Neuroinflammation, its Role in Alzheimer's Disease and Therapeutic Strategie.

Neuroinflammation precedes the clinical onset of various neurodegenerative diseases, including Alzheimer's disease (AD), by years or frequently even decades (1-3). In terms of the underlying physiology, there is a great need for understanding and controlling interactions between the central nervous system (CNS) and the immune system in an attempt to develop approaches to prevent or delay the disease's progression. Nerve cells have limited motion capability, whereas immune cells can migrate freely via circulation. This difference raises a variety of questions in the context of senile plaque formation and phagocytosis. Broad-scale unbiased genomic studies bring several genetic variants such as sialic acid binding Ig-like lectin 3 (CD33), triggering receptor expressed on myeloid cells 2 (TREM2) or complement receptor type 1 (CR1) into the focus of researchers' attention as potential risk factors for neuroinflammation. In addition, advanced proteomic analyses have been revealing links between these genetic contributors and complex, malfunctioning signaling pathways (including the upregulation of factors like tumor necrosis factor TNF-α, tumor growth factor TGF-ß and interleukin IL-1α) that promote proinflammatory mechanisms via intracellular signaling and trafficking, synaptic function, and cell metabolism/ proliferation. In AD, the brain's microglia and astrocytes, which are normally responsible for maintaining the homeostasis of synaptic transmission and its remodeling by pruning, are the initiators of neuroinflammation and toxic tau and amyloid-ß (Aß) accumulation. Thus, they drive the CNS into a state of sustained or even self-accelerated deterioration. Here we aim to review the cell types and mediators involved in neuroinflammation and AD, the symptom manifestation in clinical settings, and potential candidates for improving diagnosis and treatment.

Combined cognitive-behavioural and mindfulness programme for people living with dystonia: a proof-of-concept study.

OBJECTIVES: To design and test the delivery of an intervention targeting the non-motor symptoms of dystonia and pilot key health and well-being questionnaires in this population. DESIGN: A proof-of-concept study to test the delivery, acceptability, relevance, structure and content for a 3-day group residential programme for the management of dystonia. SETTING: Participants were recruited from a single botulinum toxin clinic. The intervention was delivered in the community. PARTICIPANTS: 14 participants consented to take part (2 withdrew prior to the starting of intervention). The average age was 60 years (range 44-77), 8 of whom were female. After drop-out, 9 participants completed the 3-day programme. INTERVENTION: A 3-day group residential programme. PRIMARY AND SECONDARY OUTCOME MEASURES: Process evaluation and interviews were carried out before and after the intervention to explore participant's views and expectations, as well as experiences of the intervention. Select questionnaires were completed at baseline, 1-month and 3-month follow-up. RESULTS: Although participants were not sure what to expect from the programme, they found it informative and for many this together with being in a group with other people with dystonia legitimised their condition. Mindfulness was accepted and adopted as a coping strategy. This was reflected in the 1-month follow-up. CONCLUSIONS: We successfully delivered a 3-day residential programme to help those living with dystonia manage their condition. Further improvements are suggested. The quantitative outcome measures were acceptable to this group of patients with dystonia.

Preoperative blood glucose concentrations and postoperative outcomes after elective non-cardiac surgery: an observational study.

BACKGROUND: The association between preoperative blood glucose (BG) concentration and outcomes after non-cardiac surgery and the impact of the diabetes diagnosis status remain unclear. We tested two hypotheses: that preoperative BG is related to surgical outcomes; and that this relationship depends on the diabetes diagnosis status of the patient. METHODS: We retrospectively analysed data on 61 536 consecutive elective non-cardiac surgery patients treated at our tertiary care facility. Logistic regression models were used to test the hypotheses before and after adjustment for baseline patient characteristics. Our primary outcome was a composite of in-hospital serious complications and mortality. A second primary outcome was 1 yr mortality. RESULTS: The crude incidence of the composite in-hospital outcome was significantly related to preoperative BG (P<0.001), but not after covariable adjustment (P=0.40). This relationship did not significantly differ between patients with and without diagnosed diabetes (P=0.09). One year mortality was significantly related to preoperative BG, both univariably (P<0.001) and after covariable-adjustment (P<0.001). Patients with diagnosed diabetes and preoperative euglycaemia generally had worse 1 yr mortality than those without diabetes at the same BG {e.g. odds ratio (OR) [95% confidence interval (CI)] of 1.27 (1.06, 1.53) at 6 mmol litre(-1) (108 mg dl(-1)), P=0.003}. Conversely, hyperglycaemic patients with diagnosed diabetes displayed a significantly lower 1 yr mortality than hyperglycaemic patients without diabetes [OR (95% CI) of 0.58 (0.44, 0.77) at 12 mmol litre(-1) (216 mg dl(-1)), P<0.001]. CONCLUSIONS: For elective non-cardiac surgery, preoperative hyperglycaemia should be given greater consideration in patients without diabetes than in those with diagnosed diabetes.

