Insulin resistance influences the association of adiponectin levels with diabetes incidence in two population-based cohorts: the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study and the Framingham Offspring Study

Aims/hypothesis

Lower adiponectin levels are associated with higher risk of incident type 2 diabetes. Most analyses have been adjusted for confounding factors, but few have taken into account insulin resistance per se. We tested the hypothesis that the association of adiponectin levels with incident type 2 diabetes differs between insulin-resistant and insulin-sensitive individuals.

Methods

We studied two prospective cohorts: the Framingham Offspring Study (n?=?2,023) and the Cooperative Health Research in the Region of Augsburg (KORA) S4/F4 study (n?=?887) cohorts. Insulin resistance was estimated by HOMA-insulin resistance (HOMA-IR). We used logistic regression analysis to test the association between adiponectin and incident type 2 diabetes overall and in insulin-resistant vs insulin-sensitive individuals (defined by ?? vs <75th percentile of HOMA-IR).

Results

At baseline, Framingham??s participants were 60?±?9?years old and 56% were women; KORA??s participants were 63?±?5?years old and 49% were women. Type 2 diabetes incidence was 5.4% over 6.5?years (n?=?109) in Framingham and 10.5% over 8?years (n?=?93) in KORA. Lower adiponectin levels were associated with type 2 diabetes incidence in both cohorts. In insulin-resistant individuals, lower adiponectin levels were associated with higher risk of type 2 diabetes incidence (OR 1.60 [95% CI 1.10?C2.31] per SD decrease in Framingham, p?=?0.01; and OR 2.34 [95% CI 1.16?C4.73] in KORA, p?=?0.02); while this was not observed in insulin-sensitive individuals (OR 1.10 [95% CI 0.73?C1.67] in Framingham, p?=?0.64; and OR 1.34 [95%CI: 0.88?C2.03] in KORA, p?=?0.18).

Conclusions/interpretation

We conclude that lower adiponectin levels are associated with higher risk of type 2 diabetes in insulin-resistant but not in insulin-sensitive individuals. This suggests that some level of insulin resistance is needed to see deleterious effects of low adiponectin.     

XPD Asp312Asn polymorphism is a risk factor for prostate cancer

Purpose

The association between Asp312Asn and Lys751Gln polymorphisms of Xeroderma pigmentosum Group D (XPD) and prostate cancer risk are still inconclusive. For better understanding of the effects of these two polymorphisms on prostate cancer risk, a meta-analysis was performed.

Methods

An extensive search was performed to identify all case–control studies investigating such association. The strength of association between these two polymorphisms and prostate cancer risk was assessed by odds ratio (OR) with the corresponding 95?% confidence interval (95?% CI).

Results

A total of seven case–control studies were identified, among which five studies (1,257 cases and 1,956 controls) were eligible for Asp312Asn polymorphism and six studies (1,451 cases and 2,375 controls) were eligible for Lys751Gln polymorphism. Asp312Asn polymorphism was associated with an increased risk of prostate cancer in additive and recessive genetic models (additive model: OR?=?1.68, 95?% CI?=?1.28–2.22, P?=?0.00; recessive model: OR?=?1.65, 95?% CI?=?1.27–2.15, P?=?0.00). In the subgroup analysis, Asp312Asn polymorphism was associated with an increased risk of prostate cancer among Asians in all three genetic models (additive model: OR?=?2.09, 95?% CI?=?1.39–3.14, P?=?0.00; dominant model: OR?=?1.49, 95?% CI?=?1.12–1.98, P?=?0.01; recessive model: OR?=?1.93, 95?% CI?=?1.31–2.83, P?=?0.00). However, no significant associations were found between Lys751Gln polymorphism and prostate cancer risk in the overall analyses or the subgroup analyses by ethnicity.

Conclusions

The results of this meta-analysis indicate that the XPD Asp312Asn polymorphism is a risk factor for prostate cancer development.     

Prognostic value of a single HVPG measurement and Doppler-ultrasound evaluation in patients with cirrhosis and portal hypertension

Background

In patients with cirrhosis the onset of clinically significant portal hypertension (CSPH; i.e., hepatic venous pressure gradient (HVPG) ???10?mmHg) is associated with an increased risk of complications. However, most cirrhotic patients already have CSPH at presentation, and limited information is available on further risk stratification in this population. This study assessed the prognostic value of a single HVPG measurement and Doppler-ultrasound (US) evaluation in patients with cirrhosis and CSPH.

