Design and development of a pool and billiards assistive device for the physically challenged.

This research entailed the development and prototyping of a bespoke assistive device for a subject who was a local pool and billiards championship player. The subject was diagnosed with a brain tumor and had to undergo surgery followed by chemotherapy to completely remove the mass in the brain. Following this, there was some loss in motor skills on the right side of his body affecting his gait and grip on objects and his ability to play pool and billiards. Concepts were developed to enable the subject to regain some form. A final design was made, with subsequent alterations for fit and comfort. Testing was done over a 7-day period and results using aid were compared without using any aid over a similar period. There was an 88% decrease in time taken to execute the shot, a 140% increase in strength of shot and a 75% increase in accuracy. The results suggest greater improvement in these performance characteristics with extended use of the device. The device also serves to improve the quality of life of the subject. Implications for Rehabilitation A subject lost some physical ability following the removal of a brain tumor. A bespoke design was found to significantly enhance the performance of the subject in pool and billiards, a game that the subject loved to play before loss of the physical ability. Of increasing importance to those that have lost physical ability is the aim to restore quality of life similar to before the loss of the physical ability, especially with respect to activities that a subject would have been motivated to do due to intrinsic love/interest of the activity.

Trehalose-Induced Activation of Autophagy Improves Cardiac Remodeling After Myocardial Infarction.

BACKGROUND: Trehalose (TRE) is a natural, nonreducing disaccharide synthesized by lower organisms. TRE exhibits an extraordinary ability to protect cells against different kinds of stresses through activation of autophagy. However, the effect of TRE on the heart during stress has never been tested. OBJECTIVES: This study evaluated the effects of TRE administration in a mouse model of chronic ischemic remodeling. METHODS: Wild-type (WT) or beclin1+/- mice were subjected to permanent ligation of the left anterior descending artery (LAD) and then treated with either placebo or trehalose (1 mg/g/day intraperitoneally for 48 h, then 2% in the drinking water). After 4 weeks, echocardiographic, hemodynamic, gravimetric, histological, and biochemical analyses were conducted. RESULTS: TRE reduced left ventricular (LV) dilation and increased ventricular function in mice with LAD ligation compared with placebo. Sucrose, another nonreducing disaccharide, did not exert protective effects during post-infarction LV remodeling. Trehalose administration to mice overexpressing GFP-tagged LC3 significantly increased the number of GFP-LC3 dots, both in the presence and absence of chloroquine administration. TRE also increased cardiac LC3-II levels after 4 weeks following myocardial infarction (MI), indicating that it induced autophagy in the heart in vivo. To evaluate whether TRE exerted beneficial effects through activation of autophagy, trehalose was administered to beclin 1+/- mice. The improvement of LV function, lung congestion, cardiac remodeling, apoptosis, and fibrosis following TRE treatment observed in WT mice were all significantly blunted in beclin 1+/- mice. CONCLUSIONS: TRE reduced MI-induced cardiac remodeling and dysfunction through activation of autophagy.

Boosting autophagy in the diabetic heart: a translational perspective.

Diabetes, obesity, and dyslipidemia are main risk factors that promote the development of cardiovascular diseases. These metabolic abnormalities are frequently found to be associated together in a highly morbid clinical condition called metabolic syndrome. Metabolic derangements promote endothelial dysfunction, atherosclerotic plaque formation and rupture, cardiac remodeling and dysfunction. This evidence strongly encourages the elucidation of the mechanisms through which obesity, diabetes, and metabolic syndrome induce cellular abnormalities and dysfunction in order to discover new therapeutic targets and strategies for their prevention and treatment. Numerous studies employing both dietary and genetic animal models of obesity and diabetes have demonstrated that autophagy, an intracellular system for protein degradation, is impaired in the heart under these conditions. This suggests that autophagy reactivation may represent a future potential therapeutic intervention to reduce cardiac maladaptive alterations in patients with metabolic derangements. In fact, autophagy is a critical mechanism to preserve cellular homeostasis and survival. In addition, the physiological activation of autophagy protects the heart during stress, such as acute ischemia, starvation, chronic myocardial infarction, pressure overload, and proteotoxic stress. All these aspects will be discussed in our review article together with the potential ways to reactivate autophagy in the context of obesity, metabolic syndrome, and diabetes.

