ST. JMC JOURNAL OF MEDICINE ISSN 0970-4221 VOL.II NO. 1 MARCH 1989
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COMMUNITY Ht'ALTH CELL
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ISSN 0970-4221
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ST. JOHN'S MEDICAL COLLEGE
JOURNAL OF MEDICINE
VOL II No. 1
MARCH 1989
EDITORIAL
1
REVIEWS
Perthe's Disease (II part)
2
Human Papillomaviruses
5
The Thalassemias
11
ORIGINAL ARTICLES
Campylobacter Pylori - A one minute endoscopy room test.
16
Intralesional Steroid Versus Pressure on keloidsA comparitive Histopathological Study
18
Stature from foot size
21
CASE REPORT
Primary adenocarcinoma of the jejunum
26
SELECTED SUMMARY
Preliminary results of the cochlear corporation multi electrode
introcochlear implant in six prelingually deaf patients
28
EDITORIAL BOARD
Ashley. J. D’Cruz
Rajini Macaden
Ravi C. Nayar
Mario Vaz,
A. B. Kilpadi,
A.S. Arvind
INFORMATION FOR CONTRIBUTORS
Submitting the Manuscript
The St. John’s Medical College Journal of Medicine accepts contributions from all fields of modern
medicine and from all institutions and health care professionals. The journal is a quarterly publication
which will be published in March, June, September and December It is published by St. John's Medical
College and Alumni Association as a part of their commitment to continuing medical education. Articles
and all editorial communications should be addressed to the Editor, Alumni Office, St. John's Medical
College, Bangalore-560 034
Original articles, short case reports and review articles are accepted for publication. Review articles and
editorials are usually on invitation by the Editorial Board. Letters to the Editor will be considered for
publication only if received at least six weeks prior to the next publication.
PREPARING THE MANUSCRIPTS
All manuscripts should be submitted in 3 copies (including the glossy prints). They should bo neatly
typewritten on bond paper, one side of the paper only, with double spacing and margins of at least 2.5 cms.
Please be sure to include an accurate address for editorial communications and for reprint requests.
A brief abstract of the material of the paper should precede the body of the paper, to run no more than 500
words. INDEX WORDS for the purpose of indexing and computer programming, should appear on the
same page
The format for articles suggested is as follows:
RESULTS, DISCUSSION. REFERENCES.
INTRODUCTION, MATERIALS AND METHODS.
Measurements should be in metric system
OVERSEAS
R. R. Baliga,
A.V. Kurupad
ILLUSTRATIONS AND TABLES
Figures and tables should be cited in order in the text; their position should be marked in the margin of
the manuscripts. Arabic numbering should be used for both figures and tables. All line drawings should be
submitted in duplicate as clear, glossy, black and white. 5" x 7" photographs. Photomicrographs should
also be submitted in duplicate, with allowance made for the effects of reduction if necessary. Legends
for illustrations should be typewritten, double-spaced, on a separate sheet, and included at the end of the
manuscripts. A legend must accompany each illustration. Each table should be typed on a separate sheet
and appropriately numbered. Legend should be typed on the same sheet as the tables. The contributors
must bear all the costs connected with printing colour illustrations.
REFERENCES
References should be compiled at the end of the articles according to the order of citation in the text, not
alphabetically. They should be typewritten, double-spaced under the heading REFERENCES. Abbreviation
for titles of medical periodicals should conform to those used in the latest edition of Index Medicus. Give
inclusive page numbers.
EXAMPLES OF REFERENCES
PUBLISHER
S. V. Srikrishna
Journal Articles upto six authors, list all names:
Kurpad AV, Shotty PS: Dietary Fibre and the colon St.John's J Med, 1988 ; 1:5-12.
Journal Articles more than six authors, list three authors followed by et al:
Complete book
Gallagher JR : Medical Care of the Adolescent (ed 2). New York. Appleton, 1966, pp 208-215
SUBSCRIPTION
Single Copy
Rs. 30/'Annual : India Rs. 100/
Abroad U.S. $ 20/-
PUBLICATION COMMITTEE
Payable in cash/ bank drafts/ cheques to the St. John's Medical College Journal of Medicine, I Floor, Robert
Koch Bhavan. St. John's Medical College, Bangalore 560 034.
C. Ramachandra
The advertisement charges:
S.C. Rajendra,
Cover (back page): Rs. 3000/- Inside Cover (back page): Rs. 2000/-
J. Alapatt
All contributions towards the Journal come under 80(G) exemption.
St. John’s Medical College Journal of Medicine
EDITORIAL
The editorial of the journal will probably be in this form for the last time. Future issues will have editorials addressing important
medical and scientific issues of the day. You will notice a few changes, to start with, the editorial board and the title. We
must gratefully acknowledge the pioneering and difficult work of Drs. R.R. Baliga and Anura Kurupad our founding editors.
They are now in the U.K and will continue to be associated with the Journal as our Overseas representatives. The Admini
stration of SJMC has, to a request of the Alumni Association, generously agreed to consider ‘adopting’ the journal as the
official scientific publication of the institution. The journal changes its name to “The St. Johns’ Medical College Journal
of Medicine". The alumini will continue to play their part in managing its affairs.
Despite thegrowingcriticismoftheburgeoning journal industry in the country, we are convinced of the need for an in-house
journal such as this. The journal will be a means of communicating the work done in this institute to all its members,
past, present and to a growing list of subscribers. It remains open to scientific contributions from all over.
Your letters, articles and support will lighten our burden and help this journal grow.
Ashley J. D'Cruz
AIDS AND THE OSTRICH APPROACH - THE CASE AGAINST
Health personnel delude themselves that they remain protected by totally eliminating AIDS & HIV - infected patients, from
their sphere of professional activity. They are seriously erring in judgement and failing in their commitment to health care.
Given the evolving state of our knowledge of the disease and the inexact tests available to detect it, especially in this country,
health personnel would be better advised to adopt appropriate preventive measure especially if they belong to high risk
groups.
Health Care Worker at Greatest Risk for Occupational HIV Infection.
Frequent blood exposure
Dialysis nurses and technicians
Laboratory technicians who handle blood samples
Exposure to blood in uncontrolled situations
Trauma, vascular and cardiac surgeons and obstetricians
At present, the test used to screen patients by the ELISA technique has a sensitivity that varies with the manufacturer.
However, the false negativity is less than 1%. On the other hand, specificity is dependent on the prevalence of infection
in the population. Given a prevalence of only 0.2%, 72% of ELISA positive will be false positive and this will reduce to 20%
only if the prevalence increases to 2%. Hence, laboratory diagnosis is confirmed only after a Western blot test. It
is apparent therefore, that laboratory testing is still inaccurate’.
The period taken to become seropositive after exposure to HIV is highly variable. Patients are known to develop AIDS even
before they are seropositive. Other concerns are the lack of a test for HIV antigen which theoretically, should be positive
early after exposure to the virus. Butthen, a possible change in antigen expression without a change in virulence could always
occur. It is clear that at any given time there may be a sizeable number of patients who are infectious despite negative results.
Given the irrefutable fact of occupational infection one is always exposed to, one is well advised to adhere to recommended
safety measures when dealing with infectious groups and not just exclude such patients from one’s practice. *
Precautions as advised by Centre for Disease Control
Use of appropriate barrier to prevent skin or mucous membranes from contact with patients blood or body fluids.
Hands should be thoroughly washed after removal of gloves, and any skin contacting patient blood or body fid should be washed immediately.
Great care should be taken to avoid injury by needles or other sharp object that have been used on patients.
Protocols for handling disposables should be rigidly followed.
Equipment for emergency ventilation should be available where resusitation is mostly likely to occur to avoid mouth to mouth contact
Health care workers with open skin lesions should avoid direct patient contact or handling of patient care equipment.
Pregnant Health care worker must follow guidelines strictly.
Ashley J. D'Cruz
1.
Meyer AA. The Surgical Management of AIDS and HIV infected patients. Adv Surg 1989; 22:57-74
MARCH 1989
1
INFORMATION FOR CONTRIBUTORS
EDITORIAL BOARD
Ashley. J. D’Cruz
Rajini Macaden
Ravi C. Nayar
Mario Vaz,
A. B. Kilpadi,
A.S. Arvind
Submitting the Manuscript
The St. John's Medical College Journal of Medicine accepts contributions from all fields of modern
medicine and from all institutions and health care professionals. The journal is a quarterly publication
which will be published in March. June. September and December. It is published by St. John's Medical
College and Alumni Association as a part of their commitment to continuing medical education. Articles
and all editorial communications should be addressed to the Editor, Alumni Office. St. John’s Medical
College, Bangalore-560 034
Original articles, short case reports and review articles are accepted for publication. Review articles and
editorials are usually on invitation by the Editorial Board. Letters to the Editor will be considered for
publication only if received at least six weeks prior to the next publication
PREPARING THE MANUSCRIPTS
All manuscripts should be submitted in 3 copies (including the glossy prints). They should be neatly
typewritten on bond paper, one side of the paper only, with double spacing and margins of at least 2.5 cms.
Please be sure to include an accurate address for editorial communications and for reprint requests.
A brief abstract of the material of the paper should precede the body of the paper, to run no more than 500
words. INDEX WORDS lor the purpose of indexing and computer programming, should appear on the
same page.
The format for articles suggested is as follows:
RESULTS. DISCUSSION. REFERENCES.
INTRODUCTION, MATERIALS AND. METHODS,
Measurements should be in metric system.
OVERSEAS
R. R. Baliga,
A.V. Kurupad
ILLUSTRATIONS AND TABLES
Figures and tables should be cited in order in the text; their position should be marked in the margin of
the manuscripts. Arabic numbering should be used for both figures and tables. All line drawings should be
submitted in duplicate as clear, glossy, black and white, 5" x 7* photographs. Photomicrographs should
also be submitted in duplicate, with allowance made for the effects of reduction if necessary. Legends
for illustrations should be typewritten, double-spaced, on a separate sheet, and included at the end of the
manuscripts A legend must accompany each illustration. Each table should be typed on a separate sheet
and appropriately numbered. Legend should be typed on the same sheet as the tables. The contributors
must bear all the costs connected with printing colour illustrations.
REFERENCES
References should be compiled at the end of the articles according to the order of citation in the text, not
alphabetically They should be typewritten, double-spaced under the heading REFERENCES. Abbreviation
tor titles of medical periodicals should conform to those used in the latest edition of Index Medicus. Give
inclusive page numbers.
EXAMPLES OF REFERENCES
PUBLISHER
S. V. Srikrishna
'Journal Articles upto six authors, list all names:
Kurpad AV. Shetty PS: Dietary Fibre and the colon St.John's J Med, 1988 ; 1:5-12.
Journal Articles more than six authors, list three authors followed by et al:
Complete book
Gallagher JR : Medical Care of the Adolescent (ed 2). New York, Appleton. 1966, pp 208-215
SUBSCRIPTION
Single Copy
Rs. 30/'Annual : India Rs. 100/
Abroad U.S. $ 20/-
PUBLICATION COMMITTEE
Payable in cash/ bank drafts/ cheques to the St. John's Medical College Journal of Medicine. 1 Floor, Robert
Koch Bhavan, St John's Medical College, Bangalore 560 034.
C. Ramachandra
The advertisement charges:
S.C. Rajendra,
Cover (back page): Rs. 3000/-
J. Alapatt
Inside Cover (back page): Rs. 2000/-
A// contributions towards the Journal come under 80(G) exemption.
St. John’s Medical College Journal of Medicine
EDITORIAL
The editorial of the journal will probably be in this form forthe last time. Future issues will have editorials addressing important
medical and scientific issues of the day. You will notice a few changes, to start with, the editorial board and the title. We
must gratefully acknowledge the pioneering and difficult work of Drs. R.R. Baliga and Anura Kurupad our founding editors.
They are now in the U.K and will continue to be associated with the Journal as our Overseas representatives. The Admini
stration of SJMC has, to a request of the Alumni Association, generously agreed to consider ‘adopting’ the journal as the
official scientific publication of the institution. The journal changes its name to ‘The St. Johns’ Medical College Journal
of Medicine". The alumini will continue to play their part in managing its affairs.
Despite the growing criticism of the burgeoning journal industry in the country, we are convinced of the need for an in-house
journal such as this. The journal will be a means of communicating the work done in this institute to all its members,
past, present and to a growing list of subscribers. It remains open to scientific contributions from all over.
Your letters, articles and support will lighten our burden and help this journal grow.
Ashley J. D’Cruz
AIDS AND THE OSTRICH APPROACH - THE CASE AGAINST
Health personnel delude themselves that they remain protected by totally eliminating AIDS & HIV - infected patients, from
their sphere of professional activity. They are seriously erring in judgement and failing in their commitment to health care.
Given the evolving state of our knowledge of the disease and the inexact tests available to detect it, especially in this country,
health personnel would be better advised to adopt appropriate preventive measure especially if they belong to high risk
groups.
Health Care Worker at Greatest Risk for Occupational HIV Infection.
Frequent blood exposure
Dialysis nurses and technicians
Laboratory technicians who handle blood samples
Exposure to blood in uncontrolled situations
Trauma, vascular and cardiac surgeons and obstetricians
At present, the test used to screen patients by the ELISA technique has a sensitivity that varies with the manufacturer.
However, the false negativity is less than 1%. On the other hand, specificity is dependent on the prevalence of infection
in the population. Given a prevalence of only 0.2%. 72% of ELISA positive will be false positive and this will reduce to 20%
only if the prevalence increases to 2%. Hence, laboratory diagnosis is confirmed only after a Western blot test. It
is apparent therefore, that laboratory testing is still inaccurate’.
The period taken to become seropositive after exposure to HIV is highly variable. Patients are known to develop AIDS even
before they are seropositive. Other concerns are the lack of a test for HIV antigen which theoretically, should be positive
early after exposure to the virus. Butthen, a possible change in antigen expression without a change invirulence could always
occur. It is clear that at any given time there may be a sizeable number of patients who are infectious despite negative results.
Given the irrefutable fact of occupational infection one is always exposed to, one is well advised to adhere to recommended
safety measures when dealing with infectious groups and not just exclude such patients from one’s practice.
Precautions as advised by Centre for Disease Control
Use of appropriate barrier to prevent skin or mucous membranes from contact with patients blood or body fluids.
Hands should be thoroughly washed after removal of gloves, and any skin contacting patient blood or body fid should be washed immediately.
Great care should be taken to avoid injury by needles or other sharp object that have been used on patients.
Protocols for handling disposables should be rigidly followed.
Equipment for emergency ventilation should be available where resusitation is mostly likely to occur to avoid mouth to mouth contact.
Health care workers with open skin lesions should avoid direct patient contact or handling of patient care equipment
Pregnant Health care worker must follow guidelines strictly.
Ashley J. D'Cruz
1.
