Metabolic osteoarthritis (OA) has now been characterized as a subtype of OA, and links have been discovered between this phenotype and metabolic syndrome (MetS)--both with individual MetS components and with MetS as a whole. Hypertension associates with OA through subchondral ischaemia, which can compromise nutrient exchange into articular cartilage and trigger bone remodelling. Ectopic lipid deposition in chondrocytes induced by dyslipidemia might initiate OA development, exacerbated by deregulated cellular lipid metabolism in joint tissues. Hyperglycaemia and OA interact at both local and systemic levels; local effects of oxidative stress and advanced glycation end-products are implicated in cartilage damage, whereas low-grade systemic inflammation results from glucose accumulation and contributes to a toxic internal environment that can exacerbate OA. Obesity-related metabolic factors, particularly altered levels of adipokines, contribute to OA development by inducing the expression of proinflammatory factors as well as degradative enzymes, leading to the inhibition of cartilage matrix synthesis and stimulation of subchondral bone remodelling. In this Review, we summarize the shared mechanisms of inflammation, oxidative stress, common metabolites and endothelial dysfunction that characterize the aetiologies of OA and MetS, and nominate metabolic OA as the fifth component of MetS. We also describe therapeutic opportunities that might arise from uniting these concepts.

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The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic has become a major challenge to public health in China and other countries, considering its pathogenicity across all age groups. Pregnancy is a unique physiological condition, and is characterized by altered immunity and elevated hormone levels to actively tolerate the semiallogeneic fetus, which undergoes a sudden and substantial fluctuation during the immediate postpartum period. Changes in clinical features, laboratory characteristics, and imaging features of pregnant women during the pre-partum and postpartum periods require further elucidation. Here, we retrospectively analyzed the clinical features, laboratory characteristics, and imaging features of eight pregnant cases of SARS-CoV-2 infection during the pre-partum and post-partum periods. Our results showed that four of the eight pregnant women were asymptomatic before delivery but became symptomatic post-partum. Correspondingly, white blood cell (WBC) counts increased and lymphocyte (LYMPH) counts decreased. C-reactive protein (CRP) levels in the serum also increased to a higher level than those in general pregnancy. Therefore, it is imperative to closely monitor laboratory parameters including the WBC count, LYMPH count, and CRP, along with other imaging features in chest CT scans, to promptly prevent, diagnose, and treat a SARS-CoV-2 infection during pregnancy.

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Amorphous engineered particle compositions of itraconazole (ITZ) and potential concentration enhancing polymers, cellulose acetate phthalate (CAP) and polyvinyl acetate phthalate (PVAP), were produced by ultra-rapid freezing to investigate the effect of these polymers on the bioavailability of ITZ solid dispersions. X-ray diffraction analyses of engineered particle compositions were shown to be amorphous. Modulated differential scanning calorimetry demonstrated that ITZ:CAP engineered particle compositions exhibited a strong correlation with the Gordon-Taylor relationship while ITZ:PVAP formulations exhibited positive deviations from predicted values attributed to hydrogen bonding interactions between the drug and polymer. Energy dispersive spectroscopy mapping demonstrated that the drug was homogenously distributed within all compositions, supporting the miscibility of the drug with the polymers. Scanning electron microscopy imaging of the particles demonstrated that the material existed in two general forms, discrete particles of approximately 5 microm and larger aggregates in excess of 30 microm, with engineered particle compositions having approximately 15 times higher measured specific surfaces areas compared to micronized ITZ. In vitro supersaturated dissolution results showed that all compositions provided significantly lower levels of supersaturation in acidic media and greater extents of supersaturation in neutral media compared to Sporanox pellets. ITZ: CAP formulations provided the greatest degree and extent of supersaturation in neutral media. Dissolution data were fitted to an exponential relationship based on a simplified model of particle growth, allowing for the determination of drug half-life in solution for evaluation of stabilization behavior. 1:2 ITZ:CAP showed superior in vitro performance compared to all other engineered particle compositions and was selected for in vivo testing. Although not fully elucidated, data indicated that the stabilization mechanism was due to interactions between the drug and polymer, primarily attributed to steric hindrance resulting from the molecular weight of the polymer chain and chemical composition of the polymer backbone relative to position of hydrogen bonding sites. In vivo testing conducted in Sprague-Dawley rats (n = 6) demonstrated a significant improvement in oral bioavailability from the 1:2 ITZ:CAP (AUC = 4,516 +/- 1,949 ng x h/mL) compared to the Sporanox pellets (AUC = 2,132 +/- 1,273 ng x h/mL) (p < or = 0.05). Additionally, the more rapid onset of action indicated superior targeting of the upper small intestines, and the prolonged half-life suggested the utility of CAP to maintain supersaturated concentrations, in vivo. These results demonstrated that amorphous compositions of ITZ and enteric concentration enhancing polymers provided improved bioavailability due to enhanced intestinal targeting and increased durations of supersaturation.

A phage display approach was utilized to modify the specificity of each of the three fingers ofthe murine transcription factor Zif268. Selections were performed by using the consensus binding sequence of the natural protein and a conserved sequence in the genome of the type 1 human immunodeficiency virus. By using an extensive randomization strategy, the entire 3-bp specificity of a finger has been changed. Rapid analysis of selected zinc fingers was facilitated by the development of an immunoscreening assay for DNA binding and specificity. To investigate the mechanism of binding and specificity, the binding kinetics of Zif268 and 10 selected variants were determined in real time with an assay based on surface plasmon resonance. Differential mechanisms for sequence-specific recognition were observed. No evidence in support of a single general coding relationship between zinc finger and target DNA sequence was observed. The prospects for the development of this class of proteins in human therapy are considered.

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