Cortical Expansion Research Articles

Mapping developmental regionalization and patterns of cortical surface area from 29 post-menstrual weeks to 2 years of age

Surface area of the human cerebral cortex expands extremely dynamically and regionally heterogeneously from the third trimester of pregnancy to 2 y of age, reflecting the spatial heterogeneity of the underlying microstructural and functional development of the cerebral cortex. However, little is known about the developmental patterns and regionalization of cortical surface area during this critical stage, due to the lack of high-quality imaging data and accurate computational tools for pediatric brain MRI data. To fill this critical knowledge gap, by leveraging 1,037 high-quality MRI scans with the age between 29 post-menstrual weeks and 24 mo from 735 pediatric subjects in two complementary datasets, i.e., the Baby Connectome Project (BCP) and the developing Human Connectome Project (dHCP), and state-of-the-art dedicated image-processing tools, we unprecedentedly parcellate the cerebral cortex into a set of distinct subdivisions purely according to the developmental patterns of the cortical surface. Our discovered developmentally distinct subdivisions correspond well to structurally and functionally meaningful regions and reveal spatially contiguous, hierarchical, and bilaterally symmetric patterns of early cortical surface expansion. We also show that high-order association subdivisions, where cortical folds emerge later during prenatal stages, undergo more dramatic cortical surface expansion during infancy, compared with the central regions, especially the sensorimotor and insula cortices, thus forming a distinct central-pole division in early cortical surface expansion. These results provide an important reference for exploring and understanding dynamic early brain development in health and disease.

Biomechanical characteristics of the ovarian cortex in POI patients and functional outcomes after drug-free IVA.

There is increasing evidence that the ovarian extracellular matrix (ECM) plays a critical role in follicle development. The rigidity of the cortical ECM limits expansion of the follicle and consequently oocyte maturation, maintaining the follicle in its quiescent state. Quiescent primordial, primary, and secondary follicles still exist in primary ovarian insufficiency (POI) patients, and techniques as in vitro activation (IVA) and drug-free IVA have recently been developed aiming to activate these follicles based on the Hippo signaling disruption that is essential in mechanotransduction. In this context, we analyze the effect of drug-free IVA in POI patients, comparing the relationship between possible resumption ovarian function and biomechanical properties of ovarian tissue. Nineteen POI patients according to ESHRE criteria who underwent drug-free IVA by laparoscopy between January 2018 and December 2019 and were followed up for a year after the intervention. A sample of ovarian cortex taken during the intervention was analyzed by atomic force microscopy (AFM) in order to quantitatively measure tissue stiffness (Young's elastic modulus, E) at the micrometer scale. Functional outcomes after drug-free were analyzed. Resumption of ovarian function was observed in 10 patients (52.6%) and two of them became pregnant with live births. There were no differences in clinical characteristics (age and duration of amenorrhea) and basal hormone parameters (FSH and AMH) depending on whether or not there was activation after surgery. However, ovarian cortex stiffness was significantly greater in patients with ovarian activity after drug-free IVA: median E = 5519Pa (2260-11,296) vs 1501 (999-3474); p-value < 0.001. Biomechanical properties of ovarian cortex in POI patients have a great variability, and higher ovarian tissue stiffness entails a more favorable status when drug-free IVA is applied in their treatment. This status is probably related to an ovary with more residual follicles, which would explain a greater possibility of ovarian follicular reactivations after treatment.

Ethylene inhibits rice root elongation in compacted soil via ABA- and auxin-mediated mechanisms.

Soil compaction represents a major agronomic challenge, inhibiting root elongation and impacting crop yields. Roots use ethylene to sense soil compaction as the restricted air space causes this gaseous signal to accumulate around root tips. Ethylene inhibits root elongation and promotes radial expansion in compacted soil, but its mechanistic basis remains unclear. Here, we report that ethylene promotes abscisic acid (ABA) biosynthesis and cortical cell radial expansion. Rice mutants of ABA biosynthetic genes had attenuated cortical cell radial expansion in compacted soil, leading to better penetration. Soil compaction-induced ethylene also up-regulates the auxin biosynthesis gene OsYUC8. Mutants lacking OsYUC8 are better able to penetrate compacted soil. The auxin influx transporter OsAUX1 is also required to mobilize auxin from the root tip to the elongation zone during a root compaction response. Moreover, osaux1 mutants penetrate compacted soil better than the wild-type roots and do not exhibit cortical cell radial expansion. We conclude that ethylene uses auxin and ABA as downstream signals to modify rice root cell elongation and radial expansion, causing root tips to swell and reducing their ability to penetrate compacted soil.