Meyer AA: The Surgical Management of AIDS and HIV infected patients. Adv Surg 1989:22:57-74
MARCH 1989
1
REVIEWS
St. John’s Medical College Journal of Medicine
PERTHES1 DISEASE (Second part)
BENJAMIN JOSEPH
INTRODUCTION
i) CONTAINMENT BY ORTHOSES
Perthes’ disease is an avascular necrosis of the capital femo
ral epiphysis. The first part of this article discussed the
aetiological features, pathogenesis of femoral head deform
ity and the prognosis. In this concluding part, the author
attempts to outline the treatment followed at his centre.
Repositioning of the anterolateral part of the femoral head
within the acetabulum can be achieved by abducting and
internally rotating the hip or by abducting and flexing the hip.
(Fig 3 a & b).
TREATMENT
Basically, two conceptsoftreatment merit consideration, viz.
weight-relief and ‘containment’. The former is based on the
belief that avoidance of weight-bearing stresses across the
acetabular margin would prevent femoral epiphyseal
deformation. The latter entails placement of the anterolateral
part of the avascular epiphysis within the confines of the
acetabulum to prevent deformation by the acetabular margin.
It needs to be emphasised that irrespective of which of these
two methods of treatment is adopted i.e., weight relief
or containment, the treatment should continue till the
avascular bone of the femoral epiphysis has been replaced
by mature lamellar bone. This implies that treatment should
cease only after Stage III of the disease. It also follows that
if either of these modalities of treatment is instituted in Stage
III or IV of the disease, little or no benefit is likely since
the ‘biologically plastic’ bone has already been subjected to
the deforming stresses.
a)
Fig. 3a . Abduction of the hip enables the avascular antero-lateral part of the
epiphysis to be relocated within the acetbulum. The avascular segment is
shaded black
WEIGHT RELIEF
Prolonged weight-relief in bed. which was in vogue in the
past, has little place in thecurrent day treatment of Perthes’
disease. However, there appears to be evidence to suggest
that weight-relief in the ambulant child in conjunction with
containment has very gratifying results. These results are
probably better than that obtained by containment
alone.39-40-41
b)
CONTAINMENT
Various methods of containment have been employed and
they include orthoses and surgicalmeans.
BENJAMIN JOSEPH M.S.'(ORTHO), M.Qh. (ORTHO)
ASSOCIATE PROFESSOR,
DEPARTMENT OF ORTHOPAEDICS,
KASTURBA MEDICAL COLLEGE.
MANIPAL576 119,
KARNATAKA
“ First Part St. John's J Med. 1988:1: (3) 2-7
2
Fig. 3b: Internal rotation of the hip helps to contain the anterior part of the
epiphysis
Orthotic appliances which hold the hip abducted and
internally rotated and/or flexed have been used with a great
deal of success eg. the Newington brace’, the Atlanta brace,
the Birmingham splint etc. The orthotic appliance is worn
constantly till revascularisation of the epiphysis is complete.
This may take upto two years. While this method has the
VOL II
No. 1 ------
St. John’s Medical College Journal of Medicine
obvious advantage of avoiding surgery, patient compliance
is imperative. In India, socio-economic factors often pre
clude the prolonged use of such appliances. Further more,
frequent radiological monitoring is necessary to assess the
process of revascularisation to determine when it is complete.
onset of Perthes’ and with the extent of femoral
epiphyseal involvement, not all affected children need
surgery and surgery is justifiable only in those children who
present early in the course of the disease. Table I outlines
a protocol of treatment taking into consideration these
aspects.
ii) SURGICAL CONTAINMENT
The reports of containment surgery from the West show that
the results have been poor in children over the age of 9 years
and in those with extensive involvement of the epiphysis.41
Unfortunately, in South India we are faced with all the poor
prognostic factors in our patients - the mean age at onset is
over 9 years, 70% have extensive femoral epiphyseal
involvement and there is a high proportion of girls. Despite
this, our results indicate that an aggressive approach to
treatment early in the course of the disease offers the best
chance of achieving a spherical femoral head.
FEMORAL OSTEOTOMY
Femoral varus derotation osteotomy and varus extension
osteotomy have been in vogue for some time.42 The
procedures ensure that the part of the femur proximal to the
site of the osteotomy is held abducted and internally rotated
or abducted and flexed to achieve containment in the same
way as that obtained by orthotic means.
The advantages of the procedure are that it avoids any
cumbersome appliance, patient compliance is not needed
and there is no need to monitor when revascularisation is
complete. However, the femur is shortened and some short
ening persists. A second operation is needed to remove the
implant which holds the osteotomy site.
INNOMINATE OSTEOTOMY
Salter advocates an innominate osteotomy to achieve
containment.43 The alignment of the acetabulum is altered so
as to cover the antero-lateral aspect of the femoral epiphy
sis. The procedure is technically more demanding than a
femoral osteotomy and there is some evidence to indicate
that the pressure on the femoral head increases following an
innominate osteotomy of the type recommended by Salter.
Nevertheless, good results have been reported with this
procedure.20
INDICATIONS FOR SURGICAL CONTAINMENT
c)
OTHER TREATMENT MEASURES
A period of traction helps to relieve muscle spasm during the
acute phase and in patients for whom surgery is planned,
traction is useful to regain a good range of hip movement
prior to surgery. Finally, in children with extensive
epiphyseal involvement and marked metaphyseal changes
there is a high risk of premature fusion of the capital physis.
In order to prevent ‘overgrowth’ of the greater trochanter it
is our practice, in these patients, to perform trochanteric
epiphyseodesis.
The treatment outlined here attempts to prevent the morpho
logical changes noted in the adult patients with osteoarthro
sis by obtaining containment it is hoped that coxa irregularis
can be avoided and coxa magna minimised; by trochanteric
epiphyseodesis it is hoped that greater trochanteric ’over
growth’ and consequent gluteus medius insufficiency is
avoided. In order to evaluate whether such treatment is
effective in preventing osteoarthrosis, the children need to be
followed up for forty years or more.
Since the prognosis varies considerably with age at the
TABLE I
INDICATIONS FOR SURGICAL CONTAINMENT IN PERTHES’ DISEASE
Under 5 years
Age
Stage
of the
disease
Over 7 years
5-7 years
Extent of
Involvement
1
II
HI
IV
I
II
-
+
Ill
IV
1
1
HI
IV
-
+
+
+
-
-
±
1
•-
li
iii
-
iv
+ : Surgical containment indicated
-
-
± : Surgical containment indicated if femoral head extrusion occurs
: Surgical containment contraindicated or unnecessary
MARCH 1989
3
St. John's Medical College Journal of Medicine
REFERENCES
22. Komp HMB, Boldero JL: Radiological changes in Perthes’disease Br
J Radiol 1966;39:744-60 -
1. Harper PS, Brotherton BJ. Cochlin D: Genetic risks in Perthes* disease.
Clinical Genetics 1976:10:178-82.
23. Meyer J : Legg-Calve-Perthes’ disease. Radiological results of treatment
and their consequences. Acta Orthop Scand 1977; Suppl 167.
2. Wynne-Davies R, Gormley J: The aetiology of Perthes’ disease. J Bone
Joint Surg (Br) 1978; 60B16-14.
24. Edgren W : Coxa plana. A clinical and radiological investigation with
particular reference to the importance of metaphyseal changes for the final
shape of the proximal part of the femur. Acta Orthop Scand 1965; Suppl 84
3. Hall AJ: Perthes’ disease; Progress in aetiological research, in Catterall A
(ed); Recent advances in Orthopaedics, London, Longman, 1985; 5; 187-99.
4. Coyle WJ : Perthes’disease in Hong Kong. J Western Pacific Assoc 1975;
XIT.1-14.
5. Thompson AG. Leong JCY, Fubg HW : Legg-Calve-Perthes’ disease in
southern Chinese children. J Western Pacific Assoc 1978; XV:63-70.
6. Ebong WW : Legg-Calve-Perthes' disease in Nigerians. Inter-National
Surgery 1977; 62:217-8.
7. Puny NA: The incidence of Perthes’ disease in three population groups
in the Eastern Cape Region of South Africa J Bone Joint Surg (Br)1982;
64B:286-8.
8.
Milsom C: Perthes'disease. J Bone Joint Surg (Br) 1975; 57B. 255.
9. Barker DJP, Dixon E. Taylor JF: Perthes’ disease of the hip in three regions
of England. J Bone Joint Surg (Br) 1978; 60B.478-80.
10. Hall AJ. Barker DJP, Dangerfield PH, Taylor JF : Perthes' disease in
Liverpool. B M J 1983; 287:1757-9.
25. Joseph B Acetabular changes in Perthes’ disease. University of Liverpool
1987, M.Ch. Orth. Thesis
26. Bensahcl H, Bok B, Cavailloles F, Csukonyi Z : Bone scintigraphy in
Perthes' disease. J Pediatr Orthop 1983,3: 302-5
27 Yngve DA, Roberts JM Acetabular hypertrophy in Legg-Calve-Perthes’
disease. J Paediatr Orthop 1985;5:416-21
28. Salter RB : Legg-Perthes’ disease - The Scientific basis for the methods
of treatment and their indications Clin Orthop 1980,150:8-11
29. Bajaj H : The late effects Perthes’disease. University of Mangalore 1986,
M S. Orth. Thesis
30 Bowen JR, Schreiber FC. Forster BK. Wein BK : Premature femoral neck
physeal closure in Perthes’ disease Clin Orthop 1982. 171.24-29.
31. Perpich M. McBeath A. Kruse D . Long-term follow-up of Perthes’
disease treated with sp'ca casts J Pediatr Orthop 1983; 3:160-5
32. Foster BK. Bowen JR Results at maturity in Perthes’ disease J Bone
Joint Surg (Br) 1983. 65:101-2
11. Joseph B. Rao BS. Chacko V, Hall AJ : Epidermiology of Perthes’
disease in South India. International J Epid 1988; (in press)
33. Ingman AM, Peterson DC. Sutherland AD :A comparison between
innominate osteotomy and hip spica in the treatment of Legg-Perthes
12. Burwell RG, Dangerfield PH, Hall DJ. Vernon CL, Harrison MHM: Perthes’ disease. Clin Orthop. 1982; 163:141-7
disease. An anthropometric study revealing impaired and disproportionate
growth. J Bone Joint Surg (Br) 1978; 60B:461-77.
34. Catterall
A :
Legg-Calve-Perthes’
syndrome.
Clin Orthop
1981; 158:41-52.
13. Harrison MHM, Turner MH, Jacobs P : Skeletal Immaturity in Perthes’
disease. J Bone Joint Surg (Br) 1976; 58B:37-40.
35 Klisic PJ : Perthes’ disease. Int Orthop 1984; 8:95-102.
14. Kristmundsdottir F, Burwell RG, Harrison MHM, Marshall WA: Bone
age retardation at the hand and wrist in children with Perthes’ disease, in
Broms et al (eds) Human growth and development, New York, Plenum
Press, 1984.
15. Tanner JM, Whitehouse RH, Marshall WA, Healy MJR, Goldstein H .
Assessment ofskeletal maturity and prediction of adult height (TW2-method).
London, Academic Press, 1975.
36 Ion’s GK, Smith Sr, Gregg PJ : Radiological features of the metaphysis in
Perthes’ disease. J Bone Joint Surg (Br) 1982; 64B:386.
37. Lovell WW, MacEwen GD et al: Legg-Perthes’ disease in girls. J Bone
Joint Surg (Br) 1982; 64A:637.
38. Stulberg SD, Salter RB: The natural course of Legg-Perthes’ disease and
its relationship to degenerative arthritis of the hip. A long-term follow-up study.
Orthop Trans 1977;1:105-6.
16. Chacko V, Joseph B, Seetharam B: Perthes' disease in South India. Clin
Orthop 1986; 209:95-9.
39. Griffin PP, Green EE, Beauchamp RD : Legg-Calve-Perthes’disease.
treatment and prognosis. Orthop Clin North Am 1980; 11 127-39.
17. Sharma SV, Sriramulu K: Natural history of Perthes’ disease.lnd J Orthop
1981; 15-16.
40. Cotier JM: Office management of Legg-Calve-Perthes' Syndrome Orthop
Clin North Am 1982;13:619-27.
18. Sinha DK, Singh RP: Perthes' disease in Chotanagpur. Ind J Orthop 1982;
1604141. Mmtowt-Czyz W,
Tayton K : Indication for weight relief
and
containment in the treatment of Perthes’ disease. Acta Orthop Scand
19. Chacko V, Joseph B : Pseudocoxalgia revisited. Ind J Orthop 1983; 1983;54:439-45.
17:105-8.
42. Axer A : Subtrochanteric osteotomy in the treatment of Perthes’disease.
20. Canale ST, D’Anca A, Cotier JM, Snedden HE : Innominate J Bone Joint Surg (Br) 1965;47B:489-99.
osteotomy in Legg-Calve-Perthes' disease. J Bone Joint Surg (Am) 1972;
54:25-40.
43. Salter RB : Current Concepts Review: The present status of surgical
treatment for Legg-Perthes’disease. J Bone Joint Surg (Am) 1984;66:961-6.
21. Catterall A : The natural history of Perthes’ disease. J Bone Joint Surg
(Br) 1971; 53B:37-53.
4
VOL II
No. 1------
St. John's Medical College Journal of Medicine
HUMAN PAPILLOMAVIRUSES - A BRIEF REVIEW
/. M. GREENFIELD
HISTORICAL OVERVIEW
The papillomaviruses occupy a unique place in the develop
ment of tumour virus research. In 1907, Ciuffo suggested
that the infectious agent for human verucca vulgaris (com
mon warts) may be of viral origin.’ This concept was not
generally accepted at that time, but it is now well established
that the papillomaviruses are the causative agents of a
wide range of benign epithelial proliferations and are also
associated with some malignancies.
The cottontail (Shope) papillomavirus (CRPV) was the first
oncogenic DNA virus to be isolated and characterised.2
They observed that in some rabbits benign papillomas pro
gressed to form carcinomas, and that these infections
could be transmitted to domestic rabbits, resulting in a higher
rate of malignant conversion.3 This experimental model re
mains an important tool for the study of viral oncology.
The
idea of carcinogenesis by a multistep process,
involving a papillomavirus
infection,
and
chemical
mutagenesis
was investigated by Rous and his co
workers.3-45 X-ray irradiation was also shown to aid malig
nant conversion in both experimental animals and in man.6-7
Thus, neoplastic progression came to be regarded as a
multistep process in which a papillomavirus infection may
play a crucial role;
Ironically, when compared to polyomavirus or SV40, the
papillomaviruses have not received much attention in
modern virology. This is mainly due to a lack of suitable in
vitro system capable of supporting vegetative viral
propagation. However, the advent of recombinant DNA
technology has permitted the isolation and characterisation of
the papillomavirus types.
enclosed by an icosohedral capsid. The mature particles
have protein capsomeres, but lack a membrane envelope.
Recent studies on papillomaviruses have shown that their
taxonomic association with the papovavirus family is
incorrect and that they should form a distinct group of viruses.
