The phrase 'The Great War' in british discourse during world war one

The association of the term ‘The Great War’ with World War One, if it began 100 years ago, could be seen as telling, not only about attitudes at the time (and whether it meant ‘jolly big’ or ‘jolly good’), but about our retrospective attitudes to those who were involved. Through an examination of propaganda, periodicals, political statements and specific pre-war literature, an assumption that as a phrase it is indicative of jingoistic and bellicose hysteria generated by influential politicians for the gullible citizens of whichever participant nation, can be shown as a misleading simplification. Instead, with a concentration on Britain, a study of its use by statesmen such as Asquith and Lloyd George, the very particular circumstances under which it appeared in Punch magazine, and the overt zeal some advocates of war with Germany displayed from several years before 1914, is revealing of very different public standpoints among supporters of the war.info:eu-repo/semantics/publishedVersio

Performance deficits of NK1 receptor knockout mice in the 5 choice serial reaction time task: effects of d Amphetamine, stress and time of day.

Background The neurochemical status and hyperactivity of mice lacking functional substance P-preferring NK1 receptors (NK1R-/-) resemble abnormalities in Attention Deficit Hyperactivity Disorder (ADHD). Here we tested whether NK1R-/- mice express other core features of ADHD (impulsivity and inattentiveness) and, if so, whether they are diminished by d-amphetamine, as in ADHD. Prompted by evidence that circadian rhythms are disrupted in ADHD, we also compared the performance of mice that were trained and tested in the morning or afternoon. Methods and Results The 5-Choice Serial Reaction-Time Task (5-CSRTT) was used to evaluate the cognitive performance of NK1R-/- mice and their wildtypes. After training, animals were tested using a long (LITI) and a variable (VITI) inter-trial interval: these tests were carried out with, and without, d-amphetamine pretreatment (0.3 or 1 mg/kg i.p.). NK1R-/- mice expressed greater omissions (inattentiveness), perseveration and premature responses (impulsivity) in the 5-CSRTT. In NK1R-/- mice, perseveration in the LITI was increased by injection-stress but reduced by d-amphetamine. Omissions by NK1R-/- mice in the VITI were unaffected by d-amphetamine, but premature responses were exacerbated by this psychostimulant. Omissions in the VITI were higher, overall, in the morning than the afternoon but, in the LITI, premature responses of NK1R-/- mice were higher in the afternoon than the morning. Conclusion In addition to locomotor hyperactivity, NK1R-/- mice express inattentiveness, perseveration and impulsivity in the 5-CSRTT, thereby matching core criteria for a model of ADHD. Because d-amphetamine reduced perseveration in NK1R-/- mice, this action does not require functional NK1R. However, the lack of any improvement of omissions and premature responses in NK1R-/- mice given d-amphetamine suggests that beneficial effects of this psychostimulant in other rodent models, and ADHD patients, need functional NK1R. Finally, our results reveal experimental variables (stimulus parameters, stress and time of day) that could influence translational studies

The catalytic subunit of the system L1 amino acid transporter (S<i>lc7a5</i>) facilitates nutrient signalling in mouse skeletal muscle

The System L1-type amino acid transporter mediates transport of large neutral amino acids (LNAA) in many mammalian cell-types. LNAA such as leucine are required for full activation of the mTOR-S6K signalling pathway promoting protein synthesis and cell growth. The SLC7A5 (LAT1) catalytic subunit of high-affinity System L1 functions as a glycoprotein-associated heterodimer with the multifunctional protein SLC3A2 (CD98). We generated a floxed Slc7a5 mouse strain which, when crossed with mice expressing Cre driven by a global promoter, produced Slc7a5 heterozygous knockout (Slc7a5+/-) animals with no overt phenotype, although homozygous global knockout of Slc7a5 was embryonically lethal. Muscle-specific (MCK Cre-mediated) Slc7a5 knockout (MS-Slc7a5-KO) mice were used to study the role of intracellular LNAA delivery by the SLC7A5 transporter for mTOR-S6K pathway activation in skeletal muscle. Activation of muscle mTOR-S6K (Thr389 phosphorylation) in vivo by intraperitoneal leucine injection was blunted in homozygous MS-Slc7a5-KO mice relative to wild-type animals. Dietary intake and growth rate were similar for MS-Slc7a5-KO mice and wild-type littermates fed for 10 weeks (to age 120 days) with diets containing 10%, 20% or 30% of protein. In MS-Slc7a5-KO mice, Leu and Ile concentrations in gastrocnemius muscle were reduced by ∼40% as dietary protein content was reduced from 30 to 10%. These changes were associated with >50% decrease in S6K Thr389 phosphorylation in muscles from MS-Slc7a5-KO mice, indicating reduced mTOR-S6K pathway activation, despite no significant differences in lean tissue mass between groups on the same diet. MS-Slc7a5-KO mice on 30% protein diet exhibited mild insulin resistance (e.g. reduced glucose clearance, larger gonadal adipose depots) relative to control animals. Thus, SLC7A5 modulates LNAA-dependent muscle mTOR-S6K signalling in mice, although it appears non-essential (or is sufficiently compensated by e.g. SLC7A8 (LAT2)) for maintenance of normal muscle mass

