Arch Osteoporos (2014) 9:177 DOI 10.1007/s11657-014-0177-0
CASE REPORT
Osteomalacia in Crohn’s disease Meryem Dedeoglu & Yesim Garip & Hatice Bodur
Received: 25 February 2014 / Accepted: 27 March 2014 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014
Abstract Summary Osteomalacia is a metabolic bone disorder characterized by impaired mineralization of the bone matrix. Vitamin D deficiency due to malabsorption syndromes may cause osteomalacia. This is a case of a patient with a 6-year history of seronegative spondyloarthropathy associated with Crohn’s disease who was admitted to our outpatient clinic with symptoms of osteomalacia. Introduction Osteomalacia is a metabolic bone disease characterized by an impaired mineralization of the bone matrix, frequently caused by disorders in vitamin D or phosphate metabolism. Vitamin D deficiency due to malabsorption syndromes (e.g., Crohn’s disease, ulcerative colitis, celiac disease, and jejuno-ileal bypass for obesity) may cause osteomalacia. Case report A 43-year-old male presented with fatigue, low back pain, and morning stiffness. He had a 6-year history of seronegative spondyloarthropathy associated with Crohn’s disease. Laboratory findings revealed low serum calcium, low 25-hydroxy vitamin D3, normal phosphorus, elevated parathyroid hormone, and alkaline phosphatase levels. Radiographs revealed grade IV sacroiliitis and Looser zones. He was diagnosed with osteomalacia due to the malabsorption of
M. Dedeoglu Department of Physical Medicine and Rehabilitation, Anamur State Hospital, Mersin, Turkey e-mail: [email protected] Y. Garip (*) Department of Physical Medicine and Rehabilitation, Basak Medical Center, Ankara, Turkey e-mail: [email protected] H. Bodur Department of Physical Medicine and Rehabilitation, Ankara Numune Training and Research Hospital, Samanpazari, Ankara, Turkey e-mail: [email protected]
vitamin D. His symptoms and signs were relieved with supplements of vitamin D and calcium. Conclusions Osteomalacia should be considered in differential diagnosis when assessing low back pain in the patients with chronic inflammatory bowel disease. Vitamin D deficiency should be treated with vitamin D supplementation in patients with Crohn's disease to prevent osteomalacia. Keywords Osteomalacia . Vitamin D deficiency . Crohn’s disease . Spondyloarthritis . Sacroiliitis
Introduction Osteomalacia is a metabolic bone disorder characterized by an impaired mineralization of the bone matrix, frequently caused by disorders in vitamin D or phosphate metabolism [1]. Clinical manifestations of osteomalacia are diffuse bone pain in the back, knee, rib cage, polyarthralgia, and proximal muscle weakness (commonly as pelvic girdle myopathy). These symptoms may mimic other musculoskeletal disorders including fibromyalgia, polymyalgia rheumatica, early rheumatoid arthritis, or spondyloarthropathy. Proximal muscle weakness may result in an antalgic or waddling gait and difficulty in ambulation. The other clinical manifestations are skeletal deformities such as kyphoscoliosis, protrusio acetabuli, and limb bowing. Fatigue, carpopedal spasm, and tetanic contractions may rarely occur due to hypocalcemia [2]. Laboratory findings often include hypocalcemia, hypophosphatemia, and elevated alkaline phosphatase level. PTH levels are usually elevated, suggesting a component of secondary hyperparathyroidism. Serum level of 1.25-dihydroxy-vitamin D may be low, normal, or increased [3]. Typical radiographic finding of osteomalacia is the presence of pseudofractures, or Looser zones, which are transverse lines
177, Page 2 of 3
Arch Osteoporos (2014) 9:177
of rarefaction through the cortices, with incomplete healing in the ribs, scapulae, long bones, or pubic rami [4]. In this case, we report a patient with a 6-year history of enteropathic spondyloarthropathy who admitted to our clinic with symptoms of osteomalacia.
