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Establishing, maintaining, and removing histone post-translational modifications associated with heterochromatin is critical for shaping genomic structure and function as a cell navigates different stages of development, activity, and disease. Dynamic regulation of the repressive chromatin landscape has been documented in several key cell states - germline cells, activated immune cells, actively replicating, and quiescent cells - with notable variations in underlying mechanisms. Here, we discuss the role of cell states of these diverse contexts in directing and maintaining observed chromatin landscapes. These investigations reveal heterochromatin architectures that are highly responsive to the functional context of a cell's existence and, in turn, their contribution to the cell's stable identity., (© 2024 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society.)

Stem cells have lower facultative heterochromatin as defined by trimethylation of histone H3 lysine 27 (H3K27me3) compared to differentiated cells. However, the mechanisms underlying these differential H3K27me3 levels remain elusive. Because H3K27me3 levels are diluted two-fold in every round of replication and then restored through the rest of the cell cycle, we reasoned that the cell cycle length could be a key regulator of total H3K27me3 levels. Here, we propose that a fast cell cycle restricts H3K27me3 levels in stem cells. To test this model, we determined changes to H3K27me3 levels in mESCs globally and at specific loci upon G1 phase lengthening - accomplished by thymidine block or growth in the absence of serum (with the "2i medium"). H3K27me3 levels in mESC increase with G1 arrest when grown in serum and in 2i medium. Additionally, we observed via CUT&RUN and ChIP-seq that regions that gain H3K27me3 in G1 arrest and 2i media overlap, supporting our model of cell cycle length as a critical regulator of the stem cell epigenome and cellular identity. Furthermore, we demonstrate the inverse effect - that G1 shortening in differentiated cells results in a loss of H3K27me3 levels. Finally, in tumor cells with extreme H3K27me3 loss, lengthening of the G1 phase leads to H3K27me3 recovery despite the presence of the dominant negative, sub-stoichiometric H3.1K27M mutation. Our results indicate that G1 length is an essential determinant of H3K27me3 landscapes across diverse cell types.

Facultative heterochromatinization of genomic regulators by Polycomb repressive complex (PRC) 1 and 2 is essential in development and differentiation; however, the underlying molecular mechanisms remain obscure. Using genetic engineering, molecular approaches, and live-cell single-molecule imaging, we quantify the number of proteins within condensates formed through liquid-liquid phase separation (LLPS) and find that in mouse embryonic stem cells (mESCs), approximately 3 CBX2 proteins nucleate many PRC1 and PRC2 subunits to form one non-stoichiometric condensate. We demonstrate that sparse CBX2 prevents Polycomb proteins from migrating to constitutive heterochromatin, demarcates the spatial boundaries of facultative heterochromatin, controls the deposition of H3K27me3, regulates transcription, and impacts cellular differentiation. Furthermore, we show that LLPS of CBX2 is required for the demarcation and deposition of H3K27me3 and is essential for cellular differentiation. Our findings uncover new functional roles of LLPS in the formation of facultative heterochromatin and unravel a new mechanism by which low-abundant proteins nucleate many other proteins to form compartments that enable them to execute their functions., Competing Interests: DECLARATION OF INTERESTS The authors declare no competing financial interest.

Lanthipeptides represent a large class of cyclic natural products defined by the presence of lanthionine (Lan) and methyllanthionine (MeLan) cross-links. With the advances in DNA sequencing technologies and genome mining tools, new biosynthetic enzymes capable of installing unusual structural features are continuously being discovered. In this study, we investigated an O -methyltransferase that is a member of the most prominent auxiliary enzyme family associated with class I lanthipeptide biosynthetic gene clusters. Despite the prevalence of these enzymes, their function has not been established. Herein, we demonstrate that the O -methyltransferase OlvS A encoded in the olv gene cluster from Streptomyces olivaceus NRRL B-3009 catalyzes the rearrangement of a highly conserved aspartate residue to a β-amino acid, isoaspartate, in the lanthipeptide OlvA(BCS A ). We elucidated the NMR solution structure of the GluC-digested peptide, OlvA(BCS A ) GluC , which revealed a unique ring topology comprising four interlocking rings and positions the isoaspartate residue in a solvent exposed loop that is stabilized by a MeLan ring. Gas chromatography-mass spectrometry analysis further indicated that OlvA(BCS A ) contains two dl-MeLan rings and two Lan rings with an unusual ll-stereochemistry. Lastly, in vitro reconstitution of OlvS A activity showed that it is a leader peptide-independent and S -adenosyl methionine-dependent O -methyltransferase that mediates the conversion of a highly conserved aspartate residue in a cyclic substrate into a succinimide, which is hydrolyzed to generate an Asp or isoAsp containing peptide. This overall transformation converts an α-amino acid into a β-amino acid in a ribosomally synthesized peptide, via an electrophilic intermediate that may be the intended product.

Background: Human immunodeficiency virus (HIV) infection remains a serious immunological disease with new infections in the U.S. disproportionately reported in minority populations. For many years, the District of Columbia (DC) has reported the highest HIV infection rate in the nation. Drug abuse and addiction is also prevalent in DC and has traditionally been linked to HIV/AIDS because of the likelihood for opportunistic infections. Despite this data, the relationship between HIV status, drugs of abuse, and the incidence of neurological disorders are scarcely reported for minority populations., Method: We carried out a retrospective study on the prevalence of substance abuse in HIV and their association with neuropsychiatric comorbidities in an African American subpopulation in Washington DC., Findings: Our data suggests an 86 percent prevalence of drug use in the HIV patients with neuropsychiatric comorbidities, with cocaine use being significantly higher in patients with major depressive disorder (MDD) and bipolar disorder (BD), whereas PCP use was associated with patients with schizophrenia. The mean CD4 count was elevated in patients with neuropsychiatric disease, and specifically in MDD patients. CD8 counts were elevated as expected for HIV status but were not influenced by disease diagnosis. A majority (2/3) of patients were on HAART therapy, however the records did not account for adherence., Conclusion: These data suggest that neuropsychiatric comorbidities are independent of HIV disease progression but are correlated with certain illicit drugs of abuse.