Data supporting this statement is as follows: Papilloma
viruses have a larger capsid (55nm as compared to 45nm),
and the genomes of the two groups of viruses show no
similarities with regard to DNA sequences, genetic
organisation, patterns of RNA synthesis, or growth require
ments.
The clinical importance of the papillomaviruses stems
from the almost ubiquitous affliction of the human popula
tion, and the severity to which some lesions progress. Over
50 types of human papillomaviruses (HPVs) have been
isolated and cloned from various lesions.10,1112 These
conditions range from benign epithelial proliferations to
epidermal, laryngeal and genital carcinomas. For a review,
see table 1.13
Table 1: Some human papillomaviruses and the lesions they
produce
Type
I.M.
deep plantar and palmar myrmecia
benign
2
common warts (vemucae vulgares),
some associated with anogenital
condylomata
benign
3,10,
28
Juvenile flat warts (verrucae
planae); associated with some
types of epidermodysplasia
verruciformis, genital infections
and some common warts
rarely
malignant
4
plantar warts and common warts
benign
5.8
pityriasis-versicolor mucules;
epidermodisplasia verruciformis
in patients with congenital cell
mediated immune deficiency and
those undergoing immuno
suppression for transplantation
30%
progress
to mali
gnancy
6,11
ano-genital condylomata acuminata;
atypical (flat) c.a. (HPV-11);
dysplasias and intraepithelial
neoplasias, grades 1 and 11; penile
warts; juvenile and adult onset
laryngeal papillomas (HPV-11)
usually
benign
GREENFIELD,
UNIVERSITY OF CAMBRIDGE,
DEPARTMENT OF PATHOLOGY,
TENNIS COURT ROAD,
CAMBRIDGE, CB2 1OP,
UNITED KINGDOM.
MARCH 1989
Oncogenic
potential
1
BASIC PROPERTIES AND CLASSIFICATION
The papillomaviruses have been classified as members of
the papovavirus family, which includes mouse polyoma,
SV40, and the human BK and JC viruses.89 All these viruses
have a closed circular double stranded DNA genome that is
complexed with histones, forming nucleosomes that are
Disease
5
St. John’s Medical College Journal of Medicine
Type
Disease
Oncogenic
potential
7
common warts of meat and
animal handlers
benign
9,12,
14
epidermodysplasia
verruciformis
HPV12,17 &
20 lesions
15,17
basiloma (type 20)
can pro
gress to
carci no
mas
19-25
VIRUS-HOST INTERACTIONS
Vegetative replication of papillomaviruses appears to be
restricted to the differentiating keratinocytes in the upper
epithelial layers. It is thought that the virus infects the basal
cells, possibly through a wound, and remains latent there.
Then, the establishment of infection may require cell division
(during wound healing), subsequently, the viral life cycle may
require specific factors only provided by the sequental
differentiated states of the host tissue. The ‘transformation
zones’ between columnar and squamous epithelia located in
the nasal mucosa, • the larynx, the uterine cervix, and the
borders of healing wounds are particularly susceptible to viral
infection. The resevoir of viral DNA in infected, but
clinically asymptomatic epithelia is possibly the basal cell
layer.
36,40
13,32
oral focal epithelial hyperplasia
(Heck’s disease)
possible
progres
sion to
carcinoma
16,18
31,33
35,39
high grade dysplasias,
intraepithelial neoplasias &
carcinomas of genital mucosa;
Bowenoid papulosis, Bowen’s
disease; laryngeal, oesophageal
high correlation
with
genital &
oral carci
nomas
and some bronchial
carcinomas
26
cutaneous wart, patient with
immune deficiencies
unknown
27
cutaneous wart, renal transplant
recipient
unknown
29
cutaneous, intermediate warts
unknown
30,40
larynx
carcinoma
34
nongenital Bowen’s
disease
carcinoma
in-situ
37
keratoacanthoma
benign
38
in a melanoma
malignant
41
multiple condylomata and
cutaneous flat warts
benign
42
genital warts
6
. benign
The papillomaviruses induce warts, which are localised
lesions with distinct morphological and histological mani
festations.14 These may be hyperplastic, benign, ordysplastic and may exhibit nuclear atypia with continued replication
and division of suprabasal cells, abnormal mitoses and
possible chromosome aneuploidy.15-16-17-18 Some papilloma
virus lesions can progress to carcinoma in situ, character
ised by the presence of dividing cells throughout the host epi
thelium and penetration of the transformed epithelial cells
through the basement membrane. This can lead to epithelial
cell metastases and death.
EPIDEMIOLOGY AND CLINICAL
MANIFESTATIONS
The World Health Organisation estimates that the annual
worldwide incidence of cervical carcinoma is about 450,000
cases, and that, other malignancies of the genital and oral
mucosa account for another 150,000 cases. Even with
medical intervention, about 45% of the patients eventually die
of the disease. Epidemiological evidence suggests that high
grade lesions of the male and female genital tracts are
derived from a sexually transmitted disease. Establishing
the association between papillomaviruses and a variety of
benign and malignant genital tract
lesions was a
gradual process. Genital warts (condylomata acuminata)
have long been recognised as a venerial disease.19-20 Char
acteristic cytological changes-notably koilocytosis was
observed in a spectrum of low to moderate grade lesions of
the female genital tract.14-21 Papillomavirus particles were
visualised in such condylomata, and in papillomas of the oral
mucosa.22-23
Progression of genital warts to carcinomas in situ can oc
cur.24-25 Such carcinomas do not synthesise viral capsid pro
teins, but have been shown to contain viral DNA and
RNA.28-27-28-29-30-31-32 Many primary carcinomas, metastatic
tumours and most cell lines derived from cervical tumours
such as HeLa, CaSki and SiHa contain HPV DNA.33-34-35 This
VOL n
No. i —
St. John's Medical College Journal of Medicine
viral
DNA
is often integrated into one or more
chromosome sites and some of the early open reading
frames are often
transcribed.36,37,38,39,40,41,42,43,44
Comparable molecular investigations of some carcinomas of
the larynx have also revealed the presence of integrated H PV
sequences.45-46-29 It is important to remember that there are
two disease of the mucosa, those caused by H PV types 6 and
11, which will remain benign, and those caused by HPV 16,
18.31,33 which may undergo oncogenic conversion. How
ever, the presence of the virus alone is not sufficient to
ensure neoplastic progression, other etiological agents may
be involved. These may include the presence of other
microbial infections, growth factor or oncogene activation,
host immune status, local inflammatory responses, radiation
exposure, exposure to carcinogens natural and contracep
tive hormones and mechanical irritation resulting in the recur
rent presence of wound epithelium.
Recent molecular epidemiological studies have also demostrated a role for HPV in neoplasias developing from the rare,
cutaneous disease, epidermodysplasia verruciformis olasiaverrucoformis (e.v).47-48-49-50-51-52-53-33 Progression of these
lesions to carcinomas occurs in about one third of e.v.
patients with HPV types 5,8,12,17 and 20 in areas exposed
to solar radiation.54 Epidermodysplasias associated with
other viral types remain benign. The resevoir of these
viruses in human population is unknown, but it is thought that
these viruses are fairly common but seldom show overt
penetrance.
The role of the immune system in papillomavirus diseases is
not clear. The ubiquity of latent HPV infections is empha
sised by frequent and often acute outbreaks of
wart development in immunocompromised individu
als. 55.56.57.58.59.6o.6i infection with one type of virus does not
influence resistence or susceptibility to others. It is not known
how the host prevents the viruses from entering a productive
phase, or what the basis for sudden emergence or regression
of lesions at discrete sites may be.
MOLECULAR BIOLOGY OF THE HUMAN
PAPILLOMAVIRUSES
Among the HPV's only HPV-1, which forms plantar and
palmar warts is very productive in vivo. However, a number
of HPV types have been sequenced. Detailed sequence
comparisons between human and animal papillomavirus
genomes have revealed homologies ranging from 45%-85%
in the most conserved genes.62-63-64-12 The human papilloma
virus genome consists of two sets of open reading frames
(ORFs), the early and the late region, all controlled by the
upstream regulatory region (URR). The early region is
composed of seven reading frames, E1 to E7 which are
located in overlapping DNA sequences arranged in three
reading frames. The products of these ORFs are involved
in viral DNA replication, regulation. of transcription and
cellular transformation. In contrast to this, there are only
-----
MARCH 1989
------------------------------------------------------------------------
two overlapping later ORFs, L1 andL2, both of which encode
viral capsid proteins.
DNA REPLICATION AND mRNA
TRANSCRIPTION
Tandem multimer of viral episomes are seen in some high
grade lesions induced byCRPV,65 HPV-6,66,35 HPV1667 and
in some BPV-1 transformed mouse cell lines.68 They may
arise as a consequence of defective segregation during
termination of replication,
or through recombination.
Multimers contain several replication origins per episome and
initiation of any of them would enable the molecule to
duplicate. Occasionally as is the case in some carcinomas,
the viral DNA can integrate into host chromosomes. It is not
yet known whether this process of integration alters host
genes expression, or whether other events make viral DNA
replication more difficult, leading to a selection of transformed
cells with integrated viral genes. Episomal integration
results in the interruption of a viral gene, most frequently the
E1 ORF, and may result in a deletion in the E2 ORF.39-43-69
Homologous and illegitimate recombination events between
viral and host DNA sequences could result in tandem
repeats of subgenomic viral sequences at more than one
host locus.40-41,43
Trancription studies have been hampered by the difficulty
in recovering undergraded RNA from natural warts in
heavily keratinized epithelia in which only a small percentage
of cells express HPV genes.70 Most transformed cells, includ
ing BPV-1 transformed mouse cells.71-72-73-74 Shoper-virus
induced carcinoma cell lines.75-76,77 genital condylomata and
cervical carcinomas36,37,40 express only viral early region
genes. From various systems and experimental approaches,
a consistent picture of papillomavirus transcription has
emerged. All transcription occcurs along a single strand of
the DNA, consistent with the asymmetric distribution of the
ORFs. Most RNAs are spiced, and the species form families
with alternative processing patterns.74,75,78 Little is known
about the transcription activity as a function of tissue
differentiation. Late region transcription may depend, in part
on cleavage of nascent region transcripts.
FUTURE CONCERNS AND PROSPECTS
Most of the critical problems of papillomavirus research can
be clearly stated, and most of the approaches towards
the elucidation of the molecular biology of these viruses
is technically possible. There is an urgent need for a better
description of the normal epithelium in vivo, and a culture
system for maintaining normal epithelial cells and enabling
them to carry out a normal programme of differentiation in
vitro. Such a system would facilitate a study of the interplay
between viral gene expression during cellular differentiation,
transformation, invasion and through the lytic cycle of the
virus. Due to the increasing avaibility of patient biopsies,
progress in the isolation of a representative set of
--------- COMMUNITY HEALTH C£LL——
47/1, (First FloorlSt. Marks Hoad
BANGAlO8E-56O 001
7 —-
St. John’s Medical College Journal of Medicine
papillomavirus types has been rapid. The unravelling of their
genetic and biochemical properties will lead to a new
generation of moleculardiagnostics, including nucleic acid
probes and specific antibodies. Such reagents are, in turn,
assisting both the clinician and the patient, and have
opened a new avenue of molecular epidemiology that has
already linked specific papillomaviruses to a number of
epithelial diseases.
REFERENCES
1. Ciuffo G Innesto postiveo con filtrado di verrucae volgare
Venereol 1907:48:12.
20.
Oriel JD: Natural history of genital warts. Br J Vener Dis 1971 ;47:1.
21.
Koss
LG, Durfee GR: Unusual patterns of squamous epithelium of
the uterine cervix and pathologic study of oilocyticatypia. Ann N Y AcadSci
1956,63:1245.
22. Dunn AE, Ogilvie MM: Intranuclear virus particles in human genital wart
tissue: Observations on the ultrastructure of the epidermal layer. J
Ultrastructure Res 1968,22:282.
23. Frithof L, Wersall J: Virus-like particles in papillomas of the human oral
cavity. Arch Virusforsohung 1967:21:31.
G. I tai Mai
2. Shope RE , Hurst EW: Infectious papillomatosis of rabbits with a note on
the histopathology. J Exp Med 1933:58:607
3. Rous P , Beard JW: The progression to carcinoma of virus induced rabbit
papilloma (Shope). J Exp Med 1935:62:523.
4. Rous P. Kidd JG: The carcinogenic effect of a virus upon tarred skin.
Science 1936:83:468.
5. Rous P, Friedewald WF: The effect of chemical carcinogens on virus
induced carcinomas. J Exp Med 1944:79:511.
6. Syverton JT. Harvey RA, Berry GP, Warren SL: The Roentgen radiation
of papillomavirus (Shope) 1. The effect of X-rays upon papillomas on domestic
rabbits. J Exp Med 1941:73:243
7. Holinger PH.
Rabbett WF: Late development of laryngeal and
pharyngeal carcinoma in previously irradiated areas. Laryngoscope
1953,63:105.
8.
19. Rowson KEK , Mahy BWJ: Human papova (wart) virus. Bacteriol. Rev
1967:31:110.
24. zur Hausen H; Human papillomaviruses and their possible role in
squamous cell carcinomas. Curr Top Microbiol Immunol 1977; 78: 1
25. Syrjanen KJ: Human papillomavirus (HPV) infections of the female
genital tract with their association with intraepithelial neoplasia and
squamous cell cercinoma. Pathol Annu (part 1) 1986:21:53.
26 Durst M, Gissman L, Ikenberg H, zur Hausen H: A papillomavirus
DNA from a cervical carcinoma and its prevalence in cancer biopsy samples
from different geographic regions. Proc Nati Acad Sci 1983:80:3812.
27. Bosh: rt M, Gissman L. Ikenberg H, Kloinheinz A, Scheurlen W , zur
Hausen H: A new type of papillomavirus DNA and its presence in genital
cancer biopsies and in cell line serived from cervical cancer. EMBO J
1984:3:1151.
28. BeaudononS, Kromsdorf D, CroissantO, JablonskaS, Wain-Hobson S„
Orth G: A novel type of human papillomavirus associated with genital
neoplasias. Nature 1986:321:426.
29. Kahn TE. Schwarz E, zur Hausen H: Molecular cloning and
characterisation of the DNA of a new human papillomavirus (HPV 30) from
a laryngeal carcinoma. Int J Cancer 1986,37:61.
Melnick JL: Papovavirus group. Science 1962,135:1128.
9. Melnick JL,
1974,3.106.
Allison AC. Butel JS, et al: Papovaviridae. Intervirology
30. Kawashima M, Jablonska S, Fabre M, Obalek S, Croissant O, Orth G:
Characterisation of a new type of human papillomavirus found in a lesion of
Bowen's disease of the skin. J Virol 1986:57:688.
10. Gissman L, Schwarz E: Cloning of papillomavirus DNA in Recombinant Lorincz
31.
