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1.  Increased Circulating Betatrophin Concentrations in Patients with Type 2 Diabetes 
Betatrophin has recently been described as a key hormone to stimulate beta-cell mass expansion in response to insulin resistance and obesity in mice. The finding has generated an interest in the development of antidiabetic drugs with betatrophin as the active component. However, the circulating levels of betatrophin in patients with type 2 diabetes are not well known. Betatrophin concentrations in plasma of 27 type 2 diabetes patients and 18 gender-, age-, and BMI-matched controls were measured. Study participants were characterized with regard to BMI, waist and hip circumference, blood pressure, and fasting plasma blood lipids, creatinine, glucose, HbA1c, and C-peptide. HOMA2 indices were calculated. Betatrophin was 40% higher in patients with type 2 diabetes (893 ± 80 versus 639 ± 66 pg/mL). Betatrophin positively correlated with age in the controls and with HbA1c in the type 2 diabetes patients. All study participants were insulin resistant with mean HOMA2B IR in both groups exceeding 2 and HOMA2%S < 50%. Control individuals had impaired fasting glucose concentrations. In this report on betatrophin concentrations in type 2 diabetes and insulin resistance, elevated betatrophin levels were measured in the patients with type 2 diabetes. Future studies are clearly needed to delineate the exact role, if any, of betatrophin in regulating human beta-cell mass.
PMCID: PMC4055101  PMID: 24963292
2.  Increased circulating levels of betatrophin in individuals with long-standing type 1 diabetes 
Diabetologia  2013;57:50-53.
The hormone betatrophin was recently described as a potent stimulator of beta cell proliferation in mice. Insulin resistance, but not insulin deficiency, caused upregulation of betatrophin expression. If these findings were found to be fully applicable in humans, this would open up the possibility of future betatrophin treatment in type 1 diabetes. The present study measured for the first time betatrophin concentrations in humans and tested the hypothesis that there would be no difference in circulating betatrophin concentrations between patients with type 1 diabetes and healthy individuals.
Betatrophin concentrations in plasma of 33 patients with type 1 diabetes and 24 age-matched healthy controls were measured by ELISA. The study participants were characterised for blood lipids, BMI, plasma glucose and HbA1c, and, for the diabetic patients, their insulin requirements and any residual C-peptide concentrations.
Plasma betatrophin concentrations were normally ∼300 pg/ml, but were approximately doubled in patients with type 1 diabetes. In the patients, there were no correlations between betatrophin and age, blood lipids, BMI, glucose control or insulin requirement, whereas in controls betatrophin levels increased with age. BMI, blood pressure and triacylglycerol, LDL-cholesterol and HDL-cholesterol levels were similar in patients and healthy controls.
Circulating concentrations of betatrophin are increased in type 1 diabetes in contrast with what was recently described in an insulin-deficient mouse model. However, increased betatrophin concentrations do not protect against loss of C-peptide. Betatrophin treatment in type 1 diabetes would therefore probably not be successful without the use of supraphysiological doses or a combination with immune regulatory treatment.
PMCID: PMC3855541  PMID: 24078058
Beta cell growth; Betatrophin; Type 1 diabetes
3.  Value of information: interim analysis of a randomized, controlled trial of goal-directed hemodynamic treatment for aged patients 
Trials  2013;14:205.
A randomized, controlled trial, intended to include 460 patients, is currently studying peroperative goal-directed hemodynamic treatment (GDHT) of aged hip-fracture patients. Interim efficacy analysis performed on the first 100 patients was statistically uncertain; thus, the trial is continuing in accordance with the trial protocol. This raised the present investigation’s main question: Is it reasonable to continue to fund the trial to decrease uncertainty? To answer this question, a previously developed probabilistic cost-effectiveness model was used. That model depicts (1) a choice between routine fluid treatment and GDHT, given uncertainty of current evidence and (2) the monetary value of further data collection to decrease uncertainty. This monetary value, that is, the expected value of perfect information (EVPI), could be used to compare future research costs. Thus, the primary aim of the present investigation was to analyze EVPI of an ongoing trial with interim efficacy observed.
