Levels of glial cell line-derived neurotrophic factor are decreased, but fibroblast growth factor 2 and cerebral dopamine neurotrophic factor are increased in the hippocampus in Parkinson's disease.

Growth factors can facilitate hippocampus-based learning and memory and are potential targets for treatment of cognitive dysfunction via their neuroprotective and neurorestorative effects. Dementia is common in Parkinson's disease (PD), but treatment options are limited. We aimed to determine if levels of growth factors are altered in the hippocampus of patients with PD, and if such alterations are associated with PD pathology. Enzyme-linked immunosorbent assays were used to quantify seven growth factors in fresh frozen hippocampus from 10 PD and nine age-matched control brains. Western blotting and immunohistochemistry were used to explore cellular and inflammatory changes that may be associated with growth factor alterations. In the PD hippocampus, protein levels of glial cell line-derived neurotrophic factor were significantly decreased, despite no evidence of neuronal loss. In contrast, protein levels of fibroblast growth factor 2 and cerebral dopamine neurotrophic factor were significantly increased in PD compared to controls. Levels of the growth factors epidermal growth factor, heparin-binding epidermal growth factor, brain-derived neurotrophic factor and mesencephalic astrocyte-derived neurotrophic factor did not differ between groups. Our data demonstrate changes in specific growth factors in the hippocampus of the PD brain, which potentially represent targets for modification to help attenuate cognitive decline in PD. These data also suggest that multiple growth factors and direction of change needs to be considered when approaching growth factors as a potential treatment for cognitive decline.

Evidence for reduced neurogenesis in the aging human hippocampus despite stable stem cell markers.

Reduced neurogenesis in the aging mammalian hippocampus has been linked to cognitive deficits and increased risk of dementia. We utilized postmortem human hippocampal tissue from 26 subjects aged 18-88 years to investigate changes in expression of six genes representing different stages of neurogenesis across the healthy adult lifespan. Progressive and significant decreases in mRNA levels of the proliferation marker Ki67 (MKI67) and the immature neuronal marker doublecortin (DCX) were found in the healthy human hippocampus over the lifespan. In contrast, expression of genes for the stem cell marker glial fibrillary acidic protein delta and the neuronal progenitor marker eomesodermin was unchanged with age. These data are consistent with a persistence of the hippocampal stem cell population with age. Age-associated expression of the proliferation and immature neuron markers MKI67 and DCX, respectively, was unrelated, suggesting that neurogenesis-associated processes are independently altered at these points in the development from stem cell to neuron. These data are the first to demonstrate normal age-related decreases at specific stages of adult human hippocampal neurogenesis.

Temporal Response of Endogenous Neural Progenitor Cells Following Injury to the Adult Rat Spinal Cord.

A pool of endogenous neural progenitor cells (NPCs) found in the ependymal layer and the sub-ependymal area of the spinal cord are reported to upregulate Nestin in response to traumatic spinal cord injury (SCI). These cells could potentially be manipulated within a critical time period offering an innovative approach to the repair of SCI. However, little is known about the temporal response of endogenous NPCs following SCI. This study used a mild contusion injury in rat spinal cord and immunohistochemistry to determine the temporal response of ependymal NPCs following injury and their correlation to astrocyte activation at the lesion edge. The results from the study demonstrated that Nestin staining intensity at the central canal peaked at 24 h post-injury and then gradually declined over time. Reactive astrocytes double labeled by Nestin and glial fibrillary acidic protein (GFAP) were found at the lesion edge and commenced to form the glial scar from 1 week after injury. We conclude that the critical time period for manipulating endogenous NPCs following a spinal cod injury in rats is between 24 h when Nestin expression in ependymal cells is increased and 1 week when astrocytes are activated in large numbers.

Differences in the Cellular Response to Acute Spinal Cord Injury between Developing and Mature Rats Highlights the Potential Significance of the Inflammatory Response.

There exists a trend for a better functional recovery from spinal cord injury (SCI) in younger patients compared to adults, which is also reported for animal studies; however, the reasons for this are yet to be elucidated. The post injury tissue microenvironment is a complex milieu of cells and signals that interact on multiple levels. Inflammation has been shown to play a significant role in this post injury microenvironment. Endogenous neural progenitor cells (NPC), in the ependymal layer of the central canal, have also been shown to respond and migrate to the lesion site. This study used a mild contusion injury model to compare adult (9 week), juvenile (5 week) and infant (P7) Sprague-Dawley rats at 24 h, 1, 2, and 6 weeks post-injury (n = 108). The innate cells of the inflammatory response were examined using counts of ED1/IBA1 labeled cells. This found a decreased inflammatory response in the infants, compared to the adult and juvenile animals, demonstrated by a decreased neutrophil infiltration and macrophage and microglial activation at all 4 time points. Two other prominent cellular contributors to the post-injury microenvironment, the reactive astrocytes, which eventually form the glial scar, and the NPC were quantitated using GFAP and Nestin immunohistochemistry. After SCI in all 3 ages there was an obvious increase in Nestin staining in the ependymal layer, with long basal processes extending into the parenchyma. This was consistent between age groups early post injury then deviated at 2 weeks. The GFAP results also showed stark differences between the mature and infant animals. These results point to significant differences in the inflammatory response between infants and adults that may contribute to the better recovery indicated by other researchers, as well as differences in the overall injury progression and cellular responses. This may have important consequences if we are able to mirror and manipulate this response in patients of all ages; however much greater exploration in this area is required.

