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.

Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus.

The purpose of this review is to assess the most recent evidence in the management of primary hyperparathyroidism (PHPT) and provide updated recommendations for its evaluation, diagnosis and treatment. A Medline search of "Hyperparathyroidism. Primary" was conducted and the literature with the highest levels of evidence were reviewed and used to formulate recommendations. PHPT is a common endocrine disorder usually discovered by routine biochemical screening. PHPT is defined as hypercalcemia with increased or inappropriately normal plasma parathyroid hormone (PTH). It is most commonly seen after the age of 50 years, with women predominating by three to fourfold. In countries with routine multichannel screening, PHPT is identified earlier and may be asymptomatic. Where biochemical testing is not routine, PHPT is more likely to present with skeletal complications, or nephrolithiasis. Parathyroidectomy (PTx) is indicated for those with symptomatic disease. For asymptomatic patients, recent guidelines have recommended criteria for surgery, however PTx can also be considered in those who do not meet criteria, and prefer surgery. Non-surgical therapies are available when surgery is not appropriate. This review presents the current state of the art in the diagnosis and management of PHPT and updates the Canadian Position paper on PHPT. An overview of the impact of PHPT on the skeleton and other target organs is presented with international consensus. Differences in the international presentation of this condition are also summarized.

Italian association of clinical endocrinologists (AME) position statement: drug therapy of osteoporosis.

Treatment of osteoporosis is aimed to prevent fragility fractures and to stabilize or increase bone mineral density. Several drugs with different efficacy and safety profiles are available. The long-term therapeutic strategy should be planned, and the initial treatment should be selected according to the individual site-specific fracture risk and the need to give the maximal protection when the fracture risk is highest (i.e. in the late life). The present consensus focused on the strategies for the treatment of postmenopausal osteoporosis taking into consideration all the drugs available for this purpose. A short revision of the literature about treatment of secondary osteoporosis due both to androgen deprivation therapy for prostate cancer and to aromatase inhibitors for breast cancer was also performed. Also premenopausal females and males with osteoporosis are frequently seen in endocrine settings. Finally particular attention was paid to the tailoring of treatment as well as to its duration.

Two methods of vitrification followed by in vitro culture of the ovine ovary: evaluation of the follicular development and ovarian extracellular matrix.

The aim of this study was to evaluate the influence of two vitrification techniques on the extra cellular matrix (ECM) and ovarian follicular development. The ovarian cortex was fragmented (9 mm(3)) and divided into six groups, viz. fresh control, cultured control, vitrified by the Ovarian Tissue Cryosystem (OTC) method, conventional solid surface vitrification (SSV) method, OTC/cultured and SSV/cultured. Follicles from all the fragments were analysed for morphology, development and viability. The ECM was evaluated based on the condition of collagen and reticular fibres and the immunolocalization of type I collagen and fibronectin. After 7 days of culture, the tissue vitrified by OTC revealed a higher percentage (p < 0.05) of morphologically normal (30.66%) and viable (60.00%) follicles when compared with those vitrified using the SSV technique (21.33% and 23.00%). In all the fragments cultured, regardless of the vitrification method, a significantly higher percentage of developing follicles was observed when compared with the non-cultured tissue. Analysis of the type I collagen showed increased immunostaining after the in vitro culture in the vitrified fragments. In conclusion, the OTC is better for preserving the follicular viability and morphology and maintaining the integrity of the extracellular matrix components of the ovine ovary.

Correlation between 25-hydroxyvitamin D levels and latitude in Brazilian postmenopausal women: from the Arzoxifene Generations Trial.