Usage of Guided Bone Regeneration in the Case of Lateral Periodontal Cyst in the Maxilla with Buccal Cortical Expansion

A lateral periodontal cyst (LPC) is a rare finding. Patients diagnosed with LPC younger than 40 years of age are not that common. Mostly asymptomatic LPCs can be discovered on routine radiographs as an oval radiolucency between two mandibular premolar teeth roots and can vary in shape and size. Most cases are treated with enucleation, bone curettage, or a combination of both, greatly depending on the surgeon’s preference. Because most LPCs are quite small, lesions do not require any regenerative procedures. In the presented case, because of cortical expansion of the lesion and loss of vital bone bridge surrounding two adjacent maxillary teeth, a guided bone regenerative procedure (GBR) with xenograft bone substitute was used. Despite that small lesions can heal on their own, nowadays the approach of full-mouth therapy (FMT), including direct soft or hard tissue reconstruction in the oral cavity, seems to be a wise treatment. The presented paper presents and describes an unusual LPC case with cortical bone expansion in a very rare maxillary canine–premolar region.

A miraculous outcome of the conservative treatment of odontogenic keratocyst: A unique case report

Background: The odontogenic keratocyst (OKC), earlier referred as the keratocystic odontogenic tumor, is a distinctive form of developmental odontogenic cyst. OKC is unique because of its distinguishing clinical features, including potentially aggressive behavior, high recurrence rate and an association with the nevoid basal cell carcinoma syndrome. Treatment options includes from conservative approach to extensive surgeries including marsupialization, enucleation or segmental resection. We hereby report a case of a massive OKC of mandible, which was treated conservatively with outstanding results.Methodology: A 27 year old male patient presented with the complaint of swelling of the lower jaw since one year. His past history revealed trauma to the lower jaw due to self fall 15 years ago. Examination revealed a single, well-defined, irregular swelling seen over the lower jaw extending from one angle to the other with both buccal and lingual cortical plate expansion along with egg shell crackling. Radiographical examination revealed unilocular radiolucency extending from one angle to the other with a paper thin lower border. On histopathological examination it was diagnosed as odontogenic keratocyst. The patient was managed with enucleation under local anaesthesia followed up by iodoform dressing every week and Carnoy’s solution application every alternate week.Results: On regular follow up of one year, significant improvement and formation of healthy bone with respect to the cortical plates and floor of the defect was noted.Conclusion: Conservative management with meticulous regular follow ups can successfully manage a massively extensive OKC with overwhelmingly miraculous results.

A central giant cell granuloma in anterior mandible- A case report

Central giant cell granuloma (CGCG) is an uncommon, benign but aggressive osteolytic neoplasm of the craniomaxillofacial region with an unknown etiology. The incidence in the general population is very low with age predilection generally younger than 30 years with a female predominance. CGCG is divided into rare aggressive variant and a common non aggressive variant based on clinicoradiographic features. It is usually unifocal and located at the anterior region of the mandible or maxilla, although are more frequently found in the mandible. A case of a large destructive CGCG involving the entire symphysis of mandible, causing extensive bony resorption, buccal and lingual cortical expansion in a female patient of age 32 years is presented.

Neurotoxicity of phenylalanine on human iPSC-derived cerebral organoids.

