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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: 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.)

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.