Orexin/hypocretin-containing neurons in lateral hypothalamus (LH) are implicated in the neurobiology of nicotine addiction. However, the neuroanatomical relationships between orexin-neurons/nerve fibers and nicotine-activated cells within the reward-addiction neurocircuitry is not known. In the present study in mice, we first used c-Fos immunohistochemistry to identify CNS cells stimulated by an acute single injection of nicotine (NIC, 2 mg/kg, IP). Sequential double-labelling was then performed to identify the location of orexin-containing neurons and nerve fibers with respect to NIC-induced c-Fos activated cells and/or tyrosine hydroxylase (TH) immunoreactive (IR) cells of the mesocorticolimbic reward-addiction pathways. Orexin-IR nerve fibers and terminals were detected at multiple sites of the NIC reward-addiction circuitry in close apposition to, and intermingled with, NIC-induced c-Fos-IR cells of locus coeruleus (LC), ventral tegmental area (VTA), nucleus accumbens (Acb), LH and paraventricular thalamic nucleus (PVT). Double-labelling of orexin with TH showed frequent contact between orexin-IR nerve fibers and noradrenergic cells of LC. However, there was infrequent contact between the orexinergic fibers and the TH-expressing dopaminergic cells of VTA, dorsal raphe nucleus (DR), posterior hypothalamus (DA11), arcuate hypothalamic nucleus (DA12) and periventricular areas (DA14). The close anatomical contact between orexinergic nerve fibers and NIC-activated cells at multiple sites of the reward-addiction pathways suggests that orexinergic projections from LH are likely to be involved in modulating activity of the neurons that are directly impacted by acute administration of nicotine., Competing Interests: The authors declare that there are no conflicts of interest.

The sensory experience of smoking is a key component of nicotine addiction known to result, in part, from stimulation of nicotinic acetylcholine receptors (nAChRs) at peripheral sensory nerve endings. Such stimulation of nAChRs is followed by activation of neurons at multiple sites in the mesocorticolimbic reward pathways. However, the neurochemical profiles of CNS cells that mediate the peripheral sensory impact of nicotine remain unknown. In the present study in mice, we first used c-Fos immunohistochemistry to identify CNS cells stimulated by nicotine (NIC, 40 μg/kg, IP) and by a peripherally-acting analog of nicotine, nicotine pyrrolidine methiodide (NIC-PM, 30 μg/kg, IP). Sequential double-labelling was then performed to determine whether noradrenergic and dopaminergic neurons of the nicotine reward-addiction circuitry were primary targets of NIC and NIC-PM. Double-labelling of NIC and/or NIC-PM activated c-Fos immunoreactive cells with tyrosine hydroxylase (TH) showed no apparent c-Fos expression by the dopaminergic cells of the ventral tegmental area (VTA). With the exception of sparse numbers of TH immunoreactive D11 cells, dopamine-containing neurons in other areas of the reward-addiction circuitry, namely periaqueductal gray, and dorsal raphe, were also devoid of c-Fos immunoreactivity. Noradrenergic neurons of locus coeruleus (LC), known to innervate VTA, were activated by both NIC and NIC-PM. These results demonstrate that noradrenergic neurons of LC are among the first structures that are stimulated by single acute IP injection of NIC and NIC-PM. Dopaminergic neurons of VTA and other CNS sites, did not respond to acute IP administration of NIC or NIC-PM by induction of c-Fos.

Background: We sought to investigate the frequency of microbleed development following intracerebral hemorrhage in a predominantly African-American population and to identify predictors of new microbleed formation., Aims And/or Hypothesis: To investigate the frequency and predictors of new microbleeds following intracerebral hemorrhage., Methods: The DECIPHER study was a prospective, longitudinal, magnetic resonance-based cohort study designed to evaluate racial/ethnic differences in risk factors for microbleeds and to evaluate the prognostic impact of microbleeds in this intracerebral hemorrhage population. We evaluated new microbleed formation in two time periods: from baseline to 30 days and from 30 days to year 1., Results: Of 200 subjects enrolled in DECIPHER, 84 had magnetic resonance imaging at all required time points to meet criteria for this analysis. In the baseline to day 30 analysis, 11 (13·1%) had new microbleeds, compared with 25 (29·8%) in the day 30 to year 1 analysis. Logistic regression analysis demonstrated that baseline number of microbleeds [odds ratio 1·05 (95% confidence interval 1·01, 1·08), P = 0·01] was associated with new microbleed formation at 30 days. A logistic regression model predicting new microbleed at one-year included baseline number of microbleeds [odds ratio 1·05 (1·00, 1·11), P = 0·046], baseline age [odds ratio 1·05 (1·00, 1·10), P = 0·04], and white matter disease score [odds ratio 1·18 (0·96, 1·45). P = 0·115]. Overall, 28 of 84 (33·3%) intracerebral hemorrhage subjects formed new microbleeds at some point in the first year post-intracerebral hemorrhage., Conclusions: We found that one-third of intracerebral hemorrhage subjects in this cohort surviving one-year developed new microbleeds, which suggests a dynamic and rapidly progressive vasculopathy. Future studies are needed to examine the impact of new microbleed formation on patient outcomes., (© 2015 World Stroke Organization.)

