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JOURNAL OF
THE ANATOMICAL SOCIETY OF INDIA

Vol. 49, No. 2, December, 2000


In this issue :

Editorial
Dr. Patnaik V.V.Gopichand

Gross Anatomy of the Caudate Lobe of the Liver
Sahni, D., Jit, I., Sodhi L. Department of Anatomy, Postgraduate Institute of Medical Education and Research, Chandigarh, India

Branching Pattern of Axillary Artery - A Morphological Study
*Patnaik V.V.G., Kalsey, G; Singla Rajan, K. Department of Anatomy, Government Medical College, Amritsar, *Patiala. INDIA

The Course, Relations and The Branching Pattern Of The Middle Meningeal Artery In South Indians
Manjunath, K.Y. & Thomas, I.M. Department of Anatomy, St. John�fs Medical College, Bangalore-560 034 INDIA

Morphometry of the Human Inferior Olivary Nucleus
Dhall, U; Chhabra, S. & Rathi, S.K. Department of Anatomy, Pt. B.D. Sharma P.G.I.M.S., Rohtak. INDIA

Management of Turner Syndrome in India Using Anthropometric Assessment of Response to Hormone Replacement Therapy.
Sehgal R. and Singh A. Department of Anatomy, Maulana Azad Medical College and Associated Lok Nayak, G.B. Pant & G.N.E.C. Hospitals, New Delhi ? 110 002 INDIA.

Insertion Of Umbilical Cord On The Placenta In Hypertensive Mother
Rath* G, Garg** K, and Sood*** M. *Department of Anatomy, ***Department of Obstetrics & Gynaecology, Lady Hardinge Medical College, New Delhi-110001 **Department of Anatomy, Santosh Medical College, Gaziabad. INDIA

Utility Of Finger Prints in Myocardial Infarction Patients
Dhall, U; Rathee, S.K; *Dhall, A; Department of Anatomy & *Medicine, Pt. B.D. Sharma, PGIMS, Rohtak. INDIA

The Prenatal Parotid Gland
Fouzia Nayeem, Sagaff S., *Krishna G., **Rao S. Department of Anatomy, K.A.A.U. Jeddah. Department of *Pediatrics & **Surgery, Osmania Medical College, Hyderabad. INDIA

Possibility of Cell Death Induced Skeletal Malformations Of The Upper Limb
Sinha, D.N. Department of Anatomy, B.R.D. Medical College, Gorakhpur?273013 INDIA,

Efficacy of Manual Bladder Expression in Relieving Urine Retention After Traumatic Paraplegia In Experimental Animals.
Preeths, T.S., Sankar, V. Muthusamy, R. Department of Anatomy, Dr. A. Lakshmanasamy Mudaliar Postgraduate Institute of Basic Medical Sciences, University of Madras, Taramani Campus, Chennai 600 113, India.

Stress And Serum Cholesterol Levels-An Experimental Study
Jain, S.K. *Pandey, S.N. *Srivastava, R.K. Ghosh, S.K. Department of Anatomy, D.R.P.G. Medical College, Kangra at Tanda. * Department of Anatomy, G.S.V. Medical College, Kanpur.

Effect of Ibuprofen On White Cell Series of Bone Marrow Of Albino Rats
* Bhargava, R., Chandra, N., Naresh, M., *Sakhuja S. * Department of Anatomy, M.L.N. Medical College, Allahabad * Lady Hardinge Medical College, N. Delhi, India.

JB4 An Embedding Medium For Flourescent Tracer Technique
*Gupta, M; **Mishra, S., ***Sengupta P. Department of Anatomy, *PGI, Chandigarh; **AIIMS, N. Delhi; ***UCMS, New Delhi. INDIA

Comparative Anatomy of Cardiac Veins in Mammals
Kumar Keshaw Department of Anatomy, Institute of Medical Sciences B.H.U., Varanasi?5. INDIA

Aplasia Cutis Type 9 With Trisomy-13 Syndrome ? A Rare Association
Adhisivam, B, Narayanan, P, Vishnu Bhat, B, *Ramachandra Rao. R*, *Rao. S*, Kusre, G.* Department Pediatrics & *Anatomy, JIPMER, Pondicherry - 605 006

Absence of Musculocutaneous Nerve And The Innervation of Coracobrachialis, Biceps Brachii And Brachialis From The Median Nerve
Sud, M.; Sharma A. Department of Anatomy, Christian Medical College, Ludhiana. Punjab INDIA.

