Joint contractures responsive to immunosuppressive therapy in a girl with childhood-onset systemic sclerosis double-seropositive for rare anti-nucleolar autoantibodies: a case report.

BACKGROUND: Systemic sclerosis (SSc; scleroderma) is an autoimmune connective tissue disease that affects the skin and subcutaneous tissue, in addition to the internal organs of the whole body. Onset in childhood is uncommon; however, both patients with childhood-onset and adult-onset SSc are positive for anti-nuclear antibodies (ANAs).Detection of SSc-related anti-nuclear antibodies is often useful for predicting clinical features, disease course, and outcomes. CASE PRESENTATION: A 5-year-old Japanese female manifested gradually progressive abnormal gait disturbance, regression of motor development, Raynaud's phenomenon, and the shiny appearance of the skin of the face and extremities at age 2. On admission, she presented a mask-like appearance, loss of wrinkles and skin folds, puffy fingers, moderate diffuse scleroderma (18/51 of the modified Rodnan total skin thickness score), and contracture in the ankle and proximal interphalangeal joints. Grossly visible capillary hemorrhage on nail fold and severe abnormal capillaroscopy findings including bleeding, giant loop and disappearance of capillaryconsistent with the late phase in SSc. A skin biopsy showed fibrous thickening of the dermis, entrapment of an eccrine sweat glands, and thickened fiber. Chest high-resolution computed tomographic scanning demonstrated patchy areas of ill-defined air-space opacity and consolidation predominantly involving the posterior basilar aspects of the lower lobes presenting withinterstitial lung disease. Positive ANA (1:160 nucleolar and homogeneous nuclear staining by indirect fluorescent antibody technique) and double-seropositive for anti-Th/To and anti-PM-Scl antibodies were identified. She was diagnosed with diffuse cutaneous SSc based on the Pediatric Rheumatology European Society/American College of Rheumatology/European League Against Rheumatism Provisional Classification Criteria for Juvenile Systemic Sclerosis and was successfully treated with immunosuppressive agents, including methylprednisolone pulses and intravenous cyclophosphamide. CONCLUSIONS: We experienced the first case of juvenile SSc with anti-PM-Scl and anti-Th/To antibodies. ILD was identified as a typical feature of patients with these autoantibodies; however, diffuse cutaneous SSc and joint contraction were uncharacteristically associated. The case showed unexpected clinical findings though the existence of SSc-related autoantibodies aids in determining possible organ involvement and to estimate the children's outcome.

Serum Mast Cell Tryptase as a Marker of Posttraumatic Joint Contracture in a Rabbit Model.

OBJECTIVES: Mast cells have been identified as key mediators of posttraumatic joint contracture, and stabilizing medications (ketotifen) have been shown to decrease contracture severity. Serum mast cell tryptase (SMCT) levels are used clinically to monitor mast cell-mediated conditions. The goals of this study were to determine if SMCT levels are elevated in the setting of joint contracture, if they can be decreased in association with ketotifen therapy, and if they correlate with contracture severity. METHODS: This study used a previously developed rabbit model in which 39 animals were divided into 4 groups: operatively created joint contracture (ORC, n = 13), operatively created contracture treated with ketotifen at 2 doses (KF0.5, n = 9; KF1.0, n = 9), and healthy rabbits (NC, n = 8). Range of motion measures were performed at 8 weeks after the surgery. Serum samples were collected on postoperative days 1, 3, 5, 7, 21, 35, and 49. SMCT levels were measured using a rabbit-specific enzyme-linked immunosorbent assay. RESULTS: Levels of SMCT were highest in the operatively created joint contracture group and were significantly greater compared with both ketotifen groups (P < 0.001). Levels were highest at postoperative day 1 with a trend to decrease over time. A positive correlation between SMCT levels and contracture severity was observed in all operative groups (P < 0.05). CONCLUSIONS: Levels of SMCT are elevated in the setting of joint contracture, decreased in association with ketotifen therapy, and positively correlated with contracture severity. This is the first study to establish a relationship between SMCT and joint injury. Measurement of SMCT may be valuable in identifying those at risk of posttraumatic joint contracture.

Fibronectin is a serum biomarker for Duchenne muscular dystrophy.

PURPOSE: To identify and validate serum biomarkers for the progression of Duchenne muscular dystrophy (DMD) using a MS-based bottom-up pipeline. EXPERIMENTAL DESIGN: We used a bottom-up proteomics approach, including a protein concentration equalization step, different proteolytic digestions, and MS detection schemes, to identify candidate biomarkers in serum samples from control subjects and DMD patients. Fibronectin was chosen for follow-up based on the differences in peptide spectral counts and sequence coverage observed between the DMD and control groups. Subsequently, fibronectin levels were determined with ELISA in 68 DMD patients, 38 milder Becker muscular dystrophy patients, 33 patients with other neuromuscular disorders, and 15 age-matched adult and child controls. RESULTS: There was a significant increase in fibronectin levels in DMD patients compared to age-matched controls. Fibronectin levels in patients with Becker muscular dystrophy, Bethlem myopathy, or myasthenia gravis were comparable to control levels. Progressive elevation in fibronectin levels was observed in longitudinal samples from 22 DMD patients followed up for a period of 6 months up to 4 years. CONCLUSION AND CLINICAL RELEVANCE: This study suggests that serum fibronectin levels may constitute a promising biomarker to monitor disease progression in DMD patients.

