Self-reported symptoms and motor tests via telemetry in a 36-month levodopa-carbidopa intestinal gel infusion trial

Objective To investigate if a home environment test battery can be used to measure effects of Parkinson’s disease (PD) treatment intervention and disease progression. Background Seventy-seven patients diagnosed with advanced PD were recruited in an open longitudinal 36-month study at 10 clinics in Sweden and Norway; 40 of them were treated with levodopa-carbidopa intestinal gel (LCIG) and 37 patients were candidates for switching from oral PD treatment to LCIG. They utilized a mobile device test battery, consisting of self-assessments of symptoms and objective measures of motor function through a set of fine motor tests (tapping and spiral drawings), in their homes. Both the LCIG-naïve and LCIG-non-naïve patients used the test battery four times per day during week-long test periods. Methods Assessments The LCIG-naïve patients used the test battery at baseline (before LCIG), month 0 (first visit; at least 3 months after intraduodenal LCIG), and thereafter quarterly for the first year and biannually for the second and third years. The LCIG-non-naïve patients used the test battery from the first visit, i.e. month 0. Out of the 77 patients, only 65 utilized the test battery; 35 were LCIG-non-naïve and 30 LCIG-naïve. In 20 of the LCIG-naïve patients, assessments with the test battery were available during oral treatment and at least one test period after having started infusion treatment. Three LCIG-naïve patients did not use the test battery at baseline but had at least one test period of assessments thereafter. Hence, n=23 in the LCIG-naïve group. In total, symptom assessments in the full sample (including both patient groups) were collected during 379 test periods and 10079 test occasions. For 369 of these test periods, clinical assessments including UPDRS and PDQ-39 were performed in afternoons at the start of the test periods. The repeated measurements of the test battery were processed and summarized into scores representing patients’ symptom severities over a test period, using statistical methods. Six conceptual dimensions were defined; four subjectively-reported: ‘walking’, ‘satisfied’, ‘dyskinesia’, and ‘off’ and two objectively-measured: ‘tapping’ and ‘spiral’. In addition, an ‘overall test score’ (OTS) was defined to represent the global health condition of the patient during a test period. Statistical methods Change in the test battery scores over time, that is at baseline and follow-up test periods, was assessed with linear mixed-effects models with patient ID as a random effect and test period as a fixed effect of interest. The within-patient variability of OTS was assessed using intra-class correlation coefficient (ICC), for the two patient groups. Correlations between clinical rating scores and test battery scores were assessed using Spearman’s rank correlations (rho). Results In LCIG-naïve patients, mean OTS compared to baseline was significantly improved from the first test period on LCIG treatment until month 24. However, there were no significant changes in mean OTS scores of LCIG-non-naïve patients, except for worse mean OTS at month 36 (p<0.01, n=16). The mean scores of all subjectively-reported dimensions improved significantly throughout the course of the study, except ‘walking’ at month 36 (p=0.41, n=4). However, there were no significant differences in mean scores of objectively-measured dimensions between baseline and other test periods, except improved ‘tapping’ at month 6 and month 36, and ‘spiral’ at month 3 (p<0.05). The LCIG-naïve patients had a higher within-subject variability in their OTS scores (ICC=0.67) compared to LCIG-non-naïve patients (ICC=0.71). The OTS correlated adequately with total UPDRS (rho=0.59) and total PDQ-39 (rho=0.59). Conclusions In this 3-year follow-up study of advanced PD patients treated with LCIG we found that it is possible to monitor PD progression over time using a home environment test battery. The significant improvements in the mean OTS scores indicate that the test battery is able to measure functional improvement with LCIG sustained over at least 24 months.