Phenylketonuria (PKU) is a common genetic metabolic disorder that causes phenylalanine accumulation in the blood. The most serious symptoms are related to the brain, as intellectual disability, seizure, and microcephaly are commonly found in poorly treated PKU patients and the babies of maternal PKU. However, the mechanism of hyperphenylalaninemia on human neurodevelopment is still unclear. Here we utilized human induced pluripotent stem cell (iPSC)-derived cerebral organoids to investigate the neurotoxicity of hyperphenylalaninemia. Cerebral organoids at days 40 or 100 were treated with different concentrations of phenylalanine for 5 days. After phenylalanine treatments, the cerebral organoids displayed alterations in organoid size, induction of apoptosis, and depletion of neural progenitor cells. However, phenylalanine did not have an impact on neurons and glia, including astrocytes, immature oligodendrocytes, and mature oligodendrocytes. Remarkably, a reduction in the thickness of the cortical rosettes and a decrease in myelination at the intermediate zone were inspected with the elevated phenylalanine concentrations. RNA-seq of phenylalanine-treated organoids revealed that gene sets related to apoptosis, p53 signaling pathway, and TNF signaling pathway via NF-kB were enriched in upregulated genes, while those related to cell cycle and amino acid metabolism were enriched in downregulated genes. In addition, there were several microcephaly disease genes, such as ASPM, LMNB1, and CENPE, ranked at the top of the downregulated genes. These findings indicate that phenylalanine exposure may contribute to microcephaly, abnormal cortical expansion, and myelination lesions in the developing human brain.

Evaluation of advances in cortical development using model systems.

Compared with that of even the closest primates, the human cortex displays a high degree of specialization and expansion that largely emerges developmentally. Although decades of research in the mouse and other model systems has revealed core tenets of cortical development that are well preserved across mammalian species, small deviations in transcription factor expression, novel cell types in primates and/or humans, and unique cortical architecture distinguish the human cortex. Importantly, many of the genes and signaling pathways thought to drive human-specific cortical expansion also leave the brain vulnerable to disease, as the misregulation of these factors is highly correlated with neurodevelopmental and neuropsychiatric disorders. However, creating a comprehensive understanding of human-specific cognition and disease remains challenging. Here, we review key stages of cortical development and highlight known or possible differences between model systems and the developing human brain. By identifying the developmental trajectories that may facilitate uniquely human traits, we highlight open questions in need of approaches to examine these processes in a human context and reveal translatable insights into human developmental disorders.

A synergistic core for human brain evolution and cognition.

How does the organization of neural information processing enable humans' sophisticated cognition? Here we decompose functional interactions between brain regions into synergistic and redundant components, revealing their distinct information-processing roles. Combining functional and structural neuroimaging with meta-analytic results, we demonstrate that redundant interactions are predominantly associated with structurally coupled, modular sensorimotor processing. Synergistic interactions instead support integrative processes and complex cognition across higher-order brain networks. The human brain leverages synergistic information to a greater extent than nonhuman primates, with high-synergy association cortices exhibiting the highest degree of evolutionary cortical expansion. Synaptic density mapping from positron emission tomography and convergent molecular and metabolic evidence demonstrate that synergistic interactions are supported by receptor diversity and human-accelerated genes underpinning synaptic function. This information-resolved approach provides analytic tools to disentangle information integration from coupling, enabling richer, more accurate interpretations of functional connectivity, and illuminating how the human neurocognitive architecture navigates the trade-off between robustness and integration.

Clinicoradiological spectrum of primary aneurysmal bone cysts of the maxillofacial region: A series of 31 cases.

The aim of the current study was to analyse the demographic, clinical and radiological features of primary aneurysmal bone cysts (ABCs) involving the maxillofacial region. Histologically confirmed cases affecting the maxillofacial region were retrospectively reviewed over a 21-year period (2000-2021). Cases were collected from the archives of five Oral Pathology laboratories from three countries: South Africa, Guatemala and Brazil. The information was analysed, with emphasis on the clinical and radiological spectrum. Following the inclusion criteria, a total of 31 cases of primary ABCs were included in the study. A nearly equal male-to-female distribution was seen, with ABCs occurring in males at an earlier age compared to females. Localised swelling was the main clinical presentation. ABCs had a mandibular predominance, particularly in the posterior regions. All ABCs presented as blow-out expansile well-demarcated radiolucent lesions with the majority having a multilocular appearance. Cortical expansion was seen in 91% of cases with loss of cortical integrity being common (78%). Primary ABCs involving the maxillofacial region are extremely rare with the majority of current published literature consisting of isolated case reports. The current study is the first large series detailing the radiological features.

Progenitor-Based Cell Biological Aspects of Neocortex Development and Evolution.

