tested in the expansion cohort were trametinib 1.5 mg once daily (QD) + uprosertib 50 mg QD. Adverse events (AEs) were consistent with those reported in monotherapy studies but occurred at lower doses and with greater severity. Diarrhea was the most common dose-limiting toxicity; diarrhea and rash were particularly difficult to tolerate. Overall, 59% and 6% of patients reported AEs with a maximum severity of grade 3 and 4, respectively. Poor tolerability prevented adequate delivery of uprosertib with trametinib at a concentration predicted to have clinical activity. The study was terminated early based on futility in the continuous-dosing expansion cohorts and a lack of pharmacological or therapeutic advantage with intermittent dosing. The objective response rate was < 5% (1 complete response, 5 partial responses). Continuous and intermittent dosing of trametinib in combination with uprosertib was not tolerated, and minimal clinical activity was observed in all schedules tested.     

Paediatric rehabilitation in a developing country—India in relation to aetiology,consequences and outcome in a group of 459 burnt children

Age, aetiology of burn, percentage body surface area burnt and post-burn sequelae have a direct relationship to the rehabilitative necessity in burnt children in a developing country—India. In spite of the gross disfigurements and sequelae, only adolescent children required psychosocial rehabilitation. These are the results following a retrospective analysis of 459 paediatric burn patients in Madras, India.     

Fos and Jun potentiate individual release sites and mobilize the reserve synaptic-vesicle pool at the Drosophila larval motor synapse

In all nervous systems, short-term enhancement of transmitter release is achieved by increasing the weights of unitary synapses; in contrast, long-term enhancement, which requires nuclear gene expression, is generally thought to be mediated by the addition of new synaptic vesicle release sites. In Drosophila motor neurons, induction of AP-1, a heterodimer of Fos and Jun, induces cAMP- and CREB-dependent forms of presynaptic enhancement. Light and electron microscopic studies indicate that this synaptic enhancement is caused by increasing the weight of unitary synapses and not through the insertion of additional release sites. Electrophysiological and optical measurements of vesicle dynamics demonstrate that enhanced neurotransmitter release is accompanied by an increase in the actively cycling synaptic vesicle pool at the expense of the reserve pool. Finally, the observation that AP-1 mediated enhancement eliminates tetanus-induced forms of presynaptic potentiation suggests: (i) that reserve-pool mobilization is required for tetanus-induced short-term synaptic plasticity; and (ii) that long-term synaptic plasticity may, in some instances, be accomplished by stable recruitment of mechanisms that normally underlie short-term synaptic change.