Are SGLT2 inhibitors reasonable antihypertensive drugs and renoprotective?

By eliminating glucose in the urine, the sodium-glucose-linked cotransporter-2 (SGLT2) inhibitors act as osmotic diuretics to lower blood pressure in addition to reducing plasma glucose and assisting with weight loss. While not approved as antihypertensive agents, the ability of this new class of antihyperglycemic agents to lower blood pressure is not insubstantial, and while not used primarily for this indication, they may assist diabetic individuals in attaining currently recommended blood pressure targets. In addition to lowering systemic pressure, preclinical and exploratory human studies suggest that SGLT2 inhibitors may also lower intraglomerular pressure, potentially reducing the rate of GFR decline in patients with diabetic nephropathy. However, given the lack of clinically meaningful endpoint data, the use of SGLT2 inhibitors, primarily, as either antihypertensive or renoprotective agents would, at present, be premature. Fortunately, further insight will be garnered from large, randomized controlled trials that will assess the effects of various SGLT2 inhibitors on cardiovascular and renal outcomes.

SGLT-2 inhibition in patients with kidney disease.

Accustomed to managing diabetes with agents that mostly act by modulating the secretion and actions of insulin, with the advent of sodium-glucose linked transporter-2 (SGLT-2) inhibitors, physicians are now aware that the kidney also needs to be considered in the spectrum of action of anti-hyperglycaemic agents. Though familiar with the need for dose adjustment when prescribing many of our current anti-hyperglycaemic drugs in the setting of kidney dysfunction, with the SGLT-2 inhibitors pharmacodynamic as well as pharmacokinetic aspects also need to be considered. Finally, through their ability to reduce intraglomerular pressure, systemic blood pressure and plasma uric acid concentration, the SGLT-2 inhibitors offers the possibility of kidney protection. An hypothesis that will need to be tested with long term studies that address changes in the kidney beyond albuminuria, assessing the rate of decline in glomerular filtration rate and 'hard'kidneyrelated endpoints such as the need for renal replacement therapy (dialysis, transplantation) will be important in this setting.

Combination angiotensin converting enzyme and direct renin inhibition in heart failure following experimental myocardial infarction.

AIMS: Diminishing the activity of the renin-angiotensin system (RAS) plays a pivotal role in the treatment of heart failure. In addition to angiotensin converting enzyme (ACE) inhibitors and angiotensin-receptor blockers, direct renin inhibition has emerged as a potential adjunctive treatment to conventional RAS blockade. We sought to determine the effectiveness of this strategy after myocardial infarction (MI) in the setting of preexisting hypertension, a common premorbid condition in patients with ischemic heart disease. METHODS AND RESULTS: Ten-week-old female heterozygous hypertensive (mRen-2)27 transgenic rats (Ren-2), were randomized to one of five groups (n = 8 per group); sham, MI, MI + aliskiren, MI + lisinopril and MI + combination lisinopril and aliskiren. Cardiac function was assessed by echocardiography and in vivo cardiac catheterization. Untreated MI animals developed heart failure with hypotension, dilation, reduced ejection fraction (EF), and raised left ventricular end-diastolic pressure (LVEDP). Treatment with single agent treatment had only modest effect on cardiac function though combination therapy was associated with significant improvements in EF and LVEDP when compared to untreated MI animals (P < 0.05). Histologic analysis demonstrated increase extracellular matrix deposition and cardiomyocyte hypertrophy in the noninfarct region of all MI groups when compared with sham operated animals (P < 0.05) that was reduced by ACE inhibitor monotherapy and combination treatment but not by aliskiren alone. CONCLUSION: In a hypertensive rat model that underwent experimental MI, EF, and LVEDP, key functional indices of heart failure, were improved by treatment with combination ACE and direct renin inhibition when compared with either agent used alone.

Outcome of meniscal repair prior compared with concurrent ACL reconstruction.

