Embryology of the upper limb

Mapping Intimacies ◽

10.1093/med/9780199682874.003.0158 ◽

2021 ◽

pp. 523-532

Author(s):

Wee-Leon Lam ◽

Megan G. Davey

Keyword(s):

Bone Morphogenetic Proteins ◽

Upper Limb ◽

Limb Development ◽

Rapid Progression ◽

Research Technology ◽

Gli Transcription Factors ◽

Molecular Anatomy ◽

Zone Of Polarizing Activity ◽

Clinical Conditions

Recent advances in research technology have allowed a rapid progression in the understanding of upper limb embryogenesis. Limb development occurs between 4 and 8 weeks of gestation and progresses along three axes, as controlled by three centres: proximal–distal by the apical ectodermal ridge, anterior–posterior by the zone of polarizing activity, and dorsal–ventral by the dorsal ectoderm. In addition, research into molecular anatomy has revealed the central role of the sonic hedgehog protein and the complex interconnections linking all three axes of development. Despite these advances in understanding normal limb development, the field of pathembryogenesis remained limited. Recent discoveries about the roles of HOX and TBX genes, as well as bone morphogenetic proteins and GLI transcription factors, have allowed important insights into the causations of common clinical conditions. This expanding field of knowledge has facilitated the establishment of a new classification system based entirely on embryogenesis, which should catalyse closer surgeon/scientist collaborations.

Download Full-text

Retinoic acid signaling is required during early chick limb development

Development ◽

10.1242/dev.122.5.1385 ◽

1996 ◽

Vol 122 (5) ◽

pp. 1385-1394 ◽

Cited By ~ 10

Author(s):

J.A. Helms ◽

C.H. Kim ◽

G. Eichele ◽

C. Thaller

Keyword(s):

Retinoic Acid ◽

Limb Development ◽

Acid Synthesis ◽

Apical Ectodermal Ridge ◽

Limb Bud ◽

Retinoid Receptor ◽

Limb Morphogenesis ◽

Wing Bud ◽

Zone Of Polarizing Activity

In the chick limb bud, the zone of polarizing activity controls limb patterning along the anteroposterior and proximodistal axes. Since retinoic acid can induce ectopic polarizing activity, we examined whether this molecule plays a role in the establishment of the endogenous zone of polarizing activity. Grafts of wing bud mesenchyme treated with physiologic doses of retinoic acid had weak polarizing activity but inclusion of a retinoic acid-exposed apical ectodermal ridge or of prospective wing bud ectoderm evoked strong polarizing activity. Likewise, polarizing activity of prospective wing mesenchyme was markedly enhanced by co-grafting either a retinoic acid-exposed apical ectodermal ridge or ectoderm from the wing region. This equivalence of ectoderm-mesenchyme interactions required for the establishment of polarizing activity in retinoic acid-treated wing buds and in prospective wing tissue, suggests a role of retinoic acid in the establishment of the zone of polarizing activity. We found that prospective wing bud tissue is a high-point of retinoic acid synthesis. Furthermore, retinoid receptor-specific antagonists blocked limb morphogenesis and down-regulated a polarizing signal, sonic hedgehog. Limb agenesis was reversed when antagonist-exposed wing buds were treated with retinoic acid. Our results demonstrate a role of retinoic acid in the establishment of the endogenous zone of polarizing activity.

Download Full-text

Involvement of T-box genes Tbx2-Tbx5 in vertebrate limb specification and development

Development ◽

10.1242/dev.125.13.2499 ◽

1998 ◽

Vol 125 (13) ◽

pp. 2499-2509 ◽

Cited By ~ 14

Author(s):

J.J. Gibson-Brown ◽

S.I. Agulnik ◽

L.M. Silver ◽

L. Niswander ◽

V.E. Papaioannou

Keyword(s):