Inflammation: planning for a source of pharmacokinetic/pharmacodynamic variability in translational studies.

The impact of inflammation on variability in the pharmacokinetics (PK) and pharmacodynamics (PD) of drugs should be considered in the design, analysis, and interpretation of clinical pharmacology studies. Data suggest that the metabolism and transport of drugs, as well as the expression of receptors, may change in the presence of inflammation. The clinical implications of these changes are not straightforward; they may vary depending on whether the inflammation is active or controlled and may change with time and successful treatment of the inflammation.

Effects of inflammation on pharmacokinetics/pharmacodynamics: increasing recognition of its contribution to variability in response.

Inflammation is an interesting phenomenon that crosses many disciplines as part of the host response to disease, whether it is the acute response to an infectious, traumatic, or surgical event or the more chronic responses to systemic disease such as malignancy, rheumatoid arthritis, asthma, inflammatory bowel disease, or diabetes. The impact of inflammatory states on the variability in drug response should be an integral part of research conducted across disciplines within clinical pharmacology.

Pharmacokinetics of alvimopan and its metabolite in healthy volunteers and patients in postoperative ileus trials.

Alvimopan, a mu-opioid antagonist without anti-analgesic effects, is being developed to manage postoperative ileus. We characterized the population pharmacokinetics of orally administered alvimopan and its primary metabolite in healthy subjects/special populations, and surgical patients at risk for ileus. Models were consistent with known physiology/pharmacology. Alvimopan's model had two compartments with first-order elimination. Metabolite was modeled with a catenary chain and lag for alvimopan's metabolism within the gut followed by absorption, one systemic compartment with first-order elimination. Weight, gender, and renal function did not affect alvimopan or metabolite. Steady-state alvimopan and metabolite concentrations were 87 and 40% higher, respectively, in patients. Alvimopan concentrations were 35% higher in the elderly, but were not affected by race, acid blockers, or antibiotics. Metabolite concentrations were 43 and 82% lower in African Americans and Hispanics, respectively, compared to Caucasians, 49% lower with acid blockers and 81% lower with preoperative antibiotics. Although alvimopan's pharmacokinetics was described with a traditional model, its metabolite required a novel model accommodating gut metabolism.

Using real time process measurements to reduce catheter related bloodstream infections in the intensive care unit.

PROBLEM: Measuring a process of care in real time is essential for continuous quality improvement (CQI). Our inability to measure the process of central venous catheter (CVC) care in real time prevented CQI efforts aimed at reducing catheter related bloodstream infections (CR-BSIs) from these devices. DESIGN: A system was developed for measuring the process of CVC care in real time. We used these new process measurements to continuously monitor the system, guide CQI activities, and deliver performance feedback to providers. SETTING: Adult medical intensive care unit (MICU). KEY MEASURES FOR IMPROVEMENT: Measured process of CVC care in real time; CR-BSI rate and time between CR-BSI events; and performance feedback to staff. STRATEGIES FOR CHANGE: An interdisciplinary team developed a standardized, user friendly nursing checklist for CVC insertion. Infection control practitioners scanned the completed checklists into a computerized database, thereby generating real time measurements for the process of CVC insertion. Armed with these new process measurements, the team optimized the impact of a multifaceted intervention aimed at reducing CR-BSIs. EFFECTS OF CHANGE: The new checklist immediately provided real time measurements for the process of CVC insertion. These process measures allowed the team to directly monitor adherence to evidence-based guidelines. Through continuous process measurement, the team successfully overcame barriers to change, reduced the CR-BSI rate, and improved patient safety. Two years after the introduction of the checklist the CR-BSI rate remained at a historic low. LESSONS LEARNT: Measuring the process of CVC care in real time is feasible in the ICU. When trying to improve care, real time process measurements are an excellent tool for overcoming barriers to change and enhancing the sustainability of efforts. To continually improve patient safety, healthcare organizations should continually measure their key clinical processes in real time.

