Review of antihemophilic factor injection for the routine prophylaxis of bleeding episodes and risk of joint damage in severe hemophilia A

Individuals with severe factor VIII deficiency experience recurrent hemorrhages and develop progressive joint damage. Large retrospective, nonrandomized studies of patient cohorts followed over decades show that factor prophylaxis initiated at an early age before the onset of recurrent bleeding reduces the incidence of hemophilic arthropathy. Two recent prospective, multicenter, randomized trials conducted in Europe (the ESPRIT study) and the USA (the Joint Outcome Study) confirm the efficacy of prophylaxis in the prevention of hemarthroses and arthropathy. Regular prophylaxis initiated in early childhood enhances the quality of life for patients with severe hemophilia and reduces the risk of inhibitor development. The substantial costs of such preventative therapy may be offset by the reduced expenditures that the care of degenerative joint disease in adult hemophilia patients would otherwise require

Mutations in SLC29A3, Encoding an Equilibrative Nucleoside Transporter ENT3, Cause a Familial Histiocytosis Syndrome (Faisalabad Histiocytosis) and Familial Rosai-Dorfman Disease

The histiocytoses are a heterogeneous group of disorders characterised by an excessive number of histiocytes. In most cases the pathophysiology is unclear and treatment is nonspecific. Faisalabad histiocytosis (FHC) (MIM 602782) has been classed as an autosomal recessively inherited form of histiocytosis with similarities to Rosai-Dorfman disease (RDD) (also known as sinus histiocytosis with massive lymphadenopathy (SHML)). To elucidate the molecular basis of FHC, we performed autozygosity mapping studies in a large consanguineous family and identified a novel locus at chromosome 10q22.1. Mutation analysis of candidate genes within the target interval identified biallelic germline mutations in SLC29A3 in the FHC kindred and in two families reported to have familial RDD. Analysis of SLC29A3 expression during mouse embryogenesis revealed widespread expression by e14.5 with prominent expression in the central nervous system, eye, inner ear, and epithelial tissues including the gastrointestinal tract. SLC29A3 encodes an intracellular equilibrative nucleoside transporter (hENT3) with affinity for adenosine. Recently germline mutations in SLC29A3 were also described in two rare autosomal recessive disorders with overlapping phenotypes: (a) H syndrome (MIM 612391) that is characterised by cutaneous hyperpigmentation and hypertrichosis, hepatomegaly, heart anomalies, hearing loss, and hypogonadism; and (b) PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus) syndrome. Our findings suggest that a variety of clinical diagnoses (H and PHID syndromes, FHC, and familial RDD) can be included in a new diagnostic category of SLC29A3 spectrum disorder

Systematic Review and Meta-Analysis of 3 Treatment Arms for Vertebral Compression Fractures: A Comparison of Improvement in Pain, Adjacent-Level Fractures, and Quality of Life Between Vertebroplasty, Kyphoplasty, and Nonoperative Management

BACKGROUND Osteoporotic vertebral fractures (OVFs) have become increasingly common, and previous nonrandomized and randomized controlled trials (RCTs) have compared the effects of cement augmentation versus nonoperative management on the clinical outcome. This meta-analysis focuses on RCTs and the calculated differences between cement augmentation techniques and nonsurgical management in outcome (e.g., pain reduction, adjacent-level fractures, and quality of life [QOL]). METHODS A systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, and the following scientific search engines were used: MEDLINE, Embase, Cochrane, Web of Science, and Scopus. The inclusion criteria included RCTs that addressed different treatment strategies for OVF. The primary outcome was pain, which was determined by a visual analog scale (VAS) score; the secondary outcomes were the risk of adjacent-level fractures and QOL (as determined by the EuroQol-5 Dimension [EQ-5D] questionnaire, the Oswestry Disability Index [ODI], the Quality of Life Questionnaire of the European Foundation for Osteoporosis [QUALEFFO], and the Roland-Morris Disability Questionnaire [RDQ]). Patients were assigned to 3 groups according to their treatment: vertebroplasty (VP), kyphoplasty (KP), and nonoperative management (NOM). The short-term (weeks), midterm (months), and long-term (>1 year) effects were compared. A random effects model was used to summarize the treatment effect, including I2 for assessing heterogeneity and the revised Cochrane risk-of-bias 2 (RoB 2) tool for assessment of ROB. Funnel plots were used to assess risk of publication bias. The log of the odds ratio (OR) between treatments is reported. RESULTS After screening of 1,861 references, 53 underwent full-text analysis and 16 trials (30.2%) were included. Eleven trials (68.8%) compared VP and NOM, 1 (6.3%) compared KP and NOM, and 4 (25.0%) compared KP and VP. Improvement of pain was better by 1.31 points (95% confidence interval [CI], 0.41 to 2.21; p < 0.001) after VP when compared with NOM in short-term follow-up. Pain effects were similar after VP and KP (midterm difference of 0.0 points; 95% CI, -0.25 to 0.25). The risk of adjacent-level fractures was not increased after any treatment (log OR, -0.16; 95% CI, -0.83 to 0.5; NOM vs. VP or KP). QOL did not differ significantly between the VP or KP and NOM groups except in the short term when measured by the RDQ. CONCLUSIONS This meta-analysis provides evidence in favor of the surgical treatment of OVFs. Surgery was associated with greater improvement of pain and was unrelated to the development of adjacent-level fractures or QOL. Although improvements in sagittal balance after surgery were poorly documented, surgical treatment may be warranted if pain is a relevant problem. LEVEL OF EVIDENCE Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence

Systematic Review and Meta-Analysis of 3 Treatment Arms for Vertebral Compression Fractures: A Comparison of Improvement in Pain, Adjacent-Level Fractures, and Quality of Life Between Vertebroplasty, Kyphoplasty, and Nonoperative Management.

