Application of Blood-Brain Barrier Permeability Imaging in Global Cerebral Edema.

BACKGROUND AND PURPOSE: Blood-brain barrier permeability is not routinely evaluated in the clinical setting. Global cerebral edema occurs after SAH and is associated with BBB disruption. Detection of global cerebral edema using current imaging techniques is challenging. Our purpose was to apply blood-brain barrier permeability imaging in patients with global cerebral edema by using extended CT perfusion. MATERIALS AND METHODS: Patients with SAH underwent CTP in the early phase after aneurysmal rupture (days 0-3) and were classified as having global cerebral edema or nonglobal cerebral edema using established noncontrast CT criteria. CTP data were postprocessed into blood-brain barrier permeability quantitative maps of PS (permeability surface-area product), K(trans) (volume transfer constant from blood plasma to extravascular extracellular space), Kep (washout rate constant of the contrast agent from extravascular extracellular space to intravascular space), VE (extravascular extracellular space volume per unit of tissue volume), VP (plasmatic volume per unit of tissue volume), and F (plasma flow) by using Olea Sphere software. Mean values were compared using t tests. RESULTS: Twenty-two patients were included in the analysis. Kep (1.32 versus 1.52, P < .0001), K(trans) (0.15 versus 0.19, P < .0001), VP (0.51 versus 0.57, P = .0007), and F (1176 versus 1329, P = .0001) were decreased in global cerebral edema compared with nonglobal cerebral edema while VE (0.81 versus 0.39, P < .0001) was increased. CONCLUSIONS: Extended CTP was used to evaluate blood-brain barrier permeability in patients with SAH with and without global cerebral edema. Kep is an important indicator of altered blood-brain barrier permeability in patients with decreased blood flow, as Kep is flow-independent. Further study of blood-brain barrier permeability is needed to improve diagnosis and monitoring of global cerebral edema.

Evaluating Permeability Surface-Area Product as a Measure of Blood-Brain Barrier Permeability in a Murine Model.

BACKGROUND AND PURPOSE: Permeability surface-area product has been suggested as a marker for BBB permeability with potential applications in clinical care and research. However, few studies have demonstrated its correlation with actual quantitative measurements of BBB permeability. Our aim was to demonstrate the correlation of quantitative permeability surface-area product and BBB permeability in a murine model by histologic confirmation. MATERIALS AND METHODS: Coronal MR imaging was performed on mice treated with mannitol (n = 6) for disruption of the BBB and controls treated with saline (n = 5). Permeability surface-area product was determined by ROI placement and was compared between saline- and mannitol-treated mice. Correlation was made with contrast-enhancement measurements and immunohistologic-stained sections of tripeptidyl peptidase-1 distribution in mice treated with mannitol and saline followed by injection of a viral vector containing the CLN2 gene, which directs production of tripeptidyl peptidase-1. RESULTS: Significantly increased permeability surface-area product was seen in mannitol- compared with saline-treated mice in the whole brain (P = .008), MCA territory (P = .014), and mixed vascular territories (P = .008). These findings were compared with contrast-enhancement measurements of BBB permeability and were correlated with immunohistologic-stained sections demonstrating BBB permeability to a large vector. CONCLUSIONS: Permeability surface-area product is increased in situations with known disruptions of the BBB, as evidenced by immunologic staining of large-vector passage through the BBB and concordance with contrast-enhancement measurements in a murine model. Quantitative permeability surface-area product has potential as an imaging marker of BBB permeability.

Penetrating trauma to the diaphragm: natural history and ultrasonographic characteristics of untreated injury in a pig model.

