Angiotensin receptor blocker vs ACE inhibitor effects on HDL functionality in patients on maintenance hemodialysis.

BACKGROUND AND AIMS: Angiotensin receptor blockers (ARB) and angiotensin converting enzyme inhibitors (ACEI) reduce cardiovascular events in the general population. Maintenance hemodialysis (MHD) patients are at high cardiovascular risk but few studies have directly addressed the comparative efficacy of these drugs. MHD disrupts the normally atheroprotective actions of high density lipoprotein (HDL), therefore, we compared ACEI or ARB treatment on HDL functions in MHD. METHODS AND RESULTS: HDL was isolated at the starting point (pre) and 3-6 months later (post) in 30 MHD randomly assigned to placebo, ramipril or valsartan. Outcomes included cholesterol efflux, inflammatory cytokine response, effects on Toll-like receptors (TLR), superoxide production, methylarginine and serum amyloid A (SAA) levels. HDL from ARB- or ACEI-treated subjects was more effective in maintaining efflux than HDL of placebo. HDL from ARB- or ACEI-treated subjects but not placebo lessened cellular superoxide production. In contrast, neither ARB nor ACEI improved HDL anti-inflammatory effect. Indeed, HDL of ACEI-treated subjects potentiated the cytokine responses in association with activation of TLR but did not alter the HDL content of methylarginines or SAA. CONCLUSION: Both ACEI and ARB stabilized HDL cholesterol acceptor function and sustained cellular anti-oxidative effects but not anti-inflammatory effects, and ACEI-treatment instead amplified the HDL inflammatory response. The findings reveal possible utility of antagonizing angiotensin actions in MDH and suggest a possible mechanism for superiority of ARB vs ACEI in the setting of advanced kidney disease.

Delineation of clinical features in Wiedemann-Steiner syndrome caused by KMT2A mutations.

Wiedemann-Steiner syndrome (WSS) is an autosomal dominant congenital anomaly syndrome characterized by hairy elbows, dysmorphic facial appearances (hypertelorism, thick eyebrows, downslanted and vertically narrow palpebral fissures), pre- and post-natal growth deficiency, and psychomotor delay. WSS is caused by heterozygous mutations in KMT2A (also known as MLL), a gene encoding a histone methyltransferase. Here, we identify six novel KMT2A mutations in six WSS patients, with four mutations occurring de novo. Interestingly, some of the patients were initially diagnosed with atypical Kabuki syndrome, which is caused by mutations in KMT2D or KDM6A, genes also involved in histone methylation. KMT2A mutations and clinical features are summarized in our six patients together with eight previously reported patients. Furthermore, clinical comparison of the two syndromes is discussed in detail.

CYP4A11 variant is associated with high-density lipoprotein cholesterol in women.

The ω-hydroxylase CYP4A11 catalyzes the transformation of epoxyeicosatrienoic acids (EETs) to ω-hydroxylated EETs, endogenous peroxisome proliferator-activated receptor-α (PPARα) agonists. PPARα activation increases high-density lipoprotein cholesterol (HDL-C). A cytosine-for-thymidine (T8590C) variant of CYP4A11 encodes for an ω-hydroxylase with reduced activity. This study examined the relationship between CYP4A11 T8590C genotype and metabolic parameters in the Framingham Offspring Study and in a clinical practice-based biobank, BioVU. In women in the Framingham Offspring Study, the CYP4A11 8590C allele was associated with reduced HDL-C concentrations (52.1±0.5 mg dl(-1) in CYP4A11 CC- or CT-genotype women versus 54.8±0.5 mg dl(-1) in TT women at visit 2, P=0.02), and with an increased prevalence of low HDL-C, defined categorically as 50 mg dl(-1) (odds ratio 1.39 (95% CI 1.02-1.90), P=0.04). In the BioVU cohort, the CYP4A11 8590C allele was also associated with low HDL-C in women (odds ratio 1.69 (95% CI 1.03-2.77, P=0.04)). There was no relationship between genotype and HDL-C in men in either cohort.

Analysis of circulating angiogenic biomarkers from patients in two phase III trials in lung cancer of chemotherapy alone or chemotherapy and thalidomide.

