Aboriginal status is a prognostic factor for mortality among antiretroviral naïve HIV-positive individuals first initiating HAART

Background  

Although the impact of Aboriginal status on HIV incidence, HIV disease progression, and access to treatment has been investigated previously, little is known about the relationship between Aboriginal ethnicity and outcomes associated with highly active antiretroviral therapy (HAART). We undertook the present analysis to determine if Aboriginal and non-Aboriginal persons respond differently to HAART by measuring HIV plasma viral load response, CD4 cell response and time to all-cause mortality.     

Loss of lipopolysaccharide receptor CD14 from the surface of human macrophage-like cells mediated by Porphyromonas gingivalis outer membrane vesicles

Porphyromonas gingivalis, the major etiologic agent of chronic periodontitis, produces a broad spectrum of virulence factors, including outer membrane vesicles. In this study, we investigated the capacity of P. gingivalis vesicles to promote the shedding or cleavage of the lipopolysaccharide (LPS) receptor CD14 from the surface of human U937 macrophage-like cells. SDS-PAGE/Western immunoblotting analysis of gingival crevicular fluid samples from patients affected by moderate or advanced periodontitis revealed the presence of soluble CD14 and CD14 fragments, thus supporting the hypothesis of an in vivo shedding and cleavage of CD14 receptors. Flow cytometry analysis of macrophage-like cells treated with a vesicle-containing culture supernatant of P. gingivalis showed a significant decrease in the binding of anti-human CD14 to the cell surface. However, no accumulation of soluble CD14 or immunoreactive CD14 fragments in the assay supernatant could be demonstrated by ELISA. Treatment of macrophage-like cells with various concentrations of P. gingivalis vesicles substantially suppressed TNF-alpha production triggered by Escherichia coli LPS. This suppressive effect was much less important using heat-treated vesicles or in the presence of leupeptin, a gingipain inhibitor, during the treatment. Recombinant human CD14 receptors were found to be susceptible to proteolytic degradation by P. gingivalis vesicles. A purified Arg-gingipain preparation produced much more degradation than a Lys-gingipain preparation. This study provides evidence that P. gingivalis outer membrane vesicles contribute to the loss of membrane-bound CD14 receptors and that gingipains degrade this LPS receptor. Such a phenomenon, which results in an hyporesponsiveness of macrophages to LPS stimulation, may contribute to an increased capacity of P. gingivalis, and other periodontopathogens, to evade the host immune system mechanisms.     

Focal synchronization of ripples (80-200 Hz) in neocortex and their neuronal correlates

Field potentials from different neocortical areas and intracellular recordings from areas 5 and 7 in acutely prepared cats under ketamine-xylazine anesthesia and during natural states of vigilance in chronic experiments, revealed the presence of fast oscillations (80-200 Hz), termed ripples. During anesthesia and slow-wave sleep, these oscillations were selectively related to the depth-negative (depolarizing) component of the field slow oscillation (0.5-1 Hz) and could be synchronized over ~10 mm. The dependence of ripples on neuronal depolarization was also shown by their increased amplitude in field potentials in parallel with progressively more depolarized values of the membrane potential of neurons. The origin of ripples was intracortical as they were also detected in small isolated slabs from the suprasylvian gyrus. Of all types of electrophysiologically identified neocortical neurons, fast-rhythmic-bursting and fast-spiking cells displayed the highest firing rates during ripples. Although linked with neuronal excitation, ripples also comprised an important inhibitory component. Indeed, when regular-spiking neurons were recorded with chloride-filled pipettes, their firing rates increased and their phase relation with ripples was modified. Thus besides excitatory connections, inhibitory processes probably play a major role in the generation of ripples. During natural states of vigilance, ripples were generally more prominent during the depolarizing component of the slow oscillation in slow-wave sleep than during the states of waking and rapid-eye movement (REM) sleep. The mechanisms of generation and synchronization, and the possible functions of neocortical ripples in plasticity processes are discussed.     