Direct actions of nicotine in the CNS appear to be essential for its reinforcing properties. However, activation of nicotinic acetylcholine receptors (nAChRs) on afferent sensory nerve fibers is an important component of addiction to, and withdrawal from, cigarette smoking. The aim of the present study was to identify the neuroanatomical substrates activated by the peripheral actions of nicotine and to determine whether these sites overlap brain structures stimulated by direct actions of nicotine. Mouse brains were examined by immunohistochemistry for c-Fos protein after intraperitoneal injection of either nicotine hydrogen tartrate salt (NIC; 30 and 40 μg/kg) or nicotine pyrrolidine methiodide (NIC-PM; 20 and 30 μg/kg). NIC-PM induced c-Fos immunoreactivity (IR) at multiple brain sites. In the brainstem, c-Fos IR was detected in the locus coeruleus, laterodorsal tegmental nucleus, and pedunculotegmental nucleus. In the midbrain, c-Fos IR was observed in areas overlapping the ventral tegmental area (VTA), which includes the paranigral nucleus, parainterfascicular nucleus, parabrachial pigmental area, and rostral VTA. Other structures of the nicotine brain-reward circuitry activated by NIC-PM included the hypothalamus, paraventricular thalamic nucleus, lateral habenular nucleus, hippocampus, amygdala, accumbens nucleus, piriform cortex, angular insular cortex, anterior olfactory nucleus, lateral septal nucleus, bed nucleus of stria terminalis, cingulate and medial prefrontal cortex, olfactory tubercle, and medial and lateral orbital cortex. NIC, acting through central and peripheral nAChRs, produced c-Fos IR in areas that overlapped NIC-PM-induced c-Fos-expressing sites. These neuroanatomical data are the first to demonstrate that the CNS structures that are the direct targets of nicotine are also anatomical substrates for the peripheral sensory impact of nicotine., (© 2014 Wiley Periodicals, Inc.)

The Korsakoff syndrome is defined as "an abnormal mental state in which memory and learning are affected out of all proportion to other cognitive functions in an otherwise alert and responsive patient." Confabulation refers to false or erroneous memories arising, not deliberately, in the context of a neurological amnesia and is often thought of as pathognomonic of the Korsakoff syndrome. Although the exact pathophysiology is unknown, various studies have identified brain lesions in the thalami, mammillary bodies, and frontal cortex. We report a case of a 68-year-old male presenting with acute altered mental status on July 16, 2015. The neuropsychological dysfunctions included prominent Korsakoff's syndrome, which became apparent when the altered mental status resolved. Amnesia was accompanied by prominent confabulation, disorientation, and lack of insight into his own disability. Neuroradiological data indicated that the intralaminar and dorsomedial nuclei in bilateral thalami were infarcted by occlusion of the artery of Percheron. We believe that ours is one of few reported cases of Korsakoff syndrome in a patient with infarction involving the territory of the artery of Percheron. We conclude that bilateral thalamic lesions could cause Korsakoff's syndrome and the intralaminar and dorsomedial nuclei might be important structures in the pathogenesis of confabulation.

Background: The goal of the present study was to determine the prevalence of left ventricular systolic dysfunction (LVSD) and associated clinical correlates in African Americans (AA) diagnosed with ischemic stroke (IS)., Methods: Retrospective chart analysis was done on all diagnosed AA IS patients between January 2010 and March 2012. Patients with atrial fibrillation were excluded. A total of 147 patients were included in the study. Transthoracic 2-dimensional echocardiography was used to assess left ventricular systolic function, and study groups were categorized as normal, mild, moderate, and severely abnormal, based on the ejection fraction (EF). Available imaging studies were analyzed for data collection. Logistic regression and Pearson chi-square tests were performed., Results: Normal EF was present in 114 of 147 patients (78%). Mild abnormality was present in 9 of 147 (6%), moderate in 8 of 147 (5%), and severe in 16 of 147 (11%) patients. In patients with mildly reduced EF, smoking was the most common (RF). In patients with moderately and severely reduced EFs, hypertension was the most common RF. History of smoking was commonly found in systolic dysfunction group compared with normal group (P = .001). Logistic regression analysis revealed that smoking and advanced age were the significant predictors for LVSD. Large-vessel IS were more common in systolic dysfunction group than normal EF group (P = .017)., Conclusions: Prevalence of LVSD in AA with IS was 22% in our study. Smoking was a significant modifiable RF associated with systolic dysfunction. A history of smoking and higher age could predict the occurrence of LVSD. There were more large-vessel IS in patients with LVSD., (Copyright © 2014 National Stroke Association. Published by Elsevier Inc. All rights reserved.)

Akinetic mutism is described in various clinical presentations but typically is defined as a state wherein the patient appears awake but does not move or speak. It can be divided into two different subtypes; the most common subtypes depend on the lesion location, mesencephalic-diencephalic region, also called apathetic akinetic mutism (somnolent mutism), and those involving the anterior cingulate gyrus and adjacent frontal lobes called hyperpathic akinetic mutism. The pathway of akinetic mutism is believed to originate from circuits that link the frontal and subcortical structures. This case reports a 48-year-old African American female with bilateral anterior cerebral artery stroke and akinetic mutism with coexisting thyroid storm. This patient with bilateral anterior cerebral artery infarcts presented with characteristics that are typical for akinetic mutism such as having intact eye movements but an inability to respond to auditory or visual commands. With the incidence of bilateral anterior cerebral artery (ACA) ischemic stroke being rare and the incidence of akinetic mutism secondary to ischemic stroke even rarer, we suspect that this patient potentially had a unilateral occlusion of anomalous anterior cerebral vasculature.

Acute disseminated encephalomyelitis is a demyelinating disease, typically occurring in children following a febrile infection or a vaccination. Primary and secondary immune responses contribute to inflammation and subsequent demyelination, but the exact pathogenesis is still unknown. Diagnosis of acute disseminated encephalomyelitis is strongly suggested by temporal relationship between an infection or an immunization and the onset of neurological symptoms. Biopsy is definitive. In general, the disease is self-limiting and the prognostic outcome is favorable with anti-inflammatory and immunosuppressive agents. Locked-in syndrome describes patients who are awake and conscious but have no means of producing limb, speech, or facial movements. Locked-in syndrome is a rare complication of acute disseminated encephalomyelitis. We present a case of incomplete locked-in syndrome occurring in a 34-year-old male secondary to acute disseminated encephalomyelitis. Our case is unique, as acute disseminated encephalomyelitis occurred in a 34-year-old which was poorly responsive to immunosuppression resulting in severe disability.

