Complete Loss Research Articles

Structure and biochemical characterization of l-2-hydroxyglutarate dehydrogenase and its role in the pathogenesis of l-2-hydroxyglutaric aciduria

l-2-hydroxyglutarate dehydrogenase (L2HGDH) is a mitochondrial membrane-associated metabolic enzyme, which catalyzes the oxidation of l-2-hydroxyglutarate (l-2-HG) to 2-oxoglutarate (2-OG). Mutations in human L2HGDH lead to abnormal accumulation of l-2-HG, which causes a neurometabolic disorder named l-2-hydroxyglutaric aciduria (l-2-HGA). Here, we report the crystal structures of Drosophila melanogaster L2HGDH (dmL2HGDH) in FAD-bound form and in complex with FAD and 2-OG and show that dmL2HGDH exhibits high activity and substrate specificity for l-2-HG. dmL2HGDH consists of an FAD-binding domain and a substrate-binding domain, and the active site is located at the interface of the two domains with 2-OG binding to the re-face of the isoalloxazine moiety of FAD. Mutagenesis and activity assay confirmed the functional roles of key residues involved in the substrate binding and catalytic reaction and showed that most of the mutations of dmL2HGDH equivalent to l-2-HGA-associated mutations of human L2HGDH led to complete loss of the activity. The structural and biochemical data together reveal the molecular basis for the substrate specificity and catalytic mechanism of L2HGDH and provide insights into the functional roles of human L2HGDH mutations in the pathogeneses of l-2-HGA.

Comparative Analysis and Assessment of Artic Sea Ice: Predictions from CMIP6 Models Amid Global Climate Change

Amid global climate change urgency, accurate model predictions are paramount for informed interventions. However, the disparity among prediction models highlights a pressing research gap requiring a deeper and more comprehensive comparison of the differences and consistency of the different models in climate change prediction. This research undertook a comprehensive analysis of 18 CMIP-6 models, aiming to provide a comprehensive comparison and cohesive prediction of ice mass and ice area from 1960 to 2050. The models consistently forecast a substantial decline in Arctic ice coverage and volume. Without marked reductions in carbon emissions, Arctic glaciers are projected to vanish entirely by the close of the century. Furthermore, the correlation analysis results indicate that there is a significant interdependence between sea ice area and sea ice mass was observed, with Pearson R2 approximately 0.908. Notably, models varied regarding the precise year of the Arctic's complete ice loss, spotlighting the inherent uncertainties of current predictions and the pressing need for mitigation measures. The study illuminates the pressing urgency for a globally coordinated response to carbon emissions and serves as a clarion call for enhanced research into the intricacies of climate change and glacier melting processes to refine future predictions.

Two-photon phototriggering of ROS storm in ruthenium(II) coordinated carbon nitride for robust cancer immunotherapy

The use of Ru(II) polypyridine complexes for photodynamic therapy is receiving much attention. Despite their promising properties, these compounds are associated with a poor excitation in the biological spectral window, a highly reduced or complete loss of the therapeutic effect under hypoxic conditions, and no immune response, limiting their application. To overcome all these limitations, herein, the coordination of Ru(II) polypyridine complexes to graphitic carbon nitride nanosheets for oxygen-self-sufficient two-photon photodynamic immunotherapy is presented. The conjugates were found with an exceptionally strong two-photon absorption and could self-sufficiently produce an ROS storm consisting of •O2-, •OH, and 1O2. Upon two-photon irradiation, the nanomaterial induced cell death in hypoxic monolayer cancer cells and multicellular tumor spheroids by a combination of apoptosis, paraptosis, ferroptosis, and immunogenic cell death. The nanomaterial was found with a strong tumor growth inhibition against the primary and secondary distant tumor in a melanoma-bearing mouse model through activation of the immune system.