Methods

Eighty-six consecutive patients with cirrhosis (73% compensated) and untreated CSPH (mean HVPG 17.8?±?5.1?mmHg) were included. All were studied by paired HVPG and US, and followed up for a minimum of 12?months (mean 28?±?20?months).

Results

Sixteen (25.3%) patients developed a first decompensation, and 11.6% died on follow-up. HVPG (per 1?mmHg increase OR 1.22, 95% CI 1.05?C1.40, p?=?0.007) and bilirubin (per 1?mg/ml increase OR 2.42, 95% CI 0.93?C6.26, p?=?0.06) independently predicted first decompensation, and Model for End-Stage Liver Disease (MELD) score (per 1 point increase OR 1.24, 95% CI 1.03?C1.51, p?=?0.03) and HVPG (per 1?mmHg increase OR 1.08, 95% CI 1.01?C1.26, p?=?0.05) independently predicted mortality. The best HVPG cutoff predicting these events was 16?mmHg. Ultrasonographic parameters lacked independent predictive value. The ultrasonographic detection of abdominal collaterals had a high positive likelihood ratio (7.03, 95% CI 2.23?C22.16) for the prediction of HVPG ???16?mmHg, implying an increase of the probability of belonging to this higher-risk population from 58 to 91%.

Conclusions

HVPG holds an independent predictive value for first decompensation and death in patients with CSPH. The ultrasonographic detection of collaterals allows the non-invasive identification of patients with HVPG ???16?mmHg, who are at higher risk.     

Angiotensin-converting enzyme gene polymorphism in north Indian population with obstructive sleep apnea

Background

A deletion of 287-bp Alu repeat of angiotensin-converting enzyme (ACE) insertion/deletion (I/D) gene is associated with hypertension.

Purpose

The aim of this study is to determine the frequency of ACE (I/D) polymorphism in patients with obstructive sleep apnea (OSA).

Methods

Genotyping of ACE (I/D) gene polymorphism and estimation of serum angiotensin-converting enzyme (SACE) activity were done in 813 subjects who underwent polysomnography. Of these, 395 were apneics and 418 were non-apneics.

Results

The frequencies of II genotype (OR = 1.8, 95 % CI 1.26–2.60, p?=?0.001) and I allele (OR = 1.4, 95 % CI 1.13–1.69, p?=?0.001) of ACE gene were found to be significantly increased in patients with OSA as compared to patients without OSA. Frequency of II genotype was significantly decreased (OR = 0.46, 95 % CI 0.28–0.77, p?=?0.003) in OSA patients with hypertension. In contrast, the frequencies of ID (OR?=?1.80, 95 % CI 1.08–2.99, p?=?0.024) and DD genotypes (OR?=?2.15, 95 % CI 1.30–3.57, p?=?0.003) were significantly increased in this group. The activity of SACE was significantly decreased in the apneic group as compared to the non-apneic group (OR?=?0.99, 95 % CI 0.98–1.00, p?=?0.04).

Conclusions

The findings suggest that II genotype confers susceptibility towards development of OSA whereas DD genotype confers susceptibility towards hypertension irrespective of OSA.     

Prevalence of irritable bowel syndrome and functional dyspepsia,overlapping symptoms,and associated factors in a general population of Bangladesh

Background

This community-based survey aimed to find out the prevalence of irritable bowel syndrome (IBS), functional dyspepsia (FD), overlapping symptoms, and associated factors for overlap.

Method

By cluster sampling method, 3,000 (1,523 male) randomly selected adult subjects in the Sylhet district of Bangladesh were interviewed by a questionnaire based on ROME III criteria. Multivariate logistic regression analyses were done to find out the factors for overlap with significance level set at ≤0.05.

Results

The mean age of the study population was 33.9?±?16.4 years. Prevalence of IBS and FD and IBS-FD were 12.9 % (n?=?387), 8.3 % (n?=?249), and 3.5 % (n?=?105), respectively. Approximately 27.1 % of IBS patients and 42.1 % of FD patients had overlapping IBS-FD. The odds ratio for IBS-FD overlap was 6.3 (95 % CI, 4.8–8.4). Mean age (p?=?0.011) and epigastric pain (p?=?0.002) were more in overlap patients than FD alone, whereas epigastric pain syndrome subtype (p?<?0.009) was more prevalent in lone FD subjects. In the multivariate logistic analysis, early satiety (OR, 3.0; 95 % CI, 1.2–7.5; p?=?0.018) and epigastric pain (OR, 14.5; 95 % CI, 5.0–42.1; p?=?0.000) in FD patients appeared as independent risk factors for overlap. Bloating (p?=?0.026), <3 stools per week (p?=?0.050), abdominal pain reduced by defecation (p?=?0.002), abdominal pain severity score (p?=?0.004), and overall symptom frequency score (p?=?0.000) were more in overlap patients than IBS-alone patients. In IBS patients, bloating (OR, 3.6; CI, 2.0–6.5; p?=?0.000) was found as potential symptom associated with IBS-FD overlap.

