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Articular Cartilage Development
Published in Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi, Articular Cartilage, 2017
Kyriacos A. Athanasiou, Eric M. Darling, Grayson D. DuRaine, Jerry C. Hu, A. Hari Reddi
Initiation of the forelimbs and hindlimbs is controlled by expression of different T-box (Tbx) DNA binding domain-containing transcription factors. Based on initial overexpression models, Tbx4 and 5 were thought to regulate forelimb and hindlimb discrimination, as the expression of tbx genes 5 and 4 differs, respectively, between forelimbs and hindlimbs. However, these have been reclassed as limb initiators, not as determiners of forelimb or hindlimb (Minguillon et al. 2005). Instead, induction of morphology specific to the hindlimb has been supported as a role for Pitx1 (DeLaurier et al. 2006). Interestingly, although the molecular components and steps of limb bud initiation are similar between eutherian (placental) and marsupial mammals, the forelimb initiation and subsequent development occur at a much earlier developmental stage, enabling ex utero migration of the joey to the pouch (Keyte and Smith 2010). A rough timeline of limb and cartilage formation is depicted in Figure 2.8.
The respiratory system
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Pulmonary hypertension is defined as a mean pulmonary arterial pressure of greater than 25 mm Hg at rest. There are a number of underlying causes, and the WHO classifies pulmonary hypertension into 5 groups. 1. Pulmonary arterial hypertension (PAH) (including familial, drug/toxin and connective tissue disorder (CTD) related, pulmonary veno-occlusive disease and pulmonary capillary haemangiomatosis) 2. Pulmonary hypertension due to left heart failure (congenital and acquired) 3. Pulmonary hypertension secondary to chronic hypoxia and/or parenchymal lung disease, 4. Chronic thromboembolic pulmonary hypertension and 5. Pulmonary hypertension due to blood and other disorders. Common to many of these causes is chronic vasoconstriction, luminal obstruction, damage and/or remodelling of the pulmonary vasculature (Figure 8.28). In some cases there is a genetic component with mutations in certain genes causing or increasing the likelihood of developing PAH. Some familial cases are associated with mutations in Bone Morphogenic Protein Receptor 2 (BMPR2). These show incomplete penetrance, with only 10%–20% of family members with the mutation developing disease. The exact pathogenesis is unclear, but the BMP-BMPR2 signal pathway is important in cell apoptosis, proliferation, and differentiation. It is thought mutations in this gene result in vascular remodelling in small vessels leading to increased pulmonary arterial pressure. Cases of hereditary PAH are rare and over 350 mutations in the BMPR2 gene have been identified. Other genes less commonly associated with hereditary PAH include BMPR1B, CAV1, KCNK3, SMAD9 and TBX4. Gene mutations are also seen in some sporadic cases of PAH. Prolonged rises in pulmonary arterial or venous pressure produces morphological vascular changes, which often include thickening of the media and intima. Patients present late in the course of disease with chronic worsening dyspnoea, fatigue, and reduced exercise tolerance. The mortality is high with the development of right sided heart failure (cor pulmonale) and secondary infection, and 80% of patients die within 5 years.
Epidemiology of clubfoot
Published in R. L. Mittal, Clubfoot, 2018
Dobbs and Gurnett9 in a comprehensive review of literature, have reported that, besides the common isolated variety of clubfoot, 20% of clubfoot cases are syndromic and are associated with arthrogryposis multiplex, congenital myotonic dystrophy, myelomeningocele, amniotic bands, or other genetic syndromes such as trisomy 18 or chromosome 22q11 deletion syndrome. They further reported many theories in clubfoot pathogenesis: anatomical abnormalities like intrauterine immobility, neurological conditions, and connective tissue fibrosis. Vascular anomalies are very commonly seen, mostly anterior tibial artery hypoplasia. Unilateral clubfoot is associated with a thinner calf as compared to the unaffected limb, but with normal electrophysiological studies of muscles and nerves, and histological muscle biopsies on the clubfoot side show only nonspecific abnormalities. Leg-length discrepancy may also be present in clubfoot. These widespread variations suggest that clubfoot is either heterogenous or due to a single primary cause leading to all of these abnormalities of tissues. The authors have tried to explain pathogenesis of clubfoot on a genetic basis, giving many reasons. In isolated clubfoot: firstly, 25% of all isolated clubfoot cases report a positive familial incidence; secondly, a higher concordance rate in identical twins than fraternal twins (33% versus 3%); and thirdly: variation in the prevalence rate in different ethnic populations. They point out that isolated clubfoot is more likely to be due to multiple factors and/or polygenic. It is unlikely to be due to mutation of a single gene because there is sex affliction discrepancy, with males affected much more commonly than females; in the absence of sex-linked inheritance. A polygenic inheritance with such a sex difference explains this, which is further supported by demonstration of the Carter effect, that is, the less commonly affected sex, that is, females, carry a greater number of susceptible genes than males and are more likely to transmit clubfoot. They also found from many recent studies that there is a key transcriptional pathway, the PITX1-TBX4 in clubfoot etiology, and both PITX1 and TBX4 are expressed specifically in lower limbs, with foot as phenotype along with mutations in these transcriptional factors. The exact mechanisms of these genetic abnormalities producing clubfoot are yet to be investigated, including many other hypotheses regarding its pathogenesis.