SUMMARY: We investigated vitamin D status in Brazilian cities located at different latitudes. Insufficiency (<50 nmol/L) was common (17 %), even in those living in a tropical climate. Vitamin D insufficiency increased as a function of latitude. Mean 25-hydroxyvitamin D (25(OH)D) levels in each site and latitude correlation were very high (r = -0.88; p=0.02). [corrected]. INTRODUCTION: Inadequate vitamin D, determined by low levels of 25(OH)D, has become very common despite the availability of sunlight at some latitudes. National data from a country that spans a wide range of latitudes would help to determine to what extent latitude or other factors are responsible for vitamin D deficiency. We investigated vitamin D status in cities located at different latitudes in Brazil, a large continental country. METHODS: The source is the Brazilian database from the Generations Trial (1,933 osteopenic or osteoporotic postmenopausal women (60 to 85 years old) with 25(OH)D measurements). 25(OH)D below 25 nmol/L (10 ng/mL) was an exclusion criterion. Baseline values were between fall and winter. The sites included Recife, Salvador, Rio de Janeiro, São Paulo, Curitiba, and Porto Alegre. Mean and standard deviation of 25(OH)D, age, spine and femoral neck T-score, calcium, creatinine, and alkaline phosphatase were calculated for each city. Pearson correlation was used for 25(OH)D and latitude. RESULTS: Insufficiency (<50 or <20 ng/mL) was common (329 subjects, 17 %). Vitamin D insufficiency increased as a function of latitude, reaching 24.5 % in the southernmost city, Porto Alegre. The correlation between mean 25(OH)D levels in each site and latitude was very high (r = -0.88, p < 0.0001). CONCLUSION: There is a high percentage of individuals with vitamin D insufficiency in Brazil, even in cities near the equator, and this percentage progressively increases with more southern latitudes.

Frequência de staphylococcus aureus em casos de mastite bovina subclínica, na região sul do Rio Grande do Sul / Staphylococcus aureus frequency of subclinical bovine mastitis in southern Rio Grande do Sul

A mastite bovina é uma doença importante na exploração leiteira, não apenas pelas perdas econômicas diretas que promove, mas também pelas perdas indiretas e o potencial risco à saúde pública. Dentre as principais causas de infecções intramamárias, destacam-se as bactérias do gênero Staphylococcus spp., sendo que Staphylococcus aureus é o agente etiológico predominante em mastite subclínica. O objetivo desse trabalho foi verificar a frequência de mastite subclínica em oito rebanhos localizados na região Sul do Rio Grande do Sul (Brasil) e a relação da enfermidade com a presença de S. aureus. Adicionalmente, pesquisou-se a presença de S. intermedius e S. hyicus nas amostras de leite obtidas. Para identificação da doença, utilizou-se o California Mastitis Test (CMT). A identificação da espécie de Staphylococcus spp. foi feita em meio de cultura ágar Baird-Parker, com posterior confirmação das colônias suspeitas em coloração de gram, prova de catalase, pesquisa de coagulase livre e pesquisa de termonuclease. A mastite subclínica foi constatada em 53,6% dos animais testados. A presença de Staphylococcus coagulase positiva foi identificada em 12,6% dos animais com mastite subclínica. Nesses mesmos animais, a bactéria identificada como S. aureus foi o agente etiológico presente em 17,6% dos casos. Adicionalmente, pode-se perceber que, dentre o grupo identificado como coagulase positiva, 85,7% corresponderam a S. aureus, enquanto8,5% mostraram características bioquímicas compatíveis com S. intermedius e 5,8% foram consideradas S. hyicus...

Bovine mastitis is an important disease in dairy farming, not only by promoting direct economic losses, but also for indirect losses and the potential risk to public health. The main causes of intramammary infections include the bacteria of the genus Staphylococcus spp., Staphylococcus aureus being the predominant etiologic agent in subclinical mastitis. The aim of this study was to determine the frequency of subclinical mastitis in eight herds from southern Rio Grande do Sul (Brazil) and the relationship of the disease with the presence of S. aureus. In addition, we checked for the presence of S. intermedius and S. hyicus in the milk samples obtained. For identification of the disease, we used the California Mastitis Test (CMT). Identification of Staphylococcus spp. species was made in Barid-Parker agar culture medium, with subsequent confirmation of suspected colonies by way of Gram stain and catalase test along with free-coagulase and thermonuclease research. Subclinical mastitis was identified in 53.6% of animals tested. The presence of coagulase-positive Staphylococcus was identified in 12.6% of animals with subclinical mastitis. In these same animals, bacteria identified as S. aureus were the etiologic agent present in 17.6% of cases. Additionally, it was revealed that among the group identified as coagulase positive, 85.7% corresponded to S. aureus, while 8.5% had biochemical characteristics consistent with S. intermedius and 5.8% were considered S. hyicus...

