Oleoyl-estrone is a precursor of an estrone-derived ponderostat signal

Oleoyl-estrone (OE) is a powerful anti-obesity compound that decreases food intake, decreases insulin resistance and circulating cholesterol. OE stimulates a severe loss of body fat by decreasing adipose tissue lipid synthesis and maintaining lipolysis. Therefore, the body economy loses lipid energy because energy expenditure is maintained. This study analyses the discrepancy between OE effects and the distribution of labelled OE in plasma. Estrone radioimmunoassay of organic solvent plasma extracts of rats treated with OE showed the massive presence of acyl-estrone, but. saponification did not release estrone, but containing similar unknown compound. Analysis of label distribution in plasma after oral gavages of 3H-OE showed the presence of a more hydrophilic compound than OE or any estrogen as well as 3H2O, formed from 3H-OE in the acidic stomach medium. OE was not attached toa specific transporter in plasma. Through serum HPLC analysis we found W, a labelled derivative more hydrophilic than OE or estrone. The results were confirmed using 14C-OE. HPLC-MS/MS studies showed that plasma OE levels were one order of magnitude lower than those of W. When liver cell cytosols from rats laden with 3H-OE were incubated with nuclei from untreated rats, the OE-derived label (i.e., W's) was found attached to nuclear DNA. Neither estradiol nor estrone interfered with its binding. W is a fairly hydrophilic compound of low molecular weight containing the estrone nucleus, but it is not an ester because saponification or esterases do not yield estrone as OE does. It is concluded that OE acts through its conversion to W, its active form; which binds to a nuclear receptor different from that of estrogen. The estimated W serum levels are proportional to the pharmacological OE effects in vivo. We postulate W as a new type of hormone that exerts the full range of in vivo effects thus far attributed to OE. The full identification of W is anticipated to open the way for the development of new OE-like anti-obesity drugs

Vertebral fracture risk in glucocorticoid-induced osteoporosis: the role of hypogonadism and corticosteroid boluses

Objective: The aim of this study was to identify the risk factors associated with fragility fracture (FF) development in glucocorticoid (GC)-treated patients. Methods: 127 patients (aged 62±18 years, 63% women) on GC-treatment (mean dose 14.5±14.1 mg/day and duration 47.7±69 months) were included. The clinical data collected included bone metabolism study (including gonadal axis), GC-treatment, disease activity, dual-energy X-ray absorptiometry analysis (evaluating densitometric osteoporosis (OP) and trabecular bone score (TBS) degraded microarchitecture values (DMA)), X-ray (assessing vertebral fractures (VF)), FRAX risk (GC-adjusted) and previous FF. Results: 17% of the patients had VF, 28% FF (VF and/or non-VF), 29% OP and 52% DMA. Patients with VF received more GC boluses (57.1% vs 29.5%, p=0.03), were older (68±13 vs 60±19 years, p=0.02), postmenopausal (100% vs 67%, p=0.02), had low testosterone levels (57% vs 11%, p=0.02), lower TBS values (1.119±0.03 vs 1.237±0.013, p100, p=0.01) and having received GC boluses (OR 3.45; 95% CI 1.04 to 12.15, p=0.01) were the main factors related to VF. Hypogonadism (OR 7.03; 95% CI 1.47 to 38.37, p=0.01) and FRAX >20 (OR 7.08; 95% CI 1.28 to 53.71, p=0.02) were factors related to FF. Conclusion: Hypogonadism is the principal risk factor for developing fractures in GC-treated men and women, whereas receiving GC boluses is a major factor for VF. These results indicate the importance of evaluating the gonadal axis in these patients

