Retinal overexpression of angiopoietin-2 mimics diabetic retinopathy and enhances vascular damages in hyperglycemia

Our previous data suggested that angiopoietin-2 (Ang-2) is linked to pericyte loss, thereby playing an important role in diabetic retinopathy. In this study, we investigated the effect of retinal overexpression of human Ang-2 (mOpsinhAng2 mouse) on vascular morphology in non-diabetic and streptozotozin-induced diabetic animals. Pericyte (PC) coverage and acellular capillary (AC) formation were quantitated in retinal digest preparations after 3 and 6 months of diabetes duration. The degree of retinopathy in non-diabetic mOpsinhAng2 mice at 3 months (-21% PC, +49% AC) was comparable to age-matched diabetic wild type mice. Diabetic mOpsinhAng2 mice exhibited significantly worse vascular pathology than wild type counterparts at 6 months. Quantitative PCR revealed that human Ang-2 mRNA was highly overexpressed in retinas of transgenic mice. Our data demonstrate that overexpression of Ang-2 in the retina enhances vascular pathology, indicating that Ang-2 plays an essential role in diabetic vasoregression via destabilization of pericytes.

Different pattern of clinical deficits in stroke mimics treated with intravenous thrombolysis

Guidelines recommend intravenous thrombolysis (IVT) to be applied as early as possible in ischemic stroke (IS), while clinical presentation is often assessed by using the National Institutes of Health Stroke Scale (NIHSS). However, diagnostic workup under time pressure bears the risk of misdiagnosis. Little is known about whether NIHSS could help to differentiate between IS and stroke mimics (SM) in patients being evaluated for IVT.

Spectroscopic properties of pyrene-containing DNA mimics

DNA mimics containing non-nucleosidic pyrene building blocks are described. The modified oligomers form stable hybrids, although a slight reduction in hybrid stability is observed in comparison to the unmodified DNA duplex. The nature of the interaction between the pyrene residues in single and double stranded oligomers is analyzed spectroscopically. Intra- and inter-strand stacking interactions of pyrenes are monitored by UV-absorbance as well as fluorescence spectroscopy. Excimer formation is observed in both single and double strands. In general, intrastrand excimers show fluorescence emission at shorter wavelengths (approx. 5-10 nm) than excimers formed by interstrand interactions. The existence of two different forms of excimers (intra- vs. interstrand) is also revealed in temperature dependent UV-absorbance spectra. (C) 2007 Elsevier Ltd. All rights reserved.

Safety of thrombolysis in stroke mimics: results from a multicenter cohort study

BACKGROUND AND PURPOSE Intravenous thrombolysis for acute ischemic stroke is beneficial within 4.5 hours of symptom onset, but the effect rapidly decreases over time, necessitating quick diagnostic in-hospital work-up. Initial time strain occasionally results in treatment of patients with an alternate diagnosis (stroke mimics). We investigated whether intravenous thrombolysis is safe in these patients. METHODS In this multicenter observational cohort study containing 5581 consecutive patients treated with intravenous thrombolysis, we determined the frequency and the clinical characteristics of stroke mimics. For safety, we compared the symptomatic intracranial hemorrhage (European Cooperative Acute Stroke Study II [ECASS-II] definition) rate of stroke mimics with ischemic strokes. RESULTS One hundred stroke mimics were identified, resulting in a frequency of 1.8% (95% confidence interval, 1.5-2.2). Patients with a stroke mimic were younger, more often female, and had fewer risk factors except smoking and previous stroke or transient ischemic attack. The symptomatic intracranial hemorrhage rate in stroke mimics was 1.0% (95% confidence interval, 0.0-5.0) compared with 7.9% (95% confidence interval, 7.2-8.7) in ischemic strokes. CONCLUSIONS In experienced stroke centers, among patients treated with intravenous thrombolysis, only a few had a final diagnosis other than stroke. The complication rate in these stroke mimics was low.

Angiomatous kaposi sarcoma: a variant that mimics hemangiomas.

We describe 14 cases of angiomatous Kaposi sarcoma (KS), a distinct histological variant of KS first mentioned by Gottlieb and Ackerman in 1988 that can easily be mistaken for a hemangioma. Intriguingly, this variant of KS has not attracted much attention and has not been studied in detail. Immunohistochemistry showed prominent staining of podoplanin (D2-40) of the neoplastic vasculature but not the preexisting vessels, suggesting lymphatic differentiation, despite the erythrocyte-filled round lumens. To test whether D2-40 staining of round vessels with erythrocytes was distinctive, we stained sinusoidal hemangiomas and cellular angiolipomas, both of which have these structures. In contrast to angiomatous KS, the vessels in both entities were podoplanin (D2-40) negative. The finding of round erythrocyte-filled vessels with podoplanin (D2-40) positivity may be distinctive for this form of KS.

