Infliximab serum concentrations and disease activity in perianal fistulizing Crohn's disease: a cross-sectional study.

INTRODUCTION: Several studies associate the presence of higher serum concentrations of infliximab (IFX) with fistula healing in perianal Crohn's disease (CD). This study aimed to evaluate serum IFX concentrations in patients with perianal fistulizing CD (PFCD) in the presence or absence of general, clinical, and radiological activities. METHODS: This was a cross-sectional study in patients with PFCD during maintenance treatment with IFX from two centers. Serum IFX concentrations were measured before their next infusion and anal fistulas were evaluated by clinical examination and magnetic resonance imaging (MRI), whenever possible, performed 90 days before or after serum collection. According to clinical scores, radiological activity, and disease markers, patients were classified as in remission or active disease. Mean serum IFX concentrations were compared between the groups. RESULTS: Thirty-eight patients with PFCD were included. Demographic characteristics were similar in patients with remission or active disease. The overall mean serum IFX concentration of the entire sample (n = 38) was 5.21 ± 4.75 µg/mL (median 3.63; IQR 1.44-8.82). Serum IFX levels were 6.25 ± 5.34 µg/mL (median 3.62; IQR 1.95-11.03) in the 23 (60.5%) patients in remission and 3.63 ± 3.24 µg/mL (median 3.63; IQR 1.32-6.43; p = 0.226) in the 15 (39 .5%) who presented active disease. When evaluating general, clinical, and radiological activity of PFCD, and deep remission in isolation, no statistical difference between the groups was observed (p = 0.226, p = 0.418, p = 0.126, and p = 0.232, respectively). The 13 (34.2%) patients with an optimized dose of IFX had significantly higher serum concentrations than the remaining 25 (65.8%) with a standard dose: 8.33 ± 4.41 µg/mL (median 8.36; IQR 3.82-11.20) vs. 3.59 ± 4.13 µg/mL (median 1.97; IQR 1.18-3.85) -p = 0.002. Patients in remission and with an optimized IFX dose had significantly higher serum IFX concentrations than those with a standard dose (p = 0.006), whereas no significant difference was observed among those with active disease (p = 0.083). CONCLUSION: There were no differences in IFX serum concentrations in patients with clinical or radiological active PFCD as compared with those in remission. Patients with an optimized IFX dose had significantly higher serum concentrations than those with a standard dose. Patients in remission and with an optimized IFX dose had significantly higher serum concentrations than those with a standard dose.

Complete physical mapping of IL6 reveals a new marker associated with chronic periodontitis.

BACKGROUND AND OBJECTIVE: Interleukin-6 (IL-6) is a powerful stimulator of osteoclast differentiation and bone resorption. Production of IL-6 is modulated by polymorphisms, and higher levels of this cytokine are found locally in patients with chronic periodontitis. In this study we performed a modern approach - Complete physical mapping of the IL6 gene - to identify the polymorphisms associated with chronic periodontitis in a southern Brazilian population sample. MATERIAL AND METHODS: One-hundred and nine individuals of both genders (mean age: 41.5 ± 8.5 years) were divided into a study group (56 participants with periodontitis) and a control group (53 individuals without periodontitis). After collection and purification of DNA, nine tag single nucleotide polymorphisms (SNPs; rs1524107, rs2069835, rs2069837, rs2069838, rs2069840, rs2069842, rs2069843, rs2069845 and rs2069849) covering the entire gene were selected according to the information available on the International HapMap Project website and evaluated using real-time PCR. RESULTS: Differences in the distribution of the following parameters were statistically significant between study and control groups: number of teeth (p = 0.030); probing depth (p < 0.001); clinical attachment level (p < 0.001); gingival index (p < 0.001); plaque index (p = 0.003); calculus index (p < 0.001); and dental mobility (p < 0.001). It was found that marker rs2069837 (located in intron 2 of IL6) under G dominant was associated with protection against chronic periodontitis in a Brazilian population in the presence of clinical variables, such as visible plaque, dentist visit frequency and dental floss use, and was suggested for the first time as a marker of susceptibility to chronic periodontitis. CONCLUSION: Complete physical mapping of IL6 (using tag SNPs) was carried out for the first time, unveiling allele G of polymorphism rs2069837 (located in the second intron of IL6) as a suggestive marker of protection against chronic periodontitis in a Brazilian population.

