The Effects of a Ketogenic Diet on Patients with Dihydrolipoamide Dehydrogenase Deficiency

Background: Dihydrolipoamide dehydrogenase (DLD lipoamide dehydrogenase, the E3 subunit of the pyruvate dehydrogenase complex (PDHC)) is the third catalytic enzyme of the PDHC, which converts pyruvate to acetyl-CoA catalyzed with the introduction of acetyl-CoA to the tricyclic acid (TCA) cycle. In humans, PDHC plays an important role in maintaining glycose homeostasis in an aerobic, energy-generating process. Inherited DLD-E3 deficiency, caused by the pathogenic variants in DLD, leads to variable presentations and courses of illness, ranging from myopathy, recurrent episodes of liver disease and vomiting, to Leigh disease and early death. Currently, there is no consensus on treatment guidelines, although one suggested solution is a ketogenic diet (KD). Objective: To describe the use and effects of KD in patients with DLD-E3 deficiency, compared to the standard treatment. Results: Sixteen patients were included. Of these, eight were from a historical cohort, and of the other eight, four were on a partial KD. All patients were homozygous for the D479V (or D444V, which corresponds to the mutated mature protein without the mitochondrial targeting sequence) pathogenic variant in DLD. The treatment with partial KD was found to improve patient survival. However, compared to a historical cohort, the patients’ quality of life (QOL) was not significantly improved. Conclusions: The use of KD offers an advantage regarding survival; however, there is no significant improvement in QOL.     

Personalised treatment for cognitive dysfunction in individuals with schizophrenia spectrum disorders

Cognitive deficits are a well-recognised issue for individuals diagnosed with schizophrenia spectrum disorders. Despite positive group findings for the use of cognitive remediation (CR) interventions, there are substantial individual differences in response to treatment. In addition, the aggregate CR literature reports low moderate effect sizes for cognitive and functional outcomes. Based on personalised medicine theory, this paper uses extant CR literature to examine the individual characteristics determined to predict treatment response. These characteristics, which fall into the broad categories of cognitive, psychological, and biological can be used as tailoring variables to personalise CR to an individual’s unique profile. Personalisation through the use of these tailoring variables has the potential to improve the delivery of CR to maximise treatment outcomes.     

Major underestimation and overestimation of visual blood loss during cesarean deliveries: can they be predicted?

Purpose

The surgeons’ visual estimation is the most widely used method for estimating blood loss (BL) while performing cesarean deliveries (CDs). Major BL underestimation may adversely influence obstetric decision making, and result in delaying interventions. Major BL overestimation may result in unnecessary costly interventions. Therefore, we aimed to identify independent predictors for major BL underestimation and overestimation during CDs.

Methods

All CDs performed between 11/2008 and 6/2016, in a university-affiliated hospital, were reviewed for demographic and surgical data, including the surgeons’ reported estimated BL (EBL). Calculated BL (CBL) was calculated by multiplying the calculated maternal blood volume by the percent of hematocrit decrease. Multivariate logistic regressions were performed to identify independent risk factors for major BL underestimation (CBL?EBL ≥ 400 ml) and overestimation (EBL?CBL ≥ 400 ml).

Results

During the study period, 3655 CDs were analyzed, of which 420 met the criterion for major BL underestimation and 1214 for major BL overestimation. Urgent surgery (aOR = 2.83; 95% CI 2.06–3.89), general anesthesia (aOR = 2.39; 95% CI 1.71–3.33), and higher surgeon experience (aOR = 1.03; 95% CI 1.01–1.06) were found to be independent risk factors for major BL underestimation, while any previous CD (aOR = 0.47; 95% CI 0.33–0.67) decreased the risk of underestimation. Any previous CD (aOR = 1.29; 95% CI 1.05–1.58) and intra-abdominal adhesions (aOR = 1.37; 95% CI 1.11–1.70) were found to be independent risk factors for major BL overestimation, while urgent CD (aOR = 0.50; 95% CI 0.41–0.60) decreased the risk of overestimation.

Conclusion

Various factors can predict major underestimation and overestimation of BL during CDs. Recognizing these factors can assist in the interpretation of visual EBL and improve obstetric decision making.