A previously developed probabilistic decision analytic cost-effectiveness model was employed to compare the routine fluid treatment to GDHT. Results from the interim analysis, published trials, the meta-analysis, and the registry data were used as model inputs. EVPI was predicted using (1) combined uncertainty of model inputs; (2) threshold value of society’s willingness to pay for one, quality-adjusted life-year; and (3) estimated number of future patients exposed to choice between GDHT and routine fluid treatment during the expected lifetime of GDHT.
If a decision to use GDHT were based on cost-effectiveness, then the decision would have a substantial degree of uncertainty. Assuming a 5-year lifetime of GDHT in clinical practice, the number of patients who would be subject to future decisions was 30,400. EVPI per patient would be €204 at a €20,000 threshold value of society’s willingness to pay for one quality-adjusted life-year. Given a future population of 30,400 individuals, total EVPI would be €6.19 million.
If future trial costs are below EVPI, further data collection is potentially cost-effective. When applying a cost-effectiveness model, statements such as ‘further research is needed’ are replaced with ‘further research is cost-effective and ‘further funding of a trial is justified’.
Trial registration NCT01141894
PMCID: PMC3717025  PMID: 23837606
Expected value of perfect information
4.  Severe diabetic ketoacidosis in combination with starvation and anorexia nervosa at onset of type 1 diabetes: A case report 
Upsala Journal of Medical Sciences  2013;118(2):130-133.
We here report a case of diabetic ketoacidosis at onset of type 1 diabetes after a prolonged period of starvation due to anorexia nervosa. A 53-year-old female with a history of anorexia nervosa was admitted to the psychiatric clinic due to psychotic behaviour and inability to take care of herself. Twenty-four hours after admission she was transferred to the clinic of internal medicine due to altered mental status, and laboratory screening revealed a pH of 6.895 and blood glucose concentration of 40 mmol/L. Due to the unusual combination of prolonged starvation and diabetic ketoacidosis we implemented some modifications of existing treatment guidelines and some special considerations regarding nutrition in order to prevent a re-feeding syndrome.
PMCID: PMC3633328  PMID: 23544963
Anorexia nervosa; diabetic ketoacidosis; starvation; type 1 diabetes
5.  Markedly Decreased Blood Perfusion of Pancreatic Islets Transplanted Intraportally Into the Liver 
Diabetes  2012;61(3):665-673.
Experimental studies indicate low revascularization of intraportally transplanted islets. This study aimed to quantify, for the first time, the blood perfusion of intrahepatically transplanted islets and elucidate necessary factors for proper islet graft revascularization at this site. Yellow chameleon protein 3.0 islets expressing fluorescent protein in all cells were transplanted. Graft blood perfusion was determined by microspheres. The vascular density and relative contribution of donor blood vessels in revascularization was evaluated using islets expressing green fluorescent protein under the Tie-2 promoter. Blood perfusion of intrahepatic islets was as a mean only 5% of that of native islets at 1-month posttransplantation. However, there was a marked heterogeneity where blood perfusion was less decreased in islets transplanted without prior culture and in many cases restored in islets with disrupted integrity. Analysis of vascular density showed that distorted islets were well revascularized, whereas islets still intact at 1-month posttransplantation were almost avascular. Few donor endothelial cells were observed in the new islet vasculature. The very low blood perfusion of intraportally transplanted islets is likely to predispose for ischemia and hamper islet function. Since donor endothelial cells do not expand posttransplantation, disruption of islet integrity is necessary for revascularization to occur by recipient blood vessels.
PMCID: PMC3282819  PMID: 22315321
6.  Setting priorities in primary health care - on whose conditions? A questionnaire study 
BMC Family Practice  2012;13:114.
In Sweden three key criteria are used for priority setting: severity of the health condition; patient benefit; and cost-effectiveness. They are derived from the ethical principles established by the Swedish parliament 1997 but have been used only to a limited extent in primary care. The aim of this study was to describe and analyse: 1) GPs', nurses', and patients' prioritising in routine primary care 2) The association between the three key priority setting criteria and the overall priority assigned by the GPs and nurses to individual patients.
