Comparison of Negative Pressure Wound Therapy with or without a Split-Thickness Skin Graft in the Surgical Management of Axillary Hidradenitis Suppurativa: A Retrospective Cohort Study.

Introduction: Negative pressure wound therapy (NPWT) alone or with the addition of a split-thickness skin graft (STSG) are 2 reconstructive options available after surgical excision of axillary hidradenitis suppurativa (HS). The aim of this study was to retrospectively examine patients undergoing these treatments and to assess clinical and patient-related outcome measures. Methods: A single-centre, retrospective analysis was conducted, evaluating surgical excision of axillary HS, with STSG and NPWT, or NPWT alone. Data collected included No. of post-operative clinic visits, time to heal, size of wound, disease recurrence, follow-up time, Dermatology Life Quality Index (DLQI), the Generalised Anxiety Disorder Assessment (GAD-7), the Patient Health Questionnaire Depression Scale (PHQ-9), Pain Visual Analogue Scale (PAINVAS2), the Brief Illness Perception Questionnaire (BIPQ), and Dermatology Visual Analogue Scale (DERMVAS). Two-tailed t-test and Mann-Whitney Wilcoxon U-tests were used to assess for significant relationships. Results: One hundred five patients were included in the study, 44 who received NPWT alone, and 61 who received NPWT + STSG. There was no significant difference in follow-up time (P = .934) or No. of follow-up appointments between groups (P = .287). There was a significant difference in time to heal between groups, with STSG + NPWT observing a mean time of 2.77 months and NPWT alone observing a mean time of 4.40 months (P = .0006). There was no difference in patient-reported outcomes between the 2 groups. Conclusion: There is no difference in patient-reported outcomes with the addition of an STSG to NPWT after surgical excision of HS. Wide excision and use of NPWT alone is an effective procedure for the treatment of axillary HS.

Introduction: Le traitement des plaies par pression négative (NPWT) seule ou associée à une greffe de peau d'épaisseur partielle (STSG) sont les deux options disponibles pour la reconstruction après excision chirurgicale d'hidradénite suppurée (HS) axillaire. Le but de cette étude rétrospective était d'examiner les patients subissant ces traitements et d'évaluer les mesures des résultats cliniques et liés aux patients. Méthodes: Une analyse rétrospective monocentrique a été menée pour évaluer l'excision chirurgicale de l'HS axillaire avec NPWT et STSG ou NPWT seule. La collecte de données a inclus : le nombre de visites cliniques postopératoires, le délai de guérison, la taille de la plaie, la récidive de la maladie, la durée du suivi, l'indice de qualité de vie dermatologique (DLQI), l'évaluation du trouble anxieux généralisé (GAD-7), l'échelle de dépression du Questionnaire sur la santé du patient (PHQ-9), l'échelle visuelle analogique de la douleur (PAINVAS2), le Court Questionnaire sur la perception de la maladie (BIPQ) et la DERMVAS. Un test t de Fisher bilatéral et un test de Mann-Whitney Wilcox ont servi à évaluer les relations significatives. Résultats: 105 patients ont été inclus dans l'étude : 44 ont reçu uniquement le traitement par pression négative et 61 ont reçu NPWT + STSG. Il n'y a pas eu de différence significative dans la durée du suivi (P = 0934) ou le nombre de rendez-vous de suivi entre les groupes (P = 0287). Il y a eu une différence significative sur le délai de guérison entre les groupes avec un délai moyen de 2,77 mois pour le groupe STSG + NPWT et de 4,40 mois pour le groupe NPWT seul (P = 0,0006). Il n'y a pas eu de différence entre les deux groupes pour ce qui concernait les résultats signalés par les patients. Conclusion: L'ajout d'une greffe de peau d'épaisseur partielle (STSG) au traitement par pression négative (NPWT) n'a pas entraîné d'augmentation de problèmes signalés par les patients après excision chirurgicale d'une hidradénite suppurée. Une excision large et l'utilisation du NPWT seul constituent une procédure efficace pour le traitement de l'HS axillaire.