BACKGROUND: Thalidomide has potent anti-inflammatory and anti-angiogenic properties. It was evaluated in combination with chemotherapy in two randomised placebo-controlled trials in patients with small cell lung cancer (SCLC, n=724) and advanced non-small cell lung cancer (NSCLC, n=722). Neither study demonstrated an improvement in overall survival with the addition of thalidomide to chemotherapy. This study investigated circulating angiogenic biomarkers in a subset of these patients. METHODS: Serial plasma samples were collected in a cohort of patients enrolled in these two trials (n=95). Vascular endothelial growth factor (VEGF), soluble truncated form of VEGF receptor-2 (sVEGFR-2), interleukin-8 (IL-8), tumour necrosis factor-α (TNF-α), basic fibroblast growth factor (bFGF) and soluble intercellular adhesion molecule-1 (sICAM-1) levels were measured by enzyme-linked immunosorbent assays. Results were correlated with patient clinical data including stage, response rate and progression-free survival (PFS). RESULTS: Baseline biomarker levels were not significantly different between SCLC and NSCLC. For pooled treatment groups, limited stage SCLC was associated with lower baseline VEGF (P=0.046), sICAM-1 (P=0.008) and IL-8 (P=0.070) than extensive stage disease. Low baseline IL-8 was associated with a significantly improved PFS in both SCLC and NSCLC (P=0.028), and a greater reduction in IL-8 was associated with a significantly improved tumour response (P=0.035). Baseline angiogenic factor levels, however, did not predict response to thalidomide. CONCLUSION: Circulating angiogenic biomarkers did not identify patients who benefited from thalidomide treatment.

Role of L-type calcium channels in altered microvascular responses to propofol in hypertension.

BACKGROUND: Propofol acts as an L-type calcium channel (LTCC) antagonist to decrease peripheral resistance and initiate hypotension. This study investigated LTCC sensitivity/expression in hypertension and the role of LTCCs in exaggerated hypotension to propofol in this situation. METHODS: Age-matched 12- to 15-week-old normotensive rats [male Wistar Kyoto (WKY)] and spontaneously hypertensive rats (SHR) were used. Propofol (10 mg kg(-1), 10-50 mg kg(-1) h(-1) i.v.) was administered and the mesenteric microcirculation (<70 µm) observed with fluorescent in vivo microscopy using fluorescein isothiocyanate-conjugated bovine serum albumin (100 mg kg(-1) i.v.). Western blotting was used to measure tissue expression of the α(1C) LTCC subtype. Pressure myography was used to assess isolated mesenteric arterioles (<350 µm) in response to BAYK8644 (0.1 nM-1 µM), a specific LTCC channel agonist. RESULTS: Propofol dilated isolated arterioles {336.6 µM [mean (sd) change 16.2 (5.8)%]}. However, constriction to BAYK8644 was reduced at this concentration of propofol [EC(50)=8.3 (0.1) log mol(-1)] compared with controls [7.4 (0.1) log mol(-1), P<0.05], suggesting that propofol inhibited LTCCs. The sensitivity of LTCCs increased during hypertension, as in vivo there was a greater increase in mean arterial pressure (MAP) to BAYK8644 [10 µg kg(-1), WKY: 59.5 (9.3)%; SHR: 97.7 (6.3)%, P<0.05] with exaggerated constriction of arterioles [10 µg kg(-1), WKY: 9.1 (2.5)%; SHR: 19.1 (2.6)%, P<0.05]. Propofol also decreased MAP in SHR over time (P<0.05), but remained unchanged in WKY. Using western blotting, expression of α(1C) was greater in SHR compared with WKY (P<0.05). CONCLUSIONS: Propofol acts via LTCC channels, with increased channel expression and sensitivity in genetically hypertensive rats. We suggest that increased sensitivity and expression of LTCCs may be a mechanism for exaggerated hypertension during propofol anaesthesia.

Aldosterone decreases glucose-stimulated insulin secretion in vivo in mice and in murine islets.