Meniscal tears are commonly associated with traumatic rupture of the anterior cruciate ligament (ACL). At our centre, if a patient presents with locked knee in conjunction with an ACL injury we perform an initial arthroscopy to remove the cause of locking and schedule ACL reconstruction once a full range of motion has returned. The aim of this study was to assess the outcome of meniscal tears stabilised prior to ACL reconstruction. We identified 24 patients who underwent repair of a torn meniscus before having their ACL reconstruction (group 1). As a comparison group we identified 148 patients who underwent meniscal repair at the time of ACL reconstruction (group 2). Twelve of the patients in group 1 underwent meniscectomy, seven at the time of reconstruction and five subsequently. This gives a success rate of 50% (12/24) in the ACL deficient patients. In comparison forty two of the patients in group 2 went on to have a meniscectomy representing a success of 72% (106/148). The odds ratio for meniscectomy in an ACL deficient meniscal repair is 2.52 (95% CI 1.07-5.97) and there is a relative risk of 1.76 (95% CI 1.05-2.63). The difference in success of the meniscal repair between the groups was significant (Fisher's exact test p=0.05). Meniscal repair and delayed ACL reconstruction is more likely to fail than a combined repair and ACL reconstruction.

Accuracy of bacterial DNA testing for central venous catheter-associated bloodstream infection in children with cancer.

BACKGROUND: Central venous catheters (CVCs) are widely used for children with cancer and are a major risk factor for bloodstream infection. Early and specific diagnosis of CVC-associated bloodstream infection allows early targeted treatment, reducing the risk of CVC removal and avoiding the operative risks and trauma of reinsertion, but peripheral vein sampling, as used in adults, improves specificity but is not usually acceptable in children. OBJECTIVE: To improve the detection and treatment of CVC-associated bloodstream infection in children (aged 0-18 years) with cancer admitted with fever. METHODS: There were four main studies: (1) evaluation of the diagnostic accuracy of a quantitative molecular method for the detection of bacterial deoxyribonucleic acid (DNA), based solely on blood samples drawn through the CVC; (2) analysis of the prognostic risk of CVC removal and duration of intravenous (i.v.) antibiotic treatment days in relation to presenting clinical features, blood culture results and bacterial DNA test results; (3) systematic reviews of treatment options for CVC-associated infection and a questionnaire survey of current practice in paediatric oncology centres; (4) evaluation of the clinical effectiveness of different test-treatment strategies to reduce i.v. antibiotic treatment days and unnecessary CVC removals. RESULTS: (1) The bacterial DNA test detected two-thirds [95% confidence interval (CI) 44% to 83%] of children classified with probable CVC-associated infection - specificity was 88% (95% CI 84% to 92%). Although high bacterial DNA concentrations were associated with subsequent CVC removal and long duration of i.v. antibiotic treatment, the test did not improve the prediction of these outcomes over and above clinical signs of CVC-associated infection combined with blood culture results. (2) High DNA load was predictive of CVC removal and i.v. treatment duration, before blood culture results became available at 48 hours after sampling. (3) There was limited evidence that antibiotic lock treatment reduces the risk of recurrent CVC-associated infection or CVC removal (pooled relative risk 0.7, 95% CI 0.47 to 1.05), but prophylactic use of antimicrobial locks halved the risk of bloodstream infection (pooled incidence rate ratio 0.43, 95% CI 0.36 to 0.51). Contrary to this, the national survey of paediatric oncology centres found that locks are being used for treatment rather than prevention and that problems related to the formulation of lock solutions currently impede a shift to their prophylactic use in children. (4) Most i.v. treatment days would be saved by early stopping of treatment for children at low risk of infection. LIMITATIONS: The accuracy study was limited primarily by the lack of an adequate reference standard, and the main limitation of the series of systematic reviews was the poor quality of included studies and lack of randomised controlled trials of CVC removal or antimicrobial locks for treatment of infection. CONCLUSIONS: There is strong evidence to support the use of antimicrobial locks for prevention of CVC-associated infection; however, few of these studies involved children with cancer. The analysis does not support routine bacterial DNA testing on admission to detect CVC-associated infection, but repeated testing (as a marker of microbial load) should be evaluated in high-risk groups. Further research should determine the effectiveness of antibiotic locks for treating CVC-associated infection. TRIAL REGISTRATION: Current Controlled Trials ISRCTN68138140. FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 15, No. 7. See the HTA programme website for further project information.