A Rare Pseudo Ansa Cervicalis: A Case Report
Indrasingh I. and Vettivel S. Department of Anatomy, Christian Medical College, Vellore, India

A Rare Variation In The Relation Of Omohyoid Muscle: A Case Report
Vettivel, S. Korula, A. and Koshy S. Department of Anatomy, Christian Medical College, Vellore, India

Surgical Incisions ? Their Anatomical Basis Part II - Upper Limb
1Patnaik V.V.G., 2Singla Rajan. K., 3 Gupta P.N. Department of Anatomy, Government Medical College, Patiala1, Amritsar2, 3Department of Orthopedics, Government Medical College, Chandigarh. INDIA

Anatomy Of Temporomandibular Joint?A Review
1Patnaik V.V.G., 3Bala Sanju; 2Singla Rajan K. Department of Anatomy, Govt. Medical College, 1Patiala, 2Amritsar, 3Department of Oral & Maxillofacial Surgery, Pb. Govt. Dental College, Amritsar


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J Anat. Soc. India 49(2) 158-160 (2000)
Possibility of Cell Death Induced Skeletal Malformations Of The Upper Limb

Sinha, D.N. Department of Anatomy, B.R.D. Medical College, Gorakhpur?273013 INDIA,

Abstract : The skeletal anomalies of the upper limb (absence of radius, major skeletal disgenesis of the fore arm) have been studied for better explanation of the possible mechanism of their genesis. The proximal distal sequence of this deranged develomental defect was seen in close approximation of the activity of the cell death �gopaque patch�h, an hypothesis proved experimentally to a larger extent by the pioneer work of Hinchliffe (1981).

Keywords : Cell Death, Malformations

Introduction

Anomalies of the limbs have been extensively reported in the various literature both related to in vitro and in vivo studies. Often during the interpretation the role of the environmental agents for the production of limb anomalies is considered enormously. However, sporadic genetic factors do play a vital role in triggering the morphogenetic aberration and therefore an anomalous limb could be noticed. The history of the thalidomide induced malformation of the limb once again emphasised to obtain a history of the drugs used during the pregnancy, so as to consider its possible effect in the production of congenital abnormalities (Lenz. 1962). Considering the facts, there are possibilities of absence of any history of the drugs being used during the pregnancy by the mother and even without any evidence of genetic correlation in establishing the aetiogenesis of these anomalies, in such circumstances, therefore these cases are more vital to probe as to how, their anomalies could be described especially, the possible mechanism resulting in the production of such anomalies. In view, to hypothesise and to reach at better scientific explanation a considerable search of literature is needed for the both in vitro and in vivo studies.

Clinical and Radiological Observations :

In this study, two case reports of limb malformations were considered for the purpose of discussion in the light of existing literature. Case No. 1 :

A male child of 3 years was seen with the deformities of the congenital absence of the radius and absence of radial component of the thumb. The wrist was seen deviated radially. The ulna showed bowing with concavity on the radial side. The carpal bones were absent. The marked shortening of the forearm was noticed. The other corresponding limb was normal. The individual growth was normal and there were no other anomalies except the anomalies of one limb, which is considered for the discussion. No history of illness and any drug intake during the pregnancy was obtained from the mother. This case appeared to be a complete paraxial hemimelia (complete absence of one of the forearm element and the corresponding portion of the hand-terminal longitudinal defect (Fig. 1).

Case No. 2

A 24 years male was seen with anomalies of the fore arm and hand. He visited the hospital for some other work. However, on request he got his upper limb X-rayed. On interrogation, he said that it was since birth. There was no history of drugs being used during the pregnancy by the mother of this individual, nor she had any illness during the pregnancy. He had humerus, but ulna and radius were markedly reduced along with considerable reduction in length of the forearm Rudimentary digital structures were seen without the formation of the carpals, metacarpals and phalanges (Fig. 2).

Discussion

Existing literature accounts for a number of explanations given for the absence of skeletal elements of the upper limb (O�f Rahilly 1957). Bhargava, Gupta and Jhori (1976) reported a case of congenital absence of the radius. They tried to utilize the monograph of Kato (1924) to explain the possibilities of production of such anomalies. Kato (1924) reviewed the archipterygeal and extraneous theory in his monograph. Farmer and Laurin (1958) described that congenital absence of radius could be both possible as a result of genetic and extraneous factors. They also found congenital absence of radius in three successive generations. Even after giving lot of informations about familial history, sporadic involvement is also considered at last (Kato, 1924). Heikel (1959) also noticed other associated anomalies of skeletal and soft tissue with congenital absence of the radius. In the event of the missing of the limb analog, Gupta and Bhargava (1976) also reported a case of double ulna (Ulna Dimelia). This indicates that radius has been found absent and the ulna was noticed in place of the radius. In argument of this very case, again archipterygeal theory was taken in consideration. It is stated that due to reduplication the main stem resulted in the development of the double ulna. In another information, Tschumi (1957) stated that prospective limb segments (buds) in a limb were set in proximal distal sequence. Therefore, it could be postulated that abnormalities of the forearm would also lead to the anomalous development of the skeletal system of the hand.

