Midterm outcomes of total hip arthroplasty with a modular Birmingham head.

INTRODUCTION: Birmingham Hip Resurfacing (BHR) implants may be combined with a conventional femoral stem to create a modular metal-on-metal total hip arthroplasty (BHR MoM THA). There is little outcome data regarding this construct. This study examines midterm outcomes of BHR MoM THA compared to oxidised zirconium total hip arthroplasty (THA). METHODS: A retrospective institutional review identified all patients receiving BHR MoM THA between April 2005 and February 2011 and a matched control cohort of zirconium THA patients. Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Harris Hip Score (HHS), and SF-12 Health status scores were obtained. Revisions and complications were collected from clinical records. Radiographs were assessed for evidence of component malposition, loosening, osteolysis, or heterotopic ossification. RESULTS: 63 modular BHR MoM THA were identified in 61 patients (36 with BHR cups, 27 with R3 cups) and 63 zirconium THA in 58 matched controls. Mean follow-up was 58 months. 14 BHR MoM THA hips (22.2%) were revised (4 infections, 1 dislocation, 9 soft tissue reactions) compared to 3 (4.8%) zirconium THA (all infections). At latest follow-up, 18.4% of surviving BHR MoM THA hips were painful compared to 0.5% of zirconium THA controls (p < 0.001). WOMAC, HHS, and SF-12 did not differ significantly between surviving members of the 2 groups. DISCUSSION: BHR MoM THA demonstrated a high revision rate, largely for adverse local soft tissue reaction and pain. Among those not revised, many reported some residual pain despite similar quality of life measures to those who received zirconium THA.

Stability of DNA methylation patterns in mouse spermatogonia under conditions of MTHFR deficiency and methionine supplementation.

Little is known about the conditions contributing to the stability of DNA methylation patterns in male germ cells. Altered folate pathway enzyme activity and methyl donor supply are two clinically significant factors that can affect the methylation of DNA. 5,10-Methylenetetrahydrofolate reductase (MTHFR) is a key folate pathway enzyme involved in providing methyl groups from dietary folate for DNA methylation. Mice heterozygous for a targeted mutation in the Mthfr gene (Mthfr(+/-)) are a good model for humans homozygous for the MTHFR 677C>T polymorphism, which is found in 10% of the population and is associated with decreased MTHFR activity and infertility. High-dose folic acid is administered as an empirical treatment for male infertility. Here, we examined MTHFR expression in developing male germ cells and evaluated DNA methylation patterns and effects of a range of methionine concentrations in spermatogonia from Mthfr(+/-) as compared to wild-type, Mthfr(+/+) mice. MTHFR was expressed in prospermatogonia and spermatogonia at times of DNA methylation acquisition in the male germline; its expression was also found in early spermatocytes and Sertoli cells. DNA methylation patterns were similar at imprinted genes and intergenic sites across chromosome 9 in neonatal Mthfr(+/+) and Mthfr(+/-) spermatogonia. Using spermatogonia from Mthfr(+/+) and Mthfr(+/-) mice in the spermatogonial stem cell (SSC) culture system, we examined the stability of DNA methylation patterns and determined effects of low or high methionine concentrations. No differences were detected between early and late passages, suggesting that DNA methylation patterns are generally stable in culture. Twenty-fold normal concentrations of methionine resulted in an overall increase in the levels of DNA methylation across chromosome 9, suggesting that DNA methylation can be perturbed in culture. Mthfr(+/-) cells showed a significantly increased variance of DNA methylation at multiple loci across chromosome 9 compared to Mthfr(+/+) cells when cultured with 0.25- to 2-fold normal methionine concentrations. Taken together, our results indicate that DNA methylation patterns in undifferentiated spermatogonia, including SSCs, are relatively stable in culture over time under conditions of altered methionine and MTHFR levels.

Strain-specific defects in testicular development and sperm epigenetic patterns in 5,10-methylenetetrahydrofolate reductase-deficient mice.

Methylenetetrahydrofolate reductase (MTHFR) is a crucial folate pathway enzyme that contributes to the maintenance of cellular pools of S-adenosylmethionine, the universal methyl donor for several reactions including DNA methylation. Whereas Mthfr(-/-) BALB/c mice show growth retardation, developmental delay, and spermatogenic defects and infertility, C57BL/6 mice appear to have a less severe phenotype. In the present study, we investigated the effects of MTHFR deficiency on early germ cell development in both strains and assessed whether MTHFR deficiency results in DNA methylation abnormalities in sperm. The reproductive phenotype associated with MTHFR deficiency differed strikingly between the two strains, with BALB/c mice showing an early postnatal loss of germ cell number and proliferation that was not evident in the C57BL/6 mice. As a result, the BALB/c MTHFR-deficient mice were infertile, whereas the C57BL/6 mice had decreased sperm numbers and altered testicular histology but showed normal fertility. Imprinted genes and sequences that normally become methylated during spermatogenesis were unaffected by MTHFR deficiency in C57BL/6 mice. In contrast, a genome-wide restriction landmark genomic scanning approach revealed a number of sites of hypo- and hypermethylation in the sperm of this mouse strain. These results showing strain-specific defects in MTHFR-deficient mice may help to explain population differences in infertility among men with common MTHFR polymorphisms.