AIMS/HYPOTHESIS: Aldosterone concentrations increase in obesity and predict the onset of diabetes. We investigated the effects of aldosterone on glucose homeostasis and insulin secretion in vivo and in vitro. METHODS: We assessed insulin sensitivity and insulin secretion in aldosterone synthase-deficient (As [also known as Cyp11b2](-/-)) and wild-type mice using euglycaemic-hyperinsulinaemic and hyperglycaemic clamps, respectively. We also conducted studies during high sodium intake to normalise renin activity and potassium concentration in As (-/-) mice. We subsequently assessed the effect of aldosterone on insulin secretion in vitro in the presence or absence of mineralocorticoid receptor antagonists in isolated C57BL/6J islets and in the MIN6 beta cell line. RESULTS: Fasting glucose concentrations were reduced in As (-/-) mice compared with wild-type. During hyperglycaemic clamps, insulin and C-peptide concentrations increased to a greater extent in As (-/-) than in wild-type mice. This was not attributable to differences in potassium or angiotensin II, as glucose-stimulated insulin secretion was enhanced in As (-/-) mice even during high sodium intake. There was no difference in insulin sensitivity between As (-/-) and wild-type mice in euglycaemic-hyperinsulinaemic clamp studies. In islet and MIN6 beta cell studies, aldosterone inhibited glucose- and isobutylmethylxanthine-stimulated insulin secretion, an effect that was not blocked by mineralocorticoid receptor antagonism, but was prevented by the superoxide dismutase mimetic tempol. CONCLUSIONS/INTERPRETATION: We demonstrated that aldosterone deficiency or excess modulates insulin secretion in vivo and in vitro via reactive oxygen species and in a manner that is independent of mineralocorticoid receptors. These findings provide insight into the mechanism of glucose intolerance in conditions of relative aldosterone excess.

Anti-tissue factor short hairpin RNA inhibits breast cancer growth in vivo.

In breast cancer, there is a correlation between tissue factor (TF) expression, angiogenesis and disease progression. TF stimulates tumour angiogenesis, in part, through up-regulation of vascular endothelial growth factor (VEGF). Therefore, this study aimed to establish whether TF stimulates angiogenesis and tumour progression directly and independent of VEGF up-regulation. Initially, the effects of TF and VEGF were assessed on endothelial cell migration (Boyden chamber) and differentiation (tubule formation on Matrigel). Subsequently, MDA-MB-436 breast cancer cells, which produce high levels of both TF and VEGF (western blot analysis), were established in vivo, following which tumours were treated three times per week for 3 weeks with intra-tumoural injections of either anti-VEGF siRNA, anti-TF shRNA, the two treatments combined, or relevant controls. Both VEGF and TF significantly stimulated endothelial cell migration and tubule formation (P < 0.02). Breast cancer xenografts (MDA-MB-436) treated with TF or VEGF-specific agents demonstrated significant inhibition in tumour growth (VEGFsiRNA 61%; final volume: 236.2 ± 23.2 mm(3) vs TFshRNA 89%; 161.9 ± 17.4 mm(3) vs combination 93%; 136.3 ± 9.2 mm(3) vs control 400.4 ± 32.7 mm(3); P < 0.005). Microvessel density (MVD), a measure of angiogenesis, was also significantly inhibited in all groups (MVD in control = 29 ± 2.9; TFshRNA = 18 ± 1.1; VEGFsiRNA = 16.7 ± 1.5; both = 12 ± 2.1; P < 0.004), whereas the proliferative index of the tumours was only reduced in the TFshRNA-treated groups (control = 0.51 ± 0.011; TFshRNA = 0.41 ± 0.014; VEGFsiRNA = 0.49 ± 0.013; both = 0.41 ± 0.004; P < 0.008). These data suggest that TF has a direct effect on primary breast cancer growth and angiogenesis, and that specific inhibition of the TF-signalling pathway has potential for the treatment of primary breast cancer.

A new species of Proegernia from the Namba Formation in South Australia and the early evolution and environment of Australian egerniine skinks.

The diverse living Australian lizard fauna contrasts greatly with their limited Oligo-Miocene fossil record. New Oligo-Miocene fossil vertebrates from the Namba Formation (south of Lake Frome, South Australia) were uncovered from multiple expeditions from 2007 to 2018. Abundant disarticulated material of small vertebrates was concentrated in shallow lenses along the palaeolake edges, now exposed on the western of Lake Pinpa also known from Billeroo Creek 2 km northeast. The fossiliferous lens within the Namba Formation hosting the abundant aquatic (such as fish, platypus Obdurodon and waterfowl) and diverse terrestrial (such as possums, dasyuromorphs and scincids) vertebrates and is hereafter recognized as the Fish Lens. The stratigraphic provenance of these deposits in relation to prior finds in the area is also established. A new egerniine scincid taxon Proegernia mikebulli sp. nov. described herein, is based on a near-complete reconstructed mandible, maxilla, premaxilla and pterygoid. Postcranial scincid elements were also recovered with this material, but could not yet be confidently associated with P. mikebulli. This new taxon is recovered as the sister species to P. palankarinnensis, in a tip-dated total-evidence phylogenetic analysis, where both are recovered as stem Australian egerniines. These taxa also help pinpoint the timing of the arrival of scincids to Australia, with egerniines the first radiation to reach the continent.

