Posterior Reversible Encephalopathy Syndrome, Part 2: Controversies Surrounding Pathophysiology of Vasogenic Edema

Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic state accompanied by a unique brain imaging pattern typically associated with a number of complex clinical conditions including: preeclampsia/eclampsia, allogeneic bone marrow transplantation, solid organ transplantation, autoimmune diseases and high dose cancer chemotherapy. The mechanism behind the developing vasogenic edema and CT or MR imaging appearance of PRES is not known. Two theories have historically been proposed: 1) Severe hypertension leads to failed auto-regulation, subsequent hyperperfusion, with endothelial injury/vasogenic edema and; 2) vasoconstriction and hypoperfusion leads to brain ischemia and subsequent vasogenic edema. The strengths/weaknesses of these hypotheses are reviewed in a translational fashion including supporting evidence and current available imaging/clinical data related to the conditions that develop PRES. While the hypertension/hyperperfusion theory has been most popular, the conditions associated with PRES have a similar immune challenge present and develop a similar state of T-cell/endothelial cell activation that may be the basis of leukocyte trafficking and systemic/cerebral vasoconstriction. These systemic features along with current vascular and perfusion imaging features in PRES appear to render strong support for the older theory of vasoconstriction coupled with hypoperfusion as the mechanism.

Related papers:

title: Responses of cerebral arteries and arterioles to acute hypotension and hypertension.
abstract: The responses of cerebral precapillary vessels to changes in arterial blood pressure were studied in anesthetized cats equipped with cranial windows for the direct observation of the pial microcirculation of the parietal cortex. Vessel responses were found to be size dependent. Between mean arterial pressures of 110 and 160 mmHg autoregulatory adjustments in caliber, e.g., constriction when the pressure rose and dilation when the pressure decreased, occurred only in vessels larger than 200 micron in diameter. Small arterioles, less than 100 micron in diameter, dilated only at pressures equal to or less than 90 mmHg; below 70 mmHg their dilation exceeded that of the larger vessels. When pressure rose to 170- 200 mmHg, small vessels dilated while the larger vessels remained constricted. At very high pressures (greater than 200 mmHg) forced dilation was frequently irreversible and was accompanied by loss of responsiveness to hypocapnia. Measurement of the pressure differences across various segments of the cerebral vascular bed showed that the larger surface cerebral vessels, extending from the circle of Willis to pial arteries 200 micron in diameter, were primarily responsible for the adjustments in flow over most of the pressure range.

title: Effects of Acutely Induced Hypertension in Cats on Pial Arteriolar Caliber, Local Cerebral Blood Flow, and the Blood‐Brain Barrier
abstract: Acute hypertension was induced in 19 anesthetized cats by the intravenous administration of angiotensin. The caliber of pial arteries was measured by a television image-splitting tech nique and local cerebral Mood flow by the hydrogen clearance technique. As the blood pressure was increased, pial arterioles constricted and cerebral blood flow remained relatively constant, showing that autoregulation of cerebral blood flow was intact. At mean arterial pressures of more than 170 mm Hg arteriolar dilation appeared. In smaller arterioles (initial diameter less than 100 μm) a segmental dilation (the "sausage-string" phenomenon) frequently preceded uniform dilation. This arteriolar dilation was associated with a marked increase in local cerebral blood flow indicating that the upper level of autoregulation had been breached. In no cat was vasospasm or a decrease in Mood flow observed during induced hypertension. Hypertension also caused dysfunction of the blood-brain barrier since, in 17 out of 19 of the cats examined, there was extravasation of protein-bound Evans blue into brain tissue. In only one of the 19 cats subjected to neuropatbological analysis was ischemic brain damage identified and this was restricted to minimal ischemic cell change. The results indicate that severe, induced hyperten sion in cats produces cerebral arteriolar dilation, an increase of cere bral blood flow, and dysfunction of the blood-brain barrier. These observations may be of importance in understanding the pathogenesis of hypertensive encephalopathy.

title: Posterior reversible encephalopathy syndrome in intensive care medicine
abstract: BackgroundPosterior reversible encephalopathy syndrome (PRES) is a well-recognized clinico-neuroradiological transient condition. Early recognition is of paramount importance for prompt control of blood pressure or removal of precipitating factors and treatment of epileptic seizures or status epilepticus. Delay in the diagnosis and treatment may in fact results in death or in irreversible neurological sequelae.DiscussionPRES is characterized by headache, altered mental status, seizures, and visual disturbances and is associated with a number of different causes, most commonly acute hypertension, preeclampsia/eclampsia, and immunosuppressive agents. Clinical symptoms and neuroradiological findings are typically indistinguishable among the cases of PRES, regardless of underlying cause. Magnetic resonance studies typically show edema involving the white matter of cerebral posterior regions, especially parieto-occipital lobes but frontal and temporal lobes, and other encephalic structures may be involved.ConclusionsIntensivists and other physicians involved in the evaluation of patients with presumed PRES must be aware of the clinical spectrum of the associated conditions, the diagnostic modalities, and the correct treatment.

title: Clinical spectrum and critical care management of Posterior Reversible Encephalopathy Syndrome (PRES).
abstract: Posterior Reversible Encephalopathy (PRES) is characterized by acute-onset headache, altered mental status, cortical blindness and seizures, with parietal-occipital involvement. We report all cases of PRES diagnosed in our intensive care unit during the last 4 years, and evaluate their outcome in terms of the different medical treatments used. Even if usually reversible, PRES can sometimes result in death or irreversible neurological deficit, such as chronic epilepsy.



From January 2001 to January 2005, we identified 8 female patients with PRES. All patients underwent basal and follow-up brain MRI. Patients referred to Epilepsy Center (about 3000 patients) were reviewed in order to identify subjects with a clinical history of PRES. These latter were clinically re-evaluated and underwent video-EEG, MRI study and neuropsychological testing.



Of the 8 patients, 5 had hypertensive encephalopathy during pregnancy; 2 had eclampsia during the postpartum period; 1 patient with chronic renal failure developed symptoms after immunosuppressive treatment. In all patients but 1, neurological and radiological abnormalities resolved after appropriate treatment. In addition, we found 2 patients with temporal lobe epilepsy subsequent to a previous PRES. MRI revealed cortical-subcortical malacia in the parietal-occipital regions.



The widespread use of MRI technology has made PRES familiar to many clinicians. Although PRES is reversible when treatment is instituted, delayed diagnosis and therapy can result in chronic neurological sequelae. The relationship between hypertensive encephalopathy and chronic epilepsy needs to be confirmed by longitudinal studies. Normalization of blood pressure and treatment of seizures deserves particular attention.

title: Clinical spectrum of reversible posterior leukoencephalopathy syndrome.
abstract: Reversible posterior leukoencephalopathy syndrome is a recently recognized disorder with characteristic radiologic findings that mainly involve the white/gray matter of the parieto-occipital lobes. This complex syndrome is associated with cyclosporine A therapy or a variety of other conditions in which blood pressure rises acutely. Twelve patients from a variety of conditions who met the diagnostic criteria for this syndrome were studied. Interestingly, three of these patients had intra-abdominal neurogenic tumors, which have rarely been reported. Initial cranial magnetic resonance imaging scans revealed fairly symmetric areas of increased T(2) signal involving both white and gray matter of parieto-occipital lobes in the majority of the patients. However, the lesions were often located outside the parieto-occipital regions. Four patients had occipital region magnetic resonance spectroscopy during the acute phase, which revealed high lactate peak and normal N-acetyl aspartate/creatine and choline peaks. With appropriate treatment, most patients recovered from this syndrome and experienced almost complete resolution of brain lesions on follow-up magnetic resonance imaging. One patient, however, continued to have small residual hemosiderin deposits on a follow-up magnetic resonance imaging with neurologic sequellae. In conclusion, a better understanding of this complex syndrome may obviate unnecessary investigations and allow management of the associated problems in prompt and appropriate ways.

title: Computerized tomographic appearance of hypertensive encephalopathy.
abstract: The computerized tomographic scan in a case of hypertensive encephalopathy showed widespread areas of diminished density in the white matter, mainly in the upper and posterior parts of the hemispheres. The abnormalities resolved within three months of the institution of treatment. We suggest that the low-density areas are focal collections of edema fluid extravasated through ischemic segments of the vessel wall.

title: Acute hypertensive encephalopathy: findings on spin-echo and gradient-echo MR imaging.
abstract: The purpose of this study was to investigate the findings on spin-echo and gradient-echo MR images obtained in patients with hypertensive encephalopathy.



