Switching from originator recombinant growth hormone (Genotropin™) to biosimilar (CRISCY™): Results from a 6-month, multicentric, non-inferiority, extension trial.

OBJECTIVE: A previous 12-month comparative trial with Criscy™ (r-hGH Cristália), a biosimilar recombinant growth hormone, demonstrated equivalent efficacy and safety to Genotropin™. This extension trial evaluated the effects of switching patients treated with Genotropin™ to the biosimilar Criscy™ over an additional 6-month treatment period, comparing efficacy, safety, and immunogenicity parameters with patients remaining in the Criscy™ arm. DESIGN: This extension study included 11 research centers and 81 patients who participated in the CERES study (Czepielewski et al., 2019 [1]). Participants from the Genotropin™ arm (n = 39) had the drug replaced by Criscy™ and the remaining participants were kept in the Criscy™ arm (n = 42) for an additional 6-month period to evaluate immunogenicity, efficacy (growth rate, height SDS), and safety (laboratory tests, and adverse events). RESULTS: Before the switch, both Criscy™ and Genotropin groups were similar concerning demographics, and auxological measures: age, sex, height, height SDS, weight, and BMI. Height velocity (HV) after 18 months of treatment was 8.7 ± 1.56 cm/year for Criscy™ group and 8.9 ± 1.36 cm/year for Genotropin™ group in the ITT population (p = 0.43). The auxological parameters and IGF-1 and IGFBP-3 SDS were comparable between both groups of patients. No participants were excluded from the study due to adverse events. There were no clinical or statistical relevant differences between the treatment groups concerning frequency, distribution, intensity, and AEs outcome. Similarly, no new anti-r-hGH (ADA) cases among patients that switched from Genotropin™ to Criscy™ were reported. No neutralizing antibody (nAb) was detected in either group. CONCLUSIONS: This trial showed that switching from originator recombinant human growth hormone to Criscy™ had no impact on efficacy, safety, nor immunogenicity as compared to continued treatment with Criscy™. Growth rates and ADA incidence remained the same as seen before the switch.

Efficacy and safety of a biosimilar recombinant human growth hormone (r-hGH Cristalia) compared with reference r-hGH in children with growth hormone deficiency (CERES study): A randomized, multicentric, investigator-blind, phase 3 trial.

OBJECTIVE: The CERES study was a randomized, multicenter, investigator-blind trial aimed to evaluate the efficacy and safety of a recombinant human growth hormone (r-hGH) developed by Cristalia, as a biosimilar product, with analytical, functional and pharmacokinetics similarities comparable to Genotropin™, in children with growth hormone deficiency (GHD). DESIGN: A total of 135 naïve prepubertal children with GHD were recruited, of whom 97 were randomized in 14 Brazilian sites to received either r-hGH Cristalia (n = 49) or Genotropin™ (n = 48). Efficacy was evaluated considering the height standard deviation score (SDS) and growth velocity as auxological parameters, IGF-1 and IGFBP-3 were measured as pharmacodynamic parameters during 12 months treatment time. Safety was assessed by monitoring adverse events, immunogenicity, blood count with platelets, biochemical profile and hormonal levels particularly fasting glucose, insulin and HbA1C. RESULTS: The auxological parameters and IGF-1 and IGFBP-3 levels were comparable between both groups of patients. At end of study or the 12th month treatment, the means growth velocity was 9.7 cm/year and 9.5 cm/year, for r-hGH Cristalia and Genotropin™, respectively. The ANCOVA mean difference between the groups was 0.16 cm/year to Cristalia group (CI 95% = -0.72 to 1.03 cm/year). There was no difference in adherence among the treatment groups. The safety profile was comparable between groups. CONCLUSIONS: The clinical similarity between r-hGH and Genotropin™ was demonstrated within 12 month of treatment. On the basis of comparability of quality, safety, and efficacy to the reference product, r-hGH from Cristalia can be considered a cost-effective therapeutic option for patients with growth disorders.

Influence of Different Ceramic Systems on Marginal Misfit.

OBJECTIVE: the aim of this study was to evaluate the marginal misfit at the interface between a ceramic coping and its abutment. METHODS: Twenty-four specimens were made with solid abutments. The specimens were divided into 3 groups according to the ceramic system (n = 8): Lava (zirconia), IPS e.max Press (lithium disilicate), and IPS Empress Esthetic (leucite). All copings were cemented with resin luting agent (RelyX U200) and the marginal misfit were evaluated at 3 different times: initial, after cementation, and after mechanical cycling using a linear measuring microscope (Measuring Microscope STM-Olympus) at a magnification of 40x. All specimens were subjected to mechanical cycling (1 million cycles) by an universal testing machine (Instron 8800). The results were statistically analyzed using Analysis of Variance and Student's t-test (α = 0.05). RESULTS: all groups showed an increase in the marginal misfit after cementation. The lithium disilicate group demonstrated the lowest interacial gap values at each evaluation (p = 0.001). The zirconia and leucite groups showed similar interfacial gap values (initial, p = 0.244; and post cementation, p = 0.751). CONCLUSIONS: the cementation increase the marginal misfit, but the mechanical cycling did not influence the marginal misfit of the ceramics systems evaluated.

