Inclusivity and decolonisation of the post-graduate public health curriculum: Reflections from a student-led approach.

The future of successful public health practice requires public health students to be educated within a decolonised curriculum that challenges the historical biases and inequalities that are deeply embedded within global public health and society. In this commentary, we reflect on what it can mean and why it's important to decolonise and diversify a public health curriculum. We describe how we used a student-led approach to begin this process, and share recommendations that are applicable to national and international curricula.

Impact of timing of urgent coronary artery bypass grafting following coronary angiography on acute kidney injury.

OBJECTIVES: Prior studies have examined the association between timing of cardiac surgery after coronary angiography with risk of acute kidney injury, but this remains controversial. The purpose of this study was to investigate the association between interval from coronary angiography to urgent coronary artery bypass grafting with acute kidney injury, and to examine this possible effect in patients with preexisting kidney disease. METHODS: Patients from a single institution undergoing urgent, isolated coronary artery bypass grafting within 7 days of coronary angiography were included. Patients were subdivided by chronic kidney disease stage and angiography-to-surgery interval. Locally estimated scatterplot smoothing was used to evaluate the functional relationship of the probability of acute kidney injury and time interval. Adjusted odds ratios were calculated for each time interval group compared against the Day 0 to 1 interval group, controlling for multiple covariates. Analyses were repeated for each chronic kidney disease subgroup. RESULTS: A total of 2249 patients were included in this study. There were 271 (12.0%) patients with postoperative acute kidney injury. Plots demonstrated a decreasing risk of kidney injury from Day 0 to 1 to Day 3 following coronary angiography. Adjusted odds ratios also showed a significant decrease in risk of kidney injury on Day 3 compared with Day 0 to 1. Analyses repeated for each chronic kidney disease stage showed similar trends. CONCLUSIONS: For patients undergoing urgent coronary artery bypass grafting, there is a decreased risk of kidney injury in those having surgery on day 3 after coronary angiography compared with those having surgery on Day 0 to 1, regardless of preexisting kidney disease.

Macrophage Transcriptional Profile Identifies Lipid Catabolic Pathways That Can Be Therapeutically Targeted after Spinal Cord Injury.

Although infiltrating macrophages influence many pathological processes after spinal cord injury (SCI), the intrinsic molecular mechanisms that regulate their function are poorly understood. A major hurdle has been dissecting macrophage-specific functions from those in other cell types as well as understanding how their functions change over time. Therefore, we used the RiboTag method to obtain macrophage-specific mRNA directly from the injured spinal cord in mice and performed RNA sequencing to investigate their transcriptional profile. Our data show that at 7 d after SCI, macrophages are best described as foam cells, with lipid catabolism representing the main biological process, and canonical nuclear receptor pathways as their potential mediators. Genetic deletion of a lipoprotein receptor, CD36, reduces macrophage lipid content and improves lesion size and locomotor recovery. Therefore, we report the first macrophage-specific transcriptional profile after SCI and highlight the lipid catabolic pathway as an important macrophage function that can be therapeutically targeted after SCI.SIGNIFICANCE STATEMENT The intrinsic molecular mechanisms that regulate macrophage function after spinal cord injury (SCI) are poorly understood. We obtained macrophage-specific mRNA directly from the injured spinal cord and performed RNA sequencing to investigate their transcriptional profile. Our data show that at 7 d after SCI, macrophages are best described as foam cells, with lipid catabolism representing the main biological process and canonical nuclear receptor pathways as their potential mediators. Genetic deletion of a lipoprotein receptor, CD36, reduces macrophage lipid content and improves lesion size and locomotor recovery. Therefore, we report the first macrophage-specific transcriptional profile after SCI and highlight the lipid catabolic pathway as an important macrophage function that can be therapeutically targeted after SCI.

Hematogenous macrophage depletion reduces the fibrotic scar and increases axonal growth after spinal cord injury.