Paired questionnaires were distributed to all patients and the GPs or nurses they had contact with during a 2-week period at four health centres in Sweden. The staff registered the health conditions or health problem, and the planned intervention. Then they estimated the severity of the health condition, the expected patient benefit, and the cost-effectiveness of the planned intervention. Both the staff and the patients reported their overall prioritisation of the patient. In total, 1851 paired questionnaires were collected.
Compared to the medical staff, the patients assigned relatively higher priority to acute/minor conditions than to preventive check-ups for chronic conditions. Severity of the health condition was the priority setting criterion that had the strongest association with the overall priority for the staff as a whole, but for the GPs it was cost-effectiveness.
The challenge for primary care providers is to balance the patients' demands with medical needs and cost-effectiveness. Transparent priority setting in primary care might contribute to a greater consensus between GPs and nurses on how to use the key priority setting criteria.
PMCID: PMC3528614  PMID: 23181453
7.  Sustained Beta-Cell Dysfunction but Normalized Islet Mass in Aged Thrombospondin-1 Deficient Mice 
PLoS ONE  2012;7(10):e47451.
Pancreatic islet endothelial cells have in recent years been shown to support beta-cell mass and function by paracrine interactions. Recently, we identified an islets endothelial-specific glycoprotein, thrombospondin-1 (TSP-1), that showed to be of importance for islet angiogenesis and beta-cell function in young mice. The present study aimed to investigate long-term consequences for islet morphology and beta-cell function of TSP-1 deficiency. Islet and beta-cell mass were observed increased at 10–12 weeks of age in TSP-1 deficient mice, but were normalized before 16 weeks of age when compared to wild-type controls. Islet vascularity was normal in 10–12 and 16-week-old TSP-1 deficient animals, whereas islets of one-year-old animals lacking TSP-1 were hypervascular. Beta-cell dysfunction in TSP-1 deficient animals was present at similar magnitudes between 10–12 and 52 weeks of age, as evaluated by glucose tolerance tests. The insulin secretion capacity in vivo of islets in one-year-old TSP-1 deficient animals was only ∼15% of that in wild-type animals. Using a transplantation model, we reconstituted TSP-1 in adult TSP-deficient islets. In contrast to neonatal TSP-1 deficient islets that we previously reported to regain function after TSP-1 reconstitution, adult islets failed to recover. We conclude that TSP-1 deficiency in islets causes changing vascular and endocrine morphological alterations postnatally, but is coupled to a chronic beta-cell dysfunction. The beta-cell dysfunction induced by TSP-1 deficiency is irreversible if not substituted early in life.
PMCID: PMC3477147  PMID: 23094049
8.  Female Mice are Protected against High-Fat Diet Induced Metabolic Syndrome and Increase the Regulatory T Cell Population in Adipose Tissue 
PLoS ONE  2012;7(9):e46057.
Sex differences in obesity-induced complications such as type 2 diabetes have been reported. The aim of the study was to pinpoint the mechanisms resulting in different outcome of female and male mice on a high-fat diet (HFD). Mice fed control or HFD were monitored for weight, blood glucose, and insulin for 14 weeks. Circulating chemokines, islet endocrine function and blood flow, as well as adipose tissue populations of macrophages and regulatory T-lymphocytes (Treg) were thereafter assessed. Despite similar weight (43.8±1.0 and 40.2±1.5 g, respectively), male but not female mice developed hyperinsulinemia on HFD as previously described (2.5±0.7 and 0.5±0.1 pmol/l, respectively) consistent with glucose intolerance. Male mice also exhibited hypertrophic islets with intact function in terms of insulin release and blood perfusion. Low-grade, systemic inflammation was absent in obese female but present in obese male mice (IL-6 and mKC, males: 77.4±17 and 1795±563; females: 14.6±4.9 and 240±22 pg/ml), and the population of inflammatory macrophages was increased in intra-abdominal adipose tissues of high-fat-fed male but not female mice. In contrast, the anti-inflammatory Treg cell population increased in the adipose tissue of female mice in response to weight gain, while the number decreased in high-fat-fed male mice. In conclusion, female mice are protected against HFD-induced metabolic changes while maintaining an anti-inflammatory environment in the intra-abdominal adipose tissue with expanded Treg cell population, whereas HFD-fed male mice develop adipose tissue inflammation, glucose intolerance, hyperinsulinemia, and islet hypertrophy.
