New insulins and newer insulin regimens: a review of their role in improving glycaemic control in patients with diabetes.

The legacy effect of early good glycaemic control in people with diabetes shows it is associated with reduction of microvascular and macrovascular complications. Insulin therapy is essential and lifesaving in individuals with type 1 diabetes and beneficial for those with type 2 diabetes who fail to achieve optimal glycaemic targets with other classes of glucose-lowering therapies. Since the introduction of insulin analogues, insulin management has changed. This follow-up review attempts to update our earlier publication from 2009 and discusses the role of new insulin analogues and newer insulin regimens. Recognising the advent of new quality and economic initiatives both in the UK and worldwide, this paper reviews current insulin prescribing and the pros and cons of prescribing analogues in comparison to the human insulins that are now gaining more acceptance in everyday clinical practice.

Phospholipid-binding proteins differ in their capacity to induce autoantibodies and murine systemic lupus erythematosus.

We have previously shown that immunization of nonautoimmune mice with the phospholipid-binding protein ß2-glycoprotein I (ß2GPI), in combination with lipopolysaccharide (LPS), induces a murine model of systemic lupus erythematosus (SLE), with sequential emergence of autoantibodies and glomerulonephritis. Here, we determine whether the paradigm for induction of murine SLE extends to other phospholipid-binding proteins. Mice were immunized with a phospholipid-binding protein (prothrombin (PT), protein S, or ß2GPI), or a nonphospholipid-binding protein (glu-plasminogen), in the presence of LPS. The breadth and degree of the autoantibody response, and the frequency of glomerulonephritis, varied among the three proteins, with ß2GPI being the most effective in inducing SLE-like disease. The phospholipid-binding proteins also differed in the pattern of serum cytokines they elicited. The most apparent difference between ß2GPI and the other phospholipid-binding proteins was in their ability to bind to LPS: ß2GPI bound to LPS, while PT and protein S did not. Our data suggest that binding to phospholipid(s) is a necessary, but not sufficient, condition for full induction of murine SLE. We propose that other properties, such as physiologic function, avidity for anionic phospholipids, and degree of interaction with other cell surface and/or circulating molecules (particularly LPS) may determine the range and severity of disease.

Expression of transglutaminase-2 isoforms in normal human tissues and cancer cell lines: dysregulation of alternative splicing in cancer.

The multiple enzymatic activities and functions of transglutaminase type 2 (TG2) may be attributed to alternative TG2 molecules produced by differential splicing of TG2 mRNA. Different RNA transcripts of the human TG2 gene (TGM2) have been identified, but the expression of TG2 multiple transcripts has never been systematically addressed. We have confirmed and rationalized the main TG2 variants and developed a screening assay for the detection of alternative splicing of TG2, based on real-time reverse-transcription PCR. We have quantified the multiple TG2 transcripts in a wide range of normal tissues and in cancer cell lines from four different sites of origin. Our data show a significant correlation in the expression of canonical and alternative TG2 isoforms in normal human tissue, but differences in alternative splicing of TG2 in cancer cell lines, suggesting that in cancer cells the alternative splicing of TG2 is a more active process.

The role of recombinant factor VIIa for obstetric block in women with severe factor XI deficiency.

Regional blocks like spinal, epidural and combined spinal epidural (CSE) are relatively contraindicated in individuals with bleeding disorders. Consequently pregnant women with severe factor XI (FXI) deficiency are often denied this option during labour and caesarean section. We describe three women with severe FXI deficiency in whom regional block was performed with low-dose recombinant factor VIIa (rFVIIa) for their operative procedures during delivery. All women achieved haemostasis and had uncomplicated regional block, delivery and surgical procedures. The point of care device--rotational thromboelastometry (ROTEM) was used to monitor the patients' coagulation and determine the dose of rFVIIa to achieve in vitro haemostasis in these women that was then subsequently used in vivo. Low-dose rFVIIa seems to be effective and safe in the management of delivery and enables provision of regional blocks in women with severe FXI deficiency.

Antioxidant and hepatoprotective activity of tubers of Momordica tuberosa Cogn. against CCl4 induced liver injury in rats.

