HYPERBARIC OXYGEN AND CORNEAL NEOVASCULARISATION

836 received

no

treatment.

HYPERBARIC OXYGEN AND CORNEAL NEOVASCULARISATION

who were considered to be the time of the episode.

Of the 24 17

patients

receiving anticoagulants, inadequately controlled at Hcemorrhage There were 160 episodes of bleeding; 28 required no active treatment, and anticoagulants were not discontinued. In 104, anticoagulants were discontinued, and in a proportion of these, patients in addition received local treatment in the form of vaginal douches and packs in the ward. No steps were taken to reverse the lowered prothrombin level. In 28 patients severe haemorrhage necessitated further intervention. All these patients received vitamin Kl intravenously until the thrombotest was within normal range. 12 were transfused only; 13 were taken to the theatre for vaginal packing, 6 needing transfusion in addition; and 3 patients underwent laparotomy for evacuation of clots or ligature of a vessel. 1 patient subsequently got staphylococcal bronchopneumonia and died. were

PAUL HENKIND M.D., M.Sc. New York SPECIAL FELLOW OF THE DIVISION OF NEUROLOGICAL DISEASES AND BLINDNESS OF THE NATIONAL INSTITUTES OF HEALTH,

BETHESDA,

operative

Summary and Conclusions 3777 patients have been treated with anticoagulants in the postoperative period. The control of treatment can be efficiently and economically carried out by means of the capillary thrombotest technique keeping the thrombotest level at 10 to 20%. Frequent estimations are necessary to The frequency of secondary ensure adequate control. not increased is (4-2%) (the majority greatly hxmorrhage of these required no treatment apart from withdrawal of anticoagulant therapy), and can be adequately controlled. The patients received phenindione from the third to the tenth postoperative day in doses sufficient to maintain the thrombotest level at between 10-20%. The frequency of thrombotic disease was reduced by a factor of 5. After ten years of experience in the use of prophylactic anticoagulants this treatment is now an established part of the postoperative gynaecological regimen. REFERENCES

Chalmers, D. G., Marks, J., Bottomley, J. C., Lloyd, O. (1960) Lancet, ii, 220. Dick, W., Matis, P., Mayer, W. (1959) Thrombos. Diathes. Hœmorrh., Stuttgart, 3 11. Morrell, M. T., Truelove, S. C., Barr, A. (1963) Brit. med. J. ii, 830. Sevitt, S., Gallagher, N. G. (1959) Lancet, ii, 981.

*

THE effects of hyperbaric oxygen are being studied both in vivo and in vitro. Apart from its proven efficacy in conditions characterised by deficient circulation or lowered oxygen tension, there is the possibility that the toxic effects of hyperbaric oxygen might prove useful therapeutically, particularly in discouraging the growth of vessels in some pathological conditions (Winstanley 1963). Heppleston and Simnett (1964) have recently demonstrated the damaging effect of pressurised oxygen on various in-vitro tissues of the mouse; they wondered whether it might similarly affect new-vessel formation in vivo. While much is known about the effect on vessels of ambient hyperoxia (Ashton 1957), few studies have been conducted with hyperbaric oxygen. The present experiment was designed to demonstrate the possible effect of hyperbaric oxygen on actively growing vessels. The cornea was chosen for this study because it is normally avascular, and any response of newly proliferating vessels could easily be recognised both in vivo and in vitro.

Discussion

We have previously discussed the prevalence of postthromboembolism and in particular, pulmonary embolism, and our views have been substantiated not only by our increased experience but by the findings of Morrell et al. (1963). The decision to introduce the study without a control group has in our view been fully justified. We consider the figures presented are impressive on their own, and taken in conjunction with other control trials-e.g., Sevitt and Gallagher (1959), Dick et al. (1959)-leave little room for argument. Criticism will no doubt be directed at the frequency of haemorrhage, and its associated dangers. It is right and proper in dealing with a complication with an overall frequency of roughly 1-2% and a fatality-rate of 3 per 1000 that the treatment should not further increase the risk. In our series, the total incidence of bleeding was 4-2%, and either transfusion or further medical treatment 1 patient died after operative was needed in 0-8%. and her death can be attributed indirectly to interference, We believe that the almost comanticoagulant therapy. elimination of thromboembolic complications, with plete the increased patient turnover that this implies and the almost total elimination of sudden loss of life in an apparently fit woman, more than justifies the possible increase of secondary haemorrhage.