Sex differences in the impact of ozone on survival and alveolar macrophage function of mice after Klebsiella pneumoniae infection

<p>Abstract</p> <p>Background</p> <p>Sex differences have been described in a number of pulmonary diseases. However, the impact of ozone exposure followed by pneumonia infection on sex-related survival and macrophage function have not been reported. The purpose of this study was to determine whether ozone exposure differentially affects: 1) survival of male and female mice infected with <it>Klebsiella pneumoniae</it>, and 2) the phagocytic ability of macrophages from these mice.</p> <p>Methods</p> <p>Male and female C57BL/6 mice were exposed to O₃or to filtered air (FA) (control) and then infected intratracheally with <it>K. pneumoniae </it>bacteria. Survival was monitored over a 14-day period, and the ability of alveolar macrophages to phagocytize the pathogen <it>in vivo </it>was investigated after 1 h.</p> <p>Results</p> <p>1) Both male and female mice exposed to O₃are significantly more susceptible to <it>K. pneumoniae </it>infection than mice treated with FA; 2) although females appeared to be more resistant to <it>K. pneumoniae </it>than males, O₃exposure significantly increased the susceptibility of females to <it>K. pneumoniae </it>infection to a greater degree than males; 3) alveolar macrophages from O₃-exposed male and female mice have impaired phagocytic ability compared to macrophages from FA-exposed mice; and 4) the O₃-dependent reduction in phagocytic ability is greater in female mice.</p> <p>Conclusion</p> <p>O₃exposure reduces the ability of mice to survive <it>K. pneumoniae </it>infection and the reduced phagocytic ability of alveolar macrophages may be one of the contributing factors. Both events are significantly more pronounced in female mice following exposure to the environmental pollutant, ozone.</p

Low-carbohydrate diet in type 2 diabetes. Stable improvement of bodyweight and glycemic control during 22 months follow-up

BACKGROUND: Low-carbohydrate diets in the management of obese patients with type 2 diabetes seem intuitively attractive due to their potent antihyperglycemic effect. We previously reported that a 20 % carbohydrate diet was significantly superior to a 55–60 % carbohydrate diet with regard to bodyweight and glycemic control in 2 non-randomised groups of obese diabetes patients observed closely over 6 months. The effect beyond 6 months of reduced carbohydrate has not been previously reported. The objective of the present study, therefore, was to determine to what degree the changes among the 16 patients in the low-carbohydrate diet group at 6-months were preserved or changed 22 months after start, even without close follow-up. In addition, we report that, after the 6 month observation period, two thirds of the patients in the high-carbohydrate changed their diet. This group also showed improvement in bodyweight and glycemic control. METHOD: Retrospective follow-up of previously studied subjects on a low carbohydrate diet. RESULTS: The mean bodyweight at the start of the initial study was 100.6 ± 14.7 kg. At six months it was 89.2 ± 14.3 kg. From 6 to 22 months, mean bodyweight had increased by 2.7 ± 4.2 kg to an average of 92.0 ± 14.0 kg. Seven of the 16 patients (44%) retained the same bodyweight from 6 to 22 months or reduced it further; all but one had lower weight at 22 months than at the beginning. Initial mean HbA1c was 8.0 ± 1.5 %. After 6 and 12 months it was 6.6 ± 1.0 % and 7.0 ± 1.3 %, respectively. At 22 months, it was still 6.9 ± 1.1 %. CONCLUSION: Advice on a 20 % carbohydrate diet with some caloric restriction to obese patients with type 2 diabetes has lasting effect on bodyweight and glycemic control

Do community medicine residency trainees learn through journal club? An experience from a developing country

