Radiosynoviorthesis of knees by means of 166Ho-holmium-boro-macroaggregates

The aim of this study was to evaluate adverse and therapeutic effects of applicated holmium-boro-macroaggregates (HBMAs) in the radiosynoviorthesis (RSO) of knees in patients suffering from chronic synovitis. We started RSO of the knees by means of a new radiopharmaceutical (RF) HBMA in patients with gonarthrosis, rheumatoid arthritis, chronic synovitis, psoriatic arthritis, and gout arthropathy. Seventeen (17) intra-articular injections were performed in 15 patients who were receiving a mean activity of 972 MBq (range, 904-1057) of 166Ho-HBMA. Patient inclusion to the study followed a series of inclusion and exclusion criterions. The patients were hospitalized for 3 days. Side-effects were evaluated during their hospital stay and again after 6-8 weeks. Static scintigraphy of knee joints and measurements of blood radioactivity were performed. Therapeutic effects were evaluated after 6-8 weeks and at 6 months. In 2 hours and 2 days following the application, we proved, by means of knee and inguinal scintigraphy, only insignificant radiopharmaceutical leakage from the joint cavity to the inguinal lymph nodes in 4 patients. In the treated patients, no serious adverse effects occurred. Nine (9) patients were without complaints, 4 patients had slight knee exudation, and 2 patients had great exudation. Therapeutic effects were as follows: 2 patients were without pain, 9 were with lower pain, 3 were with the same pain, and 1 patient was with increased pain. Joint motion was improved in 7 patients, remained the same in 7 patients, and was impaired in 1 patient. Analgesics consumption was lower in 5 patients, the same in 9 patients, and greater in 1 patient. Knee exudation was absent in 2 patients, lower in 4 patients, the same in 6 patients, and greater in 3 patients. In 3 patients it was necessary to do surgical RSO. This RF can extend the range of clinically used radiopharmaceuticals for RSO and to supplement space between 90Y with high energy and 186Re with 169Er with lower beta energy. The energy of 166Ho is suitable for great and medium joints (i.e., knees, hips, shoulders, elbows, wrists, and ankles).     

Lanthanide(III) complexes of bis(phosphonate) monoamide analogues of DOTA: bone-seeking agents for imaging and therapy

Lanthanide complexes of DOTA derivatives 2a (BPAMD) and 2b (BPAPD), having a monoamide pendant arm with a bis(phosphonate) moiety, were comparatively tested for application in MRI, radiotherapy, and bone pain palliation. (1)H, (31)P, and (17)O NMR spectroscopy show that they are nine-coordinated, with one water molecule in the first coordination sphere of the Ln(III) ion. The bis(phosphonate) moieties are not coordinated to the lanthanide and predominantly mono- and diprotonated at physiological pH. The parameters governing the longitudinal relaxivities of the Gd complexes are similar to those of other monoamides of DOTA reported in the literature. Upon adsorption on hydroxyapatite, the relaxivities at 20 MHz and 25 degrees C of Gd-2a and Gd-2b were 22.1 and 11 s(-1) mM(-1), respectively. An in vivo gamma-ray imaging study showed that the (177)Lu complexes of 2a and 2b have a high affinity for bones, particularly for growth plates and teeth with a prolonged retention.     

Prediction of long-term reverse left ventricular remodeling after revascularization or medical treatment in patients with ischemic cardiomyopathy: a comparative study between SPECT and MRI

Patients with ischemic heart disease and depressed left ventricular (LV) ejection fraction (LVEF) develop varying degrees of LV remodeling after cardiac surgical revascularization. Fifty-three patients with stable ischemic heart disease and impaired LV function (LVEF 34.9 ± 4%) were prospectively followed up for 24 months. Thirty-seven patients underwent coronary artery bypass grafting (CABG), 16 patients were treated conservatively. Cardiac magnetic resonance imaging (MRI) and SPECT were performed at baseline and after 12 and 24 months of follow-up. The patients were divided into responders and non-responders depending on the degree of LVEF improvement at 24 months follow-up (>5%—responders). MRI with ≤5 segments with DE/wall thickness ratio (DEWTR) ≥50% predicted LV reverse remodeling with a sensitivity of 86% and a specificity of 75% (AUC 0.81). An MRI finding of ≤2 segments with the DEWTR ≥75% had a corresponding sensitivity of 71% and specificity of 67% (AUC 0.75) while fixed perfusion defect on SPECT < 16.5% of LV predicted reverse remodeling with a sensitivity of 64% and a specificity of 69% (AUC 0.64). A preoperative number of segments with the DE/wall thickness ratio of ≥50 and ≥75% obtained by MRI, was found to be a better predictor of left ventricular reverse remodeling than fixed perfusion defect by SPECT. No other MRI or SPECT parameter predicted LVEF improvement at 24 months after CABG.     