Association of angiotensin-converting enzyme inhibitor-associated angioedema with transplant and immunosuppressant use.

BACKGROUND: Immunosuppressants decrease circulating dipeptidyl peptidase IV (DPPIV) activity in transplant patients, and decreased DPPIV activity has been associated with angiotensin-converting enzyme (ACE) inhibitor-associated angioedema. One study has reported an increased incidence of ACE inhibitor-associated angioedema among transplant patients compared to published rates, while several case series report angioedema in patients taking specific immunosuppressant agents. OBJECTIVE: To test the hypothesis that transplant patients are at increased risk of ACE inhibitor-associated angioedema. METHODS: We assessed the proportion of transplant patients in 145 cases with ACE inhibitor-associated angioedema and 280 ACE inhibitor-exposed controls. We measured the relationship between case-control status, transplant status, and immunosuppressant use and circulating DPPIV activity. We also assessed the incidence of angioedema among consecutive patients who underwent renal or cardiac transplant and were treated with an ACE inhibitor. RESULTS: Transplant patients were significantly overrepresented among ACE inhibitor-associated angioedema cases compared to controls (odds ratio 18.5, 95% CI 2.3-147.2, P = 0.0004). Immunosuppressant use, chronic renal failure, seasonal allergies and smoking were also associated with ACE inhibitor-associated angioedema in univariate analysis. The association of transplant status with ACE inhibitor-associated angioedema was no longer significant after inclusion of immunosuppressant therapy in a multivariate analysis. Dipeptidyl peptidase IV activity was significantly decreased in sera from cases compared to ACE inhibitor-exposed controls, as well as in individuals taking immunosuppressants. Two of 47 ACE inhibitor-treated renal transplant patients and one of 36 ACE inhibitor-treated cardiac transplant patients developed angioedema. CONCLUSION: Transplant patients are at increased risk of ACE inhibitor-associated angioedema possibly because of the effects of immunosuppressants on the activity of DPPIV.

Angiopoietin-1, angiopoietin-2 and Tie-2 receptor expression in human dermal wound repair and scarring.

BACKGROUND: The angiopoietin (Ang)/Tie-2 ligand/receptor system is known to interact with the vascular endothelial growth factor (VEGF) pathway to determine the fate of blood vessels during angiogenesis. However, the precise contribution of this system to angiogenesis and the mechanisms of vascular maturation and remodelling in human tissue repair have yet to be elucidated. OBJECTIVES: To examine the spatial and temporal expression of Ang-1, Ang-2, Tie-2 and VEGF in relation to angiogenesis in human surgical wounds. METHODS: Punch biopsies were taken either from normal unwounded skin (controls) during surgery or from mastectomy scars between 3 days and 2 years postsurgery. Ang-1, Ang-2, Tie-2 and VEGF fibroblast/myofibroblast and endothelial expression were characterized by immunohistochemistry, analysed semiquantitatively and correlated with microvessel density (MVD) and scar age. RESULTS: The expression of VEGF, Ang-1, Ang-2 and Tie-2 in fibroblasts/myofibroblasts was increased significantly in early scars, decreased in older scars and was related to scar age (P < 0·001) and MVD (P < 0·0004), with strong correlations between all factors. In contrast, vascular expression of Ang-1 was decreased slightly in early scars, vascular Ang-2 remained constant and Tie-2 vascular expression increased, although there were no correlations with scar age or MVD. CONCLUSIONS: These data demonstrate that angiopoietins and their receptor, Tie-2, are expressed in both fibroblasts/myofibroblasts and endothelial cells in healing human wounds. Fibroblast/myofibroblast expression correlates with angiogenesis and VEGF expression, suggesting a role for the angiopoietin/Tie-2 system in normal wound repair and scarring.