Systemic lupus erythematous and clinical outcomes in peritoneal dialysis.

BACKGROUND: The prevalence of systemic lupus erythematous (SLE) patients requiring renal replacement therapy (RRT) is increasing but data on clinical outcomes are scarce. Interestingly, data on technique failure and peritoneal-dialysis (PD)-related infections are rarer, despite SLE patients being considered at high risk for infections. The aim of our study is to compare clinical outcomes of SLE patients on PD in a large PD cohort. METHODS: We conducted a nationwide prospective observational study from the BRAZPD II cohort. For this study we identified all patients on PD for greater than 90 days. Within that subset, all those with SLE as primary renal disease were matched with PD patients without SLE for comparison of clinical outcomes, namely: patient mortality, technique survival and time to first peritonitis, then were analyzed taking into account the presence of competing risks. RESULTS: Out of a total of 9907 patients, we identified 102 SLE patients incident in PD and with more than 90 days on PD. After matching the groups consisted of 92 patients with SLE and 340 matched controls. Mean age was 46.9 ± 16.8 years, 77.3% were females and 58.1% were Caucasians. After adjustments SLE sub-hazard distribution ratio for mortality was 1.06 (CI 95% 0.55-2.05), for technique failure was 1.01 (CI 95% 0.54-1.91) and for time to first peritonitis episode was 1.40 (CI 95% 0.92-2.11). The probability for occurrence of competing risks in all three outcomes was similar between groups. CONCLUSION: PD therapy was shown to be a safe and equally successful therapy for SLE patients compared to matched non-SLE patients.

Recombinant human TSH increases the efficacy of a fixed activity of radioiodine for treatment of multinodular goitre.

CONTEXT: High doses of (131)I are usually needed in the treatment of multinodular goitre (MNG) for effective thyroid volume (TV) reduction. Recombinant human thyroid-stimulating hormone (rhTSH) is an adjuvant to enhance (131)I uptake, allowing a decrease in radiation activity and enhancing (131)I efficacy. OBJECTIVE: To evaluate whether rhTSH increases the efficacy of a fixed activity of (131)I for the treatment of MNG. DESIGN: Two-year, observational, placebo-controlled study. SETTING: Patients received 0.1 mg rhTSH (A), 0.005 mg rhTSH (B) or placebo (C). A fixed activity of 1.11 GBq of (131)I was administered 24 h after rhTSH or placebo. PATIENTS: A total of 28 outpatients (26 females and two males) with MNG. MEASUREMENTS: TSH, free T4, T3, thyroglobulin (Tg) and TV. RESULTS: Basal radioactive iodine uptake and TV values were comparable among all groups. After rhTSH or placebo, peak levels of TSH, free T4, T3 and Tg were higher in A than in B or in C (p < 0.05). Hyperthyroidism was observed in A (n = 2), B (n = 6) and C (n = 4). Thyroid enlargement was reported in A (n = 3) and B (n = 6). After 24 months, 10 patients developed hypothyroidism (four in A, three in B and three in C). TV reduction was similar between A and B (37.2 +/- 25.5% vs. 39.3 +/- 27.9%, p = 0.88), but different from the non-significant reduction in C (15.3 +/- 28.3%, p = 0.08). CONCLUSIONS: Followed by 1.11 GBq, a very low dose of 0.005 mg rhTSH was equally safe and effective as 0.1 mg rhTSH. Both doses increased the efficacy of radioiodine. Adverse events were mild, transient and readily treatable.

Evaluation of bone marrow mesenchymal stem cell standard cryopreservation procedure efficiency.

INTRODUCTION: Mesenchymal stem cells are obtained from a variety of sources, particularly bone marrow. These cells have great potential for clinical research due to their potential to regenerate tissue. As is well known, the cryopreservation process can store any cell type, particularly blood cells, for an indeterminate time. OBJECTIVE: The aim of this study was to analyze the efficiency of standard cryopreservation procedures for adult mesenchymal stem cells from bone marrow. METHODS: Mononuclear stem cells isolated from 10 Wistar male rats were cultivated for 4 weeks to obtain mesenchymal stem cells. The parameters considered in this study were trypan blue exclusion test and annexin V conjugated with 7-amino-actinomycin for flow cytometry before cryopreservation in liquid nitrogen vapor phase for 1 month and after thawing. RESULTS: The viabilities determined by the trypan blue exclusion test were 94.76% and 90.58%, and the flow cytometry assay (annexin V conjugated with 7-amino-actinomycin) were 85.52% and 66.25%, before cryopreservation and after thawing, respectively. CONCLUSIONS: Standard procedures for cryopreservation were not efficient for those cells. The flow cytometry assay was more sensitive than the trypan blue exclusion test to demonstrate nonviability.