During development, the decision of stem and progenitor cells to switch from proliferation to differentiation is of critical importance for the overall size of an organ. Too early a switch will deplete the stem/progenitor cell pool, and too late a switch will not generate the required differentiated cell types. With a focus on the developing neocortex, a six-layered structure constituting the major part of the cerebral cortex in mammals, we discuss here the cell biological features that are crucial to ensure the appropriate proliferation vs. differentiation decision in the neural progenitor cells. In the last two decades, the neural progenitor cells giving rise to the diverse types of neurons that function in the neocortex have been intensely investigated for their role in cortical expansion and gyrification. In this review, we will first describe these different progenitor types and their diversity. We will then review the various cell biological features associated with the cell fate decisions of these progenitor cells, with emphasis on the role of the radial processes emanating from these progenitor cells. We will also discuss the species-specific differences in these cell biological features that have allowed for the evolutionary expansion of the neocortex in humans. Finally, we will discuss the emerging role of cell cycle parameters in neocortical expansion.

Conservative Management of Unicystic Ameloblastoma- A Case Report

Ameloblastoma is the most common benign odontogenic tumor of the jaws that constitutes about 1% of all cysts and tumors of the jaws1,2. It is generally a painless, slow growing, locally aggressive tumor causing expansion of the cortical bone, perforation of the lingual or the buccal cortical plate and infiltration to the soft tissues. It has peak incidence in third and fourth decade of life but can be found in any age group with equal gender predilection (1:1)1,5. The relative frequency of mandible to maxilla is reported to be varying from 80% -20% to 99–1%. In the mandible majority of Ameloblastoma are found in the molar ramus region1,3. In a conventional radiograph, Ameloblastoma can present as either unilocular or multilocular corticated radiolucency. The bony septae results in a honey comb, soap bubble or tennis racket appearance. In some places, cortical plates are spared and expanded where as in other region they are destroyed; root resorption is a common finding6. Buccal and lingual cortical plate expansion is more common in Ameloblastoma than in other tumour7. Conventional radiograph is sufficient for small mandibular lesions but maxillary lesions and extensive lesions require CBCT, CT and MRI to establish the extent of the lesion7. The challenge in managing Ameloblastoma is by attaining complete excision and reconstruction of the defect when the tumor is large. Ameloblastoma is treated by enucleation, curettage or surgical excision depending on size and type of the lesion and conservative therapy also.&#x0D; This report gives a comprehensive knowledge regarding the conservative therapy using a Iodoform and paraffin paste which has been a boon in treatment of odontogenic tumor.

A SINGLE-CENTER CASE SERIES OF ORAL CAVITY SARCOMAS

<h3>Introduction</h3> Oral cavity sarcomas are rare and account for 1% of all malignancies in this site. This study aims to evaluate the prevalence, variety and distribution of soft tissue and gnathic sarcoma in the oral cavity. <h3>Methods</h3> An IRB approved retrospective review encompassing years 2010-2020 of the University of Florida Oral Pathology Biopsy Service was performed. All histologically proven sarcomas occurring in the oral and maxillofacial area were retrieved. Demographics, clinical data, immunohistochemical analysis, and microscopic diagnoses were recorded and analyzed. <h3>Results</h3> A total of 34 oral sarcomas were identified. The most prevalent were osteosarcoma (10 cases; 29.4%) followed by Kaposi sarcoma (9 cases; 26.4%) followed by undifferentiated sarcoma (3 cases; 8.8%). Three cases were unclassifiable due to lack of evidence of any specific lineage. Additional examples of sarcoma included; angiosarcoma, synovial sarcoma, low grade myxofibrosarcoma, rhabdomyosarcoma and chondrosarcoma. Molecular testing was performed on two cases. Age range was 11 to 82 (mean 42.35 years). Males were more affected than females (73.5% and 26.5% respectively). Central lesions accounted for 58.8% of the cases and 41.2 % were soft tissue sarcoma. All patients presented with primary tumors. The most commonly affected sites were mandible (13 cases; 65%), maxilla (11 cases; 32.4%), and tongue (4 cases; 11.8%). Malignant neoplasm was the most common reported clinical impression by submitting clinicians (18 cases; 52.9%). Lesion evolution time ranged from 3 weeks to one year. The most commonly reported symptoms with soft tissue tumors were localized pain, swelling, and bleeding. Most of the central lesions were radiolucent and caused cortical expansion. <h3>Conclusion</h3> Oral cavity sarcomas are rare neoplasms; however, they should be considered in the differential diagnosis whenever a large expansile, destructive, ill-defined or rapidly growing lesion is seen in a relatively young individual or paresthesia is reported.