Pharmacokinetic profile of epidurally administered methylnaltrexone, a novel peripheral opioid antagonist in a rabbit model.

Methylnaltrexone (MNTX) is the first peripheral opioid receptor antagonist used in man to treat acute and chronic opiate-mediated side-effects. We describe in a rabbit model the pharmacokinetics of epidurally administered MNTX 0.66 mg kg(-1), and we tested the hypothesis that epidurally administered MNTX does not penetrate the dura into the subarachnoid space. There were minimal concentrations of MNTX (40 ng ml(-1)) detected in the CSF at 10 and 20 min and none thereafter in comparison with the high serum levels. The serum drug concentration-time profile fitted a two-compartment pharmacokinetic model. Further studies are warranted as epidurally administered MNTX may have the potential to reverse epidural opioid-mediated side-effects whilst preserving analgesia.

Economics of preoperative evaluation clinics.

Studies continue to support that a process for screening patients prior to their planned anesthesia and surgery can optimize both the status of the patient, decreasing delays and cancellations, and optimize the use of resources, ensuring that needed testing is completed and unneeded testing is avoided.

A review of the potential role of methylnaltrexone in opioid bowel dysfunction.

Opioids are widely used analgesics in patients with advanced cancer. However, their effectiveness for pain relief is often limited by the most frequently occurring side effect, opioid bowel dysfunction (OBD). Because conventional laxation measures are often ineffective in treating OBD, alternative approaches need to be investigated. Opioid action on the gut appears to be mediated mainly by receptors in the gastrointestinal (GI) tract rather than by those in the central nervous system (CNS). Opioid antagonists, such as naloxone, naltrexone, and nalmefene, have been studied as a means of antagonizing the peripheral effects of opioids, but these agents can enter the CNS and reverse analgesia or cause opioid withdrawal symptoms. Methylnaltrexone (MNTX) is a novel quaternary derivative of naltrexone that does not cross the blood-brain barrier and acts as a selective peripheral opioid receptor antagonist. In normal volunteers, intravenous or oral MNTX reverses opioid-induced reduction in bowel motility without affecting analgesia. Bioavailability of MNTX is low after oral administration, and plasma levels do not correlate with its actions in the gut, suggesting a predominantly local luminal action of MNTX on the gut. In patients receiving long-term opioid therapy, MNTX administered intravenously or orally was effective in reducing the delay in oral-cecal transit and eliciting laxation responses in all subjects without causing withdrawal symptoms. MNTX is a peripherally selective opioid antagonist that may have clinical utility in managing OBD with minimal adverse effects.

Maxillofacial injuries in the pediatric patient.

Approximately 22 million children are injured in the United States annually. Children are uniquely susceptible to craniofacial trauma because of their greater cranial-mass-to-body ratio. The pediatric population sustains 1% to 14.7% of all facial fractures. The majority of these injuries are encountered by boys (53.7% - 80%) who are involved in motor vehicle accidents (up to 80.2%). The incidence of other systemic injury concomitant to facial trauma is significant (10.4% - 88%). The management of the pediatric patient with maxillofacial injury should take into consideration the differences in anatomy and physiology between children and adults, the presence of concomitant injury, the particular stage in growth and development (anatomic, physiologic, and psychologic), and the specific injuries and anatomic sites that the injuries affect. This comprehensive review, based on the last 25 years of the world's English-speaking surgical literature, presents current thoughts on the anatomic and physiologic differences between adults and children, a synopsis of childhood growth and development, and an overview of state-of-the-art management of the pediatric patient who has sustained maxillofacial injury.

Multistability in recurrent neural loops arising from delay.

The dynamics of a recurrent inhibitory neural loop composed of a periodically spiking Aplysia motoneuron reciprocally connected to a computer are investigated as a function of the time delay, tau, for propagation around the loop. It is shown that for certain choices of tau, multiple qualitatively different neural spike trains co-exist. A mathematical model is constructed for the dynamics of this pulsed-coupled recurrent loop in which all parameters are readily measured experimentally: the phase resetting curve of the neuron for a given simulated postsynaptic current and tau. For choices of the parameters for which multiple spiking patterns co-exist in the experimental paradigm, the model exhibits multistability. Numerical simulations suggest that qualitatively similar results will occur if the motoneuron is replaced by several other types of neurons and that once tau becomes sufficiently long, multistability will be the dominant form of dynamical behavior. These observations suggest that great care must be taken in determining the etiology of qualitative changes in neural spiking patterns, particularly when propagation times around polysynaptic loops are long.