Anxiety-induced antinociception in mice: effects of systemic and intra-amygdala administration of 8-OH-DPAT and midazolam

Rationale: Mice exhibit antinociception after a single experience in the elevated plus maze (EPM), an animal model of anxiety. Objective: This study investigated the mechanisms involved in this form of anxiety-induced antinociception. Methods: Nociception was evaluated by means of the writhing test in mice confined either to the open or enclosed arms of the EPM. The effects of systemic (naloxone, midazolam and 8-OH-DPAT) or intra-amygdala (8-OH-DPAT. NAN-190 and midazolam) drug infusions were investigated in mice previously treated i.p. with 0.6% acetic acid, an algic stimulus that induces abdominal contortions. The effects of these drugs on conventional measures of anxiety (% entries and % time in open arms) in a standard EPM test were also independently investigated. Results: Open-arm confinement resulted in a high-magnitude antinociception (minimum 85%, maximum 450%) compared with enclosed arm confinement. The opiate antagonist naloxone (1 mg/kg and 10 mg/kg) neither blocked this open arm-induced antinociception (OAIA) nor modified indices of anxiety in EPM. Administration of midazolam (0.5-2 mg/kg, s.c.) increased OAIA and produced antinociception in enclosed confined animals, as well as attenuating anxiety in the EPM. The 5-HT(1A) receptor agonist 8-OH-DPAT (0.05-1 mg/kg, s.c.) had biphasic effects on OAIA, antagonising the response at the lowest dose and intensifying it at the highest dose. In addition, low doses of this agent reduced anxiety in the EPM. Although bilateral injections of 8-OH-DPAT (5.6 nmol/0.4 mu l) or NAN-190 (5.6 nmol and 10 nmol/0.4 mu l) into the amygdala did not alter OAIA, increased anxiety was observed in the EPM. In contrast, intra-amygdala administration of midazolam (10 nmol and 30 nmol/0.4 mu l) blocked both OAIA and anxiety. Conclusions: These results with systemic and intracerebral drug infusion suggest that 5-HT(1A) receptors localised in the amygdala are not involved in the pain inhibitory processes that are recruited during aversive situations. However, activation of these receptors does phasically increase anxiety. Although the intrinsic antinociceptive properties of systemically administered midazolam confounded interpretation of its effects on OAIA, intra-amygdala injections of this compound suggest that benzodiazepine receptors in this brain region modulate both the antinociceptive and behavioural (anxiety) responses to the EPM.

Changes in taste reactivity to intra-oral hypertonic NaCl after lateral parabrachial injections of an alpha(2)-adrenergic receptor agonist

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Efeitos da infusão contínua de cetamina sobre a pressão intra-ocular em cães hipovolêmicos anestesiados com desflurano

Compararam-se os efeitos de duas doses de cetamina, administradas em infusão contínua, sobre a pressão intra-ocular (PIO) de 18 cães submetidos à hipovolemia e à anestesia com desflurano. Promoveu-se a hipovolemia em todos os cães, retirando-se 40 ml de sangue/kg de peso. A anestesia foi induzida com desflurano, através de máscara facial, até que a intubação orotraqueal fosse permitida. Decorridos 30 minutos, para estabilização dos parâmetros, iniciou-se a infusão contínua de cetamina. Os cães foram distribuídos, aleatoriamente, em três grupos (n= 6). O grupo I (controle) recebeu solução salina estéril; o grupo II (GII) recebeu cetamina, na dose de 100mig/kg/min, e o grupo III (GIII), cetamina na dose de 200mig/kg/min. A PIO foi medida por tonometria de aplanação. Foram mensurados freqüência cardíaca (FC), ritmo cardíaco, pressão arterial média (PAM), débito cardíaco (DC), pressão venosa central (PVC) e pressão parcial de CO2 no final da expiração (ETCO2). O desflurano não influenciou os resultados da PIO, porém observou-se discreta ação da cetamina em todos os grupos. Foi possível estabelecer relação direta entre os valores de PIO e de ETCO2. A PIO apresentou relação direta somente com a ETCO2.

