Abnormal Collagen in Ataxia Telangiectasia Maj
Edward W. McReynolds, MD; Mustafa K. Dabbous, PhD; Aram S. Hanissian, MD; Danilo Duenas, MD; Robert Kimbrell, MD \s=b\ Ataxia telangiectasia has been associated with varying clinical and laboratory abnormalities of the cutaneous, immune, neurological, and endocrine systems. Recently, a primary defect in tissue differentiation has been proposed as a probable cause of the disease. The presence of biochemically abnormal collagen in the skin of two siblings with the disease may further support this hypothesis. (Am J Dis Child 130:305-307, 1976)
Ataxia
telangiectasia
is
an
auto-
multisystem by the onset of progressive ataxia, myoclonus, and XI
somal-recessive,
disease characterized
nystagmus at about 1 year of age, fol¬
by the development of fanshaped telangiectasia of the bulbar conjunctiva, usually at 4 to 6 years of
lowed
age.1 A number of clinical and labora-
Received for publication Sept 17, 1974; ac1975. From the departments of pediatrics (Drs McReynolds, Hanissian, Kimbrell, and Duenas) and biochemistry (Dr Dabbous), University of Tennessee Medical Units, Memphis. Read in part before the subspecialty meetings of the Southern Society for Pediatric Research, New Orleans, Jan 26, 1974. Reprint requests to Milltown Medical Center, 3113 Limestone Rd, Wilmington, DE 19808 (Dr
cepted Jan 27,
McReynolds).
tory abnormalities have been de¬ scribed in
patients with the disease. However, only the presence of abnor¬ mal concentrations of a-fetoprotein seems to be a consistent finding in all
patients.2 This observation has led
to
the hypothesis that the cause of the disease may be a primary defect in tissue differentiation, resulting from faulty mesoderm-entoderm inter¬ action. Analysis of collagen obtained from skin biopsy specimens in two siblings with ataxia telangiectasia has re¬ vealed a deficiency in hydroxylysine content. These observations may fur¬ ther support the above hypothesis, and the biochemical abnormality of collagen may account for many of the clinical manifestations observed in the disease. REPORT OF CASES Case 1.—A 9-year-old girl was referred for the evaluation of ataxia, chronic lung disease, and recurrent respiratory infec¬ tions. The onset of ataxia could not be defi¬ nitely ascertained, but had been present for several years. For three years she had suffered recurrent upper respiratory tract infections, coughing spells, and otitis me¬ dia with drainage! Physical examination revealed a thin,
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/15/2015
chronically ill child with growth retarda¬ tion (height 127 cm, weight 17.3 kg) with tachypnea at rest, mild intercostal retrac¬ tions, and rales in the lung bases. Con¬ junctival and oral telangiectasias were present. There was distinct clubbing of the fingers and toes. Neurological examination revealed decreased deep tendon reflexes in the upper extremities, absent deep tendon reflexes in the lower extremities, truncal and limb ataxia, scanning speech, dysmetria, dysdiadochokinesia, and a paresis of cranial
nerves
VII, IX, and XI.
