The role of circulating glucose and triglyceride concentrations and their interactions with other "risk factors" as determinants of arterial disease in nine diabetic population samples from the WHO multinational study

In 9 of the 14 national samples of diabetic patients assembled for the WHO Multinational Study of Vascular Disease in Diabetes additional laboratory data made it possible to relate manifestations of macrovascular disease to blood glucose concentrations as well as to diabetes duration and to other potential determinants. In five of the samples, serum triglyceride concentrations were also measured and were included in simple and multivariate analyses. Ischemic heart disease defined from Minnesota-coded EKGs and standardized WHO questionnaires was more strongly associated with serum triglyceride concentrations than with serum cholesterol concentrations, an association less notable in non-insulin-dependent diabetic patients. Ischemic heart disease was not related to the single fasting plasma glucose estimated for this study. Stroke and amputation were much more strongly related to the known duration of diabetes than was ischemic heart disease, and they were both related to blood glucose concentration measured at the time of study. Despite major variation in arterial disease prevalence rates between collaborating centers, risk for diabetic women appeared to equal that for diabetic men. The major variation in arterial disease prevalence between national groups could be accounted for only in part by the risk factors studied. Other factors, genetic or more likely environmental, are likely to contribute to the variation in arterial disease susceptibility and, if definable, may be potentially preventable.     

Comparison of the smoking behaviour and attitudes of smokers who attribute respiratory symptoms to smoking with those who do not.

General practitioners' (GPs') advice against smoking helps smokers to stop; unfortunately, GPs cannot predict which patients will quit following advice. This postal questionnaire survey suggests that where smokers attribute their respiratory symptoms to smoking, they are eight times (95% confidence interval [CI] = 3.0-23.3) more likely to believe that their health will improve if they stop smoking and six times (95% CI = 1.4-23.3) more likely to intend to stop smoking.     

Tissue-engineered cartilage with inducible and tunable immunomodulatory properties

The pathogenesis of osteoarthritis is mediated in part by inflammatory cytokines including interleukin-1 (IL-1), which promote degradation of articular cartilage and prevent human mesenchymal stem cell (MSC) chondrogenesis. In this study, we combined gene therapy and functional tissue engineering to develop engineered cartilage with immunomodulatory properties that allow chondrogenesis in the presence of pathologic levels of IL-1 by inducing overexpression of IL-1 receptor antagonist (IL-1Ra) in MSCs via scaffold-mediated lentiviral gene delivery. A doxycycline-inducible vector was used to transduce MSCs in monolayer or within 3D woven PCL scaffolds to enable tunable IL-1Ra production. In the presence of IL-1, IL-1Ra-expressing engineered cartilage produced cartilage-specific extracellular matrix, while resisting IL-1-induced upregulation of matrix metalloproteinases and maintaining mechanical properties similar to native articular cartilage. The ability of functional engineered cartilage to deliver tunable anti-inflammatory cytokines to the joint may enhance the long-term success of therapies for cartilage injuries or osteoarthritis.     

Guided growth of neurons and glia using microfabricated patterns of parylene-C on a SiO2 background

This paper describes a simple technique for the patterning of glia and neurons. The integration of neuronal patterning to Multi-Electrode Arrays (MEAs), planar patch clamp and silicon based ‘lab on a chip’ technologies necessitates the development of a microfabrication-compatible method, which will be reliable and easy to implement. In this study a highly consistent, straightforward and cost effective cell patterning scheme has been developed. It is based on two common ingredients: the polymer parylene-C and horse serum. Parylene-C is deposited and photo-lithographically patterned on silicon oxide (SiO₂) surfaces. Subsequently, the patterns are activated via immersion in horse serum. Compared to non-activated controls, cells on the treated samples exhibited a significantly higher conformity to underlying parylene stripes. The immersion time of the patterns was reduced from 24 to 3 h without compromising the technique. X-ray photoelectron spectroscopy (XPS) analysis of parylene and SiO₂ surfaces before and after immersion in horse serum and gel based eluant analysis suggests that the quantity and conformation of proteins on the parylene and SiO₂ substrates might be responsible for inducing glial and neuronal patterning.     

