Thoughts about having AIDS. "Being empowered by AIDS means learning the power of freedom, acceptance, honesty, and the value of time".
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Acquired Immunodeficiency Syndrome↗
Biomedical subjects
J M Smith
Publications and source records attributed to J M Smith.
LMRPs pose another challenge for patient accounts professionals.
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Centers for Medicare and Medicaid Services, U.S.↗
Abl family kinases and Cbl cooperate with the Nck adaptor to modulate Xenopus development.
We previously showed that overexpression of the Nck Src homology (SH) 2/SH3 adaptor in Xenopus embryos induced developmental defects including anterior truncation and mesoderm ventralization. Mutagenic analysis indicated that this was due to relocalization of endogenous proteins that bind the first two SH3 domains of Nck. We therefore screened a Xenopus expression library with Nck SH3 domains to identify Nck-interacting proteins, and evaluated candidate binding proteins for a potential role in Nck-induced anterior truncation/ventralization. Of 39 binding proteins analyzed, only the Abl-related kinase Arg and the Cbl proto-oncogene product bound preferentially to the first two SH3 domains in tandem compared with the individual domains, consistent with a role in the developmental phenotype. High level overexpression of c-Abl or Arg alone induced anterior truncation, as did lower levels of an activated form of Abl; Cbl alone had no effect. In a sensitized system where subthreshold amounts of a ventralizing Nck mutant were expressed, co-expression of the combination of Abl or Arg and Cbl at modest levels strongly potentiated anterior truncation, while Arg, Abl, or Cbl alone were without effect. These results suggest a role for both Cbl and Abl family kinases in patterning the Xenopus embryo.
Adaptor Proteins, Signal Transducing↗
Direct visualisation of the beta-sheet structure of synthetic Alzheimer's amyloid.
Amyloid fibrils are a major pathological feature of Alzheimer's disease as well as other amyloidoses including the prion diseases. They are an unusual phenomenon, being made up of different, normally soluble proteins which undergo a profound conformational change and assemble to form very stable, insoluble fibrils which accumulate in the extracellular spaces. In Alzheimer's disease the amyloid fibrils are composed of the A beta protein. Knowledge of the structure of amyloid is essential for understanding the abnormal assembly and deposition of these fibrils and could lead to the rational design of therapeutic agents for their prevention or disaggregation. Here we reveal the core structure of an Alzheimer's amyloid fibril by direct visualisation using cryo-electron microscopy. Synthetic amyloid fibrils composed of A beta residues 11 to 25 and 1 to 42 were examined. The A beta (11-25) fibrils are clearly composed of beta-sheet structure that is observable as striations across the fibres. The beta-strands run perpendicular to the fibre axis and the projections show that the fibres are composed of beta-sheets with the strands in direct register. This observation has implications not only for the further understanding of amyloid, but also for the development of cryo-electron microscopy for direct visualisation of secondary structure.
Alzheimer Disease↗
The kinetics of specific immune responses in rhesus monkeys inoculated with live recombinant BCG expressing SIV Gag, Pol, Env, and Nef proteins.
Development of an effective preventive or therapeutic vaccine against HIV-1 is an important goal in the fight against AIDS. Effective virus clearance and inhibition of spread to target organs depends principally on the cellular immune response. Therefore, a vaccine against HIV-1 should elicit virus-specific cytotoxic lymphocyte (CTL) responses to eliminate the virus during the cell-associated stages of its life cycle. The vaccine should also be capable of inducing immunity at the mucosal surfaces, the primary route of transmission. Recombinant Bacille Calmette-Guérin (BCG) expressing viral proteins offers an excellent candidate vaccine in view of its safety and ability to persist intracellularly, resulting in the induction of long-lasting immunity and stimulation of the cellular immune response. BCG can be administered orally to induce HIV-specific immunity at the mucosal surfaces. The immunogenicity of four recombinant BCG constructs expressing simian immunodeficiency virus (SIV) Gag, Pol, Env, and Nef proteins was tested in rhesus macaques. A single simultaneous inoculation of all four recombinants elicited SIV-specific IgA and IgG antibody, and cellular immune responses, including CTL and helper T cell proliferation. Our results demonstrate that BCG recombinant vectors can induce concomitant humoral and cellular immune responses to the major proteins of SIV.
Animals↗
Correcting serum fructosamine concentration for total protein or albumin concentration is not appropriate during Asian pregnancy.
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Adult↗
Population structure and evolutionary dynamics of pathogenic bacteria.