Roentgenographic
examinations
re¬
pulmonary paren¬ chymal disease, pansinusitis, and a severe thoracolumbar scoliosis. Findings from routine laboratory studies, including com¬ plete blood cell count; urinalysis; electroen¬ cephalogram; cerebrospinal fluid examina¬ tion; and serum glucose, urea nitrogen, and electrolyte level determinations, were nor¬ vealed bilateral diffuse
mal. Serum protein electrophoresis revealed a total protein concentration of 9.5 gm/100 ml with 43% albumin, 3.9% ,-globulin, 9.3% a,-globulin, 8.8% /S-globulin, and 28.8% globulin. Quantitative serum immunoglobulin determinations by radial immunodiffusion revealed an IgA level of 90 mg/100 ml (normal, 44 to 208 mg/100 ml), an IgG level of 4,710 mg/100 ml (normal, 714 to 1,719 mg/100 ml), and an IgM level of 390 mg/100 ml (normal, 27 to 215 mg/100 ml). Serum IgE determination by radioimmunoassay was 50 international
units (IU)/ml (normal, 60 to 100 IU/ml). No IgE was detected by the method of Ishizaka and Ishizaka.3 Skin tests for Trichophyton, Monilia, streptokinase-streptodornase, mumps, pu¬ rified protein derivative (PPD), and histoplasmin were negative. Attempted sensitization to dinitrofluorobenzene failed. In vitro lymphoblastic transformation to phytohemagglutinin stimulation was found to be depressed both by the morphological method and by incorporation of tritiated thymidine in comparison to normal con¬ trols.4 Alpha-fetoprotein was present in excess of 30 ng/ml by the radioimmunoassay method. Case 2.-An 8-year-old female sibling of the patient in case 1 was evaluated for pos¬ sible ataxia telangiectasia. She had been normal until age 4 years when she devel¬ oped ataxia, which had become increas¬ ingly worse. Infections, however, had not been frequent. Physical examination revealed a wellnourished child with normal vital signs (temperature 37.5 C, pulse 108 beats per minute, respirations 24/min, blood pres¬ sure 105/65 mm Hg) and physical measure¬ ments (weight 25 kg, height 130 cm). Telangiectasias of the bulbar conjunctivas of both eyes were present. Truncal and limb ataxia, scanning speech, and nystagmus were noted. Roentgenographic examination revealed normal chest roentgenograms and sinus and mastoid films. Findings from other routine laboratory studies were normal as
in
case
1.
Serum protein electrophoresis revealed a total protein concentration of 6.5 gm/100 ml with 52.4% albumin, 4.9% ,-globulin, 8.7% «„-globulin, 18.5% /S-globulin, and 15.5% -globulin. Quantitative serum immunoglobulin levels were IgA 234 mg/100 ml (normal, 56 to 330 mg/100 ml), IgG 1,680 mg/100 ml (normal, 596 to 1,744 mg/100 ml), and IgM 230 mg/100 ml (normal, 54 to 260 mg/100 ml). Serum IgE by radioimmunoassay was 15 IU/ml (normal, 60 to 1,000 IU/ml). IgE was not present by the method of Ishizaka and Ishizaka.3 Skin tests were positive for delayed hy¬
persensitivity to Monilia, Trichophyton, and streptokinase-streptodornase; nega¬ tive to PPD and histoplasmin. In vitro lymphocyte stimulation to phytohemagglutinin was normal. Alpha-fetoprotein was present in excess of 30 ng/ml by the radioimmunoassay method.
Family Studies Chromosomal analysis was rendered somewhat difficult in case 1 because of lack of stimulation of lymphocyte mitosis by phytohemagglutinin. However, a normal karyotype without chromosomal breaks was observed after triple dose stimulation. Results of chromosomal analysis were also normal in case 2. Examination of the six other offspring of the parents (ages 5 to 21) revealed no evidence of neurological dys¬ function, telangiectasia, or frequent infec¬ tions. Serum immunoglobulins (including IgE), skin tests, and in vitro studies of
Amino Acid Composition* of Insoluble Dermis From Two Patients With Ataxia Telangiectasia and Two Normal Subjects Affected Sisters Amino Acid
Hydroxylysine Lysine Histidine
Arginine Hydrexyproline Aspartic acid Threonine Serine Glutamic acid Proline
Glycine Alanine Valine Methionine Isoleucine Leucine
Tyrosine Phenylalanine *
Expressed
as
Case 1 2.8 29 6.5 40 95 45 13 25
Case 2 3.0 31 7.8 45 92 44 15 25
70
69
129 323 114 30 5.7 21 34 5.7
138 324 111 30 6.1 14 30 6
Normal
Subjects
1 5.9 32 5.3 49 88 47 17 30 73 120 325 102 34 6.2 16 32 6.2
8.2 30 6.9 51 97 48 35 74 117 316 100 28 7.7 17 32
_5.1 _14_14_15_14 residues per 1,000 residues. Corrected for threonine and serine
destruction.
