Background and Purpose A primary goal of acute ischemic stroke (AIS) management is to maximize perfusion in the affected region and surrounding ischemic penumbra. However, interventions to maximize perfusion, such as flat head-of-bed (HOB) positioning, are currently prescribed empirically. Bedside monitoring of cerebral blood flow (CBF) allows the effects of interventions such as flat HOB to be monitored, and may ultimately be used to guide clinical management. Methods Cerebral perfusion was measured during head of bed (HOB) manipulations in 17 patients with unilateral acute ischemic stroke affecting large cortical territories in the anterior circulation. Simultaneous measurements of frontal CBF and arterial flow velocity were performed with diffuse correlation spectroscopy (DCS) and transcranial Doppler ultrasound, respectively. Results were analyzed in the context of available clinical data and a previous study. Results Frontal CBF, averaged over the patient cohort, decreased by 17% (p=0.034) and 15% (p=0.011) in the ipsilesional and contralesional hemispheres, respectively, when HOB was changed from flat to 30°. Significant (cohort-averaged) changes in blood velocity were not observed. Individually, varying responses to HOB manipulation were observed, including paradoxical increases in CBF with increasing HOB angle. Clinical features, stroke volume, and distance to the optical probe could not explain this paradoxical response. Conclusions A lower HOB angle results in an increase in cortical CBF without a significant change in arterial flow velocity in AIS, but there is variability across patients in this response. Bedside CBF monitoring with DCS provides a potential means to individualize interventions designed to optimize CBF in AIS.

A pilot study explores relative contributions of extra-cerebral (scalp/skull) versus brain (cerebral) tissues to the blood flow index determined by diffuse correlation spectroscopy (DCS). Microvascular DCS flow measurements were made on the head during baseline and breath-holding/hyperventilation tasks, both with and without pressure. Baseline (resting) data enabled estimation of extra-cerebral flow signals and their pressure dependencies. A simple two-component model was used to derive baseline and activated cerebral blood flow (CBF) signals, and the DCS flow indices were also cross-correlated with concurrent Transcranial Doppler Ultrasound (TCD) blood velocity measurements. The study suggests new pressure-dependent experimental paradigms for elucidation of blood flow contributions from extra-cerebral and cerebral tissues.

Injury to the blood-brain barrier (BBB) is a key feature of intracerebral hemorrhage (ICH) and may contribute to perihematomal cell injury. Pretreatment with the heme oxygenase (HO)-1 inducer hemin improves barrier function and neurological outcome in experimental models of traumatic and ischemic CNS injury. Since hemin is already in clinical use to treat acute porphyrias, this translational study was designed to test its effect on BBB function when initiated after ICH in two mouse models. At a dose similar to those used in most preconditioning studies (26 mg/kg i.p.), post-hemorrhage treatment with hemin reduced parenchymal extravasation of Evans blue by about three-quarters in both the blood injection and collagenase ICH models. Similar efficacy was observed when treatment was begun at one or three hours. At the lower dose that is currently in clinical use (4 mg/kg beginning at 3 hours), hemin also improved barrier function in both models, as assessed by both Evans blue and FITC-dextran leakage; however, it was somewhat less potent, reducing Evans blue leakage by about half. This dose was nevertheless sufficient to attenuate striatal cell loss and accelerate neurological recovery. Consistent with prior observations, striatal HO-1 expression was increased by hemin, and was localized to perivascular cells. These results suggest that hemin may be an effective therapy for ICH with a clinically relevant time window. Further study of the repurposing of this old drug seems warranted.

Neuronal loss in tissue surrounding an intracerebral hemorrhage (ICH) is usually quantified by labor-intensive histological methods that are subject to bias. Fluorescent protein expression has been successfully used as a marker of cell viability in vitro and in retinal studies in vivo, but not in any ICH model to date. The potential of this approach was investigated using transgenic mice that constitutively express the red fluorescent protein variant dTomato in central neurons under the control of the Thy1 promoter. Breeding and growth of these mice were similar to their wild-type counterparts; behavioral phenotyping by digital analysis of home cage video recordings detected no differences. Bright fluorescence was evident in fresh brain samples with minimal background fluorescence, and was reduced in tissue surrounding the hematoma. In order to assess fluorescence loss as an injury marker in a planned study, these mice were crossed with heme oxygenase (HO)-2 knockouts and wild-type controls; striatal hemorrhage was induced by stereotactic injection of collagenase. Fluorescence in hemorrhagic striata was reduced to 86.4±3.9%, 62.2±5.1%, and 58.3±3.0% of contralateral on days 1, 4 and 8, respectively, and correlated closely with reduction in striatal cell viability as quantified by MTT assay. HO-2 knockout and wild-type values did not differ significantly. Similar results were observed with stereological cell counts of striatal neurons identified by NeuN immunoreactivity. These results suggest that loss of constitutive dTomato fluorescence is an accurate and efficient marker of neuronal loss in tissue surrounding a striatal hematoma.

