bluuebunny/crossref_metadata_2025 huggingface dataset:
Rapid response to rituximab in a pediatric liver transplant recipient with post‐transplant lymphoproliferative disease and maintenance with sirolimus monotherapy
Authors: Al‐Akash Samhar I. , Al Makadma Abdulkarim S. , Al Omari Mohammad G.
Published: March 2005

Abstract:  A 12‐yr‐old girl with end‐stage renal disease secondary to primary hyperoxaluria type I received a living related (left lateral segment) liver transplant from her brother as the first step of a staged liver and kidney transplant. Renal transplantation was planned for a later date from the same donor. Nine weeks after transplantation she developed polymorphic PTLD of the tonsils and adenoids. Initial treatment with surgical resection and withdrawal of immunosuppression was insufficient as she developed recurrence of the PTLD lesion 1 wk after surgical resection and reduction of immunsuppression. Treatment with the chimeric monoclonal anti CD20 antibody, rituximab (Mabthera®, Hoffman‐La Roche AG, Grenzach‐Whylen, Germany), resulted in quick response and complete recovery from PTLD within 2 wk, with no recurrence up to 8 months after treatment. Rejection prophylaxis was successfully achieved with Sirolimus (Rapamune®, Wyeth Pharmaceuticals Inc., Philadelphia, PA, USA) monotherapy, with no episodes of acute rejection.
Post‐transplant therapy with high‐dose intravenous gammaglobulin: Applications to treatment of antibody‐mediated rejection
Authors: Jordan Stanley C. , Vo Ashley A. , Toyoda Mieko , Tyan Dolly , Nast Cynthia C.
Published: March 2005

Abstract:  B‐cells and their products (antibodies) are now recognized as important mediators of allograft rejection. This represents a significant departure from previous doctrine where the T‐cells were felt to be of paramount importance. Antibody‐mediated rejection (AMR) has emerged as a significant and common complication of transplantation. The development of donor‐specific (anti‐HLA class I and class II) antibodies is known to correlate strongly with the development of AMR. Recognition of the unique features of AMR that were often confused with non‐specific acute tubular injury is aided considerably by improvements in monitoring of anti‐HLA antibodies and the immunopathologic demonstration of C4d staining in affected capillary beds. Although imperfect, the demonstration of C4d (a complement breakdown product) staining in an allograft, especially accompanied by the presence of anti‐HLA antibodies in the recipient sera, strongly suggests a diagnosis of AMR. Thus, AMR is a complement‐dependent, antibody‐mediated disorder. AMR can occur as a de novo complication of transplantation in individuals not previously recognized to be sensitized to HLA antigens, but more often occurs as a complication of desensitization therapies in highly‐HLA sensitized patients. AMR may also constitute a significant portion of what is now referred to as chronic allograft nephropathy (CAN). The prognosis of C4d (+) AMR is poor as current therapies for treatment of AR are directed primarily at the T‐cell. Until recently, no therapeutic options existed to address this problem from a primary etiological standpoint. Here we discuss the use of high dose IVIG as an option for treatment of AMR. We have significant experience with this approach which is outlined here. IVIG has many ideal advantages as a therapy for AMR. First, it can down regulate B‐cell activation and antibody production, second, it can induce anti‐inflammatory cytokines and contains blocking antiidiotyic antibodies to anti‐HLA antibodies and third, IVIG has the unique ability to block complement‐mediated injury through inhibition of C3 activation. Further clinical trials are necessary to prove efficacy for treatment of AMR.
Caspofungin for invasive fungal infections: Combination treatment with liposomal amphotericin B in children undergoing hemopoietic stem cell transplantation
Authors: Pancham S. , Hemmaway C. , New H. , Albert E. , Dokal I. , Roberts I. A. G. , McCloy M.
Published: March 2005

Abstract:  Invasive fungal infections often prove difficult to eradicate especially in the stem cell transplant setting. Amphotericin has been the mainstay of treatment for years but has significant toxicity. Newer antifungal agents, such as caspofungin, have shown promising results in adults, particularly when used in combination with amphotericin as both drugs differ in their mode of action. However, there are few data from children and no previous published information about the use of Caspofungin after paediatric stem cell transplantation. We report our experience in children with proven invasive fungal infections after stem cell transplantation. This combination was non‐toxic, and two of three patients survived their infections.
The sensitized pediatric heart transplant candidate: Causes, consequences, and treatment options
Authors: Shaddy Robert E. , Fuller Thomas C.
Published: March 2005

Abstract:  Sensitization to HLA antigens and the subsequent development of HLA antibodies in children under consideration for heart transplantation is a significant impediment to survival after listing. This is related both to the frequent need for prospective donor‐specific crossmatching (thus limiting donor availability and increasing pretransplant morbidity and mortality), and to the increased risk of adverse outcomes after transplantation. This article will review the scope of this problem in children under consideration for heart transplantation, the different methods available for diagnosing HLA sensitization, the known causes of HLA sensitization, the consequences of these preformed antibodies on outcomes before and after heart transplantation, and the different methods of preventing and treating this sensitization that are currently available. Improved methods of diagnosing, preventing, and treating this problem can only lead to better outcomes for children who require heart transplantation.
Effect of age, ethnicity, and glucocorticoid use on tacrolimus pharmacokinetics in pediatric renal transplant patients
Authors: Kim Jung Sue , Aviles Diego H. , Silverstein Douglas M. , LeBlanc Pamela L. , Matti Vehaskari V.
Published: March 2005