Plug-and-Display: decoration of Virus-Like Particles via isopeptide bonds for modular immunization.

Virus-like particles (VLPs) are non-infectious self-assembling nanoparticles, useful in medicine and nanotechnology. Their repetitive molecularly-defined architecture is attractive for engineering multivalency, notably for vaccination. However, decorating VLPs with target-antigens by genetic fusion or chemical modification is time-consuming and often leads to capsid misassembly or antigen misfolding, hindering generation of protective immunity. Here we establish a platform for irreversibly decorating VLPs simply by mixing with protein antigen. SpyCatcher is a genetically-encoded protein designed to spontaneously form a covalent bond to its peptide-partner SpyTag. We expressed in E. coli VLPs from the bacteriophage AP205 genetically fused to SpyCatcher. We demonstrated quantitative covalent coupling to SpyCatcher-VLPs after mixing with SpyTag-linked to malaria antigens, including CIDR and Pfs25. In addition, we showed coupling to the VLPs for peptides relevant to cancer from epidermal growth factor receptor and telomerase. Injecting SpyCatcher-VLPs decorated with a malarial antigen efficiently induced antibody responses after only a single immunization. This simple, efficient and modular decoration of nanoparticles should accelerate vaccine development, as well as other applications of nanoparticle devices.

Agonist-biased signaling at the sst2A receptor: the multi-somatostatin analogs KE108 and SOM230 activate and antagonize distinct signaling pathways

Somatostatin analogs that activate the somatostatin subtype 2A (sst2A) receptor are used to treat neuroendocrine cancers because they inhibit tumor secretion and growth. Recently, new analogs capable of activating multiple somatostatin receptor subtypes have been developed to increase tumor responsiveness. We tested two such multi-somatostatin analogs for functional selectivity at the sst2A receptor: SOM230, which activates sst1, sst2, sst3, and sst5 receptors, and KE108, which activates all sst receptor subtypes. Both compounds are reported to act as full agonists at their target sst receptors. In sst2A-expressing HEK293 cells, somatostatin inhibited cAMP production, stimulated intracellular calcium accumulation, and increased ERK phosphorylation. SOM230 and KE108 were also potent inhibitors of cAMP accumulation, as expected. However, they antagonized somatostatin stimulation of intracellular calcium and behaved as partial agonists/antagonists for ERK phosphorylation. In pancreatic AR42J cells, which express sst2A receptors endogenously, SOM230 and KE108 were both full agonists for cAMP inhibition. However, although somatostatin increased intracellular calcium and ERK phosphorylation, SOM230 and KE108 again antagonized these effects. Distinct mechanisms were involved in sst2A receptor signaling in AR42J cells; pertussis toxin pretreatment blocked somatostatin inhibition of cAMP accumulation but not the stimulation of intracellular calcium and ERK phosphorylation. Our results demonstrate that SOM230 and KE108 behave as agonists for inhibition of adenylyl cyclase but antagonize somatostatin's actions on intracellular calcium and ERK phosphorylation. Thus, SOM230 and KE108 are not somatostatin mimics, and their functional selectivity at sst2A receptors must be considered in clinical applications where it may have important consequences for therapy.

Extra-intracranial blood shunt mimicking aneurysm rupture: intracranial-pressure-controlled rabbit subarachnoid hemorrhage model

The achieved degree of delayed cerebral vasospasm (DCVS) in the rabbits most frequently applied cistern magna blood injection model is often mild. The aim of this study was to characterize and evaluate the feasibility of an experimental SAH technique that mimics pathophysiological mechanisms and triggers higher degrees of DCVS.

An in vitro triple cell co-culture model with primary cells mimicking the human alveolar epithelial barrier

A triple cell co-culture model was recently established by the authors, consisting of either A549 or 16HBE14o- epithelial cells, human blood monocyte-derived macrophages and dendritic cells, which offers the possibility to study the interaction of xenobiotics with those cells. The 16HBE14o- containing co-culture model mimics the airway epithelial barrier, whereas the A549 co-cultures mimic the alveolar type II-like epithelial barrier. The goal of the present work was to establish a new triple cell co-culture model composed of primary alveolar type I-like cells isolated from human lung biopsies (hAEpC) representing a more realistic alveolar epithelial barrier wall, since type I epithelial cells cover >93% of the alveolar surface. Monocultures of A549 and 16HBE14o- were morphologically and functionally compared with the hAEpC using laser scanning microscopy, as well as transmission electron microscopy, and by determining the epithelial integrity. The triple cell co-cultures were characterized using the same methods. It could be shown that the epithelial integrity of hAEpC (mean ± SD, 1180 ± 188 Ω cm(2)) was higher than in A549 (172 ± 59 Ω cm(2)) but similar to 16HBE14o- cells (1469 ± 156 Ω cm(2)). The triple cell co-culture model with hAEpC (1113 ± 30 Ω cm(2)) showed the highest integrity compared to the ones with A549 (93 ± 14 Ω cm(2)) and 16HBE14o- (558 ± 267 Ω cm(2)). The tight junction protein zonula occludens-1 in hAEpC and 16HBE14o- were more regularly expressed but not in A549. The epithelial alveolar model with hAEpC combined with two immune cells (i.e. macrophages and dendritic cells) will offer a novel and more realistic cell co-culture system to study possible cell interactions of inhaled xenobiotics and their toxic potential on the human alveolar type I epithelial wall.

Urogenital manifestations in Wegener granulomatosis: a study of 11 cases and review of the literature

We describe the main characteristics and treatment of urogenital manifestations in patients with Wegener granulomatosis (WG). We conducted a retrospective review of the charts of 11 patients with WG. All patients were men, and their median age at WG diagnosis was 53 years (range, 21-70 yr). Urogenital involvement was present at onset of WG in 9 cases (81%), it was the first clinical evidence of WG in 2 cases (18%), and was a symptom of WG relapse in 6 cases (54%). Symptomatic urogenital involvement included prostatitis (n = 4) (with suspicion of an abscess in 1 case), orchitis (n = 4), epididymitis (n = 1), a renal pseudotumor (n = 2), ureteral stenosis (n = 1), and penile ulceration (n = 1). Urogenital symptoms rapidly resolved after therapy with glucocorticoids and immunosuppressive agents. Several patients underwent a surgical procedure, either at the time of diagnosis (n = 3) (consisting of an open nephrectomy and radical prostatectomy for suspicion of carcinoma, suprapubic cystostomy for acute urinary retention), or during follow-up (n = 3) (consisting of ureteral double J stents for ureteral stenosis, and prostate transurethral resection because of dysuria). After a mean follow-up of 56 months, urogenital relapse occurred in 4 patients (36%). Urogenital involvement can be the first clinical evidence of WG. Some presentations, such as a renal or prostate mass that mimics cancer or an abscess, should be assessed to avoid unnecessary radical surgery. Urogenital symptoms can be promptly resolved with glucocorticoids and immunosuppressive agents. However, surgical procedures, such as prostatic transurethral resection, may be mandatory in patients with persistent symptoms.

A clinical approach to arterial ischemic childhood stroke: increasing knowledge over the last decade

Childhood stroke is increasingly being recognized as an important burden not only for affected children and families, but also for socioeconomic reasons. A primary problem is delayed diagnosis, due to the many mimics of childhood stroke, and the variety of manifesting symptoms. The most important is hemiparesis (with/without dysphasia or facial palsy), but ataxia, seizures, and many more are also possible. Suspicion of stroke has to be ascertained by neuroimaging, gold standard being (diffusion weighted) magnetic resonance. Risk factors are multiple, but their presence might help to increase the suspicion of stroke. The most important factors are infectious/parainfectious etiologies, frequently possibly manifesting by transient focal cerebral arteriopathy (FCA). Cardiological underlying problems are the second most important. Arteriopathies can be detected in about half of the children, besides FCA and dissection and MoyaMoya disease are the most important. Hereditary coagulopathies increase the risk of stroke. There is still a controversy on best treatment in children: platelet antiaggregation and heparinization are used about equally. Thrombolysis is being discussed increasingly. Severity of symptoms at manifestation and on follow-up are not less significant in children than in young adults. About two-third of the children have significant residual neurological problems and a majority cognitive and behavior problems.

Management of Patients Presenting with Acute Subdural Hematoma due to Ruptured Intracranial Aneurysm

Acute subdural hematoma is a rare presentation of ruptured aneurysms. The rarity of the disease makes it difficult to establish reliable clinical guidelines. Many patients present comatose and differential diagnosis is complicated due to aneurysm rupture results in or mimics traumatic brain injury. Fast decision-making is required to treat this life-threatening condition. Determining initial diagnostic studies, as well as making treatment decisions, can be complicated by rapid deterioration of the patient, and the mixture of symptoms due to the subarachnoid hemorrhage or mass effect of the hematoma. This paper reviews initial clinical and radiological findings, diagnostic approaches, treatment modalities, and outcome of patients presenting with aneurysmal subarachnoid hemorrhage complicated by acute subdural hematoma. Clinical strategies used by several authors over the past 20 years are discussed and summarized in a proposed treatment flowchart.