Evidence concerning the significance of recombination within natural bacterial populations has historically come from two main sources: multilocus enzyme electrophoresis (MLEE) and nucleotide sequence data. Here we discuss evidence from a third method, multilocus sequence typing (MLST), which is a development of MLEE based on nucleotide sequencing that combines the advantages of both approaches. MLST has confirmed both the existence of clones and the high rates of recombination for several bacterial pathogens. The data are consistent with "epidemic" population structures, where clones are superimposed upon a backdrop of frequent recombination, thus, in the short term, resisting the homogenising effect of recombination. The nature of the selective advantage of clones, however, and how this advantage relates to virulence are unclear. The current evidence also has broader implications concerning bacterial species definition, the management of antibiotic-resistant bacteria and the assessment of the dangers of releasing genetically modified organisms into the environment.
Bacteria↗
A quantitative analysis of cortical spreading depression events in the feline brain characterized with diffusion-weighted MRI.
Cortical spreading depression (CSD) in the gyrencephalic cat brain was detected with diffusion-weighted echoplanar (DWEP) magnetic resonance imaging (4-8/min for 1-2 hours) using a horizontal imaging plane through the suprasylvian (SG) and marginal gyri. A t-statistic mapping technique allowed a quantitative characterization of the passage of events through single-image pixels (0.15 mm(2)), thus providing a resolution unavailable to previous studies in which time-dependent changes instead were derived from averaging data over relatively large ROIs. Using the enhanced analysis, CSD events initiated by KCl could be quantified for the first time as primary or secondary according to their spatial and temporal features. Primary events covered 26.2 +/- 9.9 mm(2)of cortical surface (mean +/- SD, n = 7 experiments) and propagated rapidly (3.5 +/- 0.65 mm * min(-1)) with a hemispherical geometry. In contrast, the subsequent secondary events were multiple, spatially restricted (covering 7.6 +/- 4.6 mm(2), P < 0.005), slower in propagation (2.6 +/- 0.41 mm * min(-1), P < 0.012), and often confined to the originating gyrus (26 out of 59 events). However, both event types were associated with significantly reduced apparent diffusion coefficients (ADCs; from 800 to approximately 660 x 10(-6) mm(2)* s(-1), P < 0.05) that were similar for both primary (21 +/- 5.1%) and secondary waves (18 +/- 7. 7%) and that had similar durations (full width at half-maximal height: 86 +/- 17 vs. 79 +/- 20 seconds, respectively). These findings associate CSD for the first time with two categories of ADC disturbance that are similar in amplitude and duration but that differ in spatial extent, velocity, and extensiveness of spread.
Animals↗
Upper extremity hemodynamic changes after radial artery harvest for coronary artery bypass grafting.
Twenty-seven patients were studied with arterial duplex, photoplethysmography, segmental pressures, and pulse volume recordings both preoperatively and following radial artery harvesting. The average number of days to the follow-up visit was 66. Preoperative and postoperative data were compared using the matched Student's t-test. There were no significant changes between preoperative and postoperative pressures in the brachial, radial, and ulnar arteries, and thumb, index, long, ring, or little fingers. Pressure changes in the thumb and index finger approached but did not achieve a statistical difference. Peak systolic velocity (PSV), end diastolic velocity (EDV), and resistive index (RI) in the distal ulnar artery changed significantly between preoperative and postoperative measurements. PSV changed from 0.50 +/- 0.05 m/sec to 0.67 +/- 0.04 m/sec (p = 0.02); EDV changed from 0.03 +/- 0.03 m/sec to -0.10 +/- 0.05 m/sec (p = 0.05); and RI changed from 0.97 +/- 0. 05 to 1.13 +/- 0.05 (p = 0.02). Palmar arch evaluations revealed significant changes at rest and with ulnar compression between preoperative and postoperative measurements: (1) at rest EDV changed from 0.03 +/- 0.02 m/sec to -0.05 +/- 0.02 m/sec (p < 0.01); (2) at rest RI changed from 0.96 +/- 0.05 to 1.12 +/- 0.05 (p = 0.01); (3) with ulnar compression the PSV changed from 0.23 +/- 0.05 m/sec to 0. 005 +/- 0.01 m/sec (p < 0.01); and (4) with ulnar compression the RI changed from 0.82 +/- 0.11 to 0.27 +/- 0.12 (p < 0.01). Eight patients had a variety of complaints at the follow-up visit, the majority being numbness and tingling. No patients reported symptoms of claudication or rest pain at the follow-up visit. The data suggest that while statistically significant changes in velocity and arterial resistance do occur, patients seem to tolerate radial artery harvesting without clinical consequences. The ideal method of preoperative evaluation remains to be determined.
Aged↗
Superior vena cava thrombosis after in vitro fertilization: case report and review of the literature.