Central xanthoma of the mandible in a 12-year-old boy

Xanthomas are benign proliferations of lipid-laden macrophages that most often affect the skin and extensor ten- dons. The majority of lesions occur in the setting of systemic conditions associated with altered lipid metabolism, such as hyperlipidemia and diabetes mellitus. Intraosseous xanthomas are uncommon and can affect both the axial and appendicular skeleton. We describe a 12-year-old boy who presented with a large unilocular radiolucency of the right posterior mandible pericoronal to an impacted third molar. Intraoral examination revealed no mucosal abnormalities or evidence of cortical expansion. The lesion was completely enucleated and microscopic exami- nation showed a proliferation of large cells with abundant foamy to eosinophilic, granular cytoplasm, varying in distribution from loose sheets to compact clusters with minimal intervening fibrous connective tissue. The lesional cells demonstrated strong and diffuse reactivity with CD68, favoring a non-Langerhans cell histiocytic process and supporting a diagnosis of central xanthoma. Subsequent medical evaluation was negative for lipid abnormalities, endocrinopathies, and lipidoses. Gnathic xanthomas are exceedingly rare with less than 40 cases reported to date. Lesions have a strong predilection for the mandible and most frequently present as unilocular radiolucencies with no significant symptoms. Diagnosis can be challenging due to their nonspecific clinicoradiographic presentation and microscopic overlap with other histiocytic processes. Treatment consists of thorough curettage and recurrences are uncommon, especially in the absence of systemic manifestations. Although rare, recognition of this entity is of clinical interest as lesions that precede the diagnosis of a dyslipidemia or lipidosis may serve as a harbinger of un- derlying disease.

Three Cases of Central Xanthoma of the Jaws with Review of Literature

<h3>Background</h3> Extragnathic xanthomas are rare benign tumors associated with excess lipid production. Its gnathic counterpart was first reported in 1964. Only 45 cases of central xanthoma of jaw (CXJ) have been reported in the English literature. The etiopathogenesis of CXJ is highly suggestive of a reactive process or a metabolic condition. <h3>Materials</h3> Three cases of CXJ were identified from the UF Oral Pathology Biopsy archives. Clinical, radiographic and histopathologic features of all the cases were retrospectively analyzed. Immunohistochemical (IHC) stains for S100 and CD68 were performed. <h3>Case Series</h3> All cases of CXJ involved younger females and incidental lesions discovered during routine radiographic examination. The first patient, a 36-year-old female presented with an asymptomatic swelling and cortical expansion of the mandible adjacent to tooth #31. The second patient was a 13year-old female with an asymptomatic expansion in the left mandibular ramus. Lastly, a 15-year-old female with dull pain exhibited mild buccal and lingual bony expansion of the right mandible apical to tooth #18. Radiographically, two of the cases presented as multilocular radiolucent lesions and one demonstrated as a well-circumscribed unilocular radiolucency intermixed with radiopacities. All three lesions were treated with surgical curettage and no recurrence at one-year follow up. All cases exhibited sheets of foamy macrophages similar to other lytic xanthomatous lesions such as non-ossifying fibroma, benign fibrous histiocytoma, Rosai-Dorfman disease, Erdheim disease, Gaucher disease, etc. A diagnosis of CXJ was established by exclusion and involved careful correlation of the clinical, radiographic, histopathological and IHC features. All three cases revealed diffuse positivity for CD68 and were negative for S100. <h3>Conclusion</h3> CXJ are rare gnathic lesions of unknown etiology. We highlight three rare cases of CXJ, a lesion that may mimic other benign or reactive jaw lesions especially in young patients.