Effects of enteric-coated methylnaltrexone in preventing opioid-induced delay in oral-cecal transit time.

BACKGROUND: Methylnaltrexone is the first peripheral opioid receptor antagonist. It has the potential to prevent or reverse the peripherally mediated gastrointestinal effects of opioids. In previous human volunteer trials, we demonstrated that oral uncoated methylnaltrexone prevented morphine-induced delay in gastrointestinal transit time. METHODS: This trial consisted of two studies: a pilot study and a controlled study. The lactulose hydrogen breath test was used to measure the oral-cecal transit time. RESULTS: In the pilot study with three subjects, an oral dose of 6.4 mg/kg enteric-coated methylnaltrexone effectively reversed the effects of morphine, producing transit times shorter than baseline levels. Subsequently, in the controlled study with another nine subjects, the transit time increased after intravenous morphine administration in all nine subjects, and the lower dose (3.2 mg/kg) of enteric-coated methylnaltrexone completely prevented the morphine-induced change in oral-cecal transit time in all nine subjects. Morphine significantly increased oral-cecal transit time from baseline level of 96.7 +/- 54.1 minutes (mean +/- SD) to 155.0 +/- 53.6 minutes (P = .014). After enteric-coated methylnaltrexone and morphine, the transit time returned to the baseline level (93.3 +/- 56.0 minutes; P = .55 compared with placebo). Plasma concentrations after 6.4 mg/kg and 3.2 mg/kg enteric-coated methylnaltrexone were substantially lower compared with those after 6.4 mg/kg of the uncoated formulation. CONCLUSION: Our results suggest that there is a prevailing direct and local luminal effect of enteric-coated methylnaltrexone and that the enteric-coated formulation exerts its gut pharmacologic actions more efficiently than the uncoated formulation.

Comparing methods of clinical measurement: reporting standards for bland and altman analysis.

UNLABELLED: In this era of medical technology assessment and evidence-based medicine, evaluating new methods to measure physiologic variables is facilitated by standardization of reporting results. It has been proposed that assessing repeatability be followed by assessing agreement with an established technique. If the "limits of agreement" (mean bias +/- 2SD) are not clinically important, then one could use two measurements interchangeably. Generalizability to larger populations is facilitated by reporting confidence intervals. We identified 44 studies that compared methods of clinical measurement published during 1996 to 1998 in seven anesthesia journals. Although 42 of 44 (95.4%) used the limits of agreement methodology for analysis, several inadequacies and inconsistencies in reporting the results were noted. Limits of agreement were defined a priori in 7.1%, repeatability was evaluated in 21.4%, and relationship (pattern) between difference and average was evaluated in 7.1%. Only one of the articles reported confidence intervals. A computer macro for the Minitab statistical package (State College, PA) is described to facilitate reporting of Bland and Altman analysis with confidence intervals. We propose standardization of nomenclature in clinical measurement comparison studies. IMPLICATIONS: A literature review of anesthesia journals revealed several inadequacies and inconsistencies in statistical reports of results of comparison studies with regard to interchangeability of measurement methods. We encourage journal editors to evaluate submissions on this subject carefully to ensure that their readers can draw valid conclusions about the value of new technologies.

Methylnaltrexone for reversal of constipation due to chronic methadone use: a randomized controlled trial.

CONTEXT: Constipation is the most common chronic adverse effect of opioid pain medications in patients who require long-term opioid administration, such as patients with advanced cancer, but conventional measures for ameliorating constipation often are insufficient. OBJECTIVE: To evaluate the efficacy of methylnaltrexone, the first peripheral opioid receptor antagonist, in treating chronic methadone-induced constipation. DESIGN: Double-blind, randomized, placebo-controlled trial conducted between May 1997 and December 1998. SETTING: Clinical research center of a university hospital. PARTICIPANTS: Twenty-two subjects (9 men and 13 women; mean [SD] age, 43.2 [5.5] years) enrolled in a methadone maintenance program and having methadone-induced constipation. MAIN OUTCOME MEASURES: Laxation response, oral-cecal transit time, and central opioid withdrawal symptoms were compared between the 2 groups. RESULTS: The 11 subjects in the placebo group showed no laxation response, and all 11 subjects in the intervention group had laxation response after intravenous methylnaltrexone administration (P<.001). The oral-cecal transit times at baseline for subjects in the methylnaltrexone and placebo groups averaged 132.3 and 126.8 minutes, respectively. The average (SD) change in the methylnaltrexone-treated group was -77.7 (37.2) minutes, significantly greater than the average change in the placebo group (-1.4 [12.0] minutes; P<.001). No opioid withdrawal was observed in any subject, and no significant adverse effects were reported by the subjects during the study. CONCLUSIONS: Our data demonstrate that intravenous methylnaltrexone can induce laxation and reverse slowing of oral cecal-transit time in subjects taking high opioid dosages. Low-dosage methylnaltrexone may have clinical utility in managing opioid-induced constipation.

