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Biomedical subjects

David C Hess

Publications and source records attributed to David C Hess.

At least 37 records · Page 2Linked to original sources
PubMed2005

Tactics for vascular protection after acute ischemic stroke.

BACKGROUND: The vascular events that happen during ischemic stroke worsen outcomes in patients by causing edema, hemorrhagic transformation, and general neurologic tissue compromise. In the past 2 decades, clinical trials in patients after ischemic stroke focused on neuroprotection, but these strategies have failed in providing actual benefit. Vascular protection represents a new field to be explored in acute ischemic stroke in order to develop new approaches to therapeutic intervention. PURPOSE: We identified tactics likely to provide vascular protection in patients with ischemic stroke. These tactics are based on knowledge of the molecular processes involved. SUMMARY OF REVIEW: The pathologic processes due to vascular injury after an occlusion of a cerebral artery can be separated into acute (those occurring within hrs), subacute (hrs to days), and chronic (days to mo). Targets for intervention can be identified for all three stages. In the acute phase, superoxide is the predominant mediator, followed by inflammatory mediators and proteases in the subacute phase. In the chronic phase, proapoptotic gene products have been implicated. Many already-marketed therapeutic agents (statins, angiotensin modulators, erythropoietin, minocycline, and thiazolidinediones), with proven safety in patients, have been shown to have activity against some of the key targets of vascular protection. CONCLUSION: Currently available pharmacologic agents are poised for clinical trials of vascular protection after acute ischemic stroke.

Acute Disease↗
PubMed2004

Acute functional effects of cyclosporine-A and methylprednisolone treatment in adult rats exposed to transient ischemic stroke.

The present study examined the neuroprotective effects of immunosuppressant cyclosporine-A (CsA) and anti-inflammatory methylprednisolone (MP) in a stroke model. Adult Sprague-Dawley rats were initially subjected to transient middle cerebral artery occlusion (MCAo) then randomly assigned to one of the following treatment conditions: low dose CsA, MP, low dose CsA plus MP, high dose CsA, or vehicle. Ischemic animals that received low dose CsA, MP or vehicle exhibited significant cognitive impairments, as revealed by passive avoidance and Morris water maze tasks, at days 1-3 after stroke. In contrast, ischemic animals that received high dose CsA exhibited near normal cognitive performance throughout the test period. Ischemic animals that received low dose CsA plus MP also showed significantly less cognitive deficits but such attenuation of stroke-induced behavioral impairments was only consistently reflected in the passive avoidance task, while performance in the Morris water maze task deteriorated over time. Histological analysis at 3 days post-stroke revealed that only those ischemic animals treated with high dose CsA had significantly reduced cerebral infarcts. These observations suggest that despite overt cerebral damage, alterations in simple, but not complex, cognitive tasks produced by MCAo could be ameliorated by low dose CsA when combined with MP.

Animals↗
PubMed2004

Combined cyclosporine-A and methylprednisolone treatment exerts partial and transient neuroprotection against ischemic stroke.

We investigated the neuroprotective effects of immunosuppressant cyclosporine-A (CsA) and the anti-inflammatory methylprednisolone (MP) in a stroke model. Adult Sprague-Dawley rats underwent middle cerebral artery (MCA) occlusion then were randomly treated with either: low dose CsA, MP, low dose CsA plus MP, high dose CsA, or vehicle. Ischemic animals that received low dose CsA, MP or vehicle displayed profound motor and neurological impairments at days 1-3 after stroke. In contrast, ischemic animals that received high dose CsA exhibited near normal motor and neurological functions throughout the test period. Of note, ischemic animals that received low dose CsA plus MP showed significantly less motor and neurological deficits at day 1, but thereafter displayed behavioral impairments. Histological analysis at 3 days post-stroke revealed that only those ischemic animals treated with high dose CsA had significantly reduced cerebral infarcts. This study is the first report to demonstrate partial and transient neuroprotection against stroke by low dose CsA when combined with MP.

Animals↗
PubMed2004

Targets for vascular protection after acute ischemic stroke.

