Hereditary Hypophosphatemic Rickets with Hypercalciuria (HHRH) Presenting with Genu Valgum Deformity: Treatment with Phosphate Supplementation and Surgical Correction

We describe a case of hereditary hypophosphatemic rickets with hypercalciuria (HHRH) in a 32-year-old female with short stature, chronic pathologic genu valgum deformity, and knee pain who was referred to endocrinology clinic after previous inconclusive workups. We present imaging spanning 10 years of untreated disease. Biochemical studies showed hypophosphatemia with undetectable fibroblast growth factor 23 (FGF23.) Renal ultrasound revealed bilateral medullary nephrocalcinosis despite no apparent hypercalciuria. Due to concern for HHRH, genetic testing was performed that determined this patient to be homozygous in the SLC34A3 gene for a previously described missense variant (c.1402C \u3e T, p.Arg468Trp). There was no known family history of rickets. A bone biopsy with metabolic studies was performed for diagnostic and prognostic reasons. The histopathological findings along with tetracycline uptake studies were consistent with a diagnosis of HHRH. Treatment with phosphorous supplementation and surgical correction of her valgum deformity resulted in resolution of pain, but no change in bone histomorphometry

Quality of life is associated with chronic inflammation in schizophrenia: a cross-sectional study

International audienceInflammation may play a crucial role in the pathogenesis of schizophrenia. However, the association between chronic inflammation and health outcomes in schizophrenia remains unclear, particularly for patient-reported outcomes. The aim of this study was to investigate the relationship between quality of life (QoL) and chronic inflammation assessed using C -Reactive Protein (CRP) in patients with schizophrenia. Two hundred and fifty six patients with schizophrenia were enrolled in this study. After adjusting for key socio-demographic and clinical confounding factors, patients with high levels of CRP (>3.0 mg/l) had a lower QoL than patients with normal CRP levels (OR = 0.97, 95% CI = 0.94-0.99). An investigation of the dimensions of QoL revealed that psychological well-being, physical well-being and sentimental life were the most salient features of QoL associated with CRP. Significant associations were found between lower educational level (OR = 4.15, 95% CI = 1.55-11.07), higher body mass index (OR = 1.16, 95% CI = 1.06-1.28), higher Fagerstrom score (OR = 1.22, 95% CI = 1.01-1.47) and high levels of CRP. After replications with longitudinal approaches, the association between QoL and chronic inflammation may offer interesting interventional prospects to act both on inflammation and QoL in patients with schizophrenia

1,25(OH)2D3 administration in moderate renal failure: A prospective double-blind trial

1,25(OH)2D3 administration in moderate renal failure: A prospective double blind trial. This study represents the first randomized prospective, double-blind, placebo-controlled trial of the efficacy of 1,25(OH)2D3 on bone histology and serum biochemistry in patients with mild to moderate renal failure. Sixteen patients with chronic renal impairment (creatinine clearance 20 to 59ml per min) received either 1,25(OH)2D3, at a dose of 0.25 to 0.5 µg daily (eight patients), or placebo. Transiliac crest bone biopsies were performed before entrance into the study and after 12 months of experimental observation. None of the patients were symptomatic or had radiological evidence of bone disease. Of the thirteen patients who completed the study, initial serum 1,25(OH)2D levels were low in seven patients and parathyroid hormone levels were elevated in seven patients. Bone histology was abnormal in all patients. 1,25(OH)2D3 treatment was associated with a significant fall in serum phosphorus and alkaline phosphatase concentrations as well as with histological evidence of an amelioration of hyperparathyroid changes. In contrast to previous reports, no deterioration of renal function attributable to the treatment occurred, perhaps because a modest dose of 1,25(OH)2D3 was employed combined with meticulous monitoring. Further investigation is required to determine whether alternative therapeutic strategies (smaller doses or intermittent therapy) may avoid the potential for suppressing bone turnover to abnormally low levels in the long term

Lrp5 and Lrp6 exert overlapping functions in osteoblasts during postnatal bone acquisition

