Sirolimus oral absorption in rats is increased by ketoconazole but is not affected by D-alpha-tocopheryl poly(ethylene glycol 1000) succinate

The contributions of cytochrome P450 3A (CYP3A) and P-glycoprotein to sirolimus oral bioavailability in rats were evaluated by coadministration of sirolimus (Rapamune) with the CYP3A inhibitor ketoconazole or the P-glycoprotein inhibitor D-alpha-tocopheryl poly(ethylene glycol 1000) succinate (TPGS). Groups of six male Sprague-Dawley rats (250-300 g) were administered Rapamune (1 mg/kg) by oral gavage, alone and with ketoconazole (30 mg/kg) or TPGS (50 mg/kg). Sirolimus levels were measured in whole blood over a 6-h time course. Sirolimus C(max) (6.6 +/- 1.6 versus 26 +/- 7 ng/ml) and area under the concentration versus time curve from 0 to 6 h (AUC(0-6)) (22 +/- 7 versus 105 +/- 27 ng. h/ml) were increased 3- to 5-fold by ketoconazole. Median T(max) (1.5-2 h) was unchanged. TPGS had no effect on sirolimus absorption. The interaction of sirolimus with P-glycoprotein was also evaluated in vitro using HCT-8 and Caco-2 cell monolayers. Consistent with published reports, sirolimus was a good inhibitor of P-glycoprotein, inhibiting polarized basolateral-to-apical flux of rhodamine 123 with an IC(50) of 0.625 to 1.25 microM (cyclosporine caused >80% inhibition at 5 microM). Sirolimus did not demonstrate significant polarized flux in either direction using the same monolayers (basolateral-to-apical flux was <2 times the apical-to-basolateral). Moreover, sirolimus flux was not impacted by cyclosporine, suggesting that it does not undergo P-glycoprotein-mediated transport in this system. The lack of significant sirolimus transport by P-glycoprotein may, in part, explain the lack of a TPGS effect on sirolimus absorption in rats.     

Acute lymphocytic leukemia after fulminant varicella associated with severe neutropenia

Acute lymphocytic leukemia developed within 3 weeks after a fulminant case of varicella complicated by pneumococcal sepsis and severe bone marrow suppression in a child treated with filgrastim (human granulocyte colony-stimulating factor).     

Diabetes mellitus in a subgroup of older Mexicans: prevalence,association with cardiovascular risk factors,functional and cognitive impairment,and mortality

OBJECTIVES: To examine the prevalence and effects of diabetes mellitus in a subgroup of older Mexicans to allow comparisons to older persons of Mexican origin living in the United States. DESIGN: Longitudinal study. SETTING: High-rise retirement housing in Mexico City. PARTICIPANTS: Seven hundred eighty-five public servants and their family members aged 65 and older. MEASUREMENTS: Geriatric survey of function; mental status and depression; a physical examination; and blood samples for glucose and cholesterol. RESULTS: The prevalence of diabetes mellitus in this population was 15.1%, substantially lower than the prevalence reported in people of Mexican origin living in the United States. Nondiabetics were more obese than diabetics. Diabetes mellitus was more common in men than women. The mortality rate was greater in diabetics than nondiabetics (relative risk=1.73, P <.05). Diabetics had more coronary artery disease and were more likely to die from myocardial infarction and neoplasms than nondiabetics. Diabetics were more likely to be functionally impaired (P <.0001) but no more likely to fall or to have fractures. Diabetics did not differ from nondiabetics in cognitive impairment or level of dysphoria. CONCLUSION: These studies highlight some important similarities and differences in comparing a middle class subgroup of older diabetics in Mexico City with diabetics of Mexican origin living in the United States.     

Treatment of lupus erythematosus with pulsed dye laser

BACKGROUND AND OBJECTIVES: The treatment of cutaneous lupus erythematosus (CLE) with dye and argon laser has been evaluated in a number of articles in recent years. The improvement of telangiectasias and chronic erythema of the cutaneous lesions was based on the selective photothermolysis ablation of the dilated capillaries and venules. STUDY DESIGN/MATERIALS AND METHODS: We describe the results of the treatment of cutaneous lesions of 14 patients; eight with discoid lupus erythematosus (DLE) and six with systemic lupus erythematosus (SLE). Three patients received a treatment with flashlamp pulsed dye laser (FPDL) (585 nm, 450 microseconds) with fluences in the range from 5 to 7.75 J/cm(2); the other 11 patients were treated with long pulsed dye laser (LPDL) (595 nm, 1.5-10 milliseconds) with fluences in the range from 6 to 13 J/cm(2) depending on the pulse duration. RESULTS: During a median follow-up of 10 months, we observed an average improvement in over 60% of the lesions. A few side effects were observed in all patients: four had transient hyperpigmentation and one patient had light scarring. Three patients had a relapse after more than 1 year; they were then offered conventional treatment. CONCLUSIONS: We confirm that pulsed dye laser is a good alternative treatment for the erythema in active cutaneous lesions of lupus erythematosus (LE).     

