Hybrid Fixation for Total Hip Arthroplasty Showed Improved Survival Over Cemented and Uncemented Fixation: A Single-Center Survival Analysis of 2156 Hips at 12-18 Years.

BACKGROUND: Despite increased use of uncemented and hybrid fixation, there is little evidence of their superiority over cemented implants. The aim of this study is to compare the long-term survivorship of cemented, hybrid and uncemented total hip arthroplasty (THA) at varying ages. METHODS: A total of 2156 hips (1315 cemented, 324 uncemented, and 517 hybrid) were performed in a single center between 1999 and 2005 with follow-up through to 2017. Registry and local databases were used to determine revision rates and cause. Unadjusted and adjusted competing risk survival analysis was performed. RESULTS: The cumulative incidence of all-cause revision at 18 years was cemented 10.9%, uncemented 8.9%, and hybrid 6.5%. Cemented fixation had a statistically significant higher risk of all-cause revision than hybrid in the adjusted model for all ages to 65 years (subhazard ratios [SHRs], 2.28-4.67) and a higher risk of revision for loosening, wear, or osteolysis at all ages (SHRs, 3.25-6.07). Uncemented fixation showed no advantage over hybrid fixation at any age, but did show advantages over cemented at younger ages (≤60 years) for all-cause revision (SHRs, 2.3-4.3). CONCLUSION: Hybrid fixation with conventional polyethylene shows an advantage over cemented hips at all ages. Uncemented THA showed improved survival over cemented only at younger ages and no advantage over hybrid THA.

Differential sensitivity of prefrontal cortex and hippocampus to alcohol-induced toxicity.

The prefrontal cortex (PFC) is a brain region responsible for executive functions including working memory, impulse control and decision making. The loss of these functions may ultimately lead to addiction. Using histological analysis combined with stereological technique, we demonstrated that the PFC is more vulnerable to chronic alcohol-induced oxidative stress and neuronal cell death than the hippocampus. This increased vulnerability is evidenced by elevated oxidative stress-induced DNA damage and enhanced expression of apoptotic markers in PFC neurons. We also found that one-carbon metabolism (OCM) impairment plays a significant role in alcohol toxicity to the PFC seen from the difference in the effects of acute and chronic alcohol exposure on DNA repair and from exaggeration of the damaging effects upon additional OCM impairment in mice deficient in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR). Given that damage to the PFC leads to loss of executive function and addiction, our study may shed light on the mechanism of alcohol addiction.

Impaired one carbon metabolism and DNA methylation in alcohol toxicity.

Excessive alcohol consumption is a prominent problem and one of the major causes of mortality and morbidity around the world. Long-term, heavy alcohol consumption is associated with a number of deleterious health consequences, such as cancer, heart and liver disease, a variety of neurological, cognitive, and behavioral deficits. Alcohol consumption is also associated with developmental defects. The causes of alcohol-induced toxicity are presently unclear. One of the mechanisms underlying alcohol toxicity has to do with its interaction with folic acid/homocysteine or one-carbon metabolism (OCM). OCM is a major donor of methyl groups for methylation, particularly DNA methylation critical for epigenetic regulation of gene expression, and its disturbance may compromise DNA methylation, thereby affecting gene expression. OCM disturbance mediated by nutrient deficits is a well-known risk factor for various disorders and developmental defects (e.g., neural tube defects). In this review, we summarize the role of OCM disturbance and associated epigenetic aberrations in chronic alcohol-induced toxicity. In this review, we summarize the role of one-carbon metabolism (OCM) aberrations in chronic alcohol-induced toxicity. OCM is a major donor of methyl groups for methylation reactions, particularly DNA methylation critical for epigenetic regulation of gene expression. Alcohol interference with OCM and consequent reduced availability of methyl groups, improper DNA methylation, and aberrant gene expression can play a causative role in alcohol toxicity.

Bioinformatics analyses reveal age-specific neuroimmune modulation as a target for treatment of high ethanol drinking.

BACKGROUND: Use of in silico bioinformatics analyses has led to important leads in the complex nature of alcoholism at the genomic, epigenomic, and proteomic level, but has not previously been successfully translated to the development of effective pharmacotherapies. In this study, a bioinformatics approach led to the discovery of neuroimmune pathways as an age-specific druggable target. Minocycline, a neuroimmune modulator, reduced high ethanol (EtOH) drinking in adult, but not adolescent, mice as predicted a priori. METHODS: Age and sex-divergent effects in alcohol consumption were quantified in FVB/NJ × C57BL/6J F1 mice given access to 20% alcohol using a 4 h/d, 4-day drinking-in-dark (DID) paradigm. In silico bioinformatics pathway overrepresentation analysis for age-specific effects of alcohol in brain was performed using gene expression data collected in control and DID-treated, adolescent and adult, male mice. Minocycline (50 mg/kg i.p., once daily) or saline alone was tested for an effect on EtOH intake in the F1 and C57BL/6J (B6) mice across both age and gender groups. Effects of minocycline on the pharmacokinetic properties of alcohol were evaluated by comparing the rates of EtOH elimination between the saline- and minocycline-treated F1 and B6 mice. RESULTS: Age and gender differences in DID consumption were identified. Only males showed a clear developmental increase difference in drinking over time. In silico analyses revealed neuroimmune-related pathways as significantly overrepresented in adult, but not in adolescent, male mice. As predicted, minocycline treatment reduced drinking in adult, but not adolescent, mice. The age effect was present for both genders, and in both the F1 and B6 mice. Minocycline had no effect on the pharmacokinetic elimination of EtOH. CONCLUSIONS: Our results are a proof of concept that bioinformatics analysis of brain gene expression can lead to the generation of new hypotheses and a positive translational outcome for individualized pharmacotherapeutic treatment of high alcohol consumption.

Alcohol-induced one-carbon metabolism impairment promotes dysfunction of DNA base excision repair in adult brain.

The brain is one of the major targets of chronic alcohol abuse. Yet the fundamental mechanisms underlying alcohol-mediated brain damage remain unclear. The products of alcohol metabolism cause DNA damage, which in conditions of DNA repair dysfunction leads to genomic instability and neural death. We propose that one-carbon metabolism (OCM) impairment associated with long term chronic ethanol intake is a key factor in ethanol-induced neurotoxicity, because OCM provides cells with DNA precursors for DNA repair and methyl groups for DNA methylation, both critical for genomic stability. Using histological (immunohistochemistry and stereological counting) and biochemical assays, we show that 3-week chronic exposure of adult mice to 5% ethanol (Lieber-Decarli diet) results in increased DNA damage, reduced DNA repair, and neuronal death in the brain. These were concomitant with compromised OCM, as evidenced by elevated homocysteine, a marker of OCM dysfunction. We conclude that OCM dysfunction plays a causal role in alcohol-induced genomic instability in the brain because OCM status determines the alcohol effect on DNA damage/repair and genomic stability. Short ethanol exposure, which did not disturb OCM, also did not affect the response to DNA damage, whereas additional OCM disturbance induced by deficiency in a key OCM enzyme, methylenetetrahydrofolate reductase (MTHFR) in Mthfr(+/-) mice, exaggerated the ethanol effect on DNA repair. Thus, the impact of long term ethanol exposure on DNA repair and genomic stability in the brain results from OCM dysfunction, and MTHFR mutations such as Mthfr 677C→T, common in human population, may exaggerate the adverse effects of ethanol on the brain.