Spinal cord injury (SCI) leads to formation of a fibrotic scar that is inhibitory to axon regeneration. Recent evidence indicates that the fibrotic scar is formed by perivascular fibroblasts, but the mechanism by which they are recruited to the injury site is unknown. Using bone marrow transplantation in mouse model of spinal cord injury, we show that fibroblasts in the fibrotic scar are associated with hematogenous macrophages rather than microglia, which are limited to the surrounding astroglial scar. Depletion of hematogenous macrophages results in reduced fibroblast density and basal lamina formation that is associated with increased axonal growth in the fibrotic scar. Cytokine gene expression analysis after macrophage depletion indicates that decreased Tnfsf8, Tnfsf13 (tumor necrosis factor superfamily members) and increased BMP1-7 (bone morphogenetic proteins) expression may serve as anti-fibrotic mechanisms. Our study demonstrates that hematogenous macrophages are necessary for fibrotic scar formation and macrophage depletion results in changes in multiple cytokines that make the injury site less fibrotic and more conducive to axonal growth.

Patient awareness of oral cancer health advice in a dental access centre: a mixed methods study.

OBJECTIVE: In the United Kingdom in 2006, 5,325 persons were diagnosed with oral cancer; and in 2007 it caused around 1,850 deaths. The purpose of this study was to assess the patient awareness, in a dental access centre, of a poster and leaflet campaign providing information about smoking and excess alcohol consumption as risk factors in the development of oral cancer, and to explore dental patients' beliefs and perceptions about these risk factors. METHODS: Posters and leaflets providing information about risk factors for oral cancer were displayed in the patient waiting areas of a dental access centre. Data were collected prospectively in relation to the smoking and drinking habits of patients attending the centre. This information was used to categorise patients into one of four groups ranging from low to high consumption. During triage, patients were asked if they had read any of the information about oral cancer that was on display, and patients in the high risk groups were asked to participate in a semi-structured interview that would explore their knowledge about risk factors and their views on the delivery of healthcare messages in relation to oral cancer. RESULTS: Data on risk status and exposure to the poster and leaflet campaign were collected for 1,161 patients attending during the study period. More than 50% of these patients were smokers, with 36% in the high or very high tobacco and alcohol use groups. Approximately 40% of patients within each consumption group had read any of the information available. Nine patients agreed to be interviewed and overall knowledge about risk factors for oral cancer, even after reading the information was poor. CONCLUSION: Dental access centres attract a significant number of patients with lifestyle habits that make them vulnerable to oral cancer, and as such are well placed to deliver oral health messages to this high risk group. However, the delivery of information through a simple poster and leaflet campaign is likely to have limited impact.

NF-κB in the mechanism of brain edema in acute liver failure: studies in transgenic mice.

Astrocyte swelling and brain edema are major complications of the acute form of hepatic encephalopathy (acute liver failure, ALF). While elevated brain ammonia level is a well-known etiological factor in ALF, the mechanism by which ammonia brings about astrocyte swelling is not well understood. We recently found that astrocyte cultures exposed to ammonia activated nuclear factor-κB (NF-κB), and that pharmacological inhibition of such activation led to a reduction in astrocyte swelling. Although these findings suggest the involvement of NF-κB in astrocyte swelling in vitro, it is not known whether NF-κB contributes to the development of brain edema in ALF in vivo. Furthermore, pharmacological agents used to inhibit NF-κB may have non-specific effects. Accordingly, we used transgenic (Tg) mice that have a functional inactivation of astrocytic NF-κB and examined whether these mice are resistant to ALF-associated brain edema. ALF was induced in mice by treatment with the hepatotoxin thioacetamide (TAA). Wild type (WT) mice treated with TAA showed a significant increase in brain water content (1.65%) along with prominent astrocyte swelling and spongiosis of the neuropil, consistent with the presence of cytotoxic edema. These changes were not observed in Tg mice treated with TAA. Additionally, WT mice with ALF showed an increase in inducible nitric oxide synthase (iNOS) immunoreactivity in astrocytes from WT mice treated with TAA (iNOS is known to be activated by NF-κB and to contribute to cell swelling). By contrast, Tg mice treated with TAA did not exhibit brain edema, histological changes nor an increase in iNOS immunoreactivity. We also examined astrocytes cultures derived from Tg mice to determine whether these cells exhibit a lesser degree of swelling and cytopathological changes following exposure to ammonia. Astrocyte cultures derived from Tg mice showed no cell swelling nor morphological abnormalities when exposed to ammonia for 24h. By contrast, ammonia significantly increased cell swelling (31.7%) in cultured astrocytes from WT mice and displayed cytological abnormalities. Moreover, we observed a lesser increment in iNOS and NADPH oxidase activity (the latter is also known to be activated by NF-κB and to contribute to astrocyte swelling) in astrocyte cultures from Tg mice treated with ammonia, as compared to ammonia-treated WT mice astrocytes. These findings strongly suggest that activation of NF-κB is a critical factor in the development of astrocyte swelling/brain edema in ALF.

