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Background: Quality and safety of prescribing drugs in older people remain a global healthcare concern. Inappropriate prescribing pattern in the elderly population is now considered as a major public health issue and polypharmacy is one of the common problems among the elderly patients. Aims and Objectives: The aims of this study were (1) to analyze the prevalence, pattern of polypharmacy with respect to age, and gender among the elderly patients and (2) to evaluate the most frequently prescribed drugs in the geriatric population. Materials and Methods: This prospective, cross-sectional, and observational study was conducted among the elderly patients admitted in the Department of General Medicine, Dhanalakshmi Srinivasan Medical College and Hospital, Perambalur, Tamil Nadu. The duration of research project was 12 months from May 2018 to April 2019; approval for the study was taken from the Institutional Ethical Committee. Data on total number of prescribed drugs and main and adjuvant drugs prescribed to patients during treatment were collected and analyzed. Results: A total of 289 patients, that is, 167 male and 122 female were included in the study. The prevalence of minor polypharmacy (2–4 drugs) accounted for 15.22%, major polypharmacy (≥5 drugs) for 81.35%, and hyper polypharmacy (≥10 drugs) for 3.46%. Most commonly prescribed drugs were vitamins, proton-pump inhibitors, antipyretic agents, and H2 receptor blockers. They accounted for 21.70%, 5.78%, 5.42%, and 4.94%, respectively. Conclusion: Polypharmacy is a preventable and can be rectified by prescribing appropriate medications. In future, a multidisciplinary approach which will be involving doctors, nurses, and pharmacists, shall be implemented for rational use of drugs in elderly patients.

Introduction: Postoperative pain can have detrimental effects if proper analgesia is not provided. The most widely used medicines for the management of postoperative pain is Non Steroidal Anti-Inflammatory Drugs (NSAIDs), among the NSAIDs the most commonly used drug for postoperative pain is diclofenac sodium. Repeated intramuscular/intravenous (i.m/i.v.) injections of diclofenac are associated with pain and discomfort while oral use of diclofenac before and after surgery is limited and is also associated with increased risk of gastrointestinal complications like dyspepsia, peptic ulcer, etc. Diclofenac Transdermal Patch (TD) and Rectal Suppository (RS) are good methods of drug delivery as they avoid first pass metabolism, gastrointestinal complications and pain associated with i.m/i.v. route. Aim: To evaluate the efficacy of the transdermal diclofenac patch versus the diclofenac RS for management of postoperative pain. Materials and Methods: This hospital-based, randomised, prospective, interventional, open label comparative clinical trial was conducted in Department of General Surgery and Department of Pharmacology at FH Medical College and Hospital, Agra, Uttar Pradesh, India, from April 2021 to September 2021. A total of 64 patients were included in the trial and they were randomly divided into two groups using simple randomisation technique. Group A received 100mg diclofenac TD (n=32) and group B received 100 mg diclofenac RS (n=32) just before induction of anaesthesia and repeated 12 hourly for 48 hours. Pain was assessed postoperatively at 6, 12, 24 hours, respectively using the Visual Analogue Scale (VAS) and adverse effects like gastrointestinal complications were also noted in the both groups. The student's t-test was applied to compare the mean values of quantitative variables while qualitative variables were analysed using Chi-square test. p-value

Alzheimer’s disease (AD) is a common neurodegenerative disease with poor prognosis. New options for drug discovery targets are needed. We developed an imaging based arrayed CRISPR method to interrogate the human genome for modulation of in vitro correlates of AD features, and used this to assess 1525 human genes related to tau aggregation, autophagy and mitochondria. This work revealed (I) a network of tau aggregation modulators including the NF-κB pathway and inflammatory signaling, (II) a correlation between mitochondrial morphology, respiratory function and transcriptomics, (III) machine learning predicted novel roles of genes and pathways in autophagic processes and (IV) individual gene function inferences and interactions among biological processes via multi-feature clustering. These studies provide a platform to interrogate underexplored aspects of AD biology and offer several specific hypotheses for future drug discovery efforts.

Aims: To study the concordance between clinical cure and microbial eradication in severe respiratory tract infections. Methods & Material: A prospective cohort study was done at a tertiary care teaching hospital. Patients above 18 years of age with respiratory tract infections confirmed with positive sputum cultures participated in the study. Microbiological eradication was considered complete when no microorganism was isolated on 2 consecutive sputum cultures. Results: The number of valid cases was 102. The mean age of patients was 58.6±16.1 (range, 19-82 years). Complete eradication of microorganisms was achieved in 54.5%(n=55) cases. In 33% (n=34) clinically successful cases, strains like Pseudomonas, Acinetobacter and Kleibsiella were not eradicated and were isolated at study end point on repeat sputum culture. Relapse was observed in 9.2% (n=9) cases. On multiple logistic regression to ascertain the impact of independent variables on dependent variable (clinical cure/ microbiological cure), it was observed that increasing age, odds ratio=1.66(95% CI, 1.34-2.03), patient?s background OR=6.4 (95% CI, 0.68-63.4), ventilatory support OR=2.8 (95% CI, 0.4-22.4) significantly (P