AT Lancaster WD, Temple GF: Cloning and characterisation
DNA research and virus (ed y. Becker) Boston. Martinos Nijhoff 1985; 173.
of the DNA of a new human papillomavirus from a woman with dysplasia of the
uterine cervix. J Virol 1986a;58:225.
11. McCance DJ, Kalache A, Ashdown K. etai' Human papillomavirus types
16 and 18 in carcinomas of the penis from Brazil Int J Cancer 1986:37:55.
32 Lorincz AT, Lancaster WD, Kuman RJ, Jenson AB, Temple
12. Pfister H, KrubkeJ. Dietrich W. Iftner T and Fuchs PG: Classification
of the papillomaviruses-ma ppi ng the genome.
Ciba Found Symp
1986:120:3.
GF Characterisation of human papillomaviruses in cervical neoplasia and
their detetion in routine clinical screening. Banbury Rep 1986b;21:225.
33. Ostrow R, Bender M, Niimura M Seki T, Kawasima M, Pass F, Farras A:
Human papillomavirus DNA in cutaneous primary and metastasised
13. Broker TR, Botchan M: Cancer cells 4/DNA Tumor viruses. In Botchan M, squamous cell carcinomas from
patients
with epidermodysplasia
Grodzicker T and Sharp PA eds. Papillomaviruses: Retrospectives and
verruciformis. Proc Natl Acad Sci 1982:79:1634.
prospectives, New York, Cold Spring Laboratories 1987; 17.
14. Croissant O, Breitburd F, Orth G: Specificity ofcytopathic effect of
cutaneous human papillomaviruses. Clin Dermatol 1985:3:43.
34. Stremlau A, Gissman L, Ikenberg H Stark M, Banasch P, zur Hausen H:
Human papillomavirus type 16 relate DNA in an anaplastic carcinoma of
the lung. Cancer 1985:55:1737.
15. Steinberg BM: Laryngeal papillomatosis is associated with a defect in 35. Lancaster WD. Kurman RJ, Sanz LE, Perry S’. Jenson AB Human
cellular differentiation. Ciba Found Symp 1986:120:208.
papillomavirus: Detection of viral DNA sequences and evidence for
molecular heterogeneity in metaplasias and dysplasias of the uterine cervix.
•16. Spriggs Al, Bowey CE, Cowdell RH: Chromosomes Of precancerous
Intorvirology 1983:20:202.
lesions of the cervix uteri: New data and a review. Cancer 1971 ;27:1239.
17. Fu YS, Reagan YW, Richart RM: Definition of precursors. Gynecol
Oncol. 1981; 12: s220
36, Lehn H, Ernst TM, Sauer G: Transcription of episomal papillomavirus
DNA in human condylomata acuminata and in Buschke- Lowenstein tumours.
J Gon Virol 1984:65:2003.
18. ReidR, Fu YS, Hershchman B.R. etal: Genital warts and cervical cancer
The relationship between aneuploid and polyploid cervical lesions. Am J
Obstet Gynecol 1984;6;150:189.
37. Lehn H, Krieg P, Sauer G: Papillomavirus genomes in human cervical
tumours: Analysis of their transcriptional activity. Proo Natl Acad Sci
1985:82:5540.
8
VOL II
No. 1-----
St. John's Medical College Journal of Medicine
38. Grussendorff - Cohen El. Ikenberg H. Gissman L: Demonstration of 56. Shokri-Tabibzadch S. Koss LG, Molnar J. Romney S: Association of
HPV 16 genomes in the nuclei of cervix carcinoma cells. Dermatologica
human papillomavirus with neoplastic processes in the genital tract of four
1985:170:199.
women with impaired immunity. Gynecol Oncol 1981 ;12:s129.
39 Pater MM. Pater A: Human papillomavirus types 16 and 18 sequences
in carcinomacelllines of the cervix. Virology 1985:145.313.
40. Schwarz E, Freese UK, Gissman Let al: Structure and transcription
of human papillomavirus sequences in cervical carcinoma cell. Nature
1985:314:111.
41. Yee C. Krishnan-Hewlett. Baker C, Schlegel R . Howley PM: Presence
and expression of human papillomavirus sequences in human cervical
carcinoma celllines. Am J Virol 1985:119'361.
42. Di Luca D. Pllotti S. Stefanon B et al.: Human papillomavirus type 16 DNA
in genital tumours. A pathological and molecular analysis. J Gen Virol
1986:67:583.
57. Jablonska S, Orth G. Lutzner MA: Immunopathology of papillomavirusinduced tumours in different tissues. Springer Semin, Immunopathol
1982:533.
58. Jablonska S. OrthG, Obalek S. Croissant O' Cutaneous warts, clinical.
histologic andvirologic correlations. Clin Dermatol 1985:3:71.
59. Chardonnet Y, Viac J, StaquetMJ, Thivolet J: Cell mediated immunity
to human papillomavirus Clin Dermatol 1985,3:156.
60 Lutzner MA Papillomavirus lesions in immunosuppression. Clin Dermto
1985:3.165.
61. Gassenmeier A. Fuchs P. Schell H, Pfister H: Papillomavirus DNA
in warts of immunosuppressed renal allograft recipients. Arch Dermatol Res
43. Durst M. Schwarz E and Gissman L: Integration and persistance of human 1986:278:219.
papillomavirus DNA in genital tumours. Banbury Rep 1986, 21:273.
62. Schwarz E, Durst M. Demanowski C et al: DNA sequence and genome
44. Tsunokawa Y. Takabe N. Nozawa Set al
Presence of human
organization of genital human papillomavirus type 6b. EMBO J 1983:2:2341.
papillomavirus type 16 and type 18 DNA sequences and their expression
in cervical cancers and cell lines from Japanese parents. Int J Cancer
63. Cole St. StreekRE: Genome organisation and necleotide sequence of
1986:37:499.
human papillomavirus type 33 which is associated with cervical cancer. J Virol
1986:58:99.
45. Brandsma JL. Steinberg BM, Abramson AM. Winkler B: Presence of
human papillomavirus type 16 related sequences in verrucous carcinoma of
64. Fuchs PG, Iftner T. Weininger J, Pfister H: Epidermodysplasia
the larynx. Cancer Res 1986.46:2185.
verruciformis-associated human papillomavirus 8. Genomic sequence and
comparative analysis. J Virol 1986,58:626.
46. De Villiers EM, Neumann C, Le JY. Wcidauer H, zur Hausen H: Infection
of the oral mucosa with defined types of human papillomavirus. Med Microbiol
6.5 Wcttstoin FO, Stevens JG: Variable-sized free episomes of Shope
Immunol 1986:174:287.
papillomavirus DNA are present in all non-virus producing neoplasms and
integrated episomes are detected in some. Proc Natl Acad Sci 1982:79:790.
47. Orth G, Jablonska S. Favre M. Croissant O. JarzabekChorzaleska M. Rzesa G
Characterisation of two types of human
66. Gissman L. de Valliers. zur Hausen H: Analysis of human genital warts
papillomaviruses in lesions of epidermodysplasia verruciformis. Proc Natl
(condylomata acuminata) and other genital tumours for human papillomavirus
Acad Sci 1978:75:1537.
type 6 DNA. Int J Cancer 1982:29:143.
48. Orth G. Jablonska S. Jarzbek-Chorzeleska Metal: Characteristics of the
lesions and risk of malignant conversion is related to the type of human
papillomavirus involved in epidermodysplasia verruciformis. Cancer Res
1979:39:1074.
49 Orth G. Favre M. Breitburd F. Croissant O, Jablonska S, et al:
Epidermodysplasia verruciformis: A model for the role of papillomaviruses in
human cancer. Cold Spring Harbor Conf. Cell Proliferation 1980.7:259.
50. Green M. Brackmann KH, Sanders PH et al: Isolation of a human
papillomavirus from a patient with epidermodysplasia verruciformis: presence
of related viral DNA genomes in related urogenital tumours. Proc Natl Acad
Sci 1982:79:4437.
67. Durst M, Klemheinz A, Hotz M. Gissman L: The physical state of human
papillomavirus type 16 DNA in benign and malignant genital tumors. J Gen
Virol 1985:66:1515.
68. Allshire RC, Bostock GJ: Structure of bovine papillomavirus type 1
DNA in a transformed mouse cell line. J Mol Biol 1986;188:1.
69. Matsukura T. Kanda T, Furuno A, Yoshikawa H, Kawana T, Yoshiike
K Cloning of monomeric human papillomavirus type 16 DNA integrated
within cell DNA from a cervical carcinoma. J Virol 1986:58:379.
70. Engel LW. Heilman CA, Howley PM: Transcriptional organisation of
the bovine papillomavirus type 1. J Virol1983:47:516.
51. Lutzner MA, Orth G, Dutronquay V. Ducasse MF. Kreis H, KrosnierJ:
Detection of human papillomavirus type 5 DNA in skin cancers of an
immunosuppressed renal allograft recipient. Lancet 1983;ii:422.
71. Amtmann E, Sauer G:
Bovine
papillomavirus transcription:
Polyadenylated RNA species and assessment of the direction of
transcription. J Virol 1982:43:59.
52. Pfister H, Gassenmeier A, Nurriberger F.
Stuttgen G: Human
papillomavirus 5-DNAin a carcinoma of an
epidermodysplasia
verruciformis patient infected with various papillomavirus types. Cancer Res
1983:43:1436.
72. Heilman’GA, Engel L, Lowy DR, Howley PM: Virus specific transcription
in bovine papillomavirus transformed mouse cells. Virology 1982:119:22.
73. Stenlund A. Zabielski J, Ahola H, Moreno-Lopez J, Pettersson U:
Messenger RNAs from the transforming region of bovine papillomavirus type
53. Yutsudo M, Shimakage T, Hakura A: Human papillomavirus type 17 1. J Mol Biol 1985:182:541.
DNA in skin carcinoma tissue of a patient with epidermodysplasia. Virology
74; Yang Y, Okayama H, Howley PM: Bovine papillomavirus contains
1985:144:295.
multiple transforming genes. Proc Natl Acad Sci 1985;82:1030.
54. Pfister H: Biology and biochemistry of papillomaviruses. Rev Physiol
75; Georges E, Croissant O.Bonneaud N, Orth G: Physical state and
Biophem Pharmacol 1984:99:111.
transcription of the genome of the cottontail rabbit papillomavirus in the
55. Obalek S, Gilinski W, Haftek M. Orth G, Jablonska S: Comparative warts and in the transplantable Vx2 and Vx7 carcinomas of the domestric
rabbitl J Virol 1984:51:530.
studies on cell mediated immunity in patients
with different warts.
Dermatologica 1980:161:73.
MARCH 1989
9
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76. Nasseri M, Wettstein F: Differences exist between viral transcripts in
cottontail rabbit papillomavirus induced bening and malignant tumours as well
as non-virus-producing and virus-producing tumours. J Virol 1984;51:706.
77. Danos O, Georges E, Orth G, Yaniv M: Fine structure of the cottontail
rabbit papillomavirus mRNAs expressed in the transplantable Vx2
carcinoma. J Virol 1985;53:735.
78. Yang Y, Okayama H, Howley PM : Bovine papillomavirus contains
multiple transforming genes. Proc Nati Acad Sci, 1985; 82: 1030
10
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THE THALASSEMIAS : A THERAPEUTIC REAPPRAISAL
NICHOLAS PEREIRA, JAYA THERATTIL, MALATHI YESHWANTH
ABSTRACT
The thalassemia syndromes are among the world’s most
common genetic disorders. They are a heterogenous group
of heritable hypochromic anaemias of varying degrees of
severity. The severe homozygous type requires regular
blood transfusions without which life expectancy is only a few
years. In the past several years, globin genes from a large
number of individuals with thalassemia have been cloned and
characterised leading to a nearly complete understanding of
the molecular defects responsible for these disorders. With
this knowledge, investigators are developing new strategies
for diagnosis and treatment which, it is hoped, will provide a
means for a rational genetic cure by the end of the century.
In this reappraisal we discuss the recent advances which
suggest an answer to this potentially fatal disorder.
INTRODUCTION
In
1925
Cooley and Lee described five
children
with anaemia, hepatosplenomegaly, pigmentation of skin,
prominant malar bones and decreased red cell osmotic
fragility. In 1929 they described two more cases and
clearly defined them as representing a specific condition.
The term thalassemia in Greek means 'the sea’ and was first
used in 1936 by Whipple and Bradford who stressed their
Mediteranean background. These are congenital haemo
lytic anaemias due to an inborn error of metabolism that
affects the formation of one of the polypetide chains of the
haemoglobin molecule and inherited as an autosomal
recessive trait. The heterozygous state may not produce
clinically recognisable effects or may give rise to a mild
degree of anaemia. The homozygous condition usually
results iri a severe anaemia which manifests in early
childhood (betathalassemia) or during foetal life (alpha
thalassemia).
mid-eastern Arab countries. Foci of high prevalence exist
also in India and Southeast Asia. In India the incidence
varies between 1.4- 8.78%.1 The disease is more frequently
seen in Sindhis and Lohans but cases have been encoun
tered in many other communities. It is not infrequent in South
India.2
THE THALASSEMIA SYNDROMES
In thalassemia, there is impaired production of polypeptide
chains in the haemoglobin molecule. If the production of the
ex-chains is impaired the condition is called a - thalassemia
and if the production of p - chains is impaired, it is called
p - thalassemia. The condition may be present in a heterozy
gous state when only one of two allelic genes are defective
so that the clinical picture may be mild (thalassemia minor).
When both the genes are defective i.e., in a homozygous
state, the clinical effect is severe (thalassemia major).
Table -1
Various genetic defects include abnormalities of messenger
RNA processing,
deletion
of genetic material, and
changes in DNA sequence. These result in a deficient
quantity of mRNA., which leads to deficient synthesis of
haemoglobin polypeptide chains. More than 30 distinct
mutations leading to the thalassemia phenotype have been
described. Different types of thalassemia with different
clinical and biochemical manifestations are associated with
defects in different polypeptide chains (alpha, beta, gamma,
delta). The most common genetic variety of thalassemia
involves impaired production of beta-chains ( p -thalas
semia).
TABLE I CLASSIFICATION OF THALASSEMIA
ex - Thalassemia
Clinical Features
GEOGRAPHIC DISTRIBUTION OF BETA
THALASSEMIA
1. Hydrops fetalis
Death in uteroor shortly after
birth.
The p - thalassemia gene is prevalent in ethinc groups.
From areas around the Mediterranean islands, and in the
2. HbH disease ( p4)
Haemolytic anaemia of variable
severity, Spleenomegaly, mild
Jaundice.
NICHOLAS PEREIRA-MBBS- P. G. RESIDENT
JAYA THERATTIL-MBBS - RESIDENT INTERN
MALATHI YESHWANTH - MD DCH - PROFESSOR
ft a - Thalassemia trait
Mild - moderate microcytic hypoHeterozygous (minor chromic
anaemia.