Spontaneous field potentials influence the activity of neocortical neurons during paroxysmal activities in vivo

Field-potential recordings with macroelectrodes, and extra- and intracellular potentials with micropipettes were used to determine the influence of spontaneous field potentials on the activity of neocortical neurons during seizures. In vivo experiments were carried out in cats under anesthesia. Strong negative field fluctuations of up to 20 mV were associated with electroencephalogram "spikes" during spontaneously occurring paroxysmal activities. During paroxysmal events, action potentials displayed an unexpected behavior: a more hyperpolarized firing threshold and smaller amplitude than during normal activity, as determined with intracellular recordings referenced to a distant ground. Considering the transmembrane potential (the difference between extra- and intracellular potential) qualified this observation: firing threshold determined from the transmembrane potential did not decrease, and smaller action-potential amplitude was associated with depolarized firing threshold. The hyperpolarization of intracellular firing threshold was thus related to the field potentials. Similar field-potential effects on neuronal activities were observed when the paroxysmal events included very fast oscillations or ripples (80-200 Hz) that represent rapid fluctuations of field potentials (up to 5 mV in <5 ms). Neuronal firing was phase-locked to those oscillations. These results demonstrate that: (a) strong spontaneous field potentials influence neuronal behavior, and thus play an active role during paroxysmal activities; and (b) transmembrane potentials have to be used to accurately describe the behavior of neurons in conditions in which field potentials fluctuate strongly. Since neuronal activity is presumably the main generator of field potentials, and in return these potentials may increase neuronal excitability, we propose that this constitutes a positive feedback loop that is involved in the development and spread of paroxysmal activities, and that a similar feedback loop is involved in the generation of neocortical ripples. We propose a mechanism for seizure initiation involving these phenomena.     

Neurologic crises in hereditary tyrosinemia

Hereditary tyrosinemia results from an inborn error in the final step of tyrosine metabolism. The disease is known to cause acute and chronic liver failure, renal Fanconi's syndrome, and hepatocellular carcinoma. Neurologic manifestations have been reported but not emphasized as a common problem. In this paper, we describe neurologic crises that occurred among children identified as having tyrosinemia on neonatal screening since 1970. Of the 48 children with tyrosinemia, 20 (42 percent) had neurologic crises that began at a mean age of one year and led to 104 hospital admissions. These abrupt episodes of peripheral neuropathy were characterized by severe pain with extensor hypertonia (in 75 percent), vomiting or paralytic ileus (69 percent), muscle weakness (29 percent), and self-mutilation (8 percent). Eight children required mechanical ventilation because of paralysis, and 14 of the 20 children have died. Between crises, most survivors regained normal function. We found no reliable biochemical marker for the crises (those we evaluated included blood levels of tyrosine, succinylacetone, and hepatic aminotransferases). Urinary excretion of delta-aminolevulinic acid, a neurotoxic intermediate of porphyrin biosynthesis, was elevated during crises but also during the asymptomatic periods. Electrophysiologic studies in seven patients and neuromuscular biopsies in three patients showed axonal degeneration and secondary demyelination. We conclude that episodes of acute, severe peripheral neuropathy are common in hereditary tyrosinemia and resemble the crises of the neuropathic porphyrias.     

A second locus (GLC3B) for primary congenital glaucoma (Buphthalmos) maps to the 1p36 region

Primary congenital glaucoma (gene symbol: GLC3) is an ocular disorder that occurs for 0.01-0.04% of blind people. In the majority of familial cases reported so far, this condition is inherited as an autosomal recessive trait. We have recently used a group of 17 GLC3 families with a minimum of two affected offspring and consanguinity in most of the parental generation and mapped the first GLC3 locus (GLC3A) to the 2p21 region. Six families did not show any linkage to the GLC3A locus and thus provided evidence for genetic heterogeneity of this disorder. A total of eight families unlinked to the 2p21 region were used to search for the chromosomal location of the second GLC3 locus. Herein, we describe mapping of a new locus (designated GLC3B) for primary congenital glaucoma to the short arm of chromosome 1 (1p36.2-36.1) that is situated centromeric to the neuroblastoma and Charcot-Marie-Tooth type 2A (CMT2A) loci. A total of 17 DNA markers were genotyped from this region of chromosome 1. Four families showed no recombination with the two markers D1S2834 and D1S402 with a maximum lod score of 4.510 and 4.157 respectively. Pairwise and multipoint linkage analysis and inspection of the haplotypes revealed that the remaining four families are not linked to this part of chromosome 1, thus providing further evidence that at least one more locus for the autosomal recessive form of GLC3 must exist in the genome. Based on the recombination events, the overall linkage map of this region is: tel-D1S1192-D1S1635-D1S1193 - (D1S1597/-D1S489/D1S228)- [GLC3B/D1S2834/D1S402] - (D1S1176/D1S507/D1S407) - D1S2728-(MFAP2/D1S170) - D1S1368 - D1S436- D1S1592-cen.      