Immediate dental implant placement refers to insertion of an implant directly after a tooth is extracted, whereas de layed positioning occurs at some later time. Implant-supported fixed prostheses are usually attempted before other options such as conventional bridges or removable dentures to avoid damage to adjacent teeth. Stable and predictable esthetic and functional results can be achieved with different surgical and prosthetic management techniques of the hard and soft tissue around implant restorations. It has been suggested that immediate implant placement after tooth extraction preserves the dimensions of the alveolar ridge regardless of the mode of tooth failure. After tooth extraction, the residual alveolar ridge generally provides limited bone volume because of ongoing resorbtion. In this case we extracted mandibular anterior teeth immediately placed the implants.

The dissociative anesthetic ketamine elicits symptoms of schizophrenia at subanesthetic doses by blocking N-methyl-d-aspartate receptors (NMDARs). This property led to a variety of studies resulting in the now well-supported theory that hypofunction of NMDARs is responsible for many of the symptoms of schizophrenia. However, the roles played by specific NMDAR subunits in different symptom components are unknown. To evaluate the potential contribution of GluN2D NMDAR subunits to antagonist-induced cortical activation and schizophrenia symptoms, we determined the ability of ketamine to alter regional brain activity and gamma frequency band neuronal oscillations in wild-type (WT) and GluN2D-knockout (GluN2D-KO) mice. In WT mice, ketamine (30 mg/kg, i.p.) significantly increased [(14)C]-2-deoxyglucose ([(14)C]-2DG) uptake in the medial prefrontal cortex (mPFC), entorhinal cortex and other brain regions, and decreased activity in the somatosensory cortex and inferior colliculus. In GluN2D-KO mice, however, ketamine did not significantly increase [(14)C]-2DG uptake in any brain region examined, yet still decreased [(14)C]-2DG uptake in the somatosensory cortex and inferior colliculus. Ketamine also increased locomotor activity in WT mice but not in GluN2D-KO mice. In electrocorticographic analysis, ketamine induced a 111% ± 16% increase in cortical gamma-band oscillatory power in WT mice, but only a 15% ± 12% increase in GluN2D-KO mice. Consistent with GluN2D involvement in schizophrenia-related neurologic changes, GluN2D-KO mice displayed impaired spatial memory acquisition and reduced parvalbumin (PV)-immunopositive staining compared with control mice. These results suggest a critical role of GluN2D-containing NMDARs in neuronal oscillations and ketamine's psychotomimetic, dissociative effects and hence suggests a critical role for GluN2D subunits in cognition and perception.

Subject area Marketing, new product launch and innovations. Study level/applicability Postgraduate students. Case overview Maruti Suzuki India Ltd. (MSIL), established in February 1981, formerly known as MarutiUdyog Limited, is a subsidiary of Japanese automobile Manufacturer Suzuki. It has a market share of 37 per cent in passenger car segment in India. Its product portfolio ranges from entry-level Alto to hatchbacks like A-Star, Zen Estilo, etc. to sedans like SX 4 to sports utility vehicles like Grand Vitara. MSIL is always known for delivering value on these lines – low cost of acquisition, high fuel economy, less maintenance hassles and wide service network. MSIL is planning to launch its much awaited hatchback Celerio with revolutionary auto gear shift technology for the first time in India at an affordable price. Promotional campaign is yet to be completed. Online trends reflect the consumer trends of any country. During the Auto Expo Week, Maruti Suzuki Celerio became the most searched hatchback on Google in the subcontinent according to a report published by the Indian Express citing the Google Trends Report. One of the key success factor is communicating the right message to the customers so as to attract them. So, MSIL's challenge is to plan a product launch so as to spread awareness. Expected learning outcomes To discuss the ways in which the product may be differentiated, to acquaint students with the process of developing a slogan for the introduction of Celerio to the existing market, to explain the concept of segmentation to the students, to familiarize students with communication mix and to give the students an idea about need of digital communication to promote the product. Supplementary materials Teaching Notes are available for educators only. Please contact your library to gain login details or email support@emeraldinsight.com to request teaching notes.

Purpose This report describes the efficacy of a guiding flange appliance in correcting mandibular deviation in the hemi-mandibulectomy patient and correlates the time elapsed between surgery and placement of the appliance and the extent of initial mandibular deviation to the success rate of a guiding flange appliance in correcting the deviation. Materials and Methods A total of 15 hemi-mandibulectomy patients participated in the study. All had various degree of mandibular shift consequent to surgery. The patients were given a guiding flange prosthesis for about 4 months, and the efficacy of the guiding flange prosthesis was calculated in terms of percentage deviation corrected after 4 months. Results Time elapsed between surgery and prosthetic rehabilitation was in inverse relation to the percentage correction in mandibular deviation at 4 months (B = –7.668; p = 0.002). The less the initial deviation postsurgery, the better the correction (B = 9.798; p = 0.008). Conclusion Percentage correction of mandibular deviation is dependent on the timing of prosthetic rehabilitation. The less the initial deviation, the better the correction.