The MR images of 36 patients with clinically documented acute (< 72 hr) hypertensive encephalopathy were prospectively examined. Brain swelling on short TR images, hyperintensity on long TR images, and hypointensity on long TR and gradient-echo images were assessed.



The most common finding was hyperintensity in the supratentorial white matter (n = 32), representing hypertensive encephalopathy-induced reversible edema, irreversible infarction, or preexisting ischemic disease. These entities were difficult to distinguish on the basis of the initial examination. A more characteristic finding was edema (swelling on short TR images and hyperintensity on long TR images) in the basal ganglia (n = 22), brainstem (n = 15), and cerebellum (n = 11). Punctate foci of hypointensity, seen on long TR spin-echo images but optimally visualized on gradient-echo images, were the most distinguishing feature of this disorder.



MR imaging is efficacious in revealing deep ganglionic and posterior fossa edema, which is characteristic of hypertensive encephalopathy. Serial MR studies are necessary to distinguish transient edema from permanent zones of infarction. Gradient-echo MR imaging is particularly valuable in visualizing petechial hemorrhages, the presence of which distinguishes nonspecific white matter disease from an acute or prior episode of hypertensive encephalopathy and serves as a permanent marker of this disease.

title: Computed tomographic changes of hypertensive encephalopathy.
abstract: Computed tomographic (CT) scans were evaluated in 11 patients with acute hypertensive encephalopathy. Hypertensive encephalopathy is characterized by an acute, severe rise in blood pressure associated with headache, nausea, vomiting, altered mental status, and focal neurologic deficits, and rapid improvement after control of blood pressure. The systolic blood pressure range is 200-280 mm Hg; diastolic is 130-170 mm Hg. The most common CT finding was white-matter edema, diffuse or focal, affecting the supratentorial compartment in all cases and the infratentorial compartment in eight. These changes resolved after the blood pressure was lowered in all six patients studied by follow-up CT. Permanent areas of infarction were demonstrated in three patients. These abnormalities are correlated with the neuropathologic findings in hypertensive encephalopathy.

title: Hypertensive encephalopathy: findings on CT, MR imaging, and SPECT imaging in 14 cases.
abstract: Hypertensive encephalopathy is a syndrome consisting of headache, seizures, visual changes, and other neurologic disturbances in patients with elevated systemic blood pressure. The purpose of this study was to analyze the imaging findings in 14 patients with hypertensive encephalopathy. CT (n = 13), MR (n = 12), and single-photon emission computed tomography (n = 2) examinations performed in these patients before and after resolution of symptoms were reviewed. Eight had the preeclampsia-eclampsia syndrome, and six had hypertensive encephalopathy due to other causes. CT and MR findings in all patients having these examinations were indicative of edema in the cortex and subcortical white matter in the occipital lobes. Two of the 14 patients also had similar findings in the cerebellum and frontal lobes. Single-photon emission computed tomography showed increased vascular perfusion adjacent to areas that appeared abnormal on CT and MR. The findings on the imaging studies resolved on follow-up examinations performed after the hypertension was corrected. Our results suggest that the radiologic findings associated with hypertensive encephalopathy may be useful in establishing the diagnosis in the appropriate clinical setting.

title: Autoregulation of Brain Circulation in Severe Arterial Hypertension
abstract: Cerebral blood flow was studied by the arteriovenous oxygen difference method in patients with severe hypertension and in normotensive controls. The blood pressure was lowered to study the lower limit of autoregulation (the pressure below which cerebral blood flow decreases) and the pressure limit of brain hypoxia. Both limits were shifted upwards in the hypertensive patients, probably as a consequence of hypertrophy of the arteriolar walls. These findings have practical implications for antihypertensive therapy. When the blood pressure was raised some patients showed an upper limit of autoregulation beyond which an increase of cerebral blood flow above the resting value was seen without clinical symptoms. No evidence of vasospasm was found in any patient at high blood pressure. These observations may be of importance for the understanding of the pathogenesis of hypertensive encephalopathy.

title: Distinct Imaging Patterns and Lesion Distribution in Posterior Reversible Encephalopathy Syndrome
abstract: Although the term posterior reversible encephalopathy syndrome (PRES) was popularized because of the typical presence of vasogenic edema in the parietal and occipital lobes, other regions of the brain are also frequently affected. We evaluated lesion distribution with CT and MR in a large cohort of patients who experienced PRES to comprehensively assess the imaging patterns identified.  The locations of the PRES lesion at toxicity were comprehensively identified and tabulated in 136 patients by CT (22 patients) and MR (114 patients) imaging including the hemispheric, basal ganglial, and infratentorial locations. Clinical associations along with presentation at toxicity including blood pressure were assessed.  Vasogenic edema was consistently present in the parietal or occipital regions (98%), but other locations were common including the frontal lobes (68%), inferior temporal lobes (40%), and cerebellar hemispheres (30%). Involvement of the basal ganglia (14%), brain stem (13%), and deep white matter (18%) including the splenium (10%) was not rare. Three major patterns of PRES were noted: the holohemispheric watershed (23%), superior frontal sulcal (27%), and dominant parietal-occipital (22%), with additional common partial or asymmetric expression of these primary PRES patterns (28%).  Involvement of the frontal lobe, temporal lobe, and cerebellar hemispheres is common in PRES, along with the occasional presence of lesions in the brain stem, basal ganglia, deep white matter, and splenium. Three primary PRES patterns are noted in the cerebral hemispheres, along with frequent partial or asymmetric expression of these PRES patterns. Awareness of these patterns and variations is important to recognize PRES neurotoxicity more accurately when present.

title: Etiology of cortical and white matter lesions in cyclosporin-A and FK-506 neurotoxicity.
abstract: The etiology of the neurotoxicity associated with cyclosporin-A (CsA) and FK-506 treatment is not fully understood. At our institution, we noticed a distinct, abrupt change in the imaging characteristics of CsA and FK-506 neurotoxicity, which consisted of a shift in lesion morphology from a white matter abnormality to a mixed cortical and white matter pattern. The purpose of this study was to assess clinical parameters that might explain this change.



Twenty-two patients had a neurotoxic reaction and brain imaging changes while receiving CsA or FK-506. Nineteen patients received allogeneic bone marrow transplants, and three had aplastic marrow disorders. Fifty-one imaging studies (CT or MR imaging) were obtained, and lesion characteristics, locations, and time courses were evaluated along with relevant clinical data.



Nine patients who had been conditioned for transplantation with cyclophosphamide and chemotherapy (busulfan or thiotepa) had a mixed pattern of cortical and white matter involvement (57 lesions). Isolated white matter involvement (62 lesions) developed in three nontransplant patients and 10 transplant patients conditioned with cyclophosphamide and total-body irradiation. All lesions occurred at typical brain watershed zones. Lesion enhancement was noted in two patients conditioned with chemotherapy. Initial images demonstrated characteristic lesions in 15 patients (68%). Initial images were normal in four patients (18%) and nonspecific in three patients (14%).