Oestrogen receptor beta contributes to the transient sex difference in tyrosine hydroxylase expression in the mouse locus coeruleus.

Oestrogen receptors (ERs) are important for sexual differentiation of the brain. Previous studies in rats have reported that the locus coeruleus (LC), a catecholaminergic nucleus in the brain stem, is sexually dimorphic such that females have more neurones than males. We hypothesised that ERs may be important for sexual differentiation of this nucleus in mice. Because previous studies reported conflicting results regarding ER protein expression in the mouse LC, we evaluated ER alpha and ER beta gene expression by in situ hybridisation and the real-time reverse transcription-polymerase chain reaction. We demonstrated that both ER alpha and ER beta mRNAs are present in tyrosine hydroxylase-immunoreactive (TH-ir) cells in the male LC. In the female LC, ER alpha mRNA is present at levels similar to males, whereas ER beta mRNA expression is significantly lower than in males. Similar to rats, male mice have fewer TH-ir cells in the LC than females at 60 days after birth, but the difference is absent at 120 days after birth when females exhibit a similar reduction in TH-ir cells. The transient sex difference is ER beta-dependent because is it absent in ER beta knockout mice, and is due to regulation of TH expression and not from death of TH-ir cells. Testicular hormones produced at adolescence are necessary for the regulation of TH expression in the male LC because orchidectomy of pre-pubertal males prevented the decrease in TH-ir cells, whereas treatment of gonadectomized males with testosterone or its metabolite, 5 alpha-androstan-3beta,17beta-diol, restored the intact male phenotype. Overall, these studies indicate that ER beta is important in regulating TH expression in the mouse LC.

The impact of genetic outreach education and support to primary care on practitioner's confidence and competence in dealing with familial cancers.

AIMS: To determine the level of competence and confidence in general practice in relation to the management of familial cancers and to determine the impact of providing genetic educational outreach on confidence and competence. METHODS: Confidence and competence in dealing with familial cancers was measured using a postal questionnaire sent to all general practitioners and practice nurses in 4 geographical areas in central England. In 2 areas, genetic educational outreach was provided to 10 randomly selected practices and a matched analysis of questionnaire responses before and after intervention was done to determine the impact of the intervention. RESULTS: Respondents were more confident in dealing with patient queries around familial breast cancer risk than those around bowel cancer. This was inconsistent with the ability to correctly assign familial risk, with 48% incorrectly assigning a high-risk categorisation to a low-risk breast cancer scenario. Respondents who had taken part in the intervention reported more confidence in dealing with issues related to the management of patient queries around bowel cancer. Following intervention, participants were more likely to report feeling confident in knowing the relevant family history to collect (72.4% of respondents from participating practices compared to 56.1% from non-participating practices; OR 2.39, p = 0.02, 95% CI 1.14-5.00) and in making a basic assessment of risk (72.4% compared to 38.9%; OR 3.65, p = 0.01, 95% CI 1.38-9.61). CONCLUSIONS: Providing genetic educational outreach has a positive impact upon how confident primary care staff feel in dealing with patient queries over familial cancers, particularly in relation to bowel cancer. Further research is needed to explore the impact of providing this service on other relevant outcomes such as appropriateness of referrals to genetic services.

Genetics support to primary care practitioners - a demonstration project.