Background: Depression is a major public health problem and occurs in persons of all ages, and is associated with increased morbidity, soaring costs for treatment and reduced productivity and quality of life. Vitamin D is involved in numerous brain processes including neuroimmunomodulation, neuroprotection, neuroplasticity, regulation of neurotrophic factors, and making it biologically plausible to be associated with depression. Aim of the present study is to compare the therapeutic effects of vitamin D given along with escitalopram versus escitalopram given alone in patients with major depressive disorder. Methods: In this prospective, randomized, interventional clinical study, 60 patients with a diagnosis of major depressive disorder based on ICD-10 criteria were randomly assigned into two groups, one group received 60000IU vitamin D3 weekly plus 10 mg escitalopram OD daily while the other group received escitalopram10 mg OD daily alone for 8 weeks. Depression severity was assessed at 2-week intervals using the 24-item Hamilton Depression Rating Scale (HDRS). Serum 25(OH) vitamin D levels were measured in all the patients at baseline and after intervention.Result: Fifty nine patients completed the trial. Depression severity based on HDRS decreased significantly after intervention, with a significant difference between the two groups. The vitamin D3+escitalopram combination was significantly better than escitalopram alone from the fourth week of treatment. Conclusion: Role of vitamin D in mood disorder and its dietary supplementation is effective as an adjuvant treatment along with SSRIs in depressive disorders, especially in vitamin D deficient patients.

Inhalation anesthetic isoflurane has been reported to induce caspase activation and accumulation of β-amyloid (Aβ), however, the down-stream consequences of these effects are largely unknown. Isoflurane has also been shown to impair learning and memory, however, the up-stream mechanisms of these effects remain largely to be determined. Facilitation of synaptic NMDA receptor endocytosis can reduce synaptic function, leading to learning and memory impairment. We therefore set out to determine the effects of isoflurane on synaptic NMDA receptor endocytosis. Primary neurons from wild-type and Alzheimer's disease transgenic mice were treated with 2% isoflurane for six hours. Synaptic surface levels of NMDA receptor 2B (NR2B) and NR2B internalization were determined by surface and cleavable biotinylation assay, western blot analysis and immunofluorescence. Here we show that isoflurane can induce caspase-3 activation, increase levels of β-site amyloid precursor protein-cleaving enzyme and cause accumulation of Aβ in the primary neurons. Isoflurane facilitates synaptic NR2B endocytosis as evidenced by reducing surface NR2B levels, increasing NR2B internalization, and decreasing the ratio of synaptic surface NR2B to synapsin in mice primary neurons. Moreover, caspase activation inhibitor Z-VAD and γ-secretase inhibitor L-685,458 attenuated the isoflurane-facilitated NR2B endocytosis. These results suggest that isoflurane induces caspase activation and Aβ accumulation, leading to facilitation of synaptic NMDA receptor endocytosis, which potentially serve as the upstream mechanism of the isoflurane-induced impairment of learning and memory. These findings will encourage further studies to determine the underlying mechanism by which isoflurane and other anesthetics promote Alzheimer's disease neuropathogenesis and induce cognitive dysfunction.

Background: UTI is one of the commonest domiciliary and nosocomial bacterial infection, especially affecting the females. Nowadays antibiotic resistance among uropathogens is an emerging problem in treatment of UTI. Periodic assessment of antimicrobial susceptibility among the microorganisms will be fruitful in treating UTI. Aims: To study and assess the sensitivity/resistance pattern among E.coli and other uropathogens for nitrofurantoin, ofloxacin, Cotrimoxazole & 3rd generation cephalosporins. Methods: An observational, cross sectional study of 6 months duration from March 2016 to August 2016 was conducted on patients suffering from UTI in Department of Pharmacology and Department of Microbiology in FH Medical College & Hospital, Tundla, Uttar Pradesh. A total of 100 urine samples were analysed. Results: E.coli was the predominant (46%) uropathogen followed by Klebsiella (27%), Proteus (12%), Staphylococcus (7%), Pseudomonas (5%) and Enterococcus (3%). UTI was more common among females (61%) and illiterates (62%). Nitrofurantoin was the most sensitive (58%) antimicrobial followed by ofloxacin (35%). Conclusions: 3rd generation Cephalosporins showed higher percentage of resistance (78%).