Case A 43-year-old male with a 6-year history of seronegative spondyloarthropathy was admitted to our outpatient clinic with complaints of severe pain in the shoulders, low back, and hips. He was unable to walk due to weakness in the knees. His appearance was cachectic. The patient presented with a history of several years of mild back pain which exacerbated progressively without any history of a traumatic episode. In his past medical history, he had been diagnosed with seronegative spondyloarthropathy 6 years ago when he had been evaluated for low back pain and morning stiffness lasting more than 1 h in the mornings. He was receiving sulphasalazine irregularly. The patient reported that he admitted to a gastroenterology clinic with a complaint of diarrhea 3 years ago, and he had been diagnosed with Crohn’s disease. Physical examination revealed limitation in the lumbar spine, diffuse tenderness on femur and spinous processes of the vertebrae. Hip rotations were limited in the mid-range of motion. Modified Schober revealed the following: 1.5 cm, lateral spinal flexion; 6.5 cm, fingertip-to-floor distance; 45 cm, occiput to wall distance; 18 cm, chin-manubrium distance; 5 cm, chest expansion; 2.1 cm. Straight leg raising and femoral stretch tests were negative. Sacroiliac compression tests were bilaterally positive. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI): 7.2, Bath Ankylosing Spondylitis Functional Index (BASFI): 7.4, Bath Ankylosing Spondylitis Metrology Index (BASMI): 2.2. Neurological examination was normal. Laboratory parameters showed the following: erythrocyte sedimentation rate (ESR) 90 mm/h (normal range 0–12 mm/ h), C-reactive protein (CRP) 66.4 mg/L (normal range 0,00– 5.00 mg/L), serum total calcium 8.4 mg/dL (normal range 8.5–10.6 mg/dL), serum phosphorus 3.6 mg/dL (normal range 2.4–4.7 mg/dL), vitamin D3 4.4 ng/ml (20–46.4), parathyroid hormone (PTH) 11 pmol/L (normal range 1.3–9.3 pmol/L), alkaline phosphatase 160 u/L (normal range 32–91 u/L), 24-h urinary calcium 8.2 mg/24 h (normal range 50–300 mg/24 h), urinary phosphorus 44.6 mg/24 h (normal range 40–1300 mg/ 24 h), urinary protein 24 mg/24 h (normal range 50–100 mg/ 24 h), sodium 35.6 mmol/24 h (40–220 mmol/24 h). Radiographic examination of the pelvis showed grade IV bilateral sacroiliitis (Fig. 1). An anteroposterior view of the knees showed bilateral Looser zones in the proximal tibia (Fig. 2). Bone mineral density (BMD) results, measured by dual energy X-ray absorptiometry (DXA), were as follows: lumbar spine BMD T-score −4.4, femoral neck BMD T-score
Fig. 1 Radiographic examination of the pelvis showed grade IV bilateral sacroiliitis
−4.5. Colonoscopy revealed superficial ulcers in the cecum. Cecal and transverse colon biopsies showed chronic inflammation and ulceration with no evidence of granulomas. The patient was hospitalized and underwent an enteral nutrition program. He received sulphasalazine (2 g/day), azathioprine (50 mg/day), and budesonide (9 mg/day), two doses of 300,000 IU Vitamin D3 (10-day intervals), and elementary calcium 1,200 mg/day. An antiresorptive treatment was planned based on responsiveness to the osteomalacia treatment after 1 month. He received physical therapy including electrotherapy, specific posture and breathing exercises, and range of motion and strengthening exercises to the back and hips. His low back and heel pain were reduced, and he was discharged with the present medical therapy and a home exercise program.