Ovarian hyperstimulation syndrome (OHSS) is a rare complication of fertility medication. A 33 year old female with OHSS with thrombosis of the right internal jugular vein, subclavian vein, and superior vein cava underwent in vitro fertilization following stimulation with a GnRH analog with successful implantation. The patient developed abdominal distention and dyspnea, with persistent symptoms that resulted in a 20 lb weight loss. As pregnancy progressed, edema, pain, and tingling sensations developed by the ninth week at which time a CT scan confirmed thrombus with the right internal jugular and subclavian vein and a free floating tip in the superior vena cava. Following treatment with intravenous heparin therapy and subcutaneous low-molecular weight heparin until delivery her symptoms improved. While optimal treatment remains unclear, treatment strategies remain conservative. Identifying the risk factors that lead to the development of OHSS including the identification of those patients at risk for developing OHSS, more extensive investigation of potential underlying coagulopathy in severe or recurrent cases, and consideration of prophylactic subcutaneous heparin or IV albumin supplementation, will facilitate prevention in the high risk population.
Adult↗
Elevation of plasma fatty acids by ten-hour intralipid infusion has no effect on basal or glucose-stimulated insulin secretion in normal man.
There is controversy over the effect of free fatty acids (FFAs) on insulin secretion. Previous studies have shown opposite effects of short- and long-term exposure to elevated concentrations of FFAs. We studied 8 normal subjects (mean age, 30 years; mean body mass index, 23.4 kg/m2) on 2 occasions. Each had a 10-hour overnight infusion of Intralipid 20% (Pharmacia, Milton Keynes, UK) with simultaneous infusion of heparin (0.4 U/kg body weight/min) or a control infusion of saline (150 mmol/L). Insulin secretion was assessed immediately after completion of the 10-hour infusion by an intravenous glucose tolerance test. Results were analyzed using paired ttests. Intralipid infusion caused an increase in plasma FFAs of more than 9-fold (P < .01), with a simultaneous increase in glycerol (P < .01) and hydroxybutyrate (P < .01). There was no difference in blood glucose concentrations during the infusion or intravenous glucose tolerance test. Similarly, insulin secretion was not significantly different during Intralipid infusion or in the intravenous glucose tolerance test (peak insulin achieved in glucose tolerance test, P = .51; total insulin secretion during intravenous glucose tolerance test, P = .27). In conclusion, after increasing plasma FFA concentrations over 9-fold during a 10-hour infusion of Intralipid and heparin, we found no difference in basal or glucose-stimulated insulin secretion.
Adult↗
Undetectable serum caeruloplasmin in a woman with chronic hepatitis C infection.
There are many causes of a low serum caeruloplasmin. Not only may this be a feature of Wilson's disease, but a low level may be found in association with chronic liver disease of any cause. We report here a case where undetectable serum caeruloplasmin was found during routine investigation of a woman with hepatitis C viral infection.
Ceruloplasmin↗
Exploiting rate-related hysteresis in repolarization alternans to improve risk stratification for ventricular tachycardia.
OBJECTIVES: We sought to study the effect of heart rate acceleration and deceleration on the ability of repolarization alternans (RPA) to stratify ventricular tachycardia (VT) risk. BACKGROUND: Heart rate fluctuations alter arrhythmic propensity, yet it is unclear whether fluctuations, as well as absolute rate, dynamically increase VT risk. We hypothesized that repolarization heterogeneity reflected by RPA would exhibit hysteresis during rising and falling heart rate, which may reflect arrhythmic propensity. METHODS: The RPA magnitude (absolute voltage of alternation [V(alt)] and T-wave alternans ratio [TWAR]) and temporal distribution were determined from the electrocardiogram (ECG) in 60 patients during paced heart rate acceleration from 100 to 150 beats/min, then deceleration to 100 beats/min at electrophysiologic study (EPS). The V(alt) and TWAR thresholds were varied prospectively to generate receiver-operating characteristics (ROC) for the prediction of inducible VT at EPS. RESULTS: Thirty-six patients were induced into VT and 24 were not. Hysteresis of RPA was seen. The V(alt) reached steady-state within 60 beats of each rate transition and was higher in deceleration than in acceleration at matched heart rates. In induced patients, V(alt) rose then fell with heart rate. In noninduced patients, V(alt) was insensitive to acceleration, but rose on initial deceleration. The RPA distributed later within repolarization in induced patients but, on deceleration, moved earlier in both groups. By ROC analysis, V(alt) = 2.6 microV in late repolarization at 120 beats/min provided optimal sensitivity and specificity for VT in acceleration (87.5% and 88.7%, respectively) versus deceleration (80% and 62.5%, respectively; p = 0.004, chi-square test). CONCLUSIONS: 1) Physiologic fluctuations in heart rate may affect the clinical utility of RPA for VT risk stratification; and 2) repolarization dispersion measured by RPA is more exaggerated during deceleration than acceleration at matched heart rates (rate hysteresis).
Adult↗
John Maynard Smith on ageing research. Interview by Robin Holliday.
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Aging↗
Effects of the new oral hypoglycaemic agent nateglinide on insulin secretion in Type 2 diabetes mellitus.