PMCID: PMC3458106  PMID: 23049932
9.  Increased Numbers of Low-Oxygenated Pancreatic Islets After Intraportal Islet Transplantation 
Diabetes  2011;60(9):2350-2353.
No previous study has measured the oxygenation of intraportally transplanted islets, although recent data suggest that insufficient engraftment may result in hypoxia and loss of islet cells.
After intraportal infusion into syngeneic mice, islet oxygenation was investigated in 1-day-old, 1-month-old, or 3-month-old grafts and compared with renal subcapsular grafts and native islets. Animals received an intravenous injection of pimonidazole for immunohistochemical detection of low-oxygenated islet cells (pO2 <10 mmHg), and caspase-3 immunostaining was performed to assess apoptosis rates in adjacent tissue sections.
In the native pancreas of nontransplanted animals, ∼30% of the islets stained positive for pimonidazole. In 1-day-old and 1-month-old grafts, the percentage of pimonidazole-positive islets in the liver was twice that of native islets, whereas this increase was abolished in 3-month-old grafts. Beneath the renal capsule, pimonidazole accumulation was, however, similar to native islets at all time points. Apoptosis rates were markedly increased in 1-day-old intrahepatic grafts compared with corresponding renal islet grafts, which were slightly increased compared with native islets. One month posttransplantation renal subcapsular grafts had similar frequencies of apoptosis as native islets, whereas apoptosis in intraportally implanted islets was still high. In the liver, islet graft vascular density increased between 1 and 3 months posttransplantation, and apoptosis rates simultaneously dropped to values similar to those observed in native islets.
The vascular engraftment of intraportally transplanted islets is markedly delayed compared with renal islet grafts. The prolonged ischemia of intraportally transplanted islets may favor an alternative implantation site.
PMCID: PMC3161309  PMID: 21788575
10.  A Low-Oxygenated Subpopulation of Pancreatic Islets Constitutes a Functional Reserve of Endocrine Cells 
Diabetes  2011;60(8):2068-2075.
The blood perfusion of pancreatic islets is highly variable and tightly regulated by the blood glucose concentration. Thus, oxygen levels are considered crucial for islet metabolism and function. Although islet oxygenation has been extensively studied in vitro, little is known about it in vivo. The current study aimed to investigate the oxygenation of the endocrine pancreas in vivo.
The reductive metabolism of 2-nitroimidazoles, such as pimonidazole, has previously been extensively used in studies of oxygen metabolism both in vitro and in vivo. At tissue oxygen levels <10 mmHg, pimonidazole accumulates intracellularly and may thereafter be detected by means of immunohistochemistry. Islet oxygenation was investigated in normal, 60% partially pancreatectomized, as well as whole-pancreas–transplanted rats. Moreover, leucine-dependent protein biosynthesis was performed using autoradiography to correlate islet oxygenation with metabolic activity.
In vivo, 20–25% of all islets in normal rats showed low oxygenation (pO2 <10 mmHg). Changes in the islet mass, by means of whole-pancreas transplantation, doubled the fraction of low-oxygenated islets in the endogenous pancreas of transplanted animals, whereas this fraction almost completely disappeared after a 60% partial pancreatectomy. Moreover, oxygenation was related to metabolism, since well-oxygenated islets in vivo had 50% higher leucine-dependent protein biosynthesis, which includes (pro)insulin biosynthesis.
The current study suggests a novel subpopulation of dormant low-oxygenated islets, which seems to constitute a functional reserve of endocrine cells. This study establishes a novel perspective on the use of the endocrine pancreas in glucose homeostasis.
PMCID: PMC3142080  PMID: 21788581
11.  Thrombospondin-1: An Islet Endothelial Cell Signal of Importance for β-Cell Function 
Diabetes  2011;60(7):1946-1954.