Lesion location in CsA and FK-506 neurotoxicity may depend on the presence or type of conditioning used before bone marrow transplantation. Nontransplant patients or those conditioned with total-body irradiation develop white matter lesions, whereas those conditioned with chemotherapy develop mixed cortical and white matter lesions.

title: Posterior Reversible Encephalopathy Syndrome, Part 1: Fundamental Imaging and Clinical Features
abstract: Posterior reversible encephalopathy syndrome (PRES) is a neurotoxic state coupled with a unique CT or MR imaging appearance. Recognized in the setting of a number of complex conditions (preeclampsia/eclampsia, allogeneic bone marrow transplantation, organ transplantation, autoimmune disease and high dose chemotherapy) the imaging, clinical and laboratory features of this toxic state are becoming better elucidated. This review summarizes the basic and advanced imaging features of PRES, along with pertinent features of the clinical and laboratory presentation and available histopathology. Many common imaging/clinical/laboratory observations are present among these patients, despite the perception of widely different associated clinical conditions.

title: Catheter Angiography, MR Angiography, and MR Perfusion in Posterior Reversible Encephalopathy Syndrome
abstract: In their article, “Catheter Angiography, MR Angiography, and MR Perfusion in Posterior Reversible Encephalopathy Syndrome” (PRES), Drs Bartynski and Boardman[1][1] describe their findings in hypertensive patients with PRES who were studied retrospectively with MR perfusion imaging. The authors

title: Pretransplantation conditioning influence on the occurrence of cyclosporine or FK-506 neurotoxicity in allogeneic bone marrow transplantation.
abstract: Transplantation conditioning regimens have been shown to affect the brain imaging appearance in patients with cyclosporine or FK-506 neurotoxicity. We assessed whether the occurrence of neurotoxicity was affected by the choice of conditioning regimen used before allogeneic bone marrow transplantation (allo-BMT).



An allo-BMT was performed in 290 patients conditioned before transplantation with myeloablative therapy. Neurotoxicity from cyclosporine or FK-506 developed in 21 (7.2%) of these patients, as confirmed with CT or MR imaging. Two hundred seventy-four (94%) of these 290 patients were conditioned with minor variations of one of five fundamental regimens: cyclophosphamide (Cy)/busulfan (n = 97), Cy/total body irradiation (TBI) (n = 122), Cy/thiotepa/TBI (n = 40), bischloroethylnitrosourea/etoposide/cytarabine/melphalan, or BEAM (n = 10), and Cy/thiotepa/busulfan (n = 5). The remaining 16 patients were prepared with variable regimens. The rates of occurrence of cyclosporine or FK-506 neurotoxicity relative to these conditioning regimens were compared.



The lowest rate of cyclosporine or FK-506 neurotoxicity was found in those patients conditioned with Cy (2 days)/busulfan (4 days) (5.1%) or Cy (2 days)/TBI (4 days) (5.9%). Rate of neurotoxicity increased with lengthier conditioning regimens. A high rate of neurotoxicity was present in those patients conditioned with Cy (4 days)/TBI (4 days) (13.7%), and this was statistically significant (P <.05) when compared with Cy (2 days)/busulfan (4 days).



The rate of occurrence of cyclosporine or FK-506 neurotoxicity varies with the conditioning regimen used, with lengthier regimens associated with a higher rate of neurotoxicity. As the length of the conditioning regimen equates to the total dose of chemotherapy administered, it suggests that the intensity of the regimen is correlated to the predisposition to neurotoxicity from cyclosporine or FK-506.

title: Reversible posterior leukoencephalopathy syndrome: evaluation with diffusion-tensor MR imaging.
abstract: To characterize the changes in brain water diffusion caused by reversible posterior leukoencephalopathy syndrome (RPLS).



Twelve patients with the clinical features and conventional magnetic resonance (MR) imaging findings of RPLS underwent diffusion-tensor echo-planar MR imaging. The isotropic diffusion coefficient (D) and diffusion anisotropy (A(sigma)) were measured in posterior regions of diffusion abnormality and in anterior areas of normal-appearing brain.



Across all 12 subjects, the mean D of (1.09 +/- 0.13 [SD]) x 10(-3) mm(2)/sec in affected posterior regions was 26% greater than its value of (0.87 +/- 0.07) x 10(-3) mm(2)/sec in normal-appearing anterior regions. The mean A(sigma) of 0.15 +/- 0.03 in posterior regions was 35% less than its value of 0.23 +/- 0.02 in anterior regions (t(11) = 9.58; P <.001). There was a significant inverse correlation between D and A(sigma) in posterior regions (r = -0.67; P <.018) but not in anterior regions (r = -0.12; P =.719). A follow-up study performed in one patient after resolution of symptoms documented reversal of elevated isotropic diffusion and at least partial recovery of anisotropy loss.



The increased magnitude of brain water diffusion characteristic of RPLS is accompanied by reduced A(sigma). The magnitudes of these two effects are correlated and may be reversible. These observations support the proposal that vasogenic edema due to cerebrovascular autoregulatory dysfunction is the underlying pathophysiologic mechanism in uncomplicated RPLS.

title: Neurologic complications in allogeneic bone marrow transplant patients receiving cyclosporin.
abstract: Regimens using cyclosporin (CSP) and either methylprednisolone (MP) or methotrexate (MTX) have been useful in the prophylaxis of acute graft-versus-host disease (GVHD) after allogeneic bone marrow transplantation (BMT). However, CSP produces a number of side effects, including neurologic toxicity. A retrospective review of recipients of 239 BMTs given CSP-based prophylactic regimens revealed that 10 patients (4.2%, 95% confidence interval 0% to 10.4%) experienced a syndrome characterized by hypertension, severe visual disturbances, seizures and occipital lobe density changes on brain computed tomography (nine patients) or nuclear magnetic resonance imaging (one patient). Neurologic findings were reversible in all cases, usually after temporary discontinuation of CSP. Univariate analysis identified the following risk factors for neurotoxicity: use of unrelated or HLA-mismatched related donors, administration of etoposide (VP-16) or total body irradiation as part of conditioning, use of corticosteroids for prophylaxis or treatment of acute GVHD, or development of either acute GVHD or clinically significant microangiopathic hemolytic anemia (MAHA) post-BMT. In multivariate analysis, the most important predictors were the use of VP-16 (p = 0.008), the use of a continuous infusion CSP plus MP prophylactic regimen for GVHD (p = 0.003) and the development of MAHA after BMT (p less than 0.001). The strong association with MAHA suggests that endothelial damage is related to the development of this complication.

title: Cyclosporine, sympathetic activity, and hypertension.
abstract: Cyclosporine has dramatically advanced immunosuppressive therapy following organ transplantation, but this advance has been accompanied by a high incidence of hypertension in patients receiving thi...

title: Hemodynamic and permeability changes in posterior reversible encephalopathy syndrome measured by dynamic susceptibility perfusion-weighted MR imaging.
abstract: The physiological mechanism that gives rise to posterior reversible encephalopathy syndrome (PRES) is currently unknown. We sought to better understand the mechanism of the edema formation in PRES and specifically hypothesized that this edema is caused by increased vascular permeability.



Eight consecutive patients with PRES who had been studied by using perfusion MR imaging were retrospectively identified. Perfusion images were obtained using a gradient-echo echo planar sequence with contrast enhancement. Measures of apparent diffusion coefficient (ADC), cerebral blood volume (CBV), cerebral blood flow (CBF), mean transit time (MTT) and vascular permeability (K2) were calculated in the affected posterior brain areas and normalized to values obtained in unaffected anterior brain. These values were compared with those found in healthy subjects.



Regions of interest within the posterior affected brain indicated a significant increase in ADC values in all but one patient, a significant decrease in CBV and CBF values in all patients with PRES (average 30% of control), variable changes in MTT, and no measurable change in K2.