AIMS: The new non-sulphonylurea oral hypoglycaemic agent nateglinide has been shown to enhance insulin secretion in animals and in healthy human volunteers and thus offers a potential advance in the treatment of Type 2 diabetes mellitus. This study examined whether nateglinide can enhance insulin secretion, and particularly the first phase insulin response, in patients with Type 2 diabetes. METHODS: A double-blind, placebo-controlled trial, examining the effects of a single oral dose of 60 mg nateglinide, given 20 min prior to an intravenous glucose tolerance test (IGTT), on insulin secretion in 10 otherwise healthy Caucasian men with recently diagnosed Type 2 diabetes (duration since diagnosis 0-44 months). RESULTS: Insulin secretion (both overall and first phase) was significantly increased by nateglinide (P < 0.001), as were C-peptide (P < 0.001) and proinsulin (P < 0.001) secretion. Overall glucose concentrations following glucose challenge were lower after nateglinide than after placebo (P = 0.05). CONCLUSIONS: Nateglinide significantly increases insulin secretion in Type 2 diabetic patients, in particular restoring the first phase insulin response. Further study is necessary to determine the effects of chronic administration on insulin secretion and blood glucose concentration.
Adult↗
Progress in renal transplantation for children.
Renal transplantation continues to be the goal of therapy for children with end-stage renal disease. Patient age, primary renal disease, psychosocial status, living versus cadaver donor allograft, immunosuppressive therapy, urologic status, and maximization of growth and development must be considered in determining the optimal time for transplantation. Immunizations should be up to date, and the immune status of both the donor and the recipient with regard to Epstein Barr virus (EBV), cytomegalovirus (CMV), varicella, human immunodeficiency virus (HIV) and Hepatitis A, B, and C must be known. Prednisone; cyclosporine or tacrolimus; and mycophenolate mofetil or azathioprine remain the mainstays of immunosuppression. However, new therapies such as sirolimus are under investigation for use in pediatric renal transplantation. Induction therapies include T-cell antibodies as well as the more recent addition of interleukin-2 receptor blockers. Complications including infection, rejection, and malignancy continue to be problematic in pediatric renal transplantation. There continues to be a strong focus on optimizing growth and development after transplant. Although patient and graft survival have improved over time, outcomes in pediatric renal transplantation continue to lag behind those in adults.
Child↗
Preparation and induction of immune responses by a DNA AIDS vaccine.
In an effort to evaluate the feasibility of developing a safe DNA vaccine for acquired immunodeficiency syndrome (AIDS), we have prepared a plasmid-based immunogen modeled after a naturally occurring noninfectious mutant of the simian immunodeficiency virus (SIV). The mutant SIV genome produces defective virus particles that are noninfectious in vitro and nonpathogenic in vivo in rhesus macaques. Analysis of the mutant genome revealed a 1.6 kb deletion that is in frame and spans integrase, vif, vpx, and most of vpr and results in a pol/vpr gene fusion. This deletion was introduced into the parental pathogenic molecular clone and the U3 region of the 5' LTR was replaced with a cytomegalovirus promoter to produce a candidate DNA vaccine, pIV. After transfection with this plasmid, SIV gag and envelope proteins are expressed and properly processed in vitro. When injected into rabbits, pIV elicited an antibody response to SIV gp130 envelope glycoprotein with titers reaching 1:2048, and a strong lymphoproliferative response to SIV gp130 and whole SIV. The potential to produce defective virus particles in vivo without integrating into the host genome should result in both a strong humoral and cellular immune response in rhesus macaques. In addition, this approach offers a safe alternative to live attenuated vaccines and DNA vaccines that are capable of integration.
Animals↗
Estimating recombinational parameters in Streptococcus pneumoniae from multilocus sequence typing data.
Multilocus sequence typing (MLST) is a highly discriminatory molecular typing method that defines isolates of bacterial pathogens using the sequences of approximately 450-bp internal fragments of seven housekeeping genes. This technique has been applied to 575 isolates of Streptococcus pneumoniae and identifies a number of discrete clonal complexes. These clonal complexes are typically represented by a single group of isolates sharing identical alleles at all seven loci, plus single-locus variants that differ from this group at only one out of the seven loci. As MLST is highly discriminatory, the members of each clonal complex can be assumed to have a recent common ancestor, and the molecular events that give rise to the single-locus variants can be used to estimate the relative contributions of recombination and mutation to clonal divergence. By comparing the sequences of the variant alleles within each clonal complex with the allele typically found within that clonal complex, we estimate that recombination has generated new alleles at a frequency approximately 10-fold higher than mutation, and that a single nucleotide site is approximately 50 times more likely to change through recombination than mutation. We also demonstrate how to estimate the average length of recombinational replacements from MLST data.
Alleles↗