Discussion An etiological classification of the osteomalacia includes as follows: (1) nutritional osteomalacia; (a) inadequate exposure to sunlight and/or insufficient vitamin D intake; (b) defective intestinal absorption of vitamin D because of malabsorption syndromes (e.g., Crohn’s disease, ulcerative colitis, celiac
Fig. 2 An anteroposterior view of the knees showing bilateral Looser zones in the proximal tibia
Arch Osteoporos (2014) 9:177
disease, and jejuno-ileal bypass for obesity) and (2) disorders of vitamin D metabolism [5]. The group of disorders collectively classified as spondyloarthropathies constitutes a family of interrelated, but heterogeneous conditions with similarities but also differences in clinical manifestations. Members of this group are ankylosing spondylitis (AS), psoriatic arthritis, reactive arthritis, enteropathic arthritis associated with chronic inflammatory bowel disease (Crohn’s disease and ulcerative colitis), and undifferentiated spondyloarthritis [6]. Crohn's disease is an inflammatory bowel disease which can involve the entire gastrointestinal tract, but it prefers the terminal ileum and the ascendant colon. The rheumatic manifestations of Crohn's disease have been divided into peripheral arthritis and axial involvement, including sacroiliitis, with or without spondylitis, similar to the presentation of classic ankylosing spondylitis. There may be other periarticular manifestations such as enthesopathy, tendinitis, periostitis, clubbing, and granulomatous lesions in joints and bones. There may also be osteoporosis and osteomalacia secondary to Crohn’s disease and to its treatment [7]. Vitamin D is produced in the skin in the presence of ultraviolet light or absorbed in the intestine from dietary or supplemental sources. The jejunum and ileum are the sites of absorption of vitamin D, and the proximal intestine is the site of absorption of calcium. Bone consists of organic matrix (collagen and noncollagenous proteins) and an inorganic mineral component (calcium and phosphate in hydroxyapatite crystals). Thus, the malabsorption of vitamin D, calcium, or phosphate can lead to the impaired mineralization of bony matrix and osteomalacia [8]. Vitamin D deficiency may cause osteomalacia in patients with malabsorption syndromes. Osteomalacia due to malabsorption in Crohn’s disease has been reported in previous studies [9–13]. Vitamin D deficiency must be treated in patients with Crohn's disease to prevent osteomalacia. In our case, the patient presented with a history of several years of mild back pain which worsened progressively. In his previous physical examinations, low back pain had been attributed to his current disease. Muscle weakness might not have been taken into consideration or might have been confused with fatigue due to spondyloarthropathy. As a result, the diagnosis of osteomalacia had been delayed.
Page 3 of 3, 177
In conclusion, it is important that the physician should be alert and should suspect osteomalacia in case of low back pain in the patients with chronic inflammatory bowel disease. Moreover, unlike the other musculoskeletal conditions, osteomalacia can easily be treated with calcium and vitamin D supplementation. Conflict of interest None.
References 1. Gifre L, Peris P, Monegal A, Martinez de Osaba MJ, Alvarez L, Guañabens N (2011) Osteomalacia revisited: a report on 28 cases. Clin Rheumatol 30:639–645 2. Reginato AJ, Coquia JA (2003) Musculoskeletal manifestations of osteomalacia and rickets. Best Pract Res Clin Rheumatol 17:1063– 1080 3. Russell LA (2010) Osteoporosis and osteomalacia. Rheum Dis Clin North Am 36:665–680 4. Lane NE (2009) Metabolic bone disease. In: Firestein GS (ed) Kelley’s textbook of rheumatology, 8th edn. W. B. Saunders, Philadelphia, pp 1579–1599 5. Caniggia A (1991) The osteomalacias. Ann Ital Med Int 6:476– 482 6. Bonen A, van Tubergen A, van der Linden S, Mihai C (2004) Spondyloarthropathies. In: Tugwell P (ed) Evidence-based rheumatology, 1st edition. BMJ, London, pp 393–442 7. Rodríguez-Reyna TS, Martínez-Reyes C, Yamamoto-Furusho JK (2009) Rheumatic manifestations of inflammatory bowel disease. World J Gastroenterol 15:5517–5524 8. LeBoff MS (1997) Is prolonged use of corticosteroids safe in patients with Crohn’s disease? Inflamm Bowel Dis 3:169–173 9. Talabiska DG, Seidner DL, Jensen GL (1993) Acute tetany in the Crohn's patient with osteomalacia. Nutrition 9:159–162 10. Golding DN (1985) Muscle pain and wasting in osteomalacia. JR Soc Med 78:495–496 11. Seligman JV, Basi SS, Deitel M, Bayley TA, Khanna RK (1984) Metabolic bone disease in a patient on long-term total parenteral nutrition: a case report with review of literature. Parenter Enteral Nutr 8:722–727 12. Sitrin MD, Rosenberg IH, Chawla K, Meredith S, Sellin J, Rabb JM, Coe F, Kirsner JB, Kraft SC (1980) Nutritional and metabolic complications in a patient with Crohn's disease and ileal resection. Gastroenterology 78:1069–1079 13. Victorino RM, Lucas MB, de Moura MC (1986) Severe osteomalacia associated with renal tubular acidosis in Crohn's disease. Dig Dis Sci 31:322–326