Primary care practitioners need to be supported by specialist genetics services to enable them to cope effectively with the expanding relevance of genetics to their patients. Genetic counselors could be effective in such a role. This exploratory project set out to improve the Primary-Tertiary interface through piloting such a service to general practice for 1 year. Tailored genetic educational outreach was delivered by a genetic counselor to ten randomly selected general practices in central England for 12 months. A range of services were provided to the practices these included facilitated genetic update sessions, a responsive advice service and referral guidelines. The service was evaluated through pre and post intervention questionnaires and via seven semi-structured interviews. This article presents a description of the development and delivery of this service and also reports on the experiences of a sample of the participants. Participants reported positive attitudes to the service and said that they had gained knowledge and confidence, as well as recognized limitations and gaps in their current knowledge. The consistent link with a specialist genetics service provided by a genetic counselor had a positive impact during the project and participants have continued to utilize the genetic counselor for advice and support with genetic patient issues since the project was completed. This is the first example of this model of service provision. Further research, utilizing a larger sample and other measures of behavioral change needs to be carried out to assess whether this model should be adopted on a wider basis.

Treatment of vancomycin-resistant enterococcus with quinupristin/dalfopristin and high-dose ampicillin.

OBJECTIVE: To report the successful treatment of vancomycin-resistant Enterococcus (VRE) bacteremia using the combination of quinupristin/dalfopristin and high-dose ampicillin. CASE SUMMARY: A 38-year-old African American woman with relapsed acute myeloid leukemia and neutropenic fever developed VRE bacteremia following 3 successive courses of vancomycin for methicillin-resistant staphylococcal infections. Treatment with linezolid was initiated; however, after 9 days of therapy, blood cultures continued to reveal VRE and the patient became febrile. The patient was subsequently switched to quinupristin/dalfopristin and high-dose ampicillin. The fever resolved and all subsequent blood cultures were negative after the initiation of combination therapy. DISCUSSION: The emergence of VRE infections presents a treatment challenge in immunocompromised patients. When treating VRE infections in this patient population, the effectiveness of linezolid and quinupristin/dalfopristin is limited by their bacteriostatic activity when used as monotherapy. Recent in vitro data suggest synergistic activity with quinupristin/dalfopristin when used in combination with other antimicrobials in selected isolates of VRE. CONCLUSIONS: Persistent VRE bacteremia was successfully treated in this neutropenic patient using the combination of high-dose ampicillin and quinupristin/dalfopristin. Case reports and in vitro data suggest that concomitant therapy with high-dose ampicillin may be an effective treatment alternative for VRE infections not responding to standard therapy.

Apoptotic and anti-apoptotic mechanisms following spinal cord injury.

A number of studies have provided evidence that cell death from moderate traumatic spinal cord injury (SCI) is regulated, in part, by apoptosis that involves the caspase family of cysteine proteases. However, little or no information is available about anti-apoptotic mechanisms mediated by the inhibitors of apoptosis (IAP) family of proteins that inhibit cell death pathways. In the present study, we examined caspase and IAP expression in spinal cords of rats subjected to moderate traumatic injury. Within 6 h after injury, caspase-8 and-9 (2 initiators of apoptosis) were predominantly present in gray matter neurons within the lesion epicenter. By 3 days following spinal cord injury (SCI), caspase-8 and-9 immunoreactivity was localized to gray and white matter cells, and by 7 days following SCI, both upstream caspases were expressed in cells within white matter or within foamy macrophages in gray matter. Caspase-3, an effector caspase, was evident in a few fragmented cells in gray matter at 24 h following injury and then localized to white matter in later stages. Thus, distinct patterns of caspase expression can be found in the spinal cord following injury. XIAP, cIAP-1, and cIAP-2, members of the IAP family, were constitutively expressed in the cord. Immunoblots of spinal cord extracts revealed that the processed forms of caspases-8 and-9 and cleavage of PARP are present as early as 6 h following trauma. The expression of caspases corresponded with the detection of cleavage of XIAP into 2 fragments following injury. cIAP-1 and cIAP-2 expression remained constant during early periods following SCI but demonstrated alterations by 7 days following SCI. Our data are consistent with the idea that XIAP may have a protective role within the spinal cord, and that alteration in cleavage of XIAP may regulate cell death following SCI.

Effects of interleukin-10 (IL-10) on pain behavior and gene expression following excitotoxic spinal cord injury in the rat.

