Association Analysis of Dyslipidemia-Related Genes in Diabetic Nephropathy

Type 1 diabetes (T1D) increases risk of the development of microvascular complications and cardiovascular disease (CVD). Dyslipidemia is a common risk factor in the pathogenesis of both CVD and diabetic nephropathy (DN), with CVD identified as the primary cause of death in patients with DN. In light of this commonality, we assessed single nucleotide polymorphisms (SNPs) in thirty-seven key genetic loci previously associated with dyslipidemia in a T1D cohort using a casecontrol design. SNPs (n = 53) were genotyped using Sequenom in 1467 individuals with T1D (718 cases with proteinuric nephropathy and 749 controls without nephropathy i.e. normal albumin excretion). Cases and controls were white and recruited from the UK and Ireland. Association analyses were performed using PLINK to compare allele frequencies in cases and controls. In a sensitivity analysis, samples from control individuals with reduced renal function (estimated glomerular filtration rate,60 ml/min/1.73 m2) were excluded. Correction for multiple testing was performed by permutation testing. A total of 1394 samples passed quality control filters. Following regression analysis adjusted by collection center, gender, duration of diabetes, and average HbA1c, two SNPs were significantly associated with DN. rs4420638 in the APOC1 region (odds ratio [OR] = 1.51; confidence intervals [CI]: 1.19–1.91; P = 0.001) and rs1532624 in CETP (OR = 0.82; CI: 0.69–0.99; P = 0.034); rs4420638 was also significantly associated in a sensitivity analysis (P = 0.016) together with rs7679 (P = 0.027). However, no association was significant following correction for multiple testing. Subgroup analysis of end-stage renal disease status failed to reveal any association. Our results suggest common variants associated with dyslipidemia are not strongly associated with DN in T1D among white individuals. Our findings, cannot entirely exclude these key genes which are central to the process of dyslipidemia, from involvement in DN pathogenesis as our study had limited power to detect variants of small effect size. Analysis in larger independent cohorts is required.

Activation of the ACE2/Angiotensin-(1-7)/Mas Receptor Axis Enhances the Reparative Function of Dysfunctional Diabetic Endothelial Progenitors

We tested the hypothesis that activation of the protective arm of the renin angiotensin system, the angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7) [Ang-(1-7)]/Mas receptor axis, corrects the vasoreparative dysfunction typically seen in the CD34(+) cells isolated from diabetic individuals. Peripheral blood CD34(+) cells from patients with diabetes were compared with those of nondiabetic controls. Ang-(1-7) restored impaired migration and nitric oxide bioavailability/cGMP in response to stromal cell-derived factor and resulted in a decrease in NADPH oxidase activity. The survival and proliferation of CD34(+) cells from diabetic individuals were enhanced by Ang-(1-7) in a Mas/phosphatidylinositol 3-kinase (PI3K)/Akt-dependent manner. ACE2 expression was lower, and ACE2 activators xanthenone and diminazine aceturate were less effective in inducing the migration in cells from patients with diabetes compared with controls. Ang-(1-7) overexpression by lentiviral gene modification restored both the in vitro vasoreparative functions of diabetic cells and the in vivo homing efficiency to areas of ischemia. A cohort of patients who remained free of microvascular complications despite having a history of longstanding inadequate glycemic control had higher expression of ACE2/Mas mRNA than patients with diabetes with microvascular complications matched for age, sex, and glycemic control. Thus, ACE2/Ang-(1-7)\Mas pathway activation corrects existing diabetes-induced CD34(+) cell dysfunction and also confers protection from development of this dysfunction.

Protocolized versus non-protocolized weaning for reducing the duration of mechanical ventilation in critically ill adult patients (Review)

BACKGROUND: Reducing weaning time is desirable in minimizing potential complications from mechanical ventilation. Standardized weaning protocols are purported to reduce time spent on mechanical ventilation. However, evidence supporting their use in clinical practice is inconsistent.