Effect of ferrocene as a combustion catalyst on the premixed combustion flame characteristics of Jatropha biodiesel

Fuel additives are widely used to optimize the combustion process, reduce the harmful emissions, and improve the performance of engines. Among the metal-based additives, ferrocene is soluble in most fuels, including biodiesel. Furthermore, it is easily available and has high stability, low toxicity, and high lipophilicity. It can evenly disperse in biodiesel without causing any change in the physicochemical properties. Therefore, it can serve as an effective combustion catalyst for biodiesel. In this study, the effect of ferrocene as a combustion catalyst on the pyrolysis and combustion performance of Jatropha biodiesel is investigated. The coupled technique of thermogravimetry-Fourier transform infrared spectroscopy-mass spectrometry (TG-FTIR-MS) is used to analyze the evolution characteristics of multicomponent gaseous products generated during the pyrolysis and high-temperature oxidation of Jatropha biodiesel (JB100) and Jatropha biodiesel + ferrocene (JBF). The laminar premixed combustion flame and pollutant emissions of JB100 and JBF are examined using a variety of techniques, including OH planar laser-induced fluorescence (OH-PLIF), flue gas analysis, spectral analysis, transmission electron microscopy, etc. The results reveal that after adding ferrocene, the activation energy for the pyrolysis reaction of JB100 decreases by 4.66 kJ/mol and the complete weight loss temperature decreases by 10 ℃. Further, the addition of ferrocene reduces the endothermic heat by 0.38 mW/mg during the initial stage of the high-temperature oxidation reaction of JB100, and the amounts of final products CO2 and H2O are increased. Compared with JB100, JBF shows an enhanced OH group intensity in the combustion flame and a lower soot spectral peak. Furthermore, compared with JB100, under JBF combustion, the pollutant PM2.5 emissions decrease by 13.3 %, PM10 emissions decrease by 13.2 %, PM> 10 particulate matter emissions decrease by 19.3 %, CO emissions decrease by 6.8 %, NOx emissions increase by 21.2 %, and the size of soot particles decreases by 20.8 %.

Utility of Decremental Triggered Electromyogram for Intraoperative Neuromonitoring to Identify Midline in Posterior Myelotomy for Spinal Cord Intramedullary Lesions: Technical Note of a Novel Method.

Intramedullary spinal cord lesions are eloquent lesions that are surgically resected via posterior midline myelotomy (PMM). This treatment method carries the risk of postoperative neurological deficits. Various intraoperative neuromonitoring techniques have been used to address this concern. Our study aimed to highlight a newly developed monitoring technique (decremental-triggered electromyogram [dtEMG]) as a novel method to identify the spinal cord midline during PMM. Seven patients in prone position underwent PMM for an intramedullary lesion using dtEMG for neuromonitoring. dtEMG was used to determine the threshold amplitude (ie, the lowest amplitude to elicit an EMG response) as well as a silent zone, which was determined to be the midline. The age range was 26-73 years. dtEMG detected a silent zone in 6/7 patients. The only patient in whom dtEMG was not useful was a patient with complete paraplegia and sensory loss before surgery. There were no motor evoked or somatosensory evoked potential changes related to PMM in these patients. Although the commonly used neuromonitoring techniques, including motor and sensory evoked potentials and free-run electromyograms are of utmost importance in spinal cord surgery, they lack the potential to identify midline in such cases. The currently available tools, including dorsal column mapping, are more cumbersome to use. The newly proposed dtEMG technique can safely and efficiently identify the midline when used as an intraoperative neuromonitoring technique in PMM for spinal cord intramedullary lesion resection.

Treatment of Spinal Aneurysmal Bone Cyst with Percutaneous Injection of Hydroxyapatite Osteoconductive Cement.

The aim of this study was to evaluate treatment efficacy of percutaneous injection of hydroxyapatite-osteoconductive-cement in patients with spinal aneurysmal bone cysts. The study was designed as a retrospective observational clinical study. We included patients who were diagnosed with of spinal aneurysmal bone cyst, at our institution between 2013 and 2020, and treated with percutaneous injection of osteoconductive cement: "Cerament"® (BONESUPPORT AB, Lund, Sweden). Typical clinical and radiological features of the ABCs treatment and follow-up were investigated. Our study included nine patients, two children and seven adults. Three different types of approaches were applied: (single pedicle approach in 3 patients; double pedicle approach in 2 patients; while in the remaining cases, a multiple access approach was used. VAS score decreased from 8.5 ± 0.5 before treatment to 4.1 ± 0.9 at 6-months-follow up. All of the patients reacted well to treatment, with none neurological complications, complete loss of pain and achieved osteosclerosis as radiological marker of treatment success. Treatment of symptomatic spinal ABC's with hydroxyapatite cement is effective to achieve complete pain reduction and sclerosis.