Abstract:  Tacrolimus has become an effective alternative to cyclosporine as a component of primary immunosuppression in pediatric renal transplant patients, but the information on the pharmacokinetic characteristics of tacrolimus in young patients is still limited. The primary objective of this study was to determine the effect of patient age, ethnicity, and concurrent steroid administration on tacrolimus pharmacokinetics in pediatric renal transplant patients. The study population consisted of 30 pediatric patients, age 1.5–18.6 yr, who received a kidney transplant between July 1999 and February 2004. After twice daily dosing was stabilized based on clinical judgment, at least 5 days postoperatively, tacrolimus levels were drawn prior to, and 1, 2, 4, 8, and 12 h after the morning dose. The mean dose of tacrolimus was 0.12 mg/kg/dose. Mean trough level was 11.9 ± 5.0 ng/mL. Mean area under the curve (AUC) was 192 ± 84 with a range of 78–360 h × (ng/mL). The correlation between trough level and AUC was only fair (r = 0.74); later time points correlated better with AUC, and an excellent correlation (r = 0.96) was obtained between the mean of trough and 2‐h level (C2) and AUC. There was a negative correlation between age and dose per body weight (r = −0.68). African‐American patients had marginally lower drug exposure with similar dosing. Three age groups (<5, 5–12, and >12 yr) were compared with respect to dosing and AUC. Despite similar AUC in all three groups, the mean dose per kg required to achieve the AUC was 2.7‐ and 1.9‐fold higher in the <5 and 5–12‐yr groups, respectively, compared with the >12‐yr group. Nine of the 30 patients were on a totally steroid‐free regimen. Their tacrolimus dose and trough levels were similar to those of steroid‐exposed patients, but their mean AUC was 41% higher. Our results show an inverse correlation between age and required tacrolimus dose, wide interindividual variation, and greater exposure with steroid‐free regimen despite no change in trough level.
Beyond the first year after pediatric heart or heart‐lung transplantation: Changes in cognitive function and behaviour
Authors: Wray Jo , Radley‐Smith Rosemary
Published: March 2005

Abstract:  With the increasing use and improved survival rates of heart and lung transplantation as treatments for children with end‐stage heart or lung disease, attention is focusing on the longer term psychological implications of these procedures. This paper focuses on the changes in cognitive development and behaviour in a group of 47 children who were seen 12 months and 2 yr after transplantation. There were 24 boys and 23 girls, mean age at transplantation was 8.3 yr (s.d. 5.3 yr), with a range of 0.3–15.1 yr. Assessments were made of developmental level, cognitive ability and problem behaviours, using previously validated measures, and comparisons were made with physically healthy children. For children under three and a half years of age there was a decrease over time in scores on all developmental parameters, with the change reaching significance on the scale assessing eye–hand coordination and on the overall IQ. Whilst all scores were within the normal range, they were at a significantly lower level than those of the healthy children. In contrast, there were no changes over time on any measures of cognitive or academic ability for older children, with correlations between 12 month and 2 yr scores being highly significant. The rate of behaviour problems at home at 12 months was 22%, compared with 34% at 2 yr post‐transplant, which was higher than that found in the healthy children. Conversely, there was a drop in the prevalence of behaviour problems at school from 23% at 12 months to 9% at 2 yr. It is concluded that a significant minority of children and adolescents experience psychological difficulties 2 yr after transplant, with particular areas of concern focusing on development in the younger children and the occurrence of behaviour problems at home across the age‐range.
Improved long‐term allograft function in pediatric renal transplantation with mycophenolate mofetil
Authors: Ferraris Jorge R. , Ghezzi Lidia F. R. , Vallejo Graciela , Piantanida Juan J. , Araujo Jose L. , Sojo Ernesto T.
Published: March 2005

Abstract:  MMF has been shown to decrease the incidence of acute rejection in children and adults at 1 and 3 yr. Other beneficial effects of MMF have been more difficult to demonstrate. Our open‐labeled study presents a 5‐yr data for patients and graft survival, allograft function, and growth in MMF‐treated patients. The trial included 29 patients who were treated with MMF in combination with cyclosporine and methylprednisone. Patients were compared with a preceding group of 29 patients treated with AZA instead of MMF. Patient and graft survival rate 5 yr after transplantation were 97 and 90% in the MMF group vs. 93 and 83% in the AZA group (p: NS). Acute rejection was 20.6% in the MMF group vs. 58.6% in the AZA group (p < 0.01). Chronic rejection was 10.3% in the MMF group and 25% in the AZA group (p: NS). The changes in the creatinine clearance from baseline to 5 yr (Δ) were different between groups (−6.0 ± 5.1 mL/min/1.73 m2 in the MMF group vs. −22.2 ± 7.6 mL/min/1.73 m2 in the AZA group, p < 0.05). Also, the slope of 1/Scr showed a significant lower incidence of worsening renal function after the second year of renal transplantation (p < 0.0001) in the MMF group compared with the AZA group. Δ Height SDS in prepubertal patients was 0.3 ± 0.4 SDS in the MMF group vs. −0.8 ± 0.2 SDS in the AZA group (p < 0.05).

