Miracle-dz/UniFAR-FTUs huggingface dataset:
Mutations That Alter the Carboxy‐Terminal‐Propeptide Cleavage Site of the Chains of Type I Procollagen Are Associated With a Unique Osteogenesis Imperfecta Phenotype

Osteogenesis imperfecta (OI) is a genetic bone disorder characterized by fractures, low bone mass, and skeletal fragility. It most commonly arises from dominantly inherited mutations in the genes COL1A1 and COL1A2 that encode the chains of type I collagen. A number of recent reports have suggested that mutations affecting the carboxyl‐terminal propeptide cleavage site in the products of either COL1A1 or COL1A2 give rise to a form of OI characterized by unusually dense bones. We have assembled clinical, biochemical, and molecular data from 29 individuals from 8 families with 7 different mutations affecting the C‐propeptide cleavage site. The phenotype was generally mild: The median height was ∼33th centile. Eighty percent of subjects had their first fracture by the age of 10 years, and one‐third had a femoral or tibial fracture by the age of 25 years. Fractures continued into adulthood, though rates varied considerably. Healing was normal and rarely resulted in long bone deformity. One‐third of subjects older than 15 years had scoliosis. The teeth and hearing were normal in most, and blue sclerae were not observed. Other features noted included fibro‐osseous dysplasia of the mandible and Achilles tendon calcification. The mean spinal bone mineral density Z‐score was +2.9 (SD 2.1) compared with –2.2 (0.7) in subjects with COL1A1 haploinsufficiency mutations. Bone mineral density distribution, assessed by quantitative backscattered electron imaging in bone showed higher levels of mineralization than found in any other disorder. Bone histology showed high trabecular volume and increased cortical thickness, with hyperosteoidosis and delayed mineralization. In vitro studies with cultured skin fibroblasts suggested that these mutations interfere with processing of the chain in which the sequence alteration occurs, but the C‐propeptide is eventually cleaved (and detectable in blood), suggesting there are alternative sites of cleavage. The precise mechanism of the bony pathology is not yet clear. © 2018 American Society for Bone and Mineral Research.
Exploring neuro-vascular and neuro-metabolic coupling in rat somatosensory cortex

The existence of a coupling between changes in neuronal activity, cerebral blood flow and blood oxygenation is well known. The explicit relationship between these systems, however, is complex and remains a subject of intense research. Here, we use direct electrophysiological recordings to predict blood flow and oxygenation changes measured with optical methods during parametric stimulation applied to the somatosensory cortex in rat brain. Using a multimodal model of the cerebral functional unit, we estimate a neuro-vascular and a neuro-metabolic transfer function relating the experimentally measured neural responses with the inputs to a vascular model predicting hemodynamic and blood oxygenation changes. We show that our model can accurately predict experimentally measured parametric hemodynamic evoked responses by using a single linear transfer function relationship with a reduced number of state parameters to relate the level of neural activity to evoked cerebral blood flow and oxygen metabolism changes. At the same time, we characterize the metabolic and vascular neural response functions and interpret their physiological significance.
Restless Legs Syndrome in a Rheumatoid Arthritis Patient Cohort

Objective:To use the 2003 International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria and to evaluate restless legs syndrome (RLS) prevalence in a rheumatoid arthritis (RA) and osteoarthritis (OA) population. Further, we wished to evaluate physician awareness of this disorder by as reflected in prevalence of preexisting diagnoses of RLS in these populations. Methods:This was a questionnaire study of Saskatchewan RA and OA patients enrolled in a longitudinal database study. A data collection instrument, including the 2003 IRLSSG criteria for RLS was distributed to the patients enrolled. Results:Of the 193 respondents, 158 (81.9%) were women. The population consisted of 148 RA and 45 OA patients. RA patients were younger (mean age, 65.8 years) in comparison with those in the OA group (mean age, 72.8 years; P < 0.001). All criteria for RLS were met by 27.7% of RA patients and by 24.4% of OA patients. A previous diagnosis of RLS was reported by 2.6% of patients. Conclusions:A quarter of all our patients met the 2003 IRLSSG criteria, in both RA and OA groups; however, only 2.6% of study patients reported a previous diagnosis of RLS. As RLS can significantly affect quality of life, increased awareness with improvement in surveillance, recognition, and treatment would be beneficial to patient care. We advocate screening for symptoms of sleep disorders to be incorporated into the routine rheumatologic history for all patients with RA and OA.
The renin‐angiotensin system, blood pressure, and heart structure in patients with hereditary vitamin D–resistance rickets (HVDRR)