Conclusion

FD was a less prevalent disorder than IBS in our community, and significant overlap existed between the two disorders. Early satiety, epigastric pain, and bloating were important factors associated with overlap.     

Association of genetic predisposition to obesity with type 2 diabetes risk in Han Chinese individuals

Aims/hypothesis

Obesity is a major risk factor for type 2 diabetes, but little is known about the contribution of BMI-associated loci to type 2 diabetes risk in East Asian populations.

Methods

In this study, 30 known BMI-associated variants and a genetic risk score (GRS) calculated by summing the BMI-increasing alleles of these variants were tested for associations with type 2 diabetes and related glycaemic traits in 1,873 cases of type 2 diabetes and 1,839 controls in Han Chinese individuals. Logistic and linear regression analyses were performed to determine the association with type 2 diabetes risk or related glycaemic traits, respectively, under an additive model with or without adjustment for BMI.

Results

The GRS was significantly associated with increased BMI (β [SE] 0.070 [0.016]; p?=?1.33?×?10^?5) in the overall population. Each additional BMI-increasing allele in the GRS increased type 2 diabetes risk by 1.029-fold (95% CI 1.008, 1.050; p?=?0.0056) without adjustment for BMI, and the association was slightly attenuated after adjustment for BMI (OR 1.022; 95% CI 1.002, 1.043; p?=?0.035). In non-diabetic controls, the GRS was also associated with HOMA of beta cell function (HOMA-B) with adjustment for BMI (β [SE] ?0.876 [0.345]; p?=?0.011). Notably, the association of GRS with type 2 diabetes was abolished after adjusting for HOMA-B (OR 1.012; 95% CI 0.986, 1.039; p?=?0.380).

Conclusions/interpretation

Our results suggested that genetic predisposition to obesity leads to increased risk of type 2 diabetes, independent of BMI and partly through impaired beta cell function.     

Sleep-disordered breathing and daytime napping are associated with maternal hyperglycemia

Objectives

Sleep disturbances in pregnancy may impair glucose mechanism. This study aimed to examine associations of sleep-disordered breathing, sleep, and nap duration with 1-h glucose challenge test (GCT) levels in pregnant women after controlling for known risk factors for gestational diabetes.

Methods

This is a case–control study of 104 pregnant women. All women underwent full polysomnography and a GCT and completed the multivariable apnea prediction and Pittsburgh Sleep Quality indexes. The primary outcome was maternal hyperglycemia measured by GCT. Bivariate and multivariable logistic regression analyses were performed.

Results

Over 13 % subjects reported habitual snoring in the first trimester. Only 9.3 % women with normoglycemia (GCT?<?135) were habitual snorers, whereas 45.5 % women with hyperglycemia (GCT?≥?135) had habitual snoring (p?<?0.001). Sleep-disordered breathing symptoms (loud snoring, snorting/gasping, and apneas) (odds ratio (OR) 2.85; 95 % confidence interval (CI) 1.50–5.41; p?=?0.001) and total nap duration (OR 1.48; 95 % CI 0.96–2.28; p?=?0.08) were associated with hyperglycemia. After adjusting for confounders, sleep-disordered breathing symptoms (OR 3.37; 95 % CI 1.44–8.32; p?=?0.005) and nap duration (OR 1.64; 95 % CI 1.00–2.681.02; p?=?0.05) continued to be associated with hyperglycemia. However, the primary exposure measure, the apnea/hypopnea index in the first trimester was not significantly associated with hyperglycemia (OR 1.03; 95 % CI 0.83–1.28; p?=?0.77).

Conclusions

Sleep-disordered breathing symptoms and nap duration are associated with hyperglycemia. Sleep duration was not associated with hyperglycemia. Research is needed concerning whether women with sleep-disordered breathing and/or daytime napping are at risk for gestational diabetes.     