BACKGROUND Osteoporotic vertebral fractures (OVFs) have become increasingly common, and previous nonrandomized and randomized controlled trials (RCTs) have compared the effects of cement augmentation versus nonoperative management on the clinical outcome. This meta-analysis focuses on RCTs and the calculated differences between cement augmentation techniques and nonsurgical management in outcome (e.g., pain reduction, adjacent-level fractures, and quality of life [QOL]). METHODS A systematic review was performed according to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, and the following scientific search engines were used: MEDLINE, Embase, Cochrane, Web of Science, and Scopus. The inclusion criteria included RCTs that addressed different treatment strategies for OVF. The primary outcome was pain, which was determined by a visual analog scale (VAS) score; the secondary outcomes were the risk of adjacent-level fractures and QOL (as determined by the EuroQol-5 Dimension [EQ-5D] questionnaire, the Oswestry Disability Index [ODI], the Quality of Life Questionnaire of the European Foundation for Osteoporosis [QUALEFFO], and the Roland-Morris Disability Questionnaire [RDQ]). Patients were assigned to 3 groups according to their treatment: vertebroplasty (VP), kyphoplasty (KP), and nonoperative management (NOM). The short-term (weeks), midterm (months), and long-term (>1 year) effects were compared. A random effects model was used to summarize the treatment effect, including I2 for assessing heterogeneity and the revised Cochrane risk-of-bias 2 (RoB 2) tool for assessment of ROB. Funnel plots were used to assess risk of publication bias. The log of the odds ratio (OR) between treatments is reported. RESULTS After screening of 1,861 references, 53 underwent full-text analysis and 16 trials (30.2%) were included. Eleven trials (68.8%) compared VP and NOM, 1 (6.3%) compared KP and NOM, and 4 (25.0%) compared KP and VP. Improvement of pain was better by 1.31 points (95% confidence interval [CI], 0.41 to 2.21; p < 0.001) after VP when compared with NOM in short-term follow-up. Pain effects were similar after VP and KP (midterm difference of 0.0 points; 95% CI, -0.25 to 0.25). The risk of adjacent-level fractures was not increased after any treatment (log OR, -0.16; 95% CI, -0.83 to 0.5; NOM vs. VP or KP). QOL did not differ significantly between the VP or KP and NOM groups except in the short term when measured by the RDQ. CONCLUSIONS This meta-analysis provides evidence in favor of the surgical treatment of OVFs. Surgery was associated with greater improvement of pain and was unrelated to the development of adjacent-level fractures or QOL. Although improvements in sagittal balance after surgery were poorly documented, surgical treatment may be warranted if pain is a relevant problem. LEVEL OF EVIDENCE Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence

Comparison of clinical features of families with <i>SLC29A3</i> mutations from this report and those reported with H syndrome and PHID syndrome.

<p>Clinical details were taken from published reports and unpublished updated information for the three families included in the present study. Previously unreported additional information is shown in bold. Mutation nomenclature used is based on reference sequence NM_018344.4. (Abbreviations: SHML = Sinus Histiocytosis with Massive Lymphadenopathy; IDDM = Insulin dependent diabetes mellitus; ASD = atrial septal defect; PS = Pulmonary stenosis; PDA = patent ductus areteriosis; TCC = transitional cell carcinoma).</p

Knockdown of <i>SLC29A3</i> expression by siRNA enhanced proliferation of HeLa cells.

<p>(A) Effect of <i>SLC29A3</i> siRNA on levels of <i>SLC29A3</i> mRNA assessed by real-time quantitative PCR (qRT–PCR). HeLa cells were treated with control or <i>SLC29A3</i>- 120032 or <i>SLC29A3</i>-26642 siRNA for 72 hours. Cells were harvested and total RNA was extracted. <i>SLC29A3</i> and β-actin or <i>SLC29A3</i> and β-2-microglobulin mRNA (was examined by qRT-PCR. Values are mean ± SEM from 3 controls and 3 samples. * <i>P</i><0.001 between HeLa cells treated with SLC29A3-siRNA versus luciferase siRNA control sequence. (B) <i>SLC29A3</i> knockdown elevates proliferation in HeLa cells. HeLa cells were transfected with siRNA designed to target <i>SLC29A3</i> (<i>siRNA-SLC29A3</i>) or control siRNA. Cell proliferation assays were performed 72 hours after siRNA transfection. Results areexpressed in fluorescence at 550 nm using 580 nm as a reference wavelength(fluorescence is directly proportional to the number of living cells). This figure represents 3 experiments.* P<0.05.</p

Schematic showing the minimal candidate interval on chromosome 10q22.1, positions of candidate genes taken from the Ensembl genome browser (Build 49), genomic organization of <i>SLC29A3</i>, and positions of mutations found in the 3 histiocytosis syndrome families.

<p>Schematic showing the minimal candidate interval on chromosome 10q22.1, positions of candidate genes taken from the Ensembl genome browser (Build 49), genomic organization of <i>SLC29A3</i>, and positions of mutations found in the 3 histiocytosis syndrome families.</p