Real-world accuracy of computed tomography in patients admitted with small bowel obstruction: a multicentre prospective cohort study.

PURPOSE: Small bowel obstruction (SBO) is a common surgical emergency. Previous studies have shown the value computed tomography (CT) scanning in both confirming this diagnosis and identifying indications for urgent surgical intervention, such as strangulated bowel or closed loop obstructions. However, most of the literature is based on retrospective expert review of previous imaging and little data regarding the real-time accuracy of CT reporting is available. Here, we investigated the real-world accuracy of CT reporting in patients admitted with SBO. METHODS: This was a multicentre prospective study including consecutive patients admitted with SBO. The primary outcomes were the sensitivity and specificity of CT scanning for bowel obstruction with ischaemia and closed loop obstruction. Data were retrieved from the original CT reports written by on-call radiologists and compared with operative findings. RESULTS: One hundred seventy-six patients were included, all of whom underwent CT scanning with intravenous contrast followed by operative management of SBO. Bowel obstruction with ischaemia was noted in 20 patients, with a sensitivity and specificity of CT scanning of 40.0% and 85.5%, respectively. Closed loop obstructions were noted in 26 patients, with a sensitivity and specificity of CT scanning of 23.1% and 98.0%, respectively. CONCLUSIONS: The real-world accuracy of CT scanning appears to be lower than previously reported in the literature. Strategies to address this could include the development of standardised reporting schemas and to increase the surgeon's own familiarity with relevant CT features in patients admitted with SBO.

Management and short-term outcomes of patients with small bowel obstruction in Denmark: a multicentre prospective cohort study.

AIMS: The optimal management of small bowel obstruction (SBO) remains a matter of debate and treatment varies internationally. In Denmark, a more surgically aggressive strategy has traditionally been used, but to what extent patient outcomes differ from international reports is unknown. This study aimed to describe the current management and outcomes of patients admitted with SBO in Denmark. METHODS: This was a prospective cohort study conducted at six acute hospitals in Denmark over a 4-month period. Patients aged ≥ 18 years with a clinical or radiological diagnosis of SBO were eligible. Primary outcomes were 30 day morbidity and mortality rates. RESULTS: 316 patients were included during the study period. The median age was 72 years and 56% were female. Diagnosis was made by computed tomography (CT) in 313 patients (99.1%), with the remaining three diagnosed clinically. Non-operative management was the initial strategy in 152 patients (48.1%) and successful in 119 (78.3%). Urgent surgery was performed in the remaining 164 (51.9%), with a laparoscopic approach used in 84 patients (51.2%). The entire cohort had a 30 day mortality rate of 7.3% and a 30 day morbidity rate of 17.1%. CONCLUSIONS: The management of SBO in Denmark differs markedly to previous international reports, with an almost ubiquitous use of CT for diagnosis and a high proportion of patients undergoing urgent surgery. Despite higher rates of surgery, patient outcomes are broadly similar to reports of more conservative strategies, perhaps due to a reduction in delayed operations. TRIAL REGISTRATION: Trial registration number: NCT04750811. Trial registration date: 11/02/2021.

Patients' perspectives on point-of-care diagnostics and treatment by emergency medical technicians in acute COPD exacerbations: A qualitative study.

BACKGROUND: In Denmark emergency medical technicians transport patients with acute COPD exacerbations to the nearest emergency department. From a clinical and economic perspective, this transport and assessment at the hospital may be inconvenient if the patient is immediately discharged from the emergency department. We established an emergency technical technicians point-of-care diagnostics and treatment program of patients with COPD with use of ultrasound and blood analysis. Patients' perspectives on treatment at home and sense of security are important to qualify clinical practice at home with patients with acute exacerbation. AIM AND OBJECTIVES: To explore patient's and relatives' experience of treatment at home during emergency calls due to COPD in exacerbation and to investigate their attitude to avoid hospitalization as well as experience of stress during point-of-care diagnostics in their own home. METHOD: A qualitative study comprising semi-structured interviews with 16 patients carried out from April 1st, 2019 to March 31st, 2020 in Denmark. Data was analysed inspired by Malteruds' text condensation and informed by Critical Psychology with first person perspective focusing on the patient's views on point-of-care diagnostics and treatment of their COPD in acute exacerbation. RESULTS: The interviews revealed that in order to ensure an experience of quality in the assessment and treatment of patients in their own homes, it was important that the ambulance staff showed great safety and experience in the use of the technical equipment and treatment of dyspnea. It was also of importance that the patients felt confident that their general practitioner followed up on the home treatment initiated. CONCLUSION: Patients' perspectives showed that point-of-care diagnostics and treatment of acute COPD in exacerbation was considered a qualitative offer by the patients and their relatives. At the same time, it was crucial that the emergency medical technicians showed experience and safety in handling shortness of breath as well as the technical equipment. TRIAL REGISTRATION: Approved by the Danish Data Protection Agency Project-ID: 20/24845.

