25 hydroxyvitamin D serum levels influence adequate response to bisphosphonate treatment in postmenopausal osteoporosis

It remains unclear whether vitamin D sufficiency optimizes response to bisphosphonate (BP) treatment in postmenopausal osteoporosis. We evaluated the role and possible mechanisms of vitamin D in adequate response to standard BP treatment for postmenopausal osteoporosis.MethodsWe included 120 postmenopausal osteoporotic women (aged 68 ± 8 years) receiving BP (alendronate or risedronate) at their annual follow-up, performing complete anamnesis, including treatment adherence, use of vitamin D supplements, and previous falls and fractures during the last year. We analyzed the evolution of bone mineral density (BMD) during this period and serum PTH and 25 hydroxyvitamin D (25(OH)D) and urinary NTx levels. Patients were classified as inadequate responders to antiosteoporotic treatment based on BMD loss > 2% and/or the presence of fragility fractures during the last year.ResultsThirty percent of patients showed inadequate response to BP treatment, with significantly lower levels of 25(OH)D (22.4 ± 1.3 vs. 26.6 ± 0.3 ng/ml, p = 0.01), a higher frequency of 25(OH)D levels < 30 ng/ml (91% vs. 69%, p = 0.019) and higher urinary NTx values (42.2 ± 3.9 vs. 30.9 ± 2.3 nM/mM, p = 0.01). Patients with 25(OH)D > 30 ng/ml had a greater significant increase in lumbar BMD than women with values < 30 ng/ml (3.6% vs. 0.8%, p < 0.05). The probability of inadequate response was 4-fold higher in patients with 25(OH)D < 30 (OR, 4.42; 95% CI, 1.22–15.97, p = 0.02).ConclusionsInadequate response to BP treatment is frequent in postmenopausal women with osteoporosis as is vitamin D insufficiency, despite vitamin D supplementation. Maintenance of 25(OH)D levels > 30 ng/ml is especially indicated for adequate response to BP treatment.     

Sodium retention in cirrhotic rats is associated with increased renal abundance of sodium transporter proteins

BACKGROUND: Liver cirrhosis with ascites is associated with a decrease in renal sodium excretion and therefore sodium retention. METHODS: In this paper, we utilize transporter-specific antibodies to address the hypothesis that dysregulation of one or more sodium transporters or channels is associated with sodium chloride (NaCl) retention in a rat model of cirrhosis induced by repeated exposure to carbon tetrachloride. Age-matched controls and cirrhotic rats were pair fed to ensure identical NaCl and water intake for 4 days prior to euthanasia for quantitative immunoblotting studies. RESULTS AND CONCLUSION: The rats manifested marked extracellular fluid volume expansion with massive ascites. Plasma aldosterone levels were markedly elevated. Analysis of immunoblots revealed marked increases in the abundances of both of the major aldosterone-sensitive apical transport proteins of the renal tubule, namely the thiazide-sensitive NaCl cotransporter NCC and the epithelial sodium channel alpha subunit (alpha-ENaC). These results are consistent with an important role for hyperaldosteronism in the pathogenesis of sodium retention and ascites formation in cirrhosis. In addition, we observed a large decrease in cortical NHE3 abundance (proximal tubule) and a large increase in NKCC2 abundance (thick ascending limb), potentially shifting premacula densa sodium absorption from proximal tubule to loop of Henle (which powers urinary concentration and dilution).     

Goal-Directed Fluid Therapy on Laparoscopic Sleeve Gastrectomy in Morbidly Obese Patients

Background

In bariatric surgery, there are no guidelines available for intraoperative fluid administration. Goal-directed fluid therapy (GDFT) is a new concept of perioperative fluid management that has been shown to improve the prognosis of patients undergoing abdominal surgery. The aim of our study is to assess the impact of the implementation of a GDFT protocol in morbidly obese patients who underwent laparoscopic sleeve gastrectomy (LSG).

Methods

A before-after intervention study, in morbidly obese patients who underwent LSG, was conducted at the Obesity Unit of the General University Hospital Elche. Data from the GDFT implementation group (January 2014 to December 2015) were prospectively collected and compared with a preimplementation group (January 2012 to December 2013).

Results

Baseline demographic and comorbidity data between the two groups of patients were similar. The length of stay in the hospital was significantly shortened in GDFT group from 4.5 to 3.44 days (p?<?0.001). Intraoperative fluid administration was significantly lower in the GDFT group (1002.4 vs 1687.2 ml in preimplementation group, p?<?0.001). In the postoperative period, there was a statistically significant reduction in postoperative nausea and vomiting (PONV) after GDFT implementation (48 to 14.3 %, p?<?0.001).

Conclusions

Implementation of GDFT protocols can prevent intraoperative fluid overload in patients undergoing bariatric surgery. It could improve outcomes, for example decreasing PONV or even hospital stay.

     

Prophylactic thyroidectomy in MEN 2A syndrome: experience in a single center

BACKGROUND: Genetic study of the RET proto-oncogene has modified the management, treatment, and prognosis of medullary thyroid carcinoma (MTC), multiple endocrine neoplasia 2A (MEN 2A), for patients with less advanced tumor stages. Classically, the diagnosis was based on an increase in basal and poststimulus peak calcitonin (bCT and pCT). Prophylactic thyroidectomy, based on results of genetic testing, may reduce recurrences in MTC. STUDY DESIGN: Of 82 MTC (MEN 2A) patients genetically diagnosed and surgically treated at our center, 22 received a prophylactic thyroidectomy (RET +, bCT and pCT with normal values and asymptomatic). We analyzed age, gender, phenotype, RET mutation, cervical ultrasound, laboratory tests (bCT, pCT, and CEA), surgery, histologic data, TNM, and followup. RESULTS: The 22 patients belonged to 8 families with MTC (MEN 2A). Mean age was 15.2 years (range 5 to 36 years). The RET mutation in 21 patients was Cys-->Tyr and in the remaining patient both in codon 634 in exon 11. The median values of bCT and pCT were 38 pg/mL (range < 15 to 75 pg/mL) and 148.5 pg/mL (range < 15 to 250 pg/mL), respectively. Total thyroidectomy was performed in 8 patients (age < or = 10 years) and associated central neck dissection in 14 patients (age> 10 years). Histologic study showed 7 C-cell hyperplasias and 15 MTCs (8 bilateral); the median size was 0.2 cm (range < 0.1 to 0.7cm); 1 patient had metastatic adenopathies. According to TNM, 7 were stage 0, 14 were stage I, and 1 was stage III. Postsurgery bCT and pCT values were normal in all patients, with a curative rate of 100%. MTC patients compared with C-cell hyperplasia patients were older on average, had higher mean bCT, mean pCT, and mean CEA. CONCLUSIONS: Prophylactic thyroidectomy based on genetic testing allows identification and treatment of patients at an early stage of the disease and decreases recurrence rates. pCT values above the upper limit of normal may be markers for the presence of MTC and should be considered in selecting operative procedures for these patients.     

Efectividad diagnóstica de la tomografía por emisión de positrones con 18fluorodeoxiglucosa asociada a tomografía axial en la discriminación de benignidad o malignidad de las lesiones suprarrenales

IntroductionThe usefulness of 18fluorodeoxyglucose positron emission tomography combined with axial tomography (PET-CT) in diagnosing whether adrenal tumours are benign or malignant is assessed.Material and methodsA retrospective study conducted between June 2005 and May 2009 on a consecutive series of patients on whom a PET-CT scan was performed to study suspected malignant adrenal disease. Focal uptakes were assessed, along with the maximum standard uptake value (SUV), and the ratio of the maximum adrenal/hepatic value. The sensitivity, specificity, positive and negative predictive value of the test, the maximum adrenal uptake values and the ratio for those where the diagnostic yield was maximum.ResultsFifteen patients were included. The final diagnosis showed malignancy in eight and seven were benign. Ten patients had adrenal uptake: three in benign lesions and seven in neoplasias, with a mean uptake value of 6.3 (3.2 in benign lesions and 9.0 in malignant lesions). The mean adrenal/hepatic ratio was 1.8 (0.9 in benign and 2.6 in malignant lesions). When the presence of adrenal uptake is associated with a final diagnosis of malignancy, we obtained a sensitivity of 87.5%, a specificity of 57.1%, and a positive and negative predictive value of 70% and 80%, respectively. An SUV cut-off value of 6, or an adrenal/hepatic uptake ratio of 2, gave a sensitivity of 75%, a specificity of 100%, and a positive and negative predictive value of 100% and 77.7%, respectively.ConclusionsPET-CT has a high ability to discriminate between benign and malignant lesions in the adrenal disease studied.     

Risk factors for the development of vertebral fractures after percutaneous vertebroplasty

We have recently observed an increased risk for vertebral fractures (VF) in a randomized controlled trial comparing the analgesic effect of vertebroplasty (VP) versus conservative treatment in symptomatic VF. The aim of the present study was to evaluate the risk factors related to the development of VF after VP in these patients. We evaluated risk factors including age, gender, bone mineral density, the number, type, and severity of vertebral deformities at baseline, the number of vertebral bodies treated, the presence and location of disk cement leakage, bone remodeling (determining bone turnover markers) and 25 hydroxyvitamin D [25(OH)D] levels at baseline in all patients. Twenty‐nine radiologically new VF were observed in 17 of 57 patients undergoing VP, 72% adjacent to the VP. Patients developing VF after VP showed an increased prevalence of 25(OH)D deficiency (<20 ng/mL) and higher P1NP values. The principal factor related to the development of VF after VP in multivariate analysis was 25(OH)D levels < 20 ng/mL (RR, 15.47; 95% CI, 2.99–79.86, p < 0.0001), whereas age >80 years (RR, 3.20; 95% CI, 1.70–6.03, p = 0.0007) and glucocorticoid therapy (RR, 3.64; 95% CI, 1.61–8.26, p = 0.0055) constituted the principal factors in the overall study population. Increased risk of VF after VP was also associated with cement leakage into the inferior disk (RR, 6.14; 95% CI, 1.65–22.78, p = 0.044) and more than one vertebral body treated during VP (RR, 4.19; 95% CI, 1.03–34.3, p = 0.044). In conclusion, nearly 30% of patients with osteoporotic VF treated with VP had a new VF after the procedure. Age, especially >80 years, the presence of inferior disk cement leakage after the procedure, the number of cemented vertebrae, and low 25(OH)D serum levels were related to the development of new VF in these patients, with the latter indicating the need to correct vitamin D deficiency prior to performing VP.     

The regenerative potential of fibroblasts in a new diabetes‐induced delayed humanised wound healing model

Cutaneous diabetic wounds greatly affect the quality of life of patients, causing a substantial economic impact on the healthcare system. The limited clinical success of conventional treatments is mainly attributed to the lack of knowledge of the pathogenic mechanisms related to chronic ulceration. Therefore, management of diabetic ulcers remains a challenging clinical issue. Within this context, reliable animal models that recapitulate situations of impaired wound healing have become essential. In this study, we established a new in vivo humanised model of delayed wound healing in a diabetic context that reproduces the main features of the human disease. Diabetes was induced by multiple low doses of streptozotocin in bioengineered human‐skin‐engrafted immunodeficient mice. The significant delay in wound closure exhibited in diabetic wounds was mainly attributed to alterations in the granulation tissue formation and resolution, involving defects in wound bed maturation, vascularisation, inflammatory response and collagen deposition. In the new model, a cell‐based wound therapy consisting of the application of plasma‐derived fibrin dermal scaffolds containing fibroblasts consistently improved the healing response by triggering granulation tissue maturation and further providing a suitable matrix for migrating keratinocytes during wound re‐epithelialisation. The present preclinical wound healing model was able to shed light on the biological processes responsible for the improvement achieved, and these findings can be extended for designing new therapeutic approaches with clinical relevance.     

Increased mitochondrial function downstream from KDM5A histone demethylase rescues differentiation in pRB-deficient cells

The retinoblastoma tumor suppressor protein pRb restricts cell growth through inhibition of cell cycle progression. Increasing evidence suggests that pRb also promotes differentiation, but the mechanisms are poorly understood, and the key question remains as to how differentiation in tumor cells can be enhanced in order to diminish their aggressive potential. Previously, we identified the histone demethylase KDM5A (lysine [K]-specific demethylase 5A), which demethylates histone H3 on Lys4 (H3K4), as a pRB-interacting protein counteracting pRB''s role in promoting differentiation. Here we show that loss of Kdm5a restores differentiation through increasing mitochondrial respiration. This metabolic effect is both necessary and sufficient to induce the expression of a network of cell type-specific signaling and structural genes. Importantly, the regulatory functions of pRB in the cell cycle and differentiation are distinct because although restoring differentiation requires intact mitochondrial function, it does not necessitate cell cycle exit. Cells lacking Rb1 exhibit defective mitochondria and decreased oxygen consumption. Kdm5a is a direct repressor of metabolic regulatory genes, thus explaining the compensatory role of Kdm5a deletion in restoring mitochondrial function and differentiation. Significantly, activation of mitochondrial function by the mitochondrial biogenesis regulator Pgc-1α (peroxisome proliferator-activated receptor γ-coactivator 1α; also called PPARGC1A) a coactivator of the Kdm5a target genes, is sufficient to override the differentiation block. Overexpression of Pgc-1α, like KDM5A deletion, inhibits cell growth in RB-negative human cancer cell lines. The rescue of differentiation by loss of KDM5A or by activation of mitochondrial biogenesis reveals the switch to oxidative phosphorylation as an essential step in restoring differentiation and a less aggressive cancer phenotype.