Vitamin D deficiency has been linked to hypertension and an increased prevalence of cardiovascular risk factors and disease. Studies in vitamin D receptor knockout (VDR KO) mice revealed an overstimulated renin‐angiotensin system (RAS) and consequent high blood pressure and cardiac hypertrophy. VDR KO mice correspond phenotypically and metabolically to humans with hereditary 1,25‐dihydroxyvitamin D–resistant rickets (HVDRR). There are no data on the cardiovascular system in human HVDRR. To better understand the effects of vitamin D on the human cardiovascular system, the RAS, blood pressure levels, and cardiac structures were examined in HVDRR patients. Seventeen patients (9 males, 8 females, aged 6 to 36 years) with hereditary HVDRR were enrolled. The control group included age‐ and gender‐matched healthy subjects. Serum calcium, phosphorous, creatinine, 25‐hydroxyvitamin D [25(OH)D],1,25‐dihydroxyvitamin D3 [1,25(OH)2D3], parathyroid hormone (PTH), plasma rennin activity (PRA), aldosterone, angiotensin II (AT‐II), and angiotensin‐converting enzyme (ACE) levels were determined. Ambulatory 24‐hour blood pressure measurements and echocardiographic examinations were performed. Serum calcium, phosphorus, and alkaline phosphatase values were normal. Serum 1,25(OH)2D3 and PTH but not PRA and ACE levels were elevated in the HVDRR patients. AT‐II levels were higher than normal in the HVDRR patients but not significantly different from those of the controls. Aldosterone levels were normal in all HVDRR patients. No HVDRR patient had hypertension or echocardiographic pathology. These findings reveal that 6‐ to 36‐year‐old humans with HVDRR have normal renin and ACE activity, mild but nonsignificant elevation of AT‐II, normal aldosterone levels, and no hypertension or gross heart abnormalities. © 2011 American Society for Bone and Mineral Research
Scalp necrosis in giant cell arteritis in an African-Colombian patient.

Giant cell arteritis (GCA), the most common vasculitis in elderly individuals in Western countries, is a largeand medium-sized blood vessel systemic vasculitis characterized by the granulomatous involvement of the aorta with a predilection for the extracraneal branches of the carotid artery. GCA is usually seen in patients over 50 years of age primarily of white ethnicity and less frequently among African Americans, particularly men. Characteristic manifestations include headache, scalp tenderness, jaw claudication, ocular symptoms, polymyalgia rheumatica, and an elevated erythrocyte sedimentation rate (ESR). Scalp necrosis is an extremely rare manifestation which has been associated with severity and a bad prognosis. Herein, we present an unusual case of GCA in an African-Colombian who developed an extensive scalp necrosis.
Uso de chupeta e sua relação com o desmame precoce em população de crianças nascidas em Hospital Amigo da Criança

Objective: to assess the use of pacifiers and its relationship with early weaning among children born at a Child-Friendly Hospital. Method: a cohort study was carried out with 250 healthy singleton babies, with birthweight > 2,500 g, and with ongoing breastfeeding, born at Hospital de Clinicas de Porto Alegre. All mothers lived in Porto Alegre. Data were collected through interviews with the mothers, both at the maternity ward and at their homes, at the end of the first and sixth month of life; and over the phone, in the second and fourth months. Survival curves were built to compare the prevalence of breastfeeding and exclusive breastfeeding during the first six months of life among pacifier and non-pacifier users.
The pathophysiology of early‐stage chronic kidney disease–mineral bone disorder (CKD‐MBD) and response to phosphate binders in the rat

