NT5E mutations and arterial calcifications.

BACKGROUND: Arterial calcifications are associated with increased cardiovascular risk, but the genetic basis of this association is unclear. METHODS: We performed clinical, radiographic, and genetic studies in three families with symptomatic arterial calcifications. Single-nucleotide-polymorphism analysis, targeted gene sequencing, quantitative polymerase-chain-reaction assays, Western blotting, enzyme measurements, transduction rescue experiments, and in vitro calcification assays were performed. RESULTS: We identified nine persons with calcifications of the lower-extremity arteries and hand and foot joint capsules: all five siblings in one family, three siblings in another, and one patient in a third family. Serum calcium, phosphate, and vitamin D levels were normal. Affected members of Family 1 shared a single 22.4-Mb region of homozygosity on chromosome 6 and had a homozygous nonsense mutation (c.662C→A, p.S221X) in NT5E, encoding CD73, which converts AMP to adenosine. Affected members of Family 2 had a homozygous missense mutation (c.1073G→A, p.C358Y) in NT5E. The proband of Family 3 was a compound heterozygote for c.662C→A and c.1609dupA (p.V537fsX7). All mutations found in the three families result in nonfunctional CD73. Cultured fibroblasts from affected members of Family 1 showed markedly reduced expression of NT5E messenger RNA, CD73 protein, and enzyme activity, as well as increased alkaline phosphatase levels and accumulated calcium phosphate crystals. Genetic rescue experiments normalized the CD73 and alkaline phosphatase activity in patients' cells, and adenosine treatment reduced the levels of alkaline phosphatase and calcification. CONCLUSIONS: We identified mutations in NT5E in members of three families with symptomatic arterial and joint calcifications. This gene encodes CD73, which converts AMP to adenosine, supporting a role for this metabolic pathway in inhibiting ectopic tissue calcification. (Funded by the National Human Genome Research Institute and the National Heart, Lung, and Blood Institute of the National Institutes of Health.).

Elevation of serum tumor necrosis factor α in patients with periprosthetic osteolysis: a case-control study.

BACKGROUND: Periprosthetic osteolysis is the leading reason for THA revision. The relationship of serum biomarkers with severe radiographic periprosthetic osteolysis has not been defined but may be important to direct future research and clinical therapeutics. QUESTIONS/PURPOSES: We determined whether there was an association between measurable inflammatory markers (high-sensitivity C-reactive protein [hsCRP]) or inflammatory mediators (tumor necrosis factor α [TNF-α], IL-1ß, IL-6, receptor activator of nuclear factor κB ligand [RANKL], and osteoprotegerin [OPG]) and periprosthetic osteolysis. METHODS: We identified 15 patients with THAs scheduled for revision surgery because of severe periprosthetic osteolysis. For each study patient, a nonosteolytic, pain-free control patient with THAs was identified and matched for age, sex, time since initial THA, acetabular and femoral component prosthesis material, and prosthesis wear within 1.0 mm/year using a manual wear analysis technique. Overall, the study and control patients had a mean wear rate of 0.25 mm/year since index THA. There were no differences in baseline characteristics between study and control patients in age, sex, BMI, Charlson Comorbidity Index, time since initial THA, UCLA activity score, and acetabular and femoral component type. Serum hsCRP, IL-1ß, IL-6, TNF-α, RANKL, and OPG were measured by ELISA in duplicate assays. Differences in values were assessed using the Wilcoxon rank-sum test. RESULTS: Median TNF-α levels were higher in study patients than in controls (7.1 pg/mL [SD, 11.6 pg/mL] versus 1.5 pg/mL [SD, 1.3 pg/mL]) (p < 0.01). Median IL-6 levels tended to be higher in study patients than in controls (8.9 pg/mL [SD, 13.2 pg/mL] versus 3.5 pg/mL [SD, 0.7 pg/mL]) (p = 0.09). The other serum inflammatory proteins and mediators of bone turnover were not different between groups. CONCLUSIONS: TNF-α is elevated in patients with osteolysis compared to matched controls. The role of TNF-α and its potential as a target of nonsurgical therapy to prevent osteolysis warrant further investigation in larger, prospective studies.

Antimalarial myopathy in a systemic lupus erythematosus patient with quadriparesis and seizures: a case-based review.

Weakness, seizures, and encephalopathy have a broad differential diagnosis in patients with systemic lupus erythematosus (SLE). We present a case of a 26-year-old female with a recent diagnosis of SLE who experienced a clinical deterioration with quadriparesis, seizures, and encephalopathy. Her quadriparesis was found to be secondary to biopsy-proven hydroxychloroquine-induced myopathy with concomitant inflammatory myopathy. Her seizures and encephalopathy were suspected to be multifactorial in the setting of sepsis and critical illness with possible contributions from neuropsychiatric manifestations of SLE and macrophage activation syndrome. She experienced a dramatic clinical recovery with discontinuation of hydroxychloroquine, treatment of lupus disease activity with mycophenolate mofetil and prednisone, and antibiotic treatment for methicillin-sensitive Staphylococcus aureus (MSSA) bacteremia. This case-based review provides a systematic approach to quadriparesis, seizures, and encephalopathy in patients with SLE and an evidence-based discussion of antimalarial myopathy, which is of critical importance given the widespread use of antimalarial medications for rheumatologic diseases.

Risk factors for incident osteoarthritis of the hip and knee.

This article reviews the published risk factors associated with incident osteoarthritis of the lower extremity weight-bearing joints. Systemic risk factors include factors such as age, ethnicity, gender and genetic variables. Local risk factors are variables such as obesity, previous knee injury and occupational activities. Challenges in the study of incident osteoarthritis, and promising potential future study directions are also reviewed.