Laparoscopic radical nephroureterectomy: results of an international multicenter study

OBJECTIVE: To report a multicenter analysis after laparoscopic radical nephroureterectomy for pathologically confirmed upper tract transitional cell carcinoma. MATERIALS AND METHODS: A total of 116 patients (72 males; mean age 68 years) underwent laparoscopic radical nephroureterectomy at five international institutions: 51 transperitoneally, 65 retroperitoneally. Location of the primary tumor was pelvicalyceal in 70 patients (60%), ureteral in 27 (23%), and multifocal in 19 (17%). In 18 patients (15%), transurethral resection was performed for concomitant bladder tumor. The median follow-up time was 25 months (range 3-93). A minimum follow-up of 1 and 2 years was available in 77 and 41 patients, respectively. RESULTS: Five patients (4%) were converted to open surgery. The specimen was extracted intact in all 116 patients: using an Endocatch bag in 78 patients, a Lapsac in 5, and manually in 33. Pathologic staging was pTis in 5 (4%), pTa in 41 patients (35%), pT1 in 31 (26%), pT2 in 18 (15%), pT3 in 16 (13%), and pT4 in 5 (4%). Pathological grade was grade I in 26 patients (23%), grade II in 41 (35%), grade III in 34 (29%) and grade IV in 15 (12%). Histopathology revealed a positive surgical margin in five patients (4.5%): renal hilum (one), periureteral soft tissue (two), distal edge of the ureter/ bladder cuff (two). Local recurrence was noted in two patients (1.7%). Bladder recurrence was noted in 28 patients (24%) with a mean time to recurrence of 13.9+/-11.5 months. Distant metastases occurred in 11 patients (9%): lung (5), liver (3), bones (2), adrenal (1); mean time to metastasis was 13 months. Overall, 23 patients (20%) died. One-year and 2-year cancer-specific survival was 92% and 87%, respectively. Two-year cancer-specific survival according to pathologic stage was 89% for patients with pT1 disease, 86% for pT2, 77% for pT3, and 0% for pT4 (p=0.0001). Two-year survival according to pathologic grade was 88% for grade I, 90% for grade II, 80% for grade III, and 90% for grade IV (p>0.05). CONCLUSION: Laparoscopic radical nephroureterectomy appears to be an effective minimally invasive treatment for select patients with upper tract transitional cell carcinoma. Although the 2-year survival data reported herein are encouraging, longer follow-up is needed before laparoscopy can be considered as a standard treatment.     

Local hemostasis during laparoscopic partial nephrectomy using biodegradable hydrogels: initial porcine results

BACKGROUND AND PURPOSE: Despite the advance of laparoscopic partial nephrectomy, significant technical limitations remain with regard to control of bleeding and closure of the collecting system. An attractive approach on the horizon for local hemostatic and wound control is the use of local tissue sealants. To date, sealants remain largely derived from natural biologic products and are difficult to apply laparoscopically with precise local control. In this study, we examined the novel strategy of forming occlusive tissue-adherent hydrogels utilizing a synthetic biodegradable polyethylene glycol-lactide copolymer (PEG-lactide) as an in situ occlusive barrier for hemostasis and wound control. Specifically, the objects of this study were to determine if PEG-lactide hydrogels could be formed intraperitoneally on renal tissue, to test the adhesiveness of the hydrogels to injured renal parenchyma, and to evaluate the ability of adherent hydrogel barriers to limit renal parenchymal bleeding and collecting system leakage following renal pole amputation or wedge excision. MATERIALS AND METHODS: Five kidneys from three female pigs were used in a nonsurvival study. A standardized model for laparoscopic partial nephrectomy was created by performing wedge excision or polar amputation under vascular control using a laparoscopic Satinsky clamp. Bleeding briskness following injury was assessed utilizing a scoring system and free blood quantitated comparing a conventional "clamp and wait" strategy with an adherent hydrogel strategy. For the hydrogel group, PEG-lactide hydrogel primer and macromer were applied through laparoscopic ports. The hydrogel was polymerized using a xenon light source, and the pedicle clamp was released to observe for bleeding. A subsequent opposite polar injury was created to confirm renal perfusion and the sites were compared. The kidneys were removed, and the adhesion of the hydrogel to the renal parenchyma was examined. RESULTS: The PEG-lactide macromer was effectively applied to five kidneys following partial nephrectomy. In all cases, successful intraperitoneal in situ polymerization was achieved, with resultant hydrogel formation. Polymeric hydrogel adhesion to the cut renal parenchyma was assessed semiquantitatively following vigorous cyclic washing. In all cases, polymer gels remained adherent without any evidence of peeling, delamination, or separation from the underlying tissue surface. In the control group, the mean bleeding score was 2.63 +/- 0.48 v 0.00 +/- 0.00 in the gel-treated group (P < 0.001). Blood loss in the control group was 56 +/- 5 ml v 0.00 +/- 0.00 in the gel-treated group (P < 0.001). In an ex vivo retrograde ureteral perfusion, no leakage was observed at pressure as high as 100 mm Hg. CONCLUSIONS: In this feasibility study, a biodegradable PEG-lactide polymer system photopolymerized rapidly in situ on exposed renal parenchymal surfaces, forming adherent hydrogel barriers. When applied during vascular clamping, an adequate physical bond and patch-like cap was created to prevent bleeding at physiologic renal perfusion pressures. Use of locally applied occlusive hydrogels holds promise for hemostasis and local wound control during laparoscopic urologic procedures.     