Functional outcome of bone marrow stem cells (CD45(+)/CD34(-)) after cell therapy in chronic spinal cord injury in Wistar rats.

BACKGROUND: Therapy with diverse cell types has been proposed to regenerate spinal cord injuries seeking to minimize the consequences for the lives of chronic patients. The types considered are: mononuclear and mesenchymal adult stem cells, embryonic stem cells, and Schwann cells. MATERIALS AND METHODS: Ninety male Wistar rats that underwent spinal cord contusion injury (NYU Impactor) were followed with the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale for 14 days. Animals with scores < or = 16 were randomly divided into 2 groups: control (vehicle) versus cell therapy group. The mononuclear fraction (CD45(+)/CD34(-)) obtained by puncture-aspiration of the bone marrow was isolated by a density gradient (d = 1.077). The parenchymal cell infusion was performed using a syringe (100 U/1 mL) with a 30G1/2 needle. The animals were followed for 10 days before euthanasia. Statistical analyses comparing groups were performed by the Mann-Whitney test and group comparisons by the Wilcoxon test. RESULTS: Among 90 injured rats, 65 (72.2%) survived, including 44 whose scores were < or = 16. Eleven animals finished the study in the control group (64.7%) and 17 in the therapy group (80.9%). The statistical analyses did not demonstrate significance (P > .05) for either test. CONCLUSION: Mononuclear adult stem cell therapy was not demonstrated to be functionally effective for chronic spinal cord injury.

Immunophenotypic expression by flow cytometric analysis of cocultured skeletal muscle and bone marrow mesenchymal stem cells for therapy into myocardium.

The product generated by skeletal muscle and bone marrow mesenchymal stem cell cocultures has been demonstrated to improve the functional outcomes after cell therapy in postinfarction or Chagas myocardiopathy. This coculture method allows cell interactions in vitro, diminishing the operational costs of the culture/expansion as well as leading to angiogenesis and myogenesis for regeneration of the injured heart. Flow cytometric analysis may better characterize the cellular types in this model. Our objective was to use flow cytometry to analyze the immunophenotype expressed in this coculture model. The coculture was performed in accordance with Carvalho for 21 days. Flow cytometry was performed before and after coculture to characterize the immunophenotypic profile of cellular subsets, namely, the surface markers CD31, CD34, CD44H, CD45, CD49d, CD54, CD73, CD90, CD105, CD106, Myo-D, M-cadherin, and Connexin-43. Statistics were performed by the nonparametric Friedman test (P < .05) with post-hoc analysis by the nonparametric Wilcoxon test (P < or = .017, Bonferroni correction). The results demonstrated statistical significance for CD45(+) in 89.49% of mononuclear cells, 3.58% in skeletal muscle cells, and 4.74% among cocultured cells (P = .0094); and CD90(+) in 36.18% of mononuclear cells, 6.01% in skeletal muscle cells, and 48.94% among cocultured cells (P = .0420). The cocultured cells expressed the markers CD73(++), CD90(+++), CD45(-), CD34(+), CD105(-/+), CD106(-/+), M-cadherin(-/+), and Connexin-43(-/+). In conclusion, flow cytometric analysis showed a heterogeneous adherent cell population in this coculture model.

Functional outcome of bone marrow stem cells (CD45(+)/CD34(-)) after cell therapy in acute spinal cord injury: in exercise training and in sedentary rats.