The decrease in both CBV and CBF in PRES supports the theory of autoregulatory vasoconstriction; changes in K2 were not detected.

title: Single photon emission and cerebral computerized tomographic scan and transcranial Doppler sonographic findings in eclampsia
abstract: To define more clearly the neuropathophysiology of eclampsia utilising single‐photon emission computed tomography (SPECT), cerebral computerised tomography (CT) and transcranial Doppler (TCD) ultrasonography.

title: MR Imaging of Postpartum Cortical Blindness
abstract: Cortical blindness is an unusual feature of the toxemia of pregnancy syndrome. We present the CT and magnetic resonance (MR) findings in two women who developed postpartum blindness as a manifestation of this condition. Though both CT and MR display reversible edematous changes in the occipital lobes, follow-up MR documents areas of hemorrhagic and nonhem-orrhagic infarction where the corresponding CT images are normal.

title: Production of endothelin-1 in vascular endothelial cells is regulated by factors associated with vascular injury.
abstract: We studied the effects of factors associated with vascular injury on the production of endothelin-1 (ET-1) in cultured porcine aortic endothelial cells. ET-1 mRNA expression and peptide production in endothelial cells were increased by thrombin, transforming growth factor beta 1 (TGF beta 1), interleukin-1 (IL-1) and tumor necrotizing factor alpha (TNF alpha). The analysis of the enhancer/promoter region of the human ET-1 gene showed that the ET-1 gene transcription is regulated in a cell-specific manner and is activated by thrombin, TGF beta 1 and IL-1. These results suggest that the production of ET-1 in endothelial cells is regulated by factors associated with platelet aggregation, macrophage infiltration and the formation of atherosclerotic lesions.

title: Cytokine regulation of endothelial cell function.
abstract: Endothelial cells have long been viewed as a passive lining of blood vessels endowed essentially with negative properties such as that of being nonreactive to blood components. It is now evident that upon exposure to environmental signals, cytokines in particular, vascular cells undergo profound changes in gene expression and function that allow these cells to participate actively in inflammatory reactions, immunity, and thrombosis. Different mediators (e.g., interleukin-1 [IL-1] and interferon-gamma) activate relatively distinct sets of functions. These functional programs expressed in activated endothelial cells include the production by the same cells of cytokines (e.g., IL-1, IL-6, chemotactic cytokines, and colony-stimulating factors), which regulate hematopoiesis, the differentiation and proliferation of T and B lymphocytes, and the extravasation of leukocytes. The identification of cytokine circuits through which vascular cells participate to thrombotic, inflammatory, and immune reactions provides ...

title: Transcriptional regulation of the endothelin-1 gene by TNF-alpha.
abstract: Cytokines, such as tumor necrosis factor-alpha (TNF-alpha), induce profound alterations in endothelial cell phenotype and are implicated in the organ dysfunction that characterizes septic shock. We explored whether TNF-alpha modulates cellular expression of endothelin-1 (ET-1). ET-1 is a potent vasoconstrictor peptide released by endothelial, vascular smooth muscle, and mesangial cells that could function as a paracrine/autocrine regulator of vascular tone and proliferation. We found that TNF-alpha induced release of ET-1 from bovine aortic endothelial cells (BAEC) in a time- and concentration-dependent manner. Rates of ET-1 release were maximal over 1-8 h and declined to, or below, baseline values after 16 h. When measured at 8 h, TNF-alpha augmented ET-1 release over the range 0.1-250 ng/ml (threshold, 0.1 ng/ml; 50% effective dose, 1.6 +/- 1.2 ng/ml; maximal effect, 100 ng/ml). The increase in secretion was accompanied by a corresponding increase in the transcriptional rate of the ET-1 gene resulting in augmented preproendothelin-1 mRNA transcript levels. TNF-alpha-stimulated increases in ET-1 gene transcription were not dependent on new protein synthesis. Actinomycin D chase experiments suggested that enhanced stability of preproendothelin-1 mRNA could not account for the increase in ET-1 transcript levels. TNF-alpha increased ET-1 release and preproendothelin-1 mRNA content in bovine renal artery and bovine glomerular capillary endothelial cells, demonstrating that the TNF-alpha effect was evident in endothelial cells derived from a variety of sources. Furthermore, augmented ET-1 expression in response to TNF-alpha was evident in bovine glomerular mesangial cells.(ABSTRACT TRUNCATED AT 250 WORDS)

title: Cerebral vasospasm and eclampsia.
abstract: We describe a patient who experienced focal cerebral and brainstem ischemia in the setting of postpartum eclampsia. Cerebral angiography showed spasm of large- and medium-caliber arteries. This case provides rare documentation that vasospasm may account for cerebral ischemia in eclamptic women with focal signs. This observation suggests that in such patients cerebral angiography may be informative and useful.

title: Fatal puerperal cerebral vasospasm and stroke in a young woman
abstract: A woman who experienced postpartum cerebral infarction, brain edema, and death is described. Angiography implicated cerebral vasospasm as the primary etiology.

title: CT and angiographic correlation of severe neurological disease in toxemia of pregnancy
abstract: SummaryTwo patients with severe cerebral symptoms of toxemia of pregnancy were examined using computed tomography (CT) and angiography. CT disclosed extensive areas of low attenuation within the cerebral hemispheres. Angiography revealed constriction and narrowing of proximal and peripheral vessels suggesting vasculitis with extensive areas of impaired regional cerebral blood flow. A review of the known pathology and the theories regarding the pathophysiology of the cerebral effects of toxemia is presented.

title: Association of cerebral perfusion pressure with headache in women with pre‐eclampsia
abstract: To study estimated cerebral perfusion pressure and its relation to headache and scotomata in women with pre‐eclampsia.

title: Cerebral hemodynamics in preeclampsia and eclampsia.
abstract: To test further the hypothesis that preeclampsia and eclampsia are associated with cerebral vasospasm.



Prospective case study.



Inpatient obstetrics service of an urban public hospital.



Eleven women with eclampsia (mean gestational age, 32 weeks), preeclampsia (mean gestational age, 36 weeks), or normotensive pregnancy (mean gestational age, 35 weeks). Middle cerebral artery (MCA) velocity was measured bilaterally in all patients by means of transcranial Doppler ultrasonography.



Eclamptic patients (n = 3) had significantly higher mean flow velocities and lower average pulsatility indexes than did normotensive patients (n = 4) (average MCA-mean flow velocity, 165 vs 79 cm/s [P = .007]; average MCA pulsatility index, 0.51 vs 1.1 [P < .001]). Compared with normotensive pregnant women, preeclamptic patients (n = 4) had lower average pulsatility indexes (0.76, P = .003), but similar mean flow velocities (average MCA-mean flow velocity, 82 cm/s; P = .8).



Significantly higher MCA velocities in eclamptic, but not preeclamptic, women compared with those in normotensive pregnant women suggests that moderate to severe vasospasm is associated with eclampsia.

title: Persistence of cerebral hemodynamic changes in patients with eclampsia: A report of three cases.
abstract: This study was undertaken to compare the persistence of changes in estimated cerebral perfusion pressure and the resistance area product, an index of cerebrovascular resistance, in women with preeclampsia and women with eclampsia.



The maternal middle cerebral artery was evaluated by transcranial Doppler ultrasonography in 6 patients with severe preeclampsia and 3 women with eclampsia, and cerebral blood flow velocities were determined. Estimated cerebral perfusion pressure was calculated according to the following equation: Estimated cerebral perfusion pressure = Mean cerebral blood flow velocity/(Mean cerebral blood flow velocity - Diastolic cerebral blood flow velocity) x (Mean blood pressure - Diastolic blood pressure). Because the diameters of the vessels could not be measured directly, an index of resistance was calculated according to the following equation: Resistance area product = Mean blood pressure/Mean cerebral blood flow velocity. We calculated an index of cerebral blood flow according to the following equation: Index = Estimated cerebral perfusion pressure/Resistance area product. Patients were reassessed at 24 and 48 hours after delivery.



At the initial assessment the estimated cerebral perfusion pressure was higher in women with eclampsia than in those with severe preeclampsia. In addition, cerebrovascular resistance was significantly decreased in the eclampsia group, and it remained decreased as long as 4 days in 1 patient with eclampsia.