HA2-specific monoclonal antibodies as tools for differential recognition of influenza A virus antigenic subtypes

Antigenic reactivity of a set of monoclonal antibodies (MAb) raised against the HA2 subunit of hemagglutinin of H3 subtype was characterized in a rapid culture assay. MAbs FC12 and FE1, known to recognize the same antigenic site (IV), cross-reacted with influenza viruses of H3 and H4 subtypes, regardless of their host origin. No cross-reactivity was detected with other antigenic subtypes tested (H1-H13). The involvement of conserved residues D160, N168, and F171 in the differential recognition of H3 and H4 subtypes is proposed. In contrast, MAb IIF4 that recognizes antigenic site II exhibited a broader inter-subtype reactivity including subtypes H3, H4, H5, H8 and some viruses of H2, H6 and H13 subtypes. The ability of HA2-specific antibodies to differentially react with distinct antigenic subtypes can be utilized in development of diagnostics and in the influenza virus surveillance.     

Cognitive and emotional processing at high altitude

INTRODUCTION: Exposure to altitude reduces oxygen supply to the central nervous system and may cause a variety of neuropsychological impairments. We investigated the relationship between certain cognitive functions and cardiovascular and respiratory variables during acute hypobaric hypoxia. METHODS: There were three groups of seven men who were each exposed to a 2-h altitude profile (AP) involving 30 min at each of the following simulated altitudes (m): AP1, 450-1500-3000; AP2, 450-1500-4500; Control 450-650-650. The neuropsychological tests included word fluency and three word-association tasks tapping processes of cognitive flexibility and emotion regulation. A lateralized tachistoscopic lexical decision task with high and low emotional target words was also administered to assess possible shifts in hemispheric superiorities for positive and negative affect. RESULTS: No significant differences in word fluency, word association, or lateralized lexical decision performances were found, despite a significant oxygen desaturation and a drop in diastolic BP at 4500 m, indicating the beginning of central hypoxia in terms of a functional impairment of the vasomotor center. CONCLUSION: During acute exposure to hypobaric hypoxia, selected cognitive and affective functions mediated by the frontal lobe were preserved. Functional hemispheric asymmetries for emotional processes remained unchanged.     

Effect of folic acid on fenofibrate-induced elevation of homocysteine and cysteine

Background

An elevated total plasma homocysteine (tHcy) level is considered to be an independent risk factor for atherosclerosis. It has been reported that lipid-lowering therapy with fibric acid derivatives (fibrates) increases tHcy and total plasma cysteine (tCys) levels. The aim of this study was to determine whether therapy with folic acid, a potent tHcy-lowering agent, could modify the fenofibrate-induced elevation of plasma aminothiols.

Methods

Patients with combined hyperlipidemia (n = 37) were randomized to receive 9 weeks of treatment with micronized fenofibrate 200 mg/day (F group) or fenofibrate 200 mg/day plus folic acid 10 mg/every other day (F+F group). tCys and tHcy levels were determined before and after the therapy with high performance liquid chromatography.

Results

The tHcy level increased significantly in the F group by 51.3% and in the F+F group by 14.6% (between-group difference P = .001). Total plasma cysteine (tCys) increased similarly after both treatments (P = .72). The serum creatinine level increased in the F group by 20.7% and in F+F group only by 9.8% (P = .04). The increase of tHcy level in F group correlated with an increase of tCys and creatinine levels (r = 0.74 and 0.64, respectively). The effects on the lipid profile did not differ by treatment group.

Conclusions

Folic acid effectively reduces the fenofibrate-induced elevation of tHcy and creatinine, but it does not affect the elevation of the tCys. Folic acid has neutral effect on the lipid-lowering action of fenofibrate. Clinical efficacy of fenofibrate might be improved by folic acid coadministration.     