Circulating substance P levels and shoulder joint contracture after arthroscopic repair of the rotator cuff.

OBJECTIVE: To determine the plasma levels of substance P (SP) in patients with postoperative stiffness after arthroscopic rotator cuff repair. DESIGN: Plasma samples were obtained at 15 months from surgery from two groups of patients who underwent arthroscopic repair of a rotator cuff tear. In group 1, 30 subjects (14 men, 16 women; mean age 64.6 years, range 47 to 78) with shoulder stiffness 15 months after arthroscopic rotator cuff repair were recruited. In group 2, 30 patients (11 men, 19 women; mean age 57.8 years, range 45 to 77) were evaluated 15 months after successful arthroscopic rotator cuff repair. Immunoassays were performed with commercially available assay kits to measure the plasma levels of SP. RESULTS: Plasma levels of SP in patients with postoperative stiffness were significantly greater than those in the control group (mean 81.06 (SD 27.76) versus 23.49 (5.64), p<0.05). CONCLUSIONS: The plasma concentrations of substance P in patients with shoulder stiffness after arthroscopic rotator cuff repair are higher compared with plasma levels of SP in patients with a good postoperative outcome. The neuronal upregulation of SP shown in the plasma of patients with postoperative shoulder stiffness may underlie not only the symptoms but also its development of adhesive capsulitis.

Determination of serum fibrosis indexes in patients with capsular contracture after augmentation with smooth silicone gel implants.

BACKGROUND: Several studies have confirmed a correlation between the concentration of serum hyaluronan and progressive fibrotic disorders such as liver cirrhosis. The aim of this study was to explore the relationship between serum hyaluronan levels and capsular contracture after aesthetic breast augmentation. METHODS: The study included 25 female patients (average age, 40 +/- 12 years) with capsular contracture after cosmetic breast augmentation with smooth silicone gel implants (Mentor, Santa Barbara, Calif.). The implants were placed in a submuscular position through an inframammary fold incision. The implant removals were prompted by development of capsular fibrosis (Baker grades I through IV). Samples of capsular tissue were obtained from all patients for standard histologic and immunohistochemical analysis. Blood samples were drawn from all patients immediately before operation. Sera from 20 healthy female patients (average age, 34 +/- 9 years) were used as control. RESULTS: : Capsular tissue revealed significantly higher thickness in patients with grade III/IV contracture than in women with grade II contracture, according to Baker's classification. There was a moderate (n = 15) or severe (n = 10) chronic inflammatory reaction in the capsules around the implants. Fibroblasts, fibroblast-like cells, and macrophages represented the major cell populations found within the fibrous capsules, along with scattered polymorphonuclear leukocytes, lymphocytes, plasma cells, and mast cells. In addition, activated CD4+ cells were detected. An inner layer with synovia-like metaplasia and multinucleated giant cells was found. There was a significantly higher level (p < 0.05) of hyaluronan serum concentration in patients with capsular contracture (26 +/- 14 microg/liter) compared with control subjects (12 +/- 6 microg/liter). There was a positive correlation between the grade of capsular contracture (Baker grades I through IV) and the hyaluronan serum concentration (Baker grade II, 15 +/- 3 microg/liter; Baker grade III, 34 +/- 13 microg/liter; Baker grade IV, 42 +/- 11 microg/liter) (r = 0.73; p < 0.05). CONCLUSIONS: Serum hyaluronan levels were significantly elevated in patients with capsular contracture after breast augmentation, and there was a positive correlation with stage of capsular contracture. Further study is necessary to determine whether hyaluronan might be useful as a predictor for the development and progress of capsular fibrosis.

Increased urinary excretion of pyridinoline and deoxypyridinoline in a girl with congenital contractural arachnodactyly.

Congenital contractural arachnodactyly (CCA) is caused by mutations in the gene for fibrillin 2 glycoprotein, a component of connective tissue. The causes of osteodystrophy or osteodysplasia in CCA are unknown. We report bone metabolism in a 28 month-old girl with CCA. Serum alkaline phosphatase and osteocalcin levels were 650 IU/l and 22 ng/ml at 1.5 months old (control: 530+/-65, 16.5+/-4.3), and 580 IU/l and 21 ng/ml at 28 months old (control: 465+/-58, 15.0+/-3.5), i.e. in upper-normal levels. The urinary pyridinoline and deoxypyridinoline levels were 1176 and 194 micromol/mol creatinine at 1.5 months old (control: 329+/-76, 63+/-12), and 407 and 111 micromol/mol cr at 28 months old (control: 231+/-49, 50+/-11), apparently higher than the control values. These findings may indicate that abnormal fibrillin may impair bone metabolism and cause the osteodystrophy or osteodysplasia in CCA.