Severe dissecting scalp cellulitis successfully treated with serial excisions in combination with anti-TNF therapy.

The management of dissecting scalp cellulitis involves medical treatment with oral antibiotics and isotretinoin, as well as surgical input in more severe cases. In extensive disease, a full scalpectomy with reconstruction can be required. We report a case of severe dissecting scalp cellulitis in a 34-year-old man who underwent serial scalp excisions over three years, with wounds being left to heal by secondary intention. Initially, the excisions helped to control symptoms but, once the patient was on concurrent anti-TNF therapy, further excisions were successful in reducing disease load and inducing remission. He remained disease free at the 20 months follow-up. This case is the first of its kind to be described in the literature and it highlights how a conservative, staged surgical approach, in combination with anti-TNF therapy, can be effective in the management of severe dissecting scalp cellulitis. In doing so, it offers an alternative to full scalpectomy with reconstruction.

Investigation of association of genetic variant rs3918242 of matrix metalloproteinase-9 with hypertension, myocardial infarction and progression of ventricular dysfunction in Irish Caucasian patients with diabetes: a report from the STOP-HF follow-up programme.

BACKGROUND: Hypertension and/or myocardial infarction are common causes of heart failure in Type 2 diabetes. Progression to heart failure is usually preceded by ventricular dysfunction, linked to matrix metalloproteinase (MMP) mediated extracellular matrix changes. We hypothesise that the minor allele of genetic variant rs3918242 in the promoter region of the MMP-9 gene is associated with hypertension and/or myocardial infarction, with resultant progression of dysfunctional cardiac remodelling in patients with diabetes without symptomatic heart failure. METHODS: We genotyped 498 diabetes patients participating in the St Vincent's Screening TO Prevent Heart Failure (STOP-HF) follow-up programme for the rs3918242 single nucleotide polymorphism and investigated associations with the co-primary endpoints hypertension and/or myocardial infarction using a dominant model. We also evaluated resulting cardiometabolic phenotype and progression of ventricular dysfunction and cardiac structural abnormalities over a median follow-up period of 3.5 years. RESULTS: The CT/TT genotype comprised 28.1% of the cohort and was associated with a twofold higher risk of myocardial infarction (17.9% vs 8.4%), a reduction in ejection fraction and greater left ventricular systolic dysfunction progression [adjusted OR = 2.56 (1.09, 6.01), p = 0.026] over a median follow-up of 3.5 years [IQR 2.6, 4.9 years]. Conversely, rs3918242 was not associated with hypertension, blood pressure, pulse pressure or left ventricular mass index at baseline or over follow up. CONCLUSIONS: Diabetes patients with the minor T allele of rs3918242 in the STOP-HF follow up programme have greater risk of myocardial infarction, lower ejection fraction and greater progression of left ventricular systolic abnormalities, a precursor to heart failure. These data may support further work on MMP-9 as a biomarker of ventricular dysfunction and the investigation of MMP-9 inhibitors for heart failure prevention in diabetes, particularly in the post-infarction setting. ClinicalTrials.gov Identifier: NCT00921960.

Regulation of the phosphoprotein phosphatase 2A system and its modulation during oxidative stress: A potential therapeutic target?

