MR Imaging Characteristics of Intraocular Perfluoro-n-Octane.

We describe the unique MR imaging characteristics of intraocular perfluoro-n-octane, a liquid used for intraoperative and postoperative tamponade in the context of complex retinal detachment repair, and contrast it with other intraocular pathologies. Because trace amounts of perfluoro-n-octane may be left in the globe postoperatively, it may be confused for other abnormalities, such as foreign bodies or tumors.

Physical inactivity and knee osteoarthritis in guinea pigs.

OBJECTIVE: To investigate whether and how a sedentary lifestyle contributes to knee osteoarthritis (OA) incidence and severity. DESIGN: An experiment was conducted using Hartley guinea pigs, an established idiopathic knee OA model. To simulate a sedentary lifestyle, growing animals (n = 18) were housed for 22 weeks in small cages that restricted their mobility, while another group of animals (n = 17) received daily treadmill exercise to simulate moderate physical activity. After the experiment, histological assessments, biochemical assays, and mechanical testing were conducted to compare tibial articular cartilage structure, strength, and degree of OA degeneration between sedentary and physically active animals. Groups were also compared based on body weight and composition, as well as gut microbial community composition assessed using fecal 16S rRNA gene sequencing. RESULTS: Prevalence of knee OA was similar between sedentary and physically active animals, but severity of the disease (cartilage lesion depth) was substantially greater in the sedentary group (P = 0.02). In addition, during the experiment, sedentary animals developed cartilage with lower aggrecan quantity (P = 0.03) and accumulated more body weight (P = 0.005) and visceral adiposity (P = 0.007). Groups did not differ greatly, however, in terms of cartilage thickness, collagen quantity, or stiffness, nor in terms of muscle weight, subcutaneous adiposity, or gut microbial community composition. CONCLUSIONS: Our findings indicate that a sedentary lifestyle promotes the development of knee OA, particularly by enhancing disease severity rather than risk of onset, and this potentially occurs through multiple pathways including by engendering growth of functionally deficient joint tissues and the accumulation of excess body weight and adiposity.

Role of EPI-FLAIR in patients with acute stroke: a comparative analysis with FLAIR.

BACKGROUND AND PURPOSE: Further improvement in acquisition speed is needed, if MR imaging is to compete with CT for evaluation of patients with acute ischemic stroke. The purpose of this study was to evaluate the feasibility of implementing an echo-planar fluid-attenuated inversion recovery (EPI-FLAIR) sequence into an acute MR stroke protocol with potential reduction in scan time and to compare the results with conventional FLAIR images. MATERIALS AND METHODS: Fifty-two patients (28 men and 24 women; age range, 32-96 years) with acute ischemic stroke were prospectively evaluated with an acute stroke MR protocol, which included both conventional FLAIR and EPI-FLAIR imaging with integration of parallel acquisition. The image acquisition time was 52 seconds for EPI-FLAIR and 3 minutes for conventional FLAIR. FLAIR and EPI-FLAIR studies were assessed by 2 observers independently for image quality and conspicuity of hyperintensity in correlation with DWI and were rated as concordant or discordant. Coregistered FLAIR and EPI-FLAIR images were evaluated for signal intensity ratio of the DWI-positive lesion to contralateral normal white matter. RESULTS: An estimated 96% of all FLAIR and EPI-FLAIR studies were rated of diagnostic image quality by both observers, with interobserver agreements of κ = 0.82 and κ = 0.63 for FLAIR and EPI-FLAIR, respectively. In 36 (95%) of 38 patients with acute infarction, FLAIR and EPI-FLAIR were rated concordant regarding DWI lesion. The mean ± standard deviation of the signal intensity ratio values on EPI-FLAIR and FLAIR for DWI-positive lesions were 1.28 ± 0.16 and 1.25 ± 0.17, respectively (P = .47), and demonstrated significant correlation (r = 0.899, z value = 8.677, P < .0001). CONCLUSIONS: In patients with acute stroke, EPI-FLAIR is feasible with comparable qualitative and quantitative results to conventional FLAIR and results in reduced acquisition time.

Bcl-3 deficiency protects against dextran-sodium sulphate-induced colitis in the mouse.

Bcl-3 is a member of the IκB family of proteins and is an essential negative regulator of Toll-like receptor-induced responses. Recently, a single nucleotide polymorphism associated with reduced Bcl-3 gene expression has been identified as a potential risk factor for Crohn's disease. Here we report that in contrast to the predictions of single nucleotide polymorphism (SNP) analysis, patients with Crohn's disease and ulcerative colitis demonstrate elevated Bcl-3 mRNA expression relative to healthy individuals. To explore further the potential role of Bcl-3 in inflammatory bowel disease (IBD), we used the dextran-sodium sulphate (DSS)-induced model of colitis in Bcl-3(-/-) mice. We found that Bcl-3(-/-) mice were less sensitive to DSS-induced colitis compared to wild-type controls and demonstrated no significant weight loss following treatment. Histological analysis revealed similar levels of oedema and leucocyte infiltration between DSS-treated wild-type and Bcl-3(-/-) mice, but showed that Bcl-3(-/-) mice retained colonic tissue architecture which was absent in wild-type mice following DSS treatment. Analysis of the expression of the proinflammatory cytokines interleukin (IL)-1ß, tumour necrosis factor (TNF)-α and IL-6 revealed no significant differences between DSS-treated Bcl-3(-/-) and wild-type mice. Analysis of intestinal epithelial cell proliferation revealed enhanced proliferation in Bcl-3(-/-) mice, which correlated with preserved tissue architecture. Our results reveal that Bcl-3 has an important role in regulating intestinal epithelial cell proliferation and sensitivity to DSS-induced colitis which is distinct from its role as a negative regulator of inflammation.

Syndromes of the first and second branchial arches, part 2: syndromes.

A variety of congenital syndromes affecting the face occur due to defects involving the first and second BAs. Radiographic evaluation of craniofacial deformities is necessary to define aberrant anatomy, plan surgical procedures, and evaluate the effects of craniofacial growth and surgical reconstructions. High-resolution CT has proved vital in determining the nature and extent of these syndromes. The radiologic evaluation of syndromes of the first and second BA should begin first by studying a series of isolated defects (cleft lip with or without CP, micrognathia, and EAC atresia) that compose the major features of these syndromes and allow a more specific diagnosis. After discussion of these defects and the associated embryology, we discuss PRS, HFM, ACS, TCS, Stickler syndrome, and VCFS.

Syndromes of the first and second branchial arches, part 1: embryology and characteristic defects.

A variety of congenital syndromes affecting the face occur due to defects involving the first and second BAs. Radiographic evaluation of craniofacial deformities is necessary to define aberrant anatomy, plan surgical procedures, and evaluate the effects of craniofacial growth and surgical reconstructions. High-resolution CT has proved vital in determining the nature and extent of these syndromes. The radiologic evaluation of syndromes of the first and second BAs should begin first by studying a series of isolated defects: CL with or without CP, micrognathia, and EAC atresia, which compose the major features of these syndromes and allow more specific diagnosis. After discussion of these defects and the associated embryology, we proceed to discuss the VCFS, PRS, ACS, TCS, Stickler syndrome, and HFM.

Cooking and the human commitment to a high-quality diet.

For our body size, humans exhibit higher energy use yet reduced structures for mastication and digestion of food compared to chimpanzees, our closest living relatives. This suite of features suggests that humans are adapted to a high-quality diet. Although increased consumption of meat during human evolution certainly contributed to dietary quality, meat-eating alone appears to be insufficient to support the evolution of these traits, because modern humans fare poorly on raw diets that include meat. Here, we suggest that cooking confers physical and chemical benefits to food that are consistent with observed human dietary adaptations. We review evidence showing that cooking facilitates mastication, increases digestibility, and otherwise improves the net energy value of plant and animal foods regularly consumed by humans. We also address the likelihood that cooking was adopted more than 250,000 years ago (kya), a period that we believe is sufficient in length for the proposed adaptations to have occurred. Additional experimental work is needed to help discriminate the relative contributions of cooking, meat eating, and other innovations such as nonthermal food processing in supporting the human transition toward dietary quality.

Signalling apoptosis: a radical approach.

Reactive oxygen species (ROS) are frequently associated with cytotoxicity, often being described as damaging, harmful or toxic. It is generally assumed that, under pathological circumstances, ROS elicit wide-spread and random acts of oxidation. This passive attack of cellular components by ROS, in conditions where oxidative stress is the initiating stimulus for apoptosis, is assumed to simply trigger cell death as a result of cumulative oxidative damage. However, accumulating evidence now suggests that ROS may act as signalling molecules for the initiation and execution of the apoptotic death programme in many, if not all, current models of apoptotic cell death. Signalling by ROS would not appear to be random, as previously assumed, but targeted at specific metabolic and signal transduction cellular components. There is also evidence that the enzymatic generation of ROS may not simply be an unwanted by-product of the primary reaction catalysed, but that ROS may be used as signalling molecules to regulate cellular processes including apoptosis. This view of ROS as signalling molecules (as opposed to toxic metabolites) has been further bolstered by the findings that cellular antioxidants such as glutathione and thioredoxin not only serve to regulate ROS levels but also act as reversible redox modifiers of enzyme function. This review will attempt to delineate the involvement of ROS in apoptosis in light of these recent discoveries and provide evidence for a crucial role for ROS in the initiation and execution of the death process.

Light-induced photoreceptor apoptosis in vivo requires neuronal nitric-oxide synthase and guanylate cyclase activity and is caspase-3-independent.

Apoptosis is the mode of photoreceptor cell death in inherited and induced retinal degeneration. However, the molecular mechanisms of photoreceptor cell death in human cases and animal models of retinal dystrophies remain undefined. Exposure of Balb/c mice to excessive levels of white light results in photoreceptor apoptosis. This study delineates the molecular events occurring during and subsequent to the induction of retinal degeneration by exposure to white light in Balb/c mice. We demonstrate an early increase in intracellular calcium levels during photoreceptor apoptosis, an event that is accompanied by significant superoxide generation and mitochondrial membrane depolarization. Furthermore, we show that inhibition of neuronal nitric-oxide synthase (nNOS) by 7-nitroindazole is sufficient to prevent retinal degeneration implicating a key role for neuronal nitric oxide (NO) in this model. We demonstrate that inhibition of guanylate cyclase, a downstream effector of NO, also prevents photoreceptor apoptosis demonstrating that guanylate cyclase too plays an essential role in this model. Finally, our results demonstrate that caspase-3, frequently considered to be one of the key executioners of apoptosis, is not activated during retinal degeneration. In summary, the data presented here demonstrate that light-induced photoreceptor apoptosis in vivo is mediated by the activation of nNOS and guanylate cyclase and is caspase-3-independent.

Apoptotic photoreceptor death in the rhodopsin knockout mouse in the presence and absence of c-fos.

A combined total of approximately 100 mutations have been encountered within the rhodopsin gene in retinitis pigmentosa (RP) and congenital night blindness. Mice carrying a targeted disruption of the rhodopsin gene phenotypically mimic RP, losing their photoreceptors over a period of 3 months and having no recordable rod electroretinogram. These animals will serve as a model for both recessive and dominant disease (in the latter case, the presence of normal and mutant human rod opsin transgenes on the murine Rho(-/-)background). Precise knowledge of apoptotic photoreceptor cell death, together with factors which may influence apoptosis will be required for optimum utility of Rho(-/-)mice as a model for therapeutic genetic intervention. A peak phase of apoptosis of the photoreceptors of Rho(-/-)mice was shown to occur at 24 days post-birth. The extent of apoptosis appeared to be similar, irrespective of whether or not the rod opsin knockout was present on a c-fos(+/+)or c-fos(-/-)genetic background, the latter known to favor survival of photoreceptors following exposure of mouse retinas to excessive light. These data clearly support the existence in animals of distinct apoptotic pathways in light-induced, as opposed to mutation-induced apoptosis, and together with similar observations recently reported in studies of the naturally occurring rd mouse, may assist in focusing future research on precisely defining the distinct molecular pathways giving rise to such dichotomy.

Heat shock protein 70 inhibits caspase-dependent and -independent apoptosis in Jurkat T cells.

Heat shock protein 70 (hsp70) is a stress-inducible protein that prevents apoptosis induced by a wide range of cytotoxic agents by an as yet undefined mechanism. The caspase family of cysteine proteases have been attributed a central role in the execution of apoptosis. However, several cases of caspase-independent apoptosis have been recently reported, suggesting that caspases may not be necessary for apoptosis in all cells. This study examines the protective role of hsp70 in both caspase-dependent and -independent apoptosis. Hydrogen peroxide (H2O2) used at low and high concentrations in Jurkat T cells induces caspase-dependent and -independent apoptosis, respectively. A hsp70-transfected Jurkat clone was used to observe the protection mediated by hsp70 during these two forms of apoptosis. Results reveal that hsp70 inhibits both caspase-dependent and -independent apoptosis. Furthermore, measurement of caspase-3 activity during caspase-dependent apoptosis revealed that caspase activation was inhibited in hsp70 transfectants. Early apoptotic events, such as mitochondrial depolarization, cytochrome c release, and increased intracellular calcium, were demonstrated to be common to both caspase-dependent and -independent H2O2-induced apoptosis. The inhibition of these events by hsp70 suggests that hsp70 may be an important anti-apoptotic regulator, functioning at a very early stage in the apoptotic pathway.

Gadopentetate dimeglumine as a contrast agent in common carotid arteriography.

BACKGROUND AND PURPOSE: Despite improvements in noninvasive imaging, some patients with contraindications to iodine-based contrast material still require angiography for the evaluation of carotid stenosis. Our aim was to assess the utility of gadopentetate dimeglumine as an intraarterial contrast agent in common carotid angiography. METHODS: Twelve patients with suspected carotid artery stenosis were enrolled in the study. In addition to the standard injection sequences with iohexol, common carotid arteriograms were obtained after administration of gadopentetate dimeglumine. Neurologic status and vital signs were monitored during and for 6 hours after the examination. For each injection, five independent observers, blinded to the contrast agent used, measured the percentage of carotid stenosis and assessed their confidence in grading the stenosis, the overall quality of the examination, and, in cases of decreased quality, the reason(s) for it. Statistical analysis was done with paired and unpaired t-tests with equal variances. RESULTS: No patient had an adverse clinical outcome, and measurements of carotid artery stenosis showed no statistically significant differences between the gadopentetate dimeglumine and iohexol examinations. Overall image quality and observer confidence in measurements of stenosis on the gadolinium-based studies were slightly but significantly lower than those of identical iodine-based studies. CONCLUSION: Gadopentetate dimeglumine may be an alternative to iodine in selected patients undergoing carotid angiography. Although overall image quality of the gadolinium studies is slightly inferior to that of the iohexol studies, measurements of carotid artery stenosis are similar for the two examinations.

Oxidative stress induces caspase-independent retinal apoptosis in vitro.

Apoptosis is the mode of cell death in retinitis pigmentosa (RP), a heterogeneous group of retinal degenerations. The activation of the caspase proteases forms a pivotal step in the initiation and execution phase of apoptosis in many cells. Inhibition of caspases has been reported to prevent apoptosis in many model systems. However, we demonstrate the absence of caspase activation during retinal cell apoptosis in vitro which involves phosphatidylserine (PS) externalisation, DNA nicking and cell shrinkage. In addition, zVAD-fmk, DEVD-CHO and BD-fmk, inhibitors of the caspases, were unable to alter the characteristics or kinetics of apoptosis, implying that retinal cell death in vitro follows a caspase-independent pathway. We have previously demonstrated the ability of reactive oxygen species (ROS) to act as mediators of retinal cell apoptosis in vitro as well as the ability of antioxidants to prevent retinal cell apoptosis. Here we demonstrate the oxidative inactivation of caspases in this model of retinal apoptosis and provide evidence for an oxidative stress driven cell death pathway that does not involve caspase activity and which retains key features of apoptotic cell death. Furthermore, our data indicates that apoptotic events such as PS exposure, DNA nicking and cell shrinkage may occur independently of caspase activity.

Detection of molecular events during apoptosis by flow cytometry.

Apoptosis describes an intrinsic cell suicide program that may be activated by both endogenous and exogenous stimuli. This method of cell death is characterized by specific morphological features including chromatin condensation, nuclear fragmentation, cell shrinkage, membrane blebbing, and the formation of membrane-bound vesicles termed apoptotic bodies (1). Apoptosis has come to be referred to as the physiological mode of cell death, as it allows cellular destruction in the absence of an associated inflammatory response. In contrast, necrosis is a pathological mode of cell death that occurs under circumstances of severe cellular injury/trauma. Necrotic cell death involves cell swelling and organelle disruption, followed by lysis and release of cellular debris. This form of cell death may cause damage to surrounding tissue due to the inappropriate triggering of an inflammatory response (2).

Disseminated coccidioidomycosis complicated by vasculitis: a cause of fatal subarachnoid hemorrhage in two cases.

We describe two cases of disseminated coccidioidomycosis that were complicated by fatal subarachnoid hemorrhage. In the first case, a left middle cerebral artery aneurysm and long-segment vasculitis occurred. In the second case, MR imaging revealed an enlarging coccidioidal granuloma at the tip of the basilar artery, and the artery subsequently ruptured. Fatal intracranial hemorrhage is a rare complication of disseminated coccidioidomycosis.

Reactive oxygen species as mediators of photoreceptor apoptosis in vitro.

Retinitis pigmentosa is a heterogeneous group of retinal degenerations characterized by a progressive loss of photoreceptors through the process of apoptosis. The apoptotic cell death of photoreceptors appears to represent a final common pathway in the pathology of retinitis pigmentosa. Previous studies have reported the ability of antioxidants to ameliorate light-induced retinal degeneration, suggesting a role for oxidative stress in photoreceptor cell death. This study demonstrates an early and sustained increase in intracellular reactive oxygen species accompanied by a rapid depletion of intracellular glutathione in an in vitro model of photoreceptor apoptosis. These early changes in the cellular redox state precede disruption of mitochondrial transmembrane potential, nuclear condensation, DNA nicking, and cell shrinkage, all of which are well-characterized events of apoptotic cell death. The ability of zinc chloride and pyrrolidine dithiocarbamate, two established antioxidants, to inhibit photoreceptor apoptosis through the scavenging of intracellular reactive oxygen species establishes a role for reactive oxygen species as possible mediators of in vitro photoreceptor apoptosis. This study provides a molecular basis for the inhibition of photoreceptor apoptosis by antioxidants.

MR imaging of acute coccidioidal meningitis.

BACKGROUND AND PURPOSE: Our purpose was to describe the MR imaging findings in patients with acute coccidioidal meningitis. METHODS: Fourteen patients (11 men, three women; 22-78 years old; mean age, 47 years) with coccidioidal meningitis underwent neuroimaging within 2 months of diagnosis. Thirteen patients had MR imaging and one had an initial CT study with a follow-up MR examination 5 months later. Initial and follow-up MR images were evaluated for the presence of ventricular dilatation, signal abnormalities, enhancement characteristics, sites of involvement, and evidence of white matter or cortical infarction. The patterns of enhancement were characterized as focal or diffuse. Pathologic specimens were reviewed in two patients. RESULTS: Ten of the 14 images obtained at the time of initial diagnosis showed evidence of meningitis. All of the initially abnormal studies showed enhancement in the basal cisterns, sylvian fissures, or pericallosal region. Subsequent studies, which were available for three of the four patients with normal findings initially, all eventually became abnormal, with focal enhancement seen on the initial abnormal examination. Other abnormalities seen at presentation included ventricular dilatation (six patients) and deep infarcts (four patients). Pathologic specimens in two patients showed focal collections of the organism corresponding to the areas of intense enhancement on MR images. CONCLUSION: Early in its disease course, coccidioidal meningitis may show areas of focal enhancement in the basal cisterns, which may progress to diffuse disease. Pathologically, the areas of enhancement represent focal collections of the organism. Deep infarcts and communicating hydrocephalus are associated findings.

Rapid detection of rod photoreceptor apoptosis by flow cytometry.

Apoptosis is a form of cell death that plays an important role during physiological homeostasis and numerous pathological conditions. Retinitis pigmentosa is a group of retinal degenerative disorders in which rod photoreceptors excessively die via apoptosis. Current analytical tools for the investigation of photoreceptor cell death are histological in nature and typically time-consuming and laborious; as such, they are frequently limited to small sample sizes. In recent years, apoptosis research has made extensive use of flow cytometry to analyze several cellular events characteristic of apoptosis, including DNA strand nicking and cell shrinkage. This study presents a flow cytometric assay for the detection of rod photoreceptor apoptosis using the rod-specific cell marker rhodopsin, the terminal deoxyuridine 5'-triphosphate (dUTP) transferase nick end-labeling (TUNEL) assay, and the light-scattering properties of rod photoreceptors. This technique enables the rapid and reproducible detection of rod photoreceptor apoptosis in vitro with potential applications for in vivo analysis.

Hydrogen peroxide poisoning causing brain infarction: neuroimaging findings.

OBJECTIVE: We describe the CT and MR imaging findings of the brain in patients who inadvertently poisoned themselves with concentrated hydrogen peroxide. Thirty-five percent hydrogen peroxide is commercially available as an oxidant and disinfectant. This solution is currently sold and promoted in health food stores in the United States as a means of "improving oxygenation" in people with coronary artery disease and other health problems. CONCLUSION: Our findings show the high toxicity of concentrated hydrogen peroxide. CNS damage and death are likely consequences after ingestion of this agent.