Is arterial stiffness in HIV-infected individuals associated with HIV-related factors?

We investigated the association between pulse wave velocity (PWV) and HIV infection, antiretroviral treatment-related characteristics, viral load, immune status, and metabolic changes in a cross-sectional study nested in a cohort of HIV/AIDS patients who have been followed for metabolic and cardiovascular changes since 2007. The study included patients recruited from the cohort (N = 261) and a comparison group (N = 82) of uninfected individuals, all enrolled from April to November 2009. Aortic stiffness was estimated using the carotid-femoral PWV (Complior-Artech, Paris, France). The groups were similar with respect to age, metabolic syndrome, diabetes mellitus, Framingham score, and use of antihypertensive and hypolipidemic medications. Hypertension was more frequent among the controls. Individuals with HIV had higher triglyceride, glucose and HDL cholesterol levels. Among individuals with HIV/AIDS, those with a nadir CD4+ T-cell count <200 cells/mm³ had a higher PWV (P = 0.01). There was no statistically significant difference when subjects were stratified by gender. Heart rate, age, male gender, and blood pressure were independently correlated with PWV. Nadir CD4+ T-cell count did not remain in the final model. There was no significance difference in PWV between HIV-infected individuals and uninfected controls. PWV was correlated with age, gender, and blood pressure across the entire population and among those infected with HIV. We recommend cohort studies to further explore the association between inflammation related to HIV infection and/or immune reconstitution and antiretroviral use and PWV.

Is arterial stiffness in HIV-infected individuals associated with HIV-related factors?

We investigated the association between pulse wave velocity (PWV) and HIV infection, antiretroviral treatment-related characteristics, viral load, immune status, and metabolic changes in a cross-sectional study nested in a cohort of HIV/AIDS patients who have been followed for metabolic and cardiovascular changes since 2007. The study included patients recruited from the cohort (N = 261) and a comparison group (N = 82) of uninfected individuals, all enrolled from April to November 2009. Aortic stiffness was estimated using the carotid-femoral PWV (Complior-Artech, Paris, France). The groups were similar with respect to age, metabolic syndrome, diabetes mellitus, Framingham score, and use of antihypertensive and hypolipidemic medications. Hypertension was more frequent among the controls. Individuals with HIV had higher triglyceride, glucose and HDL cholesterol levels. Among individuals with HIV/AIDS, those with a nadir CD4+ T-cell count <200 cells/mm³ had a higher PWV (P = 0.01). There was no statistically significant difference when subjects were stratified by gender. Heart rate, age, male gender, and blood pressure were independently correlated with PWV. Nadir CD4+ T-cell count did not remain in the final model. There was no significance difference in PWV between HIV-infected individuals and uninfected controls. PWV was correlated with age, gender, and blood pressure across the entire population and among those infected with HIV. We recommend cohort studies to further explore the association between inflammation related to HIV infection and/or immune reconstitution and antiretroviral use and PWV.

Normocalcemic versus Hypercalcemic Primary Hyperparathyroidism: More Stone than Bone?

Introduction. Normocalcemic primary hyperparathyroidism (NPHPT) is considered a variant of the more frequent form of the disease characterized by normal serum calcium levels with high PTH. The higher prevalence of renal stones in patients with HPTP and the well established association with bone disorders show the importance of studies on how to manage asymptomatic patients. Objective. To compare the clinical and laboratory data between the normocalcemic and mild hypercalcemic forms of PHPT. Methods. We retrospectively evaluated 70 patients with PHPT, 33 normocalcemic and 37 mild hypercalcemic. Results. The frequency of nephrolithiasis was 18.2% in normocalcemic patients and 18.9% in the hypercalcemic ones (P = 0.937). Fifteen percent of normocalcemic patients had a previous history of fractures compared to 10.8% of hypercalcemic patients, although there was no statistically significant difference (P = 0.726). Conclusion. Our data confirms a high prevalence of urolithiasis in normocalcemic primary hyperparathyroidism, but with the preservation of cortical bone. This finding supports the hypothesis that this disease is not an idle condition and needs treatment.