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/15/2015
hydrolysis
lymphocytes
on both parents revealed no abnormalities. Chromosomal analysis pro¬ duced normal results for both parents.
SUBJECTS AND METHODS Full-thickness Skin Biopsies After informed consent was obtained, samples were taken from two normal con¬ trol female subjects who were free from chronic or acute illness and who were of the same ages as the two patients.
Preparation of Tissue for Amino Acid Analysis Skin samples were iced as they were re¬ moved, and washed thoroughly with cold water. The subcutaneous fat
was mechani¬ removed. Collagen was prepared by the method of Rubin et al,5 with the follow¬ ing modifications: First, the minced skin was initially shaken with three changes of 20% sodium chloride solution for 48 hours. During this initial treatment the epidermis easily separated from the dermis. A second modification involved the stirring of the in¬ soluble collagen fraction with 0.5M acetic acid containing 4M urea for 24 hours, fol¬ lowed by washing the insoluble collagen residues with several changes of cold wa¬ ter. The insoluble collagen residue was then suspended in 10 volumes of distilled water, dialyzed against several changes of 100 volumes of distilled water, and then lyophllized. All procedures were carried out in the cold at 4 C. An amino acid analyzer utilizing the standard four-hour analysis was used for amino acid analysis. Hydrolysis was ac¬ complished in an ampule by adding 2 ml of
cally
glass-redistilled, constantly boiling hydro¬ chloric acid to 1 to 2 mg of the lyophllized collagen sample. The contents were flushed with nitrogen several times before sealing the ampule in vacuo. The sealed ampules were then placed in a temperature-regu¬ lated
oven
at 41 C for 24 hours.
RESULTS
The amino acid composition of in¬ soluble collagen (which represents the bulk of dermal collagen) is shown in the Table for the two sisters with ataxia telangiectasia and for the two normal control subjects. The data show that the hydroxyl¬ ysine content in the samples from the two sisters is lower than that of sam¬ ples from control subjects. While the hydroxyproline content did not show any apparent differences, the proline and alanine contents were slightly higher than those of the normal sub¬
jects.
COMMENT Disorders of immunological respon¬ siveness have received great empha¬ sis in the study of patients with ataxia telangiectasia. Many of the clinical manifestations observed in patients with the disease can be at¬ tributed to these defects. Immune de¬ ficiencies (and other findings), how¬ ever, are variable, as demonstrated by our patients. Investigators, there¬ fore, have sought an abnormality con¬ sistently present in all patients. The detection of unusually high concen¬ trations of a-fetoprotein in every pa¬ tient with ataxia telangiectasia they examined have led Waldmann and McIntire2 to hypothesize a defect in tis¬ sue differentiation as a likely cause of the disease, specifically a defect
in structures requiring the inductive influences of mesodermal-entodermal interaction. Abnormalities of the amino acid content of collagen have been re¬ cently reported. Pinnell et al6 have described two children with hyperelastic skin and severe scoliosis whose collagen was deficient in hydroxylysine. They have postulated the defi¬ ciency to be secondary to deficient hydroxylation of lysine. The abnormalities (moderately di¬ minished hydroxylysine and elevated proline and alanine) observed in the collagen of our two patients with ataxia telangiectasia resemble some¬ what those reported by Miller et al7 as a "second species" of less well differ¬ entiated collagen. The collagen of these patients may also represent a
poorly differentiated tissue. Since collagen is ubiquitous
in skin and vascular structures, such a bio¬ chemically inappropriate and perhaps structurally weak tissue might allow for more rapid deterioration in the face of normal or increased physical and chemical stresses. This might re¬ sult in the appearance of abnormal¬ ities in multiple systems such as is ob¬ served in the disease.
