SUMMARY: RCVS is a clinical condition of recurrent severe headaches that may be associated with ischemic or hemorrhagic stroke and that is defined by the presence of segmental vasoconstriction in multiple cerebral arteries. The angiographic appearance resembles vasculitis, except that the abnormalities resolve during the course of several months. Because the treatment of RCVS differs from that for vasculitis, radiologists must understand the clinical and radiologic features so as to better guide imaging algorithms and facilitate diagnosis. We present a series of 6 cases of RCVS that highlight the imaging features across multiple modalities.ABBREVIATIONS: IPH ϭ intraparenchymal hemorrhage; MIP ϭ maximum intensity projection; NSAID ϭ nonsteroidal anti-inflammatory drug; PACNS ϭ primary angiitis of the CNS; PRES ϭ posterior reversible encephalopathy syndrome; RCVS ϭ reversible cerebral vasoconstriction syndrome; SDH ϭ subdural hematoma; TCD ϭ transcranial Doppler R CVS is an under-recognized clinical-radiologic entity characterized by a history of sudden severe headaches, sometimes associated with ischemic or hemorrhagic stroke, focal neurologic deficits, or seizures. First described by Call et al in 19881 , RCVS encompasses a wide variety of entities previously described by other names, including postpartum angiopathy, migrainous vasospasm, migrainous stroke, druginduced angiopathy, and benign angiopathy of the CNS. 2,3The condition is defined by reversible segmental cerebral vasoconstriction on angiography.1-3 The angiographic findings are similar to those of other vasculopathies, including PACNS.4 Unlike PACNS, the vascular abnormalities of RCVS resolve within several months. 1,2,5,6 RCVS typically occurs following exposure to a trigger, commonly sympathomimetic or vasoactive agents, including amphetamines, phenylpropanolamine, pseudoephedrine, serotonergic antidepressants, nicotine, caffeine, cannabis, and triptan-or ergot-containing medications.2,7-9 Other triggers include the peripartum period, 10 eclampsia, strenuous physical activity, bathing or showering, sexual activity, and binge alcohol drinking.2 Most patients with RCVS are young and middle-aged women. 3Patients with RCVS exhibit a range of parenchymal abnormalities, including convexal SAH, IPH, ischemic infarcts, and PRES.2,9,11-13 Alternatively, imaging findings may be normal.2,9 Findings of CSF analysis are usually normal or nearnormal.3 Because of the overlap with other causes of headache and stroke in adults and because the vascular abnormalities early in the course of the disease may be subtle or absent, the diagnosis of RCVS is easily missed. Early recognition of RCVS allows appropriate clinical management aimed at reducing the frequency, duration, and severity of vascular complications, primarily through identification and removal of triggers. Because management and outcome of RCVS differ from those of other vasculopathies, it is critical that radiologists recognize its typical imaging appearance, time course, and clinical features. Case Series...
Compared with the traditional ambulance model, telemedicine-enabled ambulance-based thrombolysis resulted in significantly decreased time to imaging and treatment.
The bone morphogenic proteins (BMPs) play a key role in skeletal development and patterning. Using the technique of differential display polymerase chain reaction (ddPCR), we have identified a novel gene whose expression is increased during BMP-2-induced differentiation of the prechondroblastic cell line, MLB13MYC clone 17, to an osteoblastic phenotype. The 6.5-kilobase mRNA recognized by this ddPCR product is increased 10-fold by BMP-2 treatment of the MLB13MYC clone 17 cells. The mRNA recognized by this ddPCR product is also increased as MC3T3-E1 cells recapitulate the program of osteoblast differentiation during prolonged culture. The full-length transcript corresponding to this ddPCR product was cloned from a MLB13MYC clone 17 cell cDNA library. Analysis of the deduced amino acid sequence demonstrated that this gene encodes a novel 126-kDa putative serine/threonine protein kinase containing a nuclear localization signal. The kinase domain, expressed in Escherichia coli, is capable of autophosphorylation as well as phosphorylation of myelin basic protein. The gene was, therefore, named BIKe (BMP-2-Inducible Kinase). The BIKe nuclear localization signal is able to direct green fluorescent protein to the nucleus in transfected COS-7 cells. When stably expressed in MC3T3-E1 cells, BIKe significantly decreases alkaline phosphatase activity and osteocalcin mRNA levels and retards mineral deposition relative to vector control. This novel kinase, therefore, is likely to play an important regulatory role in attenuating the program of osteoblast differentiation.Numerous investigations have been directed at elucidating factors that regulate osteoblast differentiation (1). The bone morphogenetic proteins (BMPs) 1 are potent local factors that promote osteoblast differentiation during development as well as during bone remodeling (2). The molecular events downstream of BMP signaling that result in tissue-specific gene expression and skeletal development have only been partially elucidated. The binding of BMPs to their receptors leads to the assembly of a receptor complex in which the type II receptor phosphorylates and activates the type I receptor. As a result, pathway-restricted SMADs are phosphorylated, leading to interactions with the common mediator SMAD, smad4 (3). This complex is then translocated to the nucleus, where it modulates transcription of target genes. BMP signaling can also interfere with the effects of other growth and differentiation factors. It has been demonstrated that BMP-2 treatment of mesangial cells prevents phosphorylation of a transcription factor, Elk1, in response to platelet-derived growth factor (PDGF) signaling. This effectively inhibits PDGF-induced Elk-1-mediated transcription, and blocks PDGF-induced transcription of c-fos, an Elk-1 target (4). BMP-7 has been shown to be a potent inducer of Cbfa1, a transcription factor belonging to the runt-domain gene family that, in turn, regulates the expression of several genes in the osteoblast (5). Although Cbfa1 expression is necessary, it a...