CORRESPONDENCE ADDRESS:
NICHOLAS PEREIRA, DEPT. OF PEDIATRICS,
ST. JOHN'S MEDICAL COLLEGE HOSPITAL,
BANGALORE 560 034.
ft Silent carrier
No clinical stigmata. Detectable
through genetic interaction or by
biochemical studies.
MARCH 1989
11 —
St. John's Medical College Journal of Medicine
consists of 15ml/kg. of packed cells which raises the
haemoglobin level by 5 gm%.
0 - Thalassemia
1. Thalassemia major
Severe anaemia incompatible
with life unless regular transfu
sions are given.
2. Thalassemia
intermedia
Anaemia, Jaundice, Splenomegaly.
3. Thalassemia minor
Mild hypochromic
anaemia.
4. Silent carrier
No clinical stigmata.
microcytic
CLINICAL MANIFESTATION
Homozygous 0 - thalassemia usually becomes sympto
matic as a severe, progressive haemolytic anaemia during
the second six months of life. Severe anaemia and haemo
lysis, and hypertrophy of erythropoietic tissue occurs in
medullary and extramedullary locations (Table II) Massive
expansion of the marrow of the face and skull produces
typical faces. The spleen and liver are enlarged by
extramedullary haematopoiesis and hemosiderosis. Growth
is impaired in older children. Puberty rarely occurs because
of endocrine abnormalities. Diabetes mellitus and cardiac
complications may result due to secondary effects of
hemosiderosis.
Table II Complications of p - thalassemia major
Effects of Excessive Hematopoiesis
- Cranio-facial bone changes
- Spinal cord compression
- Pathological fractures
- Lymphadenopathy
Effects of Iron Overload
- Liver disease
- Cardiac disease
- Endocrine disease
Effects of Chronic Haemolysis
- Leg ulcers
- Gall stones
TREATMENT
In the recent years research has contributed not only to a
clearer understanding of the disease but also to a reason
able answer to the various problems of thalassemics.
“Hypertransfusion’’ is a strategy to maintain a minimum
haemoglobin level of 10gm%. This has striking clinical
benefits; it permits normal activity with comfort, it prevents
progressive marrow expansion that leads to cosmetic prob
lems associated with facial bone changes, and it minimizes
cardiac dilatation and osteoporosis.3 Also, maintaining a
higher haemoglobin level tends to reduce the hyperabsorp
tion of dietary iron that occurs with the dyserythropoietic
syndromes.4
“Super Transfusion” is a vigrous transfusional programme
devised to maintain a mean haemoglobin level above
12gm%, thereby completely suppressing endogenous
erythropoiesis.5 This also leads to shrinking of bone
marrow mass and, because of the reduction in blood
volume, the red cell transfusion requirements in a super
transfused
patient is no greater than in a hypertranfused
patient. This is supported by studies conducted on a large
group o.’ patients.6
NEOCYTE TRANSFUSION
A technique used now in some centres is to administer
’neocytes' or young red cells. This technique is known as
Neocytopheresis by some authors.5 Neocytes are collected
by continuous flow centrifugation or by fractionation of
conventionally collected blood units with a cell washer.7
Prolonged survival of such neocytes are demonstrated by
measurement of 51Cr half-life. Neocytes transfusions reduce
the red cell requirement as neocytes have prolonged survial
in vivo. Hence transfusion interval can be increased from 5 to
7 weeks and there is a proportionate decrease in the iron
overload.8 However, these units are still expensive to
prepare and must be considered experimental, since large
controlled trials demonstrating their efficacy have not yet
been performed.
The most frequent adverse reactions to transfusions is a
febrile reaction due to sensitisation to serum proteins and
leucocyte surface antigens. This complication is avoided by
transfusing washed cells, in which almost all serum proteins
and 95% of leucocytes are removed.5-7 Repeated transfu
sions increases the risk of minor blood group incompatibility,
serum hepatitis, viral diseases like cytomegalovirus, Ebstein
barr virus infection and the acquired immunodeficiency
syndrome (AIDS). Thalassemics come under the ‘high risk’
category for serum hepatitis and should be routinely admini
stered with hepatitis B vaccine.
CHELATION THERAPY
TRANSFUSIONS
Red cell transfusions are given to patients in order to sustain
life by relieving symptoms of anaemia. A single transfusion
11
An inevitable consequence of prolonged transfusion therapy
in thalassemia major is iron overload with secondary
haemochromatosis. The body iron burden is cumulative and
VOL II
No. 1-----
St. John’s Medical College Journal of Medicine
directly related to the number of transfusions. Each 250ml
of blood delivers to the tissues about 200mg of iron which
cannot be excreted by physiological means.
The cardiac complications which are the usual cause of
death appear to be a direct consequence of myocardial
siderosis. Non-chelated patients with severe p - thalassemia
die from iron overload between the age of 15 and 25 yrs.9
It is possible to reduce this lethal iron burden by treatment
with iron-chelating agents.
Desferoxamine (Desferal) is the most promising and the only
iron chelator that is currently in widespread clinical use.10
Desferoxamine is a modified hydroxamic acid compound
from Streptomyces pilosus.11lt induces iron excretion and
is relatively non-toxic. The two most effective routes are
intravenous and subcutaneous infusions.9 It is essential that
the chelation programme should be started at an early age. A
recent study showed that liver fibrosis in mullipily transfused
patients with thalassemia is a suitable measure of early
organ damage. These findings suggest that chelation
therapy in patients with transfusion dependant thalassemia
should be instituted at an early age, possibly before three
yrs., to prevent significant liver fibrosis and growth impair
ment.11 Desferoxamine may be administered as 40-60 mg/
kg. subcutaneous (SC) over 8 hrs. six days a week. The
effectiveness and the efficiency can be improved by subcu
taneous infusions utilising a portable battery-operated
pump.10 Desferoxamine should also be administered in
120mg/kg/dose IV over 8 hrs. during blood transfusions.
Desferoxamine is known to cause hypotension if rapidly
infused. Cataracts and other audiovisual toxicity has been
reported. Hence twice a year ophthalmological and ear
examination should be routinely advised to all patients on
continuous therapy with desferoxamine.
Desferoxamine has to be given parenterally and is
expensive. Research and investigations are being con
ducted at various centres to develop an agent which is less
toxic, financially a lighter burden on the patient and could
be administered orally. Another chelating agent EDHPA
(ethylene diamine N, n-bis 2-bydroxyphenyl acetic acid) has
been reported to chelate iron in animals when given orally?
Studies are being done to see if it is suitable for humans.
Other investigational chelating agents like rhodoturulic acid
and 2,3 - dihydrobenzoid acid have been found to be too toxic
or ineffective in human trials?
overloaded individuals, may be corrected by oral
administration.13 Vitamin E reduces the amount of peroxida
tionproduct (malonyldialdehyde) in red cell membranes,
but prolongation of red blood cell survival time has been
demonstrated only when Vitamin E is given parenterally
to thalassemic patients.14
Megaloblastic anaemia due to folic acid deficiency may
develop in patients with p - thalassemia major. Supplemen
tation with 1mg. of folic acid daily is recommended.15
SPLENECTOMY OR PARTIAL SPLENIC
EMBOLISATION
The main indication for splenectomy is hypersplenism re
flected by an increase in transfusion requirement of more than
300ml/kg/year to maintain a haemoglobin level of
10gm%.’6or if thrombocytopenia or neutropenia or pain due
to the size of the spleen develops. Splenectomy predis
poses the pateint to an increased
risk of severe
pneumococcal, streptococcal or haemophilus influenza
infection17-10-’9 and hence should be deferred till after the
first 5 years of life. Pneumococcal and Hemophilus vaccines
should be administered prior to splenectomy.
In an attempt to overcome the disadvantages of splenectomy
a study was conducted by Politis et al on partial spelenic
embolisation?1 The technique was described by Spigos et
al?° All patients treated by this procedure showed a reduction
in blood transfusion requirements. Serious infections that
are encountered in splenectomised patients did not occur
after emoblisation, presumably owing to preservation of
some immune function by the splenic remanant?1
BONE MARROW TRANSPLANTATION
In the recent years there has been a steady progress in the
use of allogenic bone marrow transplantation (BMT) for p thalassemia. A successful transplant offers the chance for
cure and perhaps a normal life expectancy. High success
rate is achieved in young children who have received
minimum blood transfusion prior to transplantation - (good
risk patients) in contrast to the older patients with extensive
transfusion history -(Bad-Risk patients)? Recently Lucarelli,
G. et al reported their experience of allogenic marrow trans
plantation in 40 patients with advanced thalassemia.22 Twen
tyeight patients were alive and disease free 1 to 3 years after
transplantation?2
ROLE OF VITAMINS
Vitamin C - Most thalassemic patients have low serum
levels of ascorbic acid. Its use in a dose of 100mg. orally has
shown to increase desferoxamine induced urinary iron
excretion.12
Vitamin E - (Alpha Tocopherol) deficiency is often present
because of excessive catabolism of this substance in iron
March io«9
BMT has a definite risk of death or chronic graft versus host
(CGVH) disease. Conventional therapyof blood transfusions
and chelation therapy offers a fairly good quality of life if
patient strictly adheres to the regimen. Thus the choice
between BMT and conventional therapy represents an ethical
dilemma as the specific risk of death or CGVH disease must
be weighed against the probability of a cure in an individual
patient.
13 —
St. John's Medical College Journal of Medicine
SOMATIC GENE THERAPY
The great power of recombinant DNA technology to provide
pure, cloned genes has inevitably led to the proposals for
genetic treatment of some inherited disorders.
Bone marrow stem cells being easily accessible somatic
cells, can be manipulated in vitro and reinfused. The stem
cells would then differentiatie and thereby repopulate
haemopoetic tissue completely in a suitable host environ
ment.23
ACTIVATION OF THE GAMMA - GLOBIN
GENES
c
The clinical severity of £ - thalassemia depends upon the
imbalance of a and non - a - globin synthesis. Patients
who inherit the gene responsible for increased gama
globin synthesis during the post-natal life (HPFH) have milder
clinical course than the usual patients with [3 - thalas
semia.24 Hence, reactivation of the developmentally re
pressed gama globin gene could be therapeutic modality in
treatment of patients with severe £-thalassemia. It has been
consistently observed that 5-Azacytidine an analog of
cytidine has increased gama-globin synthesis four to seven
fold in thalassemic patients.25 The mechanism by which 5azacytidine increases HbF production is not yet established.
Azacytidine is a carcinogenic compound.26 The long term
risks of the drug should be weighed against the patients
prognosis with conventional treatment.
PREVENTION
In those parts of the world where the incidence is high, the
economic burden placed on the society by thalassemia is
immense. Hence there is considerable current interest in the
development of programmes for prevention of different forms
of thalassemia. There are two ways in which this could be
achieved. The first is by prospective genetic cou nselling. This
has not been successful so far.27 More effort is being put
into developing the other major method of prevention i.e.,
Prenatal diagnosis.
Pre natal diagnosis programme for the prevention of thalas
semia entails screening of mothers at their first pre natal
visit, screening fathers in cases in which the mother is a
thalassemia carrier, and offering the couple the possibility of
pre natal diagnosis and therapeutic abortion if they are both
carriers of a gene for a severe form of thalassemia.
Amniocentesis - Amniotic fluid withdrawn under ultra
sonographic guidance around the 15th to 18th week of
gestation. It is possible to locate the £ - thalassemia gene
on amniocyte DNA. The overall accuracy was 99.4 percent
with a risk of foetal loss of about 3.5 percent.28
Chorionic villus sampling (CVS) is a recent development that
14
may have profound impact on early pre natal diagnosis. CVS
can be performed under fetoscopic control.29 The great
advantage of this method is that the result is available soon
after the biopsy at the 9th to 11th week of gestation. A
termination of pregnancy early in gestation is less risky and
stressful for the woman involved. Direct analysis of the
genetic defect or point mutation using
gene-specific
probes,30 or synthetic
oligonucleotide technique31 is
possible.
The past 20 years have witnessed dramatic improvements
in the survival andqualityof life of patients with thalassemia.
The next decade will certainly see further progress in
technology applied to cells and perhaps even gene transfer.
The thalassemia children, if well treated by their physicians,
can certainly afford to wait and see.
REFERENCES
1. Festa RS. Current concepts in the management of thalassemia. Indian J
Pediatr. 54:379, 1987.
2. Mehta BC. Haemolytic anaemia in Shah SJ., Anand PM., Mehta AB,
Sainani GS., Vishwanathan M eds API Textbook of Medicine. Bombay National Book Depot 4th ed. 943:45, 1986
3.
Piomelli S, Danoff SJ. Becker MH. Lipera MJ, Travis SF, Prevention of
1. Festa RS: Current concepts in the management of thalassemia. Indian J
Pediatr. 1987:54:379.
2 Mehta BC: HaemolyticanacmiainShahSJ, Anand PM, Mehta AB, Sainani
GS, Vishwanathan M eds: API Textbook of Medicine. Bombay - National
Book Depot 4th ed. 1986:943:45.
3. Piomelli S. Danoff SJ. Becker MH. Lipera MJ, Travis SF: Prevention
of Bone malformations and cardiomegaly in Cooley’s anaemia by early
hypertransfusion regimen. Ann NY Acad Sci 1964;165:427.
4. DeAlarcan PA, Donovan M. Forbes GB, Landow SA. Stockman JA.'lron
absorption in the thalassemia syndromes and its inhibition by tea. N Engl
J Med 1979,300:5.
5. Propper RD. Button LN. Nathan DE. New approaches to the transfusion
management of thalassemia Blood 1980:55:55.
6 Gabuttin Y, Piga A. Nicola P, et al: Haemoglobin levels and blood levels
in thalassemia. Arch Dis Child 1982;57:156.
7. Beracy AW, Klien HG, Chambers S, Corash L: Ex vivo selective isolation
of young red cells using the IBM -2991 cell washer. Blood 1983;61 1068.
8 Nicnhuis AW, AnagnonNP, LeyTJ: Advances in thalassemia research.
Blood 1984:63:738.
9. Cerami A: “Proper" use of desferoxamine. N Engl J Med 1976:294:1456.
TO. Ley TJ, Griffith P, Nienhuis AW: Trnasfusion haemosiderosis and
chelation therapy. Clin Hematol 1982:11:437.
11. Maurer HS, Lloyd-Still JD, Ingrisono Carol RN, Gonzalez-Crussi F,
Honig GR: A prospective evaluation of iron chelation therapy in children with
severe - thalassemia. Am J Dis Child 1988:142:287.
12.
Nienhuis AW: Vitamin C and iron. N Engl J Med 1981:304:170.
13. Rachmilewitz EA, Shifter A, Kahane I: Vitamin E deficiency in Bthalassemia major: Changes in hematological parameters following a
VOL II
No. 1 —
St. John’s Medical College Journal of Medicine
therapeutic trial with alpha-tocopheral. Am J Clin Nutr 1979;32:1850.