Preeclampsia is associated with increases in cerebral perfusion pressure counterbalanced by increases in cerebrovascular resistance, with no change in cerebral blood flow. In eclampsia a significant increase in cerebral perfusion pressure occurs, but a significant fall in cerebrovascular resistance also occurs and a loss of autoregulation results in cerebral overperfusion similar to that of hypertensive encephalopathy. This may persist for as long as 4 days.

title: Etiology and pathogenesis of preeclampsia: Current concepts
abstract: The etiology of preeclampsia is unknown. At present, 4 hypotheses are the subject of extensive investigation, as follows: (1) Placental ischemia-Increased trophoblast deportation, as a consequence of ischemia, may inflict endothelial cell dysfunction. (2) Very low-density lipoprotein versus toxicity-preventing activity-In compensation for increased energy demand during pregnancy, nonesterified fatty acids are mobilized. In women with low albumin concentrations, transporting extra nonesterified fatty acids from adipose tissues to the liver is likely to reduce albumin's antitoxic activity to a point at which very-low density lipoprotein toxicity is expressed. (3) Immune maladaptation-Interaction between decidual leukocytes and invading cytotrophoblast cells is essential for normal trophoblast invasion and development. Immune maladaptation may cause shallow invasion of spiral arteries by endovascular cytotrophoblast cells and endothelial cell dysfunction mediated by an increased decidual release of cytokines, proteolytic enzymes, and free radical species. (4) Genetic imprinting-Development of preeclampsia-eclampsia may be based on a single recessive gene or a dominant gene with incomplete penetrance. Penetrance may be dependent on fetal genotype. The possibility of genetic imprinting should be considered in future genetic investigations of preeclampsia.

title: Total body irradiation and acute graft-versus-host disease: the role of gastrointestinal damage and inflammatory cytokines.
abstract: The influence of bone marrow transplantation (BMT) conditioning regimens on the incidence and severity of graft-versus-host disease (GVHD) has been suggested in clinical BMT. Using murine BMT models, we show here an increase in GVHD severity in several donor-recipient strain combinations after intensification of the conditioning regimen by increasing the total body irradiation (TBI) dose from 900 cGy to 1,300 cGy. Increased GVHD was mediated by systemic increases in tumor necrosis factor alpha (TNF alpha). Histologic analysis of gastrointestinal tracts showed synergistic damage by increased TBI and allogeneic donor cells that permitted increased translocation of lipopolysacharide (LPS) into the systemic circulation. In vitro, LPS triggered excess TNF alpha from macrophages primed by the GVH reaction. In addition, macrophages isolated within 4 hours of conditioning were primed in proportion to the TBI dose itself to secrete TNF alpha. Thus, the higher TBI dose increased macrophage priming and increased gut damage after allogeneic BMT, causing higher systemic levels of inflammatory cytokines and subsequent severe GVHD. These data highlight the importance of conditioning in GVHD pathophysiology and suggest that interventions to prevent LPS stimulation of primed macrophages may limit the severity of GVHD after intensive conditioning for allogeneic BMT.

title: Cytokine dysregulation and acute graft-versus-host disease.
abstract: We suggest that acute GVHD after marrow transplantation reflects (1) host injury due to the conditioning regimen followed by the production of inflammatory cytokines; (2) stimulation of mature donor T cells in the milieu of increased cell surface expression of leukocyte adhesion molecules and HLA molecules, followed by the autocrine production of IL-2; and, finally, (3) recruitment and activation of additional mononuclear effector cells from donor marrow progenitors, which produce additional inflammatory cytokines, thus sustaining the response. The second step is critical for the amplification of the systemic inflammatory response, and it is absence in autologous, syngeneic, and T-cell-depleted transplants. These T cells may also contribute to the inflammatory cytokine network. Acute GVHD can occur in the absence of primary tissue injury in such settings as transfusion-related GVHD; however, it is likely that a greater HLA disparity between donor and host is required. We propose that inflammatory cytokine production is the final common pathway of acute GVHD. If this model is correct, control of cytokine dysregulation at any of several points should control GVHD. Further studies of GVHD and investigations of cytokine antagonists (eg, IL-4 or IL-10) or combinations of antagonists such as IL-1ra and soluble TNF receptor or pentoxifylline will allow us to determine the validity of this hypothesis.

title: Variable incidence of cyclosporine and FK-506 neurotoxicity in hematopoeitic malignancies and marrow conditions after allogeneic bone marrow transplantation
abstract: This study examines whether malignant disease under treatment influences the incidence of cyclosporine or FK-506 neurotoxicity after myeloablative conditioning and allogeneic bone marrow transplantation (allo- Review of 290 patients who received myeloablative conditioning prior to allo-BMT and cyclosporine/FK-506 identified 21 (7.2%) patients with neurotoxicity confirmed by computed tomography or magnetic resonance. Underlying malignancy necessitating allo-BMT included leukemias (67%), lymphoma (10%), myelodysplastic syndrome (10%), and multiple myeloma (MM). Frequency of neurotoxicity by disease was compared. The highest incidence of neurotoxicity was present with MM (25%), whereas the lowest incidence was present with lymphoma (2.7%). Other diseases demonstrated intermediate incidence, including acute leukemias (10%), myelodysplastic syndrome (6.4%), and chronic myelogenous leukemia (4.9%).Conclusion: Cyclosporine/FK-506 neurotoxicity varied according to the underlying malignancy. The variable susceptibility to the development of neurotoxicity in this population may depend on the interaction of host vasculature with disease specific factors. Understanding the cause of neurotoxicity could improve survival after allo-BMT.

title: Pathogenesis of acute graft-versus-host disease: cytokines and cellular effectors.
abstract: The pathogenesis of acute graft versus host disease (GVHD) is multistep process. This review considers acute GVHD in three sequential steps: conditioning regimen, donor T cell activation, and effector mechanisms. In step one, the conditioning regimen simultaneously damages and activates host tissues, amplifying antigen presentation to allogeneic donor T cells. In step two, donor T cells, activated by host alloantigens, proliferate and secrete a variety of cytokines. Type 1 cytokines (interleukin-2 and interferon-y) are critical for acute GVHD, but several regulatory mechanisms of tissue damage include inflammatory cytokines and cytolytic cellular effectors. The gastrointestinal (GI) tract is a principal target organ because damage to the GI mucosa can release inflammatory mediators such as endotoxin that amplify systemic disease. The inflammatory processes of acute GVHD can be considered as a distortion of the cellular responses to viral and bacterial infections. Cell-mediated toxicity is critical to other GVHD target organs, particularly the liver, where Fas-mediated injury predominates. The cytolytic pathways (e.g., perforin) clearly intensify acute GVHD, although they are not necessary for systemic disease in several model systems. Many of these insights come from animal models using mutant mouse strains that can clarify the role of individual proteins or cell types in the disease process. These insights should allow the testing of new classes of drugs and inhibitors in clinical bone marrow transplantation.

title: Increased serum levels of tumor necrosis factor alpha precede major complications of bone marrow transplantation.
abstract: Acute graft-versus-host disease, interstitial pneumonitis, endothelial leakage syndrome, and veno-occlusive disease are major complications of bone marrow transplantation. Though several new regimens for prophylaxis and treatment of these syndromes have been introduced, the overall incidence has been only slightly reduced over the last few years. We retrospectively analyzed tumor necrosis factor alpha (TNF alpha) serum levels between day -8 and day 100 after bone marrow transplantation in 56 patients transplanted in our unit for a variety of hematological diseases. In 34 patients with uneventful courses, mean TNF alpha levels rose to a maximum of 76 +/- 29 pg/mL. In contrast, 22 patients with major transplant related complications showed mean increases of TNF alpha of 492 +/- 235 pg/mL (P less than .0001). Increases of TNF alpha occurred before interstitial pneumonitis and severe acute graft-versus-host disease with a latency of 25 to 54 days. Early complications such as endothelial leakage syndrome and veno-occlusive disease were closely associated with increases of TNF alpha serum levels. Our study suggests two pathways of TNF alpha release: activation of host macrophages and stimulation of donor cells in the course of acute graft-versus-host disease. Cytokine monitoring should be helpful for prediction and earlier treatment of major transplant related complications.