Hyperproliferative action of bovine papillomavirus: genetic and histopathological aspects.

The bovine papillomavirus (BPV) causes papillomas that regress spontaneously, but can also progress to malignancy. This study evaluated the role of BPV in oncogenesis. Twenty-four samples from uninfected calves and the papillomas of BPV infected cattle were subjected to molecular diagnosis, as well as histopathological and immunohistochemical analyses. The comet assay (CA) was used to evaluate the clastogenic potential of BPV. The results confirmed the presence of BPV-2, 3, 5, and 9 in infected samples. Histopathological analysis revealed acanthosis, koilocytosis, hypergranulosis, hyperkeratosis, and transformed fibroblasts.E7 and L1 BPV proteins were detected in the epithelium, as well as in the connective tissues, indicating productive infection at different sites. CA results showed that BPV-2, 5, and 9 exhibit the same level of clastogenicity. These findings support the oncogenic action of BPV in establishing a favorable microenvironment for oncogenesis.

Effect of terbium(III) chloride on the micellization properties of sodium decyl- and dodecyl-sulfate solutions.

The effect of TbCl3 on the aggregation processes of the anionic surfactants sodium decyl sulfate (SDeS) and sodium dodecyl sulfate (SDS) has been investigated. Electrical conductivity data, combined with Tb(III) luminescence measurements suggest that the formation of micelles involving TbCl3 and SDS occurs at concentrations below the critical micelle concentration (cmc) of the pure surfactants; the formation of these mixed aggregates was also monitored by light scattering, which indicates that the addition of TbCl3 to surfactant concentration at values below the pure surfactant cmc results in a much greater light scattering than that found with pure sodium alkylsulfate surfactant micelles. This phenomenon is dependent upon the alkyl chain length of the surfactant. With Tb(III)/DS-, complexes are formed with a cation/anion binding ratio varying from 3 to 6, which depends upon the initial concentration of Tb(III). This suggests that the majority of the cation hydration water molecules can be exchanged by the anionic surfactant. When the carbon chain length decreases, interactions between surfactant and Tb(III) also decrease, alterations in conductivity and fluorescence data are not so significant and, consequently, no binding ratio can be detected even if existing. The surfactant micellization is dependent on the presence of electrolyte in solution with apparent cmc being lower than the corresponding cmc value of pure SDS.

Cytogenetic studies on Choeroniscus minor (Chiroptera, Phyllostomidae) from the Amazon region.

The Choeroniscus genus (Glossophaginae, Phyllostomidae) has five monotypic species: C. minor, C. godmani, C. intermedius, C. inca and C. periosus. This paper analyses the karyotype of a female C. minor, collected close to the Guama river (Belém, Para, Brazil). G-, C-banding and NOR-staining were performed. This species has 2n = 20 chromosomes, where there are two bi-armed pairs (numbers 1 and 9) and seven subtelocentric pairs (2, 3, 4, 5, 6, 7 and 8). The probable X chromosome is a submetacentric. The constitutive heterochromatin can be found in the short arm of five subtelocentric pairs (4, 5, 6, 7 and 8) and is centromeric in the bi-armed pairs numbers 1 and 9, and the X chromosome. The heterochromatic bands are heteromorphic in three pairs (1, 2 and 3). Active NOR were observed in the short arms of eight subtelocentric chromosomes, suggesting that at least four pairs are nucleolar organizers. This paper describes for the first time the karyotype of C. minor from the Amazon region.

The diagnosis of delirium in 80 emergency unit patients.

We evaluated the initial and final diagnosis of 80 patients with delirium arriving at the emergence unit of a university hospital in a large Brazilian city over a period of 30 months up to December 1991. The diagnosis was based on the DSM-IIIR criteria. Patients with a known history of head trauma or epileptic seizure and patients younger than 13 years were excluded. Only patients with a disease of up to 7 days were included. The patients were subdivided into four etiologic groups: vascular; associated with the use of alcohol; infectious-parasitic; miscellaneous. The results showed a rate of correct diagnosis ranging from 65 to 80% with the use of kappa test (standard good to excellent). Sensitivity, specificity, positive predictive and negative predictive values had results showing different conditions for initial diagnosis in each group. This study can help the initial diagnosis of delirium and the choice for diagnostic testing.

Cerebrospinal fluid syndromes in patients with acute consciousness compromise.