MARYLAND

Material and Methods Sixteen adult guineapigs were anaesthetised with intraperitoneal sodium pentobarbitone; then, using a modification of Langham’s method (Ashton et al. 1951), 0-1 ml. of sterile 0-3 M alloxan was injected into the right anterior chamber of each animal. 5 to 7 days after injection, corneal neovascularisation became evident, and eight of the animals were placed in a pressure chamber supplied continuously with 100% oxygen at 1.5 to 2 atmospheres of pressure. The chamber held two guineapigs at a time, and was provided with a ’Plexiglas’ front window through which the animals were continually observed. Carbon dioxide was absorbed with soda lime placed in a tray beneath the animal platform. The control guineapigs were kept in their usual cages. When severe respiratory difficulty ensued (after 17 to 37 hours of continuous exposure to hyperbaric oxygen) the pressure chamber was slowly decompressed, and the guineapigs were removed to the atmosphere where their eyes were examined with a hand slit-lamp (Krimsky 10 x ) and a binocular dissecting microscope. All the oxygen-treated animals died spontaneously within several hours of being removed from the pressure chamber, and after death their chests were opened and their lungs were examined. Indian ink was then injected through the left ventricle of the heart until the corneal vessels appeared filled with ink. The eyes were enucleated and placed in pots containing 10% formol-saline. Upon the death of an oxygen-treated animal a paired control was killed with intraperitoneal sodium pentobarbitone, and studied as described above. After 24 hours’ fixation the eyes of the treated and control guineapigs were compared, using a binocular dissecting microscope, and flat preparations of the cornea were then made and examined by light microscopy. Results oxygen the adult guineapigs survived from 20 to 40 hours. Approximately 3 to 4 hours before their death severe respiratory distress characterised by gasping irregular respirations developed; but, despite slow decompression and removal to normal atmospheric conditions, they all died within 1-2 hours of leaving the pressure chamber. The lungs of the

In

*

hyperbaric

On leave from the Department of Ophthalmology, New York University College of Medicine. Present address: Department of Pathology, Institute of Ophthalmology, University of London, Judd Street, London, W.C.1.

837 animals were heavy and laden with oedema while those of the controls were normal. fluid, The extent and pattern of corneal neovascularisation were similar in both the oxygen-treated and the control animals, the vascularisation being more extensive at the termination of the experiment than at its beginning (figs. 1-4). Examination with the hand slit-lamp before death, and by light microscopy of the postmortem specimens injected with Indian ink, failed to reveal any areas of vaso-obliteration, either partial or total. The untreated left eyes of all the guineapigs appeared perfectly

oxygen-treated

normal. Discussion

The idea that hyperbaric oxygen might affect newly forming vessels in proliferating and neoplastic tissue is a logical outgrowth of previous work conducted for the A most part under conditions of ambient hyperoxia. number of workers (Ashton et al. 1953, Gyllensten and Hellstrom 1954) have demonstrated that immature retinal vessels of various species can be obliterated by ambient hyperoxia-a situation which may in the premature

human infant lead to the condition known

as

retrolental fibroplasia. On the other hand, though retinal vessels become slightly constricted when a subject is placed in 100% ambient oxygen (Cusick et al. 1940), and even more so in hyperbaric oxygen (Dollery et al. 1964), they do not become obliterated. Even immature retinal vessels resist vaso-obliteration if the retina is detached from the underlying choroid (Ashton and Cook 1955). Study of proliferating corneal vessels, newly formed vessels in rabbit-ear chambers, and the growing vessels of transplanted tumours, show that they will not obliterate in high concentrations of ambient oxygen (Ashton 1957). In 1961, Pedler demonstrated that the partial vaso-obliteration of the developing retinal vessels of the ratling, caused by ambient hyperoxia, was converted to total obliteration when the pressure was raised by one atmosphere. This effect, as well as the toxic effects on in-vitro tissues noted by Heppleston and Simnett (1964), apparently depends upon a raised oxygen tension rather than any mechanical effect of pressure. It is therefore conceivable that increasing the oxygen tension mature