Loss of thrombospondin (TSP)-1 in pancreatic islets has been shown to cause islet hyperplasia. This study tested the hypothesis that endothelial-derived TSP-1 is important for β-cell function.
Islet function was evaluated both in vivo and in vitro. Messenger RNA and protein expression were measured by real-time PCR and Western blot, respectively. The role of endothelial-derived TSP-1 for β-cell function was determined using a transplantation design in which recipient blood vessels either were allowed to grow or not into the transplanted islets.
TSP-1–deficient mice were glucose intolerant, despite having an increased β-cell mass. Moreover, their islets had decreased glucose-stimulated insulin release, (pro)insulin biosynthesis, and glucose oxidation rate, as well as increased expression of uncoupling protein-2 and lactate dehydrogenase-A when compared with control islets. Almost all TSP-1 in normal islets were found to be derived from the endothelium. Transplantation of free and encapsulated neonatal wild-type and TSP-1–deficient islets was performed in order to selectively reconstitute with TSP-1–positive or –negative blood vessels in the islets and supported that the β-cell defects occurring in TSP-1–deficient islets reflected postnatal loss of the glycoprotein in the islet endothelial cells. Treatment of neonatal TSP-1–deficient mice with the transforming growth factor (TGF)β-1–activating sequence of TSP-1 showed that reconstitution of TGFβ-1 activation prevented the development of decreased glucose tolerance in these mice. Thus, endothelial-derived TSP-1 activates islet TGFβ-1 of importance for β-cells.
Our study indicates a novel role for endothelial cells as functional paracrine support for pancreatic β-cells.
PMCID: PMC3121439  PMID: 21617177
12.  Striated Muscle as Implantation Site for Transplanted Pancreatic Islets 
Journal of Transplantation  2011;2011:352043.
Islet transplantation is an attractive treatment for selected patients with brittle type 1 diabetes. In the clinical setting, intraportal transplantation predominates. However, due to extensive early islet cell death, the quantity of islets needed to restore glucose homeostasis requires in general a minimum of two donors. Moreover, the deterioration of islet function over time results in few insulin-independent patients after five-year followup. Specific obstacles to the success of islet transplantation include site-specific concerns for the liver such as the instant blood mediated inflammatory reaction, islet lipotoxicity, low oxygen tension, and poor revascularization, impediments that have led to the developing interest for alternative implantation sites over recent years. Within preclinical settings, several alternative sites have now been investigated and proven favorable in various aspects. Muscle is considered a very promising site and has physiologically properties and technical advantages that could make it optimal for islet transplantation.
PMCID: PMC3235886  PMID: 22174984
13.  Evaluation of Health Research: Measuring Costs and Socioeconomic Effects 
The topic of this work is health research evaluation including basic and clinical medical research, as well as healthcare research. The main objects are to explore possible approaches for valuing research in economic terms and to prepare an analytical model for evaluation of health research using the Swedish context. The study also aims to identify potential effects and their significance, and to provide a basis for discussions about the effects of research investments.
The study has reviewed ten articles indicating positive effects, in the form of improved health and economic growth. The study also developed a model applied to Swedish health research.
The review indicates that positive effects, in the form of improved health and economic growth, have a value that greatly exceeds the costs of the research investments. The tentative model applied to Swedish health research also indicates predominantly positive returns, but in a lower range than the review would imply. Methodological problems, however, entail major uncertainty in the cited results.
Accurate determination of the economic value of research would require significantly better basic data and better knowledge of relationships between research, implementation of new knowledge, and health effects. Information in support of decisions about future allocation of research resources is preferably produced by a combination of general analyses and strategically selected case studies.
PMCID: PMC3237262  PMID: 22174959
Medical research; Policy-making; Social impact; Innovation
14.  Clinical and Experimental Pancreatic Islet Transplantation to Striated Muscle 
Diabetes  2010;59(10):2569-2578.
Curing type 1 diabetes by transplanting pancreatic islets into the liver is associated with poor long-term outcome and graft failure at least partly due to inadequate graft revascularization. The aim of the current study was to evaluate striated muscle as a potential angiogenic site for islet transplantation.