Background Synaptic loss strongly correlates with memory deterioration. Local accumulation of amyloid β (Aβ) peptide, and neurotoxic Aβ42 in particular, due to abnormal neuronal activity may underlie synaptic dysfunction, neurodegeneration, and memory impairments. To gain an insight into molecular events underlying neuronal activity-regulated Aβ production at the synapse, we explored functional outcomes of the newly discovered calcium-dependent interaction between Alzheimer’s disease-associated presenilin 1 (PS1)/γ-secretase and synaptic vesicle proteins. Results Mass spectrometry screen of mouse brain lysates identified synaptotagmin 1 (Syt1) as a novel synapse-specific PS1-binding partner that shows Ca2+-dependent PS1 binding profiles in vitro and in vivo. We found that Aβ level, and more critically, conformation of the PS1 and the Aβ42/40 ratio, are affected by Syt1 overexpression or knockdown, indicating that Syt1 and its interaction with PS1 might regulate Aβ production at the synapse. Moreover, β-secretase 1 (BACE1) stability, β- and γ-secretase activity, as well as intracellular compartmentalization of PS1 and BACE1, but not of amyloid precursor protein (APP), nicastrin (Nct), presenilin enhancer 2 (Pen-2), or synaptophysin (Syp) were altered in the absence of Syt1, suggesting a selective effect of Syt1 on PS1 and BACE1 trafficking. Conclusions Our findings identify Syt1 as a novel Ca2+-sensitive PS1 modulator that could regulate synaptic Aβ, opening avenues for novel and selective synapse targeting therapeutic strategies. Electronic supplementary material The online version of this article (doi:10.1186/s12915-016-0248-3) contains supplementary material, which is available to authorized users.

Amphiphilic triblock copolymer, poly(ethylene oxide)-b-poly(propylene oxide)-b-poly(ethylene oxide), Pluronic® P85, is unexpectedly shown to utilize sophisticated cellular trafficking mechanisms and enter brain microvessel endothelial cells and primary neurons that are poorly penetrable. Though caveolae serve as a primary entry site for the copolymer single chains, in cells devoid of caveolae, the copolymer can still exploit caveolae- and clathrin-independent routes. This parallels the copolymer's trafficking itinerary with that of biological pathogens. The similarity is reinforced since both bypass early endosomes/lysosomes and transport to the endoplasmic reticulum. The copolymer finally reaches the mitochondrion that serves as its final destination. Notably, it also succeeds to gain entry in brain microvessel endothelial cells through caveolae and in primary neurons through caveolae- and clathrin-independent pathway. In neurons the copolymer accumulates in the cell body followed by anterograde trafficking towards the axons/dendrites. Overall, dissecting the trafficking of a synthetic polymer in multiple cell types triggers development of novel delivery systems that can selectively target intracellular compartments and provide entry in cells currently considered impenetrable.

The global flow characteristics of the cryogenic flow injected from a single-element coaxial injector have been examined experimentally to simulate the flow andmixing behavior before ignition and combustion in characteristic rocket engines. The injector simulated one element of the cryogenic rocket engine injectors under realistic operating conditions. This work focuses specifically on the evolution of liquid nitrogen jet instability, spreading, and its atomization and mixing with the surrounding coaxial gaseous jet under steady-state atmospheric conditions. The effect of some important flow parameters, such as velocity ratio and momentum ratio between jets, on the potential core length of the liquid nitrogen jet and shear angle of the flow have been analyzed. The results showed a significant role of these parameters on the instability and breakup of the liquid nitrogen jet, along with the strong heat transfer effect of the surrounding atmosphere on the cryogenic liquid nitrogen jet. The shear angle of the flow remained constant along the longitudinal axis of the injector, thus confirming fully developed steady-state jet under atmospheric conditions. The mean value of the shear angle showed the transcritical nature of the liquid nitrogen jet under atmospheric conditions. The shear angle of the flow also reduced with introduction of the helium jet and decreased uniformly with increase in helium jet velocity, which supports the effect of surrounding gas density on the jet spreading as predicted by previous researchers. The potential core length of the cryogenic liquid nitrogen showed a local peak as a function of velocity of the gaseous jet and decreased exponentially with momentum ratio for values close to and higher than one.

thermalimagingwasusedtodemonstratethecoolingeffectfromtheliquidnitrogenjetonthesurroundinggasesand entrained air moisture. Furthermore, high-speed schlieren imaging was used to examine the effect of momentum ratio on the destabilization of the liquid nitrogen jet before its breakup and eventual mixing with the surrounding gases. The experimental results showed that the liquid nitrogen jet disperses into ligaments and droplets before its vaporization. For the confined conditions, the liquid nitrogen core persists over longer distances downstream of the injectorexit before fullvaporization. Confinement alsoreduces the entrainmentof the surroundingairas well as the transfer of heat from the surroundings. The liquid nitrogen jet was found to expand earlier and reduced destabilization and mixedness with the surrounding gases with increase in momentum ratios of the coaxial jets. Changing the recess length in the injector had a negligible effect on the liquid nitrogen jet close to the injector exit. However,atdownstreamlocationstherecesslengthprovidedsignificanteffectonthe jetexpansionandentrainment of surrounding air. The effect of momentum ratio was also examined quantitatively using the particle image velocimetry diagnostics but using gas/gas (i.e., single-phase) conditions. The results showed the effect of the momentum ratio of the two coaxial gas flows on the subsequent flowfield development and mixing.