Fig. I-Guineapig eye 7 days after alloxan injection into the anterior chamber. Note the prominent

hazy corneal stroma.

Fig. 2-Same eye as in fig. 1 after 20 hours’treatment with hyperbaric

peripheral corneal neovascularisation and the (x 6.)

oxygen.

Note the increase in corneal vascularisation.

specimen

Fig. 3-Guineapig

eye 5

X

(Indian-inked

6.)

days after alloxan injection into the anterior

chamber.

Note the early peripheral corneal neovascularisation and the comeal opaqueness due to stromal oedema. ( x 6.)

Fig. same eye as in fig. 3 after 40 hours’ treatment with hyperbaric oxygen.

Note the great increase in corneal neovascularisation.

838

by putting

oxygen under pressure might cause vasoobliteration of vessels which are apparently unresponsive

multiple congenital anomalies previously ascribed to mongolism. Chromosomal studies on the family indicate

ambient hyperoxia. Winstanley (1963) attempted to affect the proliferating vessels of diabetic retinopathy by treating patients with short-term hyperbaric oxygen, without observable success. It should be pointed out that the patients received oxygen for a shorter time than that required to obliterate immature retinal vessels. In the present study no effect of hyperbaric oxygen on the newly forming vessels in the guineapig cornea could be demonstrated. The oxygen tension of the guineapig’s blood was not measured, and it is possible that in the later stages of the experiment, as respiratory difficulty ensued, the oxygen tension of the blood decreased. It is most significant that, although the oxygen-treated animals died, they survived the period necessary for obliteration of immature retinal

that the new chromosome arose from a balanced translocation between chromosomes 6 and 9 observed in the mother.

to

vessels. Conclusion

The conclusion at present, therefore, is that little or no evidence exists to suggest that oxygen can cause obliteration of vessels other than immature retinal vessels. I am indebted to Prof. Norman Ashton for his suggestions and interest in this work. I should also like to thank Mrs. P. Rawlings and Mr. G. Knight for their technical assistance. REFERENCES Ann. Rev. Med. 8, 441. Ashton, (1957) C. (1955) Brit. J. Ophthal. 39, 457. Cook, — — Langham, M. (1951) ibid. 35, 718. — Ward, B., Serpell, G. (1953) ibid. 37, 513. Cusick, P., Benson, O, Boothby, W. (1940) Proc. Mayo Clin. 15, 500. Dollery, C., Hill, D., Mailer, C., Ramalho, P. (1964) Lancet, ii, 291. Gyllensten, L., Hellstrom, B. (1954) Acta pœdiat. 43, suppl. 99, p. 1. Heppleston, A, Simnett, J. (1964) Lancet, i, 1135. Pedler, C. Cited by Ashton, N. (1961) Trans. ophthal. Soc. U.K. 81, 145. Winstanley, J. (1963) Brit. J. Ophthal. 47, 542. N.