Both vitamin D deficiency and the absence of a functional vitamin D receptor (VDR) lead to a growth plate abnormality known as rickets. Prevention of abnormal mineral ion homeostasis by early institution of dietary therapy in VDR null mice prevents rickets, demonstrating that the VDR is not required for normal growth plate maturation. We, therefore, hypothesized that rickets, in the absence of a functional VDR, is due to impaired mineral ion homeostasis. Analyses of growth plate morphology in VDR null mice demonstrated normal resting and proliferating chondrocyte layers; however an expansion of the hypertrophic chondrocyte layer was present by 24 days of age. Because extracellular calcium has been shown to play a role in chondrocyte maturation, we addressed the hypothesis that hypocalcemia led to impaired chondrocyte differentiation. However, in situ hybridization analyses revealed normal expression of hypertrophic chondrocyte markers in the tibial growth plate of 24 day old VDR null mice, suggesting that the increase in the hypertrophic chondrocyte layer was not secondary to impaired differentiation. We then addressed whether expansion of the hypertrophic chondrocyte layer was secondary to increased proliferation or decreased apoptosis. BrdU labeling failed to demonstrate an increase in chondrocyte proliferation in the VDR null mice; however, apoptosis was markedly diminished in the late hypertrophic chondrocytes of the VDR null mice, suggesting that impairment in programmed cell death of these cells leads to the characteristic findings of rickets.
Background and Purpose Fractalkine (CX3CL1) is a unique chemokine that is constitutively expressed on neurons where it serves as an adhesion molecule for lymphocytes and monocytes. CX3CL1 may also be cleaved from the surface of these cells and enter the circulation to act as a traditional chemokine. CX3CL1 could thus influence the inflammatory response following stroke. We hypothesized that patients with higher plasma CX3CL1 after stroke would have a more robust inflammatory response and experience worse outcome. Methods Plasma CX3CL1 concentrations were assessed in 85 patients who were part of a larger study evaluating immune responses following ischemic stroke; CX3CL1 values were available from day 1 to day 180 after stroke onset. CX3CL1 was correlated to measures of inflammation and its effect on outcome assessed. Results At 1 day after stroke, CX3CL1 was lower in patients with severe strokes. At 180 days after stroke, CX3CL1 concentrations were lower in patients with poor outcome. The association of CX3CL1 and outcome at 180 days was independent of initial stroke severity. Plasma CX3CL1 at 180 days was inversely associated with systemic markers of inflammation, including white blood cell counts and high sensitivity C reactive protein. Conclusions In contrast to our original hypothesis, lower concentrations of CX3CL1 are associated with worse stroke outcome. In light of recent studies suggesting an immunomodulatory and neuroprotective role for CX3CL1 in a variety of neurodegenerative diseases, a therapeutic role for CX3CL1 in stroke recovery should be considered.
