Investigation of a multi-biomarker disease activity score in rheumatoid arthritis by comparison with magnetic resonance imaging, computed tomography, ultrasonography, and radiography parameters of inflammation and damage.

OBJECTIVES: To investigate the multi-biomarker disease activity (MBDA) score by comparison with imaging findings in an investigator-initiated rheumatoid arthritis (RA) trial (HURRAH trial, NCT00696059). METHOD: Fifty-two patients with established RA initiated adalimumab treatment and had magnetic resonance imaging (MRI), ultrasonography (US), computed tomography (CT), and radiography performed at weeks 0, 26, and 52. Serum samples were analysed using MBDA score assays and associations between clinical measures, MBDA score, and imaging findings were investigated. RESULTS: The MBDA score correlated significantly with MRI synovitis (rho = 0.65, p < 0.001), MRI bone marrow oedema (rho = 0.36, p = 0.044), and US power Doppler (PD) score at week 26 (rho = 0.35, p = 0.039) but not at week 0 or week 52. In the 15 patients who had achieved a Disease Activity Score based on C-reactive protein (DAS28-CRP) < 2.6 at week 26, MRI and/or US detected subclinical inflammation and 13 (87%) had a moderate/high MBDA score. For the cohort with available data, none of the four patients in MBDA remission (score ≤ 25) at week 26 had progression of imaging damage from baseline to week 52 whereas progression was observed in three out of nine (33%) and seven out of 21 (33%) patients with moderate (30-44) and high (> 44) MBDA scores, respectively. CONCLUSIONS: In this cohort, the MBDA score correlated poorly with MRI/US inflammation. However, the MBDA score and MRI/US were generally concordant in showing signs of inflammation in most patients in clinical remission during anti-tumour necrosis factor (anti-TNF) therapy. MBDA scores were elevated in all patients with structural damage progression.

A trio of simple optimized axisymmetric kinematic dynamos in a sphere.

Planetary magnetic fields are generated by the motion of conductive fluid in the planet's interior. Complex flows are not required for dynamo action; simple flows have been shown to act as efficient kinematic dynamos, whose physical characteristics are more straightforward to study. Recently, Chen et al. (2018, J. Fluid Mech. 839, 1-32. (doi:10.1017/jfm.2017.924)) found the optimal, unconstrained kinematic dynamo in a sphere, which, despite being of theoretical importance, is of limited practical use. We extend their work by restricting the optimization to three simple two-mode axisymmetric flows based on the kinematic dynamos of Dudley & James (1989, Proc. R. Soc. Lond. A 425, 407-429. (doi:10.1098/rspa.1989.0112)). Using a Lagrangian optimization, we find the smallest critical magnetic Reynolds number for each flow type, measured using an enstrophy-based norm. A Galerkin method is used, in which the spectral coefficients of the fluid flow and magnetic field are updated in order to maximize the final magnetic energy. We consider the t 0 1 s 0 1, t 0 1 s 0 2 and t 0 2 s 0 2 flows and find enstrophy-based critical magnetic Reynolds numbers of 107.7, 142.4 and 125.5 (13.7, 19.6 and 16.4, respectively, with the energy-based definition). These are up to four times smaller than the original flows. These simple and efficient flows may be used as benchmarks in future studies.

Membrane potential determination in large unilamellar vesicles with hexakis(2-methoxyisobutylisonitrile)technetium(I).

The accumulation of the lipophilic cation hexakis (2-methoxyisobutylisonitrile)technetium (99mTc-MIBI) within large unilamellar vesicles made from egg phosphatidylcholine was examined as a function of time and membrane potential (Em). Equilibrium distribution occurred within minutes at 30 degrees C. The transmembrane distribution of Tc-MIBI was measured at Em = 0 mV and at a series of negative membrane potentials. The distribution of Tc-MIBI was in close agreement with the Nernst equation for passive distribution of a permeant ion across a bilayer, permitting the membrane potential to be predicted from Tc-MIBI distribution. In this respect, Tc-MIBI behaves similarly to other radioprobes of membrane potential, but with unique properties including high specific activity (10(9) Ci/mol), rapid kinetics of distribution, low potential-independent binding, and short half-life (6.02 h). The results indicate a mechanism for tissue accumulation of Tc-MIBI in vivo that may in part account for its utility in clinical imaging of ischemic myocardium.