This study shows that long‐term MMF therapy has resulted in a decrease in acute rejection and was associated with a protection against renal function deterioration. The use of MMF enables a reduction in the dose of steroids and leads to a linear growth improvement of children after renal transplantation.
Invasive pneumococcal disease in pediatric organ transplant recipients: A high‐risk population
Authors: Tran Leanne , Hébert Diane , Dipchand Anne , Fecteau Annie , Richardson Susan , Allen Upton
Published: March 2005

Abstract:  There are few studies on invasive pneumococcal disease in pediatric transplant recipients. Given this fact plus the advent of pneumococcal conjugate vaccines, we conducted a retrospective study at a major pediatric transplant center. The objectives were to determine the incidence and outcomes of invasive pneumococcal diseases in the patient population and to examine the timing of these infections after transplantation. We determined that invasive disease occurred at a rate that was significantly greater than the rate extrapolated from generally healthy children <5 yr of age (176 episodes per 100 000 children per year vs. 35–68.3 per 100 000 children per year). In addition, disease occurred at a median of approximately 20 months after transplantation, thereby theoretically allowing enough time for vaccination with the 7‐valent conjugate vaccine. The study also documented significant missed vaccination opportunities.
Amylopectinosis disease isolated to the heart with normal glycogen branching enzyme activity and gene sequence
Authors: Das B. B. , Narkewicz M. R. , Sokol R. J. , Chen Y. T. , Bali D. , Li S. C. , Matthews M. R. , Mierau G. W. , Ivy D. D.
Published: March 2005

Abstract:  We report a 17‐month‐old female patient with a rare cause of cardiomyopathy secondary to accumulation of amylopectin‐like material (fibrillar glycogen) isolated to the heart. Evidence of amylopectinosis isolated to cardiac myocytes in this patient was demonstrated by histology and electron microscopy. Glycogen content, glycogen branching enzyme (GBE) activity, as well as phosphofructokinase enzyme activities measured in liver, skeletal muscle, fibroblasts and ex‐transplanted heart tissue were all in the normal to lower normal ranges. Normal skeletal muscle and liver tissue histology and GBE activity, normal GBE activity in skin fibroblasts, plus normal GBE gene sequence in this patient exclude the classical branching enzyme deficiency (type IV GSD). We believe that this is an as yet uncharacterized and novel phenotype of GSD associated with cardiomyopathy, in which there is an imbalance in the regulation of glycogen metabolism limited to the heart.
Hypogammaglobulinemia in pediatric liver transplant recipients
Authors: Ganschow R. , Englert C. , Grabhorn E. , Richter A. , Hinrichs B. , Broering D. C. , Rogiers X. , Burdelski M.
Published: March 2005

Abstract:  Hypogammaglobulinemia has been reported after solid organ transplantation in adults, however immunoglobulin replacement [intravenous immunoglobulins (IVIG)] is only necessary in a minority of affected patients. We here present three pediatric patients with severe post‐transplant hypogammaglobulinemia following liver transplantation (LTx) receiving a cyclosporine‐based standard immunosuppression. Patient 1 was transplanted at the age of 10 months for biliary atresia. Eight weeks post‐Ltx the serum IgG was 1.7 g/L. Patient 2 was transplanted at the age of 12 yr for acute liver failure. Four weeks post‐Ltx the IgG dropped to 2.6 g/L. Patient 3 was transplanted at the age of 4 months for biliary atresia. Ten weeks post‐Ltx severe hypogammaglobulinemia (IgG < 1.48 g/L) was diagnosed during a severe infectious complication. Patients 1 and 3 received a steroid bolus therapy for acute graft rejection. All patients had normal IgG concentrations prior to Ltx and lymphocyte subsets were post‐operatively in the normal range. There was no extensive loss of protein by ascites. IGIV were replaced in the three patients monthly without further complications. In two of the patients (1 and 3) IVIG therapy was discontinued 8 and 10 months after Ltx when the immunosuppression has been reduced and serum IgG concentrations were found in the normal range without further immunoglobulin replacement. Severe hypogammaglobulinemia is a rare phenomenon following pediatric LTx and seems to be mainly caused by immunosuppressive drugs, however, the exact underlying mechanisms are unclear. A screening for hypogammaglobulinemia is useful after pediatric LTx, especially in patients with an intensified immunosuppression. Moreover, further immunologic research in affected patients is necessary.
Risk factors for fungal infection in paediatric liver transplant recipients
Authors: Verma Anita , Wade Jim J. , Cheeseman Paul , Samaroo Beatrice , Rela Mohemmed , Heaton Nigel D. , Mieli‐Vergani Giorgina , Dhawan Anil
Published: March 2005

Abstract:  Fungal infection (FI) is a major and potentially fatal complication in liver transplantation (LT). Published experience of FI in paediatric LT is limited. We therefore reviewed case records of 79 children, aged between 0.16 and 16 yr, who underwent LT between 1997 and 1998 to document the incidence of, and identify risk factors for, FI. Sixty‐eight pre‐, peri‐ and post‐LT variables were assessed in relation to FI by univariate and multivariate analyses. The major indications for LT were biliary atresia in 26 (33%) patients, fulminant hepatic failure in 16 (20%) and intrahepatic cholestasis in 11 (14%); eight patients required re‐LT. Thirty‐two (40.5%) children developed a FI within 1 yr of LT. The median time to FI was 42 days (range 1–342 days). Candida spp. caused 29 (90.7%) FIs; 21 (66%) of these were Candida albicans. Although FI was associated with increased mortality, most patients responded well to antifungal treatment. The variables independently associated with FI were pre‐LT fungal colonization and pyrexia and, post‐LT, bacterial infection, Epstein–Barr virus (EBV) infection and tacrolimus administration. Identifying risk factors for FI should contribute to the development of strategies for prophylaxis or preemptive therapy.
Primary focal segmental glomerulosclerosis – Long‐term outcome after pediatric renal transplantation*
Authors: Jungraithmayr Therese C. , Bulla Monika , Dippell Jürgen , Greiner Christel , Griebel Martin , Leichter Heinz E. , Plank Christian , Tönshoff Burkhard , Weber Lutz T. , Zimmerhackl Lothar B. ,   The German MMF Study Group
Published: March 2005