Phosphoprotein phosphatases are of growing interest in the pathophysiology of many diseases and are often the neglected partner of protein kinases. One family member, PP2A, accounts for dephosphorylation of ~55-70% of all serine/threonine phosphosites. Interestingly, dysregulation of kinase signalling is a hallmark of many diseases in which an increase in oxidative stress is also noted. With this in mind, we assess the evidence to support oxidative stress-mediated regulation of the PP2A system In this article, we first present an overview of the PP2A system before providing an analysis of the regulation of PP2A by endogenous inhibitors, post translational modification, and miRNA. Next, a detailed critique of data implicating reactive oxygen species, ischaemia, ischaemia-reperfusion, and hypoxia in regulating the PP2A holoenzyme and associated regulators is presented. Finally, the pharmacological targeting of PP2A, its endogenous inhibitors, and enzymes responsible for its post-translational modification are covered. There is extensive evidence that oxidative stress modulates multiple components of the PP2A system, however, most of the data pertains to the catalytic subunit of PP2A. Irrespective of the underlying aetiology, free radical-mediated attenuation of PP2A activity is an emerging theme. However, in many instances, a dichotomy exists, which requires clarification and mechanistic insight. Nevertheless, this raises the possibility that pharmacological activation of PP2A, either through small molecule activators of PP2A or CIP2A/SET antagonists may be beneficial in modulating the cellular response to oxidative stress. A better understanding of which, will have wide ranging implications for cancer, heart disease and inflammatory conditions.

Maternal hypomagnesemia alters hippocampal NMDAR subunit expression and programs anxiety-like behaviour in adult offspring.

It is well established that maternal undernutrition and micronutrient deficiencies can lead to altered development and behaviour in offspring. However, few studies have explored the implications of maternal Mg deficiency and programmed behavioural and neurological outcomes in offspring. We used a model of Mg deficiency (prior to and during pregnancy and lactation) in CD1 mice to investigate if maternal Mg deficiency programmed changes in behaviour and NMDAR subunit expression in offspring. Hippocampal tissue was collected at postnatal day 2 (PN2), PN8, PN21 and 6 months, and protein expression of NMDAR subunits GluN1, GluN2A and GluN2B was determined. At 6 months of age, offspring were subject to behavioural tasks testing aspects of anxiety-like behaviour, memory, and neophobia. Maternal hypomagnesemia was associated with increased GluN1, GluN2A and GluN2B subunit expression in female offspring at 6 months, but decreased GluN1 and GluN2A expression in males. The GluN2B:GluN2A expression ratio was increased in both sexes. Male (but not female) offspring from Mg-deficient dams showed anxiety-like behaviour, with reduced head dips (Suok test), and reduced exploration of open arms (elevated plus maze). Both male and female offspring from Mg-deficient dams also showed impaired recognition memory (novel object test). These findings suggest that maternal Mg deficiency can result in behavioural deficits in adult life, and that these changes may be related to alterations in hippocampal NMDA receptor expression.

Protein phosphatase 2A regulation of markers of extracellular matrix remodelling in hepatocellular carcinoma cells: functional consequences for tumour invasion.

BACKGROUND AND PURPOSE: A hallmark of tumour invasion is breakdown of the extracellular matrix due to dysregulation of the matrix metalloproteinase (MMP) system. While our understanding of how this is regulated by kinase signalling pathways is well established, its counter-regulation by protein phosphatases (PP) is poorly understood. Therefore, we investigated the effect of PP inhibition on markers of extracellular remodelling and how PP2A activity modulated MMP-9 abundance and function of Hep3B cells. EXPERIMENTAL APPROACH: Cells were exposed to okadaic acid (OA), tautomycetin and cyclosporin A, and the expression profile determined using PCR. Effects of OA and a protein inhibitor of PP2A, CIP2A, on MMP-9 abundance, PP2A activity and cell migration were investigated using ELISA, promoter constructs, siRNA knockdown and transwell migration assays. KEY RESULTS: OA increased expression and abundance of MMP-9 and the tissue inhibitor of MMP, TIMP-1, without affecting other MMPs, TIMPs and ADAMs. The effect on MMP-9 was mimicked by CIP2A overexpression and knockdown of the PPP2CA catalytic, but not PPP2R1A scaffolding, subunit. Cyclosporin A and PPP1CA silencing did not alter MMP-9 expression, while tautomycetin transiently increased it. Mutation of AP-1, but not NF-κB, binding sites inhibited OA-mediated MMP-9 transcriptional activity. OA and CIP2A decreased PP2A activity and increased cell migration. CONCLUSION AND IMPLICATIONS: OA increased MMP-9 by decreasing PP2A activity and PP2Ac, through AP-1 binding sites on the MMP-9 promoter. The functional consequence of this and CIP2A overexpression was increased cell migration. Hence, PP2A inhibition induced a metastatic phenotype through alterations in MMP-9 in Hep3B cells.