Mitral Regurgitation Severity and Left Ventricular Systolic Dimension Predict Survival in Young Cavalier King Charles Spaniels.

BACKGROUND: Development and progression of myxomatous mitral valve disease (MMVD) in dogs are difficult to predict. Identification at a young age of dogs at high risk of adverse outcome in the future is desirable. HYPOTHESIS/OBJECTIVES: To study the predictive value of selected clinical and echocardiographic characteristics associated with MMVD obtained at a young age for prediction of long-term cardiac and all-cause mortality in Cavalier King Charles Spaniels (CKCS). ANIMALS: 1125 privately owned CKCS. METHODS: A retrospective study including CKCS examined at the age of 1-3 years. Long-term outcome was assessed by telephone interview with owners. The value of variables for predicting mortality was investigated by Cox proportional hazard and Kaplan-Meier analyses. RESULTS: Presence of moderate to severe mitral regurgitation (MR) (hazard ratio (HR) = 3.03, 95% confidence interval (95% CI) = 1.48-6.23, P = 0.0025) even intermittent moderate to severe MR (HR = 2.23, 95% CI = 1.48-6.23, P = 0.039) on color flow Doppler echocardiography was significantly associated with increased hazard of cardiac death. An interaction between MR and sex was significant for all-cause mortality (P = 0.035), showing that males with moderate to severe MR had a higher all-cause mortality compared to males with no MR (HR = 2.38, 95% CI = 1.27-4.49, P = 0.0071), whereas no difference was found between female MR groups. The risk of cardiac (HR = 1.37, 95% CI = 1.14-1.63, P < 0.001) and all-cause (HR = 1.13, 95% CI = 1.02-1.24, P = 0.016) mortality increased with increasing left ventricular end-systolic internal dimension normalized for body weight (LVIDSN ). CONCLUSIONS AND CLINICAL IMPORTANCE: Moderate to severe MR, even if intermittent, and increased LVIDSN in dogs <3 years of age were associated with cardiac death later in life in CKCS.

Increased mortality in a Danish cohort of young people with Type 1 diabetes mellitus followed for 24 years.

AIM: To determine the mortality rate in a Danish cohort of children and adolescents diagnosed with Type 1 diabetes mellitus compared with the general population. METHODS: In 1987 and 1989 we included 884 children and 1020 adolescents aged 20 years and under, corresponding to 75% of all Danish children and adolescents with Type 1 diabetes, in two nationwide studies in Denmark. Those who had participated in both investigations (n = 720) were followed until 1 January 2014, using the Danish Civil Registration System on death certificates and emigration. We derived the expected number of deaths in the cohort, using population data values from Statistics Denmark to calculate the standardized mortality ratio. Survival analysis was performed using Cox proportional hazards model. RESULTS: During the 24 years of follow-up, 49 (6.8%) patients died, resulting in a standardized mortality ratio of 4.8 (95% confidence interval 3.5, 6.2) compared with the age-standardized general population. A 1% increase in baseline HbA1c (1989), available in 718 of 720 patients, was associated with all-cause mortality (hazard ratio = 1.38; 95% confidence interval 1.2, 1.6; P < 0.0001). Type 1 diabetes with multiple complications was the most common reported cause of death (36.7%). CONCLUSION: We found an increased mortality rate in this cohort of children and adolescents with Type 1 diabetes compared with the general population. The only predictor for increased risk of death up to 24 years after inclusion was the HbA1c level in 1989. This emphasizes the importance of achieving optimal metabolic control in young people with Type 1 diabetes.