Gene Expression ◽

Limb Development ◽

T Box ◽

Cell Pellet ◽

Wing Bud ◽

Zone Of Polarizing Activity ◽

The Relationship ◽

Tbx2 Expression ◽

Limb Specification

We have recently shown in mice that four members of the T-box family of transcription factors (Tbx2-Tbx5) are expressed in developing limb buds, and that expression of two of these genes, Tbx4 and Tbx5, is primarily restricted to the developing hindlimbs and forelimbs, respectively. In this report, we investigate the role of these genes in limb specification and development, using the chick as a model system. We induced the formation of ectopic limbs in the flank of chick embryos to examine the relationship between the identity of the limb-specific T-box genes being expressed and the identity of limb structures that subsequently develop. We found that, whereas bud regions expressing Tbx4 developed characteristic leg structures, regions expressing Tbx5 developed characteristic wing features. In addition, heterotopic grafts of limb mesenchyme (wing bud into leg bud, and vice versa), which are known to retain the identity of the donor tissue after transplantation, retained autonomous expression of the appropriate, limb-specific T-box gene, with no evidence of regulation by the host bud. Thus there is a direct relationship between the identity of the structures that develop in normal, ectopic and recombinant limbs, and the identity of the T-box gene(s) being expressed. To investigate the regulation of T-box gene expression during limb development, we employed several other embryological manipulations. By surgically removing the apical ectodermal ridge (AER) from either wing or leg buds, we found that, in contrast to all other genes implicated in the patterning of developing appendages, maintenance of T-box gene expression is not dependent on the continued provision of signals from the AER or the zone of polarizing activity (ZPA). By generating an ectopic ZPA, by grafting a sonic hedgehog (SHH)-expressing cell pellet under the anterior AER, we found that Tbx2 expression can lie downstream of SHH. Finally, by grafting a SHH-expressing cell pellet to the anterior margin of a bud from which the AER had been removed, we found that Tbx2 may be a direct, short-range target of SHH. Our findings suggest that these genes are intimately involved in limb development and the specification of limb identity, and a new model for the evolution of vertebrate appendages is proposed.

Download Full-text

Management of Pleural Effusions in the Emergency Department.

Reviews on Recent Clinical Trials ◽

10.2174/1574887115666200624194457 ◽

2020 ◽

Vol 15 ◽

Author(s):

MT Congedo ◽

GM Ferretti ◽

D Nachira ◽

MA Pennisi

Keyword(s):

Emergency Department ◽

Systematic Approach ◽

Acute Chest Pain ◽

Pleural Effusions ◽

Therapeutic Approaches ◽

Massive Pleural Effusion ◽

Emergency Department Setting ◽

Clinical Conditions ◽

Definitive Management

Background: In symptomatic patients, admitted in emergency department for acute chest pain and dyspnea, who require an urgent treatment, a rapid diagnosis and prompt management of massive pleural effusion or hemothorax can be lifesaving. The aim of this review was to summarize the current diagnostic and therapeutic approaches for the management of the main types of pleural effusions that physicians can have in an emergency department setting. Methods: Current literature about the topic was reviewed and critically reported, adding the experience of the authors in the management of pleural effusions in emergency settings. Results: The paper analyzed the main types of pleural effusions that physicians can have to treat. It illustrated the diagnostic steps by the principal radiological instruments, with a particular emphasis to the role of ultrasonography, in facilitating diagnosis and guiding invasive procedures. Then, the principal procedures, like thoracentesis and insertion of small and large bore chest drains, are indicated and illustrated according to the characteristics and the amount of the effusion and patient clinical conditions. Conclusion: The emergency physician must have a systematic approach that allows rapid recognition, clinical cause identification and definitive management of potential urgent pleural effusions.

Download Full-text

The Role of BMP Signaling in Osteoclast Regulation

Journal of Developmental Biology ◽

10.3390/jdb9030024 ◽

2021 ◽

Vol 9 (3) ◽

pp. 24

Author(s):

Brian Heubel ◽

Anja Nohe

Keyword(s):

Bone Formation ◽

Bone Morphogenetic Proteins ◽

Bone Diseases ◽

Bmp Signaling ◽

Bone Homeostasis ◽

Direct Stimulation ◽

Federal Drug Administration ◽

Bmp Pathway ◽

Stimulation Of

The osteogenic effects of Bone Morphogenetic Proteins (BMPs) were delineated in 1965 when Urist et al. showed that BMPs could induce ectopic bone formation. In subsequent decades, the effects of BMPs on bone formation and maintenance were established. BMPs induce proliferation in osteoprogenitor cells and increase mineralization activity in osteoblasts. The role of BMPs in bone homeostasis and repair led to the approval of BMP2 by the Federal Drug Administration (FDA) for anterior lumbar interbody fusion (ALIF) to increase the bone formation in the treated area. However, the use of BMP2 for treatment of degenerative bone diseases such as osteoporosis is still uncertain as patients treated with BMP2 results in the stimulation of not only osteoblast mineralization, but also osteoclast absorption, leading to early bone graft subsidence. The increase in absorption activity is the result of direct stimulation of osteoclasts by BMP2 working synergistically with the RANK signaling pathway. The dual effect of BMPs on bone resorption and mineralization highlights the essential role of BMP-signaling in bone homeostasis, making it a putative therapeutic target for diseases like osteoporosis. Before the BMP pathway can be utilized in the treatment of osteoporosis a better understanding of how BMP-signaling regulates osteoclasts must be established.