Empirical treatment of neonatal sepsis: are the current guidelines adequate?

OBJECTIVES: To use national laboratory surveillance data to determine whether pathogens responsible for neonatal bacteraemia were sensitive to nationally recommended antibiotic regimens. DESIGN: All reports of neonatal bacteraemia received by the Health Protection Agency's voluntary surveillance scheme in England and Wales from January 2006 until March 2008, were extracted from the database. Organisms were ranked by frequency, and proportions susceptible to antimicrobials recommended for empirical treatment of neonatal sepsis were determined. RESULTS: There were 1516 reports of bacteraemia for neonates <48 h old (early-onset) and 3482 reports for neonates 2-28 days old (late-onset). For early-onset bacteraemia, group B streptococcus (GBS) was the most frequent pathogen (31%) followed by coagulase-negative staphylococci (CoNS; 22%), non-pyogenic streptococci (9%) and Escherichia coli (9%). For late-onset bacteraemia, CoNS were isolated most frequently (45%), followed by Staphylococcus aureus (13%), Enterobacteriaceae (9%), E coli (7%) and GBS (7%). More than 94% of organisms (early-onset) were susceptible to regimens involving combinations of penicillin with either gentamicin or amoxicillin, amoxicillin combined with cefotaxime or cefotaxime monotherapy. More than 95% of organisms (late-onset) were susceptible to gentamicin with either flucloxacillin or amoxicillin and amoxicillin with cefotaxime, but only 79% were susceptible to cefotaxime monotherapy. CONCLUSIONS: Current guidelines for empirical therapy in neonates with sepsis are appropriate. However, gentamicin-based regimens should be used in preference to cefotaxime-based treatments, because of lower levels of susceptibility to cefotaxime and the need to avoid exerting selective pressure for resistance. Surveillance data linked to clinical data should further inform rational antibiotic prescribing in neonatal units.

Birmingham hip resurfacing: the prevalence of failure.

Despite the increasing interest and subsequent published literature on hip resurfacing arthroplasty, little is known about the prevalence of its complications and in particular the less common modes of failure. The aim of this study was to identify the prevalence of failure of hip resurfacing arthroplasty and to analyse the reasons for it. From a multi-surgeon series (141 surgeons) of 5000 Birmingham hip resurfacings we have analysed the modes, prevalence, gender differences and times to failure of any hip requiring revision. To date 182 hips have been revised (3.6%). The most common cause for revision was a fracture of the neck of the femur (54 hips, prevalence 1.1%), followed by loosening of the acetabular component (32 hips, 0.6%), collapse of the femoral head/avascular necrosis (30 hips, 0.6%), loosening of the femoral component (19 hips, 0.4%), infection (17 hips, 0.3%), pain with aseptic lymphocytic vascular and associated lesions (ALVAL)/metallosis (15 hips, 0.3%), loosening of both components (five hips, 0.1%), dislocation (five hips, 0.1%) and malposition of the acetabular component (three hips, 0.1%). In two cases the cause of failure was unknown. Comparing men with women, we found the prevalence of revision to be significantly higher in women (women = 5.7%; men = 2.6%, p < 0.001). When analysing the individual modes of failure women had significantly more revisions for loosening of the acetabular component, dislocation, infection and pain/ALVAL/metallosis (p < 0.001, p = 0.004, p = 0.008, p = 0.01 respectively). The mean time to failure was 2.9 years (0.003 to 11.0) for all causes, with revision for fracture of the neck of the femur occurring earlier than other causes (mean 1.5 years, 0.02 to 11.0). There was a significantly shorter time to failure in men (mean 2.1 years, 0.4 to 8.7) compared with women (mean 3.6 years, 0.003 to 11.0) (p < 0.001).

White on white meniscal tears to fix or not to fix?