OBJECTIVES: To assess the effects of protocolized weaning from mechanical ventilation on the total duration of mechanical ventilation for critically ill adults; ascertain differences between protocolized and non-protocolized weaning in terms of mortality, adverse events, quality of life, weaning duration, intensive care unit (ICU) and hospital length of stay (LOS); and explore variation in outcomes by type of ICU, type of protocol and approach to delivering the protocol.

SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 1, 2010), MEDLINE (1950 to 2010), EMBASE (1988 to 2010), CINAHL (1937 to 2010), LILACS (1982 to 2010), ISI Web of Science and ISI Conference Proceedings (1970 to 2010), Cambridge Scientific Abstracts (inception to 2010) and reference lists of articles. We did not apply language restrictions.

SELECTION CRITERIA: We included randomized and quasi-randomized controlled trials of protocolized weaning versus non-protocolized weaning from mechanical ventilation in critically ill adults.

DATA COLLECTION AND ANALYSIS: Three authors independently assessed trial quality and extracted data. A priori subgroup and sensitivity analyses were performed. We contacted study authors for additional information.

MAIN RESULTS: Eleven trials that included 1971 patients met the inclusion criteria. The total duration of mechanical ventilation geometric mean in the protocolized weaning group was on average reduced by 25% compared with the usual care group (N = 10 trials, 95% CI 9% to 39%, P = 0.006); weaning duration was reduced by 78% (N = 6 trials, 95% CI 31% to 93%, P = 0.009); and ICU LOS by 10% (N = 8 trials, 95% CI 2% to 19%, P = 0.02). There was significant heterogeneity among studies for total duration of mechanical ventilation (I(2) = 76%, P <0.01) and weaning duration (I(2) = 97%, P <0.01), which could not be explained by subgroup analyses based on type of unit or type of approach.

AUTHORS' CONCLUSIONS: There is some evidence of a reduction in the duration of mechanical ventilation, weaning duration and ICU LOS with use of standardized protocols, but there is significant heterogeneity among studies and an insufficient number of studies to investigate the source of this heterogeneity. Although some study authors suggest that organizational context may influence outcomes, these factors were not considered in all included studies and therefore could not be evaluated.

Diagnosing diabetes mellitus - Do we need new criteria?

The current classification and diagnostic criteria for diabetes mellitus were introduced by the United States National Data Group in 1979 and endorsed by the World Health Organization in 1980, with modifications in 1985 and 1994. The criteria, chosen to reflect the risk of complications, were the synthesis of considerable thought and expertise and represented a consensus which, it was hoped, would prove helpful to all those involved with diabetes practising clinician, research scientist and epidemiologist alike. The inconvenience, variability and nonphysiological nature of the oral glucose tolerance test (OGTT) are well-recognised. In spite of these limitations the 2-h post-load plasma glucose has remained the standard against which all other tests have been evaluated. This article reviews the original justification for the OGTT, and in the light of more recent epidemiological research seeks to place the current diagnostic criteria for diabetes into a pathophysiological, diagnostic and prognostic perspective.

Simultaneous use of mitomycin-C with Baerveldt implantation

BACKGROUND AND OBJECTIVE: To evaluate the outcome of Baerveldt implantation with adjunctive mitomycin-C in cases of complicated glaucoma. PATIENTS AND METHODS: The authors reviewed the charts of all patients who had undergone Baerveldt implantation with mitomycin-C between January 1993 and March 1995. Success was defined before data collection as an intraocular pressure (IOP) between 5 and 21 mm Hg, with or without medications. The success rate was calculated using the Kaplan-Meier actuarial method. RESULTS: Twenty-nine patients were identified. The mean preoperative IOP was 33.6 mm Hg, with an average of 2.0 antiglaucoma medications. The probability of success at 6 and 12 months for patients who received mitomycin-C during Baerveldt implantation was 82.4% and 73.3%, respectively. Choroidal effusion with a flat anterior chamber (10.3%), corneal edema (6.8%), and conjunctival erosion (6.8%) were the most frequent complications. CONCLUSION: In this retrospective series of complicated glaucoma, the implantation of a Baerveldt drainage device with adjunctive mitomycin-C had a satisfactory outcome. The complications encountered and the clinical efficacy were comparable to those of previously reported series in which mitomycin-C was not used.