Definign and implementing a model for pharmacy resident research projects / Definición e implantación de un modelo de proyectos de investigación para residentes en farmacia

Objective: To describe a standard approach to provide a support structure for pharmacy resident research that emphasizes self-identification of a residency research project. Methods: A subcommittee of the residency advisory committee was formed at our institution. The committee was initially comprised of 2 clinical pharmacy specialists, 1 drug information pharmacist, and 2 pharmacy administrators. The committee developed research guidelines that are distributed to residents prior to the residency start that detail the research process, important deadlines, and available resources. Instructions for institutional review board (IRB) training and deadlines for various assignments and presentations throughout the residency year are clearly defined. Residents conceive their own research project and emphasis is placed on completing assignments early in the residency year. Results: In the 4 years this research process has been in place, 15 of 16 (94%) residents successfully identified their own research question. All 15 residents submitted a complete research protocol to the IRB by the August deadline. Four residents have presented the results of their research at multi-disciplinary national professional meetings and 1 has published a manuscript. Feedback from outgoing residents has been positive overall and their perceptions of their research projects and the process are positive. Conclusion: Pharmacy residents selecting their own research projects for their residency year is a feasible alternative to assigning or providing lists of research projects from which to select a project (AU)

Objetivo: Describir un abordaje estándar para proporcionar una estructura de apoyo a los residentes de investigación en farmacia que enfatice la autoidentificación de un proyecto de investigación en la residencia. Métodos: En nuestra institución se creó un subcomité del comité asesor de la residencia. Inicialmente el comité se componía de 2 especialistas en farmacia clínica, un farmacéutico de información sobre medicamentos, y dos administradores de farmacia. El comité desarrolló guías que detallaban el proceso de investigación, fechas límite importantes, y recursos disponibles, y que se distribuyeron entre los residentes antes de comenzase la residencia. Se definieron claramente instrucciones para la junta de investigación de la institución (IRB) con entrenamiento y fechas límite para varias tareas y presentaciones a lo largo del año de residencia. Los residentes concebían su propio proyecto de investigación y se colocaba énfasis en completar las tareas de la parte inicial del año de residencia. Resultados: En los 4 años que este procedimiento de investigación lleva en vigor, 15 de los 16 (94%) residentes identificaron con éxito sus propias preguntas de investigación. Todos los 15 residentes enviaron un protocolo de investigación completo al IRB en la fecha límite de agosto. Cuatro residentes presentaron resultados de su investigación en reuniones profesionales nacionales multidisciplinarias y uno publicó un artículo. El retorno de los residentes salientes ha sido en general positivo y sus percepciones sobre sus proyectos de investigación y el proceso son positivas. Conclusión: Residentes de farmacia seleccionando su propio proyecto de investigación es una alternativa factible a asignar oa proporcionar listas de proyectos para que elijan uno (AU)

Dornase alpha compared to hypertonic saline for lung atelectasis in critically ill patients.

BACKGROUND: Despite the lack of randomized trials, nebulized Dornase alpha and hypertonic saline are used empirically to treat atelectasis in mechanically ventilated patients. Our objective was to determine the clinical and radiological efficacy of these medications as an adjunct to standard therapy in critically ill patients. METHODS: Mechanically ventilated patients with new onset (<48 h) lobar or multilobar atelectasis were randomized into three groups: nebulized Dornase alpha, hypertonic (7%) saline or normal saline every 12 h. All patients received standard therapy, including chest percussion therapy, kinetic therapy, and bronchodilators. The primary endpoint was the change in the daily chest X-ray atelectasis score. RESULTS: A total of 33 patients met the inclusion criteria and were randomized equally into the three groups. Patients in the Dornase alpha group showed a reduction of 2.18±1.33 points in the CXR score from baseline to day 7, whereas patients in the normal saline group had a reduction of 1.00±1.79 points, and patients in the hypertonic saline group showed a score reduction of 1.09±1.51 points. Pairwise comparison of the mean change of the CXR score showed no statistical difference between hypertonic saline, normal saline, and dornase alpha. Airway pressures as well as oxygenation, expressed as PaO(2)/F(I)O(2) and time to extubation also were similar among groups. During the study period the rate of extubation was 54% (6/11), 45% (5/11), and 63% (7/11) in the normal saline, hypertonic saline, and Dornase alpha groups, respectively (p=0.09). No treatment related complications were observed. CONCLUSIONS: There was no significant improvement in the chest X-ray atelectasis score in mechanically ventilated patients with new onset atelectasis who were nebulized with Dornase alpha twice a day. Hypertonic saline was no more effective than normal saline in this population. Larger randomized control trials are needed to confirm our results.

