Vivaria housing conditions expose sex differences in brain oxidation, microglial activation, and immune system states in aged hAPOE4 mice.

Apolipoprotein E ε4 allele (APOE4) is the predominant genetic risk factor for late-onset Alzheimer's disease (AD). APOE4 mouse models have provided advances in the understanding of disease pathogenesis, but unaccounted variables like rodent housing status may hinder translational outcomes. Non-sterile aspects like food and bedding can be major sources of changes in rodent microflora. Alterations in intestinal microbial ecology can cause mucosal barrier impairment and increase pro-inflammatory signals. The present study examined the role of sterile and non-sterile food and housing on redox indicators and the immune status of humanized-APOE4 knock-in mice (hAPOe4). hAPOE4 mice were housed under sterile conditions until 22 months of age, followed by the transfer of a cohort of mice to non-sterile housing for 2 months. At 24 months of age, the redox/immunologic status was evaluated by flow cytometry/ELISA. hAPOE4 females housed under non-sterile conditions exhibited: (1) higher neuronal and microglial oxygen radical production and (2) lower CD68+ microglia (brain) and CD8+ T cells (periphery) compared to sterile-housed mice. In contrast, hAPOE4 males in non-sterile housing exhibited: (1) higher MHCII+ microglia and CD11b+CD4+ T cells (brain) and (2) higher CD11b+CD4+ T cells and levels of lipopolysaccharide-binding protein and inflammatory cytokines in the periphery relative to sterile-housed mice. This study demonstrated that sterile vs. non-sterile housing conditions are associated with the activation of redox and immune responses in the brain and periphery in a sex-dependent manner. Therefore, housing status may contribute to variable outcomes in both the brain and periphery.

Line-1: Implications in the etiology of cancer, clinical applications, and pharmacologic targets.

Long interspersed nuclear elements-1 (Line-1 or L1) accounts for approximately 17% of the human genome. The majority of L1s are inactive, but ∼100 remain retrotransposon competent (RC-L1) and able to retrotranspose through RNA intermediates to different locations of the genome. L1 is involved in both disease initiation and progression via retrotransposition dependent and independent mechanisms. Retrotransposed L1 sequences disrupt genetic loci at sites of insertion, while the activities of L1 si/piRNAs, mRNAs, and ORF1 and ORF2 proteins, and have been implicated in the etiology and progression of several human diseases. Despite these relationships, little is known about the clinical utility of L1 as a biomarker of disease initiation and progression, or the utility of small molecules to inhibit and reverse the harmful effects of L1. In this review, we discuss the life cycle of L1, somatic and germline inhibitions, the mechanisms of L1 retrotransposition dependent and independent disease initiation and progression, clinical utilities, and potential of L1s as pharmacologic targets for the treatment of cancer.

Micromotion at the tibial plateau in primary and revision total knee arthroplasty: fixed versus rotating platform designs.

OBJECTIVES: Initial stability of tibial trays is crucial for long-term success of total knee arthroplasty (TKA) in both primary and revision settings. Rotating platform (RP) designs reduce torque transfer at the tibiofemoral interface. We asked if this reduced torque transfer in RP designs resulted in subsequently reduced micromotion at the cemented fixation interface between the prosthesis component and the adjacent bone. METHODS: Composite tibias were implanted with fixed and RP primary and revision tibial trays and biomechanically tested under up to 2.5 kN of axial compression and 10° of external femoral component rotation. Relative micromotion between the implanted tibial tray and the neighbouring bone was quantified using high-precision digital image correlation techniques. RESULTS: Rotational malalignment between femoral and tibial components generated 40% less overall tibial tray micromotion in RP designs than in standard fixed bearing tibial trays. RP trays reduced micromotion by up to 172 µm in axial compression and 84 µm in rotational malalignment models. CONCLUSIONS: Reduced torque transfer at the tibiofemoral interface in RP tibial trays reduces relative component micromotion and may aid long-term stability in cases of revision TKA or poor bone quality.Cite this article: Mr S. R. Small. Micromotion at the tibial plateau in primary and revision total knee arthroplasty: fixed versus rotating platform designs. Bone Joint Res 2016;5:122-129. DOI: 10.1302/2046-3758.54.2000481.

Botulinum toxin type A as treatment of partially accommodative esotropia.

OBJECTIVE: To determine the effectiveness of a botulinum toxin type A injection in both medial rectus muscles in patients with partially accommodative esotropia. Residual deviation and stability of strabismus were evaluated at 18 months follow up. METHOD: A prospective, analytical, quasi-experimental study was conducted on a cohort of 21 patients who underwent total cycloplegic refraction and with a residual deviation of at least 14 DP. A botulinum toxin type A dose of 5 IU was injected into each medial rectus muscle for a residual deviation greater than 18 DP, with a dose of 2.5 IU being used for a deviation between 14 and 18 DP. Multivariate logistic regression analyses were performed to relate residual deviation to variables recorded as potential predictors. RESULTS: A total of 21 patients were included, 33.3% (n=7) males and 66.6% (n=14) females. Mean visual acuity was -.28±.25 logMAR for right eye (range 0 to -1) and -.42±.31 logMAR for left eye (range 0 to -1.3). Mean angle of residual deviation before application of botulinum toxin was 40.95±8.6DP without spectacles correction, and 22.3±7.99 DP with full cycloplegic refraction. Adverse effects were ptosis in 14.2% (n=3), diplopia 23.8% (n=5), and vertical deviation in 33% (n=7). One patient had a poor outcome, therefore required surgical treatment. At one year follow up, 85.71% of patients showed good results with esotropia of 12 DP or less, dropping to 71.43% at 18 months of follow up. CONCLUSION: Botulinum toxin type A is an effective long-term treatment with a good response in 71.43% of patients. No predictors of good response were demonstrated.

Prevention of HIV transmission.

Primary care physicians continue to play an important role in preventing HIV transmission by targeting messages to their high-risk patients. The risk of HIV transmission cannot be eliminated entirely; however, clinicians have a variety of prevention interventions at their disposal. Behavioral and therapeutic interventions offered in a client-centered environment have the greatest chance of success. Patients can benefit from individualized prevention plans that decrease risk by treating drug addiction and by modifying sexual and drug-taking behaviors. The risk of HIV infection in health care workers can be reduced by strict adherence to universal precautions and the use of postexposure antiretroviral therapy.

Differential methylation in steroid 5 alpha-reductase isozyme genes in epididymis, testis, and liver of the adult rat.

DNA methylation has been largely involved in the regulation of tissue-specific gene expression. The aim of the study was to determine the methylation pattern of steroid 5 alpha-reductase genes 1 and 2 in two reproductive tissues (testis and epididymis) and a nonreproductive tissue (liver) that exhibit different contents of steroid 5 alpha-reductase isozymes. These isozymes induce the bioconversion of testosterone to dihydrotestosterone that in mammals is a key molecule for external genitalia development. Genomic DNA from the testis, the epididymis, and the liver from normal adult rats was used to determine cytosine and adenine methylation pattern of steroid 5 alpha-reductase genes 1 and 2 by restriction fragment length polymorphism (RFLP) analysis using restriction enzymes sensitive to adenine (Mbo I and Sau3A I) and cytosine (Hpa II and MSP I) methylation. We also evaluated the expression of both steroid 5 alpha-reductase genes by northern blot. When genomic DNA was digested with Hpa II or Msp I, we found that steroid 5 alpha-reductase gene 2 was less cytosine methylated in the epididymis and in the testis than in the liver. In contrast, when genomic DNA was digested with Mbo I or Sau3A I, we observed that gene 2 was more adenine methylated in the epididymis and in the testis than in the liver. 5 alpha-Reductase gene 1 presented the same adenine- and cytosine-methylation pattern in the studied tissues. We also found a differential expression of steroid 5 alpha-reductase genes. Gene 2 was expressed both in the testis and the epididymis but not in the liver; whereas gene 1 was only expressed in the latter. Our results suggest that the differential methylation pattern in 5 alpha-reductase gene 2 in reproductive and nonreproductive tissues should be involved in the regulation of its expression.