Chronic kidney disease–mineral bone disorder (CKD‐MBD) is a systemic disorder that describes the complex bone and mineral abnormalities that occur in CKD. To understand the pathophysiology of CKD‐MBD and determine whether the early use of phosphate binders would alter this physiology, we used a naturally occurring, slowly progressive model of CKD‐MBD, the Cy/+ rat. Male Cy/+ rats were compared with their normal littermates at 20 weeks of age after 1 week of no phosphate binder, calcium carbonate, or sevelamer carbonate. The Cy/+ rat had renal function that was 50% of that of normal littermates, elevated parathyroid hormone (PTH) and fibroblast growth factor 23 (FGF23), decreased 1,25‐dihydroxyvitamin D3 [1,25(OH)2D3] levels, but normal calcium and phosphorus levels. There was a significant positive correlation of blood FGF23 and phosphorus levels and blood FGF23 and urine phosphorus levels. There was an inverse correlation between FGF23 and calcium levels. mRNA from the kidney demonstrated 50% reduction in klotho and Npt2a expression but no difference in CYP27B1. In the intestine, CKD animals had reduced active phosphate absorption in the jejunum using modified Ussing chambers and a reduction in Npt2b expression throughout the small intestine compared with normal littermates. In bone, mRNA expression of FGF23 was reduced (driven by lowering with phosphate binders), and TRAP expression was increased in CKD. By histology, there was increased osteoclast activity and number, and there were reductions in some measures of femoral neck mechanical strength. One week of phosphate binders reduced intestinal phosphate flux, serum phosphorus levels, and urinary phosphate excretion. These results demonstrate marked abnormalities in kidney, intestine, and bone in early CKD‐MBD. While phosphate binders were effective in lowering urine phosphorus, they had little effect on end organs after 1 week of administration. © 2011 American Society for Bone and Mineral Research
IL-1 inhibition with anakinra in a patient with refractory gout.

There is recent literature emphasizing the role of IL-1 in the pathophysiology of gout. Upon recognition of monosodium urate crystals by phagocytes, a cascade of cellular signaling events occurs leading to activation of the NALP-3 inflammasome and secretion of the active form of IL-1. Genetic defects in NALP-3 have been described in autoinflammatory syndromes, which respond to treatment with the IL-1 inhibitor anakinra. It is believed that NALP-3 mediated production of mature IL-1 triggers the inflammatory response, which leads to the major clinical manifestations of acute gout. Clinical support for IL-1 inhibition in gout comes from a recent report describing significant improvement in an open label study of 10 patients with acute gout who responded to anakinra given daily for 3 days. Management of gout has changed relatively little in the past 50 years despite the fact that many patients have contraindications to one or more currently available gout therapies. However, recent insights into gout pathophysiology suggest that time has come for a change. IL-1 inhibition may be a potent addition to the therapeutic arsenal of gout management, especially in those who are refractory to or intolerant of current standard approaches to the treatment of gout.
Markerless gating for lung cancer radiotherapy based on machine learning techniques

In lung cancer radiotherapy, radiation to a mobile target can be delivered by respiratory gating, for which we need to know whether the target is inside or outside a predefined gating window at any time point during the treatment. This can be achieved by tracking one or more fiducial markers implanted inside or near the target, either fluoroscopically or electromagnetically. However, the clinical implementation of marker tracking is limited for lung cancer radiotherapy mainly due to the risk of pneumothorax. Therefore, gating without implanted fiducial markers is a promising clinical direction. We have developed several template-matching methods for fluoroscopic marker-less gating. Recently, we have modeled the gating problem as a binary pattern classification problem, in which principal component analysis (PCA) and support vector machine (SVM) are combined to perform the classification task. Following the same framework, we investigated different combinations of dimensionality reduction techniques (PCA and four nonlinear manifold learning methods) and two machine learning classification methods (artificial neural networks—ANN and SVM). Performance was evaluated on ten fluoroscopic image sequences of nine lung cancer patients. We found that among all combinations of dimensionality reduction techniques and classification methods, PCA combined with either ANN or SVM achieved a better performance than the other nonlinear manifold learning methods. ANN when combined with PCA achieves a better performance than SVM in terms of classification accuracy and recall rate, although the target coverage is similar for the two classification methods. Furthermore, the running time for both ANN and SVM with PCA is within tolerance for real-time applications. Overall, ANN combined with PCA is a better candidate than other combinations we investigated in this work for real-time gated radiotherapy.
A functional haplotype in EIF2AK3, an ER stress sensor, is associated with lower bone mineral density