Complications after emergency laparotomy beyond the immediate postoperative period - a retrospective, observational cohort study of 1139 patients.

Mortality and morbidity occur commonly following emergency laparotomy, and incur a considerable clinical and financial healthcare burden. Limited data have been published describing the postoperative course and temporal pattern of complications after emergency laparotomy. We undertook a retrospective, observational, multicentre study of complications in 1139 patients after emergency laparotomy. A major complication occurred in 537/1139 (47%) of all patients within 30 days of surgery. Unadjusted 30-day mortality was 20.2% and 1-year mortality was 34%. One hundred and thirty-seven of 230 (60%) deaths occurred between 72 h and 30 days after surgery; all of these patients had complications, indicating that there is a prolonged period with a high frequency of complications and mortality after emergency laparotomy. We conclude that peri-operative, enhanced recovery care bundles for preventing complications should extend their focus on continuous complication detection and rescue beyond the first few postoperative days.

Nationwide reduction in the frequency of severe hypoglycemia by half.

AIMS: To examine contemporary rates of severe hypoglycemia (SH) and identify the effect of predictors of SH in a pediatric type 1 diabetes population. METHODS: The national diabetes register provided data on children residing in Denmark from 2008 to 2013 in this register-based population study. Robust Poisson regression models were applied. RESULTS: The study population [n = 2,715 (50.9 % boys), mean (SD) age at onset; 8.1 (4.0) years, diabetes duration; 5.6 (4.9) years] comprised 7,390 person-years of data and 561 events of SH. The overall incidence of SH was 7.6 per 100 person-years. The incidence rate peaked with 16.0 per 100 person-years in 2008 reaching a nadir of 4.9 in 2011. Overall, insulin pump reduced the rate of SH with 27 % compared to any pen treatment (P = 0.003). When stratifying pen treatment, premixed insulin increased the rate of SH by 1.9-fold (P = 0.0015) and NPH increased the rate by 1.6-fold (P = 0.003) versus pump treatment, whereas long-acting insulin analogues were comparable with pump treatment (P = 0.1485). We found no association of SH with glycemic control (P > 0.05). CONCLUSIONS: A nationwide halving in rates of severe hypoglycemia was observed during the study period independent of the prevailing average HbA1c level. Changes in diabetes care and successful educational programs may have influenced the lower incidence rate of severe hypoglycemia.

National and international guidelines for rectal cancer.

AIM: Rectal cancer is a common malignancy. Differences in daily practice may influence the morbidity and mortality, and many national and international organizations have created guidelines for staging and treatment of rectal cancer. Even though consensus is reached within individual guidelines, this might not be the case between guidelines. No formal evaluation of the contrasting guidance has been reported. METHOD: A systematic search for national and international guidelines on rectal cancer was performed. Eleven guidelines were identified for further analysis. RESULTS: There was no consensus concerning the definition of rectal cancer. Ten of the 11 guidelines use the TNM staging system and there was general agreement regarding the recommendation of MRI and CT in rectal cancer. There was consensus concerning a multidisciplinary approach, preoperative chemoradiotherapy (CRT) and total mesorectal excision (TME). There was no consensus concerning local treatment of T1 tumours and adjuvant therapy, and not all guidelines included metastatic disease and recurrence. There was no consensus on the protocol for follow up. The guidelines had different approaches to evidence. All referred to evidence but not all considered the level of evidence. CONCLUSION: The intention of the study was to provide an overview of international guidelines for rectal cancer based on the underlying evidence, but despite hard evidence it was very difficult to reach general conclusions. Despite much knowledge, there is no international consensus on guidelines for the staging and treatment of rectal cancer.

Glycaemic threshold for diabetes-specific retinopathy among individuals from Saudi Arabia, Algeria and Portugal.

We studied the glycaemic threshold and prevalence of diabetic retinopathy in screen-detected diabetes in Saudi Arabia, Algeria and Portugal. The prevalence of diabetes-specific retinopathy started to increase at an HbA1c level of 6-6.4% (42-47 mmol/mol) and in individuals with HbA(1c) >7.0% the prevalence was 6.0%.

Risk scores for diabetes and impaired glycaemia in the Middle East and North Africa.