Abstract:  Recurrence of the primary disease is a significant issue in pediatric renal transplantation (RTx). According to data reported by the North American Pediatric Renal Transplantation Cooperative Study, patients with focal segmental glomerulosclerosis (FSGS) as primary renal disease have a recurrence rate of 30% after the first RTx. The relative risk of an early graft loss because of recurrent disease is increased to 1.6–3.1 in pediatric patients with FSGS. In a German open multicenter study, which was initiated to investigate mycophenolate mofetil (MMF) after pediatric RTx [Transplantation 2001:71:638, Transplantation 2003:75:454], patients with FSGS were evaluated for recurrence rate, risk factors for recurrence, long‐term graft function, glomerular filtration rate and transplant survival. All patients received immunosuppression with MMF, cyclosporine A and prednisone without induction therapy. Renal function and survival data for FSGS patients were compared with the results of patients with other primary renal diseases within the same study population. Among 86 patients transplanted between 1996 and 1999 eight patients suffered from FSGS as primary disease. Recurrence was diagnosed in two of the eight patients. One out of these two patients lost his graft as a result of recurrence. Risk factors such as time between diagnosis and end stage renal disease (ESRD) and age at onset did not predict recurrence. A three‐year patient survival in the FSGS group was 100%, graft survival 87% vs. 97% in the non‐FSGS group. Acute rejections occurred in three out of eight FSGS patients and in 37 out of 78 among the non‐FSGS group. Long‐term renal function, calculated using mathematical modeling based on glomerular filtration rate (GFR) data during 3 yr after RTx, was similar in FSGS patients – including a patient who had recurrence with a functioning graft – and those without FSGS. In patients with FSGS, recurring disease after RTx remains an important cause of graft loss (one of two patients in this population) even under modern immunosuppressants. Nevertheless, the immunosuppressive regimen used was associated with a similar graft survival rate and long‐term renal function of FSGS patients compared with patients with other primary diseases.
Tumour necrosis factor receptors (TNFRs) in Type 2 diabetes. Analysis of soluble plasma fractions and genetic variations of TNFR2 gene in a case‐control study
Authors: Vendrell J. , Broch M. , Fernandez‐Real J. M. , Gutiérrez C. , Simón I. , Megia A. , Gallart L. , Ricart W. , Richart C.
Published: March 2005

Aims  We have studied the relationships between soluble fractions of tumour necrosis factor receptors (sTNFR1 and sTNFR2) in Type 2 diabetes (DM2) and its chronic microvascular complications. Likewise, we have analysed the genetic susceptibility of 196T > G exon6/CA‐repeat intron 4 mutations in the TNFR2 gene in this population.

Methods  A case‐control study was conducted to examine the role of sTNFRs in 345 DM2 patients and 173 healthy subjects. The mutations were studied in all healthy subjects and in a subset of 232 patients.

Results  sTNFRs levels were similar in healthy and DM2 patients. A positive correlation between age and both sTNFRs was observed in healthy subjects. In DM2 patients, sTNFR1 showed a positive correlation with age, systolic blood pressure and leptin levels (r = 0.53, P < 0.0001; r = 0.28, P = 0.005; r = 0.46, P < 0.0001, respectively) and sTNFR2 was positively correlated with age, triglycerides and leptin levels (r = 0.34, P < 0.0001; r = 0.21, P < 0.0001; r = 0.28, P = 0.002, respectively). Patients with micro‐ or macroalbuminuria showed higher plasma levels of sTNFR1 and sTNFR2 than normoalbuminuric patients, after adjusting for confounding variables (B = 0.85, P = 0.022, 95% CI: 0.12–1.58 for sTNFR1 and B = 1.50, P < 0.001, 95% CI: 0.67–2.33 for sTNFR2). In DM2 patients, TT‐exon 6 homozygous showed lower levels of sTNFR1 [2,4 (1.1) vs. 3.4 (1.2) ng/ml], and the CA273‐allele tracked with elevated plasma HDL‐cholesterol [1.8 (0.7), 1.4 (0.3) and 1.3 (0.3) mm, for CA273/273, CA273/– and CA–/–, respectively]. No association was seen with other analysed variables.

Conclusions  Our findings suggest that chronic TNF activation may have some pathogenic role in diabetic nephropathy in DM2 patients. Genetic variations in exon 6/intron 4 of the TNFR2 gene do not predispose to a major risk for DM2 or its microvascular complications
A long‐term comparison of pioglitazone and gliclazide in patients with Type 2 diabetes mellitus: a randomized, double‐blind, parallel‐group comparison trial
Authors: Charbonnel B. H. , Matthews D. R. , Schernthaner G. , Hanefeld M. , Brunetti P. ,   on behalf of the QUARTET Study Group
Published: March 2005

Aims  This study compared the effects of pioglitazone and gliclazide on metabolic control in drug‐naïve patients with Type 2 diabetes mellitus.

Methods  A total of 1270 patients with Type 2 diabetes were randomized in a parallel‐group, double‐dummy, double‐blind study. Patients with poorly controlled Type 2 diabetes (HbA1c 7.5–11%), despite dietary advice, received either pioglitazone up to 45 mg once daily or gliclazide up to 160 mg two times daily. Primary efficacy endpoint was change in HbA1c from baseline to the end of the study. Secondary efficacy endpoints included change in fasting plasma glucose, fasting plasma insulin and plasma lipids. At selected centres, oral glucose tolerance tests were performed and C‐peptide and pro‐insulin levels were measured.

