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BACKGROUND: In the senescent heart, the positive inotropic response to [beta]-adrenoceptor stimulation is reduced, partly by dysregulation of [beta]1- and [beta]3-adrenoceptors. The multidrug resistance protein 4 (MRP4) takes part in the control of intracellular cyclic adenosine monophosphate concentration by controlling its efflux but the role of MRP4 in the [beta]-adrenergic dysfunction of the senescent heart remains unknown. METHODS: The [beta]-adrenergic responses to isoproterenol were investigated in vivo (stress echocardiography) and in vitro (isolated cardiomyocyte by Ionoptix with sarcomere shortening and calcium transient) in young (3 months old) and senescent (24 months old) rats pretreated or not with MK571, a specific MRP4 inhibitor. MRP4 was quantified in left ventricular homogenates by Western blotting. Data are mean ± SD expressed as percent of baseline value. RESULTS: The positive inotropic effect of isoproterenol was reduced in senescent rats in vivo (left ventricular shortening fraction 120 ± 16% vs. 158 ± 20%, P < 0.001, n = 16 rats) and in vitro (sarcomere shortening 129 ± 37% vs. 148 ± 35%, P = 0.004, n = 41 or 43 cells) as compared to young rats. MRP4 expression increased 3.6-fold in senescent compared to young rat myocardium (P = 0.012, n = 8 rats per group). In senescent rats, inhibition of MRP4 by MK571 restored the positive inotropic effect of isoproterenol in vivo (143 ± 11%, n = 8 rats). In vitro in senescent cardiomyocytes pretreated with MK571, both sarcomere shortening (161 ± 45% vs. 129 ± 37%, P = 0.007, n = 41 cells per group) and calcium transient amplitude (132 ± 25% vs. 113 ± 27%, P = 0.007) increased significantly. CONCLUSION: MRP4 overexpression contributes to the reduction of the positive inotropic response to [beta]-adrenoceptor stimulation in the senescent heart. [ABSTRACT FROM AUTHOR]

The article discusses the importance of cost-effectiveness analyses (CEA) for evaluating health care services related to cervical cancer such as screening tests and treatments, the cost factor involved and the types of resources available in different parts of the world. The article discusses how cost effectiveness of these services can be beneficial in creating and modifying optimal practices. Some of the practices discussed include liquid-based cytology (LBC), human papilloma virus (HPV) testing and the HPV vaccine.

Objective: Human papillomavirus (HPV) risk assignment influences management after a cytologic diagnosis of atypical squamous cells of undetermined significance (ASCUS) or low-grade squamous intraepithelial lesion (LSIL). This study addressed whether type-specific HPV testing predicts risk of biopsy outcome of high-grade cervical intraepithelial neoplasia (CIN 2,3).Materials and Methods: A total of 162 ASCUS or LSIL diagnoses with colposcopic follow-up were evaluated and placed in 3 groups: Analysis 1: (high-risk HPVs including types 53 and 66; Analysis 2 (high-risk HPVs excluding types 53 and 66); and Analysis 3 (high-risk HPVs including type 53 and excluding type 66).Results: CIN 2,3 biopsy results followed low-risk HPVs in 0%, 3%, and 0% of scenarios 1, 2, and 3, respectively; 21%, 40%, and 27% of smears were classified as low risk, respectively. Of HPV 53 infections, 13.6% had CIN 2,3 biopsy outcomes.Conclusions: Type-specific HPV testing accurately classifies a group of HPV-positive LSIL/ASCUS cases at low risk for CIN 2,3 at the first follow-up visit. Classifying HPV 53 as low-risk increases slightly the proportion of HSIL outcomes in the low-risk group, but may not increase cancer risk. HPV 53 merits designation as a high-risk HPV based only [corrected] on the proportion of CIN 2,3 in follow-up biopsy. [ABSTRACT FROM AUTHOR]

An editorial is presented where in the editor reflects on the reasons to determine the overall cost-effectiveness of vaccination against Human papillomavirus (HPV) infections. She talks about annual medical costs of HPV and HPV-related illnesses as its one of the most common sexually transmitted infection. Also noted is that high-risk HPV is associated with cancers of the entire lower genital tract. The author presents details on randomized HPV vaccine trials and incidence of genital warts.