Background Accumulation of the β-amyloid peptide (Aβ) is a major pathological hallmark of Alzheimer’s disease (AD). Recent studies have shown that synaptic Aβ toxicity may directly impair synaptic function. However, proteins regulating Aβ generation at the synapse have not been characterized. Here, we sought to identify synaptic proteins that interact with the extracellular domain of APP and regulate Aβ generation. Results Affinity purification-coupled mass spectrometry identified members of the Synaptotagmin (Syt) family as novel interacting proteins with the APP ectodomain in mouse brains. Syt-1, −2 and −9 interacted with APP in cells and in mouse brains in vivo. Using a GST pull-down approach, we have further demonstrated that the Syt interaction site lies in the 108 amino acids linker region between the E1 and KPI domains of APP. Stable overexpression of Syt-1 or Syt-9 with APP in CHO and rat pheochromocytoma cells (PC12) significantly increased APP-CTF and sAPP levels, with a 2 to 3 fold increase in secreted Aβ levels in PC12 cells. Moreover, using a stable knockdown approach to reduce the expression of endogenous Syt-1 in PC12 cells, we have observed a ~ 50 % reduction in secreted Aβ generation. APP processing also decreased in these cells, shown by lower CTF levels. Lentiviral-mediated knock down of endogenous Syt-1 in mouse primary neurons also led to a significant reduction in both Aβ40 and Aβ42 generation. As secreted sAPPβ levels were significantly reduced in PC12 cells lacking Syt-1 expression, our results suggest that Syt-1 regulates Aβ generation by modulating BACE1-mediated cleavage of APP. Conclusion Altogether, our data identify the synaptic vesicle proteins Syt-1 and 9 as novel APP-interacting proteins that promote Aβ generation and thus may play an important role in the pathogenesis of AD. Electronic supplementary material The online version of this article (doi:10.1186/s13024-015-0028-5) contains supplementary material, which is available to authorized users.

Carcinosarcoma of esophagus contains both the carcinomatous and sarcomatous elements. These are rare polypoidal malignancies of esophagus. One such case is presented and available literature is reviewed.

Objective—To evaluate accident and emergency (A&E) department led practice of ketamine sedation for painful, short procedures in the paediatric population and to ascertain parental response. Methods—Analysis of retrospective data for all children who received ketamine sedation over a 20 month period in a district general hospital. A data extraction form was used to record age, sex, dose, indication, side effects, and outcome. The parents were contacted by telephone afterwards and asked standardised questions about the child's treatment, their progress after discharge, and overall satisfaction with the treatment. Results—Intramuscular ketamine was administered to 100 children under 12 years of age during the study period. The drug caused no adverse events pre-operatively or intraoperatively. The main early postoperative complication was vomiting (14%). Ninety three per cent of patients were discharged the same day. No re-attendance or treatment attributable to ketamine related side effects were necessary. Over the 24 hours after discharge, vomiting occurred in 12% and ataxia in 15% of patients. Ninety nine per cent of parents were either very satisfied or satisfied with ketamine sedation and were willing for their child to receive it again, if required. Conclusion—This study, while confirming the known safety of ketamine sedation, established its suitability for "independent" use within A&E departments by suitably qualified staff.

Background Although BACE1 is a major therapeutic target for Alzheimer’s disease (AD), potential side effects of BACE1 inhibition are not well characterized. BACE1 cleaves over 60 putative substrates, however the majority of these cleavages have not been characterized. Here we investigated BACE1-mediated cleavage of human contactin-2, a GPI-anchored cell adhesion molecule. Results Our initial protein sequence analysis showed that contactin-2 harbors a strong putative BACE1 cleavage site close to its GPI membrane linker domain. When we overexpressed BACE1 in CHO cells stably transfected with human contactin-2, we found increased release of soluble contactin-2 in the conditioned media. Conversely, pharmacological inhibition of BACE1 in CHO cells expressing human contactin-2 and mouse primary neurons decreased soluble contactin-2 secretion. The BACE1 cleavage site mutation 1008MM/AA dramatically impaired soluble contactin-2 release. We then asked whether contactin-2 release induced by BACE1 expression would concomitantly decrease cell surface levels of contactin-2. Using immunofluorescence and surface-biotinylation assays, we showed that BACE1 activity tightly regulates contactin-2 surface levels in CHO cells as well as in mouse primary neurons. Finally, contactin-2 levels were decreased in Alzheimer’s disease brain samples correlating inversely with elevated BACE1 levels in the same samples. Conclusion Our results clearly demonstrate that mouse and human contactin-2 are physiological substrates for BACE1. BACE1-mediated contactin-2 cleavage tightly regulates the surface expression of contactin-2 in neuronal cells. Given the role of contactin-2 in cell adhesion, neurite outgrowth and axon guidance, our data suggest that BACE1 may play an important role in these physiological processes by regulating contactin-2 surface levels.