Intraspinal injection of quisqualic acid (QUIS) produces excitotoxic injury with pathophysiological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI). Responses to QUIS-induced injury include an inflammatory component, as well as the development of spontaneous and evoked pain behaviors. We hypothesized that QUIS-induced inflammation and subsequent gene expression contribute to the development and progression of pain-related behaviors and that blockade of inflammation-related gene expression leads to the amelioration of these behaviors. Using the QUIS model of spinal cord injury, we examined whether interleukin-10 (IL-10), a potent anti-inflammatory cytokine, is able to reduce mRNA levels of inflammatory and cell death-related genes leading to a reduction of pain behaviors. The results demonstrate that animals receiving systemic injection of IL-10, 30 minutes following QUIS-induced SCI, showed a significant delay in the onset of excessive grooming behavior, a significant reduction in grooming severity, and a significant reduction in the longitudinal extent of a pattern of neuronal loss within the spinal cord characterized as "grooming-type damage." QUIS injections also resulted in an increase in mRNA levels of interleukin-1 beta (IL-1 beta), cyclooxygenase-2 (COX-2), inducible nitric oxide synthase (iNOS), CD95 ligand (CD95-L, also called FAS-L/APO-1L), and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Results of QUIS injury plus IL-10 treatment resulted in a significant downregulation of IL1-beta and iNOS mRNA and these results were supported by Western blot analysis of protein levels following IL-10 treatment. These data suggest that IL-10 reduces inflammation and that targeting injury-induced inflammation is an effective strategy for limiting the extent of neuronal damage following excitotoxic SCI and thus the onset and progression of injury-induced pain behaviors.

The attitudes of GPs towards the nurse-practitioner role.

In recent years, nursing and health-care policy have promoted the advanced role of the nurse -- that of nurse practitioner. But such a role has not been integrated widely into the primary health-care team. This study investigates the knowledge and attitudes of GPs who do not employ nurse practitioners to find out what prevents them doing so. Ten GPs who did not already employ a nurse practitioner took part in semi-structured interviews. Our findings show that GPs, although confused about the role, were generally supportive of advanced nursing practice. Skills identified with the role were prescribing, disease diagnosis and minor-illness management. GPs thought that protocols and guidelines should govern practice, which differs fundamentally from the Royal College of Nursing definition. None of the GPs had encountered the role in primary care, and the lack of professional regulation and role definition for practice nurses and nurse practitioners who work in primary care may have affected GPs' perceptions.

Smooth muscle cell surface tissue factor pathway activation by oxidized low-density lipoprotein requires cellular lipid peroxidation.

Tissue factor, which is expressed in vascular lesions, increases thrombin production, blood coagulation, and smooth muscle cell proliferation. We demonstrate that oxidized low-density lipoprotein (LDL) induces surface tissue factor pathway activity (ie, activity of the tissue factor:factor VIIa complex) on human and rat smooth muscle cells. Tissue factor messenger RNA (mRNA) was induced by oxidized LDL or native LDL; however, native LDL did not markedly increase tissue factor activity. We hypothesized that oxidized LDL mediated the activation of the tissue factor pathway via an oxidant-dependent mechanism, because antioxidants blocked the enhanced tissue factor pathway activity by oxidized LDL, but not the increased mRNA or protein induction. We separated total lipid extracts of oxidized LDL using high-performance liquid chromatography (HPLC). This yielded 2 major peaks that induced tissue factor activity. Of the known oxysterols contained in the first peak, 7alpha- or 7beta-hydroxy or 7-ketocholesterol had no effect on tissue factor pathway activity; however, 7beta-hydroperoxycholesterol increased tissue factor pathway activity without induction of tissue factor mRNA. Tertiary butyl hydroperoxide also increased tissue factor pathway activity, suggesting that lipid hydroperoxides, some of which exist in atherosclerotic lesions, activate the tissue factor pathway. We speculate that thrombin production could be elevated via a mechanism involving peroxidation of cellular lipids, contributing to arterial thrombosis after plaque rupture. Our data suggest a mechanism by which antioxidants may offer a clinical benefit in acute coronary syndrome and restenosis.

Cytokine involvement in dynorphin-induced allodynia.