THREE CASES OF AMELOBLASTIC CARCINOMA WITH REVIEW OF CLINICAL, RADIOGRAPHIC AND HISTOPATHOLOGIC FEATURES

<h3>Introduction</h3> Ameloblastic carcinoma (AC) is a rare malignant primary epithelial odontogenic tumor demonstrat- ing histologic features of ameloblastoma with signs of overt malignancy. In this case series, we describe the clinical, radiographic and histologic features of 3 cases of AC. <h3>Methods</h3> Three cases of AC were identified from the University of Florida Oral Pathology Biopsy archives. Clinical data and original slides were retrospectively analyzed. Immuno- histochemical (IHC) stains for cytokeratin 19 (CK19) was performed on all cases to demonstrate odontogenic epithe- lial origin. <h3>Results</h3> All cases of AC in this series occurred in elderly males, with two presenting in the mandible and one in maxilla. Radiographically, all presented as ill-defined radiolucencies and demonstrated cortical expansion, consistent with features of malignancy. The first case involved a 60-year-old male with an erosive soft tissue mass along the anterior mandible between teeth #27 and #28 and corresponding radiolucent lesion on films. The second case occurred in a 75-year-old male presenting with gingival swelling and an expansile radiolucent lesion in the right maxilla, extending from tooth #3 to #7. The third case was seen in a 75-year-old male displaying a large oste- olytic lesion of the mandibular ramus surrounded by a bulky soft tissue mass extending deep into the right lateral and medial pterygoid muscles. Histologically, all cases revealed large sheets of interconnecting islands and strands of malignant cells displaying peripheral palisading, reverse nuclear polarity and apical vacuolization. In addition, the malignant islands exhibited central necrosis and neoplastic cells showed significant hyperchromatism with nu- clear pleomorphism. IHC staining with CK19 were strongly positive in two cases and focally positive in one case. <h3>Conclusion</h3> This case series documents 3 cases of a rare odontogenic malignancy and highlights the importance of including this entity in a differential diagnosis of aggressive lesions of the jaws, especially in older patients.

Focal Osteoporotic Marrow Defects – Variant of Chronic Ischemic Bone Disease? Clinicopathology Review of 596 Cases

<h3>Background</h3> Focal Osteoporotic Marrow Defects (FOMD) presents as a localized, asymptomatic, poorly-demarcated radiolucency, considered by some as a variant of normal marrow architecture. The cause of this lesion is unknown but recent examples of ischemiarelated regional osteoporosis in long bones suggest an anoxic or ischemic origin. <h3>Objective</h3> To determine the proportion of FOMD lesions showing histopathologic evidence of ischemic marrow disease. Methods: 596 intramedullary tissue samples of microscopically diagnosed FOMD were reviewed for fea- tures of regional ischemic osteoporosis. Microscopic criteria characteristic for early ischemic changes in long bones were used to compare with findings in jawbone biopsy samples of FOMD. Clinical features and patient demograph- ics were also analyzed. Results: 74% of 581 patients were female and the average age at diagnosis was 49 years. Lesions were evenly distributed between the jaws and 79% were in the retromolar/third molar area. 92% were in edentulous bone, and 77% were in old extraction sites; 3% of cases were bilateral and 30% were tender or painful. The average lesion size was 1.2 cm (range: 0.52.8 cm.) and none showed cortical expansion. 76% of FOMD lesions were comprised primarily of fatty marrow, and 88% of the total showed microscopic features of ischemic marrow damage consistent with those found in regional osteoporosis of the long bones; 9% demonstrated intravascular thrombi. Differences were found between hematopoietic and fatty FOMD lesions. <h3>Conclusions</h3> The FOMD lesion appears to be the jawbone variant of regional osteoporosis of long bones, i.e. is an ischemic phenomenon perpet- uated by compromised marrow blood flow. There are 2 subtypes of FOMD: the fatty marrow type and the less common hematopoietic marrow type; fatty lesions are much more likely to be in the maxilla, to be in males, and to be associated with pain.

Cortical porosity development and progression is mitigated after etelcalcetide treatment in an animal model of chronic kidney disease.