Characterization of neural damage and neuroinflammation in Pax6 small-eye mice

Aniridia is a panocular condition characterized by a partial or complete loss of the iris. It manifests various developmental deficits in both the anterior and posterior segments of the eye, leading to a progressive vision loss. The homeobox gene PAX6 plays an important role in ocular development and mutations of PAX6 have been the main causative factors for aniridia. In this study, we assessed how Pax6-haploinsufficiency affects retinal morphology and vision of Pax6Sey mice using in vivo and ex vivo metrics. We used mice of C57BL/6 and 129S1/Svlmj genetic backgrounds to examine the variable severity of symptoms as reflected in human aniridia patients. Elevated intraocular pressure (IOP) was observed in Pax6Sey mice starting from post-natal day 20 (P20). Correspondingly, visual acuity showed a steady age-dependent decline in Pax6Sey mice, though these phenotypes were less severe in the 129S1/Svlmj mice. Local retinal damage with layer disorganization was assessed at P30 and P80 in the Pax6Sey mice. Interestingly, we also observed a greater number of activated Iba1+ microglia and GFAP + astrocytes in the Pax6Sey mice than in littermate controls, suggesting a possible neuroinflammatory response to Pax6 deficiencies.

Classifying marine mammals signal using cubic splines interpolation combining with triple loss variational auto-encoder

In practical applications of passive sonar principles for extracting characteristic frequencies of acoustic signals, scientists typically employ traditional time-frequency domain transformation methods such as Mel-frequency, Short time Fourier transform (STFT), and Wavelet transform (WT). However, these solutions still face limitations in resolution and information loss when transforming data collected over extended periods. In this paper, we present a study using a two-stage approach that combines pre-processing by Cubic-splines interpolation (CSI) with a probability distribution in the hidden space with Siamese triple loss network model for classifying marine mammal (MM) communication signals. The Cubic-splines interpolation technique is tested with the STFT transformation to generate STFT-CSI spectrograms, which enforce stronger relationships between characteristic frequencies, enhancing the connectivity of spectrograms and highlighting frequency-based features. Additionally, stacking spectrograms generated by three consecutive methods, Mel, STFT-CSI, and Wavelet, into a feature spectrogram optimizes the advantages of each method across different frequency bands, resulting in a more effective classification process. The proposed solution using an Siamese Neural Network-Variational Auto Encoder (SNN-VAE) model also overcomes the drawbacks of the Auto-Encoder (AE) structure, including loss of discontinuity and loss of completeness during decoding. The classification accuracy of marine mammal signals using the SNN-VAE model increases by 11% and 20% compared to using the AE model (2013), and by 6% compared to using the Resnet model (2022) on the same actual dataset NOAA from the National Oceanic and Atmospheric Administration - United State of America.

Exploitation of Catalytic Dyads by Short Peptide‐Based Nanotubes for Enantioselective Covalent Catalysis

AbstractExtant enzymes with precisely arranged multiple residues in their three‐dimensional binding pockets are capable of exhibiting remarkable stereoselectivity towards a racemic mixture of substrates. However, how early protein folds that possibly featured short peptide fragments facilitated enantioselective catalytic transformations important for the emergence of homochirality still remains an intriguing open question. Herein, enantioselective hydrolysis was shown by short peptide‐based nanotubes that could exploit multiple solvent‐exposed residues to create chiral binding grooves to covalently interact and subsequently hydrolyse one enantiomer preferentially from a racemic pool. Single or double‐site chiral mutations led to opposite but diminished and even complete loss of enantioselectivities, suggesting the critical roles of the binding enthalpies from the precise localization of the active site residues, despite the short sequence lengths. This work underpins the enantioselective catalytic prowess of short peptide‐based folds and argues their possible role in the emergence of homochiral chemical inventory.

Mitochondrial Acyl Carrier Protein of Leishmania major Displays Features Distinct from the Canonical Type II ACP.