Hydro alcoholic extract of tubers of M. tuberosa was subjected to preliminary phytochemical screening and evaluated for in vitro and in vivo antioxidant and hepatoprotective activity against CCl4 induced liver damage in rats. Pretreatment with 70% ethanolic extract of M. tuberosa reversed CCl4 induced elevation of levels of serum biomarkers to near normal levels, suggesting that the tubers of M. tuberosa possess hepatoprotective property and this property may be attributed to the antioxidant property of the plant.

Practical aspects of planning, building, and interpreting tissue microarrays: the Cooperative Prostate Cancer Tissue Resource experience.

This is a review of several new approaches developed at or adopted by the Cooperative Prostate Cancer Tissue Resource (CPCTR) to resolve issues involved in tissue microarray (TMA) construction and use. CPCTR developed the first needle biopsy TMA, allowing researchers to obtain 200 or more consecutive cancer sections from a single biopsy core. Using radiographs of original paraffin blocks to measure tissue thickness we developed a method to produce TMAs with a larger number of usable sections. The modular approach to plan TMA construction is also a novel concept wherein TMAs of different types, such as tumor grade TMAs, metastasis TMA and hormone refractory tumors TMA can be combined to form an ensemble of TMAs with expanded research utility, such as support for tumor progression studies. We also implemented an open access TMA Data Exchange Specification that allows TMA data to be organized in a self-describing XML document annotated with well-defined common data elements. It ensures inter-laboratory reproducibility because it offers information describing the preparation of TMA blocks and slides. There are many important aspects that may be missed by both beginners and experienced investigators in areas of TMA experimental design, human subjects protection, population sample size, selection of tumor areas to sample, strategies for saving tissues, choice of antibodies for immunohistochemistry, and TMA data management.

Hepatoprotective activity of Calotropis procera flowers against paracetamol-induced hepatic injury in rats.

Hydro-ethanolic extract (70%) of Calotropis procera flowers was prepared and tested for its hepatoprotective effect against paracetamol-induced hepatitis in rats. Alteration in the levels of biochemical markers of hepatic damage like SGPT, SGOT, ALP, bilirubin, cholesterol, HDL and tissue GSH were tested in both treated and untreated groups. Paracetamol (2 g/kg) has enhanced the SGPT, SGOT, ALP, bilirubin and cholesterol levels and reduced the serum levels of HDL and tissue level of GSH. Treatment with hydro-ethanolic extract of C. procera flowers (200 mg/kg and 400 mg/kg) has brought back the altered levels of biochemical markers to the near normal levels in the dose dependent manner.

Hepatoprotective and antioxidant activities of flowers of Calotropis procera (Ait) R. Br. in CCl4 induced hepatic damage.

Hepatoprotective activity of 70% ethanolic extract of flowers of C. procera was studied against CCl4 induced hepatic injury in albino rats and mice. In addition, antioxidant activity was studied by in vitro models. Pre-treatment with 70% ethanolic extract (CPA) reduced the biochemical markers of hepatic injury like serum glutamate pyruvate transaminase, serum glutamate oxaloacetate transaminase, alkaline phosphatase, bilirubin, cholesterol, HDL and tissue glutathione (GSH) levels. Similarly pretreatment with CPA reduced the CCl4 induced elevation in the pentobarbitone sleeping time. Histopathological observations also revealed that pretreatment with CPA protected the animals from CCl4 induced liver damage. CPA demonstrated dose dependant reduction in the in vitro and in vivo lipid peroxidation induced by CCl4. In addition it showed dose dependant free radical scavenging activity. The results indicate that flowers of C. procera possess hepatoprotective property possibly because of its anti-oxidant activity. This property may be attributed to the quercetin related flavonoids present in the flowers of Calotropis procera.

Intraocular lens design and the inhibition of epithelium.

Of 1170 eyes implanted with posterior chamber lenses between 1981 and 1986 and having intact capsules at surgery, 1015 were examined two years after surgery, 741 were examined three years after surgery, and 308 were examined five years after surgery. At three years the capsulotomy rate for epithelium was 25% for 263 'lasergap' lenses, 2.4% for 296 convex posterior lenses, 8.2% for 73 planoposterior lenses with angulated loops. The highly significant difference for lasergap design, whether ridged, meniscus, or bossed, is of immediate interest to surgeons concerned with minimising the need for secondary capsulotomy. The two-year follow-up of soft hydrogel lenses suggested that these lenses also do not significantly retard the ingrowth of epithelium.

Analysis of the need for secondary capsulotomy during a five-year follow-up.