The mechanical disadvantage to articular cartilage following meniscectomy has been well documented in the literature. Meniscal repair in the avascular (white on white) is controversial and would be deemed inappropriate by many. We have developed criteria for repair in all meniscal tears. These are: The meniscus 1. must not be degenerated 2. must be reducible, without a rolled edge 3. the fixation must be considered sound. Between 1999 and 2008 our department prospectively collected data on meniscal repairs as part of a sports database. Four hundred and twenty three patients underwent repair during this time period. We identified 87 patients with no co existent ACL injury or instability. There were 73 males and 14 females with a mean age of 26 years (13-54). All tears were in the non peripheral (white on white) area. The criterion for failure was reoperation on the same meniscus requiring excision or re fixation. The mean follow up was 49 months (10-112). Twenty eight patients required further surgery on their repaired meniscus. There were eight re-repairs and 20 partial menisectomies. This represents a success rate of 68% (59/87). The mean pre operative Lysholm score was 61 (4-88) which rose to 75 (12-100) postoperatively, p=0.002. The mean pre op Tegner score was 6 (3-10) and this did not change significantly post operatively, mean 6 (0-10) p=0.4. Isolated white on white avascular meniscal tears can be successfully repaired in the majority of cases with a good clinical and functional result.

EGFR-PLCgamma1 signaling mediates high glucose-induced PKCbeta1-Akt activation and collagen I upregulation in mesangial cells.

Glomerular matrix accumulation is a hallmark of diabetic nephropathy. We have recently shown that epidermal growth factor receptor (EGFR) transactivation mediates high glucose (HG)-induced collagen I upregulation through PI3K-PKCbeta1-Akt signaling in mesangial cells (MC). Phospholipase Cgamma1 (PLCgamma1) interacts with activated growth factor receptors and activates classic PKC isoforms. We thus studied its role in HG-induced collagen I upregulation in MC. Primary rat MC were treated with HG (30 mM) or mannitol as osmotic control. Protein kinase activation was assessed by Western blotting and collagen I upregulation by Northern blotting. Diabetes was induced in rats by streptozotocin. HG treatment for 1 h led to PLCgamma1 membrane translocation and Y783 phosphorylation, both indicative of its activation. Mannitol was without effect. PLCgamma1 Y783 phosphorylation was also seen in cortex and glomeruli of diabetic rats. HG induced a physical association between EGFR and PLCgamma1 as identified by coimmunoprecipitation. PLCgamma1 activation required EGFR kinase activity since it was prevented by the EGFR inhibitor AG1478 or overexpression of kinase-inactive EGFR (K721A). Phosphoinositide-3-OH kinase inhibition also prevented PLCgamma1 activation. HG-induced Akt S473 phosphorylation, effected by PKCbeta1, was inhibited by the PLCgamma inhibitor U73122. PLCgamma1 inhibition or downregulation by small interference RNA also prevented HG-induced collagen I upregulation. Our results indicate that EGFR-PLCgamma1 signaling mediates HG-induced PKCbeta1-Akt activation and subsequent collagen I upregulation in MC. Inhibition of EGFR or PLCgamma1 may provide attractive therapeutic targets for the treatment of diabetic nephropathy.

Treating ocular toxoplasmosis: current evidence.

The current treatment of ocular toxoplasmosis is controversial. The mainstay of treatment has been pyrimethamine and sulphonamides with or without systemic corticosteroids, but the actual evidence that antibiotics have a beneficial effect in recurrent toxoplasmic retinochoroiditis is unsupported by randomised placebo controlled trials. Thus far there have only been three studies looking at the efficacy of antibiotic treatment, all of which were methodologically weak and two of which were perfomed more than 30 years ago. All studies reported adverse effects from treatment. There is an urgent need for further randomised, double blind, placebo controlled studies for lesions in all parts of the retina and to test the efficacy of adjunctive corticosteroid treatment.

The St. Leger total knee replacement: a 10-year clinical and radiological assessment.