23. Williams AD, Orkin HS: Somatic gene therapy. Current status and future
prospects. J Clin Invest 1986;77:1053-1056.
14. Giardini O. Cantoni A, Donfrancesco A: Vitamin E therapy in homozygous
B-thalassemia (letter). N Engl J Med 1981;305:644.
24. Wood WG, Weatherall DJ, Clegg JB: Interaction of heterocellular
hereditary persistence of fetal haemoglobin with - thalassemia and sickle
15. Robinson MG. Watson RJ: Megaloblastic anaemia complicating cell anaemia Nature 1976;264:247.
thalassemia major. Am J Dis Child 1963;105275-280.
25. Ley TJ, De Simone J. Anagnou NP, et al: 5-Azacytidine selectively
16. Modell B. Total management of thalassemia major. Arch Dis Child increases - globin synthesis in a patient with - thalassemia. N Engl. J Med
1977;52:489-500.
1982;307:1469.
17. Elin SH. Shandling V, et al: The morbidity and mortality of splenectomy in 26. Clegg JB, Weatherall DJ,
childhood. Ann Surg 1977;185307-310.
thalassemia? Lancet 1983;1.536.
Bodmer WF:
5-Azacytidine for Beta
18. Erkalis AJ, Kevy SV, Diamond LK, Cross RE. Hazard of overwhelming 27. Stamatoyannopoulos G: Problems of screening and counseling in
hemoglobinopathies proceedings of the IV international conference on birth
infection after splenectomy in childhood. N Engl J Med 1967;267:1225-9.
defects, Vienna 1973; 268.
19. Smith CH, Erlandson ME, Stern G, Hilgartner MW: Post splenectomy
28. Robert NS, Dunn LK, Weiner S, Godnislow L, Miller R: Midtrimester
infection in Cooley’s anaemia. Ann NY Acad Sci1964;119748-57.
amniocentesis. Indications, techniques, risks and potential prenatal
20. Spigos DG, Jonasson O, Mozew M, Capek V: Partial splenic diagnosis. J Reprod Med 1983;28:167.
embolisation in the treatment of hypersplenism. Am J Roentgenol
29. Gustavii B. First trimester chromosomal analysis of chorionic villi Obtained
1979;132:777-82.
by direct vision technique. Lancet 1983;ii:507.
PolitisC,
21.
Spigos DG, Georgiopoulou, et al. partial splenic embolisation for
30. Orkin SH, Markham AF, Kazazian HH: Direct detection of the
hypersplenism of thalassemia major
Five year follow-up Br Med J
common mediterranean - thalassemia gene with synthetic
DNA 1987;294:665-67.
probes. An alternative approach for prenatal diagnosis. J Clin Invest
22. Lucarelli G, Galimberti m, Polchi P, et al: Marrow transplantation in 1983;71:775-779.
patients with advanced thalassemia. N Engl J Mod 1987;316:1050-5
31. Rosatelli C, Tuven T. DiTucci A, et al: Pre-natal diagnosis of - thalassemia
with synthetic - oligmer technique. Lancet 1985;1:241-243.
MARCH 1989
15 —
ORIGINAL ARTICLES
St. John's Medical College Journal of Medicine
CAMPYLOBACTER PYLORI A ONE MINUTE ENDOSCOPY ROOM TEST.
A.S.ARVIND, R.S. COOKS. TABAOCHALI, M.J.G. FARTHING
INTRODUCTION
An association has recently been described between the
presence of Campylobacter pylori on the gastric mucosa and
histologically confirmed gastritis, duodenal ulcer, gastric
ulcer and inpatients with non-ulcer dyspepsia.1 Whether this
organism is the cause of the inflammatory change is not yet
established, though studies in a single volunteer fulfilling
Koch’s third postulate supports an aeliological role in gastrilis
at least.2
Several approaches to the diagnosis of C.pylori infection
have been described, but all have the disadvantage that
results are at best not available for several hours after
endoscopy. It may take 2-3 days for histology and 4-7 days
for culture results of C.pylori to be known.3 Although Gram
stain of the biopsy is more rapid, in practice it still lakes a few
hours before the result is available. Langenberg et al
described
the
unusual characteristic of rapid urea
hydrolysis by C.pylori indicating the presence of pre formed urease in the organisms.4 This observation was
applied by McNulty and Wise to rapid diagnosis of C.pylori in
biopsy specimens by using Christensen’s 2% urea broth and
detecting ammonia production by a pH indicator.5
Only 50% of biopsies containing C.pylori were positive by
6 hours, some requiring up to 24 hours to yield a positive
result. Morris et al described the Campylobacter-like organ
ism (CLO)-test for diagnosing C.pylori infection which re
quires the biopsy to be inserted into a small piece of agar
containing urea and observing the colour change of a pH
indicator.6 Only 77% of C.pylori containing specimens were
ST. JOHN'S MED. COLLEGE & HOSP, BANGALORE
DEPT OF GASTROENTEROLOGY
A. S. ARViND M.B., M.R.C.P.
ASST. PROF. OF GASTROENTEROLOGY
ST. BARTHOLOMEWS HOSPITAL
WESTSMITHFIELD LONDON, ECIA 7 BE
DEPARTMENTS OF GASTROENTEROLOGY
AND MEDICAL MICROBIOL OG Y
R. S. COOK F.I.M.L.S. CHIEF M.L.S.O.
S. TABAOCHALI
PROF. OF MED. MICROBIOLOGY
M. J. G. FARTHING M.D., M.R.C.P.
READER IN GASTROENTEROLOGY AND
HON. CONSULTANT PHYSICIAN
16
read as positive by 1
requiring 3 to 24 hours.
hour,
the remaining specimens
We have used pre-formed urease in C.pylori to detect the
organism but have changed the incubation conditions to
permit ultra rapid diagnosis, the results of which are available
in the endoscopy room even before the instrument is re
moved from the patient.
PATIENTS AND METHODS
Two antral biopsy specimens were taken from 40 patients
with upper gastrointestinal symptoms who had been
referred for oesophago-gastroscopy and in whom we
suspected that C.pylori might be present. We studied 13
men and 27 women with a mean age of 53.5 years (range 26
to 84 years).
Microbiological culture, Gram slain and standard urease test:
One biopsy specimen was transported to the microbiology
laboratory attached to the inside of a sterile bijoi bottle
containing approximately 0.5ml sterile saline. All specimens
were processed within two hours of receipt. Using a sterile
swab, the biopsy specimen was smeared on to a sterile
glass slide for Gram straining and using the same swab the
biopsy specimen was then smeared and innoculaled on to
selective medium (Oxoid BAB No. 2 containing Skirrow’s
formula for selective supplement) ensuring maximum con
tact.7 The remainder of the biopsy was then placed into 0.5ml
of Christensen’s broth at 37 C.5 The culture plates were then
incubated in 37 C under microaerophilic conditions using
Campypak™ envelopes in Gas Pak™ jars (BBL Microbiology
systems Becton Dickinson & Co). The cultures Were exam
ined after 4 and 7 days. Colonies were identified as C.pylori
by their characteristic morphology on Gram stain, oxidase
positive and rapid production of urease.
In vitro production of urease: One C.pylori Strain isolated from
an antral biopsy specimen was used to test ureas production
in vitro. Using unbuffered solutions of urea in deionised water
at pH 6.8 and a range of concentrations of the organism, we
were able to show an immediate colour change from yellow to
pink when 2 x 106 or more bacteria were added to 0.5ml of the
urea solution. The colour change occured instantaneously
over a range of urea concentrations from 0.025-10% (w/v).
One minute urease test: An antral mucosal biopsy specimen
was placed immediately in the endoscopy room into a
capped 1.5ml Eppendorf tube containing 1ml of freshly
prepared 10% urea (w/v) in deionised water at pH 6.8
VOL II
No. i
St. John’s Medical College Journal of Medicine
containing two drops of 1% phenol red as a pH indicator. A
positive result was recorded if the colour changed from
yellow to pink within the first minute.
RESULTS
The results of the four tests to detect C.pylori in 40 antral
mucosal biopsies are shown in Table. 1. Microbiological
culture identified C.pylori in 21 (52%) of these biopsies. In the
“One Minute Test", 19 of these 21 biopsies were positive and
there were no false positives. Gram stain detected 16 of
the 21 positive biopsies and again there were no false
positives. The conventional urease test was less reliable.
Although there were 20 positive biopsies, 3 were false
positives due almost certainly to the presence of other
bacteria (coagulase negative staphylococci and Gram nega
tive rods). In addition there were 4 false negatives.
The ranges of time taken for the results of individual tests to
become available in the present study are shown in Table 2.
The findings confirm the rapidity of the “one minute test” and
concur with previous studies with respect to Gram staining,
culture and conventional urease testing 3-5-6
indicated.
Thus, the “one minute test” is an advance for those requiring
a rapid accurate method of diagnosing C.pylori infection.. It
has the advantage that a positive result is reliable and in more
than 90% of infected patients will be available in the endo
scopy room. This will assist planning therapeutic strategies,
lead where appropriate to prompt introduction of treatment
and possibly reduce recall outpatient appointments.
TABLE 1
COMPARATIVE EFFICACY OF DIAGNOSTIC
TESTS FOR
C.PYLORI
Culture
One
minute
Gram
stain
Direct
urease
21
19
19
21
16
24
20
20
FALSE POSITIVE
FALSE NEGATIVE
-
0
2
0
5
3
4
SENSITIVITY(%)
SPECIFICITY(%)
-■
91
100
80.8
100
84
86.4
Test
POSITIVE
NEGATIVE
DISCUSSION
TABLE 2
C.pylori has recently generated considerable interest among
micro biologists and gastroenterologists. Although the
primary aetiological importance of the organism in the
production of upper gastrointestinal symptoms and disease
is not clearly established, current evidence suggests that
it may be an important cause of antral gastritis.2 Effective
antimicrobial chemotherapy is available and has been shown
to improve symptoms and reduce gastritis.8
TEST
ONE MINUTE
GRAM STAIN
DIRECT UREASE
CULTURE
TIME
1 MINUTE
1-3 HOURS
UPTO 24 HRS
4-7 DAYS
REFERENCES
Since diagnosis at present relies on obtaining biopsy material
by endoscopy it seemed to us that it would be valuable to
develop a test, the results of which would be available
immediately following the examination. We have made
relatively minor changes to the well established urease test
for C.pylori but now have a diagnostic approach that yields
a positive result in more than 90% of infected individuals
within one minute of retrieving the biopsy. We consider the
main reason why this modification produces more rapid
results is that the urea in water solution, unlike Christensen’s
urea broth, is unbuffered. Thus any changes in pH will be
rapidly seen by the pH indicator. Our modification also has
the advantage that unlike the conventional urease test there
were no false positives. Other bacteria also produce
urease, albeit in much smaller quantities, but under
prolonged culture this appears to be sufficient to effect a
colour change.
The “one minute test” will miss approximately 10% of patients
and thus one can make a strong argument for back-up
microbiological culture. However, if the test is positive,
appropriate treatment can be initiated immediately if clinically
-----
MARCH 1989
------------------------------------------------------------------------
1 Goodwin OS, Armstrong JA, Marshall BJ : Campylobacter pyloridis
Gastritis and peptic ulceration J Clin Path 1986;39:353-65.
2. Marshall BJ, Armstrong JA, McGechie DBetal. Attempts to fulfill Koch’s
Postulates for pyloric Campylobacter. Med J Aust 1985;142:436-9.
3. Marshall BJ, McGechie DB,
Rogers PA et al:
Campylobacter infection and gastroduodenal disease.; Med
1985;142:439-44.
Pyloric
J Aust
4. Langenberg ML, Tytgat GN, Schipper MEI et al: Campylobacter-like
organisms in the Stomach of patients and healthy individuals, Lancet
1984;i:1348.
5. McNulty CAM, Wise R: Rapid diagnosis of Campylobacter-associated
gastritis. Lancet 1985;i: 1443-4.
6. Morris A, McIntyre D, Rose T et al: Rapid diagnosis of Campylobacter
pyloridis infection, Lancet 1986;i:149.
7. Skirrow MB : Campylobacter enteritis, a 'new’ disease. Br Med
1977;ii:9-11.
J
8. McNulty CAM, Gearty JC, Crump B et al: Campylobacter pyloridis and
associated gastritis, investigator blind, placebo controlled trial of bismuth
salicylate and erythromycin ethylsuccinate. Br Med J 1986;292:645-649.
-----COMMUNITY HEALTH CELL-------------47/1,(First FI««r)St. Marks Road
BANGALORE-560 OO1
17 —
St. John's Medical College Journal of Medicine
INTRALESIONAL STEROID VERSUS PRESSURE ON KELOIDSA COMPARITIVE HISTOPATHOLOGICAL STUDY
JIMMY THOMAS, CHERIAN M KOSHY, K. RAMAKRISHNAN NAIR
ABSTRACT
The study attempts to correlate histopathological changes
with clinical improvement seen in keloids treated with either
compression or intralesional steroids and to compare the
histological pattern at corresponding periods.
The study group consisted of twenty patients with keloids
divided into two groups of ten each on intralesional steroids
and compression therapy respectively. Initial pretreatment
biopsy and three monthly biopsies were taken for histopathol
ogical studies. It was found that intralesional steroids pro
duced changes at the cellular level earlier, i.e., by the end of
the first month, whereas it took two to three months for the
same changes to be exhibited by those on compression
treatment. Clinical regression however manifested simulta
neously in both groups.
INDEX WORDS
1 steroid, Keloids’.
INTRODUCTION
Keloids constitute an ever present problem and the most
carefully planned and executed surgical procedure is often
defeated by keloid formation. An important milestone in the
management of keloid was the introduction of intralesional
steroid (Triamcinalone) by Murray.1
A
keloid
is an abundant abnormal fibrous
tissue
proliferation located in the dermis and characterised by
elevation and extension laterally into the surrounding normal
tissues. There is continued,
albeit intermittent growth,
JIMMY THOMAS
MS DEPT. OF SURGERY, MEDICAL COLLEGE,
TRIVANDRUM
CHERIAN M KOSHY
MS, M.Ch, ASST. PROF. DEPT. OF PLASTIC SURG.
ST. JOHNS MEDICAL COLLEGE, BANGALORE 34
K. RAMAKRISHNAN NAIR
MS, M.C h.PROF.ANDHEADOFTHEDEPT.
DEPT. OF PLASTIC SURGERY,
MEDICAL COLLEGE, TRIVANDRUM 11
REQUESTS FOR REPRINTS
K. RAMAKRISHNANNAIR, PARVATHY VILAS,
AMBUJAVILASOMROAD, TRIVANDRUM 1.