Drug-drug interaction between clopidogrel and the proton pump inhibitors.

OBJECTIVE: To evaluate the interaction between clopidogrel and proton pump inhibitors (PPIs). DATA SOURCES: Literature retrieval was accessed through PubMed (1980-January 2009), abstracts from 2008 American Heart Association and 2009 Society of Cardiovascular Angiography and Interventions Scientific Sessions, and media press releases using the terms clopidogrel, proton pump inhibitors, cytochrome 2C19, genetic cytochrome P450 polymorphisms, and drug interaction. In addition, reference citations from publications identified in the search were reviewed. STUDY SELECTION AND DATA EXTRACTION: Relevant original research articles and review articles were evaluated. Articles were selected if they were published in English and focused on any of the key words or appeared to have substantial content addressing the drug interaction. DATA SYNTHESIS: Recent attention has been placed on a potential interaction observed between clopidogrel and the widely used PPIs. Preliminary evidence suggests that omeprazole interacts with clopidogrel, reducing clopidogrel's antiplatelet effects as measured by various laboratory tests. Most data indicate that the interaction involves the competitive inhibition of the CYP2C19 isoenzyme. The interaction appears to be clinically significant, as several retrospective analyses have shown an increase in adverse cardiovascular outcomes when PPIs and clopidogrel are used concomitantly. However, this may not be a class effect. CONCLUSIONS: Available data suggest that omeprazole is the PPI most likely to have a significant interaction with clopidogrel. Further studies are needed to determine that an interaction between the other PPIs and clopidogrel does not exist. In situations in which both clopidogrel and a PPI are indicated, pantoprazole should be used since it is the PPI least likely to interact with clopidogrel.

Hyperchloremic, normal anion-gap, metabolic acidosis due to topiramate.

PURPOSE: A rare adverse effect observed after dose escalation of topiramate therapy is discussed. A review of published cases, monitoring recommendations, and important counseling information for patients who are prescribed topiramate are described. SUMMARY: A 37-year-old man hospitalized for mental status changes and possible seizure developed hyperchloremic, normal anion-gap, metabolic acidosis. His medical history was significant for AIDS, progressive multifocal leukoencephalopathy, a cerebrovascular accident, a seizure disorder for the past three years, and a pulmonary embolism five months before being admitted to the hospital. The patient was also taking topiramate for two months before being hospitalized for his seizure disorder. His dosage was increased after admission, but no changes were made to his other medications. The only new medication initiated was cefotaxime for 14 days to treat pneumonia. During the following 8 days, the patient continued to receive increased dosages of topiramate. His serum chloride concentration increased daily and his serum bicarbonate decreased. Topiramate was identified as the cause and was discontinued the next day. Six other cases of metabolic acidosis in adults are reviewed, as well as risk factors for metabolic acidosis. CONCLUSION: After receiving increased dosages of topiramate, a 37-year-old man developed hyperchloremic, normal anion-gap, metabolic acidosis, which resolved after discontinuation of the drug.

Using the Liverpool Care Pathway in a nursing home.

The Liverpool Care Pathway provides evidence-based guidelines relating to the care of dying patients. This article outlines a pilot project to introduce it to a 150-bed BUPA nursing home.

Provision of palliative care education in nursing homes.

AIM: To map the nature and extent of existing palliative care education activities. METHOD: Data was gathered from questionnaires, face-to-face and telephone interviews, visiting palliative care teams across Mount Vernon Cancer Network and attendance at conferences, meetings and seminars. A comprehensive needs assessment for palliative care education within nursing homes was completed. RESULTS: The findings revealed inequality across the network with regard to education provision and uptake of palliative care services. Recruitment of overseas staff and a transient workforce were both cited as major difficulties in implementing education programmes. Funding of these programmes and responsibility for providing the education remain unclear. CONCLUSION: There was a real and urgent need for palliative care training in the network area and there was scope for a variety of approaches to be adopted to deliver the required training.