Reference intervals for bone turnover markers in Spanish premenopausal women

BACKGROUND: The aims of this study were to establish robust reference intervals and to investigate the factors influencing bone turnover markers (BTMs) in healthy premenopausal Spanish women. METHODS: A total of 184 women (35-45 years) from 13 centers in Catalonia were analyzed. Blood and second void urine samples were collected between 8 a.m. and 10 a.m. after an overnight fast. Serum procollagen type I amino-terminal propeptide (PINP) and serum cross-linked C-terminal telopeptide of type I collagen (CTX-I) were measured by two automated assays (Roche and IDS), bone alkaline phosphatase (bone ALP) by ELISA, osteocalcin (OC) by IRMA and urinary NTX-I by ELISA. PTH and 25-hydroxyvitamin D (25OHD) levels were measured. All participants completed a questionnaire on lifestyle factors. RESULTS: Reference intervals were: PINP: 22.7-63.1 and 21.8-65.5 μg/L, bone ALP: 6.0-13.6 μg/L, OC: 8.0-23.0 μg/L, CTX-I: 137-484 and 109-544 ng/L and NTX-I: 19.6-68.9 nM/mM. Oral contraceptive pills (OCPs) influenced PINP (p=0.007), and low body mass index (BMI) was associated with higher BTMs except for bone ALP. Women under 40 had higher median values of most BTMs. CTX-I was influenced by calcium intake (p=0.010) and PTH (p=0.007). 25OHD levels did not influence BTMs. Concordance between the two automated assays for PINP and particularly CTX-I was poor. CONCLUSIONS: Robust reference intervals for BTMs in a Southern European country are provided. The effects of OCPs and BMI on their levels are significant, whilst serum 25OHD levels did not influence BTMs. Age, calcium intake, BMI and PTH influenced CTX-I. The two automated assays for measuring PINP and CTX-I are not interchangeable

Trajectories in Argentine children’s literature: Constancio C. Vigil and Horacio Quiroga

Children's author and publishing entrepreneur Constancio C. Vigil was a Uruguayan who spent most of his working life in Argentina. He was best known for his children's magazine Billiken (1919 to present). Vigil's contemporary and compatriot Horacio Quiroga also made the move across the River Plate and went on to have a transformative impact on Argentine literary culture, in part through his Jungle Tales for Children (1924). Both Quiroga and Vigil aspired to have their works for children accepted as school reading books, recognising the role of school authorities in the formation of the national canon. Vigil and Quiroga's trajectories of inclusion and exclusion, and their extraordinary contribution to the Argentine and Latin American cultural landscape in the first half of the twentieth century, provide a window onto the curation of an Argentine national children's literature at the same time as challenging the very nature of such a category

Chemokine nitration prevents intratumoral infiltration of antigen-specific T cells

Tumor-promoted constraints negatively affect cytotoxic T lymphocyte (CTL) trafficking to the tumor core and, as a result, inhibit tumor killing. The production of reactive nitrogen species (RNS) within the tumor microenvironment has been reported in mouse and human cancers. We describe a novel RNS-dependent posttranslational modification of chemokines that has a profound impact on leukocyte recruitment to mouse and human tumors. Intratumoral RNS production induces CCL2 chemokine nitration and hinders T cell infiltration, resulting in the trapping of tumor-specific T cells in the stroma that surrounds cancer cells. Preconditioning of the tumor microenvironment with novel drugs that inhibit CCL2 modification facilitates CTL invasion of the tumor, suggesting that these drugs may be effective in cancer immunotherapy. Our results unveil an unexpected mechanism of tumor evasion and introduce new avenues for cancer immunotherapy

Factores relacionados con la respuesta inadecuada al tratamiento osteoformador (teriparatida/PTH 1–84) en pacientes con osteoporosis severa. Resultados preliminares