18
absence of complete regression and a tendency to recur
after excision. Early in development or during periods of
active growth the lesion tends to be tense with a violaceous
hue, moderate vascularisation, and small blood vessals are
seen beneath the skin surface. Later in the development
and during quiscent periods, the keloid is less tense and
vascularsied. Nevertheless it remains elevated and firmer
than normal tissue. Epidermis overlying is usually smooth,
glossy and atrophic. Early in their life history the scars show
fibroblastic reaction with young collagen and young blood
vessels. In scars prone to develop into keloids, the matura
tion of the collagen, with the gradual and virtually total
disappearance of fibroblasts and development of neovascu
lature is delayed. In late established cases the fibroblasts
and blood vessels decrease in number and thick bundles
of collagen with nodular configuration is observed. The
dense sharply defined new growth in the corium has a whorl
like arrangement of collagen bundles. Superficial bundles of
collagen run parallel to epidermis but the deeper bundles
interlace in all directions. The collagen shows hyalinisation
and sclerosis.
MATERIALS AND METHODS
The twenty cases studied were those with keloids untreated
until they were taken for the study. These patients attended
the department of Plastic and Reconstructive Surgery,
Medical College, Trivandrum. The keloids were of identical
sizes and the twenty cases studied as Group I and Group II
of ten each were consecutive. Patients belonging to GM® I
were considered for intralesional steroid, and these of
Group II for compression treatment.
Group I. All ten cases were given weekly intralesional
Triamcinolone acetate (1 ml=10mg), diluted Where the le
sions were large. The injections were started after the pre
treatment biopsy. Care was taken to see that the total dose
did not exceed 80 mg.. per ‘course’. Biopsies were taken al
monthly intervals.
Group II. Of the ten patients included in this group only
one patient
coqld afford Jobst pressure garment.
Five patients were advised compression using ordinary
sponges with elastic harness. In all the other cases
elastocrepe bandage or custom made sports equipment
(ankle, knee guards etc.,) were used. Here also
compression was started after initial ‘pre-treatment’ biopsy,
and followed up with monthly biopsies. The patients were
instructed to report when they felt that the pressure was not
maintained.
VOL II
No. 4 —
St. John's Medical College Journal of Medicine
OBSERVATIONS
tissue treated with pressure of long duration.
The clincal parameters used to assess response to treatment
were the consistency of the lesion and evidence of regres
sion. In both groups clinical evidence of regression like
flattening of the lesion, softening of the keloid, and a paler
appearance were noted by the end of the first month.
Histological changes in Group I were manifested by the end
of the first month.
In both groups foreign body reaction was not seen. This was
similar to Mckenzie’s observation3. He stated that foreign
body reaction was frequently absent in keloids and serves to
distinguish it from hypertrophic scars where it is frequently
present.
Similar changes were however seen in patients in Group II
at the histologic level by the end of either the second month,
or the third month. The extent of histologic variation in both
groups was not remarkable. (Table-1)
It has been postulated that prolonged pressure does not
cause change in the thickness of the epidermis, while
pressure acting as a form of trauma may cause hyperkerato
sis and flattening. The topographical configuration of the
hypertrophic scar after pressure for six months was similar
to that observed in naturally remodelled scar tissue.2 The
TABLE 1 : HISTOPATHOLOGICAL OBSERVATIONS
GROUP II
GROUP 1
Epidermis
Atrophy in two cases
Atrophy in one
Rete ridges
absent in two cases
present in all
Dermal thickness
thinner in seven cases
thinner in three cases
Skin appendages
Normal in five cases, absent in
Present in five,
Collagen fibres
and hyalinisation
seen in all ten cases with
‘ground glass’ appearance
Collagen bundles showed an increase
in closeness and thickness
Calcification
Nil
Nil
Fibroblasts
No reduced in five cases
No: reduced in three cases
Round cell inflitration
seen in three cases
seen in three cases
Connective tissue
No degeneration or vacoulation
Degeneration or vacoulation in two cases
Foreign body reaction
Nil
Nil
DISCUSSION
Similar comparative studies of intralesional steroids versus
compression therapy have not been published so far. How
ever, certain observations are possible based on the findings
reported with either form of therapy has been used as a single
modality.
Baur et al observed the disimilarities between cell
populations of pressure and non-pressure treated scars and
this was our observation also.2 In two cases (Group II)
degeneration andvacoulation of connective tissue was seen.
The same workers also observed vacoulation, organalle dis
ruption, and frequent loss of cell membrane intregrity in scar
MARCH 1989
large collagen fibres had nearly assumed the size, structure
and orientation that can be seen in normal skin without any
evidence of nodules or their remains. Such changes were
beginning to be seen even after two months of the present
study in Group II. The effects of intralesional steroid has
been studied by Herold (1966). He states that the
‘dissolution of an established keloid is difficult to understand
with intralesional steroid’-4 One possible explanation is that
keloid is a dynamic lesion with destruction of old fibroblasts
and collagen and replacement with new tissues going on si
multaneously and continously. By blocking the fibroblasts the
steroid may upset the balance, so that the lesion regresses.
However it has also been opined that intralesional steroid
injection stimulates collagenolysis. Schetman suggested
19
St. John’s Medical College Journal of Medicine
REFERENCES
that the homogenisation and ground glass appearance of the
collagen may be related to the changed ground substance
rather than to the primary changes in the insoluble collagen
figril. In Group I of our cases we observed this characteristic
‘ground glass’ appearance of collagen with hyalinization.
Collagen having a less metabolic turn over rate would be
relatively resistant to the anti-anabolic action of steroid. It is
also stated that the atrophy and degeneration of appendages
contributed to the regression observed clinically.5 We could
also notice this atrophy or absence in five cases in the
Group I category treated with intralesional steroid.
4. Herold B: The treatment of Keloids with Triamcinolone Acetonide, Plast
Reconstr Surg 1966:38:202.
ACKNOWLEDGEMENT
5. Schetman et al: Cutaneous changes following local injection of Tri
amcinolone, Arch Dcrmat and Syph 1963:820-28.
1. Murray RD: Kcnalog and the treatment of hypertrophied scars and keloids
in Negroes and Whites. Plast and Reconstr Surg 1963.31:275.
2. Baur. PS et al: Ultrastructural analysis of
hypertrophic scars. J Trauma 1976; 16:458^961.
pressure treated human
3. Mckenzie DH: The ditterntial diagnosis of fibroblastic disorders.
Blackwell Scientific 1970:38-42
We gratefully acknowledge the sincere help and guidance of
Dr. Jayalakshmy, Assistant Professor of Pathology, Medical
College, Trivandrum, to make this study possible.
— 20
VOL II
No. 1
St. John’s Medical College Journal of Medicine
STATURE FROM FOOT SIZE
T. ABRAHAM PHILIP
ABSTRACT
The estimation of stature of an individual is of interest to the
clinician and the forensicologist. Some studies in the past
have indicated a 15% ratio relationship between foot size to
stature. To test this the foot outlines and footprints of 312
females between the ages of 20 to 32 years were examined.
In this study, Ration Index values of nearly 15% for foot
outlines to stature and 14% for footprints to stature were
developed. The results of this study have been compared
with those of previous studies. It was suggested by this study
that these index values can be used for the preliminary
prediction of stature.
KEY WORDS
Forensic Anthropology - Ratio Index - Footsize - Height.
INTRODUCTION
The need to estimate the stature of an individual is a problem
faced by both clinicians and forensicologists. The clinician
normally dealing with living subjects, may use any of the
ordinary methods to measure stature. However occasionally
he or she may be called upon to estimate the “uncoiled
height” of a child with khyphoscoliosis. This is because
many physiological values are often better correlated with
stature than age orweight.1 In Forensic work the estimation
of stature of the deceased from a few skeletal remains,
forms an important evidence in court. 2 Again if while
committing a crime, the prepetrator walked around there is
a strong possibility that footprints have been left behind.
Footprints as a means of identification has been used in
some countries, and in Hawaii an active criminal footprint file
is maintained.3
Footprints and foot outlines is thus a form of physical
evidence which has tremendous potential for use in a tropical
country like India. Regarding fpotsize to stature, Martin
enunciated a dictum, “Foot Length to stature within the
human races shows no great variation, on an average
amounting to 15%".4 This 15% ratio index has been con
firmed in studies on males and females abroad.5,6 It has
been also noted in males by one author in India.7 All these
studies however were conducted under laboratory test
DR. T.
ABRAHAM PHILIP, M.B.B.S.,
TUTOR,
DEPARTMENT OF FORENSIC MEDICINE,
KASTURBA MEDICAL COLLEGE
MANGALORE 575 001 INDIA
MARCH 1989
conditions. In this study an attempt was made to duplicate
the results under field survey conditions, the situation under
which investigating officers would be using the method in
practice.
Moreover there is an important difference between footprints
and foot outlines as shown by Robbins 6. Briefly put, the
foot outline provides the size parameters of the fleshed bare
foot, and represents the boundaries of the foot impression
on soft soil, mud or any other substance that produces
a three dimensional foot impression. The footprint on the
other hand provides the size dimensions of plantar surface
of the foot actually touching the floor, that is, the weight
bearing part of the foot. Footprints are the two dimensional
representation of the foot obtained on hard surfaces.
An extensive review of literature showed that no other author
has examined footprints and attempted to develop the ration
index values. This study was thus undertaken to fill in a
vaccum that existed.
MATERIALS AND METHODS
The subjects for this study were 312 apparently healthy
female volunteers within the ages of 20 to 32 years. The
only preselection criteria enforced was that the subjects had
both feet with all ten toes and were not grossly deformed.
Approximately half the subjects were from among the stu
dents of Kasturba Medical College Manipal and the rest were
from among the relatives of patients visiting the primary
health centres of the institution.
The height of the subjects was measured by the
methodology recommended in the Geneva Agreemet8 which
is as follows :
The subjects were asked to stand erect with no support given
on the vertical plane. The upper limbs held pendant, the heel
in contact and the axis of vision horizontal. The height of the
vertex above the ground was measured in this position. For
measurements of students, a metal scale (2 metres long),
affixed to a weighing machine was used. On field visits two
wooden scales (each 1 metre long) were affixed vertically to
the wall. The height of the subject was recorded in cen
timetres to the nearest millimetre. The minimum height re
corded was 137.50cm., while the maximum height was
177.80 cm. The mean height was 157.16cm with a standard
deviation of 6.56.
The footprints and foot outlines were taken by a method
improvised by the author. The subjects were first asked to
stand on a stamp pad (a composite made of 3 standard sized
large stamp pads) and allow the ink to spread evenly on the
21 —
St. John’s Medical College Journal of Medicine
separately for the footprint and foot
outlines
soles of the feet. The feet were then transferred one by one
onto the blank proforma sheets spread in front of the stamp
pads (Fig. 1)
identified
Fig 1 : Subject stepping off stamp pad onto proforma sheets
Fig. 3 : Landmarks pto and DLA identified on foot outline
With the subjects standing as they normally do on two feet,
the foot outlines were next drawn by the methodology recom
mended.8 With the subject's foot resting on the sheets of
paper and the leg perpendicular to the plane of this surface,
with the body erect, 4 short lines were drawn to mark the
position of the sides of the foot. These lines were drawn
below the two maleoli and along the medial and lateral
metatarsophalangeal articulations. Starting from these
points the contours of the foot were drawn using a “jotter" refill
held vertically at all times and as close as possible to the foot.
The interdigital clefts were entered into only if wide seperation existed between the toes. (Fig. 2).
b) A tangent was drawn to the footprint and foot outline
through the pte, which formed the Baseline (BL).
(Fig 3).
c) Then through the pte a perpendicular was drawn on the BL.
This perpendicular - The Designated Long Axis (DLA) was
extended such that it cut the anterior foot margin. The
perpendicular for the foot outline and footprint prdinarily co
incided,
however occasionally seperate lines had to be
drawn.
(d) The anterior margins of the toes of foot outline and
footprints were then marked out.
(e) For measurements on the parallel axis, a grid was pre
pared on tissue paper with parallel lines drawn perpendicular
to the BL. While measuring, the grid was placed such that
the two BLs coincided. The lengths of the toes were then
measured (Fig.4)
Fig. 2 : Method of drawing of foot outline
The measurement of the foot was taken by the methods
suggested by Robbins6. The procedure adopted was :
a)
The rear-most point of the heel - the pterion (pte) was first
22
Fig 4 • Foot outline with grid in situ tor measurements.
VOL II
No. 1 -----
St. John's Medical College Journal of Medicine
For ease of further study the sets of measurements were
grouped as follows:
The process was then repeated for fooprints.
(f) For measurements on the diagonal axis a grid was
prepared with radiating lines drawn at 5 angles to the DLA.
The oblique distance between the pte to the tip of the toes was
measured. The process for foot outlines was repeated for
foot prints.
All toe lengths were measured in centimetres to the closest
millimetre. The measurements were then fed into a compute
Zenith Orion 8000 for further analysis. A software package
was developed for the author by the programmer in
consultation with a statistician.
RESULTS
The measurements of the toes were taken in four sets, that
is five measurements each from the two feet on parallel and
diagonal axis from foot prints and foot outlines. The difference
between footprints and foot outlines has been explained
in the inlroducttion. The necessity of taking separate meas
urements on the parallel and diagonal axis was that at the
scene of crime the footprints or foot required for measurementson the parallel axis, the diagonal method can be used
for partial footprints.
(1)
(2)
(3)
(4)
P.F.O. - Parallel Axis Foot Outline;
D.FO. - Diagonal Axis Foot Outline;
P.F.P. - Parallel Axis Footprint; &
D.F.P. - Diagonal Axis Footprint.
The symbol R was used for right-foot and L for left foot.
After feeding of measurments the computer was pro
grammed to sort and select the toe length with the highest
measurement in each of the four sets. These Maximum Toe
Lengths were then used for further studies. Table No. 1
gives a summary of the maximum toe lengths recorded for the
two feet.
The ratio index of the maximum toe lengths to stature was
next calculated by the formula :
Ration Index % =
Maximum Toe Length x 100
------------------------------------ ;-------Stature
Table No. II gives the mean values obtained as an
percentage index in the four sets of measurements for each
foot.
Table I : Summary of Maximum Toe Measurement N = 312
TYPE
Left
Right
Max.
Mean
S.D.
27.30
23.78
1.05
19.90
25.50
22.26
1.06
1.07
21.20
27.40
23.86
1.04
1.05
19.90
25.50
22.30
1.05
Min.
Max.
Mean
S.D.
Min.
P.F.O.
21.40
27.00
23.92
1.06
21.20
p.r&;
20.20
25.90
22.32
1.05
D.F.O.
21.50
27.30
23.88
^b.F.P.
20.20
25.90
22.34
•
For explanation of P.F.O.; D.F.O.; P.F.P.; D.F.P.; see text
TABLE II: Maximum Toe Lengths to Stature as Ratio percentage Index N=312
P.F.O.
Left
Right
TYPE
Mean
I&d.
Mean
S.D.