MR arthrography of the hip: normal intra-articular structures and common disorders

This pictorial review illustrates the anatomical features of normal intra-articular components of the hip and their common disorders on MR arthrography. On T1-weighted MR arthrograms, the normal contrast-filled joint cavity shows a homogeneous high signal intensity. Normal acetabular labrum appears as a well-delineated triangle showing a low signal intensity, surrounded by contrast material in the perilabral recess. Intra-articular paramagnetic contrast outlines labral tears, loose bodies, communicating labral cysts and cartilage lesions (traumatic tears, focal defects, degenerative fissures and thinning), and improves their detection. Overall, MR arthrography enables accurate detection and staging of hip intra-articular structure abnormalities. Received: 6 June 1998; Revision received: 2 January 1999; Accepted: 2 April 1999     

Comparison of user groups' perspectives of barriers and facilitators to implementing electronic health records: a systematic review

Background  

Electronic health record (EHR) implementation is currently underway in Canada, as in many other countries. These ambitious projects involve many stakeholders with unique perceptions of the implementation process. EHR users have an important role to play as they must integrate the EHR system into their work environments and use it in their everyday activities. Users hold valuable, first-hand knowledge of what can limit or contribute to the success of EHR implementation projects. A comprehensive synthesis of EHR users' perceptions is key to successful future implementation. This systematic literature review was aimed to synthesize current knowledge of the barriers and facilitators influencing shared EHR implementation among its various users.     

The plant coumarins auraptene and lacinartin as potential multifunctional therapeutic agents for treating periodontal disease

ABSTRACT: BACKGROUND: Periodontal diseases are bacterial infections leading to chronic inflammation disorders that are frequently observed in adults. In the present study, we evaluated the effect of auraptene and lacinartin, two natural oxyprenylated coumarins, on the growth, adherence properties, and collagenase activity of Porphyromonas gingivalis. We also investigated the capacity of these compounds to reduce cytokine and matrix metalloproteinase (MMP) secretion by lipopolysaccharide (LPS)-stimulated macrophages and to inhibit MMP-9 activity. METHODS: Microplate dilution assays were performed to determine the effect of auraptene and lacinartin on P. gingivalis growth as well as biofilm formation stained with crystal violet. Adhesion of FITC-labeled P. gingivalis to oral epithelial cells was monitored by fluorometry. The effects of auraptene and lacinartin on LPS-induced cytokine and MMP secretion by macrophages were determined by immunological assays. Fluorogenic assays were used to evaluate the capacity of the two coumarins to inhibit the activity of MMP-9 and P. gingivalis collagenase. RESULTS: Only lacinartin significantly inhibited P. gingivalis growth in a complex culture medium. However, under iron-limiting conditions, auraptene and lacinartin both inhibited the growth of P. gingivalis. Lacinartin also inhibited biofilm formation by P. gingivalis and promoted biofilm desorption. Both compounds prevented the adherence of P. gingivalis to oral epithelial cells, dose-dependently reduced the secretion of cytokines (IL-8 and TNF-alpha) and MMP-8 and MMP-9 by LPS-stimulated macrophages, and inhibited MMP-9 activity. Lacinartin also inhibited P. gingivalis collagenase activity. CONCLUSIONS: By acting on multiple targets, including pathogenic bacteria, tissue-destructive enzymes, and the host inflammatory response, auraptene and lacinartin may be promising natural compounds for preventing and treating periodontal diseases.