BACKGROUND: Vascular damage caused by cerebral ischemia leads to edema, hemorrhage formation, and worsened outcomes in ischemic stroke patients. Therapeutic interventions need to be developed to provide vascular protection. The purpose of this review is to identify the pathophysiologic processes involved in vascular damage after ischemia, which may lead to strategies to provide vascular protection in ischemic stroke patients. SUMMARY OF COMMENT: The pathologic processes caused by vascular injury after an occlusion of a cerebral artery can be separated into acute (hours), subacute (hours to days), and chronic (days to months). Targets for intervention can be identified for all 3 stages. Acutely, superoxide is the predominant mediator, followed by inflammatory mediators and proteases subacutely. In the chronic phase, proapoptotic gene products have been implicated. CONCLUSIONS: Pharmacological agents designed to target specific pathologic and protective processes affecting the vasculature should be used in clinical trials of vascular protection after acute ischemic stroke.

Acute Disease↗
PubMed2004

Intracerebral transplantation of carotid body in rats with transient middle cerebral artery occlusion.

Recent laboratory and clinical studies demonstrate therapeutic efficacy of intracerebral transplantation of carotid body (CB) in Parkinson's disease, possibly through secretion of neurotrophic factors. Here, we examined the role of CB in experimental stroke. In the first experiment, we hypothesized that removal of CB would exacerbate cerebral infarction and stroke-related behavioral deficits. Eight-week-old, male Sprague-Dawley rats were randomly divided into two groups: stroke with intact CB and stroke with surgically removed CB. We used the stroke model of temporary middle cerebral artery occlusion. The ipsilateral CB was removed in animals assigned to treatment group exposed to stroke with surgically removed CB. Behavioral tests, using the elevated body swing test, were conducted at days 1-3 after surgery. Cerebral infarction was visualized by TTC staining on day 3 post-surgery. The data revealed no significant differences in behavioral deficits and infarct volumes between the two groups. In the second experiment, CB cell suspension grafts or control adult tissue grafts were intracerebally transplanted into the ischemic penumbra immediately (within 1 h) after stroke surgery. The results revealed significant reduction of behavioral deficits and infarct volumes, accompanied by increased levels of neurotrophic factors, as detected by ELISA, in transplanted ischemic striatum collected from CB-grafted stroke animals. These observations suggest that surgical resection of CB in the periphery did not alter stroke pathology; however, CB when made available in the CNS, via intracerebral transplantation, could protect against stroke possibly through the synergistic release of neurotrophic factors. The present study extends the use of CB as efficacious graft source for transplantation.

Analysis of Variance↗
PubMed2004

Bone marrow grafts restore cerebral blood flow and blood brain barrier in stroke rats.

We monitored alterations in cerebral blood flow (CBF) and blood-brain barrier (BBB) permeability following middle cerebral artery occlusion (MCAo) and intrastriatal transplantation of mouse bone marrow stromal cells (BMSCs) or saline infusion in adult Sprague-Dawley rats. Laser Doppler and Evans Blue assay revealed that BMSC grafts dose-dependently restored CBF and BBB to near normal levels at a much earlier period (Days 4-5 post-MCAo) in transplanted stroke animals compared to stroke animals that received saline infusion (Days 11-14 post-MCAo). Xenografted BMSCs survived in the absence of immunosuppression, and elevated levels of transforming growth factor-beta superfamily of neurotrophic factors were detected in transplanted stroke animals. These data suggest that early restoration of CBF and BBB following transplantation of BMSCs could mediate the reported functional outcomes in stroke animals.

Animals↗
PubMed2004

Intracerebral xenografts of mouse bone marrow cells in adult rats facilitate restoration of cerebral blood flow and blood-brain barrier.

We examined in the present study alterations in cerebral blood flow (CBF) and blood-brain barrier (BBB) permeability following intrastriatal transplantation of mouse bone marrow stromal cells (BMSCs) or saline infusion in adult Sprague-Dawley rats. Laser Doppler revealed that transplanted animals exhibited near normal cerebral blood flow (CBF, 150 perfusion units) at a much earlier period post-transplantation (day 4) compared to animals that received saline infusion (day 12) (p's<0.05). Similarly, Evans Blue assay demonstrated that transplanted animals exhibited near complete BBB reconstitution at day 5 post-transplantation, whereas animals that received saline infusion continued to display a compromised BBB up to 11 days post-transplantation. Transplanted animals displayed a cell dose-dependent CBF and BBB restoration. Enzyme-linked immunosorbent assay (ELISA) of transplanted BMSCs revealed elevated levels of transforming growth factor-beta superfamily of neurotrophic factors. Moreover, despite the absence of immunosuppression in this cross-species transplantation, at least in the acute phase (12 days post-transplantation), surviving xenografts were detected during periods of restored CBF and BBB permeability. These observations suggest that restoration of CBF and BBB permeability accompanies the reported functional outcomes associated with intracerebral transplantation of BMSCs.