Although herpes simplex virus (HSV) vectors appear to have great potential as gene delivery vectors both in vitro and in vivo, the expression of foreign genes in such vectors cannot be easily regulated. Of the known eukaryotic regulatory systems, the tetracycline-inducible gene expression system is perhaps the most widely used because of its induction characteristics and because of the well-known pharmacological properties of tetracycline (Tet) and analogs such as doxycycline. Here, we describe the adaptation of the Tet-inducible system for use in replication-incompetent HSV vectors. HSV vectors were constructed that contained several types of Tet-inducible promoters for foreign gene expression. These promoters contained a tetracycline response element (TRE) linked to either a minimal cytomegalovirus (CMV) immediate-early promoter, a minimal HSV ICP0 promoter, or a truncated HSV ICP0 promoter containing one copy of the HSV TAATGARAT cis-acting immediate-early regulatory element (where R represents a prime base). All three promoter constructs were regulated appropriately by doxycycline, as shown by the expression of the marker gene lacZ in cell lines engineered to express Tet transactivators. The ICP0 promoter constructs expressed the highest and most sustained levels of lacZ, but the CMV promoter construct had the highest relative level of induction, suggesting their use in different applications. To extend the utility of Tet-regulated HSV vectors, vectors were constructed that coexpressed an inducible Tet transactivator in addition to the inducible lacZ marker gene. This modification resulted in tetracycline-inducible gene expression that was not restricted to specific cell lines, and this vector was capable of inducible expression in irreversibly differentiated NT2 cells (NT-neurons) for several days. Finally, HSV vectors were constructed that expressed modified Tet transactivators, resulting in improved induction properties and indicating the flexibility of the Tet-regulated system for regulation of foreign gene expression in HSV vector-infected cells.
Our knowledge of the pharmacogenetics of warfarin and clopidogrel continues to expand as we learn more about the individual genetic variations that contribute to the drugs' efficacy and toxicity. We aim to review the recent developments in the field and discuss the clinical implications for the treatment of ischemic stroke patients. Despite recent advances, there is still insufficient data to suggest that routine genetic testing improves outcomes in patients treated with warfarin or clopidogrel for prevention of stroke.
A 37-year-old woman without significant medical history was seen at an outside facility with 7 days of headache and fluctuating right hemiparesis. She had a normal head computed tomography (CT). She was diagnosed with migraine, received analgesics, and was discharged. Her headache and hemiparesis had improved but did not completely resolve. Three days later, she presented to a second facility with the same symptoms of headache and right-sided weakness and more recent onset of nausea and vomiting. She was again treated for migraine but developed worsening hemiparesis and difficulty with secretions requiring intubation. Magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) revealed basilar artery occlusion (BAO) and left vertebral artery dissection. She underwent successful endovascular recanalization of the basilar artery but severe neurological deficits remained. Case TwoA 41-year-old was brought to the emergency department where she was poorly responsive but had a nonfocal neurological examination. Urine toxicology showed cocaine and marijuana. Head CT was limited by motion but was otherwise unremarkable. She was initially treated for presumed seizures, but her level of consciousness worsened and she was intubated. She was empirically treated for meningitis/encephalitis. Thirty-six hours after admission when the cerebrospinal fluid was found to be normal and she failed to improve, magnetic resonance imaging and magnetic resonance angiography was performed, which demonstrated BAO with a large pontine infarct. Work-up showed lupus anticoagulant. Case ThreeA 45-year-old woman with lupus presented with 24 hours of nausea/vomiting, intermittent dizziness, dysarthria, and rightsided hemiparesis. Head CT was unremarkable. On admission, neurological examination showed right facial droop, dysarthria, right-sided hemiparesis, hyperreflexia, and a right extensor plantar reflex. Non-vascular etiologies were pursued initially. One day after presentation, worsening of right-sided weakness and headache prompted vascular imaging showing proximal BAO. Endovascular recanalization was attempted but was unsuccessful. Case FourA 57-year-old man with a history of stent-assisted coiling of a basilar artery aneurysm presented with brief loss of consciousness, transient dysarthria, decreased sensation in his left face, and left upper extremity drift. Head CT showed stent artifact. Intravenous tPA was not given because of his low National Institute of Health stroke scale of 2. He then developed seizure-like activity, deteriorated further neurologically, and required intubation. He was treated for seizures/nonconvulsive status epilepticus and transferred to a tertiary facility. On arrival, he was unresponsive, had absent brain stem reflexes, and extremity movement limited to triple flexion. Repeat head CT demonstrated extensive brain stem hypodensity. Diagnostic angiography demonstrated BAO, but no intervention was attempted because of extensive infarction. It was later learned that he had not taken antiplatelet agent...
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