Tonic and phasic block of neuronal sodium currents by 5-hydroxyhexano-2',6'-xylide, a neutral lidocaine homologue.

The effects of a neutral lidocaine homologue, 5-hydroxyhexano-2',6'-xylidide (5-HHX), on the kinetics and amplitude of sodium currents in voltage-clamped amphibian nerve fibers are described. 5-HHX produced two types of sodium current inhibition: (a) tonic block, in resting fibers (IC50 approximately 2 mM), and (b) phasic block, an additional, incremental inhibition, in repetitively depolarized fibers (frequency greater than 1 Hz). The kinetics of phasic block were characterized by a single-receptor, switched-affinity model, in which binding increases during a depolarizing pulse and decreases between pulses. In the presence of 4 mM 5-HHX, binding increased during pulses from -80 to 0 mV, with an apparent rate constant of 6.4 +/- 1.4 s-1. Binding decreased between pulses with an apparent rate constant of 1.1 +/- 0.3 s-1. There was little effect of extracellular pH on the kinetics of phasic block. These findings demonstrate that neither the presence of a terminal amine nor a net charge on a local anesthetic is required for phasic block of sodium channels.

Cardiac manifestations of human immunodeficiency virus infection: a two-dimensional echocardiographic study.

To determine the prevalence of cardiac abnormalities in patients with human immunodeficiency virus (HIV) infection, two-dimensional Doppler echocardiography was performed on 70 consecutive patients with HIV infection, including 51 with acquired immunodeficiency syndrome (AIDS), 13 with AIDS-related complex and 6 with asymptomatic HIV infection. Of the 70 patients, 36% were hospitalized and 64% were ambulatory at the time of evaluation. The average age was 37 years; 93% were homosexual men. Echocardiographic findings included dilated cardiomyopathy in eight patients (11%), pericardial effusions in seven patients (10%) (one with impending tamponade), pleural effusion in four patients (6%) and mediastinal mass in one patient (1%). Among the 25 hospitalized patients, echocardiographic abnormalities were noted in 16 (64%), whereas among the 45 ambulatory patients, the only abnormality noted was mitral valve prolapse in 3 patients (7%) (p less than 0.0001). Dilated cardiomyopathy was the only echocardiographic lesion more common in the 25 hospitalized patients than in 20 hospitalized control patients with acute leukemia. Symptoms of congestive heart failure responded to conventional therapy. Cardiac lesions were associated with active Pneumocystis carinii pneumonia and low T helper lymphocyte counts. Dilated cardiomyopathy of unknown origin may be more common than was previously recognized in hospitalized, acutely ill patients with AIDS, but is uncommon in ambulatory patients with HIV infection. Echocardiography should be considered in the evaluation of dyspnea in hospitalized patients with HIV infection, especially those with dyspnea that is out of proportion to the degree of pulmonary disease.

Does HIV cause salivary gland disease?

HIV-associated salivary gland disease (HIV-SGD) is characterized by enlargement of the major salivary glands and/or xerostomia. HIV does not appear to play a direct role in this disease since it was detected by immunohistochemistry in only occasional lymphocytes in labial salivary glands in two out of six patients; it was not found in the salivary gland epithelial cells. Moreover, HIV was not found in any of 21 saliva samples from seven patients. We conclude that HIV-SGD is not caused by direct infection of the salivary glands with HIV.

Immunologic and virologic evaluation after influenza vaccination of HIV-1-infected patients.