BACKGROUND: Cell therapy and exercise training may be options for spinal cord regeneration. Our objective was to evaluate the functional effects of autologous bone marrow stem cell (CD45(+)/CD34(-)) transplantation in acute spinal cord injury in exercise training and in sedentary rats. MATERIALS AND METHODS: Fifty-five adult male Wistar rats underwent spinal cord contusion by Impactor (NYU). Locomotor rating scale was performed every 48 hours for 48 days. Animals with scores < or = 12 were randomly divided into 4 groups: sedentary without parenchymal cell infusion; sedentary with parenchymal cell infusion; swimming training without parenchymal cell infusion; and swimming training with parenchymal cell infusion. Bone marrow stem cells were isolated by puncture-aspiration of the bone marrow and density gradient (d = 1.077). The animals underwent a 60-minute swimming session 6 times/week supporting an overload of 3% of body weight for 6 consecutive weeks. Comparisons between the groups in relation to differences between the beginning to the end of scores used the nonparametric Bonferroni test and post-hoc Mann-Whitney U test to identify significance. RESULTS: Forty-two rats that obtained scores < or = 12 underwent therapy with 9 animals in each of the 4 groups as completors (n = 36). There was significance (P < or = .008) for sedentary without parenchymal cell infusion vs swimming training with parenchymal cell infusion. CONCLUSION: The combination of bone marrow stem cell therapy (CD45(+)/CD34(-)) and exercise training resulted in significant functional improvement in acute spinal cord injury.

Angiogenesis without functional outcome after mononuclear stem cell transplant in a doxorubicin-induced dilated myocardiopathy murine model.

OBJECTIVES: Cell transplantation is considered a novel approach in the treatment of myocardiopathy. The objective of this study was to evaluate the effects of autologous mononuclear stem cell therapy in doxorubicin-induced dilated myocardiopathy by conducting both functional and histopathologic analysis. METHODS: Seventy male rats were doxorubicin injected intraperitoneally for 2 weeks. At 1 month, the animals that had demonstrated left ventricular ejection fractions less than 40% were randomly divided into a mononuclear stem cell group and controls. Mononuclear stem cells were isolated. All animals underwent echocardiographic study: baseline, pre-cell therapy, and at 1 month post-cell therapy, and analyzed by the nonparametric Mann-Whitney test. Transplants were performed by subepicardial injections. Standard staining was performed. RESULTS: Twenty-three animals were randomly treated: mononuclear stem cell and control groups, with 11 rats completing the study. Cell viability was 85%. Mononuclear stem cells (n=5; 5x106 cells /300 microL medium) and control (n=6; 300 microL medium) were used. The resulting left ventricular ejection fraction in the cell therapy group was not significantly different compared with controls (p=0.54). New vessels were demonstrated in the subepicardial region. CONCLUSIONS: Autologous mononuclear stem cell therapy was not functionally effective in doxorubicin-induced dilated myocardiopathy in the animal model under study with the experimental conditions, despite occurrence of angiogenic activity.

Simultaneous autologous transplantation of cocultured mesenchymal stem cells and skeletal myoblasts improves ventricular function in a murine model of Chagas disease.

BACKGROUND: Cellular transplantation is emerging as a promising strategy for the treatment of postinfarction ventricular dysfunction. Whether its beneficial effects can be extended to other cardiomyopathies remains an unexplored question. We evaluated the histological and functional effects of simultaneous autologous transplantation of co-cultured stem cells and skeletal myoblasts in an experimental model of dilated cardiomyopathy caused by Chagas disease, characterized by diffuse fibrosis and impairment of microcirculation. METHODS AND RESULTS: Wistar rats weighing 200 grams were infected intraperitoneally with 15 x 10(4) trypomastigotes. After 8 months, 2-dimensional echocardiographic study was performed for baseline assessment of left ventricle (LV) ejection fraction (EF) (%), left ventricle end-diastolic volume (LVEDV) (mL), and left ventricle end-systolic volume (LVESV) (mL). Animals with LV dysfunction (EF <37%) were selected for the study. Autologous skeletal myoblasts were isolated from muscle biopsy and mesenchymal stem cells from bone marrow aspirates were co-cultured in vitro for 14 days, yielding a cell viability of >90%. Eleven animals received autologous transplant of 5.4 x 10(6)+/-8.0 x 10(6) cells (300 microL) into the LV wall. The control group (n=10) received culture medium (300 microL). Cell types were identified with vimentin and fast myosin. After 4 weeks, ventricular function was reassessed by echo. For histological analysis, heart tissue was stained with hematoxylin and eosin and immunostained for fast myosin. After 4 weeks, cell transplantation significantly improved EF and reduced LVEDV and LVESV. No change was observed in the control group. CONCLUSIONS: The co-transplant of stem cells and skeletal myoblasts is functionally effective in the Chagas disease ventricular dysfunction.