This investigation was supported by Univer¬ of Tennessee Institutional grant USPHS 1534R10; Milholim Foundation grant 4707R; Noel Memorial Foundation grant 4729R; and a Daland Fellowship grant of the American Philo¬
sity
sophical Society.
T.A. Waldmann, MD, performed the radioimmunoassay at the National Institute of Health Laboratory, Bethesda, Md.
References 1. McFarlin DE, Strober W, Waldmann TA: Ataxia-telangiectasia. Medicine 51:281-314,1972. 2. Waldmann TA, McIntire KR: Serum-alpha\x=req-\ fetoprotein levels in patients with ataxia-telangiectasia. Lancet 2:1112-1114, 1972. 3. Ishizaka K, Ishizaka T: Induction of erythema-wheal reaction by soluble IgE antibody complexes in humans. J Immunol 101:68-74, 1968.
4. Bach FH, Hirschhorn K: The in vitro response of peripheral blood lymphocytes. Semin Hematol 2:68-69, 1965. 5. Rubin AA, Drake MR, Davison PF, et al: Effects of pepsin treatment on the interaction properties of trapocollagen macromolecules. Biochemistry 4:181-190, 1965. 6. Pinnell SR, Krane SM, Kenzola JE, et al: A heritable disorder of connective tissue: Hydroxyl-
La belle naissance
a
ysine-deficient collagen disease. N Engl J Med 286:1013-1020, 1972. 7. Miller EJ, Epstein EH, Piez KA: Identification of three genetically distinct collagens by cyanide bromide cleanage of insoluble human skin and cartilage collagens. Biochem Biophys Res Commun 42:1024, 1971.
là television*
J'ai regardé la TV vu le docteur
Leboyer occupé
à essayer de délivrer un bon bébé "Quel succès" il a crié et le bébé
lui-même était tout à fait d'accord Edward Cutler Doctors Hospital Columbus, OH 43201 on a on a new television method of Thoughts viewing delivering babies, explained by obstetrician program Frederick Leboyer. The program was broadcast on April 22, 1975, as part of "A.M. America."
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/15/2015
Edward W. McReynolds, MD; Mustafa K. Dabbous, PhD; Aram S. Hanissian, MD; Danilo Duenas, MD; Robert Kimbrell, MD \s=b\ Ataxia telangiectasia has been associated with varying clinical and laboratory abnormalities of the cutaneous, immune, neurological, and endocrine systems. Recently, a primary defect in tissue differentiation has been proposed as a probable cause of the disease. The presence of biochemically abnormal collagen in the skin of two siblings with the disease may further support this hypothesis. (Am J Dis Child 130:305-307, 1976)
Ataxia
telangiectasia
is
an
auto-
multisystem by the onset of progressive ataxia, myoclonus, and XI
somal-recessive,
disease characterized
nystagmus at about 1 year of age, fol¬
by the development of fanshaped telangiectasia of the bulbar conjunctiva, usually at 4 to 6 years of
lowed
age.1 A number of clinical and labora-
Received for publication Sept 17, 1974; ac1975. From the departments of pediatrics (Drs McReynolds, Hanissian, Kimbrell, and Duenas) and biochemistry (Dr Dabbous), University of Tennessee Medical Units, Memphis. Read in part before the subspecialty meetings of the Southern Society for Pediatric Research, New Orleans, Jan 26, 1974. Reprint requests to Milltown Medical Center, 3113 Limestone Rd, Wilmington, DE 19808 (Dr
cepted Jan 27,
McReynolds).