Background and Purpose: To investigate the relationship between chronic kidney disease (CKD) and MRI-defined cerebral microbleeds (CMB), a harbinger of future intracerebral hemorrhage (ICH), among patients with a recent history of primary ICH., Methods: Using data from a predominantly black cohort of patients with a recent ICH-enrolled in an observational study between September 2007 and June 2011, we evaluated the association between CKD (defined as estimated low glomerular filtration rate<60 mL/min per 1.73 m(2)) and CMB on gradient-echo MRI. Multivariable models were generated to determine the contribution of CKD to the presence, number, and location of CMB., Results: Of 197 subjects with imaging data, mean age was 59 years, 48% were women, 73% were black, 114 (58%) had ≥1 CMBs, and 52 (26%) had CKD. Overall, CKD was associated with presence of CMB (adjusted odds ratio, 2.70; 95% confidence interval [CI], 1.10-6.59) and number of CMB (adjusted relative risk, 2.04; 95% CI, 1.27-3.27). CKD was associated with CMB presence (adjusted odds ratio, 3.44; 95% CI, 1.64-7.24) and number (adjusted relative risk, 2.46; 95% CI, 1.11-5.42) in black patients, but not CMB presence (adjusted odds ratio, 3.00; 95% CI, 0.61-14.86) or number (adjusted relative risk, 1.03; 95% CI: 0.22-4.89) in non-Hispanic white patients (interactions by race were statistically not significant)., Conclusions: CKD is associated with a greater presence and number of CMB in ICH patients, particularly in patients of black race. Future studies should assess whether low estimated glomerular filtration rate may be a CMB risk marker or potential therapeutic target for mitigating the development of CMB.

Posterior reversible encephalopathy syndrome (PRES) is a clinicoradiological syndrome in which patients present with an acute or subacute clinical presentation of seizures, visual disturbances, headache, and altered mental status. The pathophysiology of PRES may be explained by endothelial dysfunction that leads to transudation of fluids and protein, resulting in vasogenic cerebral edema. PRES is typically associated with many conditions such as hypertension, uremia, immunosuppressive drugs, and sepsis. This is a case report of a 39-year-old woman with untreated HIV infection and end-stage renal disease (ESRD) who developed PRES with a normal blood pressure and no other known causes of PRES. Untreated HIV is associated with known endothelial dysfunction and we believe that this, in combination with her untreated end-stage renal disease, contributed to her unique presentation of PRES. Although uncommon in HIV-infected patients and challenging to diagnose, prompt recognition of PRES is critical to provide appropriate care and ensure reversibility of the vasogenic edema seen in PRES.

Immune reconstitution inflammatory syndrome (IRIS) development in HIV with preexistent progressive multifocal leukoencephalopathy (PML) has been extensively studied. PML-IRIS typically manifests clinically as new or worsening neurologic symptoms in conjunction with enlarging CNS lesions and occurs in approximately 10-20 percent of HIV-infected patients with PML who begin HAART. Likewise, Multicentric Castleman's Disease (MCD), a rare malignant lymphoproliferative disorder, has a strong and well-known association with HIV. Our case provides a rare instance of PML-IRIS in combination with MCD in an HIV-positive individual. The combination of all three diseases has never been reported in the literature. Both MCD and PML were present during initial determination of HIV infection in our patient and their disease courses were altered during the subsequent development of IRIS.

Previous studies have shown that molecules of the taste transduction pathway may serve as biochemical markers for chemoreceptive cells in respiratory and gastrointestinal tracts. In this study, we tested the hypothesis that brainstem neurons contain signaling molecules similar to those in taste buds which may sense the chemical composition of brain extracellular fluids. We used the reverse transcription polymerase chain reaction (RT-PCR), Western blot and immunohistochemical techniques to evaluate presence of different bitter-responsive type 2 taste receptors (T2Rs), their associated G-protein α-gustducin, the downstream signaling molecules phospholipase C isoform β2 (PLC-β2) and transient receptor potential melastatin 5 (TRPM5) in the brainstem of rats. RT-PCR confirmed the mRNA coding for α-gustducin, PLC-β2, TRPM5 and rT2R1 but not that of rT2R16, rT2R26 and rT2R38 in the medulla oblongata. Western blotting confirmed the presence of α-gustducin at the protein level in rat brainstem. Immunohistochemistry identified cells expressing α-gustducin and PLC-β2 at multiple cardiorespiratory and CO(2)/H(+) chemosensory sites, including rostral ventral medulla, facial, parapyramidal, solitary tract, hypoglossal and raphe nuclei. In the medullary raphe, α-gustducin and PLC-β2 were colocalized with a subpopulation of tryptophan hydroxylase (TPH)-immunoreactive serotonergic neurons, a subset of which has respiratory CO(2)/H(+) chemosensitivity. Presence of the T2R1 gene and other genes and proteins of the bitter taste transduction pathway in the brainstem implies additional functions for taste receptors and their effector molecules apart from their gustatory function., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Nicotine in tobacco smoke is thought to stimulate sensory nerve fibers by receptors that are located on airway epithelial cells and on terminal branches of C-fiber afferents, but the exact neurochemical substrate that mediates the sensory effects of nicotine associated with cigarette smoking is not clear. ATP and nitric oxide (NO) have both been implicated in lung responsiveness to airborne chemicals such as nicotine. However, the neuroanatomical and functional relationships between nicotinic acetylcholine receptors (nAChRs), purinergic signaling, and NO are not known, and the main source of NO in the airways is not clear. In the present study, we performed RT-PCR to confirm the presence of mRNA for all three isoforms of nitric oxide synthase (NOS), neuronal (n-NOS), endothelial (e-NOS), and inducible (i-NOS), in the lung. Sequential double labeling was performed to assess the site of expression of the different NOS isoforms with respect to nAChRs and purinergic receptors (P2X3R) of the intrapulmonary airways. RT-PCR confirmed the presence of n-NOS, e-NOS, and i-NOS in the lung, and immunohistochemical studies verified their expression by epithelial cells at all levels of the intrapulmonary airways, including the terminal and respiratory bronchioles. Sequential double labeling demonstrated coexpression of n-NOS and/or i-NOS with nAChR- and P2X3R-expressing cells. These neuroanatomical findings suggest that bronchial epithelial cells may be a primary source of NO in the intrapulmonary airways and that the production and release of NO may be regulated by an autocrine/paracrine signaling system involving nAChRs and P2X3Rs., (© 2011 Wiley Periodicals, Inc.)

