Effect of Acute Administration of Angiopoietin-1 in Experimental Traumatic Spinal Cord Injury: Magnetic Resonance Imaging and Neurobehavioral Studies

Spinal cord injury (SCI) is a devastating condition that affects people in the prime of their lives. A myriad of vascular events occur after SCI, each of which contributes to the evolving pathology. The primary trauma causes mechanical damage to blood vessels, resulting in hemorrhage. The blood-spinal cord barrier (BSCB), a neurovascular unit that limits passage of most agents from systemic circulation to the central nervous system, breaks down, resulting in inflammation, scar formation, and other sequelae. Protracted BSCB disruption may exacerbate cellular injury and hinder neurobehavioral recovery in SCI. In these studies, angiopoietin-1 (Ang1), an agent known to reduce vascular permeability, was hypothesized to attenuate the severity of secondary injuries of SCI. Using longitudinal magnetic resonance imaging (MRI) studies (dynamic contrast-enhanced [DCE]-MRI for quantification of BSCB permeability, highresolution anatomical MRI for calculation of lesion size, and diffusion tensor imaging for assessment of axonal integrity), the acute, subacute, and chronic effects of Ang1 administration after SCI were evaluated. Neurobehavioral assessments were also performed. These non-invasive techniques have applicability to the monitoring of therapies in patients with SCI. In the acute phase of injury, Ang1 was found to reduce BSCB permeability and improve neuromotor recovery. Dynamic contrast-enhanced MRI revealed a persistent compromise of the BSCB up to two months post-injury. In the subacute phase of injury, Ang1’s effect on reducing BSCB permeability was maintained and it was found to transiently reduce axonal integrity. The SCI lesion burden was assessed with an objective method that compared favorably with segmentations from human raters. In the chronic phase of injury, Ang1 resulted in maintained reduction in BSCB permeability, a decrease in lesion size, and improved axonal integrity. Finally, longitudinal correlations among data from the MRI modalities and neurobehavioral assays were evaluated. Locomotor recovery was negatively correlated with lesion size in the Ang1 cohort and positively correlated with diffusion measures in the vehicle cohort. In summary, the results demonstrate a possible role for Ang1 in mitigating the secondary pathologies of SCI during the acute and chronic phases of injury.

Chronic administration of methylphenidate produces neurophysiological and behavioral sensitization.

The electrophysiological properties of acute and chronic methylphenidate (MPD) on neurons of the prefrontal cortex (PFC) and caudate nucleus (CN) have not been studied in awake, freely behaving animals. The present study was designed to investigate the dose-response effects of MPD on sensory evoked potentials recorded from the PFC and CN in freely behaving rats previously implanted with permanent electrodes, as well as their behavioral (locomotor) activities. On experimental day 1, locomotor behavior of rats was recorded for 2 h post-saline injection, and sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10 mg/kg, i.p., MPD administration. Animals were injected for the next five days with daily 2.5 mg/kg MPD to elicit behavioral sensitization. Locomotor recording was resumed on experimental days 2 and 6 after the MPD maintenance dose followed by 3 days of washout. On experimental day 10, rats were connected again to the electrophysiological recording system and rechallenged with saline and the identical MPD doses as on experimental day 1. On experimental day 11, rat's locomotor recording was resumed before and after 2.5 mg/kg MPD administration. Behavioral results showed that repeated administration of MPD induced behavioral sensitization. Challenge doses (0.6, 2.5, and 10.0 mg/kg) of MPD on experimental day 1 elicited dose-response attenuation in the response amplitude of the average sensory evoked field potential components recorded from the PFC and CN. Chronic MPD administration resulted in attenuation of the PFC's baseline recorded on experimental day 10, while the same treatment did not modulate the baseline recorded from the CN. Treatment of MPD on experimental day 10 resulted in further decrease of the average sensory evoked response compared to that obtained on experimental day 1. This observation of further decrease in the electrophysiological responses after chronic administration of MPD suggests that the sensory evoked responses on experimental day 10 represent neurophysiological sensitization. Moreover, two different response patterns were obtained from PFC and CN following chronic methylphenidate administration. In PFC, the baseline and effect of methylphenidate expressed electrophysiological sensitization on experimental day 10, while recording from CN did not exhibit any electrophysiological sensitization.

The effectiveness of a needleless intravenous system in prevention of percutaneous injury in two hospitals

This study assessed if hospital-wide implementation of a needleless intravenous connection system reduces the number of reported percutaneous injuries, overall and those specifically due to intravenous connection activities.^ Incidence rates were compared before and after hospital-wide implementation of a needleless intravenous system at two hospitals, a full service general hospital and a pediatric hospital. The years 1989-1991 were designated as pre-implementation and 1993 was designated as post-implementation. Data from 1992 were not included in the effectiveness evaluation to allow employees to become familiar with use of the new device. The two hospitals showed rate ratios of 1.37 (95% CI = 1.22-1.54, p $\le$.0001) and 1.63 (95% CI = 1.34-1.97, p $\le$.0001), or a 27.1% and a 38.6% reduction in overall injury rate, respectively. Rate ratios for intravenous connection injuries were 2.67 (95% CI = 1.89-3.78, p $\le$.0001) and 3.35 (95% CI = 1.87-6.02, p $\le$.0001), or a 62.5% and a 69.9% reduction in injury rate, respectively. Rate ratios for all non-intravenous connection injuries were calculated to control for factors other than device implementation that may have been operating to reduce the injury rate. These rate ratios were lower, 1.21 and 1.44, demonstrating the magnitude of injury reduction due to factors other than device implementation. It was concluded that the device was effective in reduction of numbers of reported percutaneous injuries.^ Use-effectiveness of the system was also assessed by a survey of randomly selected device users to determine satisfaction with the device, frequency of use and barriers to use. Four hundred seventy-eight surveys were returned for a response rate of 50.9%. Approximately 94% of respondents at both hospitals expressed satisfaction with the needleless system and recommended continued use. The survey also revealed that even though over 50% of respondents report using the device "always" or "most of the time" for intravenous medication administration, flushing lines, and connecting secondary intravenous lines, needles were still being used for these same activities. Compatibility, accessibility and other technical problems were reported as reasons for using needles for these activities. These problems must be addressed, by both manufacturers and users, before the needleless system will be effective in prevention of all intravenous connection injuries. ^