Prokaryotes synthesize fatty acids using a type II synthesis pathway (FAS). In this process, the central player, i.e., the acyl carrier protein (ACP), sequesters the growing acyl chain in its internal hydrophobic cavity. As the acyl chain length increases, the cavity expands in size, which is reflected in the NMR chemical shift perturbations and crystal structures of the acyl-ACP intermediates. A few eukaryotic organelles, such as plastids and mitochondria, also harbor type II fatty acid synthesis machinery. Plastid FAS from spinach and Plasmodium falciparum has been characterized at the molecular level, but the mitochondrial pathway remains unexplored. Here, we report NMR studies of the mitochondrial acyl-acyl carrier protein intermediates of Leishmania major (acyl-LmACP). Our studies show that LmACP experiences remarkably small conformational changes upon acylation, with perturbations confined to helices II and III only. CastP determined that the cavity size of apo-LmACP (PDB entry 5ZWT) is less than that of Escherichia coli ACP (PDB 1T8K). Thus, the small chemical shift perturbations observed in the LmACP intermediates, coupled with CastP results, suggest an unusually small cavity when fully expanded. The faster rate of C8-LmACP chain hydrolysis compared to E. coli ACP (EcACP) also supports these convictions. Structure comparison of LmACP with other type II ACP disclosed unique differences in the helix I and loop I conformations, as well as several residues present there. Numerous hydrophobic residues in helix I and loop I (conserved in all mitochondrial ACPs) are substituted with hydrophilic residues in the bacterial/plastid type II ACP. For instance, Phe and leucine at positions 14 and 34 in LmACP are substituted with a hydrophilic residue and Ala in bacterial/plastid type II ACP. Mutation of Leu 34 to Ala (corresponding residue in EcACP) resulted in a complete loss of structure, underscoring its importance in maintaining the ACP fold. Thus, our NMR studies, combined with insights from the crystal structure, highlight several unique features of LmACP, distinct from the prokaryote and plastid type II ACP. Given the high sequence identity, the features might be conserved in all mitochondrial ACPs.

Exploitation of Catalytic Dyads by Short Peptide-Based Nanotubes for Enantioselective Covalent Catalysis.

Extant enzymes with precisely arranged multiple residues in their three-dimensional binding pockets are capable of exhibiting remarkable stereoselectivity towards a racemic mixture of substrates. However, how early protein folds that possibly featured short peptide fragments facilitated enantioselective catalytic transformations important for the emergence of homochirality still remains an intriguing open question. Herein, enantioselective hydrolysis was shown by short peptide-based nanotubes that could exploit multiple solvent-exposed residues to create chiral binding grooves to covalently interact and subsequently hydrolyse one enantiomer preferentially from a racemic pool. Single or double-site chiral mutations led to opposite but diminished and even complete loss of enantioselectivities, suggesting the critical roles of the binding enthalpies from the precise localization of the active site residues, despite the short sequence lengths. This work underpins the enantioselective catalytic prowess of short peptide-based folds and argues their possible role in the emergence of homochiral chemical inventory.

Analysis of Carica papaya Informs Lineage-Specific Evolution of the Aquaporin (AQP) Family in Brassicales.

Aquaporins (AQPs), a type of intrinsic membrane proteins that transport water and small solutes across biological membranes, play crucial roles in plant growth and development. This study presents a first genome-wide identification and comparative analysis of the AQP gene family in papaya (Carica papaya L.), an economically and nutritionally important fruit tree of tropical and subtropical regions. A total of 29 CpAQP genes were identified, which represent five subfamilies, i.e., nine plasma intrinsic membrane proteins (PIPs), eight tonoplast intrinsic proteins (TIPs), seven NOD26-like intrinsic proteins (NIPs), two X intrinsic proteins (XIPs), and three small basic intrinsic proteins (SIPs). Although the family is smaller than the 35 members reported in Arabidopsis, it is highly diverse, and the presence of CpXIP genes as well as orthologs in Moringa oleifera and Bretschneidera sinensis implies that the complete loss of the XIP subfamily in Arabidopsis is lineage-specific, sometime after its split with papaya but before Brassicaceae-Cleomaceae divergence. Reciprocal best hit-based sequence comparison of 530 AQPs and synteny analyses revealed that CpAQP genes belong to 29 out of 61 identified orthogroups, and lineage-specific evolution was frequently observed in Brassicales. Significantly, the well-characterized NIP3 group was completely lost; lineage-specific loss of the NIP8 group in Brassicaceae occurred sometime before the divergence with Cleomaceae, and lineage-specific loss of NIP2 and SIP3 groups in Brassicaceae occurred sometime after the split with Cleomaceae. In contrast to a predominant role of recent whole-genome duplications (WGDs) on the family expansion in B. sinensis, Tarenaya hassleriana, and Brassicaceae plants, no recent AQP repeats were identified in papaya, and ancient WGD repeats are mainly confined to the PIP subfamily. Subfamily even group-specific evolution was uncovered via comparing exon-intron structures, conserved motifs, the aromatic/arginine selectivity filter, and gene expression profiles. Moreover, down-regulation during fruit ripening and expression divergence of duplicated CpAQP genes were frequently observed in papaya. These findings will not only improve our knowledge on lineage-specific family evolution in Brassicales, but also provide valuable information for further studies of AQP genes in papaya and species beyond.