Dynorphin A is an endogenous opioid peptide, which has previously been shown to produce a long-lasting allodynia and hyperalgesia in mice, behavioral states consistent with signs of clinically observed neuropathic pain. This dynorphin-induced allodynia was used as a pharmacological, central model of neuropathic pain. In this study, we examined the involvement of the cytokine IL-1beta, the transcription factor nuclear factor kappa B (NF-kappaB), and de novo protein synthesis in the development of allodynia induced by intrathecal (i.t.) administration of dynorphin in male ICR mice. Pretreatment with the protein synthesis inhibitor cycloheximide (0. 3-85nmol), the NF-kappaB inhibitor pyrrolidinedithiocarbamate (PDTC) (0.001-1000pmol), the IL-1 receptor antagonist (IL-1ra) protein (0. 01-100ng), the caspase-1 inhibitor (YVAD) (0.1-300pmol), and the anti-inflammatory cytokine IL-10 (0.1-300ng) all dose-dependently reduced the induction of dynorphin-induced allodynia. Finally, IL-10 administered within the first 24h after the dynorphin insult prevented the development of chronic allodynia. These results demonstrate that the anti-inflammatory cytokines IL-10 and IL-1ra impede the development of dynorphin-induced allodynia. These results also suggest that production of new proteins through NF-kappaB activation is required for the induction of allodynia. We speculate that IL-1ra, IL-10, PDTC and cycloheximide interfere with the central pro-inflammatory cascade. Modulation of cytokine activity in the spinal cord may therefore prove to be an effective therapeutic strategy for the treatment of chronic pain.

Systemically administered interleukin-10 reduces tumor necrosis factor-alpha production and significantly improves functional recovery following traumatic spinal cord injury in rats.

In these studies, we examined the neuroprotective effects of the potent antiinflammatory cytokine interleukin-10 (IL-10) following spinal cord injury (SCI). Neuroprotection was assessed by using behavioral and morphological end points. We hypothesized that injury-induced inflammation contributes to the resulting neuropathology and subsequent loss of function. Therefore, by attenuating injury-induced inflammation, we should promote functional recovery. The New York University device was used to induce moderate SCI and study the resulting inflammatory response and functional consequences of inhibiting this response in rats. We determined that SCI induces the expression of tumor necrosis factor-alpha (TNF-alpha) in the spinal cord and by SCI-activated monocytes isolated from the peripheral circulation. IL-10 (5.0 microg) administered 30 minutes after-injury significantly reduced the expression of TNF-alpha protein in the spinal cord and in vitro by SCI-activated monocytes. Next, we investigated whether IL-10 would improve functional recovery after SCI. Randomized, double-blinded studies demonstrated that a single injection of IL-10 significantly improves hind limb motor function 2 months after injury, as determined by the Basso, Beattie and Bresnahan (BBB) open-field behavioral test. IL-10-treated animals had a mean BBB score of 18.0+/-0.5 (SEM, n = 9) compared with a score of 12.9+/-0.6 (SEM, n = 9) for the saline-treated controls. Morphological analysis demonstrated that IL-10 reduces lesion volume by approximately 49% 2 months after injury. These data suggest that acute administration of IL-10 reduces TNF-alpha synthesis in the spinal cord and by activated macrophages, is neuroprotective, and promotes functional recovery following SCI.

Neuroprotective effects of interleukin-10 following excitotoxic spinal cord injury.

Intraspinal injection of quisqualic acid (QUIS) produces excitotoxic injury with pathological characteristics similar to those associated with ischemic and traumatic spinal cord injury (SCI). Inflammatory responses appear to be a major component of the secondary neuronal injury initiated by SCI and play a role in the pathogenesis of QUIS-induced injury. IL-10 is a potent antiinflammatory cytokine that has been shown to reduce inflammation and improve functional outcome in human and animal models of inflammatory diseases. We propose the administration of IL-10 following excitotoxic SCI will attenuate the inflammatory response, thus resulting in increased neuronal survival. Female, Sprague-Dawley rats were given intraspinal injections of QUIS followed by either intraspinal (5 ng, n = 8) or systemic injections (5 microgram n = 14) of IL-10. Survival times were varied (2-3 days) in order to produce a range of injury states and inflammatory involvement. When administered intraspinally, IL-10 significantly exacerbated the QUIS damage (P < 0.05), resulting in an 11.2% increase in lesion volume. When given systemically, IL-10 significantly decreased lesion volume by 18.1% in the more advanced injury (P < 0.05), but did not effect the more acute injury. These divergent effects were attributed to the modest inflammatory response in the short-term injury compared to the more robust inflammatory response in the more chronic injury. In conclusion, reducing the inflammatory response to SCI by systemic administration of IL-10 resulted in a significant reduction in neuronal damage, suggesting that targeting injury-induced inflammation may be an effective treatment strategy for acute SCI.