CASE REPORT
Osteomalacia in Crohn’s disease Meryem Dedeoglu & Yesim Garip & Hatice Bodur
Received: 25 February 2014 / Accepted: 27 March 2014 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014
Abstract Summary Osteomalacia is a metabolic bone disorder characterized by impaired mineralization of the bone matrix. Vitamin D deficiency due to malabsorption syndromes may cause osteomalacia. This is a case of a patient with a 6-year history of seronegative spondyloarthropathy associated with Crohn’s disease who was admitted to our outpatient clinic with symptoms of osteomalacia. Introduction Osteomalacia is a metabolic bone disease characterized by an impaired mineralization of the bone matrix, frequently caused by disorders in vitamin D or phosphate metabolism. Vitamin D deficiency due to malabsorption syndromes (e.g., Crohn’s disease, ulcerative colitis, celiac disease, and jejuno-ileal bypass for obesity) may cause osteomalacia. Case report A 43-year-old male presented with fatigue, low back pain, and morning stiffness. He had a 6-year history of seronegative spondyloarthropathy associated with Crohn’s disease. Laboratory findings revealed low serum calcium, low 25-hydroxy vitamin D3, normal phosphorus, elevated parathyroid hormone, and alkaline phosphatase levels. Radiographs revealed grade IV sacroiliitis and Looser zones. He was diagnosed with osteomalacia due to the malabsorption of
M. Dedeoglu Department of Physical Medicine and Rehabilitation, Anamur State Hospital, Mersin, Turkey e-mail: [email protected] Y. Garip (*) Department of Physical Medicine and Rehabilitation, Basak Medical Center, Ankara, Turkey e-mail: [email protected] H. Bodur Department of Physical Medicine and Rehabilitation, Ankara Numune Training and Research Hospital, Samanpazari, Ankara, Turkey e-mail: [email protected]
vitamin D. His symptoms and signs were relieved with supplements of vitamin D and calcium. Conclusions Osteomalacia should be considered in differential diagnosis when assessing low back pain in the patients with chronic inflammatory bowel disease. Vitamin D deficiency should be treated with vitamin D supplementation in patients with Crohn's disease to prevent osteomalacia. Keywords Osteomalacia . Vitamin D deficiency . Crohn’s disease . Spondyloarthritis . Sacroiliitis
Introduction Osteomalacia is a metabolic bone disorder characterized by an impaired mineralization of the bone matrix, frequently caused by disorders in vitamin D or phosphate metabolism [1]. Clinical manifestations of osteomalacia are diffuse bone pain in the back, knee, rib cage, polyarthralgia, and proximal muscle weakness (commonly as pelvic girdle myopathy). These symptoms may mimic other musculoskeletal disorders including fibromyalgia, polymyalgia rheumatica, early rheumatoid arthritis, or spondyloarthropathy. Proximal muscle weakness may result in an antalgic or waddling gait and difficulty in ambulation. The other clinical manifestations are skeletal deformities such as kyphoscoliosis, protrusio acetabuli, and limb bowing. Fatigue, carpopedal spasm, and tetanic contractions may rarely occur due to hypocalcemia [2]. Laboratory findings often include hypocalcemia, hypophosphatemia, and elevated alkaline phosphatase level. PTH levels are usually elevated, suggesting a component of secondary hyperparathyroidism. Serum level of 1.25-dihydroxy-vitamin D may be low, normal, or increased [3]. Typical radiographic finding of osteomalacia is the presence of pseudofractures, or Looser zones, which are transverse lines
177, Page 2 of 3
Arch Osteoporos (2014) 9:177
of rarefaction through the cortices, with incomplete healing in the ribs, scapulae, long bones, or pubic rami [4]. In this case, we report a patient with a 6-year history of enteropathic spondyloarthropathy who admitted to our clinic with symptoms of osteomalacia.
