ABSTRACT
The powerful regulation of bone mass exerted by the brain suggests the existence of bone-derived signals modulating this regulation or other functions of the brain. We show here that the osteoblast-derived hormone osteocalcin crosses the blood-brain barrier, binds to neurons of the brainstem, midbrain, and hippocampus, enhances the synthesis of monoamine neurotransmitters, inhibits GABA synthesis, prevents anxiety and depression, and favors learning and memory independently of its metabolic functions. In addition to these postnatal functions, maternal osteocalcin crosses the placenta during pregnancy and prevents neuronal apoptosis before embryos synthesize this hormone. As a result, the severity of the neuroanatomical defects and learning and memory deficits of Osteocalcin(-/-) mice is determined by the maternal genotype, and delivering osteocalcin to pregnant Osteocalcin(-/-) mothers rescues these abnormalities in their Osteocalcin(-/-) progeny. This study reveals that the skeleton via osteocalcin influences cognition and contributes to the maternal influence on fetal brain development.
Subject(s)
Brain/growth & development , Osteocalcin/metabolism , Signal Transduction , Aging , Animals , Brain/embryology , Brain/physiology , Female , Fetus/metabolism , Mice , Neurotransmitter Agents/metabolism , PregnancyABSTRACT
The surgical decision to attempt nephron-sparing surgery (NSS) in children with renal tumors can be difficult. In adults, nephrometric tools are used for decision-making. More than 90% of low-complexity tumors are eligible for NSS, and high-complexity tumors often require total nephrectomy. We retrospectively applied those nephrometric tools [Radius, Exophytic, Nearness to the sinus or collecting system, Anterior/posterior, Location relative to polar lines (RENAL), Preoperative Aspects and Dimensions Used for an Anatomical classification (PADUA), and Renal Tumor Invasion Index (RTII) scoring systems] to the preoperative imaging of children operated for renal tumors in our institution from 2015 to 2019 and correlated them with the type of surgery. The scores were assessed by 2 independent surgeons and 1 radiologist. Forty-four tumors were removed, including 16 NSS, 38 after neo-adjuvant chemotherapy, and 6 upfront surgeries, in 30 children. More than 50% of patients in the low and medium-risk population for RENAL, PADUA, and RTII scores, and ~15% in the high-complexity categories underwent NSS. Tumors removed through NSS were significantly less complex according to each score. Interobserver reliability was good for 3 scores. The application of the RENAL, PADUA, and RTII was able to accurately classify most of the pediatric tumors, according to their complexity. These scores could help increase the indications of NSS in renal tumor surgery.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , Adult , Child , Humans , Retrospective Studies , Reproducibility of Results , Nephrectomy/methods , Kidney Neoplasms/surgery , Kidney Neoplasms/pathology , Nephrons/surgery , Nephrons/pathology , Carcinoma, Renal Cell/pathologyABSTRACT
PURPOSE: To evaluate hyperthermic intravesical chemotherapy (HIVEC) efficacy regarding 1-year disease-free survival (RFS) rate and bladder preservation rate in patients with non-muscle invasive bladder cancer (NMIBC) who fail bacillus Calmette-Guérin (BCG) therapy. METHODS: This is a multicenter retrospective series from a national database (7 expert centers). Between January 2016 and October 2021, patients treated with HIVEC for NMIBC who failed BCG have been included in our study. These patients had a theoretical indication for cystectomy but were ineligible for surgery or refused it. RESULTS: A total of 116 patients treated with HIVEC and with a follow-up > 6 months were included in this study and retrospectively analyzed. The median follow-up was 20.6 months. The 12 month-RFS (recurrence-free survival) rate was 62.9%. The bladder preservation rate was 87.1%. Fifteen patients (12.9%) progressed to muscle infiltration, three of them having a metastatic disease at the time of progression. Predictive factors of progression were T1 stage, high grade and very high-risk tumors according to the EORTC classification. CONCLUSION: Chemohyperthermia using HIVEC achieved an RFS rate of 62.9% at 1 year and enabled a bladder preservation rate of 87.1%. However, the risk of progression to muscle-invasive disease is not negligible, particularly for patients with very high-risk tumors. In these patients who fail BCG, cystectomy should remain the standard of care and HIVEC may be discussed cautiously for patients who are not eligible for surgery and well informed of the risk of progression.