Efeitos cardiovasculares e renais da injeção intra-arterial de contraste radiológico iônico em cães com restrição hídrica

JUSTIFICATIVA E OBJETIVOS: O objetivo desta pesquisa foi estudar os efeitos agudos do contraste radiológico em situações de restrição de volume, avaliando-se os efeitos renais e cardiovasculares após a injeção intra-arterial de contraste radiológico de alta osmolaridade. MÉTODO: Participaram do estudo 16 cães anestesiados com tiopental sódico (15 mg.kg-1) e fentanil (15 µg.kg-1) em bolus, seguido de infusão contínua nas doses de 40 µg.kg-1.min-1 (tiopental sódico) e 0,1 µg.kg-1.min-1 (fentanil). Foi feita hidratação com solução de glicose a 5% (0,03 mL.kg-1.min-1) e a ventilação pulmonar foi controlada mecanicamente com ar comprimido. Foram verificados os seguintes atributos: freqüência cardíaca (FC); pressão arterial média (PAM); pressão da veia cava inferior (PVI); débito cardíaco (DC); hematócrito (Ht); fluxo plasmático efetivo renal (FPER); fluxo sangüíneo renal (FSR); ritmo de filtração glomerular (RFG); fração de filtração; resistência vascular renal (RVR); volume urinário (VU); osmolaridade plasmática e urinária; depuração osmolar, depuração de água livre e depuração de sódio e de potássio; sódio e potássio plasmáticos; excreção urinária e fracionária de sódio e potássio e temperatura retal. Estes atributos foram avaliados em quatro momentos: 30 (M1), 60 (M2), 90 (M3) e 120 (M4) minutos após o início da infusão de para-aminohipurato de sódio e creatinina (início da experiência). No momento 2, no grupo G1 foi feita injeção intra-arterial de solução fisiológica a 0,9% (1,24 mL.kg-1), e no grupo G2 foi injetado contraste radiológico (1,24 mL.kg-1) pela mesma via. RESULTADOS: O grupo G1 apresentou aumento da FC, do FPER, do FSR, da osmolaridade plasmática, da depuração de sódio e da excreção urinária de sódio; apresentou ainda diminuição da osmolaridade urinária, do potássio plasmático, da depuração de potássio e da temperatura retal. No grupo G2 ocorreu aumento da FC, da RVR, do VU, da depuração osmolar, da depuração de sódio e da excreção urinária e fracionária de sódio; ocorreu também redução do (a): hematócrito, ritmo de filtração glomerular, fração de filtração, osmolaridade urinária, depuração de água livre, sódio e potássio urinários, potássio plasmático e temperatura retal. CONCLUSÕES: Neste estudo, conclui-se que a injeção intra-arterial do contraste radiológico causou efeito bifásico na função renal. Inicialmente, provocou aumento da diurese e da excreção de sódio, mas, posteriormente, houve piora das condições hemodinâmicas e, conseqüentemente, da função renal, com aumento da resistência vascular renal e diminuição do ritmo de filtração glomerular.

Similar anxiolytic-like effects following intra-amygdala infusions of benzodiazepine receptor agonist and antagonist: Evidence for the release of an endogenous benzodiazepine inverse agonist in mice exposed to elevated plus-maze test

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Pressão intra-abdominal como preditor de lesão renal aguda no pós-operatório de cirurgias abdominais

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

Hepatic arterial infusion enhances DOTATOC radiopeptide therapy in patients with neuroendocrine liver metastases