Bi-allelic loss-of-function variants in WBP4, encoding a spliceosome protein, result in a variable neurodevelopmental syndrome

Over two dozen spliceosome proteins are involved in human diseases, also referred to as spliceosomopathies. WW domain-binding protein 4 (WBP4) is part of the early spliceosomal complex and has not been previously associated with human pathologies in the Online Mendelian Inheritance in Man (OMIM) database. Through GeneMatcher, we identified ten individuals from eight families with a severe neurodevelopmental syndrome featuring variable manifestations. Clinical manifestations included hypotonia, global developmental delay, severe intellectual disability, brain abnormalities, musculoskeletal, and gastrointestinal abnormalities. Genetic analysis revealed five different homozygous loss-of-function variants in WBP4. Immunoblotting on fibroblasts from two affected individuals with different genetic variants demonstrated a complete loss of protein, and RNA sequencing analysis uncovered shared abnormal splicing patterns, including in genes associated with abnormalities of the nervous system, potentially underlying the phenotypes of the probands. We conclude that bi-allelic variants in WBP4 cause a developmental disorder with variable presentations, adding to the growing list of human spliceosomopathies.

Pot1 promotes telomere DNA replication via the Stn1-Ten1 complex in fission yeast.

Telomeres are nucleoprotein complexes that protect the chromosome-ends from eliciting DNA repair while ensuring their complete duplication. Pot1 is a subunit of telomere capping complex that binds to the G-rich overhang and inhibits the activation of DNA damage checkpoints. In this study, we explore new functions of fission yeast Pot1 by using a pot1-1 temperature sensitive mutant. We show that pot1 inactivation impairs telomere DNA replication resulting in the accumulation of ssDNA leading to the complete loss of telomeric DNA. Recruitment of Stn1 to telomeres, an auxiliary factor of DNA lagging strand synthesis, is reduced in pot1-1 mutants and overexpression of Stn1 rescues loss of telomeres and cell viability at restrictive temperature. We propose that Pot1 plays a crucial function in telomere DNA replication by recruiting Stn1-Ten1 and Polα-primase complex to telomeres via Tpz1, thus promoting lagging-strand DNA synthesis at stalled replication forks.

Comparative transcriptomic and weighted gene co-expression network analysis to identify the core genes in the cultivars of Musa acuminata under both infected and chemical perturbated conditions

ABSTRACT Banana is a high nutrient crop, which ranks fourth in terms of gross value production. Fusarium wilt of banana, caused by Fusarium oxysporum f. sp. cubense tropical race 4 (FocTR4), is considered the most destructive disease leading to the complete loss of production of the Cavendish cultivars Berangan, Brazilian and Williams, which are vulnerable to the infection of FocTR4. However, the treatment with benzothiadiazole, a synthetic salicylic analog, is aimed to induce resistance in plants. Thus, the treatments pertaining to the banana plants subjected to the Foc infection within the chosen cultivars were compared with chemically treated samples obtained at different time intervals for a short duration (0–4 days). The integrated omics analyses considering the parameters of WGCNA, functional annotation, and protein–protein interactions revealed that many pathways have been negatively influenced in Cavendish bananas under FocTR4 infections and the number of genes influenced also increased over time in Williams cultivar. Furthermore, elevation in immune response and resistance genes were also observed in the roots of the Cavendish banana.