The canonical Wnt signaling pathway is critical for skeletal development and maintenance, but the precise roles of the individual Wnt co-receptors, Lrp5 and Lrp6, that enable Wnt signals to be transmitted in osteoblasts remain controversial. In these studies, we used Cre-loxP recombination, in which Cre-expression is driven by the human osteocalcin promoter, to determine the individual contributions of Lrp5 and Lrp6 in postnatal bone acquisition and osteoblast function. Mice selectively lacking either Lrp5 or Lrp6 in mature osteoblasts were born at the expected Mendelian frequency but demonstrated significant reductions in whole-body bone mineral density. Bone architecture measured by microCT revealed that Lrp6 mutant mice failed to accumulate normal amounts of trabecular bone. By contrast, Lrp5 mutants had normal trabecular bone volume at 8 weeks of age, but with age, these mice also exhibited trabecular bone loss. Both mutants also exhibited significant alterations in cortical bone structure. In vitro differentiation was impaired in both Lrp5 and Lrp6 null osteoblasts as indexed by alkaline phosphatase and Alizarin red staining, but the defect was more pronounced in Lrp6 mutant cells. Mice lacking both Wnt co-receptors developed severe osteopenia similar to that observed previously in mice lacking β-catenin in osteoblasts. Likewise, calvarial cells doubly deficient for Lrp5 and Lrp6 failed to form osteoblasts when cultured in osteogenic media, but instead attained a chondrocyte-like phenotype. These results indicate that expression of both Lrp5 and Lrp6 are required within mature osteoblasts for normal postnatal bone development

Ligand Trap of the Activin Receptor Type IIA Inhibits Osteoclast Stimulation of Bone Remodeling in Diabetic Mice with Chronic Kidney Disease

Dysregulation of skeletal remodeling is a component of renal osteodystrophy. Previously, we showed that activin receptor signaling is differentially affected in various tissues in chronic kidney disease (CKD). We tested whether a ligand trap for the activin receptor type 2A (RAP-011) is an effective treatment of the osteodystrophy of the CKD-mineral bone disorder. With a 70% reduction in the glomerular filtration rate, CKD was induced at 14 weeks of age in the ldlr−/− high fat-fed mouse model of atherosclerotic vascular calcification and diabetes. Twenty mice with CKD, hyperphosphatemia, hyperparathyroidism, and elevated activin A were treated with RAP-011, wherease 19 mice were given vehicle twice weekly from week 22 until the mice were killed at 28 weeks of age. The animals were then evaluated by skeletal histomorphometry, micro-computed tomography, mechanical strength testing, and ex vivo bone cell culture. Results in the CKD groups were compared with those of the 16 sham-operated ldlr−/− high fat-fed mice. Sham-operated mice had low-turnover osteodystrophy and skeletal frailty. CKD stimulated bone remodeling with significant increases in osteoclast and osteoblast numbers and bone resorption. Compared with mice with CKD and sham-operated mice, RAP-011 treatment eliminated the CKD-induced increase in these histomorphometric parameters and increased trabecular bone fraction. RAP-011 significantly increased cortical bone area and thickness. Activin A-enhanced osteoclastogenesis was mediated through p-Smad2 association with c-fos and activation of nuclear factor of activated T cells c1 (NFATc1). Thus, an ActRIIA ligand trap reversed CKD-stimulated bone remodeling, likely through inhibition of activin-A induced osteoclastogenesis

Response of different PTH assays to therapy with sevelamer or CaCO3 and active vitamin D sterols

Amino-terminally truncated parathyroid hormone (PTH) fragments are detected to differing degrees by first- and second-generation immunometric PTH assays (PTH-IMAs), and acute changes in serum calcium affect the proportion of these fragments in circulation. However, the effect of chronic calcium changes and different vitamin D doses on these PTH measurements remains to be defined. In this study, 60 pediatric dialysis patients, aged 13.9 ± 0.7 years, with secondary hyperparathyroidism were randomized to 8 months of therapy with oral vitamin D combined with either calcium carbonate (CaCO3) or sevelamer. Serum phosphorus levels did not differ between groups. Serum calcium levels rose from 9.3 ± 0.1 to 9.7 ± 0.1 mg/dl during CaCO3 therapy (p < 0.01 from baseline) but remained unchanged during sevelamer therapy. In the CaCO3 and sevelamer groups, baseline serum PTH levels (1st PTH-IMA; Nichols Institute Diagnostics, San Clemente, CA) were 964 ± 75 and 932 ± 89 pg/ml, and levels declined to 491 ± 55 and 543 ± 59 pg/ml, respectively (nonsignificant between groups). Patients treated with sevelamer received higher doses of vitamin D than those treated with CaCO3. The PTH values obtained by first- and second-generation PTH-IMAs correlated closely throughout therapy and the response of PTH was similar to both PTH-IMAs, despite differences in serum calcium levels

STC1 interference on calcitonin family of receptors signaling during osteoblastogenesis via adenylate cyclase inhibition