A Fetus with 17q23.1-q23.2 Microdeletion Presents with Primary Bilateral Lung Hypoplasia in Utero
Published in Fetal and Pediatric Pathology, 2023
Longmei Yao, Yan Xu, Yan Deng, Shi Zeng
Primary lung hypoplasia an infrequent cause of lung hypoplasia, and carries a poor prognosis, especially when bilateral, and no fetus with known outcome has survived with marked primary bilateral lung hypoplasia. Primary lung hypoplasia with chromosome 17q23.1-q23.2 microdeletion can be detected during fetal life. The underlying correlation between 17q23.1-q23.2 deletion and PLH may involve T-box genes. Recently, Karolak JA et al detected a heterozygous recurrent ∼2.2 Mb copy-number variant deletion on 17q23.1-q23.2 involving TBX2 and TBX4 in 7/26 neonatal lethal lung maldevelopment [5]. Both in vitro and in vivo observations showed that depletion of TBX4 and TBX2 as well as lower expression of T-box gene products could result in a reduction in lung branching and perturbation of lung organogenesis through various pathways [5–7].
Magnetic resonance imaging—transrectal ultrasound image fusion guidance of prostate biopsies: current status, challenges and future perspectives
Published in Scandinavian Journal of Urology, 2019
Another major challenge is that the definition of sPCa traditionally is based on TRUSbx findings and clinical parameters. However, with the introduction of mpMRI, the biopsies are now aimed and targeted directly at highly suspicious lesions. Consequently, TBx frequently demonstrate longer cancer-core length, higher ratio of positive vs negative cores and higher GS compared with TRUSbx cores. Therefore, we cannot directly apply TBx results into currently available predictive nomograms and risk calculators which are based solely on TRUSbx findings with its inherent limitations. A clear consensus for defining sPCa in mpMRI-biopsy studies is urgently needed to allow interstudy comparisons and develop redefined risk calculators that include results from additional TBx and mpMRI findings.
Hypoparathyroidism concomitant with macrothrombocytopenia in an elderly woman with 22q11.2 deletion syndrome
Published in Platelets, 2018
Hsiu-Chien Yang, Shih-Hua Lin, Yi-Ying Wu, Chih-Chien Sung
Numerous candidate genes have been linked to the different phenotype of 22q11.2DS. In 1999, TBX-1, a member of the T-box transcription factor family, was identified as one of the most vital gene controlling pharyngeal arch development. Therefore, haploinsufficiency in TBX1 compromises facial structure, parathyroid, and thymus development (1,3,7). In two studies, parathyroid hypoplasia associated with hypocalcaemia was found in approximately 50% of 22q11.2DS cases, typically in pediatric patients (1,3). However, 22q11.2DS may remain undiagnosed in adults because they may lack severe phenotypic features (8,9). A late-onset symptomatic hypocalcemia can be caused by increased calcium requirements with inadequate parathyroid hormone secretion (during adolescence, pregnancy, infection, or surgery) (10–12). Alternatively, the aging process and chronic kidney disease could aggravate hypocalcemia symptoms because of vitamin D deficiency. In this case, hypocalcemia symptoms exacerbated by chronic kidney disease and aging might be presented in the elderly life without cardiovascular abnormalities.