Case A 43-year-old male with a 6-year history of seronegative spondyloarthropathy was admitted to our outpatient clinic with complaints of severe pain in the shoulders, low back, and hips. He was unable to walk due to weakness in the knees. His appearance was cachectic. The patient presented with a history of several years of mild back pain which exacerbated progressively without any history of a traumatic episode. In his past medical history, he had been diagnosed with seronegative spondyloarthropathy 6 years ago when he had been evaluated for low back pain and morning stiffness lasting more than 1 h in the mornings. He was receiving sulphasalazine irregularly. The patient reported that he admitted to a gastroenterology clinic with a complaint of diarrhea 3 years ago, and he had been diagnosed with Crohn’s disease. Physical examination revealed limitation in the lumbar spine, diffuse tenderness on femur and spinous processes of the vertebrae. Hip rotations were limited in the mid-range of motion. Modified Schober revealed the following: 1.5 cm, lateral spinal flexion; 6.5 cm, fingertip-to-floor distance; 45 cm, occiput to wall distance; 18 cm, chin-manubrium distance; 5 cm, chest expansion; 2.1 cm. Straight leg raising and femoral stretch tests were negative. Sacroiliac compression tests were bilaterally positive. Bath Ankylosing Spondylitis Disease Activity Index (BASDAI): 7.2, Bath Ankylosing Spondylitis Functional Index (BASFI): 7.4, Bath Ankylosing Spondylitis Metrology Index (BASMI): 2.2. Neurological examination was normal. Laboratory parameters showed the following: erythrocyte sedimentation rate (ESR) 90 mm/h (normal range 0–12 mm/ h), C-reactive protein (CRP) 66.4 mg/L (normal range 0,00– 5.00 mg/L), serum total calcium 8.4 mg/dL (normal range 8.5–10.6 mg/dL), serum phosphorus 3.6 mg/dL (normal range 2.4–4.7 mg/dL), vitamin D3 4.4 ng/ml (20–46.4), parathyroid hormone (PTH) 11 pmol/L (normal range 1.3–9.3 pmol/L), alkaline phosphatase 160 u/L (normal range 32–91 u/L), 24-h urinary calcium 8.2 mg/24 h (normal range 50–300 mg/24 h), urinary phosphorus 44.6 mg/24 h (normal range 40–1300 mg/ 24 h), urinary protein 24 mg/24 h (normal range 50–100 mg/ 24 h), sodium 35.6 mmol/24 h (40–220 mmol/24 h). Radiographic examination of the pelvis showed grade IV bilateral sacroiliitis (Fig. 1). An anteroposterior view of the knees showed bilateral Looser zones in the proximal tibia (Fig. 2). Bone mineral density (BMD) results, measured by dual energy X-ray absorptiometry (DXA), were as follows: lumbar spine BMD T-score −4.4, femoral neck BMD T-score
Fig. 1 Radiographic examination of the pelvis showed grade IV bilateral sacroiliitis
−4.5. Colonoscopy revealed superficial ulcers in the cecum. Cecal and transverse colon biopsies showed chronic inflammation and ulceration with no evidence of granulomas. The patient was hospitalized and underwent an enteral nutrition program. He received sulphasalazine (2 g/day), azathioprine (50 mg/day), and budesonide (9 mg/day), two doses of 300,000 IU Vitamin D3 (10-day intervals), and elementary calcium 1,200 mg/day. An antiresorptive treatment was planned based on responsiveness to the osteomalacia treatment after 1 month. He received physical therapy including electrotherapy, specific posture and breathing exercises, and range of motion and strengthening exercises to the back and hips. His low back and heel pain were reduced, and he was discharged with the present medical therapy and a home exercise program.