The St. Leger total knee replacement (Zynergy Orthopaedics Ltd, Rotherham, UK) was developed as a cheaper alternative to similar implants of its time. Between October 1993 and June 1999, 144 St. Leger total knee replacements were implanted into 114 patients. Seventy-three patients (99 knees) were recalled for assessment (mean follow-up of 10.2 years). Eighteen patients had had their prostheses revised, 11 had died and 12 were lost to follow-up. Functional Score showed 90% poor results and the Objective Knee Score showed 31% poor results. Radiological assessment identified 12 arthroplasties that had failed and 58 that required close follow. Kaplan-Meier cumulative survivorship was 87% at 10 years. The St. Leger knee replacement did not perform as well as others of the same generation and was not worth the initial financial savings.

Changes in clinical indications for community antibiotic prescribing for children in the UK from 1996 to 2006: will the new NICE prescribing guidance on upper respiratory tract infections just be ignored?

OBJECTIVE: To analyse changes in clinical indications for community antibiotic prescribing for children in the UK between 1996 and 2006 and relate these findings to the new NICE guidelines for the treatment of upper respiratory tract infections in children. STUDY DESIGN: Retrospective cohort study. METHOD: The IMS Health Mediplus database was used to obtain annual antibiotic prescribing rates and associated clinical indications in 0-18-year-old patients between 1 January 1996 and 31 December 2006 in the UK. RESULTS: Antibiotic prescribing declined by 24% between 1996 and 2000 but increased again by 10% during 2003-2006. Respiratory tract infection was the most common indication for which an antibiotic was prescribed, followed by "abnormal signs and symptoms", ear and skin infections. Antibiotic prescriptions for respiratory tract infections have decreased by 31% (p<0.01) mainly because of reduced prescribing for lower respiratory tract infections (56% decline, p<0.001) and specific upper respiratory tract infections including tonsillitis/pharyngitis (48% decline, p<0.001) and otitis (46% decline, p<0.001). Prescribing for non-specific upper respiratory tract infection increased fourfold (p<0.001). Prescribing for "abnormal signs and symptoms" increased significantly since 2001 (40% increase, p<0.001). CONCLUSION: There has been a marked decrease in community antibiotic prescribing linked to lower respiratory tract infection, tonsillitis, pharyngitis and otitis. Overall prescribing is now increasing again but is associated with non-specific upper respiratory tract infection diagnoses. General practitioners may be avoiding using diagnoses where formal guidance suggests antibiotic prescribing is not indicated. The new NICE guidance on upper respiratory tract infections is at risk of being ignored.

Performance of screening tests for child physical abuse in accident and emergency departments.

OBJECTIVES: To determine the clinical effectiveness of screening tests for physical abuse in children attending accident and emergency (A&E) departments in the UK. DATA SOURCES: Searches were limited to studies published after 1974 and were carried out from August 2004 to October 2006 using the following methods: searching electronic databases, searching the publications catalogue of the NSPCC, scanning reference lists, hand-searching journals, searching the internet, approaching professional contacts for unpublished data, and searching in three key journals. REVIEW METHODS: A simple decision-analytic model was used to integrate the findings of nine systematic reviews regarding the incidence of physical abuse, the characteristics of children attending A&E, and the performance of screening tests for physical abuse. RESULTS: A total of 66 studies, including 11 unpublished studies, were included in the nine systematic reviews. Overall the quality was poor. There was consistent evidence that physical abuse affects about 1 in 11 children in the UK each year. The proportion of abused children requiring medical attention is small but poorly quantified. Approximately 1% of all attendances of injured children at A&E are for physical abuse. There was clear evidence that physically abused children attending A&E are missed, but the performance of the clinical screening assessment was poorly quantified. There was no evidence that any test was highly predictive of physical abuse. Among severely injured children admitted to hospital, those under 1 year were more likely to be abused than older children. However, evidence that young age was a risk factor for abuse among all injured children attending A&E was inconsistent. There was weak evidence that a community liaison nurse improved the performance of the screening assessment in A&E, and it was estimated that combining a nurse with the standard screen would result in referral to social services of about half of the abused children attending A&E. However, given the poor quality of the data, this is highly uncertain. The addition of screening protocols to the clinical screening assessment offered marginal benefits, and additional false-positive referrals exceeded additional abused children detected. The benefits of protocols declined as the accuracy of the clinical screening assessment improved. The most effective protocol was to refer all injured infants and children who were social work active. CONCLUSIONS: Improving clinical screening assessment is likely to be more useful than protocols in improving the detection of physically abused children attending A&E. Further improvements might be achieved by following up children referred to paediatricians for suspected abuse who fail to reach the high level of certainty required to justify referral to social services. Many professionals voiced a need for access to experienced social services advice that is not under pressure to minimise referrals to an overloaded service, and consideration might be given to making such advice centrally available.

