A catenary model to study transport and conjugation of baicalein, a bioactive flavonoid, in the Caco-2 cell monolayer: demonstration of substrate inhibition

The transport and metabolism of baicalein (Ba) was studied in vitro and in Caco-2 cells. Protein binding of Ba with Caco-2 lysate showed that Ba was bound to two classes of sites: a higher affinity, lower capacity site (K(A1) = 27.6 +/- 4.7 microM(-1), n(1) = 10.6 +/- 0.6 nmol/mg) and lower affinity, higher capacity site (K(A2) = 0.015 +/- 0.0013 microM(-1), n(2) = 413 +/- 21 nmol/mg). Incubation studies of Ba with Caco-2 lysate showed substrate inhibition of both glucuronidation and sulfation, with K(m) values of 0.14 +/- 0.034 and 0.015 +/- 0.0053 microM, and K(I) values of 6.75 +/- 1.70 and 0.37 +/- 0.16 microM, respectively. In the Caco-2 monolayer, Ba (8-47 microM) displayed good apparent permeabilities (P(app)) across the membrane; P(app) was found to be increased with elevated loading concentration in both the absorptive and secretory directions. However, the efflux ratio was less than unity, negating the involvement of apical efflux transporters. The concentration ratios of Ba sulfate (BS) and glucuronide (BG) decreased with increased loading Ba concentration, suggesting that BS and BG are apically excreted via transporters, likely breast cancer resistance protein and multidrug resistance-associated protein 2, respectively. Data fit to the catenary model, composed of basolateral, cellular, and apical compartments, showed a low cellular unbound fraction (0.0019 +/- 0.00018), a high passive diffusion clearance (0.012 +/- 0.00029 ml/min/mg), and substrate inhibition, with sulfation being more readily saturated and inhibited than glucuronidation, as evidenced by smaller K(m) value (0.35 +/- 0.078 versus 1.95 +/- 0.57 microM) and K(I) value (0.58 +/- 0.20 versus 7.90 +/- 1.10 microM); these patterns paralleled those observed in the lysate incubation studies. The results showed that the catenary model aptly predicts substrate inhibition kinetics and offers significant and mechanistic insight into the transport and atypical metabolism of drugs in the Caco-2 monolayer.     

Cost analysis of risperidone long-acting injection in the treatment of schizophrenia and schizoaffective disorders in Hong Kong: An approach using generalised estimating equations

Schizophrenia is one of the most expensive psychiatric illnesses. This study compared retrospectively health-care resources consumed 12 months before and 24 months after risperidone long-acting injection (RLAI) treatment in Hong Kong. A mirror-image analysis was conducted using data (N=191) from three public hospitals in Hong Kong from 2003 to 2007. The main outcome measure was hospitalisation cost. Other secondary outcomes such as hospitalisation episodes, outpatient visits and adverse events were also compared. A predictive model was established using linear regression based on generalised estimating equations. Analysis showed that RLAI was associated with a reduction in hospitalisation cost by HK$10,001,390 (24.7%) (HK$40,418,694 vs. HK$30,417,303; P-value <0.05). Days of hospitalisation were reduced by 1538 days (10.1%) (15,271 vs. 13,733; P-value <0.05). The predictive model estimated that the hospitalisation cost of patients using RLAI was only 11.1% (3.1–3.93%, 95% confidence interval (CI)) compared to those receiving conventional antipsychotics combined with oral risperidone. Cost of hospitalisation was significantly reduced after RLAI therapy. However, results should be considered as indicative or suggestive only, due to potential channelling bias where certain drug regimens are preferentially prescribed to patients with particular conditions. The findings from our study may be useful in health-care decision making considering treatment options for schizophrenia in resource-limited settings.     