The current study presents a new experimental model that is found to be applicable to clinical islet transplantation. Islets were implanted into striated muscle and intraislet vascular density and blood flow were visualized with intravital and confocal microscopy in mice and by magnetic resonance imaging in three autotransplanted pancreatectomized patients. Mice were rendered neutropenic by repeated injections of Gr-1 antibody, and diabetes was induced by alloxan treatment.
Contrary to liver-engrafted islets, islets transplanted to mouse muscle were revascularized with vessel densities and blood flow entirely comparable with those of islets within intact pancreas. Initiation of islet revascularization at the muscular site was dependent on neutrophils, and the function of islets transplanted to muscle was proven by curing diabetic mice. The experimental data were confirmed in autotransplanted patients where higher plasma volumes were measured in islets engrafted in forearm muscle compared with adjacent muscle tissue through high-resolution magnetic resonance imaging.
This study presents a novel paradigm in islet transplantation whereby recruited neutrophils are crucial for the functionally restored intraislet blood perfusion following transplantation to striated muscle under experimental and clinical situations.
PMCID: PMC3279536  PMID: 20651296
15.  Randomised prostate cancer screening trial: 20 year follow-up 
Objective To assess whether screening for prostate cancer reduces prostate cancer specific mortality.
Design Population based randomised controlled trial.
Setting Department of Urology, Norrköping, and the South-East Region Prostate Cancer Register.
Participants All men aged 50-69 in the city of Norrköping, Sweden, identified in 1987 in the National Population Register (n=9026).
Intervention From the study population, 1494 men were randomly allocated to be screened by including every sixth man from a list of dates of birth. These men were invited to be screened every third year from 1987 to 1996. On the first two occasions screening was done by digital rectal examination only. From 1993, this was combined with prostate specific antigen testing, with 4 µg/L as cut off. On the fourth occasion (1996), only men aged 69 or under at the time of the investigation were invited.
Main outcome measures Data on tumour stage, grade, and treatment from the South East Region Prostate Cancer Register. Prostate cancer specific mortality up to 31 December 2008.
Results In the four screenings from 1987 to 1996 attendance was 1161/1492 (78%), 957/1363 (70%), 895/1210 (74%), and 446/606 (74%), respectively. There were 85 cases (5.7%) of prostate cancer diagnosed in the screened group and 292 (3.9%) in the control group. The risk ratio for death from prostate cancer in the screening group was 1.16 (95% confidence interval 0.78 to 1.73). In a Cox proportional hazard analysis comparing prostate cancer specific survival in the control group with that in the screened group, the hazard ratio for death from prostate cancer was 1.23 (0.94 to 1.62; P=0.13). After adjustment for age at start of the study, the hazard ratio was 1.58 (1.06 to 2.36; P=0.024).
Conclusions After 20 years of follow-up the rate of death from prostate cancer did not differ significantly between men in the screening group and those in the control group.
Trial registration Current Controlled Trials, ISRCTN06342431.
PMCID: PMC3069219  PMID: 21454449
16.  Influence of microenvironment on engraftment of transplanted β-cells 
Pancreatic islet transplantation into the liver provides a possibility to treat selected patients with brittle type 1 diabetes mellitus. However, massive early β-cell death increases the number of islets needed to restore glucose homeostasis. Moreover, late dysfunction and death contribute to the poor long-term results of islet transplantation on insulin independence. Studies in recent years have identified early and late challenges for transplanted pancreatic islets, including an instant blood-mediated inflammatory reaction when exposing human islets to the blood microenvironment in the portal vein and the low oxygenated milieu of islets transplanted into the liver. Poor revascularization of remaining intact islets combined with severe changes in the gene expression of islets transplanted into the liver contributes to late dysfunction. Strategies to overcome these hurdles have been developed, and some of these interventions are now even tested in clinical trials providing a hope to improve results in clinical islet transplantation. In parallel, experimental and clinical studies have, based on the identified problems with the liver site, evaluated the possibility of change of implantation organ in order to improve the results. Site-specific differences clearly exist in the engraftment of transplanted islets, and a more thorough characterization of alternative locations is needed. New strategies with modifications of islet microenvironment with cells and growth factors adhered to the islet surface or in a surrounding matrix could be designed to intervene with site-specific hurdles and provide possibilities to improve future results of islet transplantation.