Results  Mean HbA1c values decreased by the same amount in the two treatment groups from baseline to week 52 [pioglitazone: −1.4%; gliclazide: −1.4%; (90% CI: −0.18 to 0.02)]. A significantly greater mean reduction in fasting plasma glucose was observed in the pioglitazone group (2.4 mmol/l) than in the gliclazide group [2.0 mmol/l; treatment difference −0.4 mmol/l in favour of pioglitazone; P = 0.002; (95% CI: −0.7 to −0.1)]. Improvements in high‐density lipoprotein cholesterol (HDL‐C) and total cholesterol/HDL‐C were greater with pioglitazone than with gliclazide (P < 0.001). The frequencies of adverse events were comparable between the two treatment groups, but more hypoglycaemic events were reported for gliclazide, whereas twice as many patients reported oedema with pioglitazone than with gliclazide.

Conclusions  Pioglitazone monotherapy was equivalent to gliclazide in reducing HbA1c, with specific differences between treatments in terms of mechanism of action, plasma lipids and adverse events.
Criteria for previously undiagnosed diabetes and risk of mortality: 15‐year follow‐up of the Edinburgh Artery Study cohort
Authors: Wild S. H. , Smith F. B. , Lee A. J. , Fowkes F. G. R.
Published: March 2005

Aims  To compare risk of all‐cause and cardiovascular mortality associated with different criteria for undiagnosed diabetes and glucose tolerance.

Methods  A population‐based cohort of 758 men and 738 women of 55–74 years of age who had an oral glucose tolerance test or known diabetes at baseline were followed up until death or for 15 years. Mortality outcomes were compared by baseline diabetes status using people with normal glucose tolerance (i.e. those without diabetes, impaired fasting glucose or impaired glucose tolerance) as the reference group.

Results  Prevalence of undiagnosed diabetes using World Health Organization (WHO) criteria (fasting glucose of ≥ 7.0 mmol/l and/or a 2‐h post‐challenge glucose of ≥ 11.1 mmol/l) was 6.6%, of which 81% was associated with fasting glucose ≥ 7.0 mmol/l and 19% was associated with isolated post‐challenge hyperglycaemia. Hazard ratios (95% CI) for all‐cause mortality adjusted for age and sex were 1.51 (1.09–2.08) for new diabetes by the American Diabetes Association (ADA) criterion (fasting glucose of ≥ 7.0 mmol/l regardless of post‐challenge glucose), 1.60 (1.20–2.13) for new diabetes by WHO criteria and 1.98 (1.14–3.44) for isolated post‐challenge hyperglycaemia. Hazard ratios (95% CI) for cardiovascular mortality adjusted for age and sex were 1.89 (1.17–3.00), 1.73 (1.12–2.66) and 1.08 (0.34–3.40) for new diabetes by ADA and WHO criteria and for isolated post‐challenge hyperglycaemia, respectively.

Conclusions  Undiagnosed diabetes was associated with increased risk of all‐cause mortality by any criteria but significantly increased cardiovascular disease mortality was only associated with diabetes diagnosed using the fasting glucose criterion. Mortality risks were similar in this population using either ADA or WHO criteria for diagnosis of diabetes.
Optimization of basal insulin delivery in Type 1 diabetes: a retrospective study on the use of continuous subcutaneous insulin infusion and insulin glargine
Authors: Fahlén M. , Eliasson B. , Odén A.
Published: March 2005

Aims  To compare the effects on glycaemic control after using continuous subcutaneous insulin infusion (CSII) or insulin glargine.

Methods  Data were obtained from 17 diabetes outpatient clinics in Sweden, employing the same diabetes data management system. Type 1 diabetic patients using multiple dose injections were included prior to starting on either CSII (n = 563) or glargine (n = 513). The median duration of therapy was 25 months for CSII and 6 months for glargine. The comparison between the treatment modalities was carried out by multiple regression analysis and logistic regression analysis in an attempt at reducing the influence of confounding factors.

Results  The mean HbA1c decrease was 0.59 ± 1.19% for CSII and 0.20 ± 1.07% for glargine (P < 0.001, when assessed by logistic regression). An additional 0.1% lower HbA1c would be expected if glargine had been optimized with basal insulin 40–60% of the daily dose. The more pronounced effect of CSII was achieved with a lower daily dosage of insulin. In a multiple regression analysis with a change of HbA1c as the dependent variable, the following variables were significant: choice of treatment (P < 0.001), HbA1c prior to treatment (P < 0.001) and BMI prior to treatment (P < 0.01).

Conclusion  Both regimes improved metabolic control, but CSII resulted in significantly higher reduction in HbA1c than after insulin glargine treatment, particularly in those individuals who had higher levels of HbA1c at baseline.
Is the relationship between adherence behaviours and glycaemic control bi‐directional at adolescence? A longitudinal cohort study
Authors: Du Pasquier‐Fediaevsky L. , Chwalow A. J. ,   the PEDIAB Collaborative Group, Tubiana‐Rufi N.
Published: March 2005

Aim  To analyse the change in adherence to diabetes treatment and its association with metabolic control from childhood to adolescence. The Tanner pubertal staging model was selected as a marker of developmental maturity.

Methods  In a multicentre, longitudinal cohort study, 142 children with Type 1 diabetes completed a scale that assessed adherence to treatment and a test of diabetes knowledge at the beginning of the study (T0) and four years later (T4). HbA1c and clinical data were collected at T0 and at T4.

Results  From T0 to T4, the mean HbA1c increased from 8.2 ± 1.6 to 9.1 ± 1.4% (P < 0.001). Among patients at pubertal stages 1–4, adherence did not decline from T0 to T4, whereas the HbA1c level increased and a positive correlation between adherence and the knowledge score was noted (r = 0.32; P < 0.02). Among adolescents at pubertal stage 5, the level of adherence decreased (P < 0.01) from T0 to T4 and the HbA1c level increased despite an increase in the knowledge score (P < 0.001), a negative correlation between HbA1c and adherence was found (r = −0.37; P = 0.001) and adherence at T4 significantly added to the prediction of HbA1c at T4.