Postischemic hypothermia and IL-10 treatment provide long-lasting neuroprotection of CA1 hippocampus following transient global ischemia in rats.

Experimental studies have demonstrated that postischemic therapeutic interventions may delay rather than provide long-lasting neuroprotection. The purpose of this study was to determine whether mild hypothermia (33-34 degrees C) combined with the anti-inflammatory cytokine interleukin-10 (IL-10) would protect the CA1 hippocampus 2 months after ischemia. Rats were subjected to 12.5 min of normothermic (37 degrees C) forebrain ischemia by two-vessel occlusion followed immediately by: (a) 4 h of normothermic (37 degrees C) reperfusion (n = 5); (b) 4 h of postischemic hypothermia (33-34 degrees C) (n = 5); (c) 4 h of normothermia plus IL-10 (5 micrograms) treatment 30 min after ischemia and at 3 days (n = 5); or (d) 4 h of hypothermia plus IL-10 treatment (n = 5). Rats survived for 2 months and were perfusion fixed for quantitative histopathological assessment of CA1 hippocampus. Postischemic normothermia and hypothermia, as well as normothermia plus IL-10 treatment led to severe damage of the CA1 hippocampus. In contrast, the combined treatment of hypothermia with IL-10 treatment improved overall neuronal survival by 49% compared to normothermic ischemia (P < 0.01). These data emphasize the detrimental consequences of secondary inflammatory responses on ischemic neuronal damage after transient global ischemia. In postinjury settings where restricted durations of mild hypothermia can be induced, anti-inflammatory treatments, including IL-10, may promote chronic neuroprotection.

Apoptosis after traumatic human spinal cord injury.

OBJECT: Apoptosis is a form of programmed cell death seen in a variety of developmental and disease states, including traumatic injuries. The main objective of this study was to determine whether apoptosis is observed after human spinal cord injury (SCI). The spatial and temporal expression of apoptotic cells as well as the nature of the cells involved in programmed cell death were also investigated. METHODS: The authors examined the spinal cords of 15 patients who died between 3 hours and 2 months after a traumatic SCI. Apoptotic cells were found at the edges of the lesion epicenter and in the adjacent white matter, particularly in the ascending tracts, by using histological (cresyl violet, hematoxylin and eosin) and nuclear staining (Hoechst 33342). The presence of apoptotic cells was supported by staining with the terminal deoxynucleotidyl transferase-mediated deoxyuridinetriphosphate nick-end labeling technique and confirmed by immunostaining for the processed form of caspase-3 (CPP-32), a member of the interleukin-1beta-converting enzyme/Caenorhabditis elegans D 3 (ICE/CED-3) family of proteases that plays an essential role in programmed cell death. Apoptosis in this series of human SCIs was a prominent pathological finding in 14 of the 15 spinal cords examined when compared with five uninjured control spinal cords. To determine the type of cells undergoing apoptosis, the authors immunostained specimens with a variety of antibodies, including glial fibrillary acidic protein, 2',3'-cyclic nucleotide 3'-phosphohydrolase (CNPase), and CD45/68. Oligodendrocytes stained with CNPase and a number of apoptotic nuclei colocalized with positive staining for this antibody. CONCLUSIONS: These results support the hypothesis that apoptosis occurs in human SCIs and is accompanied by the activation of caspase-3 of the cysteine protease family. This mechanism of cell death contributes to the secondary injury processes seen after human SCI and may have important clinical implications for the further development of protease inhibitors to prevent programmed cell death.