INFLUENCE OF A CLINIC BASED IMMUNIZATION INFORMATION SYSTEM ON INFANT IMMUNIZATIONS

This study focuses on the impact of a clinic-based intervention program on the immunization status of limited-income urban children. The intervention program consisted of an information session for clinic health care providers and the placement of individualized immunization information labels on clinic notes at the time of each visit. The degree of impact of the intervention on immunization administration was ascertained through a comparison of two similar groups of infants born in the same months of the year immediately before (N = 201) and after (N = 203) the information session and initiation of the labeling system. The timeliness of administration of each diphtheria, pertussis, tetanus and trivalent oral polio vaccine (DPT/TOPV) in the first year series of three was compared pre- to postintervention. Significantly more third immunizations were given the postintervention subjects within ten days of the recommended time of application ( p = .0361). Life table analysis indicated that the probability of an infant's passing one year of age without the administration of the third immunization decreased for postintervention infants (p = .0515). The intervention was most successful in assuring administration of the series of immunizations in those infants who were seen by the health care provider for at least 50% of their first year visits. Results indicate that minor changes in the format of information given a relatively continuous provider can increase completion of immunization series in infants. ^

Federally regulated institutional review boards: The aspects of a "model" IRB---Is the current system in need of a tune up or complete overhaul?

Institutional Review Boards (IRBs) are the primary gatekeepers for the protection of ethical standards of federally regulated research on human subjects in this country. This paper focuses on what general, broad measures that may be instituted or enhanced to exemplify a "model IRB". This is done by examining the current regulatory standards of federally regulated IRBs, not private or commercial boards, and how many of those standards have been found either inadequate or not generally understood or followed. The analysis includes suggestions on how to bring about changes in order to make the IRB process more efficient, less subject to litigation, and create standardized educational protocols for members. The paper also considers how to include better oversight for multi-center research, increased centralization of IRBs, utilization of Data Safety Monitoring Boards when necessary, payment for research protocol review, voluntary accreditation, and the institution of evaluation/quality assurance programs. ^ This is a policy study utilizing secondary analysis of publicly available data. Therefore, the research for this paper focuses on scholarly medical/legal journals, web information from the Department of Health and Human Services, Federal Drug Administration, and the Office of the Inspector General, Accreditation Programs, law review articles, and current regulations applicable to the relevant portions of the paper. ^ Two issues are found to be consistently cited by the literature as major concerns. One is a need for basic, standardized educational requirements across all IRBs and its members, and secondly, much stricter and more informed management of continuing research. There is no federally regulated formal education system currently in place for IRB members, except for certain NIH-based trials. Also, IRBs are not keeping up with research once a study has begun, and although regulated to do so, it does not appear to be a great priority. This is the area most in danger of increased litigation. Other issues such as voluntary accreditation and outcomes evaluation are slowing gaining steam as the processes are becoming more available and more sought after, such as JCAHO accrediting of hospitals. ^ Adopting the principles discussed in this paper should promote better use of a local IRBs time, money, and expertise for protecting the vulnerable population in their care. Without further improvements to the system, there is concern that private and commercial IRBs will attempt to create a monopoly on much of the clinical research in the future as they are not as heavily regulated and can therefore offer companies quicker and more convenient reviews. IRBs need to consider the advantages of charging for their unique and important services as a cost of doing business. More importantly, there must be a minimum standard of education for all IRB members in the area of the ethical standards of human research and a greater emphasis placed on the follow-up of ongoing research as this is the most critical time for study participants and may soon lead to the largest area for litigation. Additionally, there should be a centralized IRB for multi-site trials or a study website with important information affecting the trial in real time. There needs to be development of standards and metrics to assess the performance of the IRBs for quality assurance and outcome evaluations. The boards should not be content to run the business of human subjects' research without determining how well that function is actually being carried out. It is important that federally regulated IRBs provide excellence in human research and promote those values most important to the public at large.^

Errors in the administration of medication in inpatient hospitals: A systematic review of the research literature on commercial computerized physician order entry systems

Errors in the administration of medication represent a significant loss of medical resources and pose life altering or life threatening risks to patients. This paper considered the question, what impact do Computerized Physician Order Entry (CPOE) systems have on medication errors in the hospital inpatient environment? Previous reviews have examined evidence of the impact of CPOE on medication errors, but have come to ambiguous conclusions as to the impact of CPOE and decision support systems (DSS). Forty-three papers were identified. Thirty-one demonstrated a significant reduction in prescribing error rates for all or some drug types; decreases in minor errors were most often reported. Several studies reported increases in the rate of duplicate orders and failures to remove contraindicated drugs, often attributed to inappropriate design or to an inability to operate the system properly. The evidence on the effectiveness of CPOE to reduce errors in medication administration is compelling though it is limited by modest study sample sizes and designs. ^