Autologous limbal transplantation in patients with unilateral corneal stem cell deficiency

Aim - To describe a surgical technique for autologous limbal stem cell transplantation and the outcome of a series of patients with unilateral stem cell deficiency. Methods - A report of six consecutive patients who underwent autologous limbal stem cell transplantation is presented. The primary diagnosis included alkali burn (n = 3), conjunctival intraepithelial neoplasia (CIN) (n = 1), recurrent pterygium (n = 1), and contact lens induced keratopathy (n = 1). The autologous transplanted tissue consisted of peripheral cornea, limbus, and conjunctiva obtained from the contralateral eye. Three of the above patients underwent penetrating keratoplasty in association with autolimbal transplantation. A significant modification to established techniques was the close monitoring of conjunctival epithelial migration in the immediate postoperative period. If conjunctival epithelium threatened to migrate on to the corneal surface, it was mechanically removed at the slit lamp and prevented from crossing the limbus. This was required in three patients. Results - The mean follow up was 18.8 months. The outcome was satisfactory in all cases: a stable corneal surface was restored and there was a substantial improvement in vision and symptoms. One patient had a primary failure of the corneal allograft associated with glaucoma, and 6 months later developed a retinal detachment. No complications were noted in the donor eye with the exception of one patient who developed filamentary keratitis along the edge of the donor site. Conclusion - Autologous limbal transplantation with corneal, limbal, and conjunctival carriers was found to be useful for ocular surface reconstruction, over a mid-term follow up, in patients with unilateral stem cell deficiency. Close monitoring of the migration of conjunctival epithelium in the immediate postoperative period, and preventing it from crossing the limbus, ensured that the corneal surface was re-epithelialised exclusively from epithelial cells derived from the transplanted limbal tissue. This approach should improve the success of this procedure.

Recurrent vitreous occlusion of glaucoma drainage device tube in a patient with glaucoma in aphakia:A case report

Patients with spontaneous lens dislocation and glaucoma can be challenging to manage. We present a forty-six year old Caucasian lady who was referred with bilateral high intraocular pressure, and was subsequently diagnosed with glaucoma in association with lens dislocation and Marfan syndrome. Baerveldt glaucoma drainage device tubes were inserted in both eyes due to poor response to medical therapy. However, this was complicated by recurrent vitreous occlusion of both glaucoma drainage tubes requiring further multiple surgical interventions. There have not been any further recurrences of vitreous incarceration or posterior segment complications since, but the patient remains under close follow-up. © 2010 Ang et al; licensee BioMed Central Ltd.

Filtration procedures supplemented with mitomycin C in the management of childhood glaucoma

Aims - To evaluate the outcome of filtering procedures supplemented with mitomycin C in children with glaucoma. Methods - All patients aged 17 or younger with glaucoma who underwent filtering surgery supplemented with mitomycin C at a tertiary care centre (n = 21) during a 5 year interval (1992 and 1996) were included. One eye for each patient was entered into the analysis. The postoperative intraocular pressure (IOP), use of antiglaucoma medications, clinical stability of glaucoma, complications, and visual acuity were retrospectively evaluated. Kaplan-Meier survival curves were used to estimate the probability of success. Results - At the time of surgery mean age was 5.7 (SD 5.0) years. The most common diagnoses were trabeculodysgenesis (n = 6) and aphakic glaucoma (n = 8). Mean IOP before surgery was 35.7 (10.5) mmHg. Average length of follow up was 18.6 (14.7) months. The probability of having IOP less than 21 mmHg with no antiglaucoma medications and with clinically stable glaucoma 1 year after surgery was 76.9% in phakic eyes (n = 13) and 0% in aphakic eyes (n = 8). A phakic patient with Sturge-Weber's syndrome had choroidal effusion after surgery that resolved spontaneously. In the aphakic group one patient had retinal detachment and another developed an encapsulated bleb. Visual acuity deteriorated in one patient. Conclusion - A guarded filtration procedure with mitomycin C is relatively successful in phakic children with glaucoma, but unsuccessful in aphakic ones.