Cell transplantation: differential effects of myoblasts and mesenchymal stem cells.

BACKGROUND: Cellular transplantation has emerged as a novel therapeutic option for treatment of ventricular dysfunction. Both skeletal myoblasts (SM) and mesenchymal stem cells (MSC) have been proposed as ideal cell for this aim. The aim of this study is to compare the efficacy of these cells in improving ventricular function and to evaluate the different histological findings in a rat model of severe post-infarct ventricular dysfunction. METHODS: Myocardial infarction was induced in Wistar rats by left coronary occlusion. Animals with resulting ejection fraction (EF) lower than 40% were included. Heterologous SM were obtained by lower limb muscle biopsy and MSC by bone marrow aspiration. Nine days after infarction, rats received intramyocardial injection of SM (n=8), MSC (n=8) or culture medium, as control (n=11). Echocardiographic evaluation was performed at baseline and after 1 month. Histological evaluation was performed after HE and Gomori's trichrome staining and immunostainig against desmin, fast myosin and factor VIII. RESULTS: There was no difference in baseline EF and left ventricular end diastolic (LVEDV) and systolic volume (LVESV) between all groups. After 1 month a decrease was observed in the EF in the control group (27.0+/-7.10% to 21.46+/-5.96%, p=0.005) while the EF markedly improved in SM group (22.66+/-7.29% to 29.40+/-7.01%, p=0.04) and remained unchanged in the MSC group (23.88+/-8.44% to 23.63+/-10.28%, p=0.94). Histopathology identified new muscular fibers in the group that received SM and new vessels and endothelial cells in the MSC. CONCLUSION: Skeletal myoblasts transplantation resulted in myogenesis and improvement of ventricular function. In contrast, treatment with mesenchymal stem cells resulted in neoangiogenesis and no functional effect.

Functional outcome of bone marrow stem cells: mononuclear versus mesenchymal stem cells after cellular therapy in myocardial scar in Wistar rats.

Experimental studies have suggested that a bone marrow stem cell transplant into the heart produces a favorable impact on tissue perfusion, yielding a new perspective on myocardial regeneration. Studies in human beings have demonstrated an improved clinical and functional cardiac state, which has been explained mainly by the angiogenic potential of the stem cells. Our objective was to compare the functional outcome of mononuclear stem (MoSC) and mesenchymal stem (MeSC) cell therapy after myocardium infarction in rats. Forty-two rats with myocardial infarctions underwent autologous transplantation of MoSC and MeSC in animals with ejection fractions lower than 40%. The functional analysis was performed using echocardiography at baseline and at 1 month after direct injection into the ventricular wall using: 5 x 10(6) MoSC (n = 08) or 2.5 x 10(6) MeSC (n = 13) or medium controls (n = 21). Statistical significance was accepted when P < .05. Intragroup comparisons of baseline versus 1-month follow-up were performed with paired t tests. Kruskal-Wallis was used as appropriate. There was a difference in baseline left ventricular ejection fraction (LVEF) and left ventricular-end dyastolic volume between all groups. After 1 month, LVEF decreased in the control group but remained unchanged in MoSC and MeSC groups. In all groups we observed myocardial remodeling. In conclusion, we have not demonstrated functional effectiveness with either MoSC or MeSC cell type, but potentially improved myocardial perfusion needs to be analyzed.

Proliferation of bone marrow mesenchymal stem cells, skeletal muscle cells and co-culture of both for cell myocardium therapy in Wistar rats.

The best results of cell therapy are achieved by a greater quantity of cells, delivery to the correct place, and cell conditions of viability with proliferation and without apoptosis. The quantification of cellular growth, including proliferation and viability, has become an essential tool. The objective of this study was to analyze cell proliferation in 14-day cultures of bone marrow mesenchymal stem cells (BMMSC), skeletal muscle cells (SMC), and co-culture of both types of cells (CO). Forty-four adult Wistar male rats (250-300g) received cultured cells CO (n = 22), BMMSC (n = 10), and SMC (n = 12). All cultured cells were started with the same concentration: 5 x 10(5)/mL, under similar conditions and maintained in an incubator with 5% CO(2) at 37 degrees C, which was changed every 48 hours for 14 days. The cell count was performed in Neubauer's chamber to calculate the proliferation index (IP). Statistical analysis was performed by the nonparametric Kruskal-Wallis and Wilcoxon tests. P values <.05 were considered statistically significant. The results showed that IP was positive in all groups. In conclusion, proliferation capacity was demonstrated in all groups. SMC IP was greater than the others, although it was the most heterogeneous.