Intravenously administered radiolabeled peptides targeting somatostatin receptors are used for the treatment of unresectable gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Recently, we demonstrated a high first-pass effect during intra-arterial (i.a.) administration of positron emission tomography (PET) labeled (68)Ga-DOTA(0)-d-Phe(1)-Tyr(3)-octreotide (DOTATOC). In this pilot study, we investigated the therapeutic effectiveness of arterial administered DOTATOC, labeled with the therapeutic β emitters (90)Y and (177)Lu. (90)Y- and/or (177)Lu-DOTATOC were infused into the hepatic artery of 15 patients with liver metastases arising from GEP-NETs. Response was assessed using DOTATOC-PET, multiphase contrast enhanced computed tomography, magnetic resonance imaging, and the serum tumor marker chromogranin A. Pharmacokinetic data of the arterial approach were assessed using (111)In-DOTATOC scans. With the treatment regime of this pilot study, complete remission was achieved in one (7%) patient and partial remission was observed in eight (53%) patients, six patients were classified as stable (40%; response evaluation criteria in solid tumors criteria). The concomitant decrease of elevated serum tumor marker confirmed the radiologic response. Median time to progression was not reached within a mean follow-up period of 20 months. Receptor saturation and redistribution effects were identified as limiting factors for i.a. DOTATOC therapy. The high rate of objective radiologic response in NET patients treated with arterial infusion of (90)Y-/(177)Lu-DOTATOC compares favorably with systemic chemotherapy and intravenous radiopeptide therapy. While i.a. DOTATOC therapy is only applicable to patients with tumors of limited anatomic distribution, the results of this pilot study are a promising development in the treatment of GEP-NET and warrants further investigation of this novel approach.

Effects of continuous remifentanil administration on intra-operative subcutaneous tissue oxygen tension

Surgical stress response markedly increases sympathetic nerve activity and catecholamine concentrations. This may contribute to peripheral vasoconstriction, reduced wound perfusion and subsequent tissue hypoxia. Opioids are known to depress the hypothalamic-adrenal response to surgery in a dose-dependent manner. We tested the hypothesis that continuous remifentanil administration produces improved subcutaneous tissue oxygen tension compared to fentanyl bolus administration. Forty-six patients undergoing major abdominal surgery were randomly assigned to receive either fentanyl bolus administration or continuous remifentanil infusion. Mean subcutaneous tissue oxygen values over the entire intra-operative period were significantly higher in the remifentanil group, when compared to the fentanyl group: 8 (2) kPa vs 6.7 (1.5) kPa, % CI difference: - 2.3 kPa to - 0.3 kPa, p = 0.013. Continuous intra-operative opioid administration may blunt vasoconstriction caused by surgical stress and adrenergic responses more than an equi-effective anaesthetic regimen based on smaller-dose bolus opioid administration.

Intra-hippocampal administration of the VEGF receptor blocker PTK787/ZK222584 impairs long-term memory.

A number of studies have established a role for vascular endothelial growth factor (VEGF) in angiogenesis. Recent reports have shown that VEGF overexpression in the hippocampus improves learning and memory and is associated with enhanced neurogenesis. PTK787/ZK222584 (PTK/ZK) is a reported inhibitor of VEGFR signaling that is currently being tested for its effects on lung and colon cancer. However, the influence of this drug on cognition has not been examined. In the present study, we questioned if post-training administration of PTK/ZK influences hippocampus-dependent memory. When administered to rats immediately following massed training in the Morris water maze, PTK/ZK impaired spatial memory retention tested 48 h later. This impairment was evidenced by increased latency to the hidden platform and fewer platform crossings. However, this impairment was not associated with a change in neurogenesis during this time frame. PTK/ZK infusion did not reduce VEGFR or AKT phosphorylation, but increased the phosphorylation of ERK. These studies suggest that VEGFR inhibitors such as PTK/ZK may negatively influence cognition.

Continuous infusion of ticarcillin-clavulanate for home treatment of serious infections: clinical efficacy, safety, pharmacokinetics and pharmacodynamics

