Giant cellulitis-like Sweet Syndrome, a new variant of neutrophilic dermatosis

BACKGROUND Neutrophilic dermatoses comprise a wide spectrum of inflammatory diseases with overlapping features characterized histologically by the presence of an aseptic neutrophilic infiltrate in the epidermis, dermis, and/or hypodermis and are often associated with systemic inflammatory and neoplastic disorders. OBSERVATIONS We describe 3 patients with an unusual neutrophilic dermatosis characterized by relapsing episodes of fever, widespread infiltrated plaques with bullous appearance, and variable involvement of the arms, legs, abdomen, and/or trunk. Light microscopy studies showed marked edema of the papillary dermis with an inflammatory infiltrate consisting mainly of mature neutrophils. All 3 patients were morbidly obese, and workup revealed underlying cancer in 2 cases: myeloma and breast carcinoma. Management of the underlying disease resulted in long-term remission of the skin disease. CONCLUSIONS The clinicopathologic features in our 3 cases best correspond to a widespread giant cellulitis-like form of Sweet syndrome. Knowledge of this newly observed unusual variant of Sweet syndrome within the broad spectrum of neutrophilic diseases is important for its prompt and proper management.

The diabetic child in the emergency room

The WHO announced diabetes mellitus as one of the main threats to human health in the 21st century. In children and adolescents the prevalence of both the autoimmune type 1 and the obesity-related type 2 diabetes is increasing. Common to all types of diabetes is an absolute or relative lack of insulin to keep glucose homeostasis under control. Thus children and adolescents with newly diagnosed diabetes present with hyperglycemia which is often accompanied by ketoacidosis bearing the risk of cerebral edema. Children and adolescents with known diabetes treated with insulin or orale antidiabetic agents may also suffer from hyperglycemia or even ketoacidosis during times of non-compliance with diet and drugs or during concomitant illnesses. Hyperglycemia with ketoacidosis is an emergency situation for which patients need to be admitted to the next hospital for administration of insulin, fluids and potassium. In contrast, insulin treatment in diabetic patients may also lead to a hypoglycemia, the sudden drop in blood glucose, at any moment. Thus recognition and correction of mild hypoglycemia should be familiar to every diabetic child and their caretaker. Severe hypoglycemia with or without seizures may bring the diabetic child in a sudden emergency situation for which the administration of glucagon intramuscularly or glucose intravenously is mandatory. After every severe hypoglycemia the insulin and diet regimen of the diabetic child or adolescent must be reviewed with the diabetes specialist. For unexplained hypoglycemia or major treatment adjustments the diabetic child or adolescent may need to be readmitted to the diabetic ward of a hospital to avoid repeat, potentially life-threatening hypoglycemia.

C1 esterase inhibitor reduces lower extremity ischemia/reperfusion injury and associated lung damage

BACKGROUND Ischemia/reperfusion injury of lower extremities and associated lung damage may result from thrombotic occlusion, embolism, trauma, or surgical intervention with prolonged ischemia and subsequent restoration of blood flow. This clinical entity is characterized by high morbidity and mortality. Deprivation of blood supply leads to molecular and structural changes in the affected tissue. Upon reperfusion inflammatory cascades are activated causing tissue injury. We therefore tested preoperative treatment for prevention of reperfusion injury by using C1 esterase inhibitor (C1 INH). METHODS AND FINDINGS Wistar rats systemically pretreated with C1 INH (n = 6), APT070 (a membrane-targeted myristoylated peptidyl construct derived from human complement receptor 1, n = 4), vehicle (n = 7), or NaCl (n = 8) were subjected to 3h hind limb ischemia and 24h reperfusion. The femoral artery was clamped and a tourniquet placed under maintenance of a venous return. C1 INH treated rats showed significantly less edema in muscle (P<0.001) and lung and improved muscle viability (P<0.001) compared to controls and APT070. C1 INH prevented up-regulation of bradykinin receptor b1 (P<0.05) and VE-cadherin (P<0.01), reduced apoptosis (P<0.001) and fibrin deposition (P<0.01) and decreased plasma levels of pro-inflammatory cytokines, whereas deposition of complement components was not significantly reduced in the reperfused muscle. CONCLUSIONS C1 INH reduced edema formation locally in reperfused muscle as well as in lung, and improved muscle viability. C1 INH did not primarily act via inhibition of the complement system, but via the kinin and coagulation cascade. APT070 did not show beneficial effects in this model, despite potent inhibition of complement activation. Taken together, C1 INH might be a promising therapy to reduce peripheral ischemia/reperfusion injury and distant lung damage in complex and prolonged surgical interventions requiring tourniquet application.