     

The desmosterolosis phenotype: spasticity, microcephaly and micrognathia with agenesis of corpus callosum and loss of white matter

Desmosterolosis is a rare autosomal recessive disorder of elevated levels of the cholesterol precursor desmosterol in plasma, tissue and cultured cells. With only two sporadic cases described to date with two very different phenotypes, the clinical entity arising from mutations in 24-dehydrocholesterol reductase (DHCR24) has yet to be defined. We now describe consanguineous Bedouin kindred with four surviving affected individuals, all presenting with severe failure to thrive, psychomotor retardation, microcephaly, micrognathia and spasticity with variable degree of hand contractures. Convulsions near birth, nystagmus and strabismus were found in most. Brain MRI demonstrated significant reduction in white matter and near agenesis of corpus callosum in all. Genome-wide linkage analysis and fine mapping defined a 6.75 cM disease-associated locus in chromosome 1 (maximum multipoint LOD score of six), and sequencing of candidate genes within this locus identified in the affected individuals a homozygous missense mutation in DHCR24 leading to dramatically augmented plasma desmosterol levels. We thus establish a clear consistent phenotype of desmosterolosis (MIM 602398).     

Novel and Simple Carbon-11-Labeled Ammonium Salts as PET Agents for Myocardial Perfusion Imaging

Background  

Positron emission tomography (PET) has clear advantages over single photon emission computed tomography (SPECT) in the field of myocardial perfusion scintigraphy (MPS); however, there are just a small number of efficient PET tracers available today for MPS. We sought to develop and perform a preliminary biological evaluation of novel carbon-11-labeled ammonium salts as potential MPS PET agents.     

Expectancy-Value Theory in Persistence of Learning Effects in Schizophrenia: Role of Task Value and Perceived Competency

Expectancy-value theory, a widely accepted model of motivation, posits that expectations of success on a learning task and the individual value placed on the task are central determinants of motivation to learn. This is supported by research in healthy controls suggesting that beliefs of self-and-content mastery can be so influential they can predict the degree of improvement on challenging cognitive tasks even more so than general cognitive ability. We examined components of expectancy-value theory (perceived competency and task value), along with baseline arithmetic performance and neuropsychological performance, as possible predictors of learning outcome in a sample of 70 outpatients with schizophrenia randomized to 1 of 2 different arithmetic learning conditions and followed up after 3 months. Results indicated that as with nonpsychiatric samples, perceived self-competency for the learning task was significantly related to perceptions of task value attributed to the learning task. Baseline expectations of success predicted persistence of learning on the task at 3-month follow-up, even after accounting for variance attributable to different arithmetic instruction, baseline arithmetic ability, attention, and self-reports of task interest and task value. We also found that expectation of success is a malleable construct, with posttraining improvements persisting at follow-up. These findings support the notion that expectancy-value theory is operative in schizophrenia. Thus, similar to the nonpsychiatric population, treatment benefits may be enhanced and better maintained if remediation programs also focus on perceptions of self-competency for the training tasks. Treatment issues related to instilling self-efficacy in cognitive recovery programs are discussed.     

Structural analysis of receptors and actin polarity in platelet protrusions

During activation the platelet cytoskeleton is reorganized, inducing adhesion to the extracellular matrix and cell spreading. These processes are critical for wound healing and clot formation. Initially, this task relies on the formation of strong cellular–extracellular matrix interactions, exposed in subendothelial lesions. Despite the medical relevance of these processes, there is a lack of high-resolution structural information on the platelet cytoskeleton controlling cell spreading and adhesion. Here, we present in situ structural analysis of membrane receptors and the underlying cytoskeleton in platelet protrusions by applying cryoelectron tomography to intact platelets. We utilized three-dimensional averaging procedures to study receptors at the plasma membrane. Analysis of substrate interaction-free receptors yielded one main structural class resolved to 26 Å, resembling the α_IIbβ₃ integrin folded conformation. Furthermore, structural analysis of the actin network in pseudopodia indicates a nonuniform polarity of filaments. This organization would allow generation of the contractile forces required for integrin-mediated cell adhesion.