AIMS: To develop risk scores for diabetes and diabetes or impaired glycaemia for individuals living in the Middle East and North Africa region. In addition, to derive national risk scores for Algeria, Saudi Arabia and the United Arab Emirates and to compare the performance of the regional risk scores with the national risk scores. METHODS: An opportunistic sample of 6588 individuals aged 30-75 years was screened. Screening consisted of a questionnaire and a clinical examination including measurement of HbA(1c). Two regional risk scores and national risk scores for each of the three countries were derived separately by stepwise backwards multiple logistic regression with diabetes [HbA(1c) ≥ 48 mmol/mol (≥ 6.5%)] and diabetes or impaired glycaemia [HbA(1c) ≥ 42 mmol/mol (≥ 6.0%)] as outcome. The performance of the regional and national risk scores was compared in data from each country by receiver operating characteristic analysis. RESULTS: The eight risk scores all included age and BMI, while additional variables differed between the scores. The areas under the receiver operating characteristic curves were between 0.67 and 0.70, and for sensitivities approximately 75%; specificities varied between 50% and 57%. The regional and the national risk scores performed equally well in the three national samples. CONCLUSIONS: Two regional risk scores for diabetes and diabetes or impaired glycaemia applicable to the Middle East and North Africa region were identified. The regional risk scores performed as well as the national risk scores derived in the same manner.

Mutation in APOA1 predicts increased risk of ischaemic heart disease and total mortality without low HDL cholesterol levels.

OBJECTIVES: To determine whether mutations in APOA1 affect levels of high-density lipoprotein (HDL) cholesterol and to predict risk of ischaemic heart disease (IHD) and total mortality in the general population. BACKGROUND: Epidemiologically, risk of IHD is inversely related to HDL cholesterol levels. Mutations in apolipoprotein (apo) A-I, the major protein constituent of HDL, might be associated with low HDL cholesterol and predispose to IHD and early death. DESIGN: We resequenced APOA1 in 190 individuals and examined the effect of mutations on HDL cholesterol, risk of IHD, myocardial infarction (MI) and mortality in 10 440 individuals in the prospective Copenhagen City Heart Study followed for 31 years. Results were validated in an independent case-control study (n = 16 035). Additionally, we determined plasma ratios of mutant to wildtype (WT) apoA-I in human heterozygotes and functional effects of mutations in adenovirus-transfected mice. RESULTS: We identified a new mutation, A164S (1 : 500 in the general population), which predicted hazard ratios for IHD, MI and total mortality of 3.2 [95% confidence interval (CI): 1.6-6.5], 5.5 (95% CI: 2.6-11.7) and 2.5 (95% CI: 1.3-4.8), respectively, in heterozygotes compared with noncarriers. Mean reduction in survival time in heterozygotes was 10 years (P < 0.0001). Results for IHD and MI were confirmed in the case-control study. Furthermore, the ratio of mutant S164 to WT A164 apoA-I in plasma of heterozygotes was reduced. In addition, A164S heterozygotes had normal plasma lipid and lipoprotein levels, including HDL cholesterol and apoA-I, and this finding was confirmed in adenovirus-transfected mice. CONCLUSIONS: A164S is the first mutation in APOA1 to be described that predicts an increased risk of IHD, MI and total mortality without low HDL cholesterol levels.

Fat oxidation at rest predicts peak fat oxidation during exercise and metabolic phenotype in overweight men.

OBJECTIVE: To elucidate if fat oxidation at rest predicts peak fat oxidation during exercise and/or metabolic phenotype in moderately overweight, sedentary men. DESIGN: Cross-sectional study. SUBJECTS: We measured respiratory exchange ratio (RER) at rest in 44 moderately overweight, normotensive and normoglycemic men and selected 8 subjects with a low RER (L-RER, body mass index (BMI): 27.9+/-0.9 kg m(-2), RER: 0.76+/-0.02) and 8 with a high RER (H-RER; BMI 28.1+/-1.1 kg m(-2), RER: 0.89+/-0.02). After an overnight fast, a venous blood sample was obtained and a graded exercise test was performed. Fat oxidation during exercise was quantified using indirect calorimetry. RESULTS: Peak fat oxidation during exercise was higher in L-RER than in H-RER (0.333+/-0.096 vs 0.169+/-0.028 g min(-1); P<0.01) and occurred at a higher relative intensity (36.2+/-6.6 vs 28.2+/-3.1% VO(2max), P<0.05). Using the International Diabetes Federation criteria, we found that there was a lower accumulation of metabolic risk factors in L-RER than in H-RER (1.6 vs 3.5, P=0.028), and no subjects in L-RER and four of eight subjects in H-RER had the metabolic syndrome. Resting RER was positively correlated with plasma triglycerides (P<0.01) and negatively with plasma free fatty acids (P<0.05), and peak fat oxidation during exercise was positively correlated with plasma free fatty acid concentration at rest (P<0.05). CONCLUSION: A low RER at rest predicts a high peak fat oxidation during exercise and a healthy metabolic phenotype in moderately overweight, sedentary men.