Objective: This study was undertaken to determine the prevalence, characteristics, risk factors, and temporal profile of concurrent ischemic lesions in patients with acute primary intracerebral hemorrhage (ICH)., Methods: Patients were recruited within a prospective, longitudinal, magnetic resonance imaging (MRI)-based study of primary ICH. Clinical, demographic, and MRI data were collected on all subjects at baseline and 1 month., Results: Of the 138 patients enrolled, mean age was 59 years, 54% were male, 73% were black, and 84% had a history of hypertension. At baseline, ischemic lesions on diffusion-weighted imaging (DWI) were found in 35% of patients. At 1 month, lesions were present in 27%, and of these lesions, 83% were new and not present at baseline. ICH volume (p = 0.025), intraventricular hemorrhage (p = 0.019), presence of microbleeds (p = 0.024), and large, early reductions in mean arterial pressure (p = 0.003) were independent predictors of baseline DWI lesions. A multivariate logistical model predicting the presence of 1-month DWI lesions included history of any prior stroke (p = 0.012), presence of 1 or more microbleeds (p = 0.04), black race (p = 0.641), and presence of a DWI lesion at baseline (p = 0.007)., Interpretation: This study demonstrates that >⅓ of patients with primary ICH have active cerebral ischemia at baseline remote from the index hematoma, and ¼ of patients experience ongoing, acute ischemic events at 1 month. Multivariate analyses implicate blood pressure reductions in the setting of an active vasculopathy as a potential underlying mechanism. Further studies are needed to determine the impact of these lesions on outcome and optimal management strategies to arrest vascular damage., (Copyright © 2012 American Neurological Association.)

Hypercoagulability occurs in 15% of patients with malignancy and represents a clinical spectrum ranging from abnormal coagulation tests but no clinically evident thromboembolic disease, to arterial and venous thrombosis, migratory thrombophlebitis, nonbacterial thrombotic endocarditis (NBTE) and disseminated intravascular coagulation. The combination of increased procoagulant activity and decreased fibrinolytic activity accelerates the prothrombotic potential of endothelial cells in malignancy. NBTE is a rare manifestation of cancer-induced hypercoagulability and is commonly seen with mucin-producing adenocarcinomas, but rarely seen with ovarian clear cell carcinoma (OCCC). Cerebrovascular embolization ranges from 14-91% in NBTE. We report a rare case of a 62-year-old female presenting with occipital stroke as a consequence of NBTE in OCCC. Association of NBTE in OCCC has only been reported in 2 cases so far, but presentation with stroke has never been reported in the literature.

A rare case of acute ischemic stroke in a young patient with iron deficiency anemia (IDA) is reported. IDA has been suggested to have an association with stroke, but few cases have proven it thus far. Three physiological mechanisms explaining IDA to ischemic stroke include a hypercoagulable state secondary to IDA, thrombocytosis secondary to IDA, and anemic hypoxia induced by IDA. Our paper shows an example of a hypoxia-induced stroke secondary to IDA in a young woman with menorrhagia. Thrombus formation was ruled out as the Magnetic Resonance Angiogram (MRA) showed no evidence. As all other known causes for stroke were ruled out, the patient's IDA is a reasonable cause for her stroke. Iron deficiency decreases the amount of hemoglobin, which consequently decreases the amount of oxygen in the blood resulting in low-oxygen delivery to the brain. This causes hypoxic conditions in the brain, leading to death of brain tissue. Thus, we suggest a possible relationship between IDA and ischemic stroke in young adults. Considering IDA as one of the risk factors for ischemic stroke and treating with timely transfusions would be an important step one can take to prevent stroke.

Acquired myasthenia gravis is a relatively uncommon disorder, with prevalence rates that have increased to about 20 per 100,000 in the US population. This autoimmune disease is characterized by muscle weakness that fluctuates, worsening with exertion, and improving with rest. In about two-thirds of the patients, the involvement of extrinsic ocular muscle presents as the initial symptom, usually progressing to involve other bulbar muscles and limb musculature, resulting in generalized myasthenia gravis. Although the cause of the disorder is unknown, the role of circulating antibodies directed against the nicotinic acetylcholine receptor in its pathogenesis is well established. As this disorder is highly treatable, prompt recognition is crucial. During the past decade, significant progress has been made in our understanding of the disease, leading to new treatment modalities and a significant reduction in morbidity and mortality.

Rationale: PROTECT DC examines whether stroke navigators can improve cardiovascular risk factors in urban underserved individuals newly hospitalized for stroke or ischemic attack. Within one-year of hospital discharge, up to one-third of patients no longer adhere to secondary prevention behaviors. Adherence rates are lower in minority-underserved groups, contributing to health disparities. In-hospital programs increase use of stroke prevention therapies but may not be as successful in underserved individuals. In these groups, low literacy, limited healthcare access, and sparse community resources may reduce adherence. Lay community health workers (navigators) improve adherence in other illnesses through education and assisting in overcoming barriers to achieving desired health behaviors and obtaining needed healthcare services., Aims and Design: PROTECT DC is a Phase II, single-blind, randomized, controlled trial comparing in-hospital education plus stroke navigators to usual care. Atherogenic ischemic stroke and transient ischemic attack survivors are recruited from Washington, DC hospitals. Navigators meet with participants during the index hospitalization, perform home visits, and meet by phone. They focus on stroke education, medication compliance, and overcoming practical barriers to adherence. The interventions are driven by the theories of reasoned action and planned behavior., Study Outcomes: The primary dependent measure is a summary score of four objective measures of stroke risk factor control: systolic blood pressure, low-density lipoprotein, hemoglobin Hb A1C, and antiplatelet agent pill counts. Secondary outcomes include stroke knowledge, exercise, dietary modification, and smoking cessation., Conclusion: PROTECT DC will determine whether a Phase III trial of stroke navigation for urban underserved individuals to improve adherence to secondary stroke prevention behaviors is warranted., (© 2011 The Authors. International Journal of Stroke © 2011 World Stroke Organization.)