tory abnormalities have been de¬ scribed in
patients with the disease. However, only the presence of abnor¬ mal concentrations of a-fetoprotein seems to be a consistent finding in all
patients.2 This observation has led
to
the hypothesis that the cause of the disease may be a primary defect in tissue differentiation, resulting from faulty mesoderm-entoderm inter¬ action. Analysis of collagen obtained from skin biopsy specimens in two siblings with ataxia telangiectasia has re¬ vealed a deficiency in hydroxylysine content. These observations may fur¬ ther support the above hypothesis, and the biochemical abnormality of collagen may account for many of the clinical manifestations observed in the disease. REPORT OF CASES Case 1.—A 9-year-old girl was referred for the evaluation of ataxia, chronic lung disease, and recurrent respiratory infec¬ tions. The onset of ataxia could not be defi¬ nitely ascertained, but had been present for several years. For three years she had suffered recurrent upper respiratory tract infections, coughing spells, and otitis me¬ dia with drainage! Physical examination revealed a thin,
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/15/2015
chronically ill child with growth retarda¬ tion (height 127 cm, weight 17.3 kg) with tachypnea at rest, mild intercostal retrac¬ tions, and rales in the lung bases. Con¬ junctival and oral telangiectasias were present. There was distinct clubbing of the fingers and toes. Neurological examination revealed decreased deep tendon reflexes in the upper extremities, absent deep tendon reflexes in the lower extremities, truncal and limb ataxia, scanning speech, dysmetria, dysdiadochokinesia, and a paresis of cranial
nerves
VII, IX, and XI.
Roentgenographic
examinations
re¬
pulmonary paren¬ chymal disease, pansinusitis, and a severe thoracolumbar scoliosis. Findings from routine laboratory studies, including com¬ plete blood cell count; urinalysis; electroen¬ cephalogram; cerebrospinal fluid examina¬ tion; and serum glucose, urea nitrogen, and electrolyte level determinations, were nor¬ vealed bilateral diffuse
mal. Serum protein electrophoresis revealed a total protein concentration of 9.5 gm/100 ml with 43% albumin, 3.9% ,-globulin, 9.3% a,-globulin, 8.8% /S-globulin, and 28.8% globulin. Quantitative serum immunoglobulin determinations by radial immunodiffusion revealed an IgA level of 90 mg/100 ml (normal, 44 to 208 mg/100 ml), an IgG level of 4,710 mg/100 ml (normal, 714 to 1,719 mg/100 ml), and an IgM level of 390 mg/100 ml (normal, 27 to 215 mg/100 ml). Serum IgE determination by radioimmunoassay was 50 international
units (IU)/ml (normal, 60 to 100 IU/ml). No IgE was detected by the method of Ishizaka and Ishizaka.3 Skin tests for Trichophyton, Monilia, streptokinase-streptodornase, mumps, pu¬ rified protein derivative (PPD), and histoplasmin were negative. Attempted sensitization to dinitrofluorobenzene failed. In vitro lymphoblastic transformation to phytohemagglutinin stimulation was found to be depressed both by the morphological method and by incorporation of tritiated thymidine in comparison to normal con¬ trols.4 Alpha-fetoprotein was present in excess of 30 ng/ml by the radioimmunoassay method. Case 2.-An 8-year-old female sibling of the patient in case 1 was evaluated for pos¬ sible ataxia telangiectasia. She had been normal until age 4 years when she devel¬ oped ataxia, which had become increas¬ ingly worse. Infections, however, had not been frequent. Physical examination revealed a wellnourished child with normal vital signs (temperature 37.5 C, pulse 108 beats per minute, respirations 24/min, blood pres¬ sure 105/65 mm Hg) and physical measure¬ ments (weight 25 kg, height 130 cm). Telangiectasias of the bulbar conjunctivas of both eyes were present. Truncal and limb ataxia, scanning speech, and nystagmus were noted. Roentgenographic examination revealed normal chest roentgenograms and sinus and mastoid films. Findings from other routine laboratory studies were normal as
in
case
1.