Stanniocalcin 1 (STC1) and calcitonin gene-related peptide (CGRP) are involved in bone formation/remodeling. Here we investigate the effects of STC1 on functional heterodimer complex CALCRL/RAMP1, expression and activity during osteoblastogenesis. STC1 did not modify CALCRL and ramp 1 gene expression during osteoblastogenesis when compared to controls. However, plasma membrane spatial distribution of CALCRL/RAMP1 was modified in 7-day pre-osteoblasts exposed to either CGRP or STC1, and both peptides induced CALCRL and RAMP1 assembly. CGRP, but not STC1 stimulated cAMP accumulation in 7-day osteoblasts and in CALCRL/RAMP1 transfected HEK293 cells. Furthermore, STC1 inhibited forskolin stimulated cAMP accumulation of HEK293 cells, but not in CALCRL/RAMP1 transfected HEK293 cells. However, STC1 inhibited cAMP accumulation in calcitonin receptor (CTR) HEK293 transfected cells stimulated by calcitonin. In conclusion, STC1 signals through inhibitory G-protein modulates CGRP receptor spatial localization during osteoblastogenesis and may function as a regulatory factor interacting with calcitonin peptide members during bone formation. (C) 2015 Elsevier Ireland Ltd. All rights reserved.CAPES/CNPq (VS PNPD fellowship program); FAPERGS/CNPq [008/2009 (FCRG)]; Portuguese Foundation for Science and Technology (FCT) [PTDC/MAR/121279/2010, PEst-C/MAR/LA0015/2013, SFRH/BPD/89811/2012]; CNPq (SRT PhD fellowship program); CNPq (LAMM PhD fellowship program); CNPq (FCRG research productivity fellowship program); INCT Exitotoxicity and Neuroprotection (DOGS

Algebraic Cryptanalysis of STARK-Friendly Designs:Application to MARVELlous and MiMC

The block cipher Jarvis and the hash function Friday, both members of the MARVELlous family of cryptographic primitives, are among the first proposed solutions to the problem of designing symmetric-key algorithms suitable for transparent, post-quantum secure zero-knowledge proof systems such as ZK-STARKs. In this paper we describe an algebraic cryptanalysis of Jarvis and Friday and show that the proposed number of rounds is not sufficient to provide adequate security. In Jarvis, the round function is obtained by combining a finite field inversion, a full-degree affine permutation polynomial and a key addition. Yet we show that even though the high degree of the affine polynomial may prevent some algebraic attacks (as claimed by the designers), the particular algebraic properties of the round function make both Jarvis and Friday vulnerable to Gröbner basis attacks. We also consider MiMC, a block cipher similar in structure to Jarvis. However, this cipher proves to be resistant against our proposed attack strategy. Still, our successful cryptanalysis of Jarvis and Friday does illustrate that block cipher designs for “algebraic platforms” such as STARKs, FHE or MPC may be particularly vulnerable to algebraic attacks

Precision-medicine findings from the FACE-SZ cohort to develop motivation-enhancing programs in real-world schizophrenia

Background: In people with schizophrenia, major areas of everyday life are impaired, including independent living, productive activities, social relationships and overall quality of life. Enhanced understanding of factors that hinder real-life functioning is vital for treatments to translate into more positive outcomes. Aim: The goal of the present study was to identify factors associated with motivation deficits in real-life schizophrenia, and to assess its contribution to impaired functioning and quality of life. Methods: Based on previous literature and clinical experience, several factors were selected and grouped into factors potentially explaining motivation deficits. Some of these variables were never investigated before in relationship with motivation deficits. Results: In 561 patients with schizophrenia of the national FACE-SZ cohort living in the community, 235 (41.9%) reported severe motivation deficits. These deficits were found to be significantly associated with impaired socially useful activities, psychological and physical quality of life (in almost all domains), alcohol use disorder (aOR = 2.141, p = 0.021), severe nicotine dependence (aOR = 2.906, p < 0.001) independently of age and sex. No significant association was found for body mass index, metabolic syndrome or physical activity level. In the second model, we identified the following modifiable factors associated with motivation deficits: history of suicide attempt (aOR = 2.297, p = 0.001), positive symptoms (aOR = 1.052, p = 0.006), current major depressive episode (aOR = 2.627, p < 0.001), sleep disorders (aOR = 1.474, p = 0.024) and lower medication adherence (aOR = 0.836, p = 0.001) independently of gender, current alcohol use disorder, second-generation antipsychotics and akathisia. No significant association was found for negative symptoms, childhood trauma and inflammation. These results were maintained after removing patients with schizoaffective disorders or those with major depressive disorder. Interpretation: Motivation deficits are frequent and remain persistent unmet need in real-world schizophrenia that should be addressed in future guidelines. Based on our results, literature and clinical experience, we recommend to address in priority major depression, sleep, suicide, positive symptoms (when present and as early as possible) and medication adherence to improve motivation deficits of schizophrenia. © 2022 Informa UK Limited, trading as Taylor & Francis Group.Sorbonne Universités à Paris pour l'Enseignement et la RechercheFondaMental-Cohorte

LLANO DE LOS JUNCOS. TEJEDA [Material gráfico]

Copia digital. Madrid : Ministerio de Educación, Cultura y Deporte, 201