Postprandial adiponectin and gelatinase response to a high-fat versus an isoenergetic low-fat meal in lean, healthy men.

OBJECTIVE: Evidence suggests that an acute systemic inflammatory response is invoked after consumption of a high-energy meal. Postprandial regulation of adiponectin, an adipose tissue-derived, anti-inflammatory hormone, and the gelatinases, matrix metalloproteinase (MMP)-2 and MMP-9, endopeptidases implicated in a diverse range of inflammatory processes, remain inconclusive. The aim of this study was to assess the postprandial effect of a high-energy (1212 kcal) meal on plasma adiponectin, MMP-2 and MMP-9 activity, glucose, insulin, triacylglycerols, total cholesterol, high-density lipoprotein cholesterol, and the differential effects on these parameters depending on whether the test meal was high fat (HF; 46 g fat, 1210 kcal) or isoenergetic and low fat (LF; 15 g fat, 1214 kcal energy). METHODS: Test meals were consumed by 17 lean, healthy men on two separate occasions with blood samples collected by venipuncture at baseline (0 h) and 1 and 3 h after consumption of each test meal. RESULTS: At baseline, no significant difference was seen in the parameters between the two groups, except for MMP-2, MMP-9, and total cholesterol. Over the 3-h postprandial period, no significant differential effect of the HF versus the LF test meal was observed on adiponectin, MMP-2, MMP-9, or on metabolic markers other than triacylglycerol, which increased significantly in response to the HF test meal (time × treatment, P = 0.002). When analyzed independent of time, MMP-2 (treatment, P = 0.006), MMP-9 (treatment, P = 0.022), and glucose (treatment, P = 0.026) were lower after consumption of the HF meal compared with the LF test meal. When analyzed independent of treatment, adiponectin increased over the 3-h postprandial period (time, P = 0.031), but there was no change in MMP-2 or MMP-9 (time, P = 0.503 and P = 0.525, respectively). Over the 3-h postprandial period, insulin (time, P < 0.001) and total cholesterol (time, P = 0.002) increased, whereas glucose (time, P < 0.001) and high-density lipoprotein cholesterol (time, P < 0.001) decreased. CONCLUSION: No differential effects of a HF versus a LF isoenergetic meal were seen on postprandial adiponectin or the gelatinases. Adiponectin increased in response to a high-energy meal independent of treatment, and the gelatinases were lower in response to the HF versus the LF isoenergetic meal, independent of time point. Given the considerable amount of time that humans spend in the postprandial state, additional research is necessary to further understand inflammatory changes in this state.

Mid- to late term hypoxia in the mouse alters placental morphology, glucocorticoid regulatory pathways and nutrient transporters in a sex-specific manner.

Maternal hypoxia is a common perturbation that can disrupt placental and thus fetal development, contributing to neonatal impairments. Recently, evidence has suggested that physiological outcomes are dependent upon the sex of the fetus, with males more susceptible to hypoxic insults than females. This study investigated the effects of maternal hypoxia during mid- to late gestation on fetal growth and placental development and determined if responses were sex specific. CD1 mice were housed under 21% or 12% oxygen from embryonic day (E) 14.5 until tissue collection at E18.5. Fetuses and placentas were weighed before collection for gene and protein expression and morphological analysis. Hypoxia reduced fetal weight in both sexes at E18.5 by 7% but did not affect placental weight. Hypoxia reduced placental mRNA levels of the mineralocorticoid and glucocorticoid receptors and reduced the gene and protein expression of the glucocorticoid metabolizing enzyme HSD11B2. However, placentas of female fetuses responded differently to maternal hypoxia than did placentas of male fetuses. Notably, morphology was significantly altered in placentas from hypoxic female fetuses, with a reduction in placental labyrinth blood spaces. In addition mRNA expression of Glut1, Igf2 and Igf1r were reduced in placentas of female fetuses only. In summary, maternal hypoxia altered placental formation in a sex specific manner through mechanisms involving placental vascular development, growth factor and nutrient transporter expression and placental glucocorticoid signalling. This study provides insight into how sex differences in offspring disease development may be due to sex specific placental adaptations to maternal insults.