Subject(s)
Non-Muscle Invasive Bladder Neoplasms , Urinary Bladder Neoplasms , Humans , Retrospective Studies , BCG Vaccine/therapeutic use , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/pathology , Disease-Free Survival , Administration, Intravesical , Adjuvants, Immunologic/therapeutic use , Neoplasm Invasiveness , Neoplasm Recurrence, Local/pathologyABSTRACT
OBJECTIVE. Clear cell papillary renal cell carcinoma (RCC), an entity with strikingly indolent behavior, recently was added to the World Health Organization classification of renal tumors and represents the fourth most common histologic type of renal cell carcinoma. This article aims to describe the imaging features of clear cell papillary RCC along with its clinical and pathologic characteristics. MATERIALS AND METHODS. This retrospective study consisted of 27 patients with 44 clear cell papillary RCC tumors. The inclusion criteria were a pathologically proven clear cell papillary RCC and the availability of preoperative imaging including at least CT or MRI. Two experienced radiologists performed the imaging analysis independently. RESULTS. Patients (mean age, 62 years old) presented with renal failure in 26% of cases, and four had a tumor-predisposing disease. Multiple clear cell papillary RCC tumors occurred in 5 of the 27 patients. Two imaging patterns were recognizable. Solid clear cell papillary RCC (n = 23, 52%) presented as heterogeneous tumors with minor cystic changes (74%) and rarely exhibited calcifications (10%). All solid tumors showed hyperintensity on T2-weighted images compared with renal cortex and maximal enhancement on corticomedullary phase with a delayed washout. Cystic clear cell papillary RCC (n = 21, 48%) were classified as Bosniak IV (57%), III (33%), or IIF (10%), with a predominant unilocular pattern (76%). Pathologic stage according to TNM classification was mostly pT1a and low grade on nucleolar grade. All patients were alive at the date of last follow-up after treatment with no metastasis or recurrence. CONCLUSION. Clear cell papillary RCC exhibits two imaging patterns including cystic and solid in almost equal proportion. Imaging characteristics of solid clear cell papillary RCC including high signal T2 intensity and early arterial enhancement are unexpectedly distinct from papillary RCC and very similar to clear cell RCC.
Subject(s)
Carcinoma, Papillary/diagnostic imaging , Carcinoma, Renal Cell/diagnostic imaging , Kidney Neoplasms/diagnostic imaging , Adult , Aged , Aged, 80 and over , Biopsy , Carcinoma, Papillary/pathology , Carcinoma, Renal Cell/pathology , Contrast Media , Female , Humans , Kidney Neoplasms/pathology , Magnetic Resonance Imaging , Male , Middle Aged , Neoplasm Grading , Neoplasm Staging , Retrospective Studies , Tomography, X-Ray ComputedABSTRACT
OBJECTIVES: Inherited myopathies are major causes of muscle atrophy and are often characterized by rigid spine syndrome, a clinical feature designating patients with early spinal contractures. We aim to present a decision algorithm based on muscular whole body magnetic resonance imaging (mWB-MRI) as a unique tool to orientate the diagnosis of each inherited myopathy long before the genetically confirmed diagnosis. METHODS: This multicentre retrospective study enrolled 79 patients from referral centres in France, Brazil and Chile. The patients underwent 1.5-T or 3-T mWB-MRI. The protocol comprised STIR and T1 sequences in axial and coronal planes, from head to toe. All images were analyzed manually by multiple raters. Fatty muscle replacement was evaluated on mWB-MRI using both the Mercuri scale and statistical comparison based on the percentage of affected muscle. RESULTS: Between February 2005 and December 2015, 76 patients with genetically confirmed inherited myopathy were included. They were affected by Pompe disease or harbored mutations in RYR1, Collagen VI, LMNA, SEPN1, LAMA2 and MYH7 genes. Each myopathy had a specific pattern of affected muscles recognizable on mWB-MRI. This allowed us to create a novel decision algorithm for patients with rigid spine syndrome by segregating these signs. This algorithm was validated by five external evaluators on a cohort of seven patients with a diagnostic accuracy of 94.3% compared with the genetic diagnosis. CONCLUSION: We provide a novel decision algorithm based on muscle fat replacement graded on mWB-MRI that allows diagnosis and differentiation of inherited myopathies presenting with spinal rigidity. KEY POINTS: ⢠Inherited myopathies are rare, diagnosis is challenging and genetic tests require specialized centres and often take years. ⢠Inherited myopathies are often characterized by spinal rigidity. ⢠Whole body magnetic resonance imaging is a unique tool to orientate the diagnosis of each inherited myopathy presenting with spinal rigidity. ⢠Each inherited myopathy in this study has a specific pattern of affected muscles that orientate diagnosis. ⢠A novel MRI-based algorithm, usable by every radiologist, can help the early diagnosis of these myopathies.
Subject(s)
Algorithms , Magnetic Resonance Imaging/methods , Mallory Bodies/pathology , Muscle Rigidity/diagnosis , Muscle, Skeletal/pathology , Muscular Dystrophies/diagnosis , Scoliosis/diagnosis , Whole Body Imaging/methods , Adolescent , Adult , Aged , Child , Child, Preschool , Diagnosis, Differential , Female , Humans , Male , Middle Aged , Muscle Rigidity/etiology , Muscle Rigidity/physiopathology , Muscle, Skeletal/physiopathology , Muscular Dystrophies/physiopathology , Retrospective Studies , Scoliosis/physiopathology , Severity of Illness Index , Young AdultABSTRACT
In the past 15 years, the field of physiology has been radically challenged by landmark studies using novel tools of genetic engineering. Particular to our interest, the reciprocal interactions between the skeleton and the nervous system were shown to be major ones. The demonstration that brain, via multiple pathways, is a powerful regulator of bone growth, has shed light on an important central regulation of skeletal homeostasis. More recently, it was shown that bone might return the favor to the brain through the secretion of a bone-derived hormone, osteocalcin. The skeleton influences development and cognitive functions of the central nervous system at different stages throughout life suggesting an intimate dialogue between bone and brain.
Subject(s)
Bone and Bones/physiology , Brain/physiology , Cell Communication/physiology , Animals , Bone Density/genetics , Bone and Bones/metabolism , Brain/metabolism , Homeostasis/physiology , Humans , Leptin/metabolism , Leptin/physiology , Serotonin/metabolism , Serotonin/physiologyABSTRACT
The demonstration that the skeleton is an endocrine organ has enriched the physiological importance of this tissue and advanced our understanding of whole-organism homeostasis. Moreover, that bone affects powerful regulators of its own physiology such as glucose metabolism, energy expenditure, gonads and brain, reinforced the concept of interdependence between organs. This notion is particularly true for the interplay between bone and gonads. On one hand, gonads are essential for bone growth, maturation and maintenance via the secretion of the sex steroid hormones. On the other hand, bone returns this favor to the gonads, through the secretion of osteocalcin (Ocn), which promotes testosterone biosynthesis following its binding to Gprc6a, a G-protein-coupled receptor. Moreover, that a loss of function mutation in GPRC6A leads to glucose intolerance and male sterility in human, expands the biological relevance of the endocrine role of the skeleton and suggests to some extent its implication in the onset of reproductive and metabolic human diseases.
Subject(s)
Bone Development/physiology , Energy Metabolism/physiology , Gonadal Steroid Hormones/metabolism , Gonads/metabolism , Homeostasis/physiology , Animals , Feedback, Physiological/physiology , Female , Humans , MaleABSTRACT
CIS of the bladder is associated with a high risk of progression. In the case of BCG failure, radical cystectomy should be performed. For patients who refuse or are ineligible, bladder-sparing alternatives are evaluated. This study aims to investigate the efficacy of Hyperthermic IntraVesical Chemotherapy (HIVEC) depending on the presence or absence of CIS. This retrospective, multicenter study was conducted between 2016 and 2021. Patients with non-muscle-invasive bladder cancer (NMIBC) with BCG failure received 6-8 adjuvant instillations of HIVEC. The co-primary endpoints were recurrence-free survival (RFS) and progression-free survival (PFS). A total of 116 consecutive patients met our inclusion criteria of whom 36 had concomitant CIS. The 2-year RFS rate was 19.9% and 43.7% in patients with and without CIS, respectively (p = 0.52). Fifteen patients (12.9%) experienced progression to muscle-invasive bladder cancer with no significant difference between patients with and without CIS (2-year PFS rate = 71.8% vs. 88.8%, p = 0.32). In multivariate analysis, CIS was not a significant prognostic factor in terms of recurrence or progression. In conclusion, CIS may not be considered a contraindication to HIVEC, as there is no significant association between CIS and the risk of progression or recurrence after treatment.
ABSTRACT
TITLE: L'actualité scientifique de ce début 2022 vue par les étudiants de l'AMPS. ABSTRACT: L'AMPS rassemble les étudiants en santé qui, en plus de suivre une formation clinique, se forment à la recherche scientifique dans le but de devenir soignant-chercheurs. Elle promeut les interactions multidisciplinaires entre la santé et les sciences, et permet une émulation scientifique entre les étudiants des différentes facultés, aux profils, compétences et idées variés.
Subject(s)
Biomedical Research , Pharmacy , Students, Medical , Students, Pharmacy , Education, Medical, Graduate , HumansABSTRACT
The osteoblast-derived hormone osteocalcin promotes testosterone biosynthesis in the mouse testis by binding to GPRC6A in Leydig cells. Interestingly, Osteocalcin-deficient mice exhibit increased levels of luteinizing hormone (LH), a pituitary hormone that regulates sex steroid synthesis in the testes. These observations raise the question of whether LH regulates osteocalcin's reproductive effects. Additionally, there is growing evidence that osteocalcin levels are a reliable marker of insulin secretion and sensitivity and circulating levels of testosterone in humans, but the endocrine function of osteocalcin is unclear. Using mouse models, we found that osteocalcin and LH act in 2 parallel pathways and that osteocalcin-stimulated testosterone synthesis is positively regulated by bone resorption and insulin signaling in osteoblasts. To determine the importance of osteocalcin in humans, we analyzed a cohort of patients with primary testicular failure and identified 2 individuals harboring the same heterozygous missense variant in one of the transmembrane domains of GPRC6A, which prevented the receptor from localizing to the cell membrane. This study uncovers the existence of a second endocrine axis that is necessary for optimal male fertility in the mouse and suggests that osteocalcin modulates reproductive function in humans.