Updating evidence-based clinical guidelines

OBJECTIVES: To report on the updating of two evidence-based guidelines. METHODS: Development of multi-disciplinary evidence-based guidelines within the North of England Evidence Based Guideline Development Programme. RESULTS: The guideline updating groups were multi-disciplinary although the balance of disciplines was different from the original development groups; the convening of the updating groups allowed refinement of both the skills within the groups and the overall size of the groups. As both groups were starting with a previous version of the guideline, defining the scope of the guideline was more straightforward and faster than when developing the guideline de novo. The process of evidence identification for both guidelines was again by systematic review. Updating the guidelines influenced recommendations in two ways: new evidence required new recommendations; and supplementary evidence in an existing area allowed refinement of recommendations. Overall savings within the guideline updating process (compared with initial development) were modest. The major costs of both the initial guideline development and the updating process were staff costs, which were identical for the two processes. CONCLUSIONS: There is little other experience to set alongside this paper. There is a need for further sharing of experiences and the development of explicit methods for informing decisions on when and how to update evidence-based guidelines.     

Midazolam and remifentanil by bolus injection for intensely stimulating procedures of brief duration: experience with awake laryngoscopy

IMPLICATIONS: The pharmacokinetic characteristics of midazolam and remifentanil administered by bolus injection may make them advantageous for providing brief, intense analgesia without prolonged respiratory depression. This application is particularly useful for awake, direct laryngoscopy.     

Troglitazone antagonizes metabolic effects of glucocorticoids in humans: effects on glucose tolerance,insulin sensitivity,suppression of free fatty acids,and leptin

Glucocorticoids induce insulin resistance in humans, whereas thiazolidinediones enhance insulin sensitivity. Although the effects of glucocorticoids and thiazolidinediones have been assessed in isolation, interaction between these drugs, which both act as ligands for nuclear receptors, has been less well studied. Therefore, we examined the metabolic effects of dexamethasone and troglitazone, alone and in combination, for the first time in humans. A total of 10 healthy individuals with normal glucose tolerance (age 40 +/- 11 years, BMI 31 +/- 6.1 kg/m(2)) were sequentially studied at baseline, after 4 days of dexamethasone (4 mg/day), after 4-6 weeks on troglitazone alone (400 mg/day), and again after 4 days of dexamethasone added to troglitazone. Key metabolic variables included glucose tolerance assessed by blood glucose and insulin responses to an oral glucose tolerance test (OGTT), insulin sensitivity evaluated via hyperinsulinemic-euglycemic clamp, free fatty acids (FFAs) and FFA suppressibility by insulin during the clamp study, and fasting serum leptin. Dexamethasone drastically impaired glucose tolerance, with fasting and 2-h OGTT insulin values increasing by 2.3-fold (P < 0.001) and 4.4-fold (P < 0.001) over baseline values, respectively. The glucocorticoid also induced a profound state of insulin resistance, with a 34% reduction in maximal glucose disposal rates (GDRs; P < 0.001). Troglitazone alone increased GDRs by 20% over baseline (P = 0.007) and completely prevented the deleterious effects of dexamethasone on glucose tolerance and insulin sensitivity, as illustrated by a return of OGTT glucose and insulin values and maximal GDR to near-baseline levels. Insulin-mediated FFA suppressibility (FFA decline at 30 min during clamp/FFA at time 0) was also markedly reduced by dexamethasone (P = 0.002). Troglitazone had no effect per se, but it was able to normalize FFA suppressibility in subjects coadministered dexamethasone. Futhermore, the magnitudes of response of FFA suppressibility and GDR to dexamethasone were proportionate. The same was true for the reversal of dexamethasone-induced insulin resistance by troglitazone, but not in response to troglitazone alone. Leptin levels were increased 2.2-fold above baseline by dexamethasone. Again, troglitazone had no effect per se but blocked the dexamethasone-induced increase in leptin. Subjects experienced a 1.7-kg weight gain while taking troglitazone but no other untoward effects. We conclude that in healthy humans, thiazolidinediones antagonize the action of dexamethasone with respect to multiple metabolic effects. Specifically, troglitazone reverses both glucocorticoid-induced insulin resistance and impairment of glucose tolerance, prevents dexamethasone from impairing the antilipolytic action of insulin, and blocks the increase in leptin levels induced by dexamethasone. Even though changes in FFA suppressibility were correlated with dexamethasone-induced insulin resistance and its reversal by troglitazone, a cause-and-effect relationship cannot be established. However, the data suggest that glucocorticoids and thiazolidinediones exert fundamentally antagonistic effects on human metabolism in both adipose and muscle tissues. By preventing or reversing insulin resistance, troglitazone may prove to be a valuable therapeutic agent in the difficult clinical task of controlling diabetes in patients receiving glucocorticoids.