Antagonism of VIP-stimulated cyclic AMP formation in chick brain

Of eight peptides tested (0.01-5 microM), only two, that is, pituitary adenylate cyclase-activating polypeptide (PACAP27) and chicken vasoactive intestinal peptide (cVIP), potently stimulated cyclic AMP (cAMP) production in cerebral cortical slices of the chick. Mammalian VIP (mVIP) showed some activity only at the highest dose tested, whereas truncated forms of PACAP or VIP, that is, PACAP6-27, cVIP6-28, and mVIP6-28, or hybrid compounds, that is, neurotensin6-11-cVIP7-28 (NT-cVIP) and neurotensin6-11-mVIP7-28 (NT-mVIP), were inactive. Thirty-minute preincubation of chick cortical slices with 5 microM PACAP6-27, NT-cVIP, or NT-mVIP competitively antagonized the cAMP effects of cVIP (0.03-1 microM), with the truncated form of PACAP being the best antagonist. Preincubation of slices with 5 microM mVIP6-28 also produced a significant inhibition of the cVIP (0.1-1 microM)-induced increase in cAMP production; however its action was independent of the concentration of cVIP. In contrast to mVIP6-28, cVIP6-28 showed no antagonistic activity against the full-length peptide. In parallel experiments, 30-min pretreatment of cortical slices with 5 microM PACAP6-27 significantly antagonized the PACAP38-evoked increase in cAMP formation, whereas mVIP6-28 or the NT-mVIP hybrid was ineffective. It has been concluded that in the chick brain, PACAP and cVIP stimulate cAMP biosynthesis via PAC1 and VPAC-type receptors, respectively, and PACAP6-27 seems to be the most potent, yet PACAP/VIP receptor-nonselective antagonist. Unlike truncated PACAP, the NT-VIP hybrid peptides tested may represent VPACtype receptor-selective blocking activity.     

Comparison of an insulin analog,insulin aspart,and regular human insulin with no insulin in gestational diabetes mellitus

OBJECTIVE: To assess the short-term efficacy of insulin aspart in comparison with regular human insulin in women with gestational diabetes mellitus (GDM) during standardized meal tests. RESEARCH DESIGN AND METHODS: The study included 15 women with GDM who had inadequate diabetes control with diet alone. On 3 consecutive days, breakfast meal tests were performed-the first with no exogenous insulin and the other two after the injection of either regular insulin or insulin aspart. RESULTS: The peak insulin concentration was higher and the peak glucose and C-peptide concentrations were lower with both insulin preparations than with no exogenous insulin. Glucose areas under the curve above baseline were significantly lower with insulin aspart (180-min area, 7.1 mg. h. dl(-1); P = 0.018), but not with regular insulin (30.2 mg. h. dl(-1); P = 0.997), than with no insulin (29.4 mg. h. dl(-1)). CONCLUSIONS: This study demonstrates that effective postprandial glycemic control in women with GDM who required insulin was brought about by insulin aspart through higher insulin peak and lower demand on endogenous insulin secretion.     

Apigenin inhibits TGF-β1 induced fibroblast-to-myofibroblast transition in human lung fibroblast populations

BackgroundFlavonoids are dietary plant compounds suspected to reduce the incidence of chronic diseases in several regions of the world. Due to anti-allergic and anti-inflammatory activities, apigenin (4’,5,7,-trihydroxyflavone) is thought to interfere with crucial events in the pathomechanism of asthma. However, the effect of apigenin on TGF-β-induced fibroblast-to-myofibroblast transition (FMT) in human lung fibroblast populations, a key event in asthma progression, has not yet been addressed.MethodsPrimary human bronchial fibroblasts (HBFs) propagated from ex vivo bronchial biopsies derived from patients with diagnosed asthma and human embryonic lung IMR-90 fibroblasts were cultured in vitro and treated with TGF-β₁ and apigenin. The myofibroblast fraction in fibroblast populations was evaluated by immunocytochemistry. Expression of α-smooth muscle actin (α-SMA) and tenascin C were assessed at the mRNA and protein level by real-time RT-PCR and immunoblotting, respectively. Additionally, proliferation and viability tests and time lapse-monitoring ofmovement of individual HBFs and IMR-90 cellswere evaluated.ResultsWe show that apigenin attenuates TGF-β₁-induced FMT in cultures of HBFs, and the magnitude of this attenuation was found to be similar to that observed in the established cell line of lung IMR-90 fibroblasts. Notably, FMT inhibition was observed at low (~10 μM), non-cytotoxic and non-cytostatic apigenin concentrations and could be correlated with the inhibition of α-SMA and tenascin C expression in HBFs at the mRNA level.ConclusionsOur data are the first to demonstrate that apigenin inhibits the TGF-β₁-induced expansion of hyper-contractile, α-smooth muscle actin – positive myofibroblasts within populations of HBFs derived from asthmatic patients. They also indicate the possible interference of apigenin with bronchial wall remodeling during the asthmatic process in vivo.     

Functional Food and Bioactive Compounds on the Modulation of the Functionality of HDL-C: A Narrative Review

Cardiovascular diseases (CVD) remain a serious public health problem and are the primary cause of death worldwide. High-density lipoprotein cholesterol (HDL-C) has been identified as one of the most important molecules in the prevention of CVD due to its multiple anti-inflammatories, anti-atherogenic, and antioxidant properties. Currently, it has been observed that maintaining healthy levels of HDL-C does not seem to be sufficient if the functionality of this particle is not adequate. Modifications in the structure and composition of HDL-C lead to a pro-inflammatory, pro-oxidant, and dysfunctional version of the molecule. Various assays have evaluated some HDL-C functions on risk populations, but they were not the main objective in some of these. Functional foods and dietary compounds such as extra virgin olive oil, nuts, whole grains, legumes, fresh fish, quercetin, curcumin, ginger, resveratrol, and other polyphenols could increase HDL functionality by improving the cholesterol efflux capacity (CEC), paraoxonase 1 (PON1), and cholesteryl ester transfer protein (CETP) activity. Nevertheless, additional rigorous research basic and applied is required in order to better understand the association between diet and HDL functionality. This will enable the development of nutritional precision management guidelines for healthy HDL to reduce cardiovascular risk in adults. The aim of the study was to increase the understanding of dietary compounds (functional foods and bioactive components) on the functionality of HDL.