title: Proinflammatory cytokines and their role in the development of major transplant-related complications in the early phase after allogeneic bone marrow transplantation
abstract: Serum levels of interleukin-6 (IL-6), interleukin-8 (IL-8) and tumor necrosis factor (TNF)-alpha were frequently measured during the first 30 days after allogeneic bone marrow transplantation (BMT) in 84 consecutive adult patients. Major transplant-related complications (MTCs) occurred in 33% of cases and included veno-occlusive liver disease, idiopathic pneumonia syndrome, severe endothelial leakage syndrome and >grade II acute graft-versus-host disease. Compared with patients having minor complications, those with MTCs developed higher levels at times of maximal clinical signs (all cytokines, P<0.001), between days 0–5 post-BMT (IL-6 and IL-8, P<0.05) and days 6–10 (L-6, P<0.001; IL-8 and TNF, P<0.01) post-BMT. We could not discriminate patterns of cytokine release that were specific for any subtype of MTC. Higher levels of IL-8 during days 0–5 were associated (P=0.044) with early (<40 days) death. Multivariate analysis including patient and transplant characteristics as well as post-BMT levels of C-reactive protein showed that high average levels of one or more of the cytokines within the first 10 days post-BMT were independently associated with MTC (Odd's ratio: 2.3 [1.2–4.5], P=0.011). This study shows that systemic release of proinflammatory cytokines contributes to the development of MTC and provides a rationale for pre-emptive anti-inflammatory treatment in selected patients.

title: Posterior reversible encephalopathy syndrome in infection, sepsis, and shock.
abstract: The cause of "posterior reversible encephalopathy syndrome" (PRES) is not established. We recently encountered several patients who developed PRES in the setting of severe infection. In this study, we comprehensively reviewed the clinical and imaging features in a large cohort of patients who developed PRES, with particular attention to those with isolated infection, sepsis, or shock (I/S/S).



The clinical/imaging features of 106 patients who developed PRES were comprehensively evaluated. In 25 of these patients, PRES occurred in association with severe I/S/S separate from transplantation. The clinical/imaging features (computer tomography, MR imaging, and MR angiography [MRA]) of the patients with I/S/S were further evaluated, including organ/tissue/blood culture results, mean arterial blood pressure (MAP) at toxicity, extent of cerebral edema, and presence of vasospasm.



PRES occurred in association with I/S/S in 25 of 106 patients (23.6%), in addition to 4 other major clinical settings, including cyclosporine/FK-506 (post-transplant) neurotoxicity (46.2%), autoimmune disease (10.4%), postchemotherapy (3.7%), and eclampsia (10.4%). In the 25 patients with I/S/S, available cultures demonstrated a predominance of gram-positive organisms (84%). Blood pressure was "normal" at toxicity in 10 patients (MAP, 95 mm Hg); "severe" hypertension was present in 15 patients (MAP, 137 mm Hg). Extent of brain edema graded on imaging studies was greater in the normal MAP group compared with the severe hypertension group (P < .05). MRA demonstrated vasospasm in patients with severe hypertension and vessel "pruning" in the normal MAP group.



Infection/sepsis/shock may be an important cause of PRES, particularly in relation to infection with gram-positive organisms.

title: Sepsis, Severe Sepsis, and Septic Shock
abstract: The sepsis syndrome represents the wide spectrum of the deleterious inflammatory response to an infectious insult. As the most common cause of mortality in the surgical intensive care unit, understanding the diagnosis and management of sepsis is critical for the surgical ICU physician. Early identification and aggressive resuscitation of the septic patient, combined with adequate surgical source control, can be lifesaving. Surgeons and critical care physicians who care for septic patients should be familiar with current evidence-based practices in the management of sepsis. Patients with organ system dysfunction and failure should be identified and appropriate support initiated. As more patients survive severe sepsis and septic shock, a syndrome of persistent inflammation, immune suppression, and catabolism has been identified and presents a new and difficult challenge for physicians.

title: dysfunction syndrome The role of the endothelium in severe sepsis and multiple organ
abstract: http://bloodjournal.hematologylibrary.org/content/101/10/3765.full.html Updated information and services can be found at: (409 articles) Review Articles  (972 articles) Phagocytes  (4846 articles) Immunobiology  (2497 articles) Hemostasis, Thrombosis, and Vascular Biology  (790 articles) Cell Adhesion and Motility  (746 articles) Apoptosis  Articles on similar topics can be found in the following Blood collections

title: Circulating endothelial cells in patients with septic shock.
abstract: The vascular endothelium has a central role in the control of microvascular tone, and it has been proposed that vascular endothelial damage occurs in septic shock, producing multiorgan failure. We have developed a method of detecting circulating endothelial cells (EC) that provides direct evidence of EC shedding in human sepsis. Human umbilical vein endothelial cells (HUVEC) were seeded in whole blood and recovered by isopycnic centrifugation to validate the technique. Blood samples were subsequently taken from 11 healthy volunteers, nine ventilated intensive care unit (ICU) control patients without sepsis, eight patients with sepsis but without shock, and 15 patients with septic shock. EC were identified by indirect immunofluorescence, using antibodies to von Willebrand factor (vWf) and the vascular endothelial growth factor receptor KDR. Mean HUVEC recovery was 86% for 20 to 100 seeded cells/ml of blood. vWf-positive EC counts per milliliter were significantly higher (analysis of variance [ANOVA], p < 0.0001) in patients with sepsis (16.1 +/- 2.7 [mean +/- SEM]) and septic shock (30.1 +/- 3.3) than in healthy (1.9 +/- 0.5) or ICU controls (2.6 +/- 0.6). KDR-positive EC counts per milliliter were also significantly higher (ANOVA, p < 0.0001) in patients with sepsis (4.2 +/- 1.1/ml) and septic shock (10.4 +/- 1.2/ml) than in healthy (0.7 +/- 0.3/ml) or ICU controls (0.5 +/- 0.2/ml). Cell counts made with anti-vWf antibody were consistently higher than those made with anti KDR antibody, but correlation between the two counts was high (r(2) = 0.93). The number of circulating KDR-positive EC was significantly higher in patients who died of septic shock than in survivors (12.0 +/- 1.6/ml versus 7.1 +/- 1.2/ml, p = 0.026). An increase in circulating EC can be identified during sepsis and septic shock. This supports the hypothesis that endothelial damage occurs in human sepsis.

title: Neutrophil and endothelial cell interactions in sepsis. The role of adhesion molecules.
abstract: Although adhesion molecules present on circulating neutrophils and endothelial cells are essential for normal host defense, generalized activation of these molecules has been implicated in the inflammatory tissue injury occurring during sepsis and septic shock. A review of both preclinical and clinical studies suggests, however, that although these molecules mediate tissue injury related to a variety of microbial and host inflammatory mediators, their predominant role during sepsis with infection is a protective one.

title: The microcirculation during endotoxemia.
abstract: The initial responses to endotoxemia are detectable in the microcirculation as a microvascular inflammatory response characterized by activation of the endothelium stimulating these cells from their normal anticoagulant state to a procoagulant state with increased adhesiveness for leukocytes and platelets. Concomitantly, arteriolar tone is lost and reactivity to a variety of agonists is modified. Tissue damage subsequently results not only from reduced perfusion of the exchange vessels, but also from injurious substances released from activated, sequestered leukocytes as well as activated endothelial cells, macrophages, and platelets. This is the result of endotoxins inducing activation and interaction of a number of effector cells, cascades, and acute-phase responses, such as the complement, coagulation, bradykinin/kinin, and hematopoietic systems accompanied by the release of a myriad of mediators. These include eicosanoids, cytokines, chemokines, adhesion molecules, reactive free radicals, platelet-activating factor, and nitric oxide. This paper briefly reviews the microvascular responses to endotoxemia and discusses some of the mechanisms involved.