Lipoprotein lipase and endothelial lipase in human testis and in germ cell neoplasms.

The aim of this study was to investigate endothelial lipase (EL, LIPG) and lipoprotein lipase (LPL) mRNA and protein expression in normal human testis and testicular germ cell tumours (GCT). Both EL and LPL were expressed in normal seminiferous tubules and in the interstitial compartment. EL mRNA and protein were found in all germ cells as well as in Sertoli and Leydig cells. EL mRNA was abundant in pre-invasive carcinoma in situ (CIS) cells and GCTs, and EL protein was present in the cytoplasm of these cells. LPL mRNA was also relatively abundant in germ cells, Sertoli cells, CIS cells and GCTs. The LPL protein, however, was restricted to the cell membranes of pachytene spermatocytes and spermatids in normal tubules, absent from CIS cells and scarcely represented in tumours. The distribution of LPL protein in non-seminomas resembled the distribution of OCT3/4, a marker of embryonal carcinoma. The results suggest that both EL and LPL participate in the supply of nutrients and steroidogenesis in the testes, and that especially EL may be important for the supply of cholesterol for testosterone production in the Leydig cells. The partial cellular separation of the expression of the two lipases in normal testis suggests the existence of distinct biological roles, perhaps developmentally regulated, as indicated by the LPL expression in GCTs with embryonic features. A high expression of EL and abundance of lipid in tubules with CIS may have a diagnostic value.

Early activation of the coagulation system during lower body negative pressure.

We considered that a moderate reduction of the central blood volume (CBV) may activate the coagulation system. Lower body negative pressure (LBNP) is a non-invasive means of reducing CBV and, thereby, simulates haemorrhage. We tested the hypothesis that coagulation markers would increase following moderate hypovolemia by exposing 10 healthy male volunteers to 10 min of 30 mmHg LBNP. Thoracic electrical impedance increased during LBNP (by 2.6 +/- 0.7 Omega, mean +/- SD; P < 0.001), signifying a reduced CBV. Heart rate was unchanged during LBNP, while mean arterial pressure decreased (84 +/- 5 to 80 +/- 6 mmHg; P < 0.001) along with stroke volume (114 +/- 22 to 96 +/- 19 ml min(-1); P < 0.001) and cardiac output (6.4 +/- 2.0 to 5.5 +/- 1.7 l min(-1); P < 0.01). Plasma thrombin-antithrombin III complexes increased (TAT, 5 +/- 6 to 19 +/- 20 microg l(-1); P < 0.05), indicating that LBNP activated the thrombin generating part of the coagulation system, while plasma D-dimer was unchanged, signifying that the increased thrombin generation did not cause further intravascular clot formation. The plasma pancreatic polypeptide level decreased (13 +/- 11 to 6 +/- 8 pmol l(-1); P < 0.05), reflecting reduced vagal activity. In conclusion, thrombin generation was activated by a modest decrease in CBV by LBNP in healthy humans independent of the vagal activity.

Apolipoprotein M predicts pre-beta-HDL formation: studies in type 2 diabetic and nondiabetic subjects.

OBJECTIVE: Studies in mice suggest that plasma apoM is lowered in hyperinsulinaemic diabetes and that apoM stimulates formation of pre-beta-HDL. Pre-beta-HDL is an acceptor of cellular cholesterol and may be critical for reverse cholesterol transport. Herein, we examined whether patients with type 2 diabetes have reduced plasma apoM and whether apoM is associated with pre-beta-HDL formation and cellular cholesterol efflux. DESIGN: In 78 patients with type 2 diabetes and 89 control subjects, we measured plasma apoM with ELISA, pre-beta-HDL and pre-beta-HDL formation, phospholipid transfer protein (PLTP) activity and the ability of plasma to promote cholesterol efflux from cultured fibroblasts. RESULTS: ApoM was approximately 9% lower in patients with type 2 diabetes compared to controls (0.025 +/- 0.006 vs. 0.027 +/- 0.007 g L(-1), P = 0.01). The difference in apoM was largely attributable to diabetes-associated obesity. ApoM was positively related to both HDL (r = 0.16; P = 0.04) and LDL cholesterol (r = 0.28; P = 0.0003). Pre-beta-HDL and pre-beta-HDL formation were not different between diabetic and control subjects. ApoM predicted pre-beta-HDL (r = 0.16; P = 0.04) and pre-beta-HDL formation (r = 0.19; P = 0.02), even independently of positive relationships with apoA-I, HDL-cholesterol and PLTP activity. Cellular cholesterol efflux to plasma was positively related to pre-beta-HDL and PLTP activity but not significantly to apoM. CONCLUSIONS: Plasma apoM is modestly reduced in type 2 diabetes. Pre-beta-HDL and pre-beta-HDL formation are positively associated with apoM, supporting the hypothesis that apoM plays a role in HDL remodelling in humans. Lower apoM may provide a mechanism to explain why pre-beta-HDL formation is not increased in type 2 diabetes despite elevated PLTP activity.

Early atherosclerosis and vascular inflammation in mice with diet-induced type 2 diabetes.

BACKGROUND: Obesity and type 2 diabetes increase the risk of atherosclerosis. It is unknown to what extent this reflects direct effects on the arterial wall or secondary effects of hyperlipidaemia. MATERIALS AND METHODS: The effect of obesity and type 2 diabetes on the development of atherosclerosis and inflammation, in the absence or presence of hyperlipidaemia, was assed in wild-type (n = 36) and human apolipoprotein B (apoB) transgenic mice (n = 27) that were fed normal chow or 60% fat for 12 months. RESULTS: Fat-feeding caused obesity, glucose intolerance and elevated plasma leptin and soluble vascular cell adhesion molecule-1 (sVCAM-1) in both wild-type and apoB transgenic mice. In wild-type mice, plasma very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) were unaffected by fat-feeding. ApoB transgenic mice had mildly elevated plasma LDL-C (approximately 1 mmol L(-1)), which was slightly increased by fat-feeding. Sixty-four per cent of fat-fed wild-type mice vs. 7% of chow-fed wild-type mice had lipid-staining intimal lesions in the aortic root (P = 0.002). Eighty-six per cent of fat-fed apoB transgenic mice had lipid-staining lesions and the median lesion area was 8.0 times higher than in fat-fed wild-type mice (P = 0.001). Intracellular adhesion molecule-1 staining of the aortic endothelium was most pronounced in the fat-fed apoB transgenic mice. CONCLUSIONS: Our findings suggest that diet-induced type 2 diabetes causes early atherosclerosis in the absence of dyslipidaemia, and that even a moderate level of LDL-C markedly augments this effect.

Apolipoprotein M affecting lipid metabolism or just catching a ride with lipoproteins in the circulation?

Apolipoprotein M (apoM) is a novel apolipoprotein found mainly in high-density lipoproteins (HDL). Its function is yet to be defined. ApoM (25 kDa) has a typical lipocalin ss-barrel fold and a hydrophobic pocket. Retinoids bind apoM but with low affinity and may not be the natural ligands. ApoM retains its signal peptide, which serves as a hydrophobic anchor to the lipoproteins. This prevents apoM from being lost in the urine. Approximately 5% of HDL carries an apoM molecule. ApoM in plasma (1 microM) correlates strongly with both low-density lipoprotein (LDL) and HDL cholesterol, suggesting a link to cholesterol metabolism. However, in casecontrol studies, apoM levels in patients with coronary heart disease (CHD) and controls were similar, suggesting apoM levels not to affect the risk for CHD in humans. Experiments in transgenic mice suggested apoM to have antiatherogenic properties; possible mechanisms include increased formation of pre-ss HDL, enhanced cholesterol mobilization from foam cells, and increased antioxidant properties.