Background: Familial Alzheimer's disease (FAD) mutations in presenilin (PS) modulate PS/γ-secretase activity and therefore contribute to AD pathogenesis. Previously, we found that PS/γ-secretase cleaves voltage-gated sodium channel β2-subunits (Navβ2), releases the intracellular domain of Navβ2 (β2-ICD), and thereby, increases intracellular sodium channel α-subunit Nav1.1 levels. Here, we tested whether FAD-linked PS1 mutations modulate Navβ2 cleavages and Nav1.1 levels. Objective: It was the aim of this study to analyze the effects of PS1-linked FAD mutations on Navβ2 processing and Nav1.1 levels in neuronal cells. Methods: We first generated B104 rat neuroblastoma cells stably expressing Navβ2 and wild-type PS1 (wtPS1), PS1 with one of three FAD mutations (E280A, M146L or ΔE9), or PS1 with a non-FAD mutation (D333G). Navβ2 processing and Nav1.1 protein and mRNA levels were then analyzed by Western blot and real-time RT-PCR, respectively. Results: The FAD-linked E280A mutation significantly decreased PS/γ-secretase-mediated processing of Navβ2 as compared to wtPS1 controls, both in cells and in a cell-free system. Nav1.1 mRNA and protein levels, as well as the surface levels of Nav channel α-subunits, were also significantly reduced in PS1(E280A) cells. Conclusion: Our data indicate that the FAD-linked PS1(E280A) mutation decreases Nav channel levels by partially inhibiting the PS/γ-secretase-mediated cleavage of Navβ2 in neuronal cells.

NMDA receptors are a family of glutamate-gated ion channels that regulate various CNS functions such assynaptic plasticity and learning. However hypo- or hyper-activation of NMDA receptors is critically involved in many neurological and psychiatric conditions such as pain, stroke, epilepsy, neurodegeneration, schizophrenia, and depression. Thus, it is important to identify mechanisms (such as by targeted ubiquitination) that regulate the levels of individual subtypes of NMDA receptors. In this study, we used a series of tagged, carboxy terminal constructs of GluN2D to identify associating proteins from rat brain. Of seven different GluN2D C-terminal fragments used as bait, only the construct containing amino acids 983-1097 associated with an E3 ubiquitin ligase, Nedd4. A direct interaction between GluN2D and Nedd4 was confirmed both invivo and invitro. This association is mediated by an interaction between GluN2D's C-terminal PPXY motif and the 2nd and 3rd WW domains of Nedd4. Of the four GluN2 subunits, Nedd4 directly interacted with GluN2D and also weakly with GluN2A. Nedd4 coexpression with GluN2D enhances GluN2D ubiquitination and reduces GluN1/GluN2D NMDA receptor responses. These results identify Nedd4 as a novel binding partner for GluN2D and suggest a mechanism for the regulation of NMDA receptors that contain GluN2D subunits through ubiquitination-dependent downregulation. This article is part of the Special Issue entitled 'Glutamate Receptor-Dependent Synaptic Plasticity'.

Product development increasingly involves designers with different cultural backgrounds. This paper describes an investigation into the effects of these different backgrounds on the design process. An empirical study is carried out under participation of designers drawn from industrial practice in Germany, India and China. They are observed while solving a given design problem in a laboratory setting. The recorded design processes are analyzed with a focus on cultural characteristics, which were derived from literature. The paper focuses on the following design activities: analyzing problem and requirements, working on sub-functions, deriving selection criteria, and improving solutions. The results indicate that the design processes are different and that these differences can be linked to the characteristics of culture.Copyright © 2009 by ASME

The transient and steady evolutiona ry beha vior of cryogenic fluid from a sheer coaxial injector has been examined experimentally under pre -ignition (on earth and simulated in -space ) conditions . The investigated inject or simulates one element of typical cryogenic rocket injectors under reali stic pressure conditions. The diagnostic technique utilized here is high -speed Schlieren imaging to analyze the density gradients in the flow . The cryogenic jet formed distinct vortical structures upon initial emergence from the injector reve aling the onse t of unsteady behavior and strong effect of heat transfer between cold liquid nitrogen and warm surroundings . The behavior of liquid nitrogen jet was significantly affected by the low -pressure in -space conditions. The cryogenic jet undergoes extraordinary jet expansion at sub atmospheric pressure (in -space) conditions . Initial freezing of liquid nitrogen droplets and ligaments was observed close to the injector exit at low pressure operating conditions . The shear angle measurements of the steady -state flow showed the trans critical nature of the cryogenic fluid along with its cooling effect on surrounding gases. The measured jet spreading/ shear angles for the atmospheric case matched very closely with the prior results and confirmed the effects of surroundin g gas density on cryogenic jet expansion as predicted by the correlations . The potential core length measurements of the cryogenic LN 2 showed strong evidence of heat -shielding effect of the coaxial gaseous jet for momentum ratios lower than one while the c ore lengths decreased exponentially with momentum ratio v alues close to and higher than one .