Beneficial microvascular and anti-inflammatory effects of pravastatin during sepsis involve nitric oxide synthase III.

BACKGROUND: Sepsis induces microvascular inflammation and production of the vasodilator nitric oxide (NO) via endothelial and inducible nitric oxide synthase (eNOS or NOS III and iNOS or NOS II). Statins are cholesterol-lowering drugs; however, they also attenuate inflammation. This study aimed to determine whether pravastatin protected against sepsis-induced hypotension, loss of vascular tone, and microvascular inflammation via NOS pathways. METHODS: Male Wistar rats (n=18) were anaesthetized and the mesentery prepared for fluorescent intravital microscopy. Animals received either lipopolysaccharide (LPS; n=6); LPS+pravastatin (18 and 3 h before LPS; n=6), or saline as a control, for 4 h. RESULTS: Mean arterial pressure decreased in LPS-treated animals (P<0.05), but not in those also receiving pravastatin. Acetylcholine-induced relaxation of venules was abolished by LPS but improved by pravastatin. Pravastatin also reduced the increase in nitrite concentration and macromolecular leak from venules induced by LPS (P<0.05). The increased leucocyte adhesion seen in LPS-treated rats was also reduced in those also treated with pravastatin. Immunohistochemical analysis showed that pravastatin increased endothelial cell expression of NOS III during sepsis, but had no effect on LPS-induced up-regulation of NOS II. CONCLUSIONS: Pravastatin improved NOS III-mediated vessel relaxation and exerted anti-inflammatory effects within the microcirculation after LPS administration in rats. Pravastatin therefore appears to have beneficial effects during sepsis, as a result of increased microvascular expression and function of NOS III.

Angiogenesis is associated with the onset of hyperplasia in human ductal breast disease.

BACKGROUND: The precise timing of the angiogenic switch and the role of angiogenesis in the development of breast malignancy is currently unknown. METHODS: Therefore, the expression of CD31 (pan endothelial cells (ECs)), endoglin (actively proliferating ECs), hypoxia-inducible factor-1 (HIF-1alpha), vascular endothelial growth factor-A (VEGF) and tissue factor (TF) were quantified in 140 surgical specimens comprising normal human breast, benign and pre-malignant hyperplastic tissue, in situ and invasive breast cancer specimens. RESULTS: Significant increases in angiogenesis (microvessel density) were observed between normal and benign hyperplastic breast tissue (P<0.005), and between in situ and invasive carcinomas (P<0.0005). In addition, significant increases in proliferating ECs were observed in benign hyperplastic breast compared with normal breast (P<0.05) cancers and in invasive compared with in situ cancers (P<0.005). Hypoxia-inducible factor-1alpha, VEGF and TF expression were significantly associated with increases in both angiogenesis and proliferating ECs (P<0.05). Moreover, HIF-1alpha was expressed by 60-75% of the hyperplastic lesions, and a significant association was observed between VEGF and TF in ECs (P<0.005) and invasive tumour cells (P<0.01). CONCLUSIONS: These findings are the first to suggest that the angiogenic switch, associated with increases in HIF-1alpha, VEGF and TF expression, occurs at the onset of hyperplasia in the mammary duct, although the greatest increase in angiogenesis occurs with the development of invasion.

Angiogenesis, vascular endothelial growth factor and its receptors in human surgical wounds.

BACKGROUND: Angiogenesis plays an essential role in tissue repair. Vascular endothelial growth factor (VEGF) mediates angiogenesis through receptor kinases VEGF-R1 and VEGF-R2, and co-receptors, neuropilins Np1 and Np2. This study examined the spatial and temporal expression of these factors in relation to angiogenesis in surgical wounds. METHODS: Scar biopsies were obtained from patients between 3 days and 2 years after surgery. Normal skin control biopsies were taken during surgery. Microvessel density (MVD) was quantified using a Chalkley grid. VEGF, VEGF-R1, VEGF-R2, Np1 and Np2 endothelial expression was determined by immunohistochemistry, and correlated with MVD and scar age. RESULTS: Cumulative MVD was significantly greater in scars than controls (P = 0.011), and was related to scar age (P = 0.007). Expression of VEGF, VEGF-R2, Np1 and Np2 was increased significantly in all scars and correlated with MVD. In contrast, scar VEGF-R1 expression was decreased, and correlated with increased VEGF and VEGF-R2. CONCLUSION: Levels of VEGF, VEGF-R2, Np1 and Np2 are increased, whereas VEGF-R1 expression is decreased in angiogenesis, suggesting a role for VEGF-receptor complexes in early wound healing. This altered protein expression and increased presence of vessels is prolonged, suggesting that structural remodelling continues for at least 2 years after surgery.