Feasibility and potential role of ferumoxytol-enhanced neuroimaging in HIV-associated neurocognitive disorder

We assessed ferumoxytol-enhanced brain MRI to identify monocyte/macrophage accumulation in HIV-associated neurocognitive disorder (HAND). Four HIV-infected subjects with undetectable HIV RNA levels on antiretroviral therapy, HIV DNA level in CD14+ cells ≥10 copies/10⁶ cells, and cognitive impairment underwent ferumoxytol-enhanced brain MRI. On post-ferumoxytol susceptibility-weighted images, all HIV-infected subjects demonstrated a diffuse “tram track” appearance in the perivascular regions of cortical and deep white matter vessels suggesting ferumoxytol uptake in monocytes/macrophages. This finding was not present in an HIV-seronegative control. While ferumoxytol may have potential as an imaging biomarker for monocyte/macrophage accumulation in patients with HAND, future study is needed.     

Examining Sensor Agreement in Neural Network Blood Glucose Prediction

Successful measurements of interstitial glucose are a key component in providing effective care for patients with diabetes. Recently, there has been significant interest in using neural networks to forecast future glucose values from interstitial measurements collected by continuous glucose monitors (CGMs). While prediction accuracy continues to improve, in this work we investigated the effect of physiological sensor location on neural network blood glucose forecasting. We used clinical data from patients with Type 2 Diabetes who wore blinded FreeStyle Libre Pro CGMs (Abbott) on both their right and left arms continuously for 12 weeks. We trained patient-specific prediction algorithms to test the effect of sensor location on neural network forecasting (N = 13, Female = 6, Male = 7). In 10 of our 13 patients, we found at least one significant (P < .05) increase in forecasting error in algorithms which were tested with data taken from a different location than data which was used for training. These reported results were independent from other noticeable physiological differences between subjects (eg, height, age, weight, blood pressure) and independent from overall variance in the data. From these results we observe that CGM location can play a consequential role in neural network glucose prediction.     

Adipose and Plasma microRNAs miR-221 and 222 Associate with Obesity,Insulin Resistance,and New Onset Diabetes after Peritoneal Dialysis

Background: The correlation between microRNA, obesity, and glycemic intolerance in patients on peritoneal dialysis (PD) is unknown. We aimed to measure the adipose and plasma miR-221 and -222 levels, and to evaluate their association with adiposity, glucose intolerance, and new onset diabetes mellitus (NODM) after the commencement of PD. Methods: We prospectively recruited incident adult PD patients. miR-221 and -222 were measured from adipose tissue and plasma obtained during PD catheter insertion. These patients were followed for 24 months, and the outcomes were changes in adiposity, insulin resistance, and NODM after PD. Results: One hundred and sixty-five patients were recruited. Patients with pre-existing DM had higher adipose miR-221 (1.1 ± 1.2 vs. 0.7 ± 0.9-fold, p = 0.02) and -222 (1.9 ± 2.0 vs. 1.2 ± 1.3-fold, p = 0.01). High adipose miR-221 and -222 levels were associated with a greater increase in waist circumference (miR-221: beta 1.82, 95% CI 0.57–3.07, p = 0.005; miR-222: beta 1.35, 95% CI 0.08–2.63, p = 0.038), Homeostatic Model Assessment for Insulin Resistance (HOMA) index (miR-221: beta 8.16, 95% CI 2.80–13.53, p = 0.003; miR-222: beta 6.59, 95% CI 1.13–12.05, p = 0.018), and insulin requirements (miR-221: beta 0.05, 95% CI 0.006–0.09, p = 0.02; miR-222: beta 0.06, 95% CI 0.02–0.11, p = 0.002) after PD. The plasma miR-222 level predicted the onset of NODM (OR 8.25, 95% CI 1.35–50.5, p = 0.02). Conclusion: miR-221 and -222 are associated with the progression of obesity, insulin resistance, and NODM after PD.     

Ethnicity,self-care,and use of medical care among the elderly with joint symptoms

Elderly individuals with self-reported joint symp-toms representing three ethnic groups (i.e., blacks [n = 105], Hispanics[n = 100], and whites of Eastern European origin [n = 112] answered questions about their use of self-care and medical care for these symptoms. Ethnic groups differed in both self-care practices and their use of medical care for joint symptoms. Multiple regression analyses demonstrated that arthritis-specific and general health status were better predictors than ethnicity of the tendency to rely on self-care and medical care. There was no evidence that self-care served as a substitute for medical care.