HYPOTHESIS: Recent use of minimally invasive techniques to evaluate the chest and abdomen in patients with penetrating thoracoabdominal trauma has led to the discovery of many occult diaphragm injuries. Surgical repair of these injuries is relatively straightforward. However, diagnosis can be difficult, and the natural history of these injuries is controversial. By developing a penetrating diaphragm injury model, the ultrasonographic characteristics and natural history of this injury can be better understood. SETTING: Surgical laboratory of a tertiary care hospital. SUBJECTS: Seven pigs (Sus scrofa), weighing between 55 and 80 kg, received a 3-cm right-sided (n = 3) or left-sided (n = 4) diaphragm injury via thoracoscopy. INTERVENTIONS: Thoracoabdominal x-ray and ultrasonographic examinations were performed preoperatively; at 2, 4, 8, and 12 weeks postoperatively; and when symptoms related to the diaphragm injury occurred. At 12 weeks, or at the time of earlier death, a postmortem thoracoabdominal examination was performed. MAIN OUTCOME MEASURES: x-Ray and ultrasonographic characteristics, and evidence of wound healing, in a penetrating diaphragm injury model. RESULTS: Perioperative recovery occurred in all pigs. No pigs had radiographic evidence of immediate postoperative herniation. Pigs in the right-sided injury group died early (

Utilization of commercial laboratory results in management of hyperandrogenism in women.

OBJECTIVE: To compare results from testosterone radioimmunoassay kits commonly used by commercial laboratories as well as their reference ranges and to analyze the scientific literature for ranges of serum testosterone levels in normal women and those with hyperandrogenism. METHODS: We reviewed quality assurance reports of various testosterone ligand challenges from four groups of laboratories and summarized testosterone data from 17 published reports about normal women and 14 studies of hyperandrogenic women. RESULTS: A significant variability was demonstrated between the radioimmunoassay kits at all concentrations (for example, a sample with a mean testosterone level of 96.1 ng/dL was reported by some laboratories as containing 71.8 ng/dL and by others as 123.4 ng/dL). All laboratories provide essentially the same "reference range" (approximately 10 to 90 ng/dL) but do not report how the range was established. The scientific literature clearly shows a significant separation in serum testosterone levels between normal (that is, not hyperandrogenic) and hyperandrogenic women. Most hyperandrogenic women had testosterone levels >50 ng/dL, whereas most normal control subjects had levels <40 ng/dL. Thus, most of these women with hyperandrogenism would have been considered to have normal testosterone levels if the reference ranges of commercial laboratories were used. CONCLUSION: These data illustrate the difficulty that physicians face when they are required to use different commercial laboratories to measure serum testosterone levels. We propose that (1) reference ranges be established on a clinically defined population for each hormone and method used, (2) laboratory reports include information about method and reference range population, and (3) physicians be allowed to choose which laboratories are used for their patients' hormone determinations, for consistency of results.

Results of the 1996 survey of the American Association of Academic Chief Residents in Radiology.

RATIONALE AND OBJECTIVES: Diagnostic radiology chief residents were surveyed on issues related to residency training to compare features and gauge trends in training. METHODS: Questionnaires were mailed to accredited programs in the United States. A variety of demographic and common-interest questions were asked. RESULTS: Forty-three percent of surveys were returned. The percentage of female residents was similar to that reported in other recent surveys; however, the percentage of women among 1st-year residents had decreased. Resident salaries had increased, although the average salary for a 4th-year resident had decreased when adjusted for inflation. Most 1st-year residents started participating in overnight hospital coverage by their 12th month of residency, and the total number of call days during residency correlated inversely with the size of the residency program. Almost half of residency programs used a night-float resident to provide after-hours coverage. CONCLUSION: The information derived from the survey should be useful for program evaluation and future planning.

Advanced glycation endproducts (AGEs) induce oxidant stress in the gingiva: a potential mechanism underlying accelerated periodontal disease associated with diabetes.

We hypothesized that one mechanism underlying advanced periodontal disease in diabetes may involve oxidant stress in the gingiva, induced by the effects of Advanced Glycation Endproducts (AGEs), the irreversible products of non-enzymatic glycation and oxidation of proteins and lipids which accumulate in diabetic plasma and tissue. Infusion of AGE albumin, a prototypic ligand, into mice resulted in increased generation of thiobarbituric acid reactive substances (TBARS) compared with infusion of non-glycated albumin in the gingiva, as well as in the lung, kidney and brain. Pretreatment of the animals with the antioxidants probucol or N-acetylcysteine (NAC) prevented the generation of TBARS in the gingiva. Affinity-purified antibody to AGEs demonstrated increased immunoreactivity for AGEs in the vasculature and connective tissues of the gingiva in streptozotocin-induced diabetic mice compared to non-diabetic controls. Increased immunoreactivity for AGEs was also demonstrated in the gingiva of diabetic humans compared with non-diabetic individuals via immunohistochemistry and ELISA. Consistent with these data, immunohistochemistry for heme oxygenase-1, a marker of enhanced oxidant stress, was increased in the gingival vasculature of diabetic mice and humans compared with non-diabetic controls. These data suggest that AGEs present in diabetic gingiva may be associated with a state of enhanced oxidant stress, a potential mechanism for accelerated tissue injury.