Platelets are activated to form a primary adhesion at injured vessels, which leads to their aggregation and clot formation (1, 2). These processes are mediated by the activation of several adhesion receptors and downstream signaling pathways, leading to actomyosin contractility (3–5). These signals include changes in the organization of the cytoskeleton, causing distinct morphological remodeling (6). This process is followed by extensive actin polymerization, forming multiple pseudopodia, filopodia-like structures/microspikes (7).Through polymerization, F-actin pushes the cell membrane outwards, forming protruding structures, such as lamellipodia and filopodia (8). The organization of the filaments has a major impact on the interaction of the cytoskeletal network with the extracellular matrix (ECM). The mechanism of actin filament remodeling and the polarity of each filament within a platelet is still not clear. Understanding these aspects of the actin network would allow fine-grained modeling of cytoskeletal-based mechanical processes (9). Moreover, integrin-mediated cell adhesion of these cellular protrusions to the ECM, in addition to contractile force generation by myosin II (10), are crucial for platelets adhesion and the wound-healing process (11).A major family of platelet adhesion receptors (i.e., integrins) mediate a firm adhesion to exposed ECM molecules of endothelial lesions, leading to platelet contraction via binding of soluble integrin ligands, such as fibrinogen and plasma fibronectin (12). Since platelet integrins are continuously exposed to their soluble ligands, their activity must be tightly controlled to avoid deregulated thrombus formation. The integrin α_IIbβ₃ is the most abundant platelet integrin receptor, initiating platelet attachment to fibrinogen (13).Structural analysis of integrin receptors has been conducted mainly using purified receptors (14–16). Atomic resolution structural determination of the extracellular domains by X-ray crystallography provided fundamental information on integrin organization, while NMR spectroscopy of the intracellular tail and transmembrane domains resolved the organization of the membrane domain (17, 18). Two-dimensional (2D) and three-dimensional (3D) negative-stain electron microscopy provided information on the active and inactive conformations of the receptor (14, 19). Integrin activation models based on these studies suggest that the integrins have at least two conformational states: a low-affinity state, where the protein is in a bent position, imaged with X-ray crystallography (15), and a high-affinity state, where the receptor is thought to be in an extended position. More recently, the structure of the α_IIbβ₃ headpiece in complex with an antagonist was resolved by cryoelectron microscopy (cryo-EM) (20), further hinting at the integrin mode of function. However, despite this progress, contradicting views on the mechanism of integrin activation remain.The receptor structure has been further studied in its hydrated state by single-particle analysis, where the full-length protein was reconstituted in nanodiscs (21). That study demonstrated it is possible to observe extended and bent conformations, along with two intermediate conformations. The authors suggested that the integrin is in equilibrium between these conformations, and they observed that the presence of talin head domain and RGD peptide changes the relative proportion of the receptor in these conformations. This evidence proposes that the presence of physiological binders and the receptor’s environment may influence its conformations, thus indicating the necessity of resolving the integrin structure in situ.Here, we studied the structure of receptors, in situ, using human platelets spread on EM grids in the presence of divalent ions. For that purpose, we utilized cryoelectron tomography (cryo-ET), and its ability to acquire in situ structural information using intact cells. Since platelets are thin specimens lacking a nucleus, they are suitable for cryo-ET. Additionally, the α_IIbβ₃ integrin heterodimer is highly abundant, with 100,000 receptors per platelet (22). These factors make platelets ideal targets for this study. Structural information was obtained through subtomogram averaging and classification, providing insight into the structure of the most abundant platelet receptor. Additionally, we analyzed the cytoskeletal architecture of intact mouse platelets using cryo-ET. The tensile actomyosin cytoskeleton exerts forces, through integrins, onto the ECM, and thereby plays a major role in platelet spreading and contraction (23). Our analysis of the cytoskeleton architecture and actin polarity revealed a nonuniform polarity of actin in pseudopodia platelet protrusions.     

A phase II study of intra-arterial cisplatin with concurrent radiation and erlotinib for locally advanced head and neck cancer

Background

Based on the convenient oral dosing of erlotinib and the promising results of biologic therapy, we undertook a phase II study with 21 patients with locally advanced (T3–4) lesions combining radiation with intra-arterial (IA) cisplatin and oral daily erlotinib for a 7-week therapy.

Methods

Treatment for the primary tumor and upper neck was given to a total dose of 70 Gy. Chemotherapy with IA cisplatin (150 mg/m²) was given on days 1, 8, 15, and 22 concurrently with radiotherapy. During the 7-week treatment period, patients were given erlotinib 150 mg/day.

Results

Overall survival is 63 %, and the relapse/persistent disease rate stands at 36.8 %. A total of 15.2 % of serious adverse event was considered related to erlotinib.

Conclusion

Our study and several others now demonstrate the feasibility of combining anti-epidermal growth factor receptor (EGFR) therapy with chemoradiation, hint at improved survival outcomes with reduced distant metastatic rates, and suggest that maintenance therapy with anti-EGFR agent may be beneficial.