The effect of near -vacuum operating pressure on the evolutionary behavior of cryogenic fluid injected from a single -element coaxial injector has been examined experimentally . The investigated injector simulate s one element of the injector array of cryogenic rocket engine s under realistic operating c onditions. Actual rocket -engine propellants, liquid oxygen and gaseous hydrogen , are simulated by chemically inert and safe to operate liquid nitrogen and helium. This work focuses specifically on the transient evolution of liquid nitrogen jet under in -spa ce conditions. The diagnostic technique s utilized here are high -speed Mie -scattering and Schlieren imaging. The results showed that the behavior of liquid nitrogen jet wa s significant ly affected by the low -pressure conditions as well as the strong heat shi elding effect of coaxial helium jet . The cryogenic jet undergoes extraordinary jet expansion at sub -atmospheric pressures . Initial freezing of liquid nitrogen droplets and ligaments was observed close to the injector exit . The heat transfer from the warm surroundings to cold liquid nitrogen jet wa s reduced significantly in the presence of coaxial gaseous jet, which confined the cold liquid nitrogen jet and prevented its expansion to some extent .

The effect of some of the important flow parameters, such as, velocity ratio, density ratio and momentum ratio have been examined experimentally on potential core length of the cryogenic fluid injected from a single-element coaxial injector. The injector simulated one element of the cryogenic rocket engine injectors under realistic operating conditions. This work focuses specifically on the evolution of liquid nitrogen jet instability and breakup under steady state atmospheric conditions. The results showed significant role of velocity ratio, density ratio, momentum ratio along with the strong heat transfer effect of the surrounding atmosphere on the cryogenic liquid nitrogen jet behavior. The potential core length of the cryogenic liquid nitrogen showed a local peak as a function of velocity of the gaseous jet. However, the core length showed insensitivity to changes in density of the gaseous jet. The results also provided a strong evidence of the heat-shielding effect of the coaxial gaseous jet. The heat transfer from the surroundings to the cold LN2 jet is reduced significantly by the presence of the gaseous jet, which strongly affects the potential core length of liquid nitrogen jet. The experimental diagnostic technique used here is Schlieren imaging using a high speed camera to analyze the global flow behavior of liquid nitrogen jet. The Schlieren images were processed using image processing techniques to obtain quantitative information of the flow.

The flow and mixing behavior of cryogenic fluid from a single element co -axial injector is examined . The injector simulated one element of the cryogenic rocket injector under realistic operating conditions. In case of real injector s t he flow consists of a cen tral liquid oxygen (LOX) core surrounded by annular gaseous hydrogen. In this paper, t he flow, mixing and thermal behavior of the cryogenic propellant has been simulated by using liquid nitrogen (LN 2) flowing through the inner tube and gaseous Helium (He) through the outer annulus of the injector . Specifically we have examined the evolutionary behavior of liquid nitrogen (LN 2) jet flow instability, jet breakup and mixing with the surrounding coaxial gaseous jet under steady state at atmospheric pressure con ditions . The effect of some important parameters such as, momentum ratio, density ratio and swirl in the surrounding gas flow on the behavior of liquid nitrogen (LN 2) jet in a coaxial gaseous stream has been analyzed. The results provide the role of these parameters on the instability and breakup of LN 2 jet and its subsequent effect on mixing with the surrounding gas eous stream. The experimental diagnostic techniques used here inclu de high speed Schlieren imaging and IR thermal imaging. High speed Schlieren technique is used to analyze the formation of vortical structures and instability of LN 2 jet whereas IR thermal imaging technique is used to analyze the cooling effect of cryogenic LN 2 jet on the surrounding gases and flow entrainment.

Characteristi c coaxial injector geometry has been used to examine the flow and mixing behavior under non -reacting conditions for simulating the mixing performance in cryogenic rocket engines . The effects of partial or full confinement of the flows as well as momentum ratio between the inner and outer fluids from the injector have been examined at atmospheric pressure condition . The fluids used in injector s are often cryogenic liquid O 2 (LOX) through the inner tube and gaseous hydrogen through the outer annulus. In this paper we simulate th is cryogenic injector fluid mixing behavior with liquid nitrogen (LN 2) flowing through the inner tube while gaseous N 2, CO 2 or He lium (He) injected through the outer annulus. High speed cinematography has been used to examine the dynam ic al behavior of the LN 2 jet flow surround ed by a coaxial gaseous stream . Infrared ( IR ) thermal imaging technique has been used to determine the thermal field distribution associated with LN 2 jet upon its discharge from the injector exit into the surroundi ng gas flow . The role of injector -injector interaction was simulated by partial and full confinement of the injector fluids. The confinement significantly alters the dispersion of liquid jet into gaseous stream to impact flow dispersion, expansion and mixi ng. The LN 2 jet stream upon exit from the injector nozzle dispersed into ligaments and droplets prior to its vaporization . For the fully confined case the LN 2 jet persist ed over longer distances downstream of the injector exit than the unconfined or partia lly confined case s. Confinement altered the heat transfer from the surroundings to delay LN 2 vaporization in addition to expected reduction in entrainment of the surrounding air . The expansion of LN 2 jet beg an earlier with increase in momentum ratio betwee n inner and outer jets while its mixing with surrounding gases is reduced with increase in momentum ratio . These results assist one to examine flow and mixing between a cryogenic fluid and different gas density fluids as well the role of momentum ratio bet ween jets to simulate the performance at different injector operational conditions.