The aim of this study was to evaluate the long-term bone mineral density (BMD) response rate to osteoanabolic treatment in patients with severe osteoporosis and the factors related to “inadequate” response (IR). Methods: 49 patients (46F:3M) with a mean age of 69.5±11.1 years treated with teriparatide (41) or PTH1-84 (8) during 18/24months were included (84% had vertebral fractures and 84% had previously received bisphosphonates). Previous skeletal fractures and antiosteoporotic treatment, risk factors and cause of osteoporosis were recorded in all patients. Bone turnover markers (BTM) and 25-OH vitamin D (25OHD) levels were assessed before and at 3, 6, 12 and 18/24 months. Lumbar and femoral BMD and spinal X-ray were assessed at baseline and at 12 and 18/24 months. IR was defined by a lumbar BMD change <3% at 18/24 months. Results: 29% of patients showed IR to therapy. No significant differences were observed in age, baseline BMD and BTM and 25OHD levels between patients with or without IR. 92% of IR patients had been previously treated with bisphosphonates (vs 79%, p=0.34) during 7±4.8 years (vs 4.9±4.2 years, p=0.19). No significant differences were observed between groups in the magnitude of changes in BTM throughout the study. Conclusions: 29% of patients with severe osteoporosis presented IR to osteoanabolic therapy. Although no predictive factors related to this finding were identified, previous prolonged therapy with bisphosphonates may play a role.El objetivo de este estudio ha sido analizar la evolución de la masa ósea a largo plazo tras tratamiento osteoformador (teriparatida o PTH 1-84) en pacientes con osteoporosis severa, y determinar la frecuencia y los factores relacionados con una respuesta inadecuada (RI) al tratamiento. Métodos: Se incluyeron 49 pacientes (46 mujeres:3 hombres) con una edad media de 69,5±11,1 años, tratados con teriparatida (41) o PTH1-84 (8) durante 18/24 meses (84% tenían fracturas vertebrales y 84% habían recibido tratamiento previamente). Se analizaron: factores de riesgo y causa de osteoporosis, fracturas y tratamiento antiosteoporótico previo. Se valoraron los marcadores de recambio óseo (MRO), los niveles de 25-OH vitamina D (25OHD) basal y a los 3, 6, 12 y 18/24 meses, radiografías de columna dorso-lumbar y densitometría ósea (DMO) previa, a los 12 y 18/24 meses. Se definió RI cuando el cambio de DMO lumbar era <3% a los 18/24 meses. Resultados: 29% de los pacientes presentaron RI al tratamiento. No se observaron diferencias en la edad, DMO basal, valores de 25OHD y/o MRO entre los pacientes con y sin RI. El 92% de pacientes con RI había seguido tratamiento previo con bisfosfonatos (vs. el 79% de los pacientes sin RI, p=0,34) durante 7±4,8 años (vs. 4,9±4,2 años, p=0,19). No se observaron diferencias significativas en la evolución de los MRO tras iniciar el tratamiento entre ambos grupos de pacientes. Conclusión: El 29% de los pacientes con osteoporosis grave presenta una RI al tratamiento osteoformador. Aunque no se han identificado factores predictores de este tipo de respuesta, es posible que el tratamiento prolongado previo con bisfosfonatos pueda estar relacionado con este hallazgo

Clinical evolution of sacral stress fractures: influence of additional pelvic fractures

To evaluate the clinical evolution of sacral stress fractures in relation to the scintigraphic pattern and the presence of additional pelvic fractures. METHODS--This was a retrospective study of 14 patients with sacral fractures. RESULTS--Six patients had additional pelvic fractures. Four bone scintigraphic patterns were found. The resolution of symptoms was longer in patients with associated pelvic fractures (30 weeks v three weeks). No relation was found between the bone scintigraphic pattern and the time of evolution. CONCLUSION--Associated pelvic fractures delay the resolution of symptoms in patients with sacral fractures, regardless of scintigraphic pattern

Clinical evolution of sacral stress fractures: influence of additional pelvic fractures

To evaluate the clinical evolution of sacral stress fractures in relation to the scintigraphic pattern and the presence of additional pelvic fractures. METHODS--This was a retrospective study of 14 patients with sacral fractures. RESULTS--Six patients had additional pelvic fractures. Four bone scintigraphic patterns were found. The resolution of symptoms was longer in patients with associated pelvic fractures (30 weeks v three weeks). No relation was found between the bone scintigraphic pattern and the time of evolution. CONCLUSION--Associated pelvic fractures delay the resolution of symptoms in patients with sacral fractures, regardless of scintigraphic pattern