Has UK guidance affected general practitioner antibiotic prescribing for otitis media in children?

BACKGROUND: Since 1997, UK guidance has advocated limiting antibiotic prescribing for otitis media. It is not known whether this has influenced general practitioner prescribing practice. Aims and objectives To investigate the trends in diagnoses and antibiotic prescribing for otitis media in children in relation to guidance. METHODS: We used the General Practice Research Database to conduct time-trend analyses of diagnoses and antibiotic prescribing for otitis media in 3 months to 15 years old, between 1990 and 2006. RESULTS: A total of 1 210 237 otitis media episodes were identified in 464 845 children; two-thirds (68%; 818 006) received antibiotics. Twenty-two percent (267 335) were classified as acute, 85% (227 335) of which received antibiotics. Overall, antibiotic prescribing for otitis media declined by 51% between 1995 and 2000. Much of this reduction predated guidance. During this period, prescribing for otitis media coded as acute increased by 22%. Children diagnosed with acute otitis media were more likely to receive antibiotics than otitis media not coded as acute (P < 0.05). From 2000 prescribing plateaued, despite publication of further guidance. Otitis media diagnoses consistently paralleled prescribing. CONCLUSIONS: The reduction in antibiotic prescribing for otitis media predated guidance. The simultaneous decrease in prescribing for non-acute otitis media and increase for acute otitis media suggest diagnostic transfer, possibly to justify the decision to treat.

Increased renal gene transcription of protein kinase C-beta in human diabetic nephropathy: relationship to long-term glycaemic control.

AIMS/HYPOTHESIS: Activation of protein kinase C (PKC) isoforms has been implicated as a central mediator in the pathogenesis of diabetic nephropathy. Although high glucose levels stimulate catalytic activity of PKC, the effects of high glucose levels on the expression of genes encoding PKC isoforms are unknown. We sought to determine whether in addition to activation, diabetes may lead to increased transcription of two PKC isoforms that have been implicated in the pathogenesis of diabetic nephropathy, PKC-alpha and PKC-beta. METHODS: Recent advances in molecular biological techniques now permit quantitative analysis of mRNA from archival, formalin-fixed, paraffin-embedded tissue sections. RNA was extracted from scraped 6 microm sections of biopsy tissue, and PRKC-alpha and PRKC-beta (also known as PRKCA and PRKCB) mRNA measured using real-time PCR. Expression of genes encoding PKC isoforms was examined in renal biopsies (n=25) with classical histological features of diabetic nephropathy and compared with that in normal control tissue (n=6). Peptide localisation of PKC-alpha, PKC-beta and the activated forms phosphorylated PKC-alpha and -beta was also performed on matched paraffin-embedded sections of renal biopsies using immunohistochemistry. The effects of high glucose on PRKC-beta expression and peptide production in cultured human proximal tubular epithelial cells were assessed. RESULTS: Quantitative real-time PCR demonstrated a 9.9-fold increase in PRKC-beta mRNA in kidney biopsies of diabetic patients relative to control (p<0.001). No increase in PRKC-alpha expression was seen. In addition, a correlation between renal PRKC-beta mRNA and HbA(1c) was observed in diabetic patients (r=0.63, p<0.05). There was co-localisation of PKC-beta and phospho-PKC-beta predominantly to proximal tubules. A 60% increase in PRKC-beta mRNA and peptide in cultured human proximal tubular epithelial cells exposed to high glucose (p<0.05) was seen in vitro. CONCLUSIONS/INTERPRETATION: PKC-beta is upregulated at the gene expression level in human diabetic nephropathy. PRKC-beta mRNA correlates closely with serum HbA(1c), possibly partially explaining the relationship between glycaemic control and progression of diabetic nephropathy. Archival human tissue provides a valuable resource for molecular analyses.