Graduate nurses' learning trajectories and experiences of problem based learning: a focused ethnography study.

BACKGROUND: Problem-based learning seeks to foster active, collaborative and self directed learning. It is increasingly utilized in health professional education; however, it is difficult to ascertain effectiveness. Empirically, student satisfaction does not match academic achievement but the reasons for this are unclear. OBJECTIVE: To explore the experience trajectories and satisfaction of graduates who had completed an undergraduate problem-based learning nursing program. DESIGN AND METHODS: Qualitative focused ethnography using individual and group semi-structured interviews. Categories and themes were identified using inductive constant comparison. A comparative matrix analysis of differing levels of the two core processes illuminated specific experience profiles. PARTICIPANTS AND SETTING: Forty five program graduates who had graduated between one and nine years previously from a Western Canadian program offered at four academic sites. The sample was mostly female (n=37), aged 26-30 years (n=23) and graduated 5-8 years previously (n=20). RESULTS: Levels of satisfaction with the program varied markedly. Two core processes contributed to this: "understanding" and "valuing" problem-based learning. Specific experience profiles included: "Happy as fish in water" which represents those who understood and valued the approach, and flourished; "I'll do it but I won't like it" reflects those who understood and could adjust to the academic context but did not particularly value it; "I just want to be a nurse" characterized those who consistently disliked and resisted the process but endured in order to graduate. Each profile was characterized by attitudes, intentions, learning preferences and program satisfaction. CONCLUSIONS: We theorize an underlying mechanism explaining these diverse levels of satisfaction are differing orientations to studying. This approach to understanding how students typically approach learning is strongly linked to perceptions of academic quality and program satisfaction in higher education research, although it has been neglected in nursing problem-based learning research. Orientations to studying include reproductive surface learning, deep learning for understanding and meaning, and strategic approaches to maximize desired objectives. These orientations are congruent with the descriptive typologies developed in this research. This provides an effective explanation as to why some students adapt easily and flourish in problem-based learning contexts, while others continually struggle to adapt. Further research is needed to determine the relationship between deep, surface, and strategic orientations to study and student satisfaction in nursing programs.

Differential interactions of antiretroviral agents with LXR, ER and GR nuclear receptors: potential contributing factors to adverse events.

BACKGROUND AND PURPOSE: Antiretroviral (ARV) drugs activate pregnane X receptors and constitutive androstane receptors, increasing the risk of drug interactions due to altered drug metabolism and disposition. The closely related liver X receptors (LXRα/ß), oestrogen receptors (ERα/ß) and glucocorticoid receptor (GR) regulate many endogenous processes such as lipid/cholesterol homeostasis, cellular differentiation and inflammation. However, ARV drug activation of these nuclear receptors has not been thoroughly investigated. EXPERIMENTAL APPROACH: The ability of an ARV drug library to activate LXRα/ß, ERα/ß and GR was assessed using a combined in silico and in vitro approach encompassing computational docking and molecular descriptor filtering, cell-free time-resolved fluorescence resonance energy transfer co-activator assays to assess direct binding to ligand-binding domains (LBDs), cell-based reporter assays and target gene expression. KEY RESULTS: Direct LBD interactions with LXRα and/or LXRß were predicted in silico and confirmed in vitro for darunavir, efavirenz, flavopiridol, maraviroc and tipranavir. Likewise, efavirenz was also predicted and confirmed as a ligand of ERα-LBD. Interestingly, atazanavir and ritonavir also activated LXRα/ß in reporter assays, while tipranavir enhanced transcriptional activity of ERα. Effects on ER and LXR target gene expression were confirmed for efavirenz and tipranavir. CONCLUSIONS AND IMPLICATIONS: There was good agreement between in silico predictions and in vitro results. However, some nuclear receptor interactions identified in vitro were probably due to allosteric effects or nuclear receptor cross-talk, rather than direct LBD binding. This study indicates that some of the adverse effects associated with ARV use may be mediated through 'off-target' effects involving nuclear receptor activation.