Objectives: Although metabolic syndrome is associated with increased sympathetic activity that chronically stimulates β-adrenoceptors, the β-adrenoceptor signaling pathway has been poorly studied in this situation. We studied the β-adrenoceptor signaling pathway in Zucker lean, obese, and obese diabetic rats., Design: Experimental, prospective study., Setting: University medical research laboratory., Subjects: Adult male Zucker lean (control), obese, and obese diabetic rats., Interventions: The effects of β-adrenoceptor stimulation were investigated in vitro in isolated left ventricular papillary muscles in control, obese, and obese diabetic rats. β1-, β2-, and β3-adrenoceptors and multidrug resistance-associated protein 4 were quantified by Western Blotting. Triglyceride, cholesterol, leptin, adiponectin, and C-peptide plasma concentrations were measured. Data are mean ± SD., Measurements and Main Results: Hyperlipidemia, high leptin, and C-peptide concentrations were observed in obese and obese diabetic strains, whereas hyperglycemia occurred only in the diabetic strain. The positive inotropic effect of isoproterenol was slightly reduced in obese rats (183% ± 11% of baseline; p = 0.003; n = 7) and markedly reduced in obese diabetic rats (137% ± 18% of baseline; p < 0.001; n = 10) when compared with control rats (210% ± 17% of baseline; n = 9). β1-adrenoceptors were down-regulated in obese (-41%; p = 0.02) and diabetic (-54%; p = 0.003) when compared with control rats, whereas β3-adrenoceptors and multidrug resistance-associated protein expression remained unchanged. Direct stimulation of adenylate cyclase with forskolin or administration of 3',5'-cyclic adenosine monophosphate suggests that subtle impairments also occurred beside the down-regulation of β1-adrenoceptor., Conclusions: The positive inotropic effect of β-adrenoceptor stimulation is slightly decreased in Zucker obese rats and was more markedly decreased in Zucker diabetic rats. These decreases are mainly related to β1-adrenoceptor down-regulation.

Background: The effects of acute respiratory versus metabolic acidosis on the myocardium and their consequences on adrenoceptor stimulation remain poorly described. We compared the effects of metabolic and respiratory acidosis on inotropy and lusitropy in rat myocardium and their effects on the responses to α- and β-adrenoceptor stimulations., Methods: The effects of acute respiratory and metabolic acidosis (pH 7.10) and their interactions with α and β-adrenoceptor stimulations were studied in isolated rat left ventricular papillary muscle (n=8 per group). Intracellular pH was measured using confocal microscopy and a pH-sensitive fluorophore in isolated rat cardiomyocytes. Data are mean percentages of baseline±SD., Results: Respiratory acidosis induced more pronounced negative inotropic effects than metabolic acidosis did both in isotonic (45±3 versus 63±6%, P<0.001) and isometric (44±5 versus 64±3%, P<0.001) conditions concomitant with a greater decrease in intracellular pH (6.85±0.07 versus 7.12±0.07, P<0.001). The response to α-adrenergic stimulation was not modified by respiratory or metabolic acidosis. The inotropic response to β-adrenergic stimulation was impaired only in metabolic acidosis (137±12 versus 200±33%, P<0.001), but this effect was not observed with administration of forskolin or dibutiryl-cyclic adenosine monophosphate. This effect might be explained by a change in transmembrane pH gradient only observed with metabolic acidosis. The lusitropic response to β-adrenergic stimulation was not modified by respiratory or metabolic acidosis., Conclusion: Acute metabolic and respiratory acidosis induce different myocardial effects related to different decreases in intracellular pH. Only metabolic acidosis impairs the positive inotropic effect of β-adrenergic stimulation.