Animals↗
PubMed2004

Remote evaluation of acute ischemic stroke in rural community hospitals in Georgia.

BACKGROUND AND PURPOSE: Despite Food and Drug Administration approval of tissue-type plasminogen activator (tPA) for stroke, obstacles in the US health care system prevent widespread use. The Remote Evaluation for Acute Ischemic Stroke (REACH) program was developed to address these obstacles in rural settings. We have previously shown the reliability of the REACH system in performing a valid National Institutes of Health Stroke Scale (NIHSS) evaluation at the Medical College of Georgia (MCG). We now report on the performance of the system since its deployment in 5 rural hospitals in east Georgia. METHODS: The rural emergency department (ED) staff can activate a Code REACH protocol 24 hours per day, 7 days per week by calling the Emergency Communications Center (ECC, an in-house dispatch center) at MCG, who pages the on-call consultant. The consultant calls back the ECC and is connected to the waiting ED. Simultaneously, using any broadband-connected workstation, the consultant logs in to the REACH system, allowing performance of an NIHSS evaluation, review of the computerized tomography (CT) images transmitted by the local radiology staff, and then the consultant can speak to the patient and family to verify time of onset. RESULTS: The REACH system has evaluated 75 patients from March 2003 to April 2004, and 12 have received tPA, all without intracranial hemorrhage complications. NIHSS scores ranged from 0 to 30, with a mean of 14.3 (SD=8.7, median 11.5). The mean onset to door time was 70.9 minutes (SD=70.8, median 50), the mean door to consult time was 45.1 minutes (SD=39.8, median 34), and the mean door to NIHSS completion was 62.9 minutes (SD=50.8, median 51). The mean onset to needle time was 135.33 minutes (SD=51.45, median 134.5). CONCLUSIONS: The REACH system enables remote stroke physicians to direct the local ED staff to administer tPA in rural settings where thrombolytics were not previously used. REACH may be used as a rapid consult tool to provide the same quality of stroke care to patients in rural hospitals as is given in tertiary stroke centers. This supports our endeavor to bring stroke expertise to rural community hospitals.

Emergency Service, Hospital↗
PubMed2004

Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats.

BACKGROUND: Minocycline, a semi-synthetic tetracycline antibiotic, is an effective neuroprotective agent in animal models of cerebral ischemia when given in high doses intraperitoneally. The aim of this study was to determine if minocycline was effective at reducing infarct size in a Temporary Middle Cerebral Artery Occlusion model (TMCAO) when given at lower intravenous (IV) doses that correspond to human clinical exposure regimens. METHODS: Rats underwent 90 minutes of TMCAO. Minocycline or saline placebo was administered IV starting at 4, 5, or 6 hours post TMCAO. Infarct volume and neurofunctional tests were carried out at 24 hr after TMCAO using 2,3,5-triphenyltetrazolium chloride (TTC) brain staining and Neurological Score evaluation. Pharmacokinetic studies and hemodynamic monitoring were performed on minocycline-treated rats. RESULTS: Minocycline at doses of 3 mg/kg and 10 mg/kg IV was effective at reducing infarct size when administered at 4 hours post TMCAO. At doses of 3 mg/kg, minocycline reduced infarct size by 42% while 10 mg/kg reduced infarct size by 56%. Minocycline at a dose of 10 mg/kg significantly reduced infarct size at 5 hours by 40% and the 3 mg/kg dose significantly reduced infarct size by 34%. With a 6 hour time window there was a non-significant trend in infarct reduction. There was a significant difference in neurological scores favoring minocycline in both the 3 mg/kg and 10 mg/kg doses at 4 hours and at the 10 mg/kg dose at 5 hours. Minocycline did not significantly affect hemodynamic and physiological variables. A 3 mg/kg IV dose of minocycline resulted in serum levels similar to that achieved in humans after a standard 200 mg dose. CONCLUSIONS: The neuroprotective action of minocycline at clinically suitable dosing regimens and at a therapeutic time window of at least 4-5 hours merits consideration of phase I trials in humans in view of developing this drug for treatment of stroke.

Animals↗
PubMed2004

Minocycline up-regulates Bcl-2 and protects against cell death in mitochondria.

Robust neuroprotective effects have been shown for minocycline. Whether it also protects nonneuronal cells or tissues is unknown. More importantly, the mechanisms of minocycline protection appear multifaceted and remain to be clarified. Here we show that minocycline can protect kidney epithelial cells in vitro and protect the kidneys from ischemic injury in vivo. We further show that Bcl-2 is a key molecular determinant of minocycline protection. Minocycline protected kidney epithelial cells against apoptosis induced by hypoxia, azide, cisplatin, and staurosporine. The protection occurred at mitochondria, involving the suppression of Bax accumulation, outer membrane damage, and cytochrome c release. Minocycline induced Bcl-2, which accumulated in mitochondria and interacted with death-promoting molecules including Bax, Bak, and Bid. Down-regulation of Bcl-2 by specific antisense oligonucleotides abolished the cytoprotective effects of minocycline. Thus, minocycline can protect neuronal as well as nonneuronal cells and tissues. One mechanism for minocycline protection involves the induction of Bcl-2, an antiapoptotic protein.

Animals↗
PubMed2004

Hematopoietic origin of microglial and perivascular cells in brain.

BACKGROUND: Bone marrow (BM)-derived cells differentiate into a wide variety of cell types. BM contains a heterogeneous population of stem and progenitor cells including hematopoietic stem cells, marrow stromal cells, and perhaps other progenitor cells. To establish unequivocally the transdifferentiation capability of a hematopoietic cell to a nonhematopoietic cell (endothelial cells, neurons, and glial cells), it is imperative to demonstrate that a single cell or clone of that single cell (clonal analysis) differentiates into cells comprising vessels or other cells in the brain. METHODS: We generated mice that exhibited a high level of hematopoietic reconstitution from a single enhanced green fluorescent protein (EGFP) stem cell. To achieve this, we combined FACS sorting and cell culture to generate a population of cells derived from a single hematopoietic stem cell (Lin-, CD34-, c-kit+, and Sca-1+). Clonal populations of cells were then transplanted into lethally irradiated recipient mice. After 3-4 months of engraftment, some mice underwent middle cerebral artery (MCA) suture occlusion. EGFP immunocytochemistry and dual labeling was performed with cell-specific markers on tissue from various time points. RESULTS: In all transplanted mice, EGFP+ highly ramified cells were seen in the brain parenchyma. These cells stained with RCA120 lectin and had the characteristics of parenchymal microglial cells. In brains without infarction and in uninfarcted brain regions of mice that underwent MCA occlusion, there were many EGFP+ cells in a perivascular distribution, associated with both small and larger blood vessels. The cells were tightly apposed to the vessel wall and some had long processes that enveloped the endothelial cells. After MCA occlusion, there was an influx of EGFP expressing cells in the ischemic tissue that colocalized with the "neovascularization." These EGFP+ cells were wrapped around endothelial cells in an albuminal location and did not coexpress von Willebrand Factor or CD31. We detected rare dual-labeled EGFP and NeuN-expressing cells. We detected two staining patterns. The more frequent pattern was phagocytosis of NeuN cells by EGFP expressing cells. However, we also detected rarer cells where the EGFP and NeuN appeared to be colocalized by confocal microscopy. CONCLUSIONS: HSC differentiate into parenchymal microglial cells and perivascular cells in the brain. The numbers of these cells increase after cerebral ischemia. The HSC is therefore one source of parenchymal microglial cells and a source for perivascular cells. After a cerebral infarction, there are rare HSC-derived cells that stain with the neuronal marker, NeuN. However, the more common pattern appears to represent phagocytosis of damaged neurons by EGFP+ microglial cells.

Animals↗
PubMed2004

Optimal delivery of minocycline to the brain: implication for human studies of acute neuroprotection.

Minocycline is currently under development as a neuroprotective agent in many different brain diseases. In more than a dozen experimental investigations in various models of brain injury, high doses of minocycline have been administered intraperitoneally. This report details new concerns with this route of administration and makes a case for intravenous dosing in experimental animals, particularly for acute neuroprotection, to optimize delivery to the brain and facilitate translation to human studies.

Animals↗
PubMed2004

SDF-1 (CXCL12) is upregulated in the ischemic penumbra following stroke: association with bone marrow cell homing to injury.

The chemokine stromal-derived factor-1 (SDF-1, also known as CXCL12) and its receptor CXCR4 have been implicated in homing of stem cells to the bone marrow and the homing of bone marrow-derived cells to sites of injury. Bone marrow cells infiltrate brain and give rise to long-term resident cells following injury. Therefore, SDF-1 and CXCR4 expression patterns in 40 mice were examined relative to the homing of bone marrow-derived cells to sites of ischemic injury using a stroke model. Mice received bone marrow transplants from green fluorescent protein (GFP) transgenic donors and later underwent a temporary middle cerebral artery suture occlusion (MCAo). SDF-1 was associated with blood vessels and cellular profiles by 24 hours through at least 30 days post-MCAo. SDF-1 expression was principally localized to the ischemic penumbra. The majority of SDF-1 expression was associated with reactive astrocytes; much of this was perivascular. GFP+ cells were associated with SDF-1-positive vessels and were also found in the neuropil of regions with increased SDF-1 immunoreactivity. Most vessel-associated GFP+ cells resemble pericytes or perivascular microglia and the majority of the GFP+ cells in the parenchyma displayed characteristics of activated microglial cells. These findings suggest SDF-1 is important in the homing of bone marrow-derived cells, especially monocytes, to areas of ischemic injury.

Animals↗
PubMed2004

Healing a broken heart with stem cells.

We discuss here the rapid progress of stem cell therapy in myocardial infarction. In particular, we focus on the issue of transdifferentiation as a "hallmark" of the stem cell's potential to replace damaged cells of the heart. A study by Henning and colleagues in this issue of Cell Transplantation supports the alternative notion of a nontransdifferentiation-mediated protection of the heart as an equally robust mechanism underlying the therapeutic potential of stem cells.

Animals↗
PubMed2003

Tracking trends in secondary stroke prevention strategies.

BACKGROUND: Stroke is defined as a rapid onset of isolated neurologic dysfunction and is the leading cause of disability in adults, as well as the third-leading cause of death in the US. Nearly 600,000 cases of stroke are reported annually. OBJECTIVE: To quantify the impact of emerging evidence on the use of secondary stroke prevention strategies in patients discharged from a specialized stroke center in 2002 compared with those discharged in 2000. METHODS: Using a retrospective approach, data were collected on the first 100 patients cared for by the stroke service from July 1, 2000, to December 31, 2000. Using a prospective approach, the goal was to enroll 100 patients with a diagnosis of ischemic stroke and telephone the patients 1 and 3 months after discharge to determine patient adherence and persistence rate of medications. This is an interim report of the first 20 patients enrolled. RESULTS: Both studies resulted in populations of 55% women and 45% men. The most common risk factor was hypertension, with 59% on admission in 2000 and 75% in 2002. Use of antithrombotics (98% in 2000 to 100% in 2002) and antihypertensives (67% in 2000 to 90% in 2002) was high in both studies and not significantly different. The 2 most significant changes in prescribing were increased use of statins (13% in 2000 to 50% in 2002, p = 0.0007) and combination clopidogrel and aspirin use (0% in 2000 to 20% in 2002, p = 0.001). At 3 months, 66.7% of patients were on the same antithrombotic medication as at discharge. CONCLUSIONS: The dedicated stroke service was able to effectively translate emerging evidence and guidelines into practice and significantly change the use of prescribed medications for secondary stroke prevention.

Antihypertensive Agents↗
PubMed2003

Remote evaluation of acute ischemic stroke: reliability of National Institutes of Health Stroke Scale via telestroke.

BACKGROUND AND PURPOSE: Despite Food and Drug Administration approval of tissue-type plasminogen activator for stroke, obstacles in the US healthcare system prevent its widespread use. The Remote Evaluation for Acute Ischemic Stroke (REACH) program was developed to address these issues in rural settings. A key component of stroke assessment in the REACH system is the National Institutes of Health Stroke Scale (NIHSS) evaluation. We sought to determine whether, using the REACH system, NIHSS values of bedside and remote evaluators would correspond. METHODS: Twenty patients were recruited. On obtaining consent, a neurologist performed a bedside NIHSS evaluation on each patient. Within 1 hour, using any broadband-connected workstation-either office or home personal computer and a landline phone to speak with the patient-a second neurologist remotely evaluated the patient through the REACH system. Paired t tests and Pearson correlation coefficients were used to examine NIHSS reliability performed bedside and remotely. RESULTS: NIHSS ranged from 1 to 24. Correlations between bedside and remote locations (r=0.9552, P=0.0001) were very strong, and t tests indicate that the means were not different. CONCLUSIONS: The NIHSS can be reliably performed over the REACH system. This supports our endeavor to bring stroke expertise to rural community hospitals.

Acute Disease↗