Background and Purpose: Some prior studies have shown that racial disparities exist in intravenous tissue plasminogen activator (tPA) use for acute ischemic stroke. We sought to determine whether race was associated with tPA treatment for stroke in a predominantly black urban population., Methods: Systematic chart abstraction was performed on consecutive hospitalized patients with ischemic stroke from all 7 acute care hospitals in the District of Columbia from February 1, 2008, to January 31, 2009., Results: Of 1044 patients with ischemic stroke, 74% were black, 19% non-Hispanic white, and 5% received intravenous tPA. Blacks were one third less likely than whites to receive intravenous tPA (3% versus 10%, P<0.001). However, blacks were also less likely than whites to present within 3 hours of symptom onset (13% versus 21%, P=0.004) and also less likely to be tPA-eligible (5% versus 13%, P<0.001). Of those who presented within 3 hours, blacks were almost half as likely to be treated with intravenous tPA than whites (27% versus 46%, P=0.023). The treatment rate for tPA-eligible patients was similar for blacks and whites (70% versus 76%, P=0.62)., Conclusions: In this predominantly black urban population hospitalized for acute ischemic stroke, blacks were significantly less likely to be treated with intravenous tPA due to contraindications to treatment, delayed presentation, and stroke severity. Effective interventions designed to increase treatment in this population need to focus on culturally relevant education programs designed to address barriers specific to this population.

Objective: The protective effect of physical activity (PA) on risk of stroke remains controversial as a result of lack of insight into the sources of heterogeneity between studies. We performed a comprehensive meta-analysis of studies to (1) quantify the association between PA level and risk of stroke outcomes and (2) test the hypothesis that the association of PA level with stroke outcomes will be similar between men and women. The outcome measures are stroke incidence, stroke mortality, or both., Methods: Cohort studies were identified by searching MEDLINE and EMBASE (from 1986 to 2005) and meta-analysis conducted according to meta-analysis of Observational Studies in Epidemiology (MOOSE) group recommendations. Data were reported as pooled relative risk (RR) and 95% confidence intervals (CI) using random-effects models to assess the association of stroke outcomes with PA level. Heterogeneity was investigated, and sensitivity analysis was performed. Stratified analysis by gender was performed., Results: Of 992 articles, 13 satisfied all eligibility criteria and were studied. Compared with low PA, moderate PA caused an 11% reduction in risk of stroke outcome (RR = 0.89, 95% CI 0.86-0.93, p < 0.01) and high PA a 19% reduction (RR = 0.81, CI 0.77-0.84, p < 0.01). Among the men, results showed a 12% reduction in risk associated with moderate PA (RR = 0.88, CI 0.82-0.94, p < 0.01) and 19% reduction for high PA (RR = 0.81, CI 0.75-0.87, p < 0.01). Among the women, results showed a 24% reduction in risk for high PA (RR = 0.76, CI 0.64-.89, p < 0.01). There was, however, no significant risk reduction associated with a moderate PA level in women., Conclusions: Increased PA level appears beneficial in reduction of risk of stroke and related outcomes. However, higher levels of PA may be required in women to achieve as significant a risk reduction as in men. An exercise regimen tailored to women to improve related physiological mechanisms will likely be beneficial.

Aims: The ability to sense the bitter taste of nicotine is an important component of addiction to, and withdrawal from, cigarette smoking. alpha-Gustducin and phospholipase C-beta2 (PLC-beta2), molecules involved in the taste transduction pathway, have been identified in airway epithelial solitary chemosensory cells (SCCs). Airway epithelial cells also express multiple nicotinic acetylcholine receptors (nAChRs). However, the relationship between nAChRs and molecules of taste transduction in response to nicotine is not known. This study was designed to determine whether nAChRs and the taste transduction molecules alpha-gustducin, PLC-beta2 and bitter taste receptors (T2R38) reside at sites of the intrapulmonary airways where interaction with the nicotine components of cigarette smoke is likely., Main Methods: We used the reverse transcription-polymerase chain reaction (RT-PCR) to detect alpha-gustducin, PLC-beta2 and T2R38 mRNA and immunohistochemistry to localize expression of these proteins by nAChR expressing cells of the airway., Key Findings: RT-PCR demonstrated the presence of mRNA for alpha-gustducin, PLC-beta2 and T2R38. Immunohistochemistry showed the expression of alpha-gustducin, PLC-beta2 and T2R38 by subsets of epithelial cells at all levels of the intrapulmonary airways including bronchi, terminal and respiratory bronchioles. Double labeling demonstrated the co-expression of alpha-gustducin with alpha3, alpha4, alpha5, alpha7 and beta2, as well as, PLC-beta2 and T2R38 with alpha4, alpha5 and beta2 nAChR subunits., Significance: These findings provide morphological evidence for the presence of molecules of the bitter taste transduction pathway in nAChR expressing SCCs of the intrapulmonary airways. These SCCs may, thus, constitute a peripheral component of the bitter taste signal transduction pathway for nicotine., (Copyright 2010 Elsevier Inc. All rights reserved.)