Conclusions  In this longitudinal study, an initial worsening of glycaemic control as a result of puberty preceded worsening of adherence behaviours. Low levels of adherence become predictive of HbA1c degradation among pubertal stage 5 adolescents. These results suggest a potential bi‐directional relationship between glycaemic control and adherence.
Effect of maternal diabetes on phosphorylation of insulin‐like growth factor binding protein‐1 in cord serum
Authors: Loukovaara M. , Leinonen P. , Teramo K. , Nurminen E. , Andersson S. , Rutanen E.‐M.
Published: March 2005

Aims  The insulin‐like growth factor (IGF) system is considered important in the regulation of fetal growth. Binding of IGFs to specific binding proteins (IGFBPs) modifies their actions. In fetal blood, IGFBP‐1 is the primary IGF binding protein whose phosphorylation generates proteins with different affinities for IGF‐I. We studied cord serum IGFBP‐1 phosphoisoform profiles in normal pregnancies and in diabetic pregnancies, which are frequently complicated by macrosomia.

Research design and methods  Cord serum IGFBP‐1 phosphoisoform concentrations were measured at birth by two immunoenzymometric assays in 67 pregnancies complicated by Type 1 diabetes, in 28 pregnancies complicated by insulin‐treated gestational diabetes, and in 62 normal pregnancies.

Results  Cord serum highly phosphorylated IGFBP‐1 (hpIGFBP‐1) concentrations were lower in pregnancies complicated by Type 1 diabetes (204 ± 36 µg/l, P = 0.032) and in pregnancies complicated by gestational diabetes (170 ± 28 µg/l, P = 0.031) than in controls (316 ± 34 µg/l). Cord serum lesser phosphorylated IGFBP‐1 (lpIGFBP‐1) concentrations were similar in diabetic and normal pregnancies (P = 0.692 between groups by analysis of variance). Relative birth weight correlated negatively with cord serum hpIGFBP‐1 and lpIGFBP‐1 in diabetic pregnancies, and with cord serum lpIGFBP‐1 in normal pregnancies.

Conclusions  Maternal diabetes is associated with suppressed hpIGFBP‐1 but unaltered lpIGFBP‐1 concentrations in cord serum, suggesting that IGFBP‐1 phosphoisoforms are differentially regulated in the fetus. Because hpIGFBP‐1 has a higher affinity for IGF‐I than does lpIGFBP‐1, diabetes‐related changes in fetal IGFBP‐1 phosphorylation may increase IGF‐I bioavailability and, consequently, stimulate fetal growth. This may partly explain the increased occurrence of macrosomia in diabetic pregnancies.
Birthweight and other pregnancy outcomes in a cohort of women with pre‐gestational insulin‐treated diabetes mellitus, Scotland, 1979–95
Authors: Silva I. dos Santos , Higgins C. , Swerdlow A. J. , Laing S. P. , Slater S. D. , Pearson D. W. M. , Morris A. D.
Published: March 2005

Aims  To assess pregnancy outcomes, in particular birthweight, in a large population‐based cohort of women in Scotland with pre‐gestational insulin‐treated diabetes mellitus.

Methods  Data about diabetes from the Diabetes UK cohort were linked to data on births from the Scottish Hospital In‐Patient Record System. This identified 1112 eligible singleton deliveries during 1979–95 to 706 insulin‐treated women.

Results  One thousand and eighty‐four (97.5%) deliveries resulted in a live‐born infant and 28 (2.5%) in a stillbirth. There were 13 (1.2%) neonatal deaths. The mean birthweight of the live‐born infants was 3421 g, 1.06 standard deviations greater than that of infants in the Scottish general population after correcting for sex and gestational age. Forty‐three per cent of live‐born babies in the study were large (> Scottish 90th percentile) and 4% small (< 10th percentile) for their sex and gestational age. Macrosomia, defined as birthweight ≥ 4000 g, occurred in 23% live‐born babies and its prevalence was significantly inversely related to duration of maternal diabetes. However, the mean birthweight of infants born to mothers with diabetes for 20 or more years was still 0.90 standard deviations greater than in the general population. Prevalence of macrosomia increased with increasing number of previous pregnancies, but was not associated with maternal height or smoking habits. Stillbirth and neonatal death rates were, respectively, 4.7 (95% confidence interval = 3.3, 6.8) and 2.4 (1.4, 4.1), times higher than those in the general population.

Conclusions  The frequency of adverse pregnancy outcomes in women with pre‐existing insulin‐treated diabetes was much higher than in the Scottish general population, and changed little during the study period. A detailed quantification of the independent effect of duration of mother's diabetes on birthweight revealed a continuous inverse correlation between these two variables.
Autoantibodies to GAD and IA‐2 in Saudi Arabian diabetic patients
Authors: Damanhouri L. H. , Dromey J. A. , Christie M. R. , Nasrat H. A. , Ardawi M. S. M. , Robins R. A. , Todd I.
Published: March 2005

Aims  To determine the prevalence of autoantibodies in sera of Saudi diabetic patients including Type 1 and Type 2 diabetes mellitus (DM) and gestational diabetes mellitus (GDM) living in Jeddah, Saudi Arabia. Apart from data on the prevalence of islet‐cell antibodies in patients in Ryhadh (Al‐Attas et al. Freqency of islet cell antibodies in adult newly diagnosed diabetic patients. Ann Saudi Med 1990; 10: 369–373) immunological markers of autoimmune diabetes have not been explored in Saudi Arabians.