Shear layer mixing between two coaxial jets of different density gases has been examined to simulate and analyze mixing and ignition between fuel and oxidizer from a single element injector of a rocket engine. An experimental combustion facility has been designed and fabricated to simulate the behavior of single element coaxial injector. The flow and mixing characteristics of this injector are examined under non-reacting conditions at normal atmospheric pressure. PIV (Particle Image Velocimetry) diagnostics is used to obtain the flowfield distribution of two different density gases that simulates the behavior of gaseous H2/O2 flows from the injector. The results are then used to validate the calculated results obtained from a CFD -model. A RANS type code has been used to simulate the dynamics of the 2-D axisymmetric simulated coaxial injector used in rocket combustors. The model can predict flowfield, turbulence characteristics and species distribution inside the combustor for a range of operating conditions. The code is then used to obtain the flow dynamic behavior as well as species distribution of H2/O2 flows inside a combustion chamber under sub-atmospheric conditions. These results provide useful information on the mixing, ignition and combustion for in-space combustion conditions. The model can be extended to include more realistic operational conditions for the injector as well as the injector-wall interactions.

Thermal field distribution of turbulent hydrocarbon flames has been analyzed for various fuel/air equivalence ratios. An experimental double concentric swirl burner with centrally located fuel injection was used that simulates one injector cap of a practical gas turbine combustor. Flame temperature distributions have been examined at three different fuel/air equivalence ratios, i.e., fuel-lean (φ = 0.625), stoichiometric (φ = 1.0), and fuel-rich (φ = 1.2). Each flame is examined for co-swirl and counter-swirl configurations, Mean and fluctuating temperature maps and thermal time scales are obtained using thermocouple measurements compensated with time constant measurements in order to achieve high frequency response. Direct flame photographs and infrared (IR) thermal images have been obtained to determine the global flame characteristics, and thermal flame shape/size, intensity and temperature distribution of the various flames. The results showed strong dependence of fuel/air equivalence ratio on global features and temperature distribution inside the flame. Flame volume increased significantly with increase in fuel-air equivalence ratio but the flame became non-uniform and unstable. As expected the maximum temperatures are found for stoichiometric case. The reaction zone of the flame moved downstream of the burner with increase in fuel-air equivalence ratio. For all the fuel-air equivalence ratios counter-swirl case provided compact reaction zones than the corresponding co-swirl case. Mean and fluctuating temperature maps showed that maximum temperatures inside the flame occur at mixing interface and downstream regions of the flame. Fluctuating temperature are found higher inside shear layer and post flame region. Both mean and fluctuating maps are asymmetrical which suggests higher turbulence and presence of large vertical structures in some regions of the flame. Integral- and micro-thermal scales also supported the above mentioned results.

Chemiluminescence and thermal imaging techniques have been used to examine the chemical and thermal behavior of turbulent flames with practical application to TBCC propulsion systems. The present study examines single swirler using an experimental double concentric swirl burner that simulates one swirler in a practical gas turbine combustor. The optical emission spectroscopy (OES) technique have been used to provide information on selected species in flames that mark the flame reaction zone and heat release rate. The instantaneous images are then integrated to obtain time-averaged information. Spatial distribution of OH, CH, C2 species from within the flames have been obtained at selected wavelengths using an ICCD camera and narrow band interference filters. The vibrational temperature distributions are obtained from the ratio of intensities of two discrete C2 bands of 470nm and 515nm. The time-averaged spatial distribution of flame generated radicals is processed using the Abel Inversion technique to project the initial 2-D image to represent the 3-D distribution of species and temperature in the flame. The results show that swirl distribution affects the shape of the spatial distribution by spreading the high intensity regions radially outwards with increase in swirl strength at inner regions of the fuel injector. Co-swirl distribution in the burner provided decrease in temperature and species intensity due to greater entrainment of the surrounding fluid. Calculated flame thermal strain rates were found to be significantly different for the co- and counter-swirl flames.Copyright © 2004 by ASME

The management of 104 patients complaining of foreign body (FB) in the throat in an accident and emergency (A&E) department was analysed over a period of 7 months. The majority of these patients (88.4%), underwent a soft tissue radiograph of the neck. Less than 10% of the radiographs were thought to be abnormal by the A&E staff. Two thirds of the patients (69.2%) were referred to the ear, nose and throat (ENT) surgeons. Of these 84.7% had indirect laryngoscopy. Eighteen (17.3%) FBs were found in addition to five (4.8%) other causes of the symptom. It is concluded that routine use of radiographs in the assessment of FB in the throat is inappropriate. By contrast thorough clinical examination and indirect laryngoscopy (IDL) have a high diagnostic yield. A protocol is suggested for managing the condition.