Oral prednisone in guarded filtration procedures supplemented with antimetabolites

BACKGROUND AND OBJECTIVE: To evaluate whether a three-day course of oral prednisone perioperatively improves the surgical outcome of guarded filtering procedures supplemented with antifibrosis agents. DESIGN, MATERIALS AND METHODS: A prospective, randomized, double-masked, placebo-controlled, clinical trial was designed. Adult patients with non-inflammatory glaucoma undergoing a guarded filtration procedure supplemented with antimetabolite were enrolled. Patients received a three-day course of prednisone (50 mg BID) or placebo perioperatively. The main outcome measures were intraocular pressure (IOP) and number of antiglaucoma medications. Surgical success was defined before data collection according to two different criteria: 'success- I': IOP level = 15 mmHg with no more than one anti-glaucoma medication, and 'success-II': IOP reduction of at least 20% of baseline level with no more than one antiglaucoma medication. RESULTS: Thirty-five subjects were enrolled. Seventeen patients were treated with prednisone and eighteen with placebo. Mean follow-up was 9.2 months ± 6.2 months. The probability of success-I at 9 months was 63.0% in the study group and 65.6% in the control groups (p>0.05). The probability of success-II at 9 months was 60.2% in the study group and 55.0% in the control groups, (p>0.05). The difference in frequency of postoperative complications between groups was not statistically significant. The most common complication was choroidal detachment (n=2) in the prednisone-treated group and bleb leak (n=2) in the control group. CONCLUSION: The perioperative use of oral prednisone did not alter the surgical outcome of filtering procedures associated with antifibrosis agents in this population of glaucoma patients.

Infectious keratitis in a paracentesis tract

A paracentesis is performed in glaucoma procedures as a flat, beveled tract to allow access into the anterior chamber after the filtration fistula is made. Complications related to the paracentesis are infrequent because it is a self-sealing wound. The authors report a case of infectious keratitis that developed in a paracentesis tract.

Severe visual loss after autologous blood injection for mitomycin-C- associated hypotonous maculopathy

It has been shown that mitomycin-C increases the success rate of trabeculectomy; however, a rise in the incidence of postoperative complications has also been reported. Consequently, the use of antimetabolite is usually reserved for patients who are at high risk of surgical failure or for patients with advanced glaucoma in whom low intraocular pressure is desired. This report describes a patient who suffered severe visual loss which was a direct result of hypotonous maculopathy after trabeculectomy with mitomycin-C and various other complications from the subsequent interventions.

Autologous scleral patch graft in tube shunt surgery

Purpose . To investigate alternative surgical method to cover subconjunctival portion of the tube in tube shunt surgery in glaucoma Methods. In thirteen eyes of twelve patients who underwent tube shunt surgery at WEH between July 1991 to November 1996 a "rotating" autologous scleral lamellar graft was created to cover the subconjuctival course of the tube. These patients were followed for clinical signs of conjuctival breakdown, graft melt, tube erosion, anterior staphylomas, graft related inflammation, infections or graft related complications. Results. The patients were followed up for a mean of 16 5 months( range 1-60 months). All eyes tolerated the autologous graft well without any clinical evidence of tube erosions, graft melting , graft related or intraocular inflammation Conclusions The use of autologous sciera, to cover the tube in a tube shunt procedure appears to be effective and without inappropriate short term risk. It offers the advantages of availability , lower cost, and eliminates the potential risk of transmission of infectious disease( i.e. slow-virus, HIV etc.).