Obtaining clear margins by craniofacial resection is essential to the management of adenocarcinoma of the ethmoid sinuses. Radiotherapy is reserved for positive margins, cribriform plate penetration, dural invasion, and high-grade lesions that are close to the cribriform plate. Local control was obtained in 87% of our patients.

Heat shock proteins (HSPs) are a family of polypeptides which are induced in response to diverse forms of cell injury including hyperthermia, anoxia, ethanol, heavy metals, and others, with a presumably protective function. Among several species of HSPs, the 70 kD protein (HSP70) is the most abundant and consistently induced in mammalian cells. Anti‐HSP70 monoclonal antibody and a standard immunocytochemical method were used to study the expression of HSP70 in 28 surgical specimens of small and large intestines from patients with ischaemic bowel disease. Strong immunoreactivity was observed in viable, regenerating cells of both the crypt and surface epithelium within or adjacent to the necrotic foci in 86 per cent of the ischaemic bowel specimens. Staining was mostly cytoplasmic, but focally both cytoplasmic and nuclear. Smooth muscle cells of the muscularis mucosae in the ischaemic areas of some cases also showed immunoreactivity. On the other hand, HSP70 was not expressed in control specimens of small and large intestine or in colonic specimens of Crohn's disease, ulcerative colitis, and adenocarcinoma. These findings suggest a possible role of HSP70 in intestinal epithelial and smooth muscle cell response to ischaemic injury, especially in the recovery phase.

Intracerebral hemorrhage (ICH) is the primary event in approximately 10% of strokes, and has higher rates of morbidity and mortality than ischemic stroke. Experimental evidence suggests that the toxicity of hemoglobin and its degradation products contributes to secondary injury that may be amenable to therapeutic intervention. Hemin, the oxidized form of heme, accumulates in intracranial hematomas to cytotoxic levels. The rate limiting step of its breakdown is catalyzed by the heme oxygenase (HO) enzymes, which consist of inducible HO-1 and constitutively-expressed HO-2. The effect of these enzymes on perihematomal injury and neurological outcome has been investigated in ICH models using both genetic and pharmacological approaches to alter their expression, with variable results reported. These findings are summarized and reconciled in this review; therapeutic strategies that may optimize HO expression and activity after ICH are described.

Hemin accumulates in intracerebral hematomas and may contribute to cell injury in adjacent tissue. Despite its relevance to hemorrhagic CNS insults, very little is known about hemin trafficking by neural cells. In the present study, hemin uptake and release were quantified in primary murine cortical cultures, and the effect of the hemin-binding compound deferoxamine (DFO) was assessed. Net uptake of 55Fe-hemin was similar in mixed neuron-glia, neuron, and glia cultures, but was 2.6–3.6-fold greater in microglia cultures. After washout, 40–60% of the isotope signal was released by mixed neuron-glia cultures into albumin-containing medium within 24 hours. Inhibiting hemin breakdown with tin protoporphyrin IX (SnPPIX) had minimal effect, while release of the fluorescent hemin analog zinc mesoporphyrin was quantitatively similar to that of 55Fe-hemin. Isotope was released most rapidly by neurons (52.2±7.2% at 2 hours), compared with glia (15.6±1.3%) and microglia (17.6±0.54%). DFO did not alter 55Fe-hemin uptake, but significantly increased its release. Mixed cultures treated with 10 μM hemin for 24 hours sustained widespread neuronal loss that was attenuated by DFO. Concomitant treatment with SnPPIX had no effect on either enhancement of isotope release by DFO or neuroprotection. These results suggest that in the presence of a physiologic albumin concentration, hemin uptake by neural cells is followed by considerable extracellular release. Enhancement of this release by DFO may contribute to its protective effect against hemin toxicity.