OBJECTIVE: The present study was designed to determine the effect of immune activation, achieved by influenza vaccination, on plasma HIV RNA levels and immunological parameters including CD4 cell levels, antigen-stimulated T-cell function and apoptotic death of peripheral blood mononuclear cells. DESIGN AND METHODS: Thirty-four HIV-infected individuals and nine uninfected controls were immunized with influenza vaccine and blood was collected at weeks 0, 2, 4 and 16. Plasma was isolated and used for HIV RNA and influenza-specific antibody qualifications. CD4 cell counts, activation and maturation markers of T-lymphocyte subsets were determined by flow cytometry. In vitro T-helper responses, spontaneous- and activation-induced cell death assays were also performed. RESULTS: Influenza-specific humoral and cellular immune responses correlated with CD4 count. Only in patients with CD4 counts > 300 x 10(6)/l there was a modest increase in T-cell responses to influenza virus, which was less than control subjects, observed after vaccination. Immunization had no significant effect on CD4 counts or plasma viral levels in the HIV-positive patients. Baseline apoptosis inversely correlated with CD4 counts and directly correlated with viral load. Activation-induced apoptosis did not change appreciably after vaccination and spontaneous apoptosis increased only in the < 300 CD4 group. CONCLUSION: These results indicate that immune stimulation resulting from influenza vaccination did not significantly change the levels of plasma virus, CD4 cell counts, or activation-induced apoptosis in HIV-infected individuals, although an increase in the T-cell response to influenza and spontaneous apoptosis was observed in the > 300 and < 300 CD4 groups, respectively.

Safety and immunogenicity of Env 2-3, a human immunodeficiency virus type 1 candidate vaccine, in combination with a novel adjuvant, MTP-PE/MF59. NIAID AIDS Vaccine Evaluation Group.

We investigated the safety and immunogenicity of a candidate HIV-1 vaccine, Env 2-3 (Chiron Biocine Co.), in combination with an adjuvant emulsion, MF59, with or without an additional immune modulator, MTP-PE 78 healthy HIV-1-seronegative adults. Sixteen subjects participated in a dose escalation study of MTP-PE in MF59 without Env 2-3, given at 0 and 1 months; 48 subjects participated in a study of a fixed dose of 30 micrograms of Env 2-3 in MF59 with increasing doses of MTP-PE (0, 5, 10, 25, 50, and 100 micrograms), and 14 subjects participated in a study of 100 micrograms of Env 2-3 in MF59 without MTP-PE. Subjects were assigned to study groups under a randomized, double-blind allocation. Subjects received immunization at 0, 1, and 6 months, and had the option of receiving a fourth dose at 12-18 months. Env 2-3 in MTP-PE/MF59 was associated with significant reactogenicity, in that severe, although self-limited systemic and/or local reactions occurred in 15 of 30 vaccinees. In contrast, Env 2-3 in MF59 without MTP-PE was relatively well tolerated, and severe local and/or systemic reactions occurred in only 2 of 18 subjects. Env 2-3 stimulated serum antibodies to HIV-1 envelope protein (gp120) as detected by Western blot in 39 of 43 subjects and to HIV-1 virus lysate by EIA in 28 of 43 subjects after three injections. The majority of subjects also developed EIA antibodies to recombinant gp120 (SF-2), gp120 (LAI), and V3 peptide (SF-2). Neutralizing antibodies to the homologous SF-2 strain developed in 30 of 43 and 27 of 34 subjects, and fusion inhibition antibodies in 25 of 43 and 15 of 36 subjects after three and four injections, respectively. Lymphoproliferative responses to the immunogen, Env 2-3 were observed in over 80% of the vaccinees examined, and CD4+ cytotoxic T cell activity directed against HIV-1 was noted transiently in 2 of 20 vaccinees. Addition of MTP-PE to Env 2-3 or increasing the dose of Env 2-3 from 30 to 100 micrograms did not augment immunogenicity. Env 2-3 in MF59 was well tolerated and immunogenic in HIV-1-seronegative individuals. The addition of MTP-PE significantly increased reactogenicity, but had little, if any, effect on immunogenicity.

A randomized comparison of once-monthly or twice-monthly high-dose aerosolized pentamidine prophylaxis.