PMCID: PMC3039754  PMID: 21288056
Engraftment; implantation site; islet transplantation
17.  Priority setting in primary health care - dilemmas and opportunities: a focus group study 
BMC Family Practice  2010;11:71.
Swedish health care authorities use three key criteria to produce national guidelines for local priority setting: severity of the health condition, expected patient benefit, and cost-effectiveness of medical intervention. Priority setting in primary health care (PHC) has significant implications for health costs and outcomes in the health care system. Nevertheless, these guidelines have been implemented to a very limited degree in PHC. The objective of the study was to qualitatively assess how general practitioners (GPs) and nurses perceive the application of the three key priority-setting criteria.
Focus groups were held with GPs and nurses at primary health care centres, where the staff had a short period of experience in using the criteria for prioritising in their daily work.
The staff found the three key priority-setting criteria (severity, patient benefit, and cost-effectiveness) to be valuable for priority setting in PHC. However, when the criteria were applied in PHC, three additional dimensions were identified: 1) viewpoint (medical or patient's), 2) timeframe (now or later), and 3) evidence level (group or individual).
The three key priority-setting criteria were useful. Considering the three additional dimensions might enhance implementation of national guidelines in PHC and is probably a prerequisite for the criteria to be useful in priority setting for individual patients.
PMCID: PMC2955602  PMID: 20863364
18.  Improved Vascular Engraftment and Graft Function After Inhibition of the Angiostatic Factor Thrombospondin-1 in Mouse Pancreatic Islets 
Diabetes  2008;57(7):1870-1877.
OBJECTIVE—Insufficient development of a new intra-islet capillary network after transplantation may be one contributing factor to the failure of islet grafts in clinical transplantation. The present study tested the hypothesis that the angiostatic factor thrombospondin-1 (TSP-1), which is normally present in islets, restricts intra-islet vascular expansion posttransplantation.
RESEARCH DESIGN AND METHODS—Pancreatic islets of TSP-1–deficient (TSP-1−/−) mice or wild-type islets transfected with siRNA for TSP-1 were transplanted beneath the renal capsule of syngeneic or immunocompromised recipient mice.
RESULTS—Both genetically TSP-1−/− islets and TSP-1 siRNA-transfected islet cells demonstrated an increased vascular density when compared with control islets 1 month after transplantation. This was also reflected in a markedly increased blood perfusion and oxygenation of the grafts. The functional importance of the improved vascular engraftment was analyzed by comparing glucose-stimulated insulin release from islet cells transfected with either TSP-1 siRNA or scramble siRNA before implantation. These experiments showed that the increased revascularization of grafts composed of TSP-1 siRNA-transfected islet cells correlated to increments in both their first and second phase of glucose-stimulated insulin secretion.
CONCLUSIONS—Our findings demonstrate that inhibition of TSP-1 in islets intended for transplantation may be a feasible strategy to improve islet graft revascularization and function.
PMCID: PMC2453615  PMID: 18420490
19.  Variations in HSP70 genes associated with noise-induced hearing loss in two independent populations 
Noise-induced hearing loss (NIHL) is one of the most important occupational health hazards. Millions of people worldwide are exposed daily to harmful levels of noise. NIHL is a complex disease resulting from an interaction between genetic and environmental factors. Although the environmental risk factors have been studied extensively, little is known about the genetic factors. Heat-shock proteins (HSPs) are induced after exposure to severe noise. When first induced by exposure to moderate sound levels, they can protect the ear from damage from excessive noise exposure. This protection is highly variable between individuals. An association of HSP70 genes with NIHL has been described by Yang et al (2006) in a Chinese sample set of noise-exposed workers. In this study, three polymorphisms (rs1043618, rs1061581 and rs2227956) in HSP70-1, HSP70-2 and HSP70-hom, respectively, were genotyped in 206 Swedish and 238 Polish DNA samples of noise-exposed subjects and analyzed. One SNP, rs2227956 in HSP70-hom, resulted in a significant association with NIHL in both sample sets. In addition, rs1043618 and rs1061581 were significant in the Swedish sample set. Analysis of the haplotypes composed of the three SNPs revealed significant associations between NIHL and haplotype GAC in both sample sets and with haplotype CGT in the Swedish sample set. In conclusion, this study replicated the association of HSP70 genes with NIHL in a second and third independent noise-exposed sample set, hereby adding to the evidence that HSP70 genes may be NIHL susceptibility genes.