Thigh Abscess Caused by Yersinia enterocolitica in an Immunocompetent Host.

Yersinia enterocolitica is primarily a gastrointestinal tract pathogen known to cause gastroenteritis, although it may produce extra-intestinal infections like sepsis and its sequelae. However, primary cutaneous infections are extremely rare. We present a case of Y. enterocolitica thigh abscess in an immunocompetent adult. The portal of entry is unclear in this case. He did many outdoor activities that involved skin injuries and exposure to soil and contaminated water. Hence, direct inoculation as a result of exposure to contaminated water is postulated in the absence of evidence for a gastrointestinal route of infection.

Atrial Coronary Arteries: Anatomy And Atrial Perfusion Territories.

Coronary anatomy has traditionally focused on ventricular circulation. This is largely due to the extent to which coronary artery disease contributes to ischemic heart disease through ventricular myocardial damage. Atrial fibrillation and other tachyarrhythmias that involve the atria, however, remain a major cause of morbidity and mortality. In order to increase mechanistic research and therapeutic interventional procedures for diseases of the atria, an optimal knowledge of atrial anatomy is necessary. While substantial clarity exists regarding the distribution of nerve terminals and the organization of muscle bundles, the anatomy of coronary atrial circulation remains understudied. Historically, the high anatomical variability of atrial coronary branches led to unstandardized nomenclature in the literature. In this review, we delineate the anatomic courses of key atrial coronary branches and their perfusion territories, clarify their nomenclature, and propose unifying anatomical concepts of atrial circulation that we believe to be critical to the success of modern electrophysiologic and surgical procedures.

SAAG-4 is a novel mosquito salivary protein that programmes host CD4 T cells to express IL-4.

Mosquitoes represent the most important vector for transmitting pathogens that cause human disease. Central to pathogen transmission is the ability to divert the host immune system away from Th1 and towards Th2 responsiveness. Identification of the mosquito factor(s) critical for programming Th2 responsiveness should therefore lead to strategies to neutralize their function and thus prevent disease transmission. In the current study, we used a TCR transgenic adoptive transfer system to screen gene products present in the saliva of the mosquito Aedes aegypti for their ability to programme CD4 T cells to express the signature Th2 cytokine IL-4. The clone SAAG-4 encodes a secreted protein with a predicted size of 20 kDa whose function has previously been uncharacterized. Notably, SAAG-4 reduced host CD4 T cell expression of the signature Th1 cytokine IFN-gamma while simultaneously increasing expression of IL-4. SAAG-4 is therefore the first identified mosquito factor that can programme Th2 effector CD4 T cell differentiation.

A novel sphingomyelinase-like enzyme in Ixodes scapularis tick saliva drives host CD4 T cells to express IL-4.

Tick feeding modulates host immune responses. Tick-induced skewing of host CD4(+) T cells towards a Th2 cytokine profile facilitates transmission of tick-borne pathogens that would otherwise be neutralized by Th1 cytokines. Tick-derived factors that drive this Th2 response have not previously been characterized. In the current study, we examined an I. scapularis cDNA library prepared at 18-24 h of feeding and identified and expressed a tick gene with homology to Loxosceles spider venom proteins with sphingomyelinase activity. This I. scapularis sphingomyelinase-like (IsSMase) protein is a Mg(2+)-dependent, neutral (pH 7.4) form of sphingomyelinase. Significantly, in an in vivo TCR transgenic adoptive transfer assay IsSMase programmed host CD4(+) T cells to express the hallmark Th2 effector cytokine IL-4. IsSMase appears to directly programme host CD4 T cell IL-4 expression (as opposed to its metabolic by-products) because induced IL-4 expression was not altered when enzymatic activity was neutralized. TCR transgenic CD4 T cell proliferation (CFSE-dilution) was also significantly increased by IsSMase. Furthermore, a Th2 response is superimposed onto a virally primed Th1 response by IsSMase. Thus, IsSMase is the first identified tick molecule capable of programming host CD4(+) T cells to express IL-4.

Feeding by the tick, Ixodes scapularis, causes CD4(+) T cells responding to cognate antigen to develop the capacity to express IL-4.

Effects of tick feeding on an early antigen-specific T cell response were studied by monitoring a clonotypic population of adoptively transferred T cell receptor (TCR) transgenic CD4 cells responding to a tick-associated antigen. When recipient mice were infested with pathogen-free Ixodes scapularis nymphs several days prior to T cell transfer and intradermal injection of soluble cognate antigen at the feeding site, the clonotypic CD4 cells gained the ability to express the Th2 effector cytokine IL-4. Notably, this effect was not only observed in BALB/c mice predisposed towards developing Th2 responses but also in B10.D2 mice predisposed towards Th1 responsiveness. Furthermore, tick feeding was able to superimpose IL-4 expression potential onto a strong Th1 response (indicated by robust IFN-gamma expression potential) elicited by immunization with a vaccinia virus expressing the cognate antigen. The magnitude to which tick feeding was able to programme IL-4 expression potential in CD4 cells was partially reduced in mice that had been previously exposed to pathogen-free tick nymphs 6 weeks earlier, as well as when the nymphs were infected with Borrelia burgdorferi. Intradermal injection of salivary gland extract programmed IL-4 expression potential similar to that of tick infestation, suggesting that IL-4 programming activity is contained within tick saliva.

Pharmacokinetics of a hematoregulatory peptide (SK&F107647) in healthy male volunteers and in patients with colorectal or pancreatic adenocarcinoma not amenable to standard therapy.

PURPOSE: To describe the pharmacokinetics of SK&F 107647, a synthetic hematoregulatory peptide, in healthy volunteers and in patients with adenocarcinoma. METHODS: SK&F 107647 pharmacokinetics were evaluated in 2 dose-escalation studies. Volunteers received SK&F 107647 as single 15-minute iv infusion doses of 1, 10, 100, 500, and 1,000 microg/kg. Cancer patients received 2-hour iv infusions of 0.001, 0.01, 0.1 and 1 microg/kg once daily for 10 days. Drug concentrations were quantified in plasma and urine of healthy volunteers and on days 1 and 10 in plasma of cancer patients receiving the two top dose levels. RESULTS: In volunteers, mean clearance (CL) ranged from 76.7 to 101 ml/hour/kg; mean volume of distribution at steady-state (Vss) ranged from 175 to 268 ml/kg. Most of the administered dose was renally excreted as intact peptide within 24 hours postinfusion. In patients, mean CL was 57.6 ml/hour/kg, mean Vss ranged from 128 to 150 ml/kg and terminal half-life from 2.1 to 3.4 hours. There was little accumulation of drug. In both studies, linear pharmacokinetics was observed. Clearance approached normal glomerular filtration rate (GFR) in volunteers and correlated with creatinine clearance in cancer patients. CONCLUSIONS: SK&F 107647 exhibits linear pharmacokinetics, a small Vss, and clearance, primarily renal, approaching normal GFR.

Lithium treatment of conduct disorders in adolescents.

OBJECTIVE: The authors examined the efficacy of lithium carbonate for treating conduct disorder in adolescents. METHOD: The subjects were 33 inpatients aged 12-17 years. Lithium or placebo was administered in a double-blind fashion for 2 weeks. RESULTS: On several measures of clinical change the groups showed no significant differences. Of the patients who completed the study, 8.3% of those receiving placebo (one of 12) versus 21.4% (three of 14) of those receiving lithium were considered responders. CONCLUSIONS: Lithium does not appear beneficial for this indication.

Interspecies pharmacokinetics of a novel hematoregulatory peptide (SK&F 107647) in rats, dogs, and oncologic patients.