Serum protein electrophoresis revealed a total protein concentration of 6.5 gm/100 ml with 52.4% albumin, 4.9% ,-globulin, 8.7% «„-globulin, 18.5% /S-globulin, and 15.5% -globulin. Quantitative serum immunoglobulin levels were IgA 234 mg/100 ml (normal, 56 to 330 mg/100 ml), IgG 1,680 mg/100 ml (normal, 596 to 1,744 mg/100 ml), and IgM 230 mg/100 ml (normal, 54 to 260 mg/100 ml). Serum IgE by radioimmunoassay was 15 IU/ml (normal, 60 to 1,000 IU/ml). IgE was not present by the method of Ishizaka and Ishizaka.3 Skin tests were positive for delayed hy¬
persensitivity to Monilia, Trichophyton, and streptokinase-streptodornase; nega¬ tive to PPD and histoplasmin. In vitro lymphocyte stimulation to phytohemagglutinin was normal. Alpha-fetoprotein was present in excess of 30 ng/ml by the radioimmunoassay method.
Family Studies Chromosomal analysis was rendered somewhat difficult in case 1 because of lack of stimulation of lymphocyte mitosis by phytohemagglutinin. However, a normal karyotype without chromosomal breaks was observed after triple dose stimulation. Results of chromosomal analysis were also normal in case 2. Examination of the six other offspring of the parents (ages 5 to 21) revealed no evidence of neurological dys¬ function, telangiectasia, or frequent infec¬ tions. Serum immunoglobulins (including IgE), skin tests, and in vitro studies of
Amino Acid Composition* of Insoluble Dermis From Two Patients With Ataxia Telangiectasia and Two Normal Subjects Affected Sisters Amino Acid
Hydroxylysine Lysine Histidine
Arginine Hydrexyproline Aspartic acid Threonine Serine Glutamic acid Proline
Glycine Alanine Valine Methionine Isoleucine Leucine
Tyrosine Phenylalanine *
Expressed
as
Case 1 2.8 29 6.5 40 95 45 13 25
Case 2 3.0 31 7.8 45 92 44 15 25
70
69
129 323 114 30 5.7 21 34 5.7
138 324 111 30 6.1 14 30 6
Normal
Subjects
1 5.9 32 5.3 49 88 47 17 30 73 120 325 102 34 6.2 16 32 6.2
8.2 30 6.9 51 97 48 35 74 117 316 100 28 7.7 17 32
_5.1 _14_14_15_14 residues per 1,000 residues. Corrected for threonine and serine
destruction.
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/15/2015
hydrolysis
lymphocytes
on both parents revealed no abnormalities. Chromosomal analysis pro¬ duced normal results for both parents.
SUBJECTS AND METHODS Full-thickness Skin Biopsies After informed consent was obtained, samples were taken from two normal con¬ trol female subjects who were free from chronic or acute illness and who were of the same ages as the two patients.
Preparation of Tissue for Amino Acid Analysis Skin samples were iced as they were re¬ moved, and washed thoroughly with cold water. The subcutaneous fat
was mechani¬ removed. Collagen was prepared by the method of Rubin et al,5 with the follow¬ ing modifications: First, the minced skin was initially shaken with three changes of 20% sodium chloride solution for 48 hours. During this initial treatment the epidermis easily separated from the dermis. A second modification involved the stirring of the in¬ soluble collagen fraction with 0.5M acetic acid containing 4M urea for 24 hours, fol¬ lowed by washing the insoluble collagen residues with several changes of cold wa¬ ter. The insoluble collagen residue was then suspended in 10 volumes of distilled water, dialyzed against several changes of 100 volumes of distilled water, and then lyophllized. All procedures were carried out in the cold at 4 C. An amino acid analyzer utilizing the standard four-hour analysis was used for amino acid analysis. Hydrolysis was ac¬ complished in an ampule by adding 2 ml of
cally
glass-redistilled, constantly boiling hydro¬ chloric acid to 1 to 2 mg of the lyophllized collagen sample. The contents were flushed with nitrogen several times before sealing the ampule in vacuo. The sealed ampules were then placed in a temperature-regu¬ lated
oven
at 41 C for 24 hours.
RESULTS
The amino acid composition of in¬ soluble collagen (which represents the bulk of dermal collagen) is shown in the Table for the two sisters with ataxia telangiectasia and for the two normal control subjects. The data show that the hydroxyl¬ ysine content in the samples from the two sisters is lower than that of sam¬ ples from control subjects. While the hydroxyproline content did not show any apparent differences, the proline and alanine contents were slightly higher than those of the normal sub¬
jects.