Human experiments are very limited to find out the genesis or possible mode of development of such anomalies. Therefore to arrive at certain conclusion and to adduce the possible mechanism, one has to look towards the literature basically pertaining to the experimental morphology of the limb. Analysis of the limb morphogenesis is a subject of much interest to the developmental biologist in recent year, who has largely been dependent on the experiments on chick limb buds.

The experimental work concerning the chick limb bud are not necessarily applicable to other amniotes, though in fact the principle factors (Apical Ectodermal ridge (AER), Apical Ectodermal Maintenance Factor (AEMF), and zone of polarizing activity (ZPA) described for chick limb bud did seem to operate throughout the amniotic limb development (Hinchliffe and Gumpelpinot 1981). Hinchliffe (1981) also clearly ascertained that involved growth and differentiation, the role of cell death was a prominant feature of the limb development. It is also stated that �gopaque patch�h separates the zeugopod skeletal condensations (radius and ulna, tibia and fibula). The opaque patch is also noticed in the mouse and rat. Sinha (1990) also reported presence of �gopaque patch�h in the histological feature of the limb bud of rat embryos grown in whole embryo culture technique. Cell death area has been also described in the interdigital zones (Saunders and Fallon 1967) and it is also noticed in the amniotes e.g. human, rat mouse, lizards and turtle embryos. Hinchliffe (1981) stated that cell death also affected atleast one of the wing chondrogenic elements the ulnare, a wrist element distal to the ulna, degenerated and disappeared. Genetic control of the cell death patterns also provide evidence that the changes in the area of the cell death in the limb bud adjacent to the first digit were associated with the changes in the digital number. According to Dawd and Hinchliffe (1971), who further observed that opaque patch although initially involved in the separation of radius and ulna, it was also associated in condition generated model at a certain thrashold of cell density to also produce �eY�f shaped of three blastemata of humerus, radius and ulna. Hinchliffe (1981) described that mutant embryo provides evidence that the area of cell death was under genetic control but whether this was direct or indirect, was not clear. It was observed that in mutant leg buds, the effect of enlarging ANZ (Anterior Necrotic Zones) resulted in missing or reduction of preaxial skeletal elements. The luxate group of mutant mouse posseses essentially the same syndrome of tibial and/or radial reduction usually compensated by polydactyly. According to this view, cell death is a form of differentiation similar to other examples such as chondrogenesis or myogenesis.

Hincliffe (1981) also worked out the prospective fate of anterior and posterior halves of the wingbud. He observed that anterior half normally formed radius and digit 2, the posterior half forming ulna and digit 3 and 4, while both halves contributed humerus. During the amputation experiments they also observed that posterior half of the limb also kept the zone of polarising activity. Summerbell (1979) suggested that ZPA was a source of morphogen (Whose nature remains at present unknown). It is suggested that barrier interferes with the flow of morphogens. In another work regarding the distal limb malformation, Amprino (1965) tried to emphasis that removal of Apical Ectodermal Ridge (AER) was followed by death of the exposed underlying distal mesenchyme and thus he postulated that AER removal accounted for the distal skeletal deficiencies.

Kaprio and Tahka (1978) supported that removal of the posterior one third of AER or whole AER both resulted in distal deficiencis. The role of teratogens causing malformation can not be ruled out in lack of any supportive evidence. However, some teratogens have a general cytotoxic effect on the embryo as a whole retarding growth and thus involving the limb secondarily and in a nonspecific way. Other teratogens act more specifically by modifying existing areas of the cell death. The role of the cell death has also been observed by Zwilling (1959). Micromelia in chick embryos might also be insulin induced and it is considered that it was due to extension of an existing area of cell death (Zwilling (1959). The opaque patch cell death in teratogenically malformed limb was common, but it was clearly in many cases secondary and related to the programmed cell death in normal limb morphogenesis (Hinchliffe 1981). The Lysomal concept has provided an attractive model for the control of the cell death, which contains acid hydrolases.

The appendicular skeletons of upper limb appear distinctly in the embryo of about 5 mm CR length (or 35th day) when arm and leg limb buds appear on its surface. By the 9.6 cm CR stage the upper limb shows primary differentiation into arm, forearm and the hand. By the 47th day the digits of the hand separate. By the end of the 3rd month one upper limb grows into a relatively normal length. In view of the above information of a very rapid embryological history, it is much difficult to pin point and extract any conclusive evidence in support of the anomalies referred to the present case studies.

Taking into account, the various experimental evidences as described in historical review of this paper, the possibilities of the production of these malformations could be searched some where in between the various morphogenetic scenario of the limb development. The role of the cell death �gopaque patch�h appeared to be playing extensively in various forms of its magnitude, either failure to separate between radius and ulna or an extension of the opaque area towards the radial component of the forearm rudiment in way to finally remove the rudiment itself thus designating the term-absence of the rudiment or loss of rudiment. The role of AEM does not appear to be involved in the case no. 1. In the second case, the role of extensive distribution of the cell death area might have resulted in missing of the larger part of the radius and ulna and thus skeletal structure of the hand could not be laid down. The role of distruction of the AER (apical ectodermal ridge) could also be hypothesised in this case because this has also resulted in the distal limb malformation. The role of the cell death in an area where digital rays are going to be formed, could be emphasised, possibly resulting in the splitting of presumptive mesoderm of the digit thus resulting in a situation of the development of the polydactly as noticed in X-ray of the fig (3). The role of AER in the production of polydactyly could easily be ruled out at this stage. The experimental evidence of the polydactylism in mice has been observed by Holt (1945).

All the anomalies which are discussed in this paper do not appear to be caused by the drugs. However it is derangement in the proximal distal developmental process of the upper limb. Extrapolation of the results of experimental evidence are not an absolute acceptance in this explanatory exercise, moreover it has also a profound limitation, especially when it is thoughtfully advocated that majority of the congenital malformations are polygenic and multifactorial in origin in present scenario of the concept of teratogenesis.

References

1. Amprino, R : Aspects of limb morphogenesis in Chicken. In: organogenesis, eds R.L. deHaan and H. Ursprung. Holt, Richart and Winston. New York: pp 255-282, (1965)
2. Bhargava, S.K. Gupta, R. and Jhori S.K. (1976): Congenital absence of radius. Indian Journal of Radiology, 30 (3) 229-230.
3. Dawd, D.S. and Hinchliffe J.R. (1971) : Cell death in �gOpaque patch�h in the central mesenchyme of the developing chick limb, a cytological, cyto-chemical and electron microscope analysis. Journal of Embryology and Experimental morphology. 26, 401-424.
4. Farmer, A.W. and Laurin, C.A. (1958) : Congenital absence of radius. Canadian Journal of Surgery. 1, 301-308.
5. Gupta, R., Bhargava, S.K. (1976) : Double Ulna (Ulnar Dimelia). Indian Journal of Radiology. 30 (3) 241-242.
6. Holt, S.B. (1945) : A polydactyl Gene in mice capable of nearly regular manifestation. Annals of Eugenics. 12, 220.
7. Heikel, H.V.A (1959) : Aplasia and hypoplasia of radius. Acta. Orthopaedics scandenevia Suppliments 39.
8. Hinchliffe, J.R. : Cell death in Embryogenesis. In: cell death. eds I.D. Bowen & R.A. Lockshin Chapman and Hall. London : pp 35-78. (1981)
9. Hinchliffe, J.R. and Gunepel-Pinot, M. (1981); Control of maintenance of antero-posterior differentiation of the anterior mesenchyme of the chick wing bud by its posterior margin (the ZPA). Journal of Embryology and Experimental morphology, 62, 63-82.
10. Kaprio, E.A. and Tahka, S. (1978) : Lack of correlation between mesenchymal cell death and morphogenesis after different extents of apical ectodermal ridge/rim ectodermal removal in chick embryo wing bud. Medical Biology. 56, 321-327.
11. Kato, K. (1924) : Congenital absence of the radius. Journal of Bone and joint surgery. 22, 589-626.
12. Lenz, W. (1962) : Thalidomide and congenital abnormalities. Lancet, 1: 271.
13. O�f Rahilly, R. (1957) : An analysis of cases of Radial hemimelia. Archives of Pathology (Chicago). 44, 28-33.
14. Sinha, D.N. (1990) : Histological features of limb bud of Rat embryos grown in whole embryo culture technique. Journal of Anatomical Sciences 12: 19-22.
15. Saunders, J.W. and Fallon, J.F. : major problems in developmental Biology. In: Cell death in morphogenesis. ed. M. Locke. Academic press. New York London: pp 289-314, (1967).
16. Summerbell, D. (1979) : The zone of polarising activity: evidence for a role in normal chick morphogenesis. Journal of embryology and Experimental morphology, 50, 217-233.
17. Tschumi, P.A. (1957) : The growth of the hind limb bud of xenopus Laevis and its dependence upon epidermis, Journal of Anatomy, 91, 149-173.
18. Zwilling, E. (1959) : Micromelia as a direct effect of insulin. Evidence from in vitro and in vivo experiments. Journal of morphology, 104, 159-179.



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