BACKGROUND: Journal clubs are an internationally recognized teaching tool in many postgraduate medical education fields. In developing countries lack of funds for current print materials may have limited journal club use. But with advancing information technology trainees in developing countries increasingly have more access to high quality journals online. However, we are aware of no studies describing journal club existence and effectiveness in postgraduate medical training in Pakistan. Also we have found no published effectiveness studies of this teaching modality in Community Medicine (Public Health) in any country. This study evaluated the effectiveness of Community Medicine (Public Health) Resident Journal Club (CMR-JC) in Aga Khan University, Pakistan using international criteria for successful journal clubs (2 years continuous existence and more than 50% attendance) and examining resident and alumni satisfaction. METHODS: Journal club effectiveness criteria were searched using electronic search databases. Departmental records were reviewed from September1999–September 2005. Ninety percent of residents and alumni of Community Medicine Residency Programme participated voluntarily in a confidential survey. RESULTS: The CMR-JC was regularly conducted. More than 95% of residents attended. (Total residents in the CMR-Programme: 32). Twenty-seven out of 29 current residents/alumni responded to the anonymous questionnaire. Acquisition of critical appraisal skills (23 respondents) and keeping up with current literature (18 respondents) were the two most important objectives achieved. Respondents recommended improved faculty participation and incorporating a structured checklist for article review. CONCLUSION: CMR-JC fulfils criteria for effective journal clubs. Residents and alumni agree CMR-JC meets its objectives. Incorporating suggested recommendations will further improve standards. The journal club learning modality should be included in residency training programs in developing countries. Effective use of online resources to support journal clubs is demonstrated as a successful alternative to excessive expenditure for obtaining print journals. Those trying to start or improve journal clubs can benefit from our experience

Designing Nanoconjugates to Effectively Target Pancreatic Cancer Cells In Vitro and In Vivo

Pancreatic cancer is the fourth leading cause of cancer related deaths in America. Monoclonal antibodies are a viable treatment option for inhibiting cancer growth. Tumor specific drug delivery could be achieved utilizing these monoclonal antibodies as targeting agents. This type of designer therapeutic is evolving and with the use of gold nanoparticles it is a promising approach to selectively deliver chemotherapeutics to malignant cells. Gold nanoparticles (GNPs) are showing extreme promise in current medicinal research. GNPs have been shown to non-invasively kill tumor cells by hyperthermia using radiofrequency. They have also been implemented as early detection agents due to their unique X-ray contrast properties; success was revealed with clear delineation of blood capillaries in a preclinical model by CT (computer tomography). The fundamental parameters for intelligent design of nanoconjugates are on the forefront. The goal of this study is to define the necessary design parameters to successfully target pancreatic cancer cells.The nanoconjugates described in this study were characterized with various physico-chemical techniques. We demonstrate that the number of cetuximab molecules (targeting agent) on a GNP, the hydrodynamic size of the nanoconjugates, available reactive surface area and the ability of the nanoconjugates to sequester EGFR (epidermal growth factor receptor), all play critical roles in effectively targeting tumor cells in vitro and in vivo in an orthotopic model of pancreatic cancer.Our results suggest the specific targeting of tumor cells depends on a number of crucial components 1) targeting agent to nanoparticle ratio 2) availability of reactive surface area on the nanoparticle 3) ability of the nanoconjugate to bind the target and 4) hydrodynamic diameter of the nanoconjugate. We believe this study will help define the design parameters for formulating better strategies for specifically targeting tumors with nanoparticle conjugates

The Chromatin Modifier MSK1/2 Suppresses Endocrine Cell Fates during Mouse Pancreatic Development

Type I diabetes is caused by loss of insulin-secreting beta cells. To identify novel, pharmacologically-targetable histone-modifying proteins that enhance beta cell production from pancreatic progenitors, we performed a screen for histone modifications induced by signal transduction pathways at key pancreatic genes. The screen led us to investigate the temporal dynamics of ser-28 phosphorylated histone H3 (H3S28ph) and its upstream kinases, MSK1 and MSK2 (MSK1/2). H3S28ph and MSK1/2 were enriched at the key endocrine and acinar promoters in E12.5 multipotent pancreatic progenitors. Pharmacological inhibition of MSK1/2 in embryonic pancreatic explants promoted the specification of endocrine fates, including the beta-cell lineage, while depleting acinar fates. Germline knockout of both Msk isoforms caused enhancement of alpha cells and a reduction in acinar differentiation, while monoallelic loss of Msk1 promoted beta cell mass. Our screen of chromatin state dynamics can be applied to other developmental contexts to reveal new pathways and approaches to modulate cell fates