COMMENT Disorders of immunological respon¬ siveness have received great empha¬ sis in the study of patients with ataxia telangiectasia. Many of the clinical manifestations observed in patients with the disease can be at¬ tributed to these defects. Immune de¬ ficiencies (and other findings), how¬ ever, are variable, as demonstrated by our patients. Investigators, there¬ fore, have sought an abnormality con¬ sistently present in all patients. The detection of unusually high concen¬ trations of a-fetoprotein in every pa¬ tient with ataxia telangiectasia they examined have led Waldmann and McIntire2 to hypothesize a defect in tis¬ sue differentiation as a likely cause of the disease, specifically a defect
in structures requiring the inductive influences of mesodermal-entodermal interaction. Abnormalities of the amino acid content of collagen have been re¬ cently reported. Pinnell et al6 have described two children with hyperelastic skin and severe scoliosis whose collagen was deficient in hydroxylysine. They have postulated the defi¬ ciency to be secondary to deficient hydroxylation of lysine. The abnormalities (moderately di¬ minished hydroxylysine and elevated proline and alanine) observed in the collagen of our two patients with ataxia telangiectasia resemble some¬ what those reported by Miller et al7 as a "second species" of less well differ¬ entiated collagen. The collagen of these patients may also represent a
poorly differentiated tissue. Since collagen is ubiquitous
in skin and vascular structures, such a bio¬ chemically inappropriate and perhaps structurally weak tissue might allow for more rapid deterioration in the face of normal or increased physical and chemical stresses. This might re¬ sult in the appearance of abnormal¬ ities in multiple systems such as is ob¬ served in the disease.
This investigation was supported by Univer¬ of Tennessee Institutional grant USPHS 1534R10; Milholim Foundation grant 4707R; Noel Memorial Foundation grant 4729R; and a Daland Fellowship grant of the American Philo¬
sity
sophical Society.
T.A. Waldmann, MD, performed the radioimmunoassay at the National Institute of Health Laboratory, Bethesda, Md.
References 1. McFarlin DE, Strober W, Waldmann TA: Ataxia-telangiectasia. Medicine 51:281-314,1972. 2. Waldmann TA, McIntire KR: Serum-alpha\x=req-\ fetoprotein levels in patients with ataxia-telangiectasia. Lancet 2:1112-1114, 1972. 3. Ishizaka K, Ishizaka T: Induction of erythema-wheal reaction by soluble IgE antibody complexes in humans. J Immunol 101:68-74, 1968.
4. Bach FH, Hirschhorn K: The in vitro response of peripheral blood lymphocytes. Semin Hematol 2:68-69, 1965. 5. Rubin AA, Drake MR, Davison PF, et al: Effects of pepsin treatment on the interaction properties of trapocollagen macromolecules. Biochemistry 4:181-190, 1965. 6. Pinnell SR, Krane SM, Kenzola JE, et al: A heritable disorder of connective tissue: Hydroxyl-
La belle naissance
a
ysine-deficient collagen disease. N Engl J Med 286:1013-1020, 1972. 7. Miller EJ, Epstein EH, Piez KA: Identification of three genetically distinct collagens by cyanide bromide cleanage of insoluble human skin and cartilage collagens. Biochem Biophys Res Commun 42:1024, 1971.
là television*
J'ai regardé la TV vu le docteur
Leboyer occupé
à essayer de délivrer un bon bébé "Quel succès" il a crié et le bébé
lui-même était tout à fait d'accord Edward Cutler Doctors Hospital Columbus, OH 43201 on a on a new television method of Thoughts viewing delivering babies, explained by obstetrician program Frederick Leboyer. The program was broadcast on April 22, 1975, as part of "A.M. America."
Downloaded From: http://archpedi.jamanetwork.com/ by a UQ Library User on 06/15/2015