Angiogenesis in pre-malignant conditions.

Evidence from human studies suggests that angiogenesis commences during the pre-malignant stages of cancer. Inhibiting angiogenesis may, therefore, be of potential value in preventing progression to invasive cancer. Understanding the mechanisms inducing angiogenesis in these lesions and identification of those important in human tumourigenesis are necessary to develop translational strategies that will help realise the goal of angioprevention.

Male-female differences in the genetic regulation of t-PA and PAI-1 levels in a Ghanaian population.

Tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) directly influence thrombus formation and degradation, and have been identified as risk factors for thromboembolic disease. Prior studies investigated determinants of t-PA and PAI-1 expression, but mainly in Caucasian subjects. The aim of this study was to identify the contributions of genetic and other factors to inter-individual variation in plasma levels of t-PA and PAI-1 in a large-scale population-based sample from urban West Africa. t-PA, PAI-1 and several demographic, anthropometric, and metabolic parameters were measured in 992 residents of Sunyani, the capital of the Brong-Ahafo region of Ghana. In addition, nine gene polymorphisms associated with components of the renin-angiotensin and fibrinolytic systems were determined. We found that BMI, systolic and diastolic blood pressure, total cholesterol, glucose, and triglycerides were all significant predictors of t-PA and PAI-1 in both females and males. In addition, a significant relationship was found between the PAI-1 4G/5G (rs1799768) polymorphism on PAI-1 levels in females, the TPA I/D (rs4646972) polymorphism on t-PA and PAI-1 in males, the renin (rs3730103) polymorphism on t-PA and PAI-1 in males, the ethanolamine kinase 2 (rs1917542) polymorphism on PAI-1 in males, and the renin (rs1464816) polymorphism on t-PA in females and on PAI-1 in males. This study of urban West Africans shows that t-PA and PAI-1 levels are determined by both genetic loci of the fibrinolytic and renin-angiotensin systems and other factors often associated with cardiovascular disease, and that genetic factors differ between males and females.

Identification of key residues involved in mediating the in vivo anti-tumor/anti-endothelial activity of Alphastatin.

BACKGROUND: We have recently shown that Alphastatin, a 24-amino-acid peptide (ADSGEGDFLAEGGGVRGPRVVERH) derived from human fibrinogen has anti-endothelial properties in vitro and in vivo. OBJECTIVES: The aim of this study was to determine the activity of a terminally modified (stabilized) form of Alphastatin in vitro and in vivo and to identify the key residues required for this activity. METHODS: The in vitro activity of modified Alphastatin, truncates and mutants was determined by endothelial cell (HuDMEC) tubule formation and migration. Active peptides were then assessed in vivo using syngeneic murine subcutaneous 4T1 mammary carcinomas. RESULTS: Modified Alphastatin-inhibited HuDMEC migration and tubule formation in response to multiple growth factors and caused a 45% inhibition in tumor growth when administered intravenously at 0.25 mg kg(-1) (three times per week). Intravenous (i.v.) administration proved non-toxic at all doses investigated, whereas oral and intraperitoneal (i.p.) administration demonstrated neither anti-tumor activity nor toxicity. Truncations of Alphastatin revealed an 11-amino-acid peptide (DFLAEGGGVRG), termed AHN419, which inhibited endothelial cell activity in vitro; however, intravenous AHN419 caused a non-significant growth inhibition in vivo. Single amino acid substitutions to alanine along the entire length of Alphastatin indicated that additional residues outside the AHN419 sequence were required for full activity. CONCLUSIONS: Terminal modification of Alphastatin altered the in vivo efficacy and these studies suggest that a hydrophobic cluster (Phe8, Leu9, Ala10 and Val15) is essential for the biological activity, but additional residues, including Ser3-Gly14, Pro18-Val20 and Arg23 are required for full inhibitory activity of Alphastatin.

Interleukin gene polymorphisms and breast cancer: a case control study and systematic literature review.