EIF2AK3 is a type I transmembrane protein that functions as an endoplasmic reticulum (ER) stress sensor to regulate global protein synthesis. Rare mutations in EIF2AK3 cause Wolcott‐Rallison syndrome (OMIM 226980), an autosomal recessive disorder characterized by diabetes, epiphyseal dysplasia, osteoporosis, and growth retardation. To investigate the role of common genetic variation in EIF2AK3 as a determinant of bone mineral density (BMD) and osteoporosis, we sequenced all exons and flanking regions, then genotyped six potentially functional single nucleotide polymorphisms (SNPs) in this gene in 997 Amish subjects for association analysis, and attempted replication in 887 Mexican Americans. We found that the minor allele of a nonsynonymous SNP rs13045 had borderline associations with decreased forearm BMD in both discovery and replication cohorts (unadjusted p = 0.036 and β = − 0.007 for the Amish; unadjusted p = 0.031 and β = − 0.008 for Mexican Americans). A meta‐analysis indicated this association achieved statistical significance in the combined sample (unadjusted p = 0.003; Bonferroni corrected p = 0.009). Rs13045 and three other potentially functional SNPs, a promoter SNP (rs6547787) and two nonsynonymous SNPs (rs867529 and rs1805165), formed two haplotypes: a low‐BMD associated haplotype, denoted haplotype B [minor allele frequency (MAF) = 0.311] and a common haplotype A (MAF = 0.676). There were no differences in mRNA expression in lymphoblastoid cell lines between the two haplotypes. However, after treating lymphoblastoid cell lines with thapsigargin to induce ER stress, cell lines with haplotype B showed increased sensitivity to ER stress (p = 0.014) compared with cell lines with haplotype A. Taken together, our results suggest that common nonsynonymous sequence variants in EIF2AK3 have a modest effect on ER stress response and may contribute to the risk for low BMD through this mechanism. © 2012 American Society for Bone and Mineral Research
Vitamin D, osteocalcin, and risk for adiposity as comorbidities in middle school children

Nonclassic actions of vitamin D include potential regulation of immune function and glucose homeostasis. The bone‐metabolism loop has recently been expanded to include osteocalcin, which appears to play a more direct role in pancreatic beta cell function and energy metabolism. We hypothesized that both vitamin D and osteocalcin would correlate negatively with indices of adiposity‐related comorbidity risk in periadolescents, varying by ethnic group. We analyzed anthropometric, metabolic, and inflammatory markers from a multiethnic population of 106 school children 11 to 14 years of age studied as part of the Reduce Obesity and Diabetes (ROAD) consortium. As expected, 25‐hydroxyvitamin D (25‐OH vitamin D) was inversely correlated with intact parathyroid hormone (iPTH); total osteocalcin (OCN) and uncarboxylated osteocalcin (uOCN) were directly correlated with each other. OCN and uOCN concentrations correlated inversely with age. Vitamin D deficiency was most prevalent among East Asians (EA) and African Americans (AA). The highest lipid risk scores and homeostatic model for assessment of insulin resistance (HOMA‐IR) values were seen in the South Asian (SA) group. Overall, adiposity measures were inversely correlated with OCN and iPTH, whereas such relationships were not observed for vitamin D. Acute insulin response to glucose challenge correlated negatively with uOCN in all subjects; however, lipid risk score correlated negatively with uOCN only in whites. The relationships between markers of calcium metabolism and body composition, glucose homeostasis, lipids, and inflammation all showed racial and ethnic differences. No consistent relationship was found between vitamin D and adiposity or vitamin D and glucose metabolism; instead vitamin D levels varied by race and ethnicity in this school‐based group. These findings are consistent with the hypothesis that markers of calcium and bone metabolism may reflect risk for adiposity‐related comorbidities in children. © 2012 American Society for Bone and Mineral Research
Primary hypertrophic osteoarthropathy with hypertrophic gastropathy.

Pachydermoperiostosis (PDP), or primary hypertrophic osteoarthropathy (PHO), is a rare genetic disease affecting both skin and bones. The 3 major diagnostic criteria include digital clubbing, periostosis, and pachydermia. The minor criteria include seborrhoea with sebaceous hyperplasia, folliculitis, acne, hyperhidorosis, and cutis verticis gyrata. Some of the earliest descriptions of the abnormalities caused by this syndrome were described by Hippocrates in 459 BC. We report the case of a 25-year-old man presenting with widening of the wrist and ankles, broadening of the fingers and toes, and clubbing for the previous 5 years who also had hypertrophic gastropathy.
Ronacaleret, a calcium‐sensing receptor antagonist, increases trabecular but not cortical bone in postmenopausal women

Intermittent injections of parathyroid hormone have osteoanabolic effects that increase bone mineral density (BMD). Ronacaleret is an orally administered calcium‐sensing receptor antagonist that stimulates endogenous parathyroid hormone release from the parathyroid glands. Our objective was to compare the effects of ronacaleret and teriparatide on volumetric BMD (vBMD) measured by quantitative computed tomography (QCT). We conducted a randomized, placebo‐controlled, dose‐ranging trial at 45 academic centers with 31 sites participating in the substudy. Patients included 569 postmenopausal women with low bone mineral density; vBMD was assessed at the spine and hip in a subset of 314 women. Patients were treated for up to 12 months with open‐label teriparatide 20 µg subcutaneously once daily or randomly assigned in a double‐blind manner to ronacaleret 100 mg, 200 mg, 300 mg, or 400 mg once daily, alendronate 70 mg once weekly, or matching placebos. Ronacaleret increased spine integral (0.49% to 3.9%) and trabecular (1.8% to 13.3%) vBMD compared with baseline, although the increments were at least twofold lower than that attained with teriparatide (14.8% and 24.4%, respectively) but similar or superior to that attained with alendronate (5.0% and 4.9%, respectively). There were small non‐dose‐dependent decreases in integral vBMD of the proximal femur with ronacaleret (−0.1 to −0.8%) compared with increases in the teriparatide (3.9%) and alendronate (2.7%) arms. Parathyroid hormone (PTH) elevations with ronacaleret were prolonged relative to that seen historically with teriparatide. Ronacaleret preferentially increased vBMD of trabecular bone that is counterbalanced by small decreases in BMD at cortical sites. The relative preservation of trabecular bone and loss at cortical sites are consistent with the induction of mild hyperparathyroidism with ronacaleret therapy. © 2012 American Society for Bone and Mineral Research
Cardiotoxin III‐induced apoptosis is mediated by Ca2+‐dependent caspase‐12 activation in K562 cells

Cardiotoxin III (CTX III), a basic polypeptide with 60 amino acid residues isolated from Naja naja atra venom, has been reported to have anticancer activity. When K562 cells were treated with CTX III, cytosolic calcium concentration was rapidly and persistently increased. This CTX III‐induced cell death was partially reversed by pretreatment with BAPTA/AM (20 µM), a chelator of intracellular Ca2+. Moreover, CTX III‐induced apoptotic signals, such as caspase‐12 and c‐Jun N‐terminal kinase (JNK) activation, were induced in a time‐dependent manner and inhibited by BAPTA/AM. In contrast, the neutral protease µ‐calpain, a key enzyme in endoplasmic reticulum (ER) stress‐related apoptosis via caspase‐12 activation, was unchanged during apoptosis. Taken together, our findings suggest CTX III‐induced apoptosis is triggered by Ca2+ influx, then activated caspase‐12 and JNK through µ‐calpain‐independent cascade, and consequently caused apoptosis. © 2008 Wiley Periodicals, Inc. J Biochem Mol Toxicol 22:209–218, 2008; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20231
Effects of low‐level light therapy on hepatic antioxidant defense in acute and chronic diabetic rats

Diabetes causes oxidative stress in the liver and other tissues prone to complications. Photobiomodulation by near infrared light (670 nm) has been shown to accelerate diabetic wound healing, improve recovery from oxidative injury in the kidney, and attenuate degeneration in retina and optic nerve. The present study tested the hypothesis that 670 nm photobiomodulation, a low‐level light therapy, would attenuate oxidative stress and enhance the antioxidant protection system in the liver of a model of type I diabetes. Male Wistar rats were made diabetic with streptozotocin (50 mg/kg, ip) then exposed to 670 nm light (9 J/cm2) once per day for 18 days (acute) or 14 weeks (chronic). Livers were harvested, flash frozen, and then assayed for markers of oxidative stress. Light treatment was ineffective as an antioxidant therapy in chronic diabetes, but light treatment for 18 days in acutely diabetic rats resulted in the normalization of hepatic glutathione reductase and superoxide dismutase activities and a significant increase in glutathione peroxidase and glutathione‐S transferase activities. The results of this study suggest that 670 nm photobiomodulation may reduce, at least in part, acute hepatic oxidative stress by enhancing the antioxidant defense system in the diabetic rat model. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:1–8, 2009; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/jbt.20257