Mortality after bloodstream infections in allogeneic haematopoietic stem cell transplant (HSCT) recipients

Purpose

Bloodstream infections (BSIs) are frequent after allogeneic haematopoietic stem cell transplantation (HSCT). The aim of this study was to identify predictors of mortality after BSI in patients who undergo HSCT.

Methods

Patients who underwent HSCT between 1 January 2004 and 31 January 2008 and developed BSI during the first year post-transplantation were included. Variables influencing overall mortality at 7 and 30?days after BSI were analysed.

Results

BSIs developed in 149 patients, within a median of 9?days after undergoing HSCT. Early and late mortality were 15 and 27%, respectively. Of the BSI, 54% were due to Gram-positive microorganisms, 33% were due to Gram-negative microogranisms, 10% were polymicrobial and 3% were fungal. The associated 7-and 30-day mortality was respectively 10 and 24% (Gram positive), 22 and 31% (Gram negative; Pseudomonas aeruginosa mortality 67%, all within 7?days), 13 and 27% (polymicrobial) and 40% (fungal, all within 7?days). Early mortality was higher in relapsed disease at HSCT (25.9%, p?=?0.01), but lower in early (i.e. within 20?days of HSCT) BSI (11.7%, p?=?0.03) and BSI due to Gram-positive infective agents (10%, p?=?0.05). Multivariate analysis confirmed a higher mortality in late BSI [odds ratio (OR)?3.29, p?=?0.03] and relapsed disease at HSCT (OR?2.2, p?=?0.04). Late mortality was associated with the type of underlying disease (OR?0.44 for diseases other than acute leukaemia, p?=?0.05) and its status (OR?6.04 for relapse at HSCT, p?=?0.001). Appropriate empirical therapy was associated with lower early and late mortality in single Gram-negative BSI (16 vs. 45% for 7-day mortality, p?=?0.09; 21 vs. 64% for 30-day mortality, p?=?0.02).

Conclusions

BSIs are frequent during the first year after HSCT and are associated with a high mortality rate. The aetiology influenced early mortality, while the type and phase of the underlying disease played a pivotal role in late mortality. Appropriate empirical therapy is crucial in BSI due to Gram-negative infective agents.     

Risk profile for gallstone disease in southern Indian population: Is there anything new?

Aim

There are reports of changes in demographic and morphological characteristics of gallstone (GS) disease in South Asian countries. The changes in dietary factors have not been previously reported. The aim of the study was to identify dietary factors and lifestyle patterns among southern Indian patients with GS disease.

Methodology

Seventy-one consecutive patients with GS disease were compared with age- and sex-matched controls. Baseline demographic characteristics, alcohol intake and smoking, and dietary details were noted and associations examined statistically.

Results

The demographic and lifestyle variables were similar in both groups. Family history of GS disease and diabetes mellitus was higher among cases (16.9 %; p?=?0.01; odds ratio (OR) 2.02; 95 % CI 1.58 to 2.58 for both). Vegetables consumed ≥2 times per week (OR 0.09; 95 % CI 0.04 to 0.21), fruits (OR 0.45; 95 % CI 0.20 to 0.99), and sugar (OR 0.27; 95 % CI 0.07 to 0.95) consumed ≥3 times per week were negatively associated with GS. Tea and coffee were taken less frequently by cases (2.5 vs. 2.9 cups/day; ANOVA p?<?0.01). Tamarind (OR 27.6; 95 % CI 9.5 to 84.4), spicy foods (OR 6.6; 95 % CI 2.8 to 16.3), and fried foods (OR 9.1; 95 % CI 2.8 to 33.2) when taken ≥4 times per week and cooking oil ≥300 mL per month (OR 62.0; p?<?0.0000) increased the risk for GS.

Conclusions

Several dietary preferences were associated with GS disease in this southern Indian population.     

Variants associated with type 2 diabetes identified by the transethnic meta-analysis study: assessment in American Indians and evidence for a new signal in LPP

Aim/hypothesis

A recent genome-wide trans-ancestry meta-analysis identified seven new loci associated with type 2 diabetes. We assessed the replication of the seven lead single nucleotide polymorphisms (SNPs) and evaluated these loci for additional signals in American Indians.

Methods

Seven SNPs were genotyped in 7,710 individuals from a longitudinally studied American Indian population, and associations with type 2 diabetes, BMI and related phenotypes were assessed. Previous genome-wide association study (GWAS) data from these individuals were used to screen for additional type 2 diabetes signals at these loci. A variant independent of the trans-ancestry meta-analysis was identified within LPP, and its replication was assessed in an additional 3,106 urban American Indians.