PMCID: PMC2986160  PMID: 18813331
noise-induced hearing loss; HSP70; association study; replication
20.  Primary care patients’ attitudes to priority setting in Sweden 
To analyse attitudes to priority setting among patients in Swedish primary healthcare.
A questionnaire was given to patients comprising statements on attitudes towards prioritizing, on the role of politicians and healthcare staff in prioritizing, and on patient satisfaction with the outcome of their contact with primary healthcare (PHC).
Four healthcare centres in Sweden, chosen through purposive sampling.
All the patients in contact with the health centres during a two-week period in 2004 (2517 questionnaires, 72% returned).
Main outcomes
Patient attitudes to priority setting and satisfaction with the outcome of their contact.
More than 75% of the patients agreed with statements like “Public health services should always provide the best possible care, irrespective of cost”. Almost three-quarters of the patients wanted healthcare staff rather than politicians to make decisions on priority setting. Younger patients and males were more positive towards priority setting and they also had a more positive view of the role of politicians. Less than 10% of the patients experienced some kind of economic rationing but the majority of these patients were satisfied with their contact with primary care.
Primary care patient opinions concerning priority setting are a challenge for both politicians and GPs. The fact that males and younger patients are less negative to prioritizing may pave the way for a future dialogue between politicians and the general public.
PMCID: PMC3410460  PMID: 19466679
Health priorities; family practice; patient participation; patient satisfaction; primary healthcare; rationing
21.  Non-randomised patients in a cholecystectomy trial: characteristics, procedures, and outcomes 
BMC Surgery  2006;6:17.
Laparoscopic cholecystectomy is now considered the first option for gallbladder surgery. However, 20% to 30% of cholecystectomies are completed as open operations often on elderly and fragile patients. The external validity of randomised trials comparing mini-laparotomy cholecystectomy and laparoscopic cholecystectomy has not been studied. The aim of this study is to analyse characteristics, procedures, and outcomes for all patients who underwent cholecystectomy without being included in such a trial.
Characteristics (age, sex, co-morbidity, and ASA-score), operation time, hospital stay, and mortality were compared for patients who underwent cholecystectomy outside and within a randomised controlled trial comparing mini-laparotomy and laparoscopic cholecystectomy.
During the inclusion period 1719 patients underwent cholecystectomy. 726 patients were randomised and 724 of them completed the trial; 993 patients underwent cholecystectomy outside the trial. The non-randomised patients were older – and had more complications from gallstone disease, higher co-morbidity, and higher ASA – score when compared with trial patients. They were also more likely to undergo acute surgery and they had a longer postoperative hospital stay, with a median 3 versus 2 days (p < 0.001 for all comparisons). Standardised mortality ratio within 90 days of operation was 3.42 (mean) (95% CI 2.17 to 5.13) for non-randomised patients and 1.61 (mean) (95%CI 0.02 to 3.46) for trial patients. For non-randomised patients, operation time did not differ significantly between mini-laparotomy and open cholecystectomy in multivariate analysis. However, the operation for laparoscopic cholecystectomy lasted 20 minutes longer than open cholecystectomy. Hospital stay was significantly shorter for both mini-laparotomy and laparoscopic cholecystectomy compared to open cholecystectomy.
Non-randomised patients were older and more sick than trial patients. The assignment of healthier patients to trials comparing mini-laparotomy cholecystectomy and laparoscopic cholecystectomy limits the external validity of conclusions reached in such trials.
PMCID: PMC1769514  PMID: 17190587

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