Medicinal and cosmetic products used in treatment of hair loss

Abstract Hair loss or alopecia is a reduction in the volume or complete loss of hair and is a fairly common clinical problem, especially in the geriatric population. Androgenetic alopecia (AGA) is the most common type of hair loss in men. Androgenetic alopecia in women most often occurs before the age of 60. We also distinguish androgenetic alopecia in postmenopausal women and scarring, areata, telogen and drug-induced alopecia. The aim of the study was to analyze the composition of medicinal and cosmetic preparations available on the Polish market, recommended for people struggling with alopecia. In 2022, the composition of preparations used in alopecia available in pharmacies and drugstores was analyzed. In total 57 medicinal and cosmetic preparations recommended for people suffering from alopecia have been identified. The most common active substance in the analyzed preparations is finasteride. Frequently used active substances are biotin and minoxidil, rarely prednisolone. Conclusions: 1. In preparations intended for people with alopecia, the most frequently used active substance is finasteride. 2. Statistically, preparations for hair loss are most often in the form of tablets and shampoos. 3. The analyzed preparations for alopecia belong to the category of prescription drugs and cosmetics, less often in the category of OTC drugs or dietary supplements.

Reverse shoulder arthroplasty in obstetric brachial plexus injury: our experience with shoulder motion analysis

BackgroundObstetric brachial plexus injury (OBPI) is a weakening or paralysis of the upper arm caused by brachial plexus injury followed by a muscle paralysis with severe repercussions on the movement of the shoulder joint following a progressive glenohumeral joint deformity.This case series analyzes the clinical and radiological outcomes of reverse total shoulder arthroplasty (RSA) in OBPI patients with a follow-up of 2 years.Materials and methodsOBPI patients with secondary end-stage glenohumeral arthritis were enrolled in the study and they were treated with RSA. Patient demographics and clinical outcomes [Range of Motion (ROM), Visual Analog Scale (VAS), Oxford Shoulder Score (OSS)] were evaluated. A novel Shoulder motion analysis was carried out to investigate specific movement patterns of scapulothoracic movements in these patients. This study is a prospective cohort study.ResultsFour Patients (M: F = 1:3) were enrolled in the study, the mean age was 49.3 years (+ 2.75), the mean OSS (Oxford Shoulder Score) decreased from 48.8 (± 2.5) preoperatively to 18.30 (± 2.78), the mean VAS (Visual Analog Scale) decreased from 7.25 (± 0.5) to 1.7 (± 0.3) in the follow up (∆% relative pain reduction:− 76.5%), Shoulder ROM obtained an improvement (p < 0.05) except for abduction and external rotation. The average follow-up time was 26.3 months (+− 4.5). Shoulder motion analysis showed a complete loss of the scapular tilting above 90 degrees of flexion compared to the typical one of standard RSA with a pattern shifted towards scapular retraction (engaging trapezius and rhomboid muscles) to compensate the loss of the posterior tilting.ConclusionsRSA in OBPI patients demonstrated a significant improvement of pain symptoms and a moderate improvement in daily activities, anyway with a more appreciable quality of life over time even if the marked hypotrophy especially of the posterior shoulder muscles showed some limits in maintaining suspension of the upper limb and a minor external rotation, with an internal rotation attitude during the movements.Level of evidence: Level IV, Case series.

Promotion of structural plasticity in area V2 of visual cortex prevents against object recognition memory deficits in aging and Alzheimer's disease rodents.