Discussion An etiological classification of the osteomalacia includes as follows: (1) nutritional osteomalacia; (a) inadequate exposure to sunlight and/or insufficient vitamin D intake; (b) defective intestinal absorption of vitamin D because of malabsorption syndromes (e.g., Crohn’s disease, ulcerative colitis, celiac
Fig. 2 An anteroposterior view of the knees showing bilateral Looser zones in the proximal tibia
Arch Osteoporos (2014) 9:177
disease, and jejuno-ileal bypass for obesity) and (2) disorders of vitamin D metabolism [5]. The group of disorders collectively classified as spondyloarthropathies constitutes a family of interrelated, but heterogeneous conditions with similarities but also differences in clinical manifestations. Members of this group are ankylosing spondylitis (AS), psoriatic arthritis, reactive arthritis, enteropathic arthritis associated with chronic inflammatory bowel disease (Crohn’s disease and ulcerative colitis), and undifferentiated spondyloarthritis [6]. Crohn's disease is an inflammatory bowel disease which can involve the entire gastrointestinal tract, but it prefers the terminal ileum and the ascendant colon. The rheumatic manifestations of Crohn's disease have been divided into peripheral arthritis and axial involvement, including sacroiliitis, with or without spondylitis, similar to the presentation of classic ankylosing spondylitis. There may be other periarticular manifestations such as enthesopathy, tendinitis, periostitis, clubbing, and granulomatous lesions in joints and bones. There may also be osteoporosis and osteomalacia secondary to Crohn’s disease and to its treatment [7]. Vitamin D is produced in the skin in the presence of ultraviolet light or absorbed in the intestine from dietary or supplemental sources. The jejunum and ileum are the sites of absorption of vitamin D, and the proximal intestine is the site of absorption of calcium. Bone consists of organic matrix (collagen and noncollagenous proteins) and an inorganic mineral component (calcium and phosphate in hydroxyapatite crystals). Thus, the malabsorption of vitamin D, calcium, or phosphate can lead to the impaired mineralization of bony matrix and osteomalacia [8]. Vitamin D deficiency may cause osteomalacia in patients with malabsorption syndromes. Osteomalacia due to malabsorption in Crohn’s disease has been reported in previous studies [9–13]. Vitamin D deficiency must be treated in patients with Crohn's disease to prevent osteomalacia. In our case, the patient presented with a history of several years of mild back pain which worsened progressively. In his previous physical examinations, low back pain had been attributed to his current disease. Muscle weakness might not have been taken into consideration or might have been confused with fatigue due to spondyloarthropathy. As a result, the diagnosis of osteomalacia had been delayed.
Page 3 of 3, 177
In conclusion, it is important that the physician should be alert and should suspect osteomalacia in case of low back pain in the patients with chronic inflammatory bowel disease. Moreover, unlike the other musculoskeletal conditions, osteomalacia can easily be treated with calcium and vitamin D supplementation. Conflict of interest None.
References 1. Gifre L, Peris P, Monegal A, Martinez de Osaba MJ, Alvarez L, Guañabens N (2011) Osteomalacia revisited: a report on 28 cases. Clin Rheumatol 30:639–645 2. Reginato AJ, Coquia JA (2003) Musculoskeletal manifestations of osteomalacia and rickets. Best Pract Res Clin Rheumatol 17:1063– 1080 3. Russell LA (2010) Osteoporosis and osteomalacia. Rheum Dis Clin North Am 36:665–680 4. Lane NE (2009) Metabolic bone disease. In: Firestein GS (ed) Kelley’s textbook of rheumatology, 8th edn. W. B. Saunders, Philadelphia, pp 1579–1599 5. Caniggia A (1991) The osteomalacias. Ann Ital Med Int 6:476– 482 6. Bonen A, van Tubergen A, van der Linden S, Mihai C (2004) Spondyloarthropathies. In: Tugwell P (ed) Evidence-based rheumatology, 1st edition. BMJ, London, pp 393–442 7. Rodríguez-Reyna TS, Martínez-Reyes C, Yamamoto-Furusho JK (2009) Rheumatic manifestations of inflammatory bowel disease. World J Gastroenterol 15:5517–5524 8. LeBoff MS (1997) Is prolonged use of corticosteroids safe in patients with Crohn’s disease? Inflamm Bowel Dis 3:169–173 9. Talabiska DG, Seidner DL, Jensen GL (1993) Acute tetany in the Crohn's patient with osteomalacia. Nutrition 9:159–162 10. Golding DN (1985) Muscle pain and wasting in osteomalacia. JR Soc Med 78:495–496 11. Seligman JV, Basi SS, Deitel M, Bayley TA, Khanna RK (1984) Metabolic bone disease in a patient on long-term total parenteral nutrition: a case report with review of literature. Parenter Enteral Nutr 8:722–727 12. Sitrin MD, Rosenberg IH, Chawla K, Meredith S, Sellin J, Rabb JM, Coe F, Kirsner JB, Kraft SC (1980) Nutritional and metabolic complications in a patient with Crohn's disease and ileal resection. Gastroenterology 78:1069–1079 13. Victorino RM, Lucas MB, de Moura MC (1986) Severe osteomalacia associated with renal tubular acidosis in Crohn's disease. Dig Dis Sci 31:322–326