Results

SNP rs6813195 near to TMEM154 was nominally associated with type 2 diabetes (p?=?0.01, OR 1.12 [95% CI 1.03, 1.22]) and adiposity: the type 2 diabetes risk allele was associated with a lower percentage body fat (β?=??1.451%, p?=?4.8?×?10^?4). Another SNP, rs3130501 near to POU5F1–TCF19, was associated with BMI (β?=??0.012, p?=?0.004), type 2 diabetes adjusted for BMI (p?=?0.02, OR 1.11 [95% CI 1.02, 1.22]), 2 h glucose concentrations (β?=?0.080 mmol/l, p?=?0.02) and insulin resistance estimated by homeostatic model (β?=?0.039, p?=?0.009). The independent variant identified at the LPP locus in our American Indian GWAS for type 2 diabetes was replicated in the additional samples (all American Indian meta-analysis, p?=?8.9?×?10^?6, OR 1.29 [95% CI 1.15, 1.45]).

Conclusions/interpretation

For two of the seven newly identified variants, there was nominal evidence for association with type 2 diabetes and related traits in American Indians. Identification of an independent variant at the LPP locus suggests the existence of more than one type 2 diabetes signal at this locus.     

Variants of ADRA2A are associated with fasting glucose, blood pressure, body mass index and type 2 diabetes risk: meta-analysis of four prospective studies

Aims/hypothesis

We quantified the effect of ADRA2A (encoding ??-2 adrenergic receptor) variants on metabolic traits and type 2 diabetes risk, as reported in four studies.

Methods

Genotype data for ADRA2A single nucleotide polymorphisms (SNPs) rs553668 and rs10885122 were analysed in >17,000 individuals (1,307 type 2 diabetes cases) with regard to metabolic traits and type 2 diabetes risk. Two studies (n?=?9,437), genotyped using the Human Cardiovascular Disease BeadChip, provided 12 additional ADRA2A SNPs.

Results

Rs553668 was associated with per allele effects on fasting glucose (0.03?mmol/l, p?=?0.016) and type 2 diabetes risk (OR 1.17, 95% CI 1.04?C1.31; p?=?0.01). No significant association was observed with rs10885122. Of the 12 SNPs, several showed associations with metabolic traits. Overall, after variable selection, rs553668 was associated with type 2 diabetes risk (OR 1.38, 95% CI 1.09?C1.73; p?=?0.007). rs553668 (per allele difference 0.036?mmol/l, 95% CI 0.008?C0.065) and rs17186196 (per allele difference 0.066?mmol/l, 95% CI 0.017?C0.115) were independently associated with fasting glucose, and rs17186196 with fasting insulin and HOMA of insulin resistance (4.3%, 95% CI 0.6?C8.1 and 4.9%, 95% CI 1.0?C9.0, respectively, per allele). Per-allele effects of rs491589 on systolic and diastolic blood pressure were 1.19?mmHg (95% CI 0.43?C1.95) and 0.61?mmHg (95% CI 0.11?C1.10), respectively, and those of rs36022820 on BMI 0.58?kg/m² (95% CI 0.15?C1.02).

Conclusions/interpretation

Multiple ADRA2A SNPs are associated with metabolic traits, blood pressure and type 2 diabetes risk. The ??-2 adrenergic receptor should be revisited as a therapeutic target for reduction of the adverse consequences of metabolic trait disorders and type 2 diabetes.     

PTGER4 modulating variants in Crohn’s disease

Purpose

Variants modulating expression of the prostaglandin receptor 4 (PTGER4) have been reported to be associated with Cohn’s disease (CD), but the clinical impact remains to be elucidated. We analyzed these variants in a large German inflammatory bowel disease (IBD) cohort and searched for a potential phenotype association.

Methods

The variants rs4495224 and rs7720838 were studied in adult German IBD patients (CD, n?=?475; ulcerative colitis (UC), n?=?293) and healthy controls (HC, n?=?467). Data were correlated to results from NOD2 genotyping and to clinical characteristics.

Results

We found a significant association for the rs7720838 variant with overrepresentation of the T allele to CD (p?=?0.0058; OR 0.7703, 95 % CI 0.641–0.926) but not to UC. Furthermore, logistic regression analysis revealed that the presence of the T allele was associated with stricturing disease behavior in CD patients (p?=?0.03; OR 1.84, 95 % CI 1.07–3.16). Interestingly, the chance for developing stricturing disease behavior was enhanced if mutant alleles in both rs7720838 and NOD2 were present (OR 2.87, 95 % CI 1.42–5.81; p?=?0.003). No overall association to CD or UC was found for the rs4495224 variant.