RESULTS: Ten of the 146 (7 percent) evaluable subjects developed PCP during the year study period, and there was no difference in the efficacy of the two regimens. Among patients receiving secondary prophylaxis, the attack rate of PCP at 1 year was 11 percent. This compares favorably with a 1-year attack rate of 19 percent in similar patients receiving standard dose (300 mg) prophylaxis and suggests, but does not prove, a dose-response effect. Concentrations of pentamidine in BAL fluid were not significantly different among the three lobes of the lung. Intrapulmonary pentamidine did not accumulate during the year of study. Aerosolized pentamidine was associated with a marginal but statistically significant increase in the residual volume, decreased flow rates, and increased airway reactivity. OBJECTIVE: The optimal regimen of aerosolized pentamidine in unknown. Published data suggest that there is a dose-response effect and that the occurrence of Pneumocystis carinii pneumonia (PCP) has been associated with prolongation of the interval between doses. The purpose of this study was to compare the efficacy, pharmacokinetics, and physiologic effects of two high-dose regimens of aerosolized pentamidine prophylaxis. DESIGN: Prospective, randomized study of 300 mg twice monthly vs 600 mg once monthly during a 1-year observation period. Pentamidine concentrations in plasma and bronchoalveolar lavage (BAL) fluid were measured and serial pulmonary function was measured. SETTING: A large teaching hospital in San Francisco. PATIENTS: One hundred fifty-one adult (age > 18 years) men with human immunodeficiency virus infection. Of 146 evaluable patients, prophylaxis was primary (no prior PCP) in 108 (75 percent) and secondary (one prior episode of PCP) in 38 (25 percent). MEASUREMENTS: Date and diagnosis of PCP, occurrence of drug toxicity, pulmonary function testing, and concentrations of pentamidine in BAL and plasma. CONCLUSIONS: The data suggest, but do not prove, that a dose-response effect has been demonstrated, and that high-dose aerosolized pentamidine may further reduce the attack rate of PCP. These preliminary observations should be confirmed in a double-blind trial comparing 300 mg with 600 mg administered once monthly. The clinical relevance of the adverse pulmonary effects is unclear and requires further investigation.

Three-dimensional imaging and display of renal tumors using spiral CT: a potential aid to partial nephrectomy.

OBJECTIVE: A new technique for creating three-dimensional (3D) images of renal tumors using contrast-enhanced spiral computed tomography (CT) is described and preliminarily investigated. METHODS: 3D spiral CT was employed in 2 patients before radical nephrectomy and in 5 patients before partial nephrectomy. Preoperative and postoperative image analyses were conducted to evaluate the ability of the images to depict key anatomic relationships in planning partial nephrectomies. RESULTS: 3D spiral CT defined the tumor's location and relationship to the kidney surface better than the tumor's proximity to renal hilar vessels and collecting system. Negative surgical margins were obtained in all 4 patients with renal cell carcinoma, and post-operative serum creatinine remained less than 2 mg/dL in all 5 patients after partial nephrectomy. CONCLUSIONS: This early experience suggests that 3D spiral CT can help in the planning of partial nephrectomy and in attaining complete resection of renal cell carcinoma while conserving normal renal tissue.

Oral histoplasmosis in HIV-infected patients. A report of two cases.

Histoplasmosis is a fungal infection caused by the organism Histoplasma capsulatum. Disseminated disease usually occurs in immunosuppressed patients or in patients with chronic illnesses. Although relatively uncommon, histoplasmosis has been reported in patients with AIDS, and oral lesions have been noted on multiple sites and in various clinical presentations. We present two HIV-positive cases with oral lesions as the initial signs of histoplasmosis. Both patients responded well to IV amphotericin B but later suffered recurrences despite being maintained on systemic antifungal therapy.

Kinetic analysis of phasic inhibition of neuronal sodium currents by lidocaine and bupivacaine.

Phasic ("use-dependent") inhibition of sodium currents by the tertiary amine local anesthetics, lidocaine and bupivacaine, was observed in voltage-clamped node of Ranvier of the toad, Bufo marinus. Local anesthetics were assumed to inhibit sodium channels through occupation of a binding site with 1:1 stoichiometry. A three-parameter empirical model for state-dependent anesthetic binding to the Na channel is presented: this model includes two discrete parameters that represent the time integrals of binding and unbinding reactions during a depolarizing pulse, and one continuous parameter that represents the rate of unbinding of drug between pulses. The change in magnitude of peak sodium current during a train of depolarizing pulses to 0 mV was used as an assay of the extent of anesthetic binding at discrete intervals; estimates of model parameters were made by applying a nonlinear least-squares algorithm to the inhibition of currents obtained at two or more depolarizing pulse rates. Increasing the concentration of drug increased the rate of binding but had little or no effect on unbinding, as expected for a simple bimolecular reaction. The dependence of the model parameters on pulse duration was assessed for both drugs: as the duration of depolarizing pulses was increased, the fraction of channels binding drug during each pulse became significantly larger, whereas the fraction of occupied channels unbinding drug remained relatively constant. The rate of recovery from block between pulses was unaffected by pulse duration or magnitude. The separate contributions of open (O) and inactivated (I) channel binding of drug to the net increase in block per pulse were assessed at 0 mV: for lidocaine, the forward binding rate ko was 1.3 x 10(5) M-1 s-1, kl was 2.4 x 10(4) M-1 s-1; for bupivacaine, ko was 2.5 x 10(5) M-1 s-1, kl was 4.4 x 10(4) M-1 s-1. These binding rates were similar to those derived from time-dependent block of maintained Na currents in nodes where inactivation was incomplete due to treatment with chloramine-T. The dependence of model parameters on the potential between pulses (holding potential) was examined. All three parameters were found to be nearly independent of holding potential from -70 to -100 mV. These results are discussed with respect to established models of dynamic local anesthetic-Na channel interactions.

Identification of the minor guanylated tRNA of rabbit reticulocytes.

Two of the tRNA's found in rabbit reticulocytes are substrates for a post-transcriptional modification leading to the incorporation of guanine into the polynucleotide chain. The major guanylated tRNA was previously identified as tRNA (His). In the present report we show that the minor guanylated tRNA is tRNA (Asn), and that just as in the case of tRNA (His), the guanine is located in an internal position. There are only two tRNA (Asn) in reticulocytes. We further show that one of these, the one that is not labeled with guanine, contains the hypermodified base known as Q. tRNA (Asn) does not contain Q.

Kinetics of local anesthetic inhibition of neuronal sodium currents. pH and hydrophobicity dependence.

This study assesses the importance of local anesthetic charge and hydrophobicity in determining the rates of binding to and dissociation from neuronal Na channels. Five amide-linked local anesthetics, paired either by similar pKa or hydrophobicity, were chosen for study: lidocaine, two tertiary amine lidocaine homologs, a neutral lidocaine homolog, and bupivacaine. Voltage-clamped nodes of Ranvier from the sciatic nerve of Bufo marinus were exposed to anesthetic externally, and use-dependent ("phasic") block of Na current was observed. Kinetic analysis of binding (blocking) rates was performed using a three parameter, piecewise-exponential binding model. Changes in extracellular pH (pHo) were used to assess the role of drug protonation in determining the rate of onset of, and recovery from, phasic block. For those drugs with pKa's in the range of pHo tested (6.2-10.4), the forward binding rate during a depolarizing pulse increased at higher pH, consistent with an increase in either intracellular or intramembrane concentration of drug. The rate for unbinding during depolarization was independent of pHo. The dissociation rate between pulses also increased at higher pHo. The pHo dependence of the dissociation rate was not consistent with a model in which the cation is trapped relentlessly within a closed channel. Quantitative estimates of dissociation rates show that the cationic form of lidocaine dissociates at a rate of 0.1 s-1 (at 13 degrees C); for neutral lidocaine, the dissociation rate is 7.0 s-1. Furthermore, the apparent pKa of bound local anesthetic was found to be close to the pKa in aqueous solution, but different than the pKa for "free" local anesthetic accessible to the depolarized channel.

Evaluation of electron beam CT coronary angiography in healthy subjects.

OBJECTIVE: This study evaluated the performance characteristics of electrocardiographically triggered, contrast-enhanced electron beam CT (EBCT) in defining the coronary artery lumen in healthy subjects. SUBJECTS AND METHODS: The coronary arteries of 11 healthy young men (mean age, 24 years old) were evaluated by contrast-enhanced EBCT. Measured parameters included degree of luminal enhancement, intravascular contrast-to-noise ratio, apparent luminal diameter, and length of continuously visualized lumen (100-H threshold for diameter and length measurements). RESULTS: Aortic blood pool attenuation was 44 +/- 5 H (mean +/- SD) before and 278 +/- 35 H after IV injection of contrast material. Contrast-to-noise ratios ranged from a high of 10.0 +/- 2.6 in the proximal right coronary artery to a low of 3.2 +/- 2.7 in the distal left circumflex artery, decreasing from proximal to distal within each vessel. Apparent luminal diameters were as follows: left main coronary artery, 4.5 +/- 0.6 mm; left anterior descending artery, 3.7 +/- 0.5 mm; left circumflex artery, 2.9 +/- 0.6 mm; and right coronary artery, 3.5 +/- 0.5 mm. The mean lengths of visualized lumina were as follows: left main coronary artery, 10 +/- 4 mm; left anterior descending artery, 65 +/- 26 mm; left circumflex artery, 45 +/- 20 mm; and right coronary artery, 58 +/- 24 mm. CONCLUSION: EBCT angiography can reveal the lumen of long segments of the major coronary arteries.