Cell transplantation after the coculture of skeletal myoblasts and mesenchymal stem cells in the regeneration of the myocardium scar: an experimental study in rats.

UNLABELLED: In myocardial infarction and Chagas's disease, some physiopathological aspects are common: cardiomyocyte loss due to ischemia leads to a reduction of contractility and heart function. Different cells have been proposed for cellular cardiomioplasty. OBJECTIVE: Our goal was to evaluate the method of co-culture of skeletal muscle (SM) and mesenchymal stem cells (MSC) for cell therapy of heart failure in Chagas's disease (CD) and myocardium postinfarction (MI). METHODS: For MI, 39 rats completed the study at 1 month. Seventeen rats received cell therapy into the scar and 22 rats only medium. For CD, 15 rats completed the study at 1 month including 7 that received cell therapy and eight followed the natural evolution. All animals underwent ecocardiographic analysis at baseline and 1 month. Left ventricular, ejection fraction, end systolic, and end dyastolic volume were registered and analyzed by ANOVA. The co-culture method of SM and MSC was performed at 14 days (DMEM, with 15% FCS, 1% antibiotic, IGF-I, dexamethasone). Standard stain analysis was performed. RESULTS: For MI ejection fraction in the animals that received the co-cultured cells increased from 23.52+/-8.67 to 31.45+/-8.87 (P=.006) versus the results in the control group: 26.68+/-6.92 to 22.32+/-6.94 (P=.004). For CD, ejection fraction in animals that received the co-cultured cells increased from 31.10+/-5.78 to 53.37+/-5.84 (P<.001) versus the control group values of 36.21+/-3.70 to 38.19+/-7.03 (P=0.426). Histopathological analysis of the animals receiving co-cultured cells demonstrated the presence of myogenesis and angiogenesis. CONCLUSION: The results validated the product of SM and MSC co-cultures for treatment of diseases.

Outcome of orthodontic mini-implant loss in relation to interleukin 6 polymorphisms.

Mini-implants (MIs) are used increasingly for orthodontic anchorage and their success may require some osseointegration, which is affected by the underlying host immune-inflammatory response. Interleukin 6 (IL-6) is a cytokine expressed during the host response after a trauma or infection. The aim of this study was to investigate the association of clinical characteristics and IL6 tag single nucleotide polymorphisms (which capture the information of the whole gene in terms of genetic variability) with the loss of MIs for orthodontic anchorage. A total of 487 patients were treated with orthodontic MIs between 2004 and 2010. After the application of inclusion and exclusion criteria, the sample comprised 104 patients with one or more MIs that had been in function for at least 6 months with no loss, and 31 patients who had lost one or more MIs. Allele A of rs2069843 and allele T of rs2069849 were suggestively associated with the loss of MIs for orthodontic anchorage and were in complete linkage disequilibrium, which means that one of them is sufficient to capture the same information. The location of installation (mandible) and the number of MIs installed per patient were also associated with the loss of MIs.

Recombinant human thyrotropin as adjuvant in the treatment of multinodular goiters with radioiodine.