BACKGROUND: Interleukins and cytokines play an important role in the pathogenesis of many solid cancers. Several single nucleotide polymorphisms (SNPs) identified in cytokine genes are thought to influence the expression or function of these proteins and many have been evaluated for their role in inflammatory disease and cancer predisposition. The aim of this study was to evaluate any role of specific SNPs in the interleukin genes IL1A, IL1B, IL1RN, IL4R, IL6 and IL10 in predisposition to breast cancer susceptibility and severity. METHODS: Candidate single nucleotide polymorphisms (SNPs) in key cytokine genes were genotyped in breast cancer patients and in appropriate healthy volunteers who were similar in age, race and sex. Genotyping was performed using a high throughput allelic discrimination method. Data on clinico-pathological details and survival were collected. A systematic review of Medline English literature was done to retrieve previous studies of these polymorphisms in breast cancer. RESULTS: None of the polymorphisms studied showed any overall predisposition to breast cancer susceptibility, severity or to time to death or occurrence of distant metastases. The results of the systematic review are summarised. CONCLUSION: Polymorphisms within key interleukin genes (IL1A, IL1B, IL1RN, IL4R, IL6 and IL10 do not appear to play a significant overall role in breast cancer susceptibility or severity.

Prevalence of primary hyperaldosteronism in mild to moderate hypertension without hypokalaemia.

Screening for primary hyperaldosteronism (PHA) is often indicated in individuals with resistant hypertension or hypokalaemia. However, in the far larger subset of the hypertensive population who do not fit into these criteria, the evidence for screening is conflicting and dependent on the disease prevalence. The purpose of this study was to examine the prevalence of PHA in a large population with mild to moderate hypertension and without hypokalaemia using a carefully controlled study protocol including a normotensive control population. Hypertensive subjects underwent medication washout and both hypertensive and normotensive subjects placed on a high-sodium diet prior to biochemical and haemodynamic testing. Study specific cutoff values were based on results from the normotensive population studied under identical conditions. A screening test (serum aldosterone/PRA ratio [ARR]>25 with a serum aldosterone level >8 ng/dl) was followed by a confirmatory test (urine aldosterone excretion rate [AER] >17 microg/24 h) to demonstrate evidence of PHA. An elevated ARR with a concomitant elevated serum aldosterone was present in 26 (7.5%) individuals. Of these, 11 (3.2%) had an elevated AER, consistent with evidence of PHA. Individuals with PHA had higher blood pressure and lower serum potassium levels while on a high-sodium diet. Sodium restriction neutralized these differences between PHA and essential hypertensives. The prevalence of PHA in this mild to moderate hypertensive population without hypokalaemia is at most 3.2%, a rate that might lead to excessive false positives with random screening in comparable populations. Hyperaldosteronism, when present, is responsive to sodium restriction.

The effect of photodynamic therapy (PDT) on oesophageal motility and acid clearance in patients with Barrett's oesophagus.

BACKGROUND: Barrett's oesophagus is the major risk factor for oesophageal adenocarcinoma. It is proposed that long-term re-epithelialisation, which has been achieved following ablation using 5-aminolaevulinic acid (5-ALA) photodynamic therapy (PDT) may reduce the risk of malignant change. However, it is not known whether PDT modifies oesophageal motility. AIM: To assess oesophageal pH and motility before and after PDT ablation in treated and untreated areas of the oesophagus. METHODS: Twelve patients (10 male) with Barrett's oesophagus, median segment length 4 cm, were treated with PDT ablation. Twenty-four hours pH assessment and oesophageal manometry were performed before and 4-6 weeks after ablation. PDT was carried out using 635 nm red light, 4-6h after administration of 30 mg/kg 5-ALA. Proximal (untreated) and distal (treated) oesophageal resting pressure, wave amplitude, percentage peristalsis and percentage study time oesophageal pH<4, were assessed. Proton pump inhibitors (PPI) were administered throughout the study. RESULTS: There were no significant differences in oesophageal motility in treated or untreated areas of the oesophagus after PDT compared to pre-treatment values. Patients who continued to experience oesophageal acid exposure required more treatments to achieve complete Barrett's ablation. CONCLUSIONS: Oesophageal motility following ALA-PDT suggests a trend toward enhanced wave propagation however continued oesophageal acid exposure may affect PDT efficacy.