Dysfunctional filtering blebs

Guarded filtration surgery is commonly used to control the intraocular pressure (IOP) in glaucomatous patients. Filtration surgery lowers the IOP by creating a fistula between the inner compartments of the eye and the subconjunctival space (i.e., filtering bleb). There are several options to improve the function of filtering blebs and to prevent their failure. However, improvement of IOP control after guarded filtration procedures is associated with a higher frequency of bleb-related complications. Early (e.g., bleb leak, excessive filtration, flat anterior chamber, filtration failure) and late (e.g., bleb leak, excessive filtration and hypotony, symptomatic blebs, bleb encapsulation, filtration failure, bleb infection) complications associated with filtering procedures should be managed adequately to prevent further problems. Techniques to improve the function of filtering blebs and to treat postoperative complications have progressed over the past decade.

Attitudes of consultant ophthalmologists in the UK to initial management of glaucoma patients presenting with severe visual field loss: a national survey

BACKGROUND: Recent National Institute of Clinical Excellence guidance suggests primary surgery should be offered to patients presenting with glaucoma with severe visual field loss. We undertook a survey of UK consultant ophthalmologists to determine if this represents current practice and explore attitudes towards managing patients with advanced glaucoma at presentation.

DESIGN: Questionnaire evaluation study.

PARTICIPANTS: All consultant ophthalmologists currently practicing in the UK.

METHODS: A single-page questionnaire was posted to all consultants (n = 910) currently practicing in the UK along with a pre-paid return envelope. A second questionnaire was sent to non-responders (n = 459).

MAIN OUTCOME MEASURES: Questionnaire responses.

RESULTS: 626 responses were received representing 68.8% of the population surveyed. 152 (24%) volunteered a specialist interest in glaucoma. Consensus opinion for both glaucoma specialists (64.9%) and non-glaucoma specialists (62.4%) was to start with primary medical therapy, most commonly citing surgical risk as the primary reason (23% and 22%, respectively) for this approach. Most felt the highest intraocular pressure measurement during follow up (measured in clinic) was the most important variable for prevention of further visual loss (60% of glaucoma specialists and 55% of non-glaucoma specialists). Eighty-three per cent of all responders suggested they would change their practice if evidence supporting primary surgery as a safe and more effective approach existed.

CONCLUSIONS: Recent National Institute of Clinical Excellence guidance does not reflect the current management approach of UK ophthalmologists. The primary concern was related to potential complications of surgery although most practitioners would be willing to change their practice if evidence existed supporting primary surgery in patients presenting with advanced glaucoma.

Subconjunctival versus peribulbar anesthesia in trabeculectomy:A prospective, randomized study

BACKGROUND AND OBJECTIVE: To compare the use of subconjunctival and peribulbar anesthesia for trabeculectomy. PATIENTS AND METHODS: Sixty patients undergoing trabeculectomy were prospectively randomized to receive either peribulbar or subconjunctival anesthesia. Peribulbar anesthesia consisted of a 3-ml inferior and a 1-ml superior injection of a 1:1 mixture of 2% mepivacaine, 0.75% bupivacaine, and hyaluronidase. Subconjunctival anesthesia consisted of a 1- to 2-ml injection of the same mixture without hyaluronidase in the superotemporal quadrant. Intraoperative pain, presence of eye movements, and complications during surgery were evaluated. RESULTS: The frequency and intensity of pain was statistically similar between the two groups. All episodes of pain (20% in the subconjunctival group and 6.6% in the peribulbar group) were rated as mild. Eye movement was more common in the subconjunctival group than in the peribulbar group, but it was controlled by verbal command and did not interfere with the procedure. No clinically significant complications occurred during surgery. CONCLUSION: Subconjunctival anesthesia is an effective alternative to peribulbar anesthesia for trabeculectomy.