Apolipoprotein M: progress in understanding its regulation and metabolic functions.

ApoM is a novel apolipoprotein mainly present in high-density lipoprotein (HDL). It belongs to the lipocalin protein superfamily and may bind a small but so far unknown lipophilic ligand. It is secreted without cleavage of its hydrophobic signal peptide, which probably anchors apoM in the phospholipid moiety of plasma lipoproteins. Recent studies suggest that apoM may affect HDL metabolism and have anti-atherogenic functions. The subfraction of human HDL that contains apoM therefore protects LDL from oxidation and mediates cholesterol efflux more efficiently then HDL without apoM. In addition to hepatocytes, apoM is highly expressed in kidney proximal tubule cells. Recent data suggest that apoM is secreted into the pre-urine from the tubule cells but is normally taken up again in a megalin-dependent fashion. Further studies of mice with genetically modified apoM expression will be essential to unravel the potential roles of apoM in lipoprotein metabolism, atherosclerosis and kidney biology.

Heart specific up-regulation of genes for B-type and C-type natriuretic peptide receptors in diabetic mice.

BACKGROUND: Diabetes may cause cardiomyopathy characterized by cardiac fibrosis. Recent studies of genetically modified mice have elucidated a role of the natriuretic peptides (NP), type-A and type-B (ANP and BNP), and their common receptor [natriuretic peptide receptor (NPR), type-A] in development of cardiac fibrosis. The role of NP type-C (CNP) and NPR type-B (NPR-B) in the heart is less well established. In this study we examined if diabetes alters heart expression of the genes encoding the NP and its receptors. MATERIALS AND METHODS: Cardiac mRNA was quantified by real-time PCR in diabetic streptozotocin (STZ)-treated and ob/ob-mice and nondiabetic control mice. RESULTS: The ob/ob-mice with type-II diabetes displayed highly significant increases of the cardiac mRNA expression of NPR-B and NPR-C while the expression levels of NPR-A, ANP, BNP, and CNP mRNA were similar in ob/ob-mice and controls. Mice with STZ-induced type-I diabetes also showed an increase of heart NPR-B mRNA expression at 12 weeks, but not at 3, 6 or 9 weeks after STZ-treatment. The ANP and NPR-C mRNA expressions were only altered after 3 weeks, whereas BNP, CNP and NPR-A mRNA expressions were not altered in STZ-treated-mouse hearts at any of the time points. CONCLUSIONS: The results show that diabetes in mice confers increased NPR-B gene expression in the heart, suggesting that increased NPR-B signalling may affect development of diabetic cardiomyopathy.

Impact of IDDM2 on disease pathogenesis and progression in children with newly diagnosed type 1 diabetes: reduced insulin antibody titres and preserved beta cell function.

AIMS/HYPOTHESIS: The insulin-dependent diabetes mellitus 2 gene (IDDM2) is a type 1 diabetes susceptibility locus contributed to by the variable number of tandem repeats (VNTR) upstream of the insulin gene (INS). We investigated the association between INS VNTR class III alleles (-23HphIA/T) and both insulin antibody presentation and residual beta cell function during the first year after diagnosis in 257 children with type 1 diabetes. MATERIALS AND METHODS: To estimate C-peptide levels and autoantibody presentation, patients underwent a meal-stimulated C-peptide test 1, 6, and 12 months after diagnosis. The insulin -23HphIA/T variant was used as a marker of class III alleles and genotyped by PCR-RFLP. RESULTS: The insulin antibody titres at 1 and 6 months were significantly lower in the class III/III and class I/III genotype groups than in the class I/I genotype group (p = 0.01). Class III alleles were also associated with residual beta cell function 12 months after diagnosis and independently of age, sex, BMI, insulin antibody titres, and HLA-risk genotype group (p = 0.03). The C-peptide level was twice as high among class III/III genotypes as in class I/I and class I/III genotypes (319 vs 131 and 166 pmol/l, p=0.01). Furthermore, the class III/III genotype had a 1.1% reduction in HbA(1)c after adjustment for insulin dose (p = 0.04). CONCLUSIONS/INTERPRETATION: These findings suggest a direct connection in vivo between INS VNTR class III alleles, a decreased humoral immune response to insulin, and preservation of beta cell function in recent-onset type 1 diabetes.