PURPOSE: To study the pharmacokinetics of SK&F 107647, a novel hematoregulatory agent, in rats, dogs, and patients with non-lymphoid solid tumor malignancy. METHODS: Sprague Dawley rats and beagle dogs (n = 6 each; 3 M, 3 F) were given 25 mg/kg of SK&F 107467 as an iv bolus injection, and patients (n = 6; 4 M, 2 F) received 100 mg/kg as a 2 hour iv infusion. Plasma samples were assayed for drug using either HPLC (rat and dog) or RIA (human). RESULTS: In each species the plasma clearance (CL) of SK&F 107647 was low in relation to hepatic blood flow, and the volume of distribution (Vd ss) was reflective of distribution to extracellular body water. The plasma CL in humans was near that of average glomerular filtration rate. Using allometric equations for interspecies scaling (Y = a.W(b)), body-weight normalized human pharmacokinetic data were reasonably predicted using either the body weight normalized rat or the dog data. The allometric exponents (b) for CL, Vd(ss), and T(1/2) of SK&F 107647 were 0.63, 0.94, and 0.29, respectively. CONCLUSIONS: Use of a limited pool of available animal data allowed for reasonable predictions of human pharmacokinetics of SK&F 107647.

Direct plasma liquid chromatographic-tandem mass spectrometric analysis of granisetron and its 7-hydroxy metabolite utilizing internal surface reversed-phase guard columns and automated column switching devices.

An alternative on-line automated sample enrichment technique useful for the direct determination of various drugs and their metabolites in plasma is described for rapid development of highly sensitive and selective liquid chromatographic methods using mass spectrometric detection. The method involves direct injection of plasma onto an internal surface reversed-phase (ISRP) guard column, washing the proteins from the column to waste with aqueous acetonitrile, and backflushing the analytes onto a reversed-phase octyl silica column using switching valves. The analytes were detected using a tandem mass spectrometer operated in selected reaction monitoring (SRM) mode using atmospheric pressure chemical ionization (APCI). Use of two ISRP guard columns in parallel configuration allowed alternate injections of plasma samples on these columns for sample enrichment and shortened the column equilibration and LC-MS-MS analysis times, thereby increasing the sample throughput. The total run time, including both sample enrichment and chromatography, was about 6 min. Using this technique, an analytical method was developed for the quantitation of granisetron and its active 7-hydroxy metabolite in dog plasma. Granisetron is a selective 5-HT3 receptor antagonist used in the prevention and treatment of cytostatic induced nausea and vomiting. Recovery of the analytes was quantitative and the method displayed excellent linearity over the concentration ranges tested. Results from a three day validation study for both compounds demonstrated excellent precision (1.3-8.7%) and accuracy (93-105%) across the calibration range of 0.1 to 50 ng/ml using an 80 microliters plasma sample. The automated method described here was simple, reliable and economical. This on-line approach using ISRP columns and column switching with LC-MS-MS is applicable for the quantification of other pharmaceuticals in pharmacokinetic studies in animals and humans which require high sensitivity.

Simultaneous determination of granisetron and its 7-hydroxy metabolite in human plasma by reversed-phase high-performance liquid chromatography utilizing fluorescence and electrochemical detection.

A highly sensitive and selective high-performance liquid chromatographic method was developed for the determination of granisetron and its active metabolite, 7-hydroxygranisetron (7OH-G) in human plasma. Granisetron is a selective 5-hydroxytryptamine receptor antagonist used in the treatment of cytotoxic drug-induced emesis. The method involves isolation of granisetron, 7OH-G and the internal standards from plasma by solid-phase extraction prior to reversed-phase ion-pair chromatographic separation on an octyl silica column with subsequent quantification of analytes simultaneously either with electrochemical (7OH-G) or fluorescence (granisetron) detectors which are placed in series. The recovery of granisetron and 7OH-G from human plasma was quantitative. Using 1 ml of plasma, the limits of quantification for granisetron and 7OH-G were 0.1 and 0.25 ng/ml, respectively. Linear responses in analyte/internal standard peak-area ratios were observed for analyte concentrations ranging from 0.1 to 50 ng/ml plasma. Precision and accuracy were within 13% across the calibration range for both granisetron and 7OH-G. The method was sufficiently sensitive, accurate and precise to support pharmacokinetic studies for granisetron and 7OH-G, in both normal and patient populations.

High-performance liquid chromatographic determination of the N-ethyl tricarbamate ester pro-drug of fenoldopam utilizing simultaneous post-column hydrolysis and fluorescence derivatization.

A high-performance liquid chromatographic (HPLC) method was developed for the determination of SK&F 105058 (I), the N-ethyl tricarbamate ester pro-drug of fenoldopam, in dog plasma. Fenoldopam is a selective agonist of peripheral dopaminergic (DA-1) receptors and has been shown to improve blood flow and lower blood pressure. The method involves isolation of I and the internal standard (I.S.) from plasma by solid-phase extraction prior to chromatographic separation on an octyl silica column. Following chromatographic separation, the carbamate esters of I and I.S. were simultaneously hydrolyzed and the liberated alkylamines were derivatized, by mixing the column effluent with an alkaline solution of o-phthaldialdehyde and a thiol, to generate a highly fluorescent isoindole product which was subsequently detected with a fluorometer. Optimization of chromatographic and post-column reaction conditions resulted in an on-column detection limit of 0.4 ng. The recoveries for I and I.S. from plasma were 80.0 +/- 5.0% and 62.0 +/- 4.0%, respectively. The limit of quantification for I using 0.2 ml of plasma was 5 ng/ml. Linear response was observed for concentrations of I ranging from 5 to 2000 ng/ml plasma. The method was suitably specific and sensitive for pharmacokinetic and metabolic studies of I in dogs. The methodology developed should be generally applicable to the determination of carbamate-type pro-drugs in biological media.

The in vivo pharmacological profile of the novel glycoprotein IIb/IIIa antagonist, SK&F 106760.

The in vivo pharmacological profile of SK&F 106760 [N alpha-acetyl-cyclo(S,S)-cysteinyl-N alpha-methylarginyl-glycyl-aspartyl-penicillamine-amide], a novel, potent glycoprotein IIb/IIIa (GPIIb/IIIa) antagonist has been investigated. In conscious dogs, SK&F 106760 (0.3-3 mg/kg i.v.) produced a dose-related inhibition of ex vivo whole blood platelet aggregation induced by collagen (5 micrograms/ml) with complete inhibition being produced for 5, 90 and 165 min after administration of 0.3, 1 and 3 mg/kg i.v., respectively. Plasma levels of SK&F 106760 were measured by high-performance liquid chromatography after i.v. bolus administration of 1 mg/kg. An initial alpha-disposition phase with a T1/2 of 11 +/- 6 min was followed by a longer terminal beta-elimination phase with a T1/2 of 66 +/- 12 min, which accounted for 79 +/- 9% of the total area under the plasma concentration-time curve. The apparent steady-state volume of distribution was 259 +/- 26 ml/kg and the plasma clearance was 3.4 +/- 0.8 ml/min/kg. The plasma concentration of SK&F 106760 at which collagen-induced ex vivo whole blood aggregation was inhibited by 50% was estimated to be 593 +/- 52 nM. After intraduodenal and intrajejunal administration of 3 mg/kg, SK&F 106760 had a bioavailability of 3 to 6% and produced a peak inhibition of ex vivo platelet aggregation of 40 to 50%. In anesthetized dogs, SK&F 106760 (0.3-3.0 mg/kg i.v.) produced a complete inhibition of platelet-dependent coronary artery thrombosis, with a dose-related duration of action.(ABSTRACT TRUNCATED AT 250 WORDS)

Determination of a novel hematoregulatory peptide in dog plasma by reversed-phase high-performance liquid chromatography and an amine-selective o-phthaldialdehyde-thiol post-column reaction with fluorescence detection.

A sensitive and selective high-performance liquid chromatographic method was developed for the determination of SB 107647 (I), a novel synthetic hematoregulatory peptide, in plasma samples of dog and rat. The method involves isolation of I and the internal standard (SB 203285, IS) from plasma by a solid-phase anion-exchange extraction column prior to reversed-phase ion-pair chromatographic separation on an octyl silica column. Following separation, a selective post-column reaction of the epsilon-amino groups of the lysine moieties of the peptide with o-phthaldialdehyde and a thiol under basic conditions was used to generate a highly fluorescent isoindole product, which was subsequently detected on-line with a fluorometer. Optimization of chromatographic conditions resulted in an on-column detection limit of 1 ng. The recovery of I from dog plasma at 20 and 4000 ng/ml was 50.0 +/- 5.94 and 56.6 +/- 1.45% (Mean +/- S.D.), respectively. The limit of quantification for I, for 0.25-ml plasma samples, was 20 ng/ml. Linear response was observed for concentrations of I ranging from 20 to 4000 ng/ml of plasma. The assay was sufficiently sensitive, accurate and precise to support toxicokinetic studies in animal species.

Disposition of growth hormone-releasing peptide (SK&F 110679) in rat and dog following intravenous or subcutaneous administration.

The disposition of growth hormone releasing peptide (SK&F 110679) has been studied in male Sprague-Dawley rats and in male and female beagle dogs following intravenous (iv) and subcutaneous (sc) administration. Mass balance/excretion of [3H]SK&F 110679 was assessed in bile duct-exteriorized rats from which radiolabeled biliary and urinary excreta were quantified and characterized. [3H]SK&F 110679 was excreted, predominantly in the bile, and to a large extent as intact peptide following either iv or sc administration. Although the extent of biliary excretion of radiolabel was similar following iv or sc administration (60-70% of the dose), the rate was significantly higher following iv administration. Using a specific plasma HPLC/fluorescence assay, the iv and sc pharmacokinetics of SK&F 110679 were investigated in both species. Following iv bolus administration, biphasic plasma concentration-time profiles were observed, and the initial phases were characterized by 2-4 min half-lives. Systemic plasma clearance was 27 ml/min/kg in the rat (0.4 mg/kg dose) and 17 ml/min/kg in the dog (0.5 mg/kg dose). High sc bioavailability (89-103%) was observed in both species; an apparent terminal half-life of 1 hr likely reflected slow absorption from the injection site.

Determination of oxiracetam in human plasma by reversed-phase high-performance liquid chromatography with fluorimetric detection.

Reversed-phase HPLC methodology utilizing pre-column derivatization and post-column reaction fluorimetric detection has been developed and applied to the determination of oxiracetam in human plasma. The method involves preliminary isolation of oxiracetam and internal standard from plasma by solid-phase extraction prior to the formation of their n-propyl carbamate derivatives. The carbamate derivatives were subsequently isolated by solid-phase extraction and subjected to a gradient liquid chromatographic separation on an octadecylsilica column prior to on-line post-column alkaline hydrolysis to produce the corresponding primary amine, which was in turn derivatized with o-phthalaldehyde and 3-mercaptopropionic acid to yield a fluorescent isoindole. The isoindole was then quantified using a fluorescence detector. The method provided an on-column detection limit of 0.5 ng of oxiracetam and was sufficiently sensitive, accurate, and precise to support pre-clinical or clinical pharmacokinetic studies.

Column-switching high-performance liquid chromatographic method for the determination of SK&F 106203 in human plasma after fluorescence derivatization with 9-anthryldiazomethane.

A sensitive and selective high-performance liquid chromatographic method was developed for the determination of SK&F 106203 3-(2-carboxyethylthio)-3-[2-(8-phenyloctyl)phenyl]propanoic acid, a potent peptidoleukotriene end organ receptor antagonist, in human plasma. The method involves isolation of SK&F 106203 and the internal standard (SK&F 104736) from plasma samples by liquid-liquid extraction prior to derivatization with 9-anthryldiazomethane. The derivatized samples were first subjected to a solid-phase extraction procedure prior to injection onto a short silica column, which is part of a chromatographic system equipped with an automated column-switching device. Column switching was used to heart-cut the chromatographic zone containing the peaks of interest from this first column and transfer it to an analytical silica column for further chromatographic separation. The peaks were quantified with an in-line fluorometer by measuring the fluorescence emission intensity at 415 nm after excitation at 365 nm. An on-column detection limit of 0.625 ng was achieved for SK&F 106203 by optimizing the derivatization and chromatography conditions. The limit of quantification for SK&F 106203, using 250 microliters of plasma, was 20 ng/ml. Linear response in SK&F 106203/internal standard peak-height ratios was observed for SK&F 106203 concentrations ranging from 10 to 5000 ng/ml of plasma. Precision and accuracy were within 5% across the calibration range. The assay was sufficiently sensitive, accurate, and precise to support pharmacokinetic studies in humans.