—

MATERNAL TRANSMISSION OF A NEW GROUP-C(6/9) CHROMOSOMAL SYNDROME RUSSELL A. ROHDE M.D. Harvard DIRECTOR,

HUMAN CYTOGENETICS

RESEARCH LABORATORY

LOS ANGELES COUNTY

BORIS CATZ M.D. Mexico

City

ATTENDING PHYSICIAN, DEPARTMENT OF MEDICINE

HOSPITAL,

CALIFORNIA

THE congenital chromosomal syndromes are those in which a causal relationship probably exists between identifiable chromosomal aberrations and congenital malformations or biochemical disorders. The pathogenetic mechanisms are not known precisely, but probably they derive from genic imbalance of entire chromosomes or of chromosome fragments (Rohde and Berman 1963). Patau (1964) has suggested that simple trisomy of entire autosomes may be restricted to the Dl (13-15), El (16-18), and the G, (21-22) syndromes. Failure to observe simple trisomy of other autosomes could be due either to the presence of triplicated lethal loci and/or to excessive genic imbalance, the latter also being responsible for the rarity. of monosomies (except in the sex chromosomes). However, partial trisomies and partial monosomies due to translocations have been reported for some of the group D, E, and G chromosomes (Lindsten et al. 1962, Walker. and Harris 1962, Rohde et al. 1963) and for several of the larger autosomes (Edwards and Clarke 1960, Böök et al. 1961, Edwards et al. 1962, Lee et al. 1964). Such cases are especially important since cytogenetic investigation of other family members may reveal balanced carriers of structurally aberrant chromosomes. We report here the association of a hitherto undescribed group-C translocation chromosome in a young girl with juvenile hypothyroidism, thyroglobulin antibodies, and

Case-report The proposita, a Negro girl, was born on May 3, 1945, after a 40-week gestation. She weighed 5 lb. 11 oz. (2590 g.) at birth. During the 7th month the mother had had a threatened miscarriage with profuse haemorrhage. Delivery was uneventful; but the baby was suspected of having mongolism, although the mother was told that the test results were not entirely conclusive. The mother was 27 and the father 33 when the child was born. Both parents were healthy, and they later had three sons whose growth and development were normal. In 1948 there was a miscarriage after a 4-month pregnancy. From infancy until age 12 the girl had frequent unexplained episodes of nausea and vomiting. Childhood diseases included measles, mumps, and chickenpox. Because of mental deficiency she attended a workshop and school for the handicapped. Desiccated thyroid was prescribed at age 11, when hypothyroidism was suspected. The drug was discontinued at age 16 because improvement was negligible, but it was resumed at l71/2 when examination revealed a goitre, obvious hypothyroidism, and sexual infantilism. Genetic investigation was done on the family and proposita when she was 18. The girl was mentally retarded and obese. Her weight was 109 lb. (49-5 kg.), and height 4 ft. 41/2 in. (133 cm.). Blood-pressure was 140/106 mm. Hg. The facies was peculiar, and there was micrognathia and flattened superior helices of the ears. The skin was dry and coarse, with roughened areas in both antecubital fossa:. Lanugo-like hair covered the back and extremities, but pubic and axillary hair were sparse. Ophthalmological study showed ectopic pupils, bilateral myopia and astigmatism, and tonic pupil and exotropia of the right eye. Also present were macroglossia, malocclusion of teeth, goitre, short stenotic vagina, small cervix, and impalpable corpus and adnexa. The feet had prehensile clefts, widely spaced halluces, syndactylism of 2nd and 3rd toes, and tiny 5th digits. The palms had full simian lines, and the 5th fingers were very small and incurved, and bore single flexion creases (fig. 1). Chemical studies showed a serum protein-bound iodine of 2-8 flg. per 100 ml., serum-cholesterol 310 mg. per 100 ml., thyroglobulin antibody titre 1/16,400, and urinary folliclestimulating hormone 16-50 mouse units per 24 hr. Fingerprint analyses showed 6 ulnar loops and 4 whorls. The total ridge countsof the hands were 93 for the right and 99 for the left. The palmar atd angles were both 48°. Dr. Irene Uchida, of the Children’s Hospital, Winnipeg, Manitoba, made print analyses and concluded that they were " not suggestive of any known

syndrome ". a

A neutrophil alkaline-phosphatase test yielded value of 117 units on the patient, and 120 units on a control.

Cytogenetic Studies Sex-chromatin was observed in 32% of buccal nuclei. The modal chromosome count (Rohde 1963) of cultured lympho-

Fig. 1-Hands of proposita, showing simian folds and small incurved 5th digits bearing single creases.