Atypical femoral fractures during prolonged use of bisphosphonates: short-term responses to strontium ranelate and teriparatide.

CONTEXT: Atypical femoral fractures have rarely been reported in women taking bisphosphonates, but this is still a controversial issue. Data are derived mainly from observation studies because a post hoc analysis from a randomized clinical trial did not find any such association. OBJECTIVE: The aim of this study was to report three cases of what are considered atypical femoral fractures and their responses to the use of strontium ranelate and teriparatide. PATIENTS: We studied three postmenopausal women with a diagnosis of osteoporosis who suffered fractures of the subtrochanteric region and femoral diaphysis with no major trauma while on long-term use of bisphosphonates. RESULTS: All the major features of atypical femoral fractures highlighted in the Task Force Report of the American Society for Bone and Mineral Research were present in the three cases. They had had unconsolidated fractures for approximately 1 yr before being referred to our center. After 3 months on strontium ranelate 2 g/d, serum osteocalcin and serum ß-carboxyterminal telopeptide had increased in case 1 by 125 and 100%, respectively, and in case 2 by 50 and 22%, respectively, with total closure of the fracture. In case 3, after 1 month on teriparatide 20 µg/d, a radiographic closure of the fracture was achieved, and 3 months later serum osteocalcin and serum ß-carboxyterminal telopeptide had increased by 300 and 22%, respectively. CONCLUSION: Our finding showed that both teriparatide and strontium ranelate had a rapid bone anabolic effect on unhealed atypical fractures associated with chronic bisphosphonate use.

Abdominal wall fat index in neonates: correlation with birth size.

Low birth weight is associated with obesity in later life and a more central fat distribution has a positive correlation with cardiovascular disease. However, the correlation between visceral adiposity in newborns and birth size is unknown. We measured the visceral adiposity in 118 newborns using the abdominal wall fat index (AFI), ratio between the maximum thickness of preperitoneal and the minimum thickness of subcutaneous fat evaluated by ultrasound. There was a weak negative correlation between AFI and birth weight (r = -0.197; P = 0.033) but not with birth length (r = -0.118; P = 0.201), body mass index (r = -0.138; P = 0.176) and abdominal circumference (r = 0.063; P = 0.497). In conclusion, we suggest that AFI is a useful parameter for evaluating the fat distribution in newborns and that visceral adiposity has a weak negative correlation with birth weight.

Postoperative incidence of deep vein thrombosis after major lower extremity amputation.

AIM: To determine the incidence of deep vein thrombosis of lower extremities up to the seven day after major lower extremity amputation in the amputated and contralateral limbs using color Doppler ultrasound. METHODS: One hundred and twenty-eight patients (67 men) underwent major lower extremity amputation (69 above-knees and 59 below-knees). All participants received unfractioned subcutaneous heparin (5000 IU TID) as prophylaxis and were evaluated using color Doppler ultrasound immediately before amputation and on the second and seventh days after amputation. The sample was composed of patients with critical limb ischemia and a primary or secondary amputation. Prophylaxis was initiated at the time of hospitalization, discontinued 12 hours before operation, and resumed 12 hours postoperatively. The primary variable was postoperative venous thrombosis. Secondary variables were: age, obesity, myocardial infarction, heart failure, immobilization and level of amputation. RESULTS: Of the 128 patients evaluated (age range: 44 to 97 years), 12 (9.4%) had venous thrombosis; in 8 (6.3%), thrombosis was ipsilateral, and in 4 (3.1%), contralateral to the amputated limb. Thrombosis was found in the thigh stump of 5 patients (3.9%); the other cases were found in the following venous segments: proximal in 2 (1.6%) patients; distal in 4 (3.1%); and proximal/distal in 1 (0.8%). CONCLUSIONS: The incidence of deep vein thrombosis of lower extremities was 9.4% in a group of patients with ischemia who underwent primary or secondary major lower extremity amputation and received prophylaxis with unfractioned heparin.