Aliskiren, a novel renin inhibitor, is renoprotective in a model of advanced diabetic nephropathy in rats.

AIMS/HYPOTHESIS: Blockade of the renin-angiotensin system (RAS) with either ACE inhibitors or angiotensin receptor blocker is a key therapeutic strategy in slowing progression of diabetic nephropathy. Interruption of the RAS may also be achieved by blocking the activity of renin, the rate-limiting step in angiotensin II biosynthesis. However, it is not known whether drugs in this class also reduce the structural and functional manifestations of diabetic nephropathy. METHODS: Using diabetic transgenic (mRen-2)27 rats, a rodent model of advanced diabetic nephropathy, we compared the efficacy of the renin inhibitor, aliskiren (10 mg kg(-1) day(-1) by osmotic mini-pump), with the ACE inhibitor, perindopril (0.2 mg kg(-1) day(-1) in drinking water), over a 16 week period. RESULTS: Both perindopril and aliskiren reduced blood pressure, albuminuria and structural injury in experimental diabetic nephropathy, although not to the same extent. Aliskiren, at the dose used, did not reduce systemic blood pressure as much as perindopril, but both compounds were equally effective in reducing albuminuria and glomerulosclerosis in diabetic animals. The magnitude of interstitial fibrosis was attenuated to a greater degree by aliskiren than by perindopril. CONCLUSIONS/INTERPRETATION: These findings suggest that therapies aimed at different targets within the RAS may not have identical effects in attenuating structural injury in experimental diabetic nephropathy.

Functional, structural and molecular aspects of diastolic heart failure in the diabetic (mRen-2)27 rat.

OBJECTIVE: Diabetic cardiomyopathy is an increasingly recognized cause of cardiac failure despite preserved left ventricular systolic function. Given the over-expression of angiotensin II in human diabetic cardiomyopathy, we hypothesized that combining hyperglycaemia with an enhanced tissue renin-angiotensin system would lead to the development of diastolic dysfunction with adverse remodeling in a rodent model. METHODS: Homozygous (mRen-2)27 rats and non-transgenic Sprague Dawley (SD) rats were randomized to receive streptozotocin (diabetic) or vehicle (non-diabetic) and followed for 6 weeks. Prior to tissue collection, animals underwent pressure-volume loop acquisition. RESULTS: Diabetic Ren-2 rats developed impairment of both active and passive phases of diastole, accompanied by reductions in SERCA-2a ATPase and phospholamban along with activation of the fetal gene program. Structural features of diabetic cardiomyopathy in the Ren-2 rat included interstitial fibrosis, cardiac myocyte hypertrophy and apoptosis in conjunction with increased activity of transforming growth factor-beta (p<0.01 compared with non-diabetic Ren-2 rats for all parameters). No significant functional or structural derangements were observed in non-transgenic, SD diabetic rats. CONCLUSION: These findings indicate that the combination of enhanced tissue renin-angiotensin system and hyperglycaemia lead to the development of diabetic cardiomyopathy. Fibrosis, and myocyte hypertrophy, a prominent feature of this model, may be a consequence of activation of the pro-sclerotic cytokine, transforming growth factor-beta, by the diabetic state.

Prenatal screening and treatment strategies to prevent group B streptococcal and other bacterial infections in early infancy: cost-effectiveness and expected value of information analyses.