Methods  Autoantibodies to GAD65 (GADA) and IA‐2 (IA‐2A) were determined using radio‐immunoprecipitation assays.

Results  In Type 1 DM patients, 54% were GADA+ and 27% were IA‐2A+. A greater negative effect of disease duration was noted for IA‐2A than for GADA positivity. Autoantibodies were more prevalent with younger age of onset. GADA were slightly more common in female Type 1 DM patients. In Type 2 DM, 8/99 patients were GADA+, and three of these patients with shorter disease duration were also IA‐2A+. GADA, and particularly IA‐2A, were associated with a younger age of onset of Type 2 DM and all the autoantibody‐positive Type 2 DM patients were insulin‐treated. GADA were detected in 2.2% of GDM patients, but none of these patients possessed IA‐2A.

Conclusions  The prevalence and associations of autoantibodies in Saudi diabetic patients are very similar to those reported for diabetic patients in other ethnic groups.
Preserved insulin response to tolbutamide in hepatocyte nuclear factor‐1α mutation carriers
Authors: Sagen J. V. , Pearson E. R. , Johansen A. , Spyer G. , Søvik O. , Pedersen O. , Njølstad P. R. , Hattersley A. T. , Hansen T.
Published: March 2005

Aims  Diabetic subjects with mutations in the gene encoding hepatocyte nuclear factor (HNF)‐1α (MODY3) are prone to develop hypoglycaemia at low doses of glibenclamide, interpreted as sulphonylurea hypersensitivity. The present study was undertaken to compare the plasma insulin responses to glucose and tolbutamide in HNF‐1α mutation carriers with those of healthy control subjects.

Methods  Seven mutation carriers; three normoglycaemic, two with impaired glucose tolerance, and two with newly detected diabetes, underwent an oral glucose tolerance test and a tolbutamide‐modified intravenous glucose tolerance test with measurements of plasma insulin. Twenty‐two healthy subjects served as controls.

Results  The plasma insulin response to intravenous glucose was reduced in the HNF‐1α mutation carriers compared to the control subjects, with an area under the curve (median (interquartile range)) of 812 min pmol/l (421, 1647) and 1933 min pmol/l (1521, 2908), respectively (P = 0.03). In striking contrast, the plasma insulin response to tolbutamide was preserved, with an area under the curve of 2109 min pmol/l (1126, 3172) and 2250 min pmol/l (1614, 3276) in the mutation carriers and control subjects, respectively.

Conclusions  HNF‐1α mutation carriers are characterized by preserved tolbutamide‐induced insulin secretion. Compared to healthy subjects, our MODY3 individuals did not show any increased serum insulin response to tolbutamide, suggesting that HNF‐1α mutation carriers are not characterized by sulphonylurea hypersensitivity.
School attendance in children with Type 1 diabetes
Authors: Glaab L. A. , Brown R. , Daneman D.
Published: March 2005

Aims  To determine whether children with Type 1 diabetes mellitus (DM) miss more school than their non‐DM siblings and peers and to identify factors associated with school absenteeism in children with DM.

Methods  School absenteeism data for the 2000–01 school year were obtained for 78 children with DM, 38 non‐DM siblings and 118 269 age‐matched peers in Toronto, Ontario. Questionnaires and hospital records were utilized to evaluate child‐, family‐ and diabetes‐related factors associated with school absenteeism in children with DM.

Results  Children with DM missed only slightly, albeit significantly more school than both their non‐DM siblings (mean ±sd: 10.9 ± 8.9 vs. 8.1 ± 8.1 days, P < 0.001) and peers (median: 8.8 vs. 5.5 days, P = 0.0005). A multiple regression analysis indicated that school absenteeism in children with DM was associated with their parents’ attitudes towards school attendance (P = 0.002), poorer metabolic control (P = 0.006), shorter disease duration (P = 0.006) and a lack of aggressive behaviour (P = 0.02).

Conclusions  With current management strategies, near normal school attendance is a reasonable goal for all children with DM and should be strongly encouraged by parents, educators and health care professionals.
Transcutaneous oxygen tension msonitoring after successful revascularization in diabetic patients with ischaemic foot ulcers
Authors: Caselli A. , Latini V. , Lapenna A. , Di Carlo S. , Pirozzi F. , Benvenuto A. , Uccioli L.
Published: March 2005

Objective  To monitor transcutaneous oxygen tension (TcPO2) after percutaneous transluminal angioplasty (PTA) in diabetic patients with ischaemic foot ulcers.

Research Design and Methods  Twenty‐three diabetic patients with ischaemic foot ulcers who underwent successful revascularization by PTA (SR group) were retrospectively selected. Twenty diabetic patients who underwent unsuccessful revascularization (UR group) were also included. Transcutaneous oxygen tension was measured at the dorsum of the foot before and 1 (± 1), 7 (± 1), 14 (± 1), 21 (± 1) and 28 (± 1) days after the surgical procedure.

Results  After PTA, TcPO2 progressively improved in the SR group, reaching its peak 4 weeks after angioplasty. A concomitant decrease of cutaneous carbon dioxide tension (TcPCO2) was also observed immediately after PTA which reached the lowest levels 3 weeks later. In the UR group, TcPO2 showed a slight improvement immediately after PTA but remained stable throughout the observation, while TcPCO2 levels did not change. Finally, the percentage of SR patients with a TcPO2 ≥ 30 mmHg was 38.5% 1 week after PTA, while it increased to 75% 3 weeks later.