HIV-1 Tat clade-specific cytokine induction in monocytes/macrophages is not evidenced in total or Vγ9Vδ2 T lymphocytes.

HIV-1 Tat exhibits clade-specific cytokine induction in monocytes. We investigated if Tat clades A-D can alter tumour necrosis factor (TNF)-α and interferon (IFN)-γ production by total and Vγ9Vδ2 T cells in vitro. Tat clade B, but not C, augmented TNF-α production by THP-1 cells. However, Tat clades A-D did not affect TNF-α or IFN-γ production or secretion by resting or activated conventional and Vγ9Vδ2 T cells. Therefore, transactivation of cytokines by Tat is immune cell-specific.

Okadaic acid induces matrix metalloproteinase-9 expression in fibroblasts: crosstalk between protein phosphatase inhibition and ß-adrenoceptor signalling.

BACKGROUND AND PURPOSE: Interactions between protein phosphatase inhibition and matrix metalloproteinase (MMP)-9 expression have implications for tissue remodelling after injury. Stimulation of ß-adrenoceptors could affect such interactions as isoprenaline increases protein phosphatase 2A (PP2A) activity and MMP-9 abundance. We investigated the effect of okadaic acid (OA) on MMP-9 expression to assess interactions between phosphatase inhibition and ß-adrenoceptor signalling in fibroblasts. EXPERIMENTAL APPROACH: Fibroblasts were exposed to OA alone and in combination with isoprenaline. Effects on MMP-9 expression and intracellular signalling were studied using promoter assays, Western blot analysis and siRNA methodologies. KEY RESULTS: Okadaic acid increased MMP-9 abundance in human cardiac ventricular fibroblasts, NIH3T3 fibroblasts and hepatic stellate cells. This effect was unaffected by PP2A knockdown in NIH3T3 cells. OA increased phosphorylation of NF-κB, but not NF-κB promoter activity, IκBα degradation, or nuclear translocation of p65-NF-κB. Exposure to SB202190 (p38 MAPK), U0126 (ERK1/2) and NF-κB III inhibitor revealed that OA induced MMP-9 activity through p38 MAPK. Isoprenaline inhibited OA-mediated MMP-9 expression in NIH3T3, in a ß-arrestin 2- and PP2A-dependent manner. Mutation of the activator protein-1 (AP-1) and NF-κB binding sites demonstrated that OA-induced MMP-9 activity was mediated through the AP-1 but not NF-κB sites. The latter mediated the inhibitory effect of isoprenaline on OA-induced MMP-9 promoter activity. CONCLUSION AND IMPLICATIONS: Okadaic acid induced MMP-9 activity through p38 MAPK and was inhibited by isoprenaline via a pathway involving ß-arrestin 2, PP2A and an NF-κB binding motif. These findings elucidate how phosphoprotein phosphatases and adrenoceptors may modulate tissue remodelling by affecting fibroblast function.

Long-term statin therapy in patients with systolic heart failure and normal cholesterol: effects on elevated serum markers of collagen turnover, inflammation, and B-type natriuretic peptide.