From 783 consecutive extracapsular cataract extractions with intact posterior capsules at the close of surgery, 655 eyes were available for examination three years after surgery and 447 eyes were available five years after surgery. By five years postoperatively, the need for secondary capsulotomy was 49% of 67 eyes that had not received an implant, 23% of 159 eyes that had received a Binkhorst iridocapsular lens, and 13% of 221 eyes that had received a posterior chamber lens. Among posterior chamber lenses, the surface area of the implant was considered to be a more important factor in inhibiting capsule opacification than posterior vaulting of the lens. Posterior vaulting was associated with a lower incidence of epithelialization but a higher incidence of capsular fibrosis. A small subgroup of 19 glaucoma triple procedures examined at three years showed a significantly higher incidence of capsulotomy (21.0%) than the other 369 posterior chamber lens implantations examined at three years (6.8%).

Prospectively randomized trial comparing the pseudoaccommodation of the AMO ARRAY multifocal lens and a monofocal lens.

A prospective trial was set up to compare pseudoaccommodation. Fifty patients were randomized into two groups. Group 1 comprised 25 patients who had a monofocal implant and a postoperative refractive aim of -0.3 to -1.3 diopter (D) spherical equivalent and an astigmatic component between 1.0 and 1.75 D cylinder. Group 2 comprised 25 patients who had a new multizone refraction style multifocal implant and a postoperative refractive aim of -0.5 to +0.5 D spherical equivalent and an astigmatic component of less than 1.0 D cylinder. Eighty percent of postoperative refractions in Group 1 and 88% in Group 2 were within 0.5 D either side of the refractive aim. Forty-eight percent of Group 1 and 72% of Group 2 could see both 20/40 and J3 unaided. Four percent of Group 1 and 84% of Group 2 could read J2 with the distance correction. Sixteen percent of Group 1 and 48% of Group 2 could read J2 at 25 cm unaided (P = .03). Sixty-four percent of Group 1 and 88% of Group 2 stated they could manage daily activities without glasses. However, 88% of Group 1 and 52% of Group 2 requested reading glasses to improve clarity of the smallest print.

Noninvasive ultrasound measurement of shear rate in leg bypass grafts.

Shear has been implicated in the etiology of atherosclerosis, thrombosis and graft stenosis. We measured shear rate noninvasively in infrainguinal bypasses. Velocity profiles were recorded from 35 femoropopliteal and 40 tibial grafts. Flow rate (Q), systolic shear rate (SSR), diameter, and bluntness factor (BF) were measured at midgraft using ultrasound (US). Mean shear rate (MSR) was calculated from flow and diameter. SSR, 671 +/- 260 (SD) vs. 659 +/- 304 s(-1) (p = 0.85), and MSR, 168 +/- 84 vs. 193 +/- 110 s(-1) (p = 0.26), were similar for popliteal and tibial bypasses, but differences in Q, 126 +/- 57 vs. 104 +/- 38 mL/min, were borderline significant (p = 0.058). Popliteal grafts had larger diameters, 5.2 +/- 1.1 mm vs. 4.7 +/- 0.8 mm (p = 0.048), and BF, 3.4 +/- 0.9 vs. 2.8 +/- 0.7 (p = 0.0014). Shear rates were obtained noninvasively in humans. Larger diameters in popliteal vs. tibial bypasses did not result in lower shear rates and were compensated for by larger bluntness factors. Velocity profile bluntness cannot be ignored in shear rate analysis.

Prospective audit comparing ambulatory day surgery with inpatient surgery for treating cataracts.

OBJECTIVES: To compare the cost effectiveness and safety of inpatient cataract surgery (with one night in hospital postoperatively) with ambulatory day case surgery under local anaesthesia. DESIGN: Prospective study of patients receiving inpatient (group 1) or day case (group 2) surgery. SETTING: One ophthalmic surgical firm. PATIENTS: 100 patients in each group, excluding those with coexisting ocular conditions, contraindications to local or request for general anaesthesia, ill health, or lack of agreed minimum social care; four patients died during follow up. INTERVENTIONS: Envelope method and implantation of the posterior chamber lens into the capsular sac in both groups. MAIN MEASURES: Perioperative complications, operating and turnover times, visual outcome at three to six days and 10 weeks to six months after operation, patient satisfaction (according to self administered questionnaire) at three to six days, and total costs (1989 salaries) for both groups. RESULTS: Patients in both groups did not differ significantly in age or sex, perioperative complications, visual outcome (6/9 or better in 78 patients in group 1 and 75 in group 2 at one month after operation and 6/12 or better in 92/98 in group 1, 90/98 in group 2 at final follow up), or patient satisfaction. The mean total cost per patient for group 1 patients was 365.99 pounds and for group 2, 221.62 pounds. CONCLUSIONS: Day case surgery for cataract is safe and more cost effective. IMPLICATIONS: Day case surgery should be recommended to increase availability of cataract surgery and thereby improve quality of life for more patients.