Conclusions

The PTGER4 modulating variant rs7720838 increases susceptibility for CD and might resemble a risk factor for stricturing disease behavior.     

Fragmented QRS as a predictor of arrhythmic events in patients with hypertrophic obstructive cardiomyopathy

Objectives

This study aims to determine whether fragmented QRS (fQRS) in the surface electrocardiogram (ECG) at implantable cardioverter defibrillator (ICD) implant can predict arrhythmic events using appropriate therapy delivered by the ICD as a surrogate.

Background

Hypertrophic obstructive cardiomyopathy (HOCM) is a genetic disorder associated with life-threatening arrhythmias frequently requiring an ICD. Seeking a noninvasive method of risk stratification remains a challenge.

Methods

This paper is a retrospective, multicenter study of patients with HOCM and ICD. Surface 12-lead ECGs were analyzed. Appropriate therapy was validated by a blinded Core Lab. Univariate and multivariate analyses were performed. A p value of <0.05 was considered significant.

Results

We included 102 patients from 13 centers. Mean age at implant was 41.16?±?18.25 years, 52 % were male. Mean left ventricular ejection fraction was 61.56?±?9.46 % and two thirds had heart failure according to the New York Heart Association class I. Secondary prophylaxis ICD implantation was the indication for implant in 40.2 % of cases. About half received a single-chamber ICD. fQRS was present at the time of diagnosis in 21 and in 54 % at ICD implant. At a mean follow-up of 47.8?±?39.3 months, 41 patients (40.2 %) presented with appropriate therapy. In a multivariate logistic regression, predictors of appropriate therapy included fQRS at implant (odds ratio [OR], 16.4; 95 % confidence interval [CI], 3.6–74.0; p?=?0.0003), history of combined ventricular tachycardia/fibrillation/sudden death (OR, 14.3; 95 % CI, 3.2–69.3; p?=?0.001) and history of syncope (OR, 5.5; 95 % CI, 1.5–20.4; p?=?0.009). Ten deaths (9.8 %) occurred during the follow-up. fQRS in the lateral location increased the risk of appropriate therapy (p?<?0.0001).

Conclusions

fQRS predicts arrhythmic events in patients with HOCM and should be considered in a model of risk stratification.     

A variant in the G6PC2/ABCB11 locus is associated with increased fasting plasma glucose, increased basal hepatic glucose production and increased insulin release after oral and intravenous glucose loads

Aims/hypothesis

An association between elevated fasting plasma glucose and the common rs560887 G allele in the G6PC2/ABCB11 locus has been reported. In Danes we aimed to examine rs560887 in relation to plasma glucose and serum insulin responses following oral and i.v. glucose loads and in relation to hepatic glucose production during a hyperinsulinaemic–euglycaemic clamp. Furthermore, we examined rs560887 for association with impaired fasting glycaemia (IFG), impaired glucose tolerance (IGT), type 2 diabetes and components of the metabolic syndrome.

Methods

rs560887 was genotyped in the Inter99 cohort (n?=?5,899), in 366 young, healthy Danes, in non-diabetic relatives of type 2 diabetic patients (n?=?196), and in young and elderly twins (n?=?159). Participants underwent an OGTT, an IVGTT or a 2 h hyperinsulinaemic–euglycaemic clamp.

Results

The rs560887 G allele associated with elevated fasting plasma glucose (p?=?2?×?10^?14) but not with plasma glucose levels at 30 min (p?=?0.9) or 120 min (p?=?0.9) during an OGTT. G allele carriers had elevated levels of serum insulin at 30 min during an OGTT (p?=?1?×?10^?4) and relatives of type 2 diabetes patients carrying the G allele had an increased acute insulin response (p?=?4?×?10^?4) during an IVGTT. Among elderly twins, G allele carriers had higher basal hepatic glucose production (p?=?0.04). Finally, the G allele associated with the risk of having IFG (OR 1.26, 95% CI 1.08–1.47, p?=?0.002), but not with IGT (OR 0.94, 95% CI 0.82–1.08, p?=?0.4) or type 2 diabetes (OR 0.93, 95% CI 0.84–1.04, p?=?0.2).