Double mutant and formaldehyde inactivated TSST-1 as vaccine candidates for TSST-1-induced toxic shock syndrome

Up to now there is no treatment for staphylococcal toxic shock syndrome, a disease mainly induced by toxic shock syndrome toxin-1(TSST-1). There is great demand in finding means to control the disease, one of them is the development of an effective and safe vaccine against TSST-1. In this study we constructed a series of vaccine candidates and investigated their biological activity, toxicity, and potential to invoke an immune response. TSST-1 was isolated from Stahylococcus aureus supernatants and recombinantly expressed as a N-terminal 6x histidine-tagged protein in Escherichia coli. In order to obtain molecules with minimal toxicity we constructed single mutants (G31R and H135A) and one double mutant (G31R/H135A) with both residues exchanged. We also detoxified native TSST-1 isolated from S. aureus, and recombinantly expressed TSST-1 by treatment with formaldehyde. Functional activity of native and recombinant TSST-1 and grade of inocuity of mutants and toxoids was determined by investigating mitogenity, T-cell activation, and cytokine release upon stimulation of human mononuclear cells with the vaccine candidates. All substances were tested in a rabbit immunization study. After primary immunization and three additional boosts all vaccinated animals developed antibody titers against TSST-1 and were protected against challenge with a lethal doses of superantigen potentiated with lipopolysaccharide.     

Monoclonal antibodies generated in carbonic anhydrase IX-deficient mice recognize different domains of tumour-associated hypoxia-induced carbonic anhydrase IX

Transmembrane carbonic anhydrase IX (CA IX) is frequently expressed in human tumours in response to hypoxia and may serve as a tumour marker and therapeutic target. So far, only a single monoclonal antibody (MAb) M75 with an epitope in the N-terminal proteoglycan (PG)-like region has been available for detection purposes. Attempts to produce MAbs against other parts of CA IX were unsuccessful due to the immunodominance of the PG region that significantly differs between human and mouse homologues. To overcome this problem, we used various forms of human CA IX antigen to immunize CA IX-deficient mice recently produced by targeted disruption of Car9 gene. Here, we describe new MAbs that react with human, but not mouse CA IX in different immunodetection settings, and show no cross-reactivity with CA I, II and XII. MAb IV/18 is directed to the PG region, while the other six antibodies bind to the CA domain, as determined by CA IX deletion variants. IV/18 recognizes a linear epitope, while anti-CA MAbs V/10, V/12, VII/20, VII/28, VII/32 and VII/38 react with conformational epitopes clustered into three antigenic sites. The new antibodies represent important tools for improving our knowledge of structure-function relationships in the CA IX molecule and a better understanding of the role of CA IX in cancer development. Moreover, the availability of the MAbs specific for distinct antigenic regions on two separate extracellular domains offers an opportunity to elaborate a sensitive assay that could be particularly important for CA IX detection in body fluids of cancer patients.     

Combined grading for choroidal neovascularisation: colour,fluorescein angiography and autofluorescence images

BACKGROUND: Patients with age-related macular degeneration (ARMD) have several imaging techniques carried out regularly. In this study we introduce a new grading model of autofluorescence images (AF), compare it with fluorescein angiography (FFA) and digital colour fundus photos (COL) and test for inter- and intraobserver reliability. METHODS: A total of 71 eyes of 54 patients with bilateral or unilateral CNV had COL, FFA and AF, fulfilling the inclusion criterion of having all 3 types of imaging carried out on the same day or within 14 days. The grading of COL was performed by a trained grader based on the International ARM classification; FFA and AF images were independently graded by two trained retinal specialists in order to assess inter-observer reliability. Overall, 30% of all images were regraded after at least 14 days interval to assess intra-observer variability. RESULTS: The intergrader agreement was exact for classification of CNV (k = 1.00); almost perfect for FFA features (k = 0.83) and correspondence of decreased AF to COL (k = 0.94); substantial for patterns of decreased and increased AF (k = 0.80, k = 0.78), correspondence of patterns of increased AF to FFA and to COL (k = 0.78, k = 0.74) and background AF (k = 0.72); moderate for CNV diameter in FFA (k = 0.45), FFA pattern (k = 0.43), dimension of increased and decreased AF (k = 0.5, k = 0.56); fair for quality of FFA and AF images (k = 0.21, k = 0.26) respectively. The intragrader agreement varied from exact to substantial for all categories. Diffuse and reticular patterns of decreased AF and reticular pattern of increased AF correlated well, with visual acuity worse than 6/24. CONCLUSION: The combined grading system was reliable for evaluating the three imaging techniques, and might be suitable for epidemiological studies and therapeutic trials where such grading is warranted. Certain AF patterns seem to predict VA outcome better than one might have predicted based on FFA. Further studies are needed to evaluate its usefulness in clinical settings for predicting outcomes for patients receiving therapy for end-stage disease.