The use of 131I in the treatment of multinodular goiters (MNG) is well established. We evaluated the effect of 30 microCi 131I (1.11 GBq) in 18 patients with MNG with the aid of two injections of 0.1 mg recombinant human TSH (rhTSH), given on d 1 and 2. A dose of 30 microCi 131I was given on d 3. TSH, T3, free T4, and thyroglobulin were measured on d 1, 2, 3, 5, 10, 30, 60, 90, and 180, and antithyroid antibodies were measured on d 1, 30, 90, and 180. Twenty-four-hour 131I uptake measured 1-3 months before rhTSH increased from 12.3 +/- 6.2 to 53.5 +/- 10.9% (P < 0.0001), free T4 from 1.3 +/- 0.2 to peak 3.2 +/- 1.1 ng/dl levels (P < 0.0001), T3 from 113.9 +/- 35.0 to peak 332.2 +/- 123.0 ng/dl levels (P < 0.0001), TSH from 0.76 +/- 0.71 to peak 18.9 +/- 5. 3 mU/liter levels (P < 0.0001), and thyroglobulin from 280.9 +/- 370.0 to peak 1838.5 +/- 1360.7 ng/dl levels (P = 0.001). Painful thyroiditis (33%) and mild thyrotoxicosis (39%) constituted minor side effects. There were no changes in echocardiographic parameters, done before and after rhTSH administration, on d 3. Hypothyroidism developed in 65%. Mean goiter size, measured by computed tomography, decreased from 97.9 +/- 45.4 to 65.5 +/- 47.3 ml (P < 0.0001; reduction: 39 +/- 19%) after 6 months. We conclude that rhTSH is a safe and efficient therapeutic tool in the treatment of MNG allowing the use of outpatient therapeutic 131I doses.

Expression level of quiescin sulfhydryl oxidase 1 (QSOX1) in neuroblastomas.

Neuroblastoma is the most common extracranial solid malignant tumor observed during childhood. Although these tumors can sometimes regress spontaneously or respond well to treatment in infants, genetic alterations that influence apoptosis can, in some cases, confer resistance to chemotherapy or result in relapses and adversely affect prognosis for these patients. The aim of this study was to correlate immunohistochemical expression of the protein QSOX1 (quiescin sulfhydryl oxidase 1) in samples obtained from untreated neuroblastomas with the patients' clinical and pathological prognostic factors and clinical course. Neuroblastoma samples (n=23) obtained from histology blocks were arrayed into tissue microarrays and analysed by immunohistochemistry. The cases were classified according to the following clinical and pathological prognostic factors: age at diagnosis greater or less than/equal to 18 months; location of the lesion at diagnosis (abdominal or extra-abdominal); presence or absence of bone-marrow infiltration; tumor differentiation (well or poorly differentiated); Shimada histopathologic classification (favourable or unfavourable); state of the tumor extracellular matrix (Schwannian-stroma rich or poor); amplification of the MYCN oncogene; and clinical course (dead or alive with or without relapses/residual lesions). Twelve of the cases were female, 9 children were over 18 months old, 9 cases presented with extra-abdominal tumors and 9 cases exhibited tumors with unfavourable histologies. Fifteen patients underwent bone-marrow biopsy, and 4 of these were positive for metastasis. Nine patients died. The higher immunohistochemical expression of QSOX1 was more common in well-differentiated samples (P=0.029), in stroma-rich samples (P=0.029) and in samples from patients with a high prevalence of relapses/residual disease. The functions of QSOX1 include extracellular matrix maturation and the induction of apoptosis. Therefore, QSOX1 may be involved in neuroblastoma differentiation and regression and may thus function as a biomarker for identifying risk groups for this neoplasm.

Radioiodine plus recombinant human thyrotropin do not cause acute airway compression and are effective in reducing multinodular goiter.

Recombinant human thyrotropin (rhTSH) reduces the activity of radioiodine required to treat multinodular goiter (MNG), but acute airway compression can be a life-threatening complication. In this prospective, randomized, double-blind, placebo-controlled study, we assessed the efficacy and safety (including airway compression) of different doses of rhTSH associated with a fixed activity of 131I for treating MNG. Euthyroid patients with MNG (69.3 +/- 62.0 mL, 20 females, 2 males, 64 +/- 7 years) received 0.1 mg (group I, N = 8) or 0.01 mg (group II, N = 6) rhTSH or placebo (group III, N = 8), 24 h before 1.11 GBq 131I. Radioactive iodine uptake was determined at baseline and 24 h after rhTSH and thyroid volume (TV, baseline and 6 and 12 months after treatment) and tracheal cross-sectional area (TCA, baseline and 2, 7, 180, and 360 days after rhTSH) were determined by magnetic resonance; antithyroid antibodies and thyroid hormones were determined at frequent intervals. After 6 months, TV decreased significantly in groups I (28.5 +/- 17.6%) and II (21.6 +/- 17.8%), but not in group III (2.7 +/- 15.3%). After 12 months, TV decreased significantly in groups I (36.7 +/- 18.1%) and II (37.4 +/- 27.1%), but not in group III (19.0 +/- 24.3%). No significant changes in TCA were observed. T3 and free T4 increased transiently during the first month. After 12 months, 7 patients were hypothyroid (N = 3 in group I and N = 2 in groups II and III). rhTSH plus a 1.11-GBq fixed 131I activity did not cause acute or chronic changes in TCA. After 6 and 12 months, TV reduction was more pronounced among patients treated with rhTSH plus 131I.