BACKGROUND: The role of statin therapy in heart failure (HF) is unclear. The amino-terminal propeptide of procollagen type III (PIIINP) predicts outcome in HF, and yet there are conflicting reports of statin therapy effects on PIIINP. OBJECTIVES: This study determined whether there was an increase in serum markers of inflammation, fibrosis (including PIIINP), and B-type natriuretic peptide (BNP) in patients with systolic HF and normal total cholesterol and determined the effects of long-term treatment with atorvastatin on these markers. METHODS: Fifty-six white patients with systolic HF and normal cholesterol levels (age 72 [13] years; 68% male; body mass index 27.0 [7.3] kg/m(2); ejection fraction 35 [13]%; 46% with history of smoking) were randomly allocated to atorvastatin treatment for 6 months, titrated to 40 mg/d (A group) or not (C group). Age- and/or sex-matched subjects without HF (N group) were also recruited. Biomarkers were measured at baseline (all groups) and 6 months (A and C groups). RESULTS: Serum markers of collagen turnover, inflammation, and BNP were significantly elevated in HF patients compared with normal participants (all P < 0.05). There were correlations between these markers in HF patients but not in normal subjects. Atorvastatin treatment for 6 months caused a significant reduction in the following biomarkers compared with baseline: BNP, from median (interquartile range) 268 (190-441) pg/mL to 185 (144-344) pg/mL; high-sensitivity C-reactive protein (hs-CRP), from 5.26 (1.95 -9.29) mg/L to 3.70 (2.34-6.81) mg/L; and PIIINP, from 4.65 (1.86) to 4.09 (1.25) pg/mL (all P < 0.05 baseline vs 6 months). Between-group differences were significant for PIIINP only (P = 0.027). There was a positive interaction between atorvastatin effects and baseline hs-CRP and PIIINP (P < 0.01). CONCLUSIONS: Long-term statin therapy reduced PIIINP in this small, selected HF population with elevated baseline levels. Further evaluation of statin therapy in the management of HF patients with elevated PIIINP is warranted.

Ribavirin and interferon alter MMP-9 abundance in vitro and in HIV-HCV-coinfected patients.

BACKGROUND: Matrix metalloproteinases (MMPs) and their endogenous tissue inhibitors (TIMPs) are central to tissue remodelling during HIV-HCV infection. Here, we assess the potential for antiviral therapy to modulate MMP abundance in THP-1 monocyte/macrophages and LX-2 hepatic stellate cells, and in a coinfected patient cohort. METHODS: THP-1 and LX-2 cells were treated with ribavirin (RBV)/interferon-α (IFN-α) and select HIV antivirals. Venous blood was reserved from HIV-HCV-coinfected patients, HIV- and HCV-monoinfected patients, and healthy controls, with the HIV-HCV cohort being sampled again at day 3 and 14 subsequent to the start of combination therapy with RBV/pegylated IFN-α. Samples were subjected to gelatin zymography, real-time RT-PCR and/or ELISA, where appropriate. RESULTS: RBV/IFN-α decreased MMP-9 activity, and increased MMP-9 mRNA and protein expression in THP-1 cells, but not in LX-2 cells. Decreases in MMP-9 activity were mediated by IFN-α, which also attenuated RBV induction of MMP-9 activity and protein expression in THP-1 cells. Saquinavir and lopinavir, HIV protease inhibitors, reduced MMP-9 activity in THP-1 and LX-2 cells, respectively. Plasma MMP-9 activity and expression was higher in HIV-HCV and HIV patients compared with HCV patients and healthy controls. MMP-2 and TIMP-2 levels were similar in all groups. RBV/pegylated IFN-α decreased plasma MMP-9 abundance in HIV-HCV patients. CONCLUSIONS: These data demonstrate that RBV/pegylated IFN-α reduce plasma MMP-9 abundance in vivo and may reduce its activity in vitro through immune cells, such as monocyte/macrophages, rather than hepatic stellate cells. The results of this study indicate that such therapy may mediate tissue remodelling associated with HIV-HCV coinfection through effects on MMP-9.

Nuclear receptor-mediated induction of CYP450 by antiretrovirals: functional consequences of NR1I2 (PXR) polymorphisms and differential prevalence in whites and sub-Saharan Africans.