Previous studies have suggested that sensory mechanisms may be important components of addiction to, and withdrawal from, cigarette smoking. The sensory and respiratory responses to nicotine are mediated, in part, by bronchopulmonary C-fiber afferents. Nicotine has a direct stimulatory effect on pulmonary sensory neurons, and nicotinic cholinergic receptors (nAChRs) composed of various combinations of alpha and beta subunits are known to be present in pulmonary ganglia. At the subcellular level, however, little is known about expression of nAChRs on sensory fibers in the intrapulmonary airways. The present study was therefore designed to evaluate the expression of nAChRs on a subset of intrapulmonary sensory nerve endings known to exhibit immunoreactivity for substance P (SP). The presence of nAChR subunits was first confirmed at the mRNA and protein levels in rat lung tissues by using RT-PCR and Western blot techniques. Then, double labeling of SP-immunoreactive (-IR) C-fibers and different nAChR subunits was performed. Alpha2, alpha3, alpha4, alpha5, alpha7, and beta2 subunits were detected at all levels of the intrapulmonary airways; including bronchi, terminal and respiratory bronchioles, alveolar walls, and alveolar macrophages. None of the nAChR subunits studied was expressed by the SP-IR C-fibers. However, SP-expressing C-fibers were observed in close proximity to and intermingling with nAChR-expressing airway epithelial cells. The close proximity of C-fibers to nAChR-expressing airway epithelial cells suggests that a component of nicotinic stimulation of SP-IR C-fiber afferents may be mediated by endogenous chemical substances released by nAChR-expressing epithelial cells., (Copyright 2008 Wiley-Liss, Inc.)

Introduction: Lemierre's syndrome is an extremely rare and almost universally fatal disease characterized as thrombophlebitis of the internal jugular venous system with subsequent metastatic infection. Fusobacterium necrophorum is the most common organism implicated in causation of Lemierre's syndrome. Group A Streptococcus has mainly been observed as a polymicrobial organism in the syndrome. We report a rare finding of a rare disease where Group A Streptococcus was the sole organism triggering Lemierre's syndrome. To our knowledge, this is only the third recorded patient with such an occurrence., Case Presentation: We describe a 9-year-old African American boy, who presented with otitis media and mastoiditis that culminated in Lemierre's syndrome. Isolates bore only Group A Streptococcus. The patient was appropriately treated and responded with full recovery from the syndrome., Conclusion: Since Lemierre's syndrome is classically detected by clinical diagnosis, these findings should prompt clinicians to consider Group A Streptococcus as an alternative catalyst. It should be pondered that patients who present with typical Group A streptococcal infections have the possibility for developing Lemierre's syndrome. Though this complication appears to be rare, early diagnosis and prompt intervention have proven critical in survival outcome. Indeed, what would seem to be a routine case of strep throat or otitis media easily treated with antibiotics could end up being an unalterable progression to death unless Lemierre's syndrome is immediately diagnosed and treated.

Introduction: The association of thymoma with myasthenia gravis (MG) is well known. Thymoma with sarcoidosis however, is very rare. We presented an interesting case with coexisting thymoma, MG and sarcoidosis., Case Presentation: A 59-year-old female patient with a history of sarcoidosis was admitted to the hospital with a one-day history of sudden onset of right-sided partial ptosis and diplopia. Neurosarcoidosis with cranial nerve involvement was considered, but was ruled out by the clinical findings, and MG was confirmed by the positive tensilon test, electrophysiological findings and positive acetylcholine receptor binding antibodies. On further evaluation, a CT chest scan showed a left anterior mediastinal mass and bilateral lymphadenopathy. Post surgical diagnosis confirmed the thymoma and sarcoidosis in the lymph nodes., Conclusion: When two or more diseases of undetermined origin are found together, several interesting questions are raised. It is important to first confirm the diagnoses individually. Immunologic mechanisms triggering the occurrence of these diagnoses together, are difficult to address. Although the coexistence of thymoma, MG and sarcoidosis may be coincidental, it is noteworthy to report this case because of the multiple interesting features observed as well as the rarity of occurrence.

Rostral ventral medulla (RVM) contains significant numbers of local GABAergic neurons which may subserve respiratory chemosensory and baroreceptor reflexes. Nicotinic mechanisms stimulate release of GABA in certain brainstem neurons. Whether the GABAergic neurons at RVM express nicotinic cholinergic receptors (nAChRs) is not known. We used glutamic acid decarboxylase 67-kDa isoform (GAD67) and parvalbumin (PV) as anatomical markers to identify the GABAergic neurons of the RVM and caudal pons and performed double labeling to evaluate the expression of alpha-7 and alpha-4 nAChRs by GAD67 and PV-imnunoreactive (ir) cells at these sites. GAD67-ir cells were found at the ventrolateral pontomedullary border in areas adjacent to the A5 noradrenergic cell group and overlapping the facial nucleus lateral subnuclei and para-facial zones. Of 205 GAD67-ir cells labeled at these sites, 74% exhibited immunoreactivity for alpha-7 nAChRs. Alpha-4 immunoreactivity was also present in 35% of GAD67-ir cells at these sites. The PV-ir cells of RVM and caudal pons were found medial to the facial nucleus and lateral to the pyramid in a column distinct from the GAD67-ir cells. Virtually all the PV-ir cells demonstrated immunoreactivity for alpha-4 nAChR (95%) and alpha-7 (93%) subunits of nAChRs. Differential expression of GAD67 and PV by neurons at the pontomedullary border implies that PV may not be a valid marker for GABAergic neurons. The expression of alpha-4 and alpha-7 nAChRs by GAD67-ir cells suggests nicotinic cholinergic modulation of GABAergic signaling at these ventrolateral pontomedullary sites.