Conclusions/interpretation

The common rs560887 G allele in the G6PC2/ABCB11 locus is associated with increased fasting glycaemia and increased risk of IFG, associations that may be partly related to an increased basal hepatic glucose production rate.     

Urinary Neutrophil Gelatinase-Associated Lipocalin Predicts Mortality and Identifies Acute Kidney Injury in Cirrhosis

Background

Kidney failure predicts mortality in patients with cirrhosis. Identification of kidney failure etiology and recognition of those at the highest mortality risk remains a challenge.

Aims

We hypothesized that urinary neutrophil gelatinase-associated lipocalin (uNGAL) predicts mortality and identifies hepatorenal syndrome (HRS) in patients with cirrhosis.

Methods

Prospectively enrolled patients with cirrhosis were investigated by uNGAL immunoblot upon hospital admission. Kidney failure type was determined blinded to NGAL measurements.

Results

One hundred eighteen patients were enrolled. Fifty-two (44?%) patients had normal kidney function, 14 (12?%) stable chronic kidney disease, 17 (14?%) prerenal azotemia, 20 (17?%) HRS, and 15 (13?%) intrinsic acute kidney injury (iAKI). Patients with HRS had uNGAL levels intermediate between prerenal azotemia [median (IQR) 105 (27.5–387.5) vs. 20 (15–45) ng/mL, p?=?0.004] and iAKI [325 (100–700), p??110?ng/mL (OR 6.05, 95?% CI 1.35–27.2) and HRS (OR 6.71, 95?% CI 1.76–25.5) independently predicted mortality, adjusting for age and serum creatinine?>1.5?mg/dL.

Conclusions

uNGAL strongly predicts short-term inpatient mortality in both unadjusted and adjusted models. Patients with HRS may have uNGAL levels intermediate between those with prerenal azotemia and iAKI. Further studies are needed to determine if uNGAL can improve discrimination of HRS from other types of acute kidney injury and predict short- and long-term cirrhosis outcomes.     

Factors associated with lateral pelvic recurrence after curative resection following neoadjuvant chemoradiotherapy in rectal cancer patients

Purpose

This study aims to determine the risk factors for lateral pelvic recurrence (LPR) in rectal cancer patients treated with neoadjuvant chemoradiotherapy (CRT) and curative surgery.

Methods

Four hundred forty-three patients treated with neoadjuvant CRT and curative surgery from October 1999 through June 2009 were analyzed. All patients underwent total mesorectal resection without lateral pelvic lymph node (LPLN) dissection. Recurrence patterns and lateral pelvic recurrence-free survival (LPFS) were evaluated relative to clinicopathologic parameters including pelvic LN status.

Results

Median follow-up was 52 months, with locoregional recurrence in 53 patients (11.9 %). Of the 53 patients, 28 (52.8 %) developed LPR, of which eight had both central and lateral PR. Multivariate analysis showed a significant relationship between LPFS and the number of lateral pelvic LN (p?=?0.010) as well as the ratio of the number of positive LN/number of dissected LN (p?=?0.038). The relationship between LPFS and LPLN size had a marginal trend (p?=?0.085). Logistic regression analysis showed positive relationships between LPR probability and the number of LPLN (odds ratio [OR] 1.507; 95 % confidence interval [CI] 1.177–1.929; p?=?0.001) as well as LPLN size (OR 1.124; CI 1.029–1.227, p?=?0.009).

Conclusions

LPLN?≥?2 and a ratio of the number of positive LN/number of dissected LN?>?0.3 were prognostic of poor LPFS. The prediction curve of LPR according to the number and size of LPLN could be useful for determining the benefit of additional lateral pelvic treatment.     

Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight

Aims/hypothesis

The fetal insulin hypothesis suggests that variation in the fetal genotype influencing insulin secretion or action may predispose to low birthweight and type 2 diabetes. We examined associations between 25 confirmed type 2 diabetes risk variants and birthweight in individuals from the Danish Inter99 population and in meta-analyses including Inter99 data and reported studies.

Methods

Midwife records from the Danish State Archives provided information on mother’s age and parity, as well as birthweight, length at birth and prematurity of the newborn in 4,744 individuals of the population-based Inter99 study. We genotyped 25 risk alleles showing genome-wide associations with type 2 diabetes.