BAEPs in infants with myelomeningocele and later development of Chiari II malformation-related brainstem dysfunction.

Thirty-seven infants with myelomeningocele received brainstem auditory evoked potentials (BAEPs) at a median age of eight days. No infant had brainstem dysfunction at the time of testing. Median follow-up was at 30 months. Of 12 infants who subsequently developed brainstem dysfunction at a median age of three months, 11 had had abnormal neonatal BAEPs. In contrast, only 10 of 25 infants who did not develop brainstem dysfunction had abnormal BAEPs. The mean average I-V interpeak latencies was greater among those who developed symptoms than among those who did not. Neonatal BAEPs can identify a group of asymptomatic infants with myelomeningocele who need close follow-up for the subsequent development of brainstem dysfunction.

Survey of the distribution of a newly characterized receptor for advanced glycation end products in tissues.

Advanced glycation end products (AGEs), the final products of nonenzymatic glycation and oxidation of proteins, are found in the plasma and accumulate in the tissues during aging and at an accelerated rate in diabetes. A novel integral membrane protein, termed receptor for AGE (RAGE), forms a central part of the cell surface binding site for AGEs. Using monospecific, polyclonal antibody raised to human recombinant and bovine RAGE, immunostaining of bovine tissues showed RAGE in the vasculature, endothelium, and smooth muscle cells and in mononuclear cells in the tissues. Consistent with these data, RAGE antigen and mRNA were identified in cultured bovine endothelium, vascular smooth muscle, and monocyte-derived macrophages. RAGE antigen was also visualized in bovine cardiac myocytes as well as in cultures of neonatal rat cardiac myocytes and in neural tissue where motor neurons, peripheral nerves, and a population of cortical neurons were positive. In situ hybridization confirmed the presence of RAGE mRNA in the tissues, and studies with rat PC12 pheochromocytes indicated that they provide a neuronal-related cell culture model for examining RAGE expression. Pathological studies of human atherosclerotic plaques showed infiltration of RAGE-expressing cells in the expanded intima. These results indicate that RAGE is present in multiple tissues and suggest the potential relevance of AGE-RAGE interactions for modulating properties of the vasculature as well as neural and cardiac function, prominent areas of involvement in diabetes and in the normal aging process.

Muscle activity localization with 31P spectroscopy and calculated T2-weighted 1H images.

Using 31P spectroscopy and magnetic resonance imaging (MRI), the authors studied changes in muscle phosphorous metabolites and T2 with isometric knee extension to evaluate the potential role of T2 images in coil placement for exercise spectroscopy studies. Increased signal intensity was visible in active muscles on T2 images after exercise. Calculated T2-weighted values were elevated immediately after exercise in the quadriceps (P less than .01). T2 increases for individual quadricep muscles varied, with the largest changes in the rectus femoris and the least in the vastus lateralis. 31P spectroscopy studies demonstrated similar findings: percent change in T2 correlated positively with inorganic phosphorus to phosphocreatine ratio (Pi/PCr) (r = 0.89, P less than .01) and negatively with pH (r = -0.88, P less than .01). The correlations between imaging and spectroscopy suggest that T2 images may allow more precise placement of phosphorous coils in exercise studies. The heterogeneity of T2 changes within the quadriceps with exercise suggests that assumptions about muscle activity may be misleading. T2 images may provide muscle activity verification for exercise studies.

Glucocorticoid therapy in hyperandrogenism.