BACKGROUND: Antiretroviral therapy including HIV protease inhibitors and nonnucleoside reverse transcriptase inhibitors can both inhibit and induce expression of cytochrome P450s, potentially leading to drug interactions. However, information is lacking on the impact of genetic polymorphism on this interaction. METHODS: This study examines the prevalence of 33 polymorphisms in NR1I2 (pregnane X receptor [PXR]), CYP3A4, and CYP2B6 in 1013 white and sub-Saharan African patients with HIV; explores the inductive ability of 16 antiretrovirals on CYP3A4 and CYP2B6 promoter activity through nuclear receptors PXR and constitutive androstane receptor (CAR); and evaluates the influence of naturally occurring PXR genetic variants on antiretroviral activation. RESULTS: Seventeen polymorphisms were present at different frequencies between the two ethnicities. Darunavir, fosamprenavir, lopinavir, nelfinavir, tipranavir, efavirenz, and abacavir increased CYP3A4 and/or CYP2B6 promoter activity, some through constitutive androstane receptor but mainly through PXR. Addition of low-dose ritonavir enhanced levels of CYP promoter activity for several protease inhibitors. Some PXR variants displayed lower fosamprenavir- and lopinavir-induced CYP3A4 promoter activity than the PXR reference sequence, whereas efavirenz and nelfinavir induction was unchanged. CONCLUSIONS: The presence of NR1I2 polymorphisms can alter the induction of CYP3A4 and CYP2B6 promoter activity, potentially adding to the unpredictable nature of antiretroviral drug interactions. These polymorphisms differ in prevalence between whites and sub-Saharan Africans.

Culture, context and community: ethical considerations for global nursing research.

High-quality research is essential for the generation of scientific nursing knowledge and the achievement of the Millennium Development Goals. However, the incorporation of Western bioethical principles in the study design may not be suitable, sufficient or relevant to participants in low-income countries and may indeed be harmful and disrespectful. Before engaging in global health studies, nurses must consider carefully the cultural and social context and values of the proposed setting in order to situate the research within the appropriate ethical framework. The purpose of this paper was to examine the ethical principles and considerations that guide health research conducted in international settings using the example of a qualitative study of Ugandan nurses and nurse-midwives by a Canadian researcher. The application of Western bioethical principles with their emphasis on autonomy fails to acknowledge the importance of relevant contextual aspects in the conduct of global research. Because ethics is concerned with how people interact and live together, it is essential that studies conducted across borders be respectful of, and congruent with, the values and needs of the community in which it occurs. The use of a communitarian ethical framework will allow nurse scientists to contribute to the elimination of inequities between those who enjoy prosperity and good health, and those who do not.

Matrix metalloproteinase-9 polymorphism contributes to blood pressure and arterial stiffness in essential hypertension.

Arterial stiffness is an independent predictor of cardiovascular events in a hypertensive population. Serum levels of matrix metalloproteinase (MMP)-9 are associated with arterial stiffness and predict cardiovascular risk. We investigated the role of MMP-9 polymorphism -1562C>T on blood pressure (BP) and arterial stiffness in a newly diagnosed hypertensive population. Untreated hypertensive patients (n=215, mean age 46+/-13 years) were studied. Supine BP, carotid-femoral pulse wave velocity (PWV) and augmentation index were assessed. Serum biochemistry and plasma MMP-9 concentrations were measured and genotyping performed following extraction of genomic DNA. BP, aortic PWV and serum MMP-9 levels were significantly higher in T-allele carriers of the -1562C>T polymorphism with a significant gene-dose effect (P<0.0001). In a stepwise regression model adjusting for known or likely determinants, the 1562C>T polymorphism emerged as an independent predictor of systolic BP (R(2)=0.25, P<0.0001), diastolic BP (R(2)=0.16, P<0.0001) and PWV (R(2)=0.47,P<0.0001). This is the first study to show the effect of MMP-9 polymorphism on BP and aortic stiffness in a hypertensive population. These results suggest that hypertensive patients carrying the T allele may be at increased risk of cardiovascular events.