Results

Birthweight was inversely associated with the type 2 diabetes risk alleles of ADCY5 rs11708067 (β?=??33 g [95% CI ?55, ?10], p?=?0.004) and CDKAL1 rs7756992 (β?=??22 g [95% CI ?43, ?1], p?=?0.04). The association for the latter locus was confirmed in a meta-analysis (n?=?24,885) (β?=??20 g [95% CI ?29, ?11], p?=?5?×?10^?6). The HHEX-IDE rs1111875 variant showed no significant association among Danes (p?=?0.09); however, in a meta-analysis (n?=?25,164) this type 2 diabetes risk allele was associated with lower birthweight (β?=??16 g [95% CI ?24, ?8], p?=?8?×?10^?5). On average, individuals with high genetic risk (≥25 type 2 diabetes risk alleles) weighed marginally less at birth than those with low genetic risk (<25 type 2 diabetes risk alleles) (β?=??35 g [95% CI ?69, ?2], p?=?0.037).

Conclusions/interpretation

We report a novel association between the fetal ADCY5 type 2 diabetes risk allele and decreased birthweight, and confirm in meta-analyses associations between decreased birthweight and the type 2 diabetes risk alleles of HHEX-IDE and CDKAL1. No strong general effect on birthweight can be ascribed to the 25 common type 2 diabetes risk alleles.     

The enhanced recovery after surgery (ERAS) pathway for patients undergoing colorectal surgery: an update of meta-analysis of randomized controlled trials

Objective

This study aimed to produce a comprehensive, up-to-date meta-analysis exploring the safety and efficacy of enhanced recovery programs after colorectal resection.

Method

Medline, Embase, and Cochrane database searches were performed for relevant studies published between January 1966 and April 2012. All randomized controlled trials on fast track (FT) colorectal surgery were reviewed systematically. The main end points were short-term morbidity, length of primary postoperative hospital stay, length of total postoperative stay, readmission rate, and mortality.

Results

Seven randomized controlled trials with 852 patients were included. The total length of hospital stay [mean difference (95?% confidence interval), ?1.88 (?2.91, ?0.86), p?=?0.0003] and total complication rates [relative risk (95?% confidence interval), 0.69 (0.51, 0.93), p?=?0.01] were significantly reduced in the enhanced recovery group. There was no statistically significant difference in readmission (risk ratio (RR) 0.90; 95?% confidence interval (CI) 0.52 to 1.53, p?=?0.69) and mortality rates (RR 1.02; 95?% CI 0.40 to 2.57, p?=?0.97).

Conclusion

Results suggested that enhanced recovery after surgery pathways can be able to reduce the length of stay and complication rates after major colorectal surgery without compromising patient safety. Future studies have to define the active elements in order to improve future fast track protocols.     

Caucasian ethnicity as a risk factor for more severe mucosal damage in gastroesophageal reflux disease

Background and aims

In the Western world, 10?C20?% of patients with GERD complain of at least weekly episodes of heartburn and/or acid regurgitation, while the corresponding value for GERD patients in Asia is <5?%. Reports of the risk factors for mucosal damage in patients with GERD are scarce. The aim of this study was to compare the severity of mucosal damage according to the Los Angeles system in Japanese and Caucasian residents of Japan who have GERD.

Methods

We conducted a retrospective cross-sectional study using 537 patients who visited St. Luke??s International Hospital and Mie University Hospital in Japan with symptoms of heartburn from January 2003 through December 2011. We divided the participants into two ethnic groups: 116 Caucasians (84 males and 32 females), mean age (SD) 43.8 (13.2) years old; and 375 Japanese (192 males and 183 females), mean age (SD) 53.2 (15.5) years old. Patients with a history of previous abdominal surgery or Helicobacter pylori eradication were excluded from the analysis. All patients were examined by esophagogastroduodenoscopy (EGD) to evaluate the severity of mucosal injury and hiatal hernia before medical treatment.

Results

With multivariate ordinal logistic regression analysis, age (OR 1.03, 95?% CI 1.02?C1.04, p?<?0.001), male gender (OR 2.71, 95?% CI 1.84?C4.01), Caucasian ethnicity (OR 1.65, 95?% CI 1.06?C2.58, p?=?0.0268), and the presence of hiatal hernia (OR 3.35, 95?% CI 2.06?C5.46, p?=?0.0012) were associated with more severe mucosal injury in GERD.

Conclusions

Patients with reflux symptoms tend to have more severe mucosal damage if they are male, older, Caucasian, or have a hiatal hernia. These patients should be evaluated by EGD more frequently.     

Clinically Significant Endoscopic Findings in a Multi-Ethnic Population With Uninvestigated Dyspepsia

Introduction

The proportion of clinically significant endoscopