Alterations in liver triglyceride profiles in CCl4-induced liver regeneration.

Lipid metabolism, particularly triglyceride (TG) metabolism, is crucial for liver regeneration. During the early phase of liver regeneration, the liver temporarily accumulates a substantial amount of TG-dominated lipids. However, the specific composition of the TG profile during this phase is not yet fully understood. Here, we showed that the TG molecular composition in the liver was significantly altered during liver regeneration following carbon tetrachloride (CCl4)-induced liver injury. Lipid accumulation in livers was observed as early as 12 hours after CCl4 treatment, with transient regeneration-associated steatosis (TRAS) lasting until 24 hours. Hepatocyte proliferation began only after liver lipid levels returned to baseline at 48 hours. Furthermore, the profile of TG species changed significantly during liver regeneration. During the TRAS period, the accumulated TGs in the liver were mainly long-chain triglycerides, with most of the fatty acids constituting these triglycerides having fewer than 20 carbon atoms. In the proliferation phase, the fatty acid composition of these triglycerides shifted from long-chain to ultra-long-chain fatty acids. Our results suggest a significant TRAS-related change in the TG lipid profile of the liver during liver regeneration.

Recent updates for biomaterials used in total hip arthroplasty.

BACKGROUND: Total hip arthroplasty (THA) is probably one of the most successful surgical interventions performed in medicine. Through the revolution of hip arthroplasty by principles of low friction arthroplasty was introduced by Sir John Charnley in 1960s. Thereafter, new bearing materials, fixation methods, and new designs has been improved. The main concern regarding failure of THA has been the biological response to particulate polyethylene debris generated by conventional metal on polyethylene bearing surfaces leading to osteolysis and aseptic loosening of the prosthesis. To resolve these problems, the materials of the modern THA were developed since then. METHODS: A literature search strategy was conducted using various search terms in PUBMED. The highest quality articles that met the inclusion criteria and best answered the topics of focus of this review were selected. Key search terms included 'total hip arthroplasty', 'biomaterials', 'stainless steel', 'cobalt-chromium', 'titanium', 'polyethylene', and 'ceramic'. RESULTS: The initial search retrieved 6921 articles. Thirty-two articles were selected and used in the review. CONCLUSION: This article introduces biomaterials used in THA and discusses various bearing materials in currentclinical use in THA as well as the newer biomaterials which may even further decrease wear and improve THA survivorship.

Comparison of bone tunnel and suture anchor techniques in the modified Broström procedure for chronic lateral ankle instability.

BACKGROUND: The modified Broström procedure is frequently used to treat chronic lateral ankle instability. There are 2 common methods of the modified Broström procedure, which are the bone tunnel and suture anchor techniques. PURPOSE: To compare the clinical outcomes of the modified Broström procedure using the bone tunnel and suture anchor techniques. STUDY DESIGN: Cohort study; Level of evidence, 2. METHODS: Eighty-one patients (81 ankles) treated with the modified Broström procedure for chronic lateral ankle instability constituted the study cohort. The 81 ankles were divided into 2 groups, namely, a bone tunnel technique (BT group; 40 ankles) and a suture anchor technique (SA group; 41 ankles). The Karlsson score, American Orthopaedic Foot and Ankle Society (AOFAS) ankle-hindfoot score, anterior talar translation, and talar tilt angle were used to evaluate clinical and radiographic outcomes. The BT group consisted of 32 men and 8 women with a mean age of 34.8 years at surgery and a mean follow-up duration of 34.2 months. The SA group consisted of 33 men and 8 women with a mean age of 33.3 years at surgery and a mean follow-up duration of 32.8 months. RESULTS: Mean Karlsson scores improved significantly from 57.0 points preoperatively to 94.9 points at final follow-up in the BT group and from 59.9 points preoperatively to 96.4 points at final follow-up in the SA group. Mean AOFAS scores also improved from 64.2 points preoperatively to 97.8 points at final follow-up in the BT group and from 70.3 points preoperatively to 97.4 points at final follow-up in the SA group. Mean anterior talar translations in the BT group and SA group improved from 9.0 mm and 9.2 mm preoperatively to 6.5 mm and 6.8 mm at final follow-up, respectively. Mean talar tilt angles were 12.0° in the BT group and 12.5° in the SA group preoperatively and 8.8° at final follow-up for both groups. No significant differences were found between the 2 groups in terms of the Karlsson score, AOFAS score, anterior talar translation, and talar tilt angle. CONCLUSION: The bone tunnel and suture anchor techniques of the modified Broström procedure showed similar good functional and radiographic outcomes. Both techniques appear to be effective and reliable methods for the treatment of chronic lateral ankle instability.

Spontaneous reduction finding: magnetic resonance imaging evaluation of segmental instability in spondylolisthesis.

STUDY DESIGN: Retrospective chart review. PURPOSE: To assess whether spontaneous reduction of spondylolisthesis, as seen on magnetic resonance imaging (MRI), is related to the degree of segmental instability and low back pain. OVERVIEW OF LITERATURE: The flexion-extension radiographs obtained in the sagittal plane are frequently used when segmental instability of spondylolisthesis is evaluated. METHODS: We retrospectively reviewed 137 patients and measured the differences of the percentage of sagittal translation and sagittal angulation to determine the segmental instability between the flexion and extension radiographs, and the spontaneous reduction on MRI. We then compared the degrees of segmental instability and the degrees of spontaneous reduction. To assess the effect of low back pain on segmental motion in regards to the flexion-extension radiographs, we compared the preoperative visual analogue scales (VAS) score for low back pain between the more and the less spontaneous reduction groups. RESULTS: The mean degree of spontaneous reduction was 5.2%. A statistically significant correlation was found between the sagittal translation on the flexion-extension radiographs and the degree of spontaneous reduction (r = 0.557, p < 0.001) and between the sagittal angulation on the flexion-extension radiographs and the degree of spontaneous reduction (r = 0.215, p = 0.012). The preoperative VAS scores for low back pain of the more spontaneous reduction group and the less spontaneous reduction group were 4.6 and 3.6 points, respectively, and this difference was statistically significant (p = 0.002). CONCLUSIONS: Spontaneous reduction of spondylolisthesis on MRI was found to be closely related to segmental instability, and the degree of spontaneous reduction seen on MRI could be useful for the evaluation of segmental instability in patients with spondylolisthesis, especially with severe low back pain.

Preclinical metabolism and disposition of SB939 (Pracinostat), an orally active histone deacetylase inhibitor, and prediction of human pharmacokinetics.

The preclinical absorption, distribution, metabolism, and excretion (ADME) properties of Pracinostat [(2E)-3-[2-butyl-1-[2-(diethylamino) ethyl]-1H-benzimidazol-5-yl]-N-hydroxyarylamide hydrochloride; SB939], an orally active histone deacetylase inhibitor, were characterized and its human pharmacokinetics (PK) was predicted using Simcyp and allometric scaling. SB939 showed high aqueous solubility with high Caco-2 permeability. Metabolic stability was relatively higher in dog and human liver microsomes than in mouse and rat. The major metabolites formed in human liver microsomes were also observed in preclinical species. Human cytochrome P450 (P450) phenotyping showed that SB939 was primarily metabolized by CYP3A4 and CYP1A2. SB939 did not significantly inhibit human CYP3A4, 1A2, 2D6, and 2C9 (>25 µM) but inhibited 2C19 (IC(50) = 5.8 µM). No significant induction of human CYP3A4 and 1A2 was observed in hepatocytes. Plasma protein binding in mouse, rat, dog, and human ranged between ∼84 and 94%. The blood-to-plasma ratio was ∼1.0 in human blood. SB939 showed high systemic clearance (relative to liver blood flow) of 9.2, 4.5, and 1.5 l · h(-1) · kg(-1) and high volume of distribution at steady state (>0.6 l/kg) of 3.5, 1.7, and 4.2 l/kg in mouse, rat, and dog, respectively. The oral bioavailability was 34, 65, and ∼3% in mice, dogs, and rats, respectively. The predicted oral PK profile and parameters of SB939, using Simcyp and allometric scaling, were in good agreement with observed data in humans. Simcyp predictions showed lack of CYP3A4 and 2C19 drug-drug interaction potential for SB939. In summary, the preclinical ADME of SB939 supported its preclinical and clinical development as an oral drug candidate.

SB939, a novel potent and orally active histone deacetylase inhibitor with high tumor exposure and efficacy in mouse models of colorectal cancer.

Although clinical responses in liquid tumors and certain lymphomas have been reported, the clinical efficacy of histone deacetylase inhibitors in solid tumors has been limited. This may be in part due to the poor pharmacokinetic of these drugs, resulting in inadequate tumor concentrations of the drug. SB939 is a new hydroxamic acid based histone deacetylase inhibitor with improved physicochemical, pharmaceutical, and pharmacokinetic properties. In vitro, SB939 inhibits class I, II, and IV HDACs, with no effects on other zinc binding enzymes, and shows significant antiproliferative activity against a wide variety of tumor cell lines. It has very favorable pharmacokinetic properties after oral dosing in mice, with >4-fold increased bioavailability and 3.3-fold increased half-life over suberoylanilide hydroxamic acid (SAHA). In contrast to SAHA, SB939 accumulates in tumor tissue and induces a sustained inhibition of histone acetylation in tumor tissue. These excellent pharmacokinetic properties translated into a dose-dependent antitumor efficacy in a xenograft model of human colorectal cancer (HCT-116), with a tumor growth inhibition of 94% versus 48% for SAHA (both at maximum tolerated dose), and was also effective when given in different intermittent schedules. Furthermore, in APC(min) mice, a genetic mouse model of early-stage colon cancer, SB939 inhibited adenoma formation, hemocult scores, and increased hematocrit values more effectively than 5-fluorouracil. Emerging clinical data from phase I trials in cancer patients indicate that the pharmacokinetic and pharmacologic advantages of SB939 are translated to the clinic. The efficacy of SB939 reported here in two very different models of colorectal cancer warrants further investigation in patients.

Apolipoprotein D in the Niemann-Pick type C disease mouse brain: an ultrastructural immunocytochemical analysis.

Enhanced apoD gene expression and abnormally high levels of apoD protein accumulation in the brain have been previously documented as features of the neurodegenerative disorder, Niemann-Pick Type C disease (NP-C). In the present study we have used immunocytochemistry and light and electron microscopy to elucidate the cellular and subcellular distribution of apoD in the Balb/c NIH npc1(-/-) mouse brain. The normal mouse brain demonstrates low levels of apoD-expressing glia particularly in the cerebellar white matter. In contrast, abundant, strongly apoD-immunolabeled cells were observed in select grey matter nuclei, including the globus pallidus, thalamus, and substantia nigra, and in white matter tracts within the internal capsule and cerebellum of NP-C mouse brain. These brains regions have been previously shown to display the most significant neurodegenerative changes in the NP-C mouse. Ultrastructural analysis revealed dense apoD immunoreactivity on the nuclear envelopes of cells that have the morphological features of oligodendrocyte precursor-like cells and light staining on astrocytes. These results define the cellular and subcellular pattern of expression of apoD in NP-C mouse brain and suggest a possible role for this lipocalin in the pathophysiology of this disorder.