Congenital esophageal stenosis: a case report and review of the literature.

A child with congenital esophageal stenosis (CES) demonstrates the need for accuracy in the diagnosis and management of this rare problem. Other etiologies of dysphagia must be looked into, but when the expected results are not realized CES should be considered. A range of diagnoses and diagnostic studies may help to get children with dysphagia the treatment that they need to resolve their symptoms.

Hypoglycemic activity of Abutilon indicum leaf extracts in rats.

Alcohol and water extracts of Abutilon indicum leaves (400 mg/kg, p.o.) showed significant hypoglycemic effect in normal rats 4 h after administration (23.10% and 26.95%, respectively).

Antiphospholipid antibody syndrome. A literature review.

Antiphospholipid syndrome (APS) occurs as a primary or secondary syndrome and has various manifestations, including arterial and venous thrombosis, thrombocytopenia, fetal loss, livedo reticularis, and cardiac and neurological sequelae. APS is linked with autoantibodies that were originally thought to have specificity for negatively charged phospholipids. Recent data suggest specificity for different phospholipid-binding plasma proteins, including 2-glycoprotein I, prothrombin, protein C, and protein S. The most well-known antiphospholipid antibodies are lupus anticoagulant and anticardiolipin antibody. These antibodies are detected through lupus anticoagulant assays, anticardiolipin assays, and certain serologic tests for syphilis. This article describes 2 cases encountered in our clinical work and reviews the literature on APS.

Nephroprotective and Nitric oxide Scavenging Activity of Tubers of Momordica tuberosa in Rats.

Hydroalcoholic extract (70% ethanol extract) of tubers of Momordica tuberosa Cogn. (Cucurbitaceae) was subjected to preliminary phytochemical screening by qualitative tests. Nitric oxide scavenging activity was performed by Griess reagent method. And nephroprotective activity was assessed in gentamicin, cisplatin and paracetamol induced renal damage in wistar rats (150-200 g) by standard methods. The protective property of 70% ethanol extract was assessed by measuring the levels of body weight, blood urea, serum creatinine, tissue glutathione and lipid peroxidation in administered doses. The extract exhibited free radical scavenging activity in dose dependant manner. And 100 µg/ml dose produced significantly higher scavenging activity than standard sodium metabisulphate at 25 µg/ml. Also, it significantly reduced the renal damage caused by cisplatin, gentamicin and paracetamol at a dose of 40 mg/kg.

Application of the paraboloidal model to assess mucosal changes following segmental intestinal transplantation in children.

Segmental living related small intestinal transplantation (LRSITx) is a therapeutic option for conditions that present with short gut syndromes. Recovery of small intestinal mucosa after transplantation is critical to function. We examined the posttransplant mucosal changes to understand the absorptive capabilities of transplanted small intestine. The study of human subjects is constrained by limited biopsy material; therefore, we developed a technique of villus area measurement by extrapolation from two-dimensional surgical biopsy images. Using a detailed model of the villus as the gold standard, two simpler models (cylindrical and paraboloid) were tested. Comparisons with the accurate measurement revealed that the cylinder model does not compare well in early posttransplant biopsies. The paraboloid function developed in this article worked very well under all conditions. The simplicity of the paraboloid model and its robustness made high-quality estimates of the absorptive surface area from abundant data relatively easy. The remodeling expected in the initial stages of growth was also captured by this model. Time-dependent villus growth curves were obtained for transplanted bowel. Serial biopsies showed an initial "reconstruction" dip around 2 weeks after transplant, followed by continuous growth of villus surface area. An eventual plateau resulted at an average of 6 months after transplant. This growth of villi was shown to parallel the improved absorption of electrolytes, amino acids, and water.