Continuous infusion (CI) ticarcillin-clavulanate is a potential therapeutic improvement over conventional intermittent dosing because the major pharmacodynamic (PD) predictor of efficacy of beta-lactams is the time that free drug levels exceed the MIC. This study incorporated a 6-year retrospective arm evaluating efficacy and safety of CI ticarcillin-clavulanate in the home treatment of serious infections and a prospective arm additionally evaluating pharmacokinetics (PK) and PD. In the prospective arm, steady-state serum ticarcillin and clavulanate levels and MIC testing of significant pathogens were performed. One hundred and twelve patients (median age, 56 years) were treated with a CI dose of 9.3-12.4 g/day and mean CI duration of 18.0 days. Infections treated included osteomyelitis (50 patients), septic arthritis (6), cellulitis (17), pulmonary infections (12), febrile neutropenia (7), vascular infections (7), intra-abdominal infections (2), and Gram-negative endocarditis (2); 91/112 (81%) of patients were cured, 14 (13%) had partial response and 7 (6%) failed therapy. Nine patients had PICC line complications and five patients had drug adverse events. Eighteen patients had prospective PK/PD assessment although only four patients had sufficient data for a full PK/PD evaluation (both serum steady-state drug levels and ticarcillin and clavulanate MICs from a bacteriological isolate), as this was difficult to obtain in home-based patients, particularly as serum clavulanate levels were found to deteriorate rapidly on storage. Three of four patients with matched PK/PD assessment had free drug levels exceeding the MIC of the pathogen. Home Cl of ticarcillin-clavulanate is a safe, effective, convenient and practical therapy and is a therapeutic advance over traditional intermittent dosing when used in the home setting. (c) 2005 Elsevier B.V. and the International Society of Chemotherapy. All rights reserved.

The critical competences needed for innovative organizational inter-firm and intra-firm integration

In today's highly challenging business environment, an innovative and systemic approach is imperative to survival and growth. Organisational integration and technological integration, are often seen as a catalyst of change that could lead to significant improvements in organisations. The levels of improvement in inter and intra firm integration should arise from a detailed understanding and development of competences within and between organisations. Preliminary findings suggest that lack of trust across organisational cultures within the firms has a negative influence on the development of the capabilities to integrate and align technological innovations and hinders implementation and the effectiveness of the operations. Additionally, poor communication and conflict effects customer satisfaction. Firms need to transfer the competences that support cooperative integration, developed through interaction with supply chain partners, to their relationship arrangements with other supply chain partners, as these are key to ensuring low operational costs.

Granule-based knowledge representation for intra and inter transaction association mining

Abstract With the phenomenal growth of electronic data and information, there are many demands for the development of efficient and effective systems (tools) to perform the issue of data mining tasks on multidimensional databases. Association rules describe associations between items in the same transactions (intra) or in different transactions (inter). Association mining attempts to find interesting or useful association rules in databases: this is the crucial issue for the application of data mining in the real world. Association mining can be used in many application areas, such as the discovery of associations between customers’ locations and shopping behaviours in market basket analysis. Association mining includes two phases. The first phase, called pattern mining, is the discovery of frequent patterns. The second phase, called rule generation, is the discovery of interesting and useful association rules in the discovered patterns. The first phase, however, often takes a long time to find all frequent patterns; these also include much noise. The second phase is also a time consuming activity that can generate many redundant rules. To improve the quality of association mining in databases, this thesis provides an alternative technique, granule-based association mining, for knowledge discovery in databases, where a granule refers to a predicate that describes common features of a group of transactions. The new technique first transfers transaction databases into basic decision tables, then uses multi-tier structures to integrate pattern mining and rule generation in one phase for both intra and inter transaction association rule mining. To evaluate the proposed new technique, this research defines the concept of meaningless rules by considering the co-relations between data-dimensions for intratransaction-association rule mining. It also uses precision to evaluate the effectiveness of intertransaction association rules. The experimental results show that the proposed technique is promising.

The intra-aortic balloon pump in heart failure management : implications for nursing practice

Management of acute heart failure is an important consideration in critical care. Mechanical support of the failing heart is crucial for improving health outcomes. The most common Australasian application of intraaortic balloon counterpulsation (IABP) is in the setting of cardiogenic shock. High end users of IABP (>37/annum) demonstrate significantly lower mortality for cardiogenic shock managed with IABP (p <0.001) in contrast to hospitals which employ limited IABP (<4/annum). This underscores the importance of proficiency in managing patient receiving IABP support. Nurses play a crucial role in carding for patients with acute heart failure. This paper summarises care considerations for management of the IABP.