The paraventricular nucleus of the hypothalamus (PVN) integrates multiple inputs via projections from arginine vasopressin (AVP)- and oxytocin (OXT)-containing neurons to the brain stem and spinal cord as well as regulates respiratory and cardiovascular stress-related responses, which also affect airway function. In the present study, we used immunocytochemistry and the retrograde transneuronal tracer, Bartha strain of pseudorabies virus expressing green fluorescent protein (PRV-GFP), to localize AVP- and OXT-producing neurons that project to airway-related vagal preganglionic neurons (AVPNs) innervating intrapulmonary airways. PRV-GFP was microinjected into the upper right lung lobe, and after 4 days survival, hypothalamic tissue sections were processed for co-expression of PRV-GFP and AVP or PRV-GFP and OXT. In addition, in a separate group of five rats, Phaseolus vulgaris leucoagglutinin (PHAL), an anterograde tracer, was injected unilaterally into the PVN and cholera toxin beta subunit was microinjected into the tracheal wall. Analysis of five successfully infected animals showed that 14% of PRV-GFP labeled neurons express AVP traits and 18% of transneuronally-labeled neurons contain OXT. Furthermore, the identified AVPNs innervating extrathoracic trachea receive axon terminals of the PVN neurons. The results indicate that AVP- and OXT-producing PVN cells, via direct projections to the AVPNs, could modulate cholinergic outflow to the airways, as a part of overall changes in response to stress.

Vascular occlusive diseases affect brain blood flow, brain metabolism and are associated with arterial ischemic stroke. This study was designed to measure the brain blood flow velocity, brain oxygenation, hemoglobin concentrations, hematocrit, and cell free hemoglobin at pre- and post-exchange red cell transfusion in an 18 year old male patient with sickle cell disease and moyamoya syndrome (MMS). Exchange transfusion increased cerebral oxygen saturation 12%, total hemoglobin concentration 2%, hemoglobin AA 80%, and reduced sickle (SS) hemoglobin 12%, arterializations 33%, and cell free hemoglobin 33%. Brain blood flow velocity values were unaffected by transfusion. These observations suggest that exchange transfusion increases the hemoglobin carrying capacity and reduces sickle hemoglobin and shunting of blood, which may improve the peripheral and cerebral oxygenation. Transfusion did not affect the brain blood flow in this patient. Therefore the risk of transient ischemic attack and arterial ischemic stroke from mms still exist.

Paroxysmal bi-parietal (vertex) discharges are evoked during sleep by full field stroboscopic light stimulation in approximately 20 per cent of children with a diagnosis of various seizure phenomena.

The most widely advocated drug that has been developed to decrease and possibly reverse the crippling effect of stroke is recombinant tissue plasminogen activator (rt-PA). In the treatment of ischemic stroke, rt-PA must be administered within the first 3 hr after the onset of symptoms for optimal efficacy and avoidance of life-threatening cerebral hemorrhage. This study sought to determine whether African-American stroke victims presented for treatment within the first 3 hr. In the study, we identified some of the more common reasons for the lack of prompt presentation. A prospective survey of 103 randomly selected acute stroke patients was performed. We found that less than half of this population sought assistance in the emergency department in time to take advantage of rt-PA therapy. When confronted with symptoms that were consistent with acute stroke, many patients either chose to ignore them or thought that they were experiencing transient phenomena. Three factors were identified as possible reasons for the lack of prompt response: (a) a lack of information about available treatment options; (b) the inability to recognize the early warning signs of an impending stroke; and (c) denial of illness. This study may help to evolve strategies that must be instituted to better educate the community about the early recognition of stroke and available treatment alternatives.

Subarachnoid space enlargement is a benign clinical entity characterized by rapid head enlargement in an infant with normal neurodevelopment. We report on two infants who had rapid increases in head circumference, family histories of macrocephaly, and normal neurodevelopment. Radiologic investigations in both infants showed subarachnoid space fluid collection but normal ventricular size. They both had a benign clinical course with resolution of the subarachnoid space fluid collection by the second year of life. The head circumference, however, remained at or above the 95th percentile. There is a need for pediatricians to be aware of this clinical entity and its benign nature.

The occurrence of craniosynostosis (premature closure of cranial sutures) has been reported to be 3 to 5 per 10,000 live births. The incidence is even lower among African-American infants. The District of Columbia General Hospital serves primarily the African-American population with approximately 2000 deliveries a year. In the last 10 years, three neonates with craniosynostosis have been born at DC General Hospital; all three infants were African Americans. These infants were exposed to cocaine and tobacco in utero, which suggests a possible association between intrauterine cocaine and tobacco exposure and premature closure of cranial sutures. Possible pathogenesis of craniosynostosis in association with cocaine and tobacco use is discussed.

This article describes the first case of Pneumocystis carinii pneumonia in a human immunodeficiency virus (HIV) seropositive infant in whom apnea was the earliest presenting clinical finding. Pediatricians treating infants with HIV infection need to be aware of this unusual clinical presentation of P carinii pneumonia to avoid a delay in diagnosis and management of this disease.

Alcohol is increasingly being described in the literature as a teratogenic agent producing dysmorphism and multisystem problems. The child described herein demonstrates the occurrence of myasthenia gravis and mitral incompetence with fetal alcohol syndrome. The association of myasthenia gravis in this case is unique, and could be suggestive of an immunological component to this syndrome.

The mortality and morbidity of salmonella meningitis in infancy is high. For infants and especially those younger than 6 months of age with salmonellosis, close observation is needed because of increased incidence of salmonella meningitis. A minimum duration of five weeks of susceptible antibiotic therapy may be indicated to prevent relapse or reinfection of salmonella meningitis. The role of a carrier in relapse needs to be evaluated.

Brachial plexus neuropathy is an acute neurologic disorder characterized by pain, weakness, and atrophy of the muscle groups affected. Although well documented in the adult literature, relatively few cases have been reported in children. Despite the lack of knowledge concerning its etiology, and lack of an effective therapy, the long-term prognosis is excellent. It is perhaps for these reasons that spinal fluid analysis is not routinely performed during the acute phase of this illness. An evaluation of the clinical course of three children, together with epidemiologic data, suggests that early lumbar punctures and an extensive search for an infecting viral agent, notably coxsackievirus B, are warranted.