title: Nitric oxide in the pathogenesis of sepsis.
abstract: In sepsis and septic shock, inflammatory mediators result in the production of increased concentrations of nitric oxide (NO) from the enzymatic breakdown of the amino acid L-arginine. The increased amounts of NO are responsible for changes in vasomotor tone, decreased vasopressor responsiveness, and decreased myocardial function, characteristic of septic insult. Therapeutic strategies designed to reduce the concentration of NO by inhibiting the action of the nitric oxide synthase enzyme, or by scavenging the excess NO, offer the potential to treat directly the vasomotor abnormalities and myocardial depression seen in sepsis and other inflammatory states. This article reviews the biology of NO in sepsis and discusses strategies for neutralization of the increased NO production, in the setting of severe sepsis and septic shock.

title: Structure and function of streptococcal and staphylococcal superantigens in septic shock.
abstract: The pyrogenic exotoxins of Group A Streptococci and enterotoxins of Staphylococcus aureus constitute a family of related toxins that acts as "superantigens" because of their ability to stimulate large numbers of T-cell subsets. These toxins have been implicated in gastrointestinal food poisoning, toxic shock syndromes, Gram-positive sepsis, and, possibly, septic shock. There is increasing evidence that Gram-positive infections frequently coexist in septic shock and that bacterial superantigens play a major role.

title: Bacterial pyrogenic exotoxins as superantigens
abstract: The recent discovery of the mode of interaction between a group of microbial proteins known as superantigens and the immune system has opened a wide area of investigation into the possible role of these molecules in human diseases. Superantigens produced by certain viruses and bacteria, including Mycoplasma species, are either secreted or membrane-bound proteins. A unique feature of these proteins is that they can interact simultaneously with distinct receptors on different types of cells, resulting in enhanced cell-cell interaction and triggering a series of biochemical reactions that can lead to excessive cell proliferation and the release of inflammatory cytokines. However, although superantigens share many features, they can have very different biological effects that are potentiated by host genetic and environmental factors. This review focuses on a group of secreted pyrogenic toxins that belong to the superantigen family and highlights some of their structural-functional features and their roles in diseases such as toxic shock and autoimmunity. Deciphering the biological activities of the various superantigens and understanding their role in the pathogenesis of microbial infections and their sequelae will enable us to devise means by which we can intervene with their activity and/or manipulate them to our advantage.

title: Gram-positive sepsis. Mechanisms and differences from gram-negative sepsis.
abstract: This article has reviewed the mechanisms by which gram-positive bacteria lead to septic shock, with regard to bacterial structure and toxicology and the host responses elicited both in animal models and in the clinical setting. Gram-positive organisms are better suited to invade host tissues and elicit, in general, a brisker phagocytic response than gram-negative organisms. The lack of endotoxin in the outer cell wall is compensated for by the presence of exposed peptidoglycan and a range of other toxic secreted products. It appears that cell wall components of gram-positive bacteria may signal via the same receptor as gram-negative endotoxin, although the type of signal and coreceptor may differ. Both animal and clinical data suggest that, unlike endotoxin-mediated shock, gram-positive infection produces a modest TNF response only and does not respond well to anti-TNF therapies. This leads one to conclude that the mechanisms leading to shock in gram-positive infection may be multifactorial and perhaps more difficult to treat. A thorough review of gram-positive mechanisms of sepsis is hampered by a lack of basic research in this field. Understanding of gram-negative bacterial structure and the regulation of virulence genes is at an advanced stage, yet the molecular tools to analyse virulence factors in the gram-positive genome have only recently become available. There is a paucity of good animal models of gram-positive infection and a lack of microbiologic data from some of the major trials in sepsis that might have given greater insight into the mechanisms leading to shock in various infections.

title: Male fetal progenitor cells persist in maternal blood for as long as 27 years postpartum.
abstract: Rare nucleated fetal cells circulate within maternal blood. Noninvasive prenatal diagnosis by isolation and genetic analysis of these cells is currently being undertaken. We sought to determine if genetic evidence existed for persistent circulation of fetal cells from prior pregnancies. Venous blood samples were obtained from 32 pregnant women and 8 nonpregnant women who had given birth to males 6 months to 27 years earlier. Mononuclear cells were sorted by flow cytometry using antibodies to CD antigens 3, 4, 5, 19, 23, 34, and 38. DNA within sorted cells, amplified by PCR for Y chromosome sequences, was considered predictive of a male fetus or evidence of persistent male fetal cells. In the 32 pregnancies, male DNA was detected in 13 of 19 women carrying a male fetus. In 4 of 13 pregnancies with female fetuses, male DNA was also detected. All of the 4 women had prior pregnancies; 2 of the 4 had prior males and the other 2 had terminations of pregnancy. In 6 of the 8 nonpregnant women, male DNA was detected in CD34+CD38+ cells, even in a woman who had her last son 27 years prior to blood sampling. Our data demonstrate the continued maternal circulation of fetal CD34+ or CD34+CD38+ cells from a prior pregnancy. The prolonged persistence of fetal progenitor cells may represent a human analogue of the microchimerism described in the mouse and may have significance in development of tolerance of the fetus. Pregnancy may thus establish a long-term, low-grade chimeric state in the human female.

title: Identification of fetal DNA and cells in skin lesions from women with systemic sclerosis.
abstract: Systemic sclerosis is a disease of unknown origin which often occurs in women after their childbearing years. It has many clinical and histopathological similarities to chronic graft-versus-host disease. Recent studies indicate that fetal stem cells can survive in the maternal circulation for many years post partum. This finding suggests that fetal cells persisting in the maternal circulation or tissues could be involved in the pathogenesis of systemic sclerosis by initiating a graft-versus-host reaction.



We used the polymerase chain reaction (PCR) to identify Y-chromosome sequences in DNA extracted from peripheral-blood cells and skin lesions from women with systemic sclerosis of recent onset. To confirm the PCR findings, we used fluorescence in situ hybridization of peripheral-blood cells and cells within chronic inflammatory-cell infiltrates in biopsy specimens of affected skin.



Y-chromosome sequences were found in DNA from peripheral-blood cells in 32 of 69 women with systemic sclerosis (46 percent), as compared with 1 of 25 normal women (4 percent, P<0.001), and in T lymphocytes from 3 women with systemic sclerosis who had male offspring. Furthermore, Y-chromosome sequences were identified in skin-biopsy specimens from 11 of 19 women with systemic sclerosis (58 percent); 9 of the 11 were known to have carried male fetuses. Nucleated cells containing Y chromosomes were detected by fluorescence in situ hybridization in paraffin-embedded sections of skin lesions from all seven women we tested whose skin-biopsy specimens contained Y-chromosome sequences.



Fetal antimaternal graft-versus-host reactions may be involved in the pathogenesis of systemic sclerosis in some women.

title: MR angiography of cerebral vasospasm in preeclampsia.
abstract: Cerebral vasospasm was demonstrated with MR angiography in a patient with preeclampsia. MR angiography 5 days after the onset of symptoms clearly demonstrated diffuse intracranial vasospasm. The follow-up study confirmed the resolution of vasospasm successfully.

title: Prolonged reversible vasospasm in cyclosporin A-induced encephalopathy.
abstract: The mechanisms responsible for cyclosporin-induced encephalopathy remain controversial. Herein we present a case of cyclosporin-induced encephalopathy with unusually prolonged vasospasm, which might have contributed to the slow recovery of the patient.

title: Cyclosporin A-related cerebral vasculopathy
abstract: The use of cyclosporin A has been associated with several side-effects, including neurotoxicity. The mechanism of toxicity is not well known. We report two patients treated with cyclosporin A who developed lesions in the cerebral white matter associated with abnormally elevated cerebral blood flow velocities on transcranial doppler ultrasound and abnormal vascular appearance on magnetic resonance angiography. Bone Marrow Transplantation (2000) 26, 801–804.