A pattern-oriented approach to splenic imaging in infants and children.

The spleen in infants and children is commonly involved in a variety of pathologic processes. Some of these processes cause isolated splenic disease, whereas others involve the spleen as part of a systemic illness. To facilitate differential diagnosis of splenic abnormalities, a pattern-oriented approach to the imaging evaluation of the pediatric spleen was developed. With this approach, splenic anomalies are categorized as anomalies of splenic shape (clefts, notches, lobules), location (eg, wandering spleen), number (polysplenia, asplenia), or size (splenomegaly, splenic atrophy); solitary lesions (eg, cysts, lymphangiomas, hemangiomas, hamartomas); multiple focal lesions (eg, trauma, infection and inflammation, neoplasms, storage disorders); and diffuse disease without focal lesions (eg, infarction, heavy metal deposition, hemangioendotheliomas, peliosis). A variety of imaging modalities can be used in splenic assessment, including computed tomography, magnetic resonance imaging, ultrasound, and technetium-99m scintigraphy. The imaging appearance of the pediatric spleen depends on the patient's age and the modality used; however, familiarity with the spectrum of radiologic patterns of splenic involvement will facilitate correct diagnosis and prompt treatment.

Anterior chest wall: frequency of anatomic variations in children.

PURPOSE: To evaluate the frequency of anterior chest wall variations in children. MATERIALS AND METHODS: The computed tomographic (CT) images of 200 consecutive infants and children (114 boys and 86 girls; mean age, 10.5 years; age range, 3 months to 19 years) who underwent chest CT during a 20-month period were evaluated for chest wall variations. Children who had undergone chest wall surgery or were suspected of having a chest wall abnormality were excluded. The frequency of chest wall anomalies was compared with age and sex (Fisher exact test). RESULTS: The CT scans of 65 children (33%) depicted one or more variations in the anterior chest wall: titled sternum (n = 29), prominent convexity of anterior rib or costal cartilage (n = 19), prominent asymmetric costal cartilage (n = 20), well-defined paracostal subcutaneous nodule (n = 4), mild pectus excavatum (n = 4), or mild pectus carinatum (n = 4). The frequency of these findings did not vary significantly with age (P = .96) or sex (P = .36). CONCLUSION: Variations in the anterior chest wall are common, occurring in one-third of children, and should be considered normal. These asymptomatic variations should not be considered alarming when palpated at physical examination.

Lack of developmental neurotoxicity of MN rgp 120/HIV-1 administered subcutaneously to neonatal rats.

The potential for neurotoxic effects was evaluated in rat off-spring after exposure in utero and/or during the neonatal period to a recombinant subunit vaccine of gp120 prepared from the MN strain of HIV-1 (MN rgp 120/HIV-1). Thirty pregnant female rats were given MN rgp120/HIV-1 with alum adjuvant, and 30 rats were given vehicle, once every 3 days from Day 1 of presumed gestation until parturition. One pup/sex/litter from treated and control group dams were given a daily subcutaneous injection, from Day 1 through Day 22 postpartum (PP) of vehicle, MN rgp120/HIV-1, MN rgp120/HIV-1 with alum, or MN rgp120/HIV-1 with QS-21 adjuvant. Neurobehavioral and physical development were evaluated (preweaning reflex and development, sexual maturation, motor activity, acoustic startle, passive avoidance, functional observational battery, and water M-maze testing), and tissues were processed for anatomical examination (whole and regional brain weights, and neuropathology). Administration of MN rgp120/HIV-1, with or without adjuvant, to pups did not cause any persistent effect on any parameter evaluated. Neurohistological examination did not reveal any pathological effects related to treatment. Thus, MN rgp120/HIV-1 alone or formulated as a vaccine does not cause neurotoxicity or developmental toxicity in neonatal rats after exposure in utero and/or during the neonatal period.