Geminate recombination of O2 and hemoglobin.

The photolysis of HbO2 and HbCO has been studied by measuring transient absorption spectra in the Soret region after excitation with picosecond pulses at 530 nm. Dissociation occurred promptly in both cases, followed (for HbO2) by geminate recombination of ca. 40% of the photodissociated O2 with a lifetime of 200 +/- 70 psec (25 degrees C). No recombination of Hb + CO was observed up to 1200 psec after photolysis. The HbO2 and HbCO photoproduct spectra were broader, weaker, and red-shifted in comparison to the spectrum of stable Hb and Gibson's fast-reacting form, Hb. For HbO2 the spectrum was initially much broader to longer wavelengths but relaxed to a constant shape within 90 psec, whereas for HbCO there was no spectral evolution. The photophysics is analyzed by considering the effect of spin constraints as well as spin--orbit coupling and orbital correlation among the various electronic states of liganded and deoxy hemoglobins. The small quantum yield of HbO2 dissociation is not primarily due to rebinding but rather to electronic relaxation to nonreactive states.

Effect of splenectomy on T-cell subsets and plasma HIV viral titers in HIV-infected patients.

OBJECTIVE: In previous studies we have shown that removal of the spleen in HIV-infected people during the asymptomatic phase of disease results in slower time to AIDS and may also result in improved survival. In this paper, we examine whether splenectomy affects lymphocyte counts, T-cell subsets, and HIV plasma viremia in a manner that could explain the clinical benefits associated with this intervention. METHODS: 10 HIV-infected patients who underwent splenectomy and 23 HIV-infected controls with idiopathic thrombocytopenia purpura who did not undergo splenectomy were studied. These groups were compared for changes in cell subpopulations and HIV plasma viremia. RESULTS: Splenectomy resulted in increases in absolute lymphocyte numbers with rises in both CD4 and CD8 counts, whereas CD4 and CD8 percentage levels remained unchanged. In controls, absolute and percentage CD4+ T-cell counts declined with time from date of HIV infection. Plasma viremia decreased more than threefold, the limit of biologic variation, after splenectomy in 4 of 9 subjects and in only 1 of 18 controls. The proportion of subjects exhibiting reduced viremia following splenectomy was greater than that in HIV-infected patients that did not undergo splenectomy (chi 2 test, P = .015). CONCLUSIONS: Improved survival and time to AIDS in splenectomized HIV-infected patients is associated with temporary reduction of plasma viremia and increase in absolute CD4 and CD8 counts. These effects could not be attributed to antiretroviral therapy because subjects were either untreated or treated with antiretroviral monotherapy during the observation period. These observations may have importance in the understanding of T-cell dynamics and the potential for splenectomy as an HIV reservoir-debulking procedure.

Asymptomatic functional popliteal artery entrapment: demonstration at MR imaging.

PURPOSE: To determine if functional popliteal entrapment can occur in healthy subjects and to define the mechanism of vascular compression. MATERIALS AND METHODS: The right lower extremities were examined in 13 subjects (nine men 27-34 years of age, mean age 31 years; four women 29-44 years of age, mean age 34 years) with no symptoms of popliteal artery entrapment. Magnetic resonance (MR) and Doppler ultrasound images were obtained while the subjects were at rest and while they performed plantar flexion against resistance. RESULTS: Blood flow during plantar flexion ceased in nine of 13 subjects (69%) and was impaired in three of 13 (23%). MR images showed muscular compression of the popliteal artery at two levels: between the plantaris muscle and the medial head of the gastrocnemius muscle and between the plantaris and popliteus muscles. CONCLUSION: Functional impairment of popliteal arterial flow during plantar flexion occurs in subjects who have no symptoms of popliteal entrapment syndrome.