title: Vascular Permeability Factor/Vascular Endothelial Cell Growth Factor-mediated Permeability Occurs through Disorganization of Endothelial Junctional Proteins*
abstract: Vascular permeability factor/vascular endothelial growth factor stimulates endothelial proliferation, angiogenesis, and increased vascular permeability in vivo. We investigated mechanisms of vascular permeability factor-mediated endothelial monolayer permeability changes in vitro. [14C]Albumin flux across endothelial monolayers was measured following a 90-min exposure to vascular permeability factor (660 pm). Vascular permeability factor increased albumin flux to 3.4 times that of control albumin flux. Endothelial monolayers were also incubated for 90 min with vascular permeability factor plus Gö6976 (10 nm), staurosporine (1 μm), wortmannin (10 nm), AG126 (1 and 2.67 μm), and PD98059 (20 μm). Vascular permeability factor-mediated permeability was not blocked by Gö6976, an antagonist of “classical” protein kinase C, staurosporine, a pan-protein kinase C antagonist, nor wortmannin, a PI3-kinase blocker, but was blocked by incubation with AG126 or PD98059, inhibitors of mitogen-activated protein kinase activation. Immunofluorescent staining of the junctional proteins VE-cadherin and occludin showed a loss of these proteins from the endothelial junction that was prevented by co-incubation with AG126 or PD98059. These data demonstrate that vascular permeability factor increases albumin permeability across endothelial monolayers in vitro and suggests that permeability increases through rearrangement of endothelial junctional proteins involving the mitogen-activated protein kinase signal transduction pathway.

title: Transcriptional Regulation of the Rat Vascular Endothelial Growth Factor Gene by Hypoxia (*)
abstract: Vascular endothelial growth factor (VEGF), a potent angiogenic factor and endothelial cell-specific mitogen, is up-regulated by hypoxia. However, the mechanism(s) responsible for hypoxic induction of VEGF has not been clearly delineated. We report that the steady state VEGF mRNA levels are increased 12 ± 0.6-fold, but the transcriptional rate for VEGF is increased only 3.1 ± 0.6-fold by hypoxia in PC12 cells. In order to investigate cis-regulatory sequences which mediate this response to hypoxia, we cloned the rat genomic sequences encoding VEGF and identified a 28-base pair element in the 5′ promoter that mediates hypoxia-inducible transcription in transient expression assays. This element has sequence and protein binding similarities to the hypoxia-inducible factor 1 binding site within the erythropoietin 3′ enhancer. Post-transcriptional mechanisms have also been suggested to play a role in the hypoxic induction of VEGF. Evidence is provided that a frequently used polyadenylation site is 1.9 kilobases downstream from the translation termination codon for rat VEGF. This site is 1.5 kilobases further downstream from the polyadenylation site previously reported for VEGF. This new finding reveals sequence motifs in the 3′-untranslated region that may mediate VEGF mRNA stability.

title: Expression of hypoxia-inducible factor-1alpha in the brain of rats during chronic hypoxia.
abstract: Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that regulates adaptive responses to the lack of oxygen in mammalian cells. HIF-1 consists of two proteins, HIF-1alpha and HIF-1beta. HIF-1alpha accumulates under hypoxic conditions, whereas HIF-1beta is constitutively expressed.  Immunostaining showed that neurons, astrocytes, ependymal cells, and possibly endothelial cells were the cell types expressing HIF-1alpha. Genes with hypoxia-responsive elements were activated under these conditions, as evidenced by elevated vascular endothelial growth factor and glucose transporter-1 mRNA levels. When 21-day-adapted rats were exposed to a more severe hypoxic challenge (8% oxygen), HIF-1alpha accumulated again. On the basis of these results, we speculate that the vascular remodeling and metabolic changes triggered during prolonged hypoxia are capable of restoring normal tissue oxygen levels.

title: MR imaging, MR angiography, and MR spectroscopy of the brain in eclampsia.
abstract: To compare the MR imaging and MR angiographic changes with in vivo proton MR spectroscopic findings and to determine the spectral differences between edema and ischemia in patients with eclampsia.



Spin-echo MR imaging, MR angiography, and single-voxel proton MR spectroscopy were performed in 10 patients with eclampsia. MR studies were obtained within 3 to 5 days of diagnosis and repeated after 2 weeks with identical parameters.



Multifocal subcortical/cortical hyperintensities were noted in all 10 patients on T2-weighted images; in two patients, hyperintensities were seen in both cerebral hemispheres. In nine patients, MR angiograms showed narrowing of the major vessels constituting the circle of Willis that resolved after 2 weeks. In one patient with subtle imaging changes, MR angiography showed mild bilateral narrowing of the proximal middle and posterior cerebral arteries that did not change after 2 weeks, whereas imaging abnormalities worsened. Findings at single-voxel MR spectroscopy of the reversible T2 hyperintense lesions were significantly different from findings in the control group for N-acetylaspartate (NAA)/creatine ratios. One patient with mild abnormalities at MR imaging and MR angiography had lactate and decreased creatine and NAA, and on a follow-up study had a further decrease of NAA and creatine as well as a decrease in lactate.



In vivo proton MR spectroscopy may help to differentiate cerebral edema from ischemia in patients with eclampsia and thus may help to determine the prognosis for these patients.

title: Magnesium Sulfate in Aneurysmal Subarachnoid Hemorrhage: A Randomized Controlled Trial
abstract: Magnesium reverses cerebral vasospasm and reduces infarct volume after experimental subarachnoid hemorrhage (SAH) in rats. We aimed to assess whether magnesium reduces the frequency of delayed cerebral ischemia (DCI) in patients with aneurysmal SAH.  Patients were randomized within 4 days after SAH. Magnesium sulfate therapy consisted of a continuous intravenous dose of 64 mmol/L per day, to be started within 4 days after SAH and continued until 14 days after occlusion of the aneurysm. The primary outcome DCI (defined as the occurrence of a new hypodense lesion on computed tomography compatible with clinical features of DCI) was analyzed according to the “on-treatment” principle. For the secondary outcome measures “poor outcome” (Rankin >3) and “excellent outcome” (Rankin 0), we used the “intention-to-treat” principle.  A total of 283 patients were randomized. Magnesium treatment reduced the risk of DCI by 34% (hazard ratio, 0.66; 95% CI, 0.38 to 1.14). After 3 months, the risk reduction for poor outcome was 23% (risk ratio, 0.77; 95% CI, 0.54 to 1.09). At that time, 18 patients in the treatment group and 6 in the placebo group had an excellent outcome (risk ratio, 3.4; 95% CI, 1.3 to 8.9).  This study suggests that magnesium reduces DCI and subsequent poor outcome, but the results are not yet definitive. A next step should be a phase III trial to confirm the beneficial effect of magnesium therapy, with poor outcome as primary outcome.

title: Magnesium sulfate reverses experimental delayed cerebral vasospasm after subarachnoid hemorrhage in rats.
abstract: We induced experimental delayed cerebral vasospasm by the intracisternal injection of greater than 0.5 ml blood in 30 rats. Seventy-two hours later the basilar artery was exposed via the transclival approach and photographed at high-power magnification through an operating microscope. We then evaluated the effect of topical (n = 30) and intravenous (n = 20) magnesium sulfate on the spastic artery by computerized image analysis. A greater than 50% reduction in baseline diameter of the basilar artery was observed in the rats subjected to subarachnoid hemorrhage compared with the 10 controls (p less than 0.0001). Intravenous magnesium sulfate dilated the spastic artery to approximately 75% of the baseline diameter in control rats (p less than 0.0001). Topical magnesium sulfate caused dramatic dilation of the basilar artery in both the control and the subarachnoid hemorrhage groups to near 150% of the baseline diameter in the controls (p less than 0.001). All rats receiving intravenous magnesium sulfate reached therapeutic plasma levels of the ion. Hemodynamic effects were mild and immediately reversible upon cessation of magnesium sulfate administration. We suggest that magnesium has a role in the treatment of subarachnoid hemorrhage-induced vasospasm in humans.