Chronic kidney disease (CKD) leads to increased bone fragility and risk of fracture. Cortical deteriorations, including cortical porosity, are key factors in fracture susceptibility in CKD. Since secondary hyperparathyroidism is common in CKD individuals and contributes to cortical deterioration, we hypothesized that reducing parathyroid hormone (PTH) may modulate CKD-induced cortical porosity. The goal of this pilot study was to assess the effects of lowering PTH, via the preclinical analogue of the FDA-approved calcimimetic etelcalcetide (KP-2326), on the development and progression of cortical pores in the setting of CKD. Male Cy/+ Sprague Dawley rats with clinical biochemistries consistent with CKD (N=8) were assigned to the study. At 30-32weeks of age, cortical bone was assessed via In vivo μCT and blood collected for biochemistries to create baseline measures. Calcimimetic treatment with KP-2326 (KP) was then administered 3× weekly for 2-4weeks. Cortical bone and biochemical parameters were repeated at study endpoint (33-37 wks of age). A group of age- and cohort-matched CKD rats (N=4) were utilized as untreated controls. Untreated CKD rats had significantly increased cortical porosity over time, while porosity in KP-treated CKD rats was not significantly changed over time. Individual pore analysis revealed that pore area was significantly higher for expanding pores in untreated CKD rats compared to KP-treated CKD rats. Mechanical properties of KP-treated animal femora were similar to historical values of age-matched CKD animals and lower than those of age-matched non-diseased animals. Our pilot preclinical study demonstrates that etelcalcetide treatment can mitigate the progression of cortical bone changes in an animal model of CKD through suppression of pre-existing cortical pore expansion and limiting the size of new pore development. While stabilization of porosity is beneficial it remains likely that infilling of porosity will be needed to positively affect mechanical properties of bones in the setting of CKD.

Callosal Fiber Length Scales with Brain Size According to Functional Lateralization, Evolution, and Development.

Brain size significantly impacts the organization of white matter fibers. Fiber length scaling, the degree to which fiber length varies according to brain size, was overlooked. We investigated how fiber lengths within the corpus callosum, the most prominent white matter tract, vary according to brain size. The results showed substantial variation in length scaling among callosal fibers, replicated in two large healthy cohorts (∼2000 human subjects, including both sexes). The underscaled callosal fibers mainly connected the precentral gyrus and parietal cortices, whereas the overscaled callosal fibers mainly connected the prefrontal cortices. The variation in such length scaling was biologically meaningful: larger scaling corresponded to larger neurite density index but smaller fractional anisotropy values; cortical regions connected by the callosal fibers with larger scaling were more lateralized functionally as well as phylogenetically and ontogenetically more recent than their counterparts. These findings highlight an interaction between interhemispheric communication and organizational and adaptive principles underlying brain development and evolution.SIGNIFICANCE STATEMENT Brain size varies across evolution, development, and individuals. Relative to small brains, the neural fiber length in large brains is inevitably increased, but the degree of such increase may differ between fiber tracts. Such a difference, if it exists, is valuable for understanding adaptive neural principles in large versus small brains during evolution and development. The present study showed a substantial difference in the length increase between the callosal fibers that connect the two hemispheres, replicated in two large healthy cohorts. Together, our study demonstrates that reorganization of interhemispheric fibers length according to brain size is intrinsically related to fiber composition, functional lateralization, cortical myelin content, and evolutionary and developmental expansion.

Sfrp4 and the Biology of Cortical Bone.

Periosteal apposition and endosteal remodeling regulate cortical bone expansion and thickness, both critical determinants of bone strength. Yet, the cellular characteristics and local or paracrine factors that regulate the periosteum and endosteum remain largely elusive. Here we discuss novel insights in cortical bone growth, expansion, and homeostasis, provided by the study of Secreted Frizzled Receptor Protein 4 (Sfrp4), a decoy receptor for Wnt ligands. SFRP4 loss-of function mutations cause Pyle disease, a rare skeletal disorder characterized by cortical bone thinning and increased fragility fractures despite increased trabecular bone density. On the endosteal surface, Sfrp4-mediated repression of non-canonical Wnt signaling regulates endosteal resorption. On the periosteum, Sfrp4 identifies as a critical functional mediator of periosteal stem cell/progenitor expansion and differentiation. Analysis of signaling pathways regulating skeletal stem cells/progenitors provides an opportunity to advance our understanding of the mechanisms involved in cortical bone biology.