We reviewed the laboratorycards of 200 analysis of cerebrospinal fluid (CSF) performed to evaluate acute alterations of consciousness in adult patients attended in a neurological emergency room. 61% were men; the mean age was 46 years. The most common clinical data were infective and neurologic. The CSF was abnormal in 149 (74.5%) patients and the most common syndromes were: compressive (21%), hemorrhagic (11.5%), "viral" (8.5%), septic (7.5%), moderate hyperglycorrachia (6.5%), hydroelectrolytic disturbances (5.5%). There were some statistically significant correlations between CSF syndromes and clinical data: septic syndrome and fever and meningeal signs, hemorrhagic syndrome and headache and meningeal signs, CSF hydroelectrolytic disturbance syndrome and seizures, severe hyperproteinorrachia and headache, fever, meningeal signs and vomiting, moderate hyperproteinorrachia and age over 65 and male sex. We classified the abnormal results in two groups: 1--sufficient for an immediate clinical decision; 2--nonspecific. The former group was found in 27.5% of the patients and in 36.9% of the abnormal CSF results. In patients attending to neurologic emergency rooms with acute alterations of consciousness, the examination of the CSF frequently could contribute to an etiologic diagnosis. It must be performed after a rigorous clinical evaluation of the patient.

Isolated angiitis of central nervous system with pleocytosis in the cerebrospinal fluid.

We report the case of a 32-year-old woman with isolated angiitis of the central nervous system. This case shows that high levels of pleocytosis may not rule out isolated angiitis of the central nervous system if this diagnosis can be considered on clinical grounds.

[Subarachnoidal hemorrhage with cranial tomography without bleeding signals]. / Hemorragia subaracnoídea com tomografia de crânio sem sinais de sangramento.

UNLABELLED: We observed 23 patients with clinical hypothesis of subarachnoidal hemorrhage (SAH) having cranial tomography (CT) without bleeding signals. The final diagnosis of SAH was made upon the cerebrospinal fluid (CSF) results. Twenty cases were submitted to brain angiography. They were focused under the clinical classification of Hunt & Hess. The main results were 1) 1/3 of patients had interval time between 24 and 48 hours after ictus and before CT and CSF making; this was the most sensitive CT time; 2) 55% of patients with brain angiography had aneurysm predominantly in the carotid and anterior cerebral artery territory; 3) the dominant clinical degree was Hunt & Hess I e II. CONCLUSION: the results demonstrate the need of CSF test in case of SAH clinical diagnosis with CT showing no bleeding signals.

[Percutaneous mitral valvuloplasty with the single balloon technique. Short-term results, complications and in-hospital follow-up]. / Valvoplastia mitral percutânea com a técnica do balão único. Resultados imediatos, complicações e evolução intra-hospitalar.

PURPOSE: To study the short-term results, complication and in-hospital follow-up of 268 percutaneous mitral balloon valvuloplasty (PMBV) procedures performed with the low-profile monofoil balloon (LPMB) technique from 1990 to 1995. METHODS: A single 30mm balloon diameter was used in 247 (92.9%) procedures, a single 25mm balloon diameter in 9 (3.3%), a single 25mm balloon followed by a single 30mm balloon diameter in 7 (2.6%) and in 5 procedures a balloon was not used. The mean age group was 36 +/- 12 years. Two hundred nineteen (81.7%) procedures were performed in women (mean age 36 +/- 12 years) and 49 (18.3%) in men (mean age, 35 +/- 14 years) (p = 0.78). Patients were in functional class II (NYHA) in 39 (14.5%), class III in 198 (73.9%) and class IV in 31 (11.6%). Patients were in sinus rhythm in 228 (85.1%) procedures and in atrial fibrillation in 40 (14.9%). The echocardiographic score ranged from 4 to 14 (mean 7.2 +/- 1.5). RESULTS: There were 256 complete procedures, 249 of which were successful (mitral valve area (MVA) > or = 1.5cm2 after PMBV). Echocardiographic calculated MVA before PMBV was 0.9 +/- 0.2cm2. Hemodynamic calculated MVA before PMBV was 0.9 +/- 0.2cm2 and after was 2.0 +/- 0.4cm2 (p < 0.000001). Mean pulmonary artery pressure decreased from 40 +/- 15mmHg to 28 +/- 10mmHg (p < 0.000001) and mitral mean gradient from 20 +/- 7mmHg to 5 +/- 4mmHg (p < 0.000001). In the 256 complete procedures mitral valve (MV) was competent in 214 and there was 1+ mitral regurgitation (MR) in 42. After PMBV, MV was competent in 166 and there was 1+ MR in 68, 2+ in 16, 3+ in 5 and 4+ MR in 1. There were complications in 14 (5.2%) procedures, severe MR in 6 (3 or 4+), stroke in 2 and cardiac tamponade in 6. Two patients died during emergency cardiac surgery after left ventricular perforation and 1 after stroke. CONCLUSION: PMBV with the LPMB was an effective procedure with a high success rate and a low rate of complications as the more usual double-balloon and Inoue balloon techniques.