Hyperandrogenism is a common disorder in the reproductive age female. It is associated with cutaneous manifestations and ovulatory dysfunction. The degree of hyperandrogenaemia is directly related to the severity of ovulatory dysfunction. The ovulatory dysfunction frequently leads to infertility. The most common form of hyperandrogenism is idiopathic glucocorticoid-suppressible hyperandrogenism (IGSH). The management of this disorder involves appropriate use of physiological doses of glucocorticoids. This treatment leads not only to normalization of serum androgen levels but also to amelioration of cutaneous symptoms and improvement in ovulatory function. In infertile women with ovulatory dysfunction secondary to IGSH, occurrence of pregnancy after treatment with glucocorticoids is directly related to the degree of the suppression of serum androgen levels. In other words, this treatment does not 'induce ovulation', but its effectiveness in improving ovulatory function is a result of a correction of the hyperandrogenic state. At physiological doses glucocorticoid therapy does not appear to be associated with significant side-effects. With appropriate management, androgen levels can be maintained within the normal range indefinitely. Furthermore, in a majority of patients, androgen levels remain within the normal range for a long time (years) after discontinuation of chronic glucocorticoid therapy.

The distribution of cells killed by Trichinella spiralis in the mucosal epithelium of two strains of mice.

Dead and dying cells were localized by light microscopy in the mucosal epithelium of the intestine of an outbred strain (CD1) and an inbred strain (B10A) of mice by vital staining with the dye, trypan blue. In whole mounts of the intestinal wall, trails, or variable-sized clusters of blue-stained cells were seen throughout the course of infection and in mice given a range of inoculum levels. In CD1 mice, irregular trails of dead cells were seen in the intestine floor and clusters of them along the villi. In B10A mice, dead cells were seen only as trails or clusters in the intestinal floor. The results suggest that worms move through the epithelium only in the intestinal floor. Cells killed by this activity may be sloughed from the epithelium more rapidly by B10A mice than by CD1 mice where the dead cells migrate up villi before being sloughed.

Release of somatomedin-like activity by cultured WI-38 human fibroblasts.

Confluent cultures of normal diploid WI-38 human embryonic lung fibroblasts released somatomedin (SM)-like activity into their incubation medium during culture in serum-free medium. This postculture medium (conditioned medium) stimulated cell division in these same cultured WI-38 fibroblasts and 35SO4 uptake by hypophysectomized rat cartilage in vitro. The conditioned medium also contained immunoreactive SM (IRSM) activity which yielded parallel dose-response curves to human serum in a RIA for SM. The IRSM activity measured in conditioned medium was not the artifactual result of effects of possible SM-binding proteins or proteolytic enzymes in conditioned medium. These studies suggest that cultured WI-38 fibroblasts produce and release SM-like activity which has SM-like biological activity and is immunoreactive with a basic SM purified from human plasma Cohn fraction and having similarity with SM-C and insulin-like growth factor-I. Human GH appears to stimulate production and release of IRSM activity by these cells.

Hormonal regulation of initiation of DNA synthesis and of differentiated function in Y-1 adrenal cortical cells.

ACTH, 8-Br-cAMP, and serum deprivation arrested Y-1 functional mouse adrenal tumor cells in the G1 phase of the cell cycle. Though ACTH and 8-Br-cAMP treated cells were larger with increased macromolecular synthetic rates compared to cells arrested in G1 by serum removal, a similar 8- to 10-hours lag to initiation of DNA synthesis was observed after either ACTH or 8-Br-cAMP removal or after serum addition. After the 8- to 10-hour lag period, cells entered S phase exponentially. ACTH or 8-Br-cAMP opposed serum induced DNA synthesis initiation only when added prior to S. Once commitment to DNA synthesis occurred, ACTH or 8-Br-cAMP addition did not inhibit DNA synthesis although 8-Br-cAMP induced a secondary block in G2. Though ACTH and 8-Br-cAMP inhibited serum induced initiation of DNA synthesis and did not affect serum induced cellular hypertrophy, both substances increased the steroidogenic capacity of the cell. ACTH and 8-Br-cAMP thus appear to specifically oppose the stimulatory effects of serum on initiation of DNA synthesis while inducing the differentiated function of the cell.