15.16
0.54
15.14
0.54
15.19
0.55
14.17
0.53
14.19
0.54
D.F.O.
P.F.P.
14.21
D.F.P.
14.22
MARCH 1989
0.50
23 —
St. John’s Medical College Journal of Medicine
DISCUSSION
Table No. 1 shows that the measurements on the diagonal
axis are slighly higher than on the parallel axis. This is due
to the obliquity of measurements on the diagonal axis. The
difference though small is significant when it is kept in mind
that partial footprints may be obtained at the scene of crime.
The ratio index values developed are also slightly higher on
the diagonal axis than on the parallel axis. The ratios are
however similar for the two feet. This indicates that the ratio
index values for either foot can be used. Table No III shows
a comparison of the results of variouis authors.
It can be seen that the Martin Dictum stands substantiated by
this study.4 The results are slightly higherthan those obtained
by Davenport.5 The validity of the 15% ratio index has so far
been reported in India by Charnalia in his study of males of
Pondicherry.7 A review of literature showed no ratio index
values on females in India. This study attempts to fill this void.
The ratio index values are relevant for a population based
in Manipal.
One other point that needs to be made is that the studies
by Davenport5, Chharrnalia7 and in the reports cited by Martin
the feet were measured only in the parallel axis and use of
calipers was made. Robbins6 recorded foot outlines by the
TABLE
YEAR
method adopted for this study but took only the maximum
toe length without separating them into the parallel and
diagonal axes.
The ratio index values for footprints as seen on Table No
II shows a difference of 1% between foot outlin and
footprints. The value for footprints are around 14% on both
parallel and diagonal axis. This 1% difference was also
noticed by Robbins6 who is the only author to have developed
a ratio for footprints. Table No. IV gives a comparison of the
results, of the two studies. The Robbins6 study used only
maximum toe length of either feet without separating the
diagonal from parallel axis measurements. In the present
study the work has been taken a step further.
Another more significant point that has to be made is that
while the previous studies were carried out under laboratory
test conditions in this study field survey conditions was opted
for. That the results are comparable is significant.
Robbins first showed that the ratio relationship can be. used
as a method for predicting the stature of an individual.6 If a
foot print or foot outline is available at the scene of a crime,
then by using the appropriate ratio index value the approxi
mate stature can be predicted. Hence a preliminary alert tor
suspectscan be raised, even while more detailed investiga
tions at the Forensic Science Laboratories of the tootprint is
III : Comparison of Foot Outline Stature Ratio of Various Authors
AUTHOR
POPULATION
RATIO INDEX
1929
Martin (4)
Males & Females
15
1932
Davenport (5)
Females
14.5
1986
Robbins (6)
Americans Total
Females > 14 yrs
14.928
14.726
1989
Present Study
Rt. Parallel
Rt. Diagonal
Lt. Parallel
Lt. Diagonal
15.16
15.20
15.14
15.19
TABLE IV : Comparision of Footprint to Stature Ratio Index of Various Authors
Year
Author
Population
Ratio Index
1986
Robbins (6)
Americans Total
14.098
13.903
Females over 14
1989
Present Study
Rt. Parallel
Rt. Diagonal
Lt. Parallel
Lt. Diagonal
24
14.21
14.22
14.17
15.19
VOL II
No. i
St. John’s Medical College Journal of Medicine
made to obtain more clues.
REFERENCES
CONCLUSIONS
1. Zorab PA. Prime FJ and Harrison A: "Estimation of Height from Tibial
Length". Lancet 1963; 1; 195-196
The footprints of 312 females between 20-32 years were
studied. The study showed that the ratio relationship of 15%
exists between stature and foot outline and 14% between
stature and footprints. This ratio index values is in
concordance with studies in India and abroad. A possiblity of
the use of the Ratio Index value for estimation of stature is
suggested by this study.
2 Athavalc MC: "Estimation of Heights from Lengths of Forearm bones - A
study of One Hundred Maharastrian Male Adults of age between 25-30 years"
Am J Phys Anthropol 1978;48:105-112.
3 Petty CS: "Identification Procedures in Death Investigation" Modern Legal
Medicine, Psychiatry & Forensic Science; Eds-Curran WJ, MacGarry AL,
and Potty CS, FA Davis Company Philadelphia. 1211.
ACKNOWLEDGEMENTS
4. Martin R ed: Lehrbuch Dor Anthropologic; Gustav Fisher Verlag;
Stuttgart 1929. English translation of relevant portion sent by Prof. E.
Giles, Illinois, Personnel Communication.
The author hereby wishes to acknowledge and thank Mr. G.
5. Davenport CB: "The growth of Human Foot". Am J Phys Anthropol
1932;17(2);167-211
Nayak, Programmer, E.D.P. Centre, K.M.C. Manipal, and Mr.
T.K. Rao, Ass. Prof.
Statistics,
K.M.C. Manipal, without
whose help this study would not have been possible.
6. Robbins LM. “Footprints Collection. Analysis and Interpretation". CC
Thomas Springfield U.S.A. 1985.
7. Charnalia VM; "Anthropological Study of Foot and its relationship to
stature in different castes and tribes of Pondicherry state". J Anat Soc India
1961;10:26-31.
8. Comas J ed: Manual of Physical Anthropology. CC Thomas springfield
U.S A. 1960; 713-717.
MARCH 1989
25
CASE REPORT
St. John’s Medical College Journal of Medicine
PRIMARY ADENOCARCINOMA OF THE JEJUNUM
LEO THEOBALD MENEZES, ARUN B. KILPADI
ABSTRACT
A case of primary jejunal adenocarcinoma occuring in a
middle aged lady is reported because of its rairty. The
literature on this pathological entity is reviewed.
growth was found at the Duodenojejunal flexure occluding the
lumen of the jejunum. There were 3-4 hard lymph nodes
palpable in the vicinity(Fig. 2).
CASE REPORT
A middle aged lady presented with epigastric pain aggravated
by food present since 1 month and increased since 4 days.
She also complained of vomiting after food and anorexia.
There was nohematemesisormelena. There was a history
of weight loss.
General examination showed pallor, no icterus, pulse 80/m
regular and BP 120/80mm, Hg. There were no significant
findings. Examination of the abdomen revealed an
epigastric fullness, visible gastric peristalsis and succussion
splash. There was no palpable mass or organomegally.
Examination of other systems, rectal and vaginal examina
tion revealed no abnormalities.
Fig. 1 : Barium meal study showing a sub total obstruction at D J flexure
With a clinical diagnosis of gastric outlet obstruction probably
due to a chronic duodenal ulcer, the patients was investi
gated. Haemogram, urine analysis, Blood urea, Blood
sugar and serum electrolytes were within normal limits. An
X-ray of the chest was also normal. Gastroscopy was
reported as ‘normal subtotal obstruction at the Duodeno
jejunal flexure with a possible intraluminal pathology’.
(Figure 1)
The patient was prepared with stomach washes and at
laparotomy the stomach and duodenum were normal, the
pylorus was scarred and fibrotic. A 3 cm. long, hard, annular
DEPARTMENT OF GENERAL SURGERY
ST. JOHNS MEDICAL COLLEGE AND HOSPITAL
dr. leg Theobald menezes b.sc., m.b.,b.s.
SENIOR M.S. RESIDENT
Fig. 2 : like resected segment of the jejunum showing the lesion
DR . ARUN B. KILPADI. M.B..B.S., M.S.
ASSISTANT PROFESSOR
All other viscera OB normal.
There were no other
significant lymph nodes or ascitis. The peritoneum and pelvic
cavity OB normal.
CORRESPONDENCE AND REPRINT REQUEST:
DR. ARUN B. KILPADI M.B..B.S., M.S.
ASSISTANT PROFESSOR
-DEPT,
GENERAL SURGERY
ST.JOHNS MEDICAL COLLAGE AND HOSPITAL
THE JOHN MC CORMACK HEALTH CENTRE
BANGALORE-560 034. KARNATAKA STATE INDIA.
The growth, along with the lymph nodes was resected with a
margin of 3-4 cms. on either side of it. Ah end to end
anastomosis was constructed between the duodenum and
jejunum. Truncal Vagotomy and Pyloroplasty were done.
The biopsy reported well differentiated mucin producing
adenocarcinoma of the jejunum, 4/7 serosal lymph nodes
with metastasis and surgical margins free of tumor(Fig. 3).
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St. John’s Medical College Journal of Medicine
adenocarcinoma as a complication of regional entertis;1,8 or
originating in Peutz - Jeuger Polyp.7
Adenocarcinoma of the jejunum is more common in males (1)
and has a peak incidence between the ages of 40-50 years.
The symptoms are often nonspecific and chronic resulting
in a delay in diagnosis.
The important symptoms are intermittent epigastric pain,
bleeding or signs of obstruction, perforation or a palpable
mass. Prigdon(1950) describes three symptoms complexes
for adenocarcinoma of the jejunum.4 (a) anaemia syndrome,
found in 68% of cases (b) obstructive syndrome found in
13% of cases, (c) perforative syndrome, found in 16% of
cases.
Fig. 3 : Photomicrograph .
Hematoxylin-Eosin x 100 showing well
differentiated mucin producing adeno*carcinoma of the jejunum.
The post operative course was uneventful and the patient
received a full course of chemotherapy with 600 mg. of 5
Flurouracil I.V. She has been followed up for one year now,
and is in good health and asymptomatic.
DISCUSSION
Malignant tumors of the small intestine are uncommon and
comprise only 3.6% of all gastrointestinal malignancies.3
Jejunal malignancies are extremely rare and may be primary
or secondary adenocarcinomas or metastatic.1 The latter
are more common and can occur as direct extension from
contiguous viscera such as the Pancreas, stomach or colon1
The rarity of malignancy in the jejunum, is incongruous
considering that, having a high cell turnover and constituting
several different types of cells such as columnar cells,
argentaffin cells, lymphoid tissue etc., the jejunum is an ideal
setting for development of malignancy.2 This rarity is
explained by (a) The rapid transit time which minimises the
exposure to ingested carcinogens, (b) The relatively sterile.
and fluid nature of the luminal contents, (c) The rapid
proliferation of mucosal cells which is said to inhibit the
growth of tumour microsomal enzymes particularly
benzpyrene hydrochloride and (e) Local immune responses
which may be able to suppress the tumour.1 The uncommon
nature of this lesion has caused a paucity of literature on the
subject which consists mainly of isolated case reports5.
The Barnes Hospital series of 1971 consists of only 5 cases
over a period of 21 years.1 Other reports have been from
Mittal et al., in 1980, four cases in ten years;3 Eduardo and
associates, nine cases in fifteen years reported in 1976;6
R.K. Gupta in 1978 reported one case of gastric outlet
obstruction which proved to be a jejunal adenocarcinoma.5
There
have
MARCH 1989
been
rare
case
reports
of
Jejunal adenocarcinomas are usually located within 15-30
cms. of the ligament of Trietz. Grossdy the tumour is
usually an encircling napkin ring type lesion, but it can be
sessile or polypoid.
The treatment of primary adenocarcinoma of jejunum in
general consists of wide resection of the lesion along with the
mesentric lymph nodes, and anastomosis. If resection is not
possible a palliative short circuiting is of value. Most of the
patients already have metastases at the time of diagnosis and
prognosis is dismal regardless of the mode of treatment.3
The overall survival rate is 20%. Paradoxically a higher rate
of survival is noted with surgery alone than with surgery and
radiotherapy.2 The higher the grade of the lesion and greater
the percentage of lymph node involvement the poorer is the
prognosis.
REFERENCES
1. Michael Kyriakos: Malignant tumours of the small intestine. Current
concepts in cancer 41(1)' 1973 pp 55-57.
2. Philip Rubin : Cancer of the G.l. Tract - Small Intestine diagnosis and
treatment". Current concepts in cancer 41(1), 1973: pp 54.
3. Mittal VK, BoozinJH: Primary malignant tumours of the small bowel. Am
JSur 1980;140:396-399.
4. Pridgon JE,
Mayo CW, and Dockerty MB: Cardnoma Jejunum
and Ileum exclusive of carcinoid tumours. Surg Gynae and Obst 1950,90:513524.
5. Gupta RK, BhargavaKN, Singh MP: Primary Adenocardnoma of Jejunum
- a case report. Ind J of Surg 1978,40:400-402.
6. Edwards IR, Robert WT: Primary malignant tumours of small intestine. Am
J of Gastroenterology 1970.54:30-43.
7. Alan E, Cordts and Richard Chabot J: Jejunal Carcinoma in a child. J of
Paed Surg 1983;18(2):180-181.
8. Paul E Collier, Paul Turowski, Daniel L Diamond : Small bowel
adenocarcinoma complicating regional enterities. Cancer, 1985;55(3):516521.
jejunal
27 —
SELECTED SUMMARY
St. John s Medical College Journal of Medicine
PRELIMINARY RESULTS OF THE COCHLEAR
CORPORATIONS MULTI ELECTRODE INTRACOCHLEAR
IMPLANT IN SIX PRELINGUALLY DEAF PATIENTS
CLARK G.M., BUSLAY P.A., ROBERTS S.A. ETAL. AM. J. OTOL 1987;8(3):234-239
SUMMARY
Cochlear Implants were inserted in six prelingual deaf
patients (3 adults, 1 juvenile and 2 children). Analysis of
hearing improvement post implant was encouraging. All
patients reported ability to detect loudness change and
improved ability to discriminate discrete auditory stimuli at
increased rates. Vowel and consonant identification scores
were improved as was the lip reading scores.
However, the post implant running speech identification
scores were improved only in the two children. The signifi
cance of this finding awaits elucidation.
COMMENTS
In 1973, a team of workers lead by W. House, an Otologist
and Jack Urban, a Bio-medical Engineer, first successfully
implanted an intra cochlear implant, hearing prosthesis in a
deaf adult. This seminal work, sparked off a flood of research
all over the world.1
However, the initial enthusiasm with which cochlear implants
was received is now tempered with the understanding that the
implant does not invoke a sensation of “sound" as is under
stood by normal individuals.
28
In this article the authors describe the results of extending the
use of the cochlear implant to prelingually deaf patients.
Prelingually deaf patients are either born deaf or become
deaf prior to speech acquisition.
It should be noled that the issue of the ideal implant (whether
single or multi channel, intra or extra cochlear, etc) is still far
from settled. Also implants in children should be approached
with caution as there are chances of electrode dissolution,
new bone formation in the cochlea, and electrical damage
to the spiral ganglion cells.2
Cochlear Implants are here to stay-and even in the present
uncertain state of the art - exlens ion of its benefits to new
groups of patients cannot be denied.
RAVLC.NAYAR.
REFERENCES
1 Clark GM et al . Development of Cochlear implants in Pfaltz CR (cd):
Advances in Otorhinolaryngology. Vol. 38, Karger Basel. 1987.
2. Long term effects of multi channel cochlear implants usage.Watlzman SB
et al; Laryngoscope, 1986:96(10): 1083-1087.
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