Effect of 30 mCi radioiodine on multinodular goiter previously treated with recombinant human thyroid-stimulating hormone.

Recombinant human thyroid-stimulating hormone (rhTSH) enhances 131I uptake, permitting a decrease in radiation for the treatment of multinodular goiter (MNG). Our objective was to evaluate the safety and efficacy of a single 0.1-mg dose of rhTSH, followed by 30 mCi 131I, in patients with MNG. Seventeen patients (15 females, 59.0 +/- 13.1 years), who had never been submitted to 131I therapy, received a single 0.1-mg injection of rhTSH followed by 30 mCi 131I on the next day. Mean basal thyroid volume measured by computed tomography was 106.1 +/- 64.4 mL. 131I 24-h uptake, TSH, free-T4, T3, thyroglobulin, anti-thyroid antibodies, and thyroid volume were evaluated at regular intervals of 12 months. Mean 131I 24-h uptake increased from 18.1 +/- 9.7 to 49.6 +/- 13.4% (P < 0.001), a median 2.6-fold increase (1.2 to 9.2). Peak hormonal levels were 10.86 +/- 5.44 mU/L for TSH (a median 15.5-fold increase), 1.80 +/- 0.48 ng/dL for free-T4, 204.61 +/- 58.37 ng/dL for T3, and a median of 557.0 ng/mL for thyroglobulin. The adverse effects observed were hyperthyroidism (17.6%), painful thyroiditis (29.4%) and hypothyroidism (52.9%). Thyroid volume was reduced by 34.3 +/- 14.3% after 6 months (P < 0.001) and by 46.0 +/- 14.6% after 1 year (P < 0.001). Treatment of MNG with a single 0.1-mg dose of rhTSH, followed by a fixed amount of radioactivity of 131I, leads to an efficacious decrease in thyroid volume for the majority of the patients, with a moderate incidence of non-serious and readily treatable adverse effects.

Radioiodine plus recombinant human thyrotropin do not cause acute airway compression and are effective in reducing multinodular goiter

Recombinant human thyrotropin (rhTSH) reduces the activity of radioiodine required to treat multinodular goiter (MNG), but acute airway compression can be a life-threatening complication. In this prospective, randomized, double-blind, placebo-controlled study, we assessed the efficacy and safety (including airway compression) of different doses of rhTSH associated with a fixed activity of 131I for treating MNG. Euthyroid patients with MNG (69.3 ± 62.0 mL, 20 females, 2 males, 64 ± 7 years) received 0.1 mg (group I, N = 8) or 0.01 mg (group II, N = 6) rhTSH or placebo (group III, N = 8), 24 h before 1.11 GBq 131I. Radioactive iodine uptake was determined at baseline and 24 h after rhTSH and thyroid volume (TV, baseline and 6 and 12 months after treatment) and tracheal cross-sectional area (TCA, baseline and 2, 7, 180, and 360 days after rhTSH) were determined by magnetic resonance; antithyroid antibodies and thyroid hormones were determined at frequent intervals. After 6 months, TV decreased significantly in groups I (28.5 ± 17.6 percent) and II (21.6 ± 17.8 percent), but not in group III (2.7 ± 15.3 percent). After 12 months, TV decreased significantly in groups I (36.7 ± 18.1 percent) and II (37.4 ± 27.1 percent), but not in group III (19.0 ± 24.3 percent). No significant changes in TCA were observed. T3 and free T4 increased transiently during the first month. After 12 months, 7 patients were hypothyroid (N = 3 in group I and N = 2 in groups II and III). rhTSH plus a 1.11-GBq fixed 131I activity did not cause acute or chronic changes in TCA. After 6 and 12 months, TV reduction was more pronounced among patients treated with rhTSH plus 131I.