OBJECTIVES: To determine the cost-effectiveness of prenatal strategies for preventing group B streptococci (GBS) and other serious bacterial infections in early infancy and to establish the expected value of further information. DATA SOURCES: Electronic databases were searched up to March 2006. Expert opinion was also sought. REVIEW METHODS: Twelve mutually exclusive maternal risk groups were defined at presentation in labour and the consequences considered of early-onset GBS and non-GBS bacterial infections and late onset GBS infection, measured in terms of lifetime NHS costs and quality-adjusted life-years (QALYs). These were for preterm delivery (<37 weeks): (1) planned Caesarean section, (2) previous baby with GBS disease, (3) positive urine or vaginal swab for GBS in current pregnancy, (4) fever >or=38 degrees C during labour, (5) membrane rupture >or=2 hours before labour onset, (6) membrane rupture <2 hours before labour onset. For term delivery (>or=37 weeks): (7) planned Caesarean section, (8) previous baby with GBS disease, (9) positive urine or vaginal swab for GBS in current pregnancy, (10) fever >or=38 degrees C during labour, (11) membrane rupture >or=18 hours, and (12) none of the above risk factors. Fourteen intervention strategies were applied to each maternal risk group. Data inputs were obtained from systematic reviews, primary data and expert opinion. The model parameters were simultaneously estimated from the data inputs using Bayesian evidence synthesis. The expected net benefit was calculated relative to no intervention for each intervention within each risk group for two scenarios, with and without vaccination. Interventions with more than a 1% probability of being cost-effective (i.e. maximising net benefit at a threshold of 25,000 pounds per QALY gained) in a specific risk group were combined to form strategies. To limit antibiotic exposure, women who were low risk at presentation could not be treated without a positive culture or polymerase chain reaction result. RESULTS: Current best practice, comprising intravenous treatment for pyrexia, previous GBS baby and previous GBS swab or urine culture, and oral treatment for preterm pre-labour membrane rupture (groups 2-5 and 8-10) was not cost-effective. All cost-effective options involved treatment of all preterm groups and high-risk term groups (groups 8-10). Testing high-risk women for maternal GBS colonisation would not be cost-effective, as even those with negative results would be better off treated to reduce the risk of early-onset non-GBS infection. In the absence of vaccination, culture-based testing of women in groups 11 and 12, combined with treatment for the rest, would be the most cost-effective strategy. If vaccination was available, vaccination for all and treatment for groups 1-10 would be marginally more cost-effective than treatment for groups 1-10 and culture for groups 11 and 12, but this is uncertain and is based on expert opinion on vaccine efficacy. The expected value of perfect information results suggest that moderate investment in research would be worthwhile. CONCLUSIONS: Based on our findings, immediate extension of current practice to treat all preterm and high-risk term groups would be beneficial. Further research aimed at the realisation of a GBS vaccine should be prioritized.

Advanced glycation end products decrease mesangial cell MMP-7: a role in matrix accumulation in diabetic nephropathy?

Increased extracellular matrix material is a pathological hallmark of diabetic nephropathy. In addition to collagens, a variety of non-collagenous glycoproteins such as fibronectin also accumulate in the kidney of diabetics. The effect of diabetes on degradative pathways, in particular those involving non-collagenous proteins, are relatively unexplored. In this study, we determined the expression of the major matrix metalloproteinase (MMP) responsible for degrading the non-collagenous matrix glycoprotein fibronectin. Furthermore, the modulation of these MMPs by advanced glycation end products (AGE), a key factor in the diabetic milieu, was explored. Exposure of mesangial cells to AGEs led to a significant reduction in MMP-7, but not MMP-3 or -10. MMP-7 expression was normalized by both aminoguanidine, an inhibitor of glycation product formation, or by a neutralizing anti-transforming growth factor-beta (TGF-beta) antibody. In streptozotocin-induced diabetic rats, the diminution in MMP-7 expression and excessive fibronectin accumulation were attenuated by aminoguanidine. Humans with type 2 diabetes and nephropathy displayed similar alterations in MMP-7 to their rodent counterparts. Our findings suggest that diminished expression of the glycoprotein-degrading enzyme, MMP-7, may play a role in fibronectin accumulation in the diabetic kidney in response to AGEs and/or TGF-beta.