[Hemoglobin "S" positive newborn detected by cord blood and its characteristics] / Características de recém-nascidos portadores de hemoglobina.

OBJECTIVE: To evaluate the prevalence of hemoglobin "S" (Hb "S") in babies born at the Instituto Materno Infantil de Pernambuco (IMIP) and its occurrence according to sex, birth weight and Apgar score. METHODS: We carried out a cross-sectional descriptive study of all babies born in the IMIP from October 1996 to March 1997. We used alkaline electrophoresis to analyze cord blood samples (1,988). Data for other variables were collected from medical reports. EPI-Info 6.0 was used to analyze the data.RESULTS: We found 105 (5.3%) newborns with Hb "S": 102 (5.1%.) as sickle cell trait (Hb "FAS"), and 3 (0.2%) as sickle cell disease (Hb "SC"). No cases of homozygosis were found. Newborns with and without Hb "S" did not differ in relation to sex, birth weight and Apgar score. CONCLUSIONS: We suggest the implementation of neonatal screening for hemoglobinopathies for all the newborns in Recife, Brazil, with further follow up focusing on genetic counseling for suspected and positive cases.

Cardiac tamponade: an unusual complication of pericardial cyst.

Pericardial cysts are not common and rarely cause symptoms. We report a unique case of a 15-year-old male patient with cardiac tamponade clinically diagnosed who was referred for echocardiography. Transthoracic echocardiography revealed, in addition to a large pericardial effusion associated with echocardiographic signs of cardiac tamponade, an 8 x 5 cm echofree image suggesting a pericardial cyst adjacent to the right atrium. Immediately after pericardiocentesis, yielding a serosanguinous liquid, the patient showed striking clinical improvement and echocardiography demonstrated minimal pericardial effusion with persistence of the cystic image. At surgery a pericardial cyst containing a sanguinous fluid was found and the pathologic findings were consistent with hematic pericardial cyst. Thus echocardiography played a fundamental role for the diagnosis and treatment of the rare complication of a pericardial cyst documented in this patient.

[Use of recombinant human erythropoietin in the treatment of anemia in hemodialyzed patients: a multicentric study]. / Uso da eritropoetina recombinante humana no tratamento da anemia do paciente em hemodiálise: um estudo multicêntrico.

Recombinant human erythropoietin (rHu-EPO) therapy was given to 25 patients undergoing long-term hemodialysis, for 12 weeks, in 5 Brazilian dialysis centers. The dose of rHu-EPO was given intravenously thrice weekly, initially at 50 Units/kg/dose. If the target hemoglobin concentration (10g/dL) was not achieved by four weeks the dose was increased to 75 and 100 Units/kg/dose. After 4 weeks hemoglobin concentration had achieved 10g/dL in only one patient, and, after 8 weeks, 10 patients (40% of all cases) had hemoglobin levels higher than the target concentration. After 12 weeks, the hemoglobin increased from 7.1 +/- 1.1 to 9.6 +/- 1.2 g/dL, the target hemoglobin concentration was achieved in 15 patients (60% of all cases). There was a significant (p < 0.05) increase in hematocrit (from 22 +/- 4 to 31 +/- 4 vol%), in body weight (from 55.03 +/- 12.24 to 56.16 +/- 12.86kg), and in serum phosphorus (from 5.85 +/- 2.02 to 6.82 +/- 2.34 mg/dL). There were no significant changes in blood pressure, serum levels of creatinine, of potassium, and of transferrin. Increase in blood pressure (in 3 patients), fever (in 2 patients), increase in the heparin dose needs (in 2 cases), and vascular access thrombosis (in 1 patient) were the most important adverse effects observed during rHu-EPO therapy. Thus, the anemia of chronic renal failure may be easily corrected with adequate amounts of recombinant human erythropoietin. Attention must be paid to some adverse effects during reversal of anemia.