JOURNAL/nrgr/04.03/01300535-202408000-00038/figure1/v/2023-12-16T180322Z/r/image-tiff Memory deficit, which is often associated with aging and many psychiatric, neurological, and neurodegenerative diseases, has been a challenging issue for treatment. Up till now, all potential drug candidates have failed to produce satisfactory effects. Therefore, in the search for a solution, we found that a treatment with the gene corresponding to the RGS14414 protein in visual area V2, a brain area connected with brain circuits of the ventral stream and the medial temporal lobe, which is crucial for object recognition memory (ORM), can induce enhancement of ORM. In this study, we demonstrated that the same treatment with RGS14414 in visual area V2, which is relatively unaffected in neurodegenerative diseases such as Alzheimer's disease, produced long-lasting enhancement of ORM in young animals and prevent ORM deficits in rodent models of aging and Alzheimer's disease. Furthermore, we found that the prevention of memory deficits was mediated through the upregulation of neuronal arborization and spine density, as well as an increase in brain-derived neurotrophic factor (BDNF). A knockdown of BDNF gene in RGS14414-treated aging rats and Alzheimer's disease model mice caused complete loss in the upregulation of neuronal structural plasticity and in the prevention of ORM deficits. These findings suggest that BDNF-mediated neuronal structural plasticity in area V2 is crucial in the prevention of memory deficits in RGS14414-treated rodent models of aging and Alzheimer's disease. Therefore, our findings of RGS14414 gene-mediated activation of neuronal circuits in visual area V2 have therapeutic relevance in the treatment of memory deficits.

Converging diencephalic and hippocampal supports for episodic memory

To understand the neural basis of episodic memory it is necessary to appreciate the significance of the fornix. This pathway creates a direct link between those temporal lobe and medial diencephalic sites responsible for anterograde amnesia. A collaboration with Andrew Mayes made it possible to recruit and scan 38 patients with colloid cysts in the third ventricle, a condition associated with variable fornix damage. Complete fornix loss was seen in three patients, who suffered chronic long-term memory problems. Volumetric analyses involving all 38 patients then revealed a highly consistent relationship between mammillary body volume and the recall of episodic memory. That relationship was not seen for working memory or tests of recognition memory. Three different methods all supported a dissociation between recollective-based recognition (impaired) and familiarity-based recognition (spared). This dissociation helped to show how the mammillary body-anterior thalamic nuclei axis, as well as the hippocampus, is vital for episodic memory yet is not required for familiarity-based recognition. These findings set the scene for a reformulation of temporal lobe and diencephalic amnesia. In this revised model, these two regions converge on overlapping cortical areas, including retrosplenial cortex. The united actions of the hippocampal formation and the anterior thalamic nuclei on these cortical areas enable episodic memory encoding and consolidation, impacting on subsequent recall.

Abstract 13381: Syncope as a Presentation of Waldenstrom Macroglobulinemia

Syncope as defined by ACC/AHA is defined as a symptom that presents with an abrupt, transient, complete loss of consciousness, associated with inability to maintain postural tone with rapid and spontaneous recovery without clinical features of other non-syncope causes of loss of consciousness, such as seizure, antecedent head trauma, or apparent loss of consciousness. Syncope is a common complaint treated in the emergency department and a major reason for hospital admissions. A rare etiology to this common symptom is Waldenstrom macroglobulinemia. Case: A 49-year-old man presented to the emergency department, referred for hypercalcemia. On review of records, the patient was noticed to have been seen previously in emergency visits for two episodes of syncope and recurrent anemia. The laboratory studies at the time of admission were remarkable for hemoglobin of 7.3, WBC of8.32, hematocrit of 28.5, MCV 77.2, platelets of 124,000. Complete metabolic panel showed a total protein of 13.1, calcium of 11.2 with an albumin of 1.6 and corrected sodium of 117. EKG demonstrated a sinus rhythm with left atrial enlargement and nonspecific T wave abnormalities. Echocardiogram demonstrated a LVEF of 60-65% with normal LV wall motion, posterior wall thickness, and septal wall thickness with grade 1 diastolic dysfunction. CT of the head was unremarkable. Further work up for recurrent microcytic anemia. Bone marrow biopsy was obtained which demonstrated a Waldenstrom macroglobulinemia. Further follow up revealed that the patient has not had any other syncopal episodes since initiation of treatment. Conclusion: Although current literature suggests a broad differential diagnosis for the symptom of syncope, Waldenström macroglobulinemia remains a rare etiology of syncope with an estimated incidence of 1000 to 1500 cases diagnosed per year. Waldenstrom macroglobulinemia can cause hyperviscosity syndrome in about 30 percent of the population with Waldentroms, which when severe and coupled with anemia and plasma volume expansion has been reported as arare cause of syncope. Syncope evaluation should be detailed with history and physical examination and hyper-viscosity syndromes, a medical emergency, should be considered as differential diagnosis of syncope.