Download Full-text

Parental perspective: The role of prostheses and prosthetics services in adjusting to a child’s upper limb difference

Technology and Disability ◽

10.3233/tad-200300 ◽

2020 ◽

pp. 1-7

Author(s):

Tara Sims

Keyword(s):

Coping Strategies ◽

Peer Support ◽

Upper Limb ◽

Family Members ◽

Parental Adjustment ◽

Prosthetic Devices ◽

The Family ◽

The Impact

BACKGROUND: The impact of paediatric upper limb difference may extend beyond the child themselves to their parents and other family members. Previous research has found that feelings of shock, numbness and loss are common amongst parents and that peer support can be a buffer against stress. OBJECTIVE: The current study aimed to explore the experiences of parents of children with limb difference, and the role of services and prosthetic devices in these experiences. METHODS: Nine parents of children with limb difference participated in either a group (n= 2) or individual (n= 7) interview. RESULTS: Analysis of the interview transcripts revealed four themes – ‘grief and guilt’, ‘prosthesis as a tool for parental adjustment’, ‘support’ and ‘fun and humour’. CONCLUSIONS: Parents may employ coping strategies to help them adjust to their child’s limb difference, including use of a prosthesis, accessing support from statutory services and peers, and use of fun and humour within the family.

Download Full-text

Role of Multiple Comorbidities and Therapies in Conditioning the Clinical Severity of DRESS: A Mono-Center Retrospective Study of 25 Cases

International Journal of Molecular Sciences ◽

10.3390/ijms22137072 ◽

2021 ◽

Vol 22 (13) ◽

pp. 7072

Author(s):

Andrea Toniato ◽

Chiara Gamba ◽

Jan Walter Schroeder ◽

Valeria Fabbri ◽

Scarlett Valeria Bernal Ortiz ◽

...

Keyword(s):

Risk Factors ◽

Drug Reaction ◽

Retrospective Study ◽

Clinical Severity ◽

Severe Reaction ◽

Skin Involvement ◽

Inflammatory State ◽

Reaction Severity ◽

Clinical Conditions

DRESS/DiHS is a complex and potentially fatal drug reaction. Little is known about risk factors and elements that can help to identify patients with a severe reaction early. The aim of the study was to investigate those factors favoring the disease and its severity by analyzing the clinical conditions and therapies preceding the reaction. We conducted a retrospective analysis on patients admitted to our center between 2010 and 2020 who were discharged with a diagnosis of DRESS. We used the RegiSCAR diagnostic criteria. We defined the severity of DRESS using the criteria of Mizukawa et al. We included 25 patients (15 females) with a median age of 66 years. Skin involvement, eosinophilia, and liver injury were the most important aspects. Allopurinol was found to be the most involved drug. Reaction severity was significantly associated with the number of daily medications (p=0.0067) and an age of at least 68 years (p=0.013). In addition, 75% of severe cases had at least three comorbidities in history, and most of the severe cases were female. In our study the advanced age, the high number of comorbidities and home therapies, and the inflammatory state were found to be predisposing elements to the development of the disease and its severity.

Download Full-text

The Pleiotropic Intricacies of Hedgehog Signaling: From Craniofacial Patterning to Carcinogenesis

FACE ◽

10.1177/27325016211024326 ◽

2021 ◽

pp. 273250162110243

Author(s):

Mikhail Pakvasa ◽

Andrew B. Tucker ◽

Timothy Shen ◽

Tong-Chuan He ◽

Russell R. Reid

Keyword(s):

Intracellular Signaling ◽

Limb Development ◽

Hedgehog Signaling ◽

Target Genes ◽

Craniofacial Development ◽

Signaling Cascade ◽

Signaling Mechanisms ◽

Intracellular Signaling Cascade ◽

And Function

Hedgehog signaling was discovered more than 40 years ago in experiments demonstrating that it is a fundamental mediator of limb development. Since that time, it has been shown to be important in development, homeostasis, and disease. The hedgehog pathway proceeds through a pathway highly conserved throughout animals beginning with the extracellular diffusion of hedgehog ligands, proceeding through an intracellular signaling cascade, and ending with the activation of specific target genes. A vast amount of research has been done elucidating hedgehog signaling mechanisms and regulation. This research has found a complex system of genetics and signaling that helps determine how organisms develop and function. This review provides an overview of what is known about hedgehog genetics and signaling, followed by an in-depth discussion of the role of hedgehog signaling in craniofacial development and carcinogenesis.

Download Full-text

Identification of Autosomal Regions Involved in Drosophila Raf Function

Genetics ◽

10.1093/genetics/156.2.763 ◽

2000 ◽

Vol 156 (2) ◽

pp. 763-774 ◽

Cited By ~ 2

Author(s):

Willis Li ◽

Elizabeth Noll ◽

Norbert Perrimon

Keyword(s):

Limb Development ◽

Target Gene ◽

Biological Function ◽

Genetic Interaction ◽

Ectopic Expression ◽

Tor Signaling ◽

Downstream Effector ◽

Early Embryos ◽

Genomic Regions

Abstract Raf is an essential downstream effector of activated p21Ras (Ras) in transducing proliferation or differentiation signals. Following binding to Ras, Raf is translocated to the plasma membrane, where it is activated by a yet unidentified “Raf activator.” In an attempt to identify the Raf activator or additional molecules involved in the Raf signaling pathway, we conducted a genetic screen to identify genomic regions that are required for the biological function of Drosophila Raf (Draf). We tested a collection of chromosomal deficiencies representing ∼70% of the autosomal euchromatic genomic regions for their abilities to enhance the lethality associated with a hypomorphic viable allele of Draf, DrafSu2. Of the 148 autosomal deficiencies tested, 23 behaved as dominant enhancers of Draf Su2, causing lethality in Draf Su2 hemizygous males. Four of these deficiencies identified genes known to be involved in the Drosophila Ras/Raf (Ras1/Draf) pathway: Ras1, rolled (rl, encoding a MAPK), 14-3-3ϵ, and bowel (bowl). Two additional deficiencies removed the Drosophila Tec and Src homologs, Tec29A and Src64B. We demonstrate that Src64B interacts genetically with Draf and that an activated form of Src64B, when overexpressed in early embryos, causes ectopic expression of the Torso (Tor) receptor tyrosine kinase-target gene tailless. In addition, we show that a mutation in Tec29A partially suppresses a gain-of-function mutation in tor. These results suggest that Tec29A and Src64B are involved in Tor signaling, raising the possibility that they function to activate Draf. Finally, we discovered a genetic interaction between Draf Su2 and Df(3L)vin5 that revealed a novel role of Draf in limb development. We find that loss of Draf activity causes limb defects, including pattern duplications, consistent with a role for Draf in regulation of engrailed (en) expression in imaginal discs.

Download Full-text

The OMT Classification of Congenital Anomalies of the Hand and Upper Limb

Hand Surgery ◽

10.1142/s0218810415400055 ◽

2015 ◽

Vol 20 (03) ◽

pp. 336-342 ◽

Cited By ~ 12

Author(s):

Michael A. Tonkin ◽

Kerby C. Oberg

Keyword(s):

Upper Limb ◽

Congenital Anomalies ◽

Limb Development ◽

Main Group ◽

International Federation ◽

Scientific Committee ◽

Current Status ◽

Thumb Duplication ◽

The Common

The Oberg, Manske and Tonkin (OMT) Classification of congenital anomalies of the hand and upper limb uses dysmorphological terminology, placing conditions in one of three groups: Malformations, Deformations and Dysplasias. The main group, Malformations, is further subdivided according to whether the whole of the limb is affected or the hand plate alone, and whether the primary insult involves one of the three axes of limb development and patterning or is non-axial. The common surgical diagnoses, such as thumb duplication and thumb hypoplasia, are then placed within this framework. Recently the International Federation of Societies for Surgery of the Hand Scientific Committee for Congenital Conditions approved the OMT Classification as a timely and appropriate replacement of the previously accepted Swanson Classification. This review charts the development of and modifications to the OMT Classification and its current status.

Download Full-text