Firm myocardium in cardiopulmonary resuscitation.

Firm myocardium in cardiopulmonary resuscitation (CPR) is a rarely described yet potentially important condition. To investigate the clinical nature and implications of firm myocardium in CPR, we retrospectively analyzed 59 adult patients with nontraumatic out-of-hospital cardiac arrest who underwent open-chest CPR in the emergency department and had heart consistency recorded. Consistency of the myocardium varied considerably between patients. Firm myocardium was noticed in 36 cases, mainly in the left ventricle (firm myocardium group). The remaining 23 hearts were not firm (soft myocardium group). Some hearts had an increase in their consistency during CPR. Patient characteristics were similar in the two groups. The firm myocardium group showed greater base deficit on arterial blood gas analysis, suggesting more severe ischemic injury. Very firm heart had a close association with an extremely low end-tidal CO2 tension. Histopathological examination revealed hypertrophy and fibrosis common to the two groups. Both groups received similar treatment except for a shorter duration of direct cardiac massage in the firm myocardium group, although a reasonably prolonged effort was made in most cases. The firm myocardium group responded poorly to treatment. Very firm myocardium never contracted, whereas less firm myocardium usually showed some, albeit insufficient, activity. Most cases in the soft myocardium group regained a pulse. Our results suggest that firm myocardium: (1) is common in patients who receive CPR in the emergency department, (2) indicates ischemic contracture, (3) is not uniform in firmness, reflecting the degree of ischemia and (4) is a grave prognostic factor in cardiac resuscitation.

Frozen shoulder and lipids.

We prospectively studied 50 patients with the diagnosis of primary frozen shoulder. The serum lipid levels were measured in 43 of these patients and compared with those in 43 age-matched and sex-matched control subjects. The fasting serum triglyceride and cholesterol levels were significantly elevated in the frozen-shoulder group (cholesterol p < 0.01; triglyceride p < 0.02).

Immunoassay of platelet-derived growth factor in the blood of patients with diabetes mellitus.

Platelet-derived growth factor (PDGF) is a powerful mitogen for many cell types, and is believed to play a major role in wound healing when released from platelets at sites of injury. In diabetes mellitus, it has been proposed that premature release of PDGF from platelets impairs the ability of platelets to initiate healing, and also accelerates the development of diabetic complications such as angiopathy by increasing plasma-borne PDGF. However, plasma samples from diabetic patients have not previously been assayed for PDGF using suitable techniques. A sensitive monoclonal enzyme-linked immunoassay for PDGF was applied to plasma and serum samples from 18 healthy control subjects and 60 diabetic patients. Neither plasma nor serum PDGF concentrations differed significantly between control subjects, insulin-dependent, and non-insulin-dependent diabetic patients. However, 23% of the diabetic subjects had serum PDGF levels above the control range. Limited joint mobility, which is characterised by joint contractures and collagen deposition in the skin, and is associated with microvascular disease, was used as a marker of diabetic complications. Limited joint mobility affected 43% of the diabetic subjects. Patients with moderate limited joint mobility had had diabetes significantly longer than those without limited joint mobility (means 17 years and 9 years, respectively, p = 0.008). However, limited joint mobility was not associated with elevated serum or plasma PDGF in insulin-dependent or non-insulin-dependent diabetes. We conclude that complications of diabetes are unlikely to be caused by changes in systemic levels of PDGF.(ABSTRACT TRUNCATED AT 250 WORDS)

Clinical characteristics and circulating collagen and laminin metabolites in insulin-dependent diabetic children with joint and skin manifestations.

One hundred seventy-four children and adolescents with insulin-dependent diabetes mellitus were examined for joint contractures and skin manifestations in their hands. Joint contractures were found in 52 (29.8%) and skin manifestations in 29 (16.6%) patients. To eliminate the possible confounding effects of age and duration of diabetes on the variables to be studied, patients younger than 7 y and with a duration of diabetes shorter than 3 y were excluded from the subsequent analyses. Of the remaining 108 children, those with joint contractures had lower serum concentrations of the 7-S domain of type IV collagen and the P1 fragment of laminin than the other patients (p = 0.033) but higher mean glycated Hb levels (p = 0.048). A clear association was noted between the occurrence of joint contractures and skin changes (p = 0.007). Background retinopathy was found in six patients (5.6%), three of whom had stage II joint contractures (p = 0.064). The children with skin changes and those with combined joint and skin manifestations more often had insulin-dependent diabetes mellitus in their first-degree relatives (p = 0.038 and p = 0.043, respectively). No difference in relative height was found between the groups. No association could be seen between disease susceptibility antigens in the HLA-D locus and joint or skin manifestations. The lower levels of circulating collagen and laminin metabolites in the diabetic children with joint contractures suggest that these patients are characterized by a reduced turnover of basement membranes in tissues.(ABSTRACT TRUNCATED AT 250 WORDS)