Conclusion  Transcutaneous oxygen tension monitoring showed that after successful revascularization it takes 3–4 weeks for cutaneous oxygenation to improve and reach the optimal levels for wound healing. Transcutaneous carbon dioxide tension monitoring may be more useful to identify the negative outcome of a revascularization procedure. Our findings suggest that, when the surgical approach can be delayed, the best timing to perform a more aggressive debridement or minor amputations is 3–4 weeks after successful revascularization.
Reduced cardiovascular morbidity and mortality associated with metformin use in subjects with Type 2 diabetes
Authors: Johnson J. A. , Simpson S. H. , Toth E. L. , Majumdar S. R.
Published: March 2005

Aim Metformin therapy reduces microvascular complications in Type 2 diabetes; questions remain, however, regarding its impact on macrovascular events. This study examined metformin use in relation to risk of cardiovascular‐related hospitalization and mortality.

Methods We conducted a retrospective cohort analysis, using Saskatchewan Health administrative databases to identify new users of oral antidiabetic drugs. Subject groups were defined by medication use during 1991–1999: sulphonylurea monotherapy, metformin monotherapy, or combination therapy. Deaths and non‐fatal hospitalizations recorded during the study period were identified as cardiovascular‐related from ICD‐9 codes. The main outcome was a composite of first non‐fatal hospitalization or death. Standard multivariate techniques, including propensity scores, were used to adjust for potential confounding. Multivariate Cox proportional hazard models were used to examine the relationship between metformin use and the composite endpoint.

Results Metformin monotherapy was associated with a lower risk of the composite endpoint (adjusted hazard ratio 0.81; 95% confidence interval 0.68, 0.97) compared with sulphonylurea monotherapy. Combination therapy with meformin and a sulphonylurea was associated with lower mortality, but had similar hospitalization rates, to sulphonylurea monotherapy.

Conclusions Metformin monotherapy was associated with a lower risk of cardiovascular‐related morbidity and mortality, and combination metformin and sulphonylurea therapy was associated with a reduced risk of fatal cardiovascular events, when compared with sulphonylurea monotherapy.
Prevalence and risk factors for stroke in Type 2 diabetic patients in Taiwan: a cross‐sectional survey of a national sample by telephone interview
Authors: Tseng C.‐H. , Chong C.‐K. , Sheu J.‐J. , Wu T.‐H. , Tseng C.‐P.
Published: March 2005

Aims  To determine the prevalence and risk factors for stroke in patients with Type 2 diabetes mellitus (T2DM) and the age‐specific prevalence odds ratios (POR) in comparison with the general population in Taiwan.

Methods  A total of 16 994 T2DM patients were randomly selected for telephone interview from a group covered by the National Health Insurance programme. Lifetime prevalence of stroke was calculated and various risk factors were analysed. Age‐specific POR was calculated using previously reported prevalence of stroke in the general population from a nationwide survey across Taiwan. Standardized prevalence and POR were also calculated using the 2000–2025 population of the World Health Organization.

Results  A total of 12 531 cases (73.7%) were successfully interviewed. Stroke prevalence was 7.5%. In multivariate logistic regression, independent predictors were: increasing age, male gender, lower body mass index, ex‐smokers, hyperlipidaemia, systolic pressure (or diastolic pressure when systolic pressure was not adjusted), education level below high school, and living in eastern or southern Taiwan. When compared with the general population, POR for stroke in the age groups < 45, 45–54, 55–64 and ≥ 65 years were 82.29 (9.60, 705.57), 5.43 (2.33, 12.68), 3.73 (2.20, 6.33) and 2.14 (1.59, 2.89), respectively. The age‐standardized prevalence of stroke was 2.3% in the diabetic patients and 0.6% in the general population.

Conclusions  Stroke prevalence in Taiwanese T2DM is 7.5%. Diabetic patients have a higher risk of stroke than the general population, but the relative risk attenuates with age. Besides conventional atherosclerotic risk factors, stroke patients in Taiwan are characterized by lower body mass index, lower education level and residence in southern or eastern Taiwan. The negative association between body mass index and stroke in Taiwanese T2DM is in contrast to the generally accepted concept that obesity is a major risk factor as seen in most western countries.
Animal models of diabetes mellitus
Authors: Rees D. A. , Alcolado J. C.
Published: March 2005

Animal models have been used extensively in diabetes research. Early studies used pancreatectomised dogs to confirm the central role of the pancreas in glucose homeostasis, culminating in the discovery and purification of insulin. Today, animal experimentation is contentious and subject to legal and ethical restrictions that vary throughout the world. Most experiments are carried out on rodents, although some studies are still performed on larger animals. Several toxins, including streptozotocin and alloxan, induce hyperglycaemia in rats and mice. Selective inbreeding has produced several strains of animal that are considered reasonable models of Type 1 diabetes, Type 2 diabetes and related phenotypes such as obesity and insulin resistance. Apart from their use in studying the pathogenesis of the disease and its complications, all new treatments for diabetes, including islet cell transplantation and preventative strategies, are initially investigated in animals. In recent years, molecular biological techniques have produced a large number of new animal models for the study of diabetes, including knock‐in, generalized knock‐out and tissue‐specific knockout mice.
The Implementation of an International Market Servicing Strategy in UK Manufacturing Firms
Authors: Buckley Peter J , Pass C. L. , Prescott Kate
Published: March 2005

This paper presents results from an empirical investigation into the impact of foreign market servicing strategies on the competitiveness of UK manufacturing firms in five industry sectors. Competitiveness is defined by performance, competitive potential and management process. Although the choice of foreign market servicing mode is highly constrained, there is a range of choice available to firms, although this choice is often reactive rather than proactive. The impact of market servicing switches on competitiveness is often profound, although it is not always positive. Moreover, these effects may be in different directions on the three components of competitiveness. Attention to foreign market servicing policies is crucial for achieving international competitiveness.