THE EXPRESSION AND CELLULAR LOCALIZATION OF CC-CHEMOKINE RECEPTOR 5 (CCR5) AFTER TRAUMATIC BRAIN INJURY

Traumatic brain injury results from a primary insult and secondary events that together result in tissue injury. This primary injury occurs at the moment of impact and damage can include scalp laceration, skull fraction, cerebral contusions and lacerations as well as intracranial hemorrhage. Following the initial insult, a delayed response occurs and is characterized by hypoxia, ischemia, cerebral edema, and infection. During secondary brain injury, a series of neuroinflammatory events are triggered that can produce additional damage but may also help to protect nervous tissue from invading pathogens and help to repair the damaged tissue. Brain microglia and astrocytes become activated and migrate to the site of injury where these cells secrete immune mediators such as cytokines and chemokines. CC-chemokine receptor 5 (CCR5) is a member of the CC chemokine receptor family of seven transmembrane G protein coupled receptors. CCR5 is expressed in the immune system and is found in monocytes, leukoctyes, memory T cells, and immature dendritic cells. Upon binding to its ligands, CCR5 functions in the chemotaxis of these immune cells to the site of inflammation. In the CNS, CCR5 and its ligands are expressed in multiple cell types. In this study, I investigated whether CCR5 expression is altered in brain after traumatic brain injury. I examined the time course of CCR5 protein expression in cortex and hippocampus using quantitative western analysis of tissues from injured rat brain after mild impact injury. In addition, I also investigated the cellular localization of CCR5 before and after brain injury using confocal microscopy. I have observed that after brain injury CCR5 is upregulated in a time dependent manner in neurons of the parietal cortex and hippocampus. The absence of CCR5 expression in microglia and its delayed expression in neurons after injury suggests a role for CCR5 in neuronal survival after injury.

THE EXPRESSION AND CELLULAR LOCALIZATION OF CC-CHEMOKINE RECEPTOR 5 (CCR5) AFTER TRAUMATIC BRAIN INJURY

Traumatic brain injury results from a primary insult and secondary events that together result in tissue injury. This primary injury occurs at the moment of impact and damage can include scalp laceration, skull fraction, cerebral contusions and lacerations as well as intracranial hemorrhage. Following the initial insult, a delayed response occurs and is characterized by hypoxia, ischemia, cerebral edema, and infection. During secondary brain injury, a series of neuroinflammatory events are triggered that can produce additional damage but may also help to protect nervous tissue from invading pathogens and help to repair the damaged tissue. Brain microglia and astrocytes become activated and migrate to the site of injury where these cells secrete immune mediators such as cytokines and chemokines. CC-chemokine receptor 5 (CCR5) is a member of the CC chemokine receptor family of seven transmembrane G protein coupled receptors. CCR5 is expressed in the immune system and is found in monocytes, leukoctyes, memory T cells, and immature dendritic cells. Upon binding to its ligands, CCR5 functions in the chemotaxis of these immune cells to the site of inflammation. In the CNS, CCR5 and its ligands are expressed in multiple cell types. In this study, I investigated whether CCR5 expression is altered in brain after traumatic brain injury. I examined the time course of CCR5 protein expression in cortex and hippocampus using quantitative western analysis of tissues from injured rat brain after mild impact injury. In addition, I also investigated the cellular localization of CCR5 before and after brain injury using confocal microscopy. I have observed that after brain injury CCR5 is upregulated in a time dependent manner in neurons of the parietal cortex and hippocampus. The absence of CCR5 expression in microglia and its delayed expression in neurons after injury suggests a role for CCR5 in neuronal survival after injury.

Analyzing the Role of αvβ8 Integrin in Glioma-Induced Angiogenesis

In this study we aimed to determine the functional roles for αvβ8 integrin in astrocytoma-induced angiogenesis. These studies originate from our analyses of αvβ8 integrin in developmental brain angiogenesis. αv and β8 knockout (KO) mice develop brain-specific vascular phenotypes that resemble vascular pathologies observed in the malignant astrocytoma, glioblastoma multiforme (GBM). Indeed, a murine xenograft model of astrocytoma suggested a role for the integrin in glioma-induced angiogenesis. Primary mouse astroglia were cultured from wild type (WT) and β8 KO neonates and were immortalized (HPV:E6/E7) and transformed (HRas:G12V). WT and β8 KO transformed astroglia were intracranially injected into athymic mice. WT tumors displayed pathological features of grade III astrocytomas, whereas β8 KO tumors resembled grade IV GBMs. KO tumors contained widespread edema and hemorrhage as well as pathological angiogenesis, as assessed by quantitation of microvascular density and blood vessel morphology. Additionally, exogenous expression of β8 integrin in β8 KO transformed astroglia resolved the pathologies observed in KO tumors giving further credence to the idea that loss of αvβ8 integrin expression correlates with tumorigenic potential of oncogene-transformed astroglia. To compliment our mouse model, several established human glioma cell lines were characterized for expression of αvβ8 integrin protein. Some of the cell lines displayed low expression of αvβ8 integrin, whereas others showed high levels, as compared to non-malignant human astrocytes. Intracranial implantation of high and low β8 integrin-expressing human glioma cell lines resulted in tumors exhibiting similar phenotypes to those observed in the mouse model; low expressers were marked by vascular pathologies indicative of β8 KO mouse tumors. Upon overexpression of β8 integrin in a low β8 integrin-expressing human glioma cell line, angiogenic pathologies were largely resolved. Moreover, intracranially injected αvHI- and αvLO-sorted GBM stem cells (GSCs) resulted in significantly different tumor sizes, where those GSCs endogenously expressing low levels of αv integrin formed two to three fold larger tumors. Furthermore, lentiviral knockdown of β8 integrin in transformed human astrocytes formed tumors that strikingly recapitulated the characteristics of the murine β8-/- tumors, exhibiting a significant increase in microvascular density leading to decreased overall survival. A paracrine mechanism was discovered involving endothelial cell homeostatic control governed by canonical TGFβ signaling initiated by αvβ8 integrin’s role in the latent cytokine’s activation. Diminished TGFβ signaling in tumor-associated endothelial cells promoted increased angiogenesis and decreased overall survival as a result of αvβ8 integrin’s loss on the tumor cell. Collectively, these data suggest an important functional role for αvβ8 integrin in glioma angiogenesis.

A Hybrid Model for Multimodal Brain Tumor Segmentation

We present a fully automatic segmentation method for multi-modal brain tumor segmentation. The proposed generative-discriminative hybrid model generates initial tissue probabilities, which are used subsequently for enhancing the classi�cation and spatial regularization. The model has been evaluated on the BRATS2013 training set, which includes multimodal MRI images from patients with high- and low-grade gliomas. Our method is capable of segmenting the image into healthy (GM, WM, CSF) and pathological tissue (necrotic, enhancing and non-enhancing tumor, edema). We achieved state-of-the-art performance (Dice mean values of 0.69 and 0.8 for tumor subcompartments and complete tumor respectively) within a reasonable timeframe (4 to 15 minutes).

Sulforaphane improves cognitive function administered following traumatic brain injury.

Recent studies have shown that sulforaphane, a naturally occurring compound that is found in cruciferous vegetables, offers cellular protection in several models of brain injury. When administered following traumatic brain injury (TBI), sulforaphane has been demonstrated to attenuate blood-brain barrier permeability and reduce cerebral edema. These beneficial effects of sulforaphane have been shown to involve induction of a group of cytoprotective, Nrf2-driven genes, whose protein products include free radical scavenging and detoxifying enzymes. However, the influence of sulforaphane on post-injury cognitive deficits has not been examined. In this study, we examined if sulforaphane, when administered following cortical impact injury, can improve the performance of rats tested in hippocampal- and prefrontal cortex-dependent tasks. Our results indicate that sulforaphane treatment improves performance in the Morris water maze task (as indicated by decreased latencies during learning and platform localization during a probe trial) and reduces working memory dysfunction (tested using the delayed match-to-place task). These behavioral improvements were only observed when the treatment was initiated 1h, but not 6h, post-injury. These studies support the use of sulforaphane in the treatment of TBI, and extend the previously observed protective effects to include enhanced cognition.

Quantitative MRI of spinal cord injury in a rat model: Correlative studies

Serial quantitative and correlative studies of experimental spinal cord injury (SCI) in rats were conducted using three-dimensional magnetic resonance imaging (MRI). Correlative measures included morphological histopathology, neurobehavioral measures of functional deficit, and biochemical assays for N-acetyl-aspartate (NAA), lactate, pyruvate, and ATP. A spinal cord injury device was characterized and provided a reproducible injury severity. Injuries were moderate and consistent to within $\pm$20% (standard deviation). For MRI, a three-dimensional implementation of the single spin-echo FATE (Fast optimum angle, short TE) pulse sequence was used for rapid acquisition, with a 128 x 128 x 32 (x,y,z) matrix size and a 0.21 x 0.21 x 1.5 mm resolution. These serial studies revealed a bimodal characteristic in the evolution in MRI pathology with time. Early and late phases of SCI pathology were clearly visualized in $T\sb2$-weighted MRI, and these corresponded to specific histopathological changes in the spinal cord. Centralized hypointense MRI regions correlated with evidence of hemorrhagic and necrotic tissue, while surrounding hyperintense regions represented edema or myelomalacia. Unexpectedly, $T\sb2$-weighted MRI pathology contrast at 24 hours after injury appeared to subside before peaking at 72 hours after injury. This change is likely attributable to ongoing secondary injury processes, which may alter local $T\sb2$ values or reduce the natural anisotropy of the spinal cord. MRI, functional, and histological measures all indicated that 72 hours after injury was the temporal maximum for quantitative measures of spinal cord pathology. Thereafter, significant improvement was seen only in neurobehavioral scores. Significant correlations were found between quantitated MRI pathology and histopathology. Also, NAA and lactate levels correlated with behavioral measures of the level of function deficit. Asymmetric (rostral/caudal) changes in NAA and lactate due to injury indicate that rostral and caudal segments from the injury site are affected differently by the injury. These studies indicate that volumetric quantitation of MRI pathology from $T\sb2$-weighted images may play an important role in early prediction of neurologic deficit and spinal cord pathology. The loss of $T\sb2$ contrast at 24 hours suggests MR may be able to detect certain delayed mechanisms of secondary injury which are not resolved by histopathology or other radiological modalities. Furthermore, in vivo proton magnetic resonance spectroscopy (MRS) studies of SCI may provide a valuable addition source of information about changes in regional spinal cord lactate and NAA levels, which are indicative of local metabolic and pathological changes. ^

Regulatory factors and control of anthrax toxin gene expression

Bacillus anthracis plasmid pXO1 carries genes for three anthrax toxin proteins, pag (protective antigen), cya (edema factor), and lef (lethal factor). Expression of the toxin genes is enhanced by two signals: CO$\sb2$/bicarbonate and temperature. The CO$\sb2$/bicarbonate effect requires the presence of pXO1. I hypothesized that pXO1 harbors a trans-acting regulatory gene(s) required for CO$\sb2$/bicarbonate-enhanced expression of the toxin genes. Characterization of such a gene(s) will lead to increased understanding of the mechanisms by which B. anthracis senses and responds to host environments.^ A regulatory gene (atxA) on pXO1 was identified. Transcription of all three toxin genes is decreased in an atxA-null mutant. There are two transcriptional start sites for pag. Transcription from the major site, P1, is enhanced in elevated CO$\sb2$. Only P1 transcripts are significantly decreased in the atxA mutant. Deletion analysis of the pag upstream region indicates that the 111-bp region upstream of the P1 site is sufficient for atxA-mediated increase of this transcript. The cya and lef genes each have one apparent transcriptional start site. The cya and lef transcripts are significantly decreased in the atxA mutant. The atxA mutant is avirulent in mice. The antibody response to all three toxin proteins is significantly decreased in atxA mutant-infected mice. These data suggest that the atxA gene product activates expression of the toxin genes and is essential for virulence.^ Since expression of the toxin genes is dependent on atxA, whether increased toxin gene expression in response to CO$\sb2$/bicarbonate and temperature is associated with increased atxA expression was investigated. I monitored steady state levels of atxA mRNA and AtxA protein in different growth conditions. The results indicate that expression of atxA is not influenced by CO$\sb2$/bicarbonate. Steady state levels of atxA mRNA and AtxA protein are higher at 37$\sp\circ$C than 28$\sp\circ$C. However, increased pag expression at high temperature can not be attributed directly to increased atxA expression.^ There is evidence that an additional factor(s) may be involved in regulation of pag. Expression of pag in strains overproducing AtxA is significantly decreased compared to the wildtype strain. A specific interaction of tagged-AtxA with the pag upstream DNA has not been demonstrated. Furthermore, four proteins in B. anthracis extract can be co-immunoprecipitated with tagged-AtxA. Amino-terminal sequence of one protein has been determined and found highly homologous to chaperonins of GroEL family. Studies are under way to determine if this GroEL-like protein interactions with AtxA and plays any role in atxA-mediated activation of toxin genes. ^

Cardiovascular magnetization transfer ratio imaging compared with histology: A postmortem study

Cardiovascular magnetization transfer ratio (MTR) imaging by steady state free precession is a promising imaging method to assess microstructural changes within the myocardium. Hence, MTR imaging was correlated to histological analysis. Three postmortem cases were selected based on a suspicion of myocardial infarction. MTR and T2 -weighted (T2w ) imaging was performed, followed by autopsy and histological analysis. All tissue abnormalities, identified by autopsy or histology, were retrospectively selected on visually matched MTR and T2w images, and corresponding MTR values compared with normal appearing tissue. Regions of elevated MTR (up to approximately 20%, as compared to normal tissue), appearing hypo-intense in T2w -images, revealed the presence of fibrous tissue in microscopic histological analysis. Macroscopic observation (autopsy) described scar tissue only in one case. Regions of reduced MTR (up to approximately 20%) corresponded either to (i) the presence of edema, appearing hyperintense in T2w -images and confirmed by autopsy, or to (ii) inflammatory granulocyte infiltration at a microscopic level, appearing as hypo-intense T2w -signal, but not observed by autopsy. Findings from cardiovascular MTR imaging corresponded to histology results. In contrast to T2w -imaging, MTR imaging discriminated between normal myocardium, scar tissue and regions of acute myocardial infarction in all three cases. J. Magn. Reson. Imaging 2013. © 2013 Wiley Periodicals, Inc.

Factors Affecting Post-Capture Survivability of Lobster Homarus Americanus

Technological advances in gear and fishing practices have driven the global expansion of the American lobster live seafood market. These changes have had a positive effect on the lobster industry by increasing capture efficiency. However, it is unknown what effect these improved methods will have on the post-capture fitness and survival of lobsters. This project utilized a repeated measures design to compare the physiological changes that occur in lobsters over time as the result of differences in depth, hauling rate, and storage methodology. The results indicate that lobsters destined for long distance transport or temporary storage in pounds undergo physiological disturbance as part of the capture process. These changes are significant over time for total hemocyte counts, crustacean hyperglycemic hormone, L-lactate, ammonia, and glucose. Repeated measures multivariate analysis of variance (MANOVA) for glucose indicates a significant interaction between depth and storage methodology over time for non-survivors. A Gram-negative bacterium, Photobacterium indicum, was identified in pure culture from hemolymph samples of 100% of weak lobsters. Histopathology revealed the presence of Gram-negative bacteria throughout the tissues with evidence of antemortem edema and necrosis suggestive of septicemia. On the basis of these findings, we recommend to the lobster industry that if a reduction in depth and hauling rate is not economically feasible, fishermen should take particular care in handling lobsters and provide them with a recovery period in recirculating seawater prior to land transport. The ecological role of P. indicum is not fully defined at this time. However, it may be an emerging opportunistic pathogen of stressed lobsters. Judicious preemptive antibiotic therapy may be necessary to reduce mortality in susceptible lobsters destined for high-density holding facilities.

Multi-modal glioblastoma segmentation: man versus machine

BACKGROUND AND PURPOSE Reproducible segmentation of brain tumors on magnetic resonance images is an important clinical need. This study was designed to evaluate the reliability of a novel fully automated segmentation tool for brain tumor image analysis in comparison to manually defined tumor segmentations. METHODS We prospectively evaluated preoperative MR Images from 25 glioblastoma patients. Two independent expert raters performed manual segmentations. Automatic segmentations were performed using the Brain Tumor Image Analysis software (BraTumIA). In order to study the different tumor compartments, the complete tumor volume TV (enhancing part plus non-enhancing part plus necrotic core of the tumor), the TV+ (TV plus edema) and the contrast enhancing tumor volume CETV were identified. We quantified the overlap between manual and automated segmentation by calculation of diameter measurements as well as the Dice coefficients, the positive predictive values, sensitivity, relative volume error and absolute volume error. RESULTS Comparison of automated versus manual extraction of 2-dimensional diameter measurements showed no significant difference (p = 0.29). Comparison of automated versus manual segmentation of volumetric segmentations showed significant differences for TV+ and TV (p<0.05) but no significant differences for CETV (p>0.05) with regard to the Dice overlap coefficients. Spearman's rank correlation coefficients (ρ) of TV+, TV and CETV showed highly significant correlations between automatic and manual segmentations. Tumor localization did not influence the accuracy of segmentation. CONCLUSIONS In summary, we demonstrated that BraTumIA supports radiologists and clinicians by providing accurate measures of cross-sectional diameter-based tumor extensions. The automated volume measurements were comparable to manual tumor delineation for CETV tumor volumes, and outperformed inter-rater variability for overlap and sensitivity.

Idiopathic chylothorax and lymphedema in 2 whippet littermates.

Idiopathic chylothorax and limb edema was diagnosed in two 2-year-old male whippet siblings. The fact that the 2 related animals developed similar clinical signs at a young age may suggest a congenital or hereditary etiology.

Doramectin-Intoxikation bei drei Katzenwelpen

Dieser Fallbericht beschreibt drei Katzenwelpen mit Verdacht auf Doramectin-Intoxikation. Ein Wurf von insgesamt 7 Katzenwelpen wurde mit Doramectin behandelt, woraufhin drei Welpen neurologische Symptome entwickeltena Ein Welpe zeigte leichte Apathie und Zittern, ein weiterer zusätzlich Verhaltensänderungen und epileptiforme Anfälle, die mit Diazepam behandelt werden mussten. Beide Welpen erholten sich vollständig. Ein dritter Welpe wurde 3 Tage nach Doramectin-Gabe stuporös vorgestellt und zeigte im weiteren Verlauf Verhaltensänderungen wie Aggressivität, Hyperästhesie, Tremor und epileptiforme Anfälle. Er verstarb 36 Stunden nach Vorstellung. Bei der histopathologischen Untersuchung des Gehirns konnten ein zytotoxisches Ödem und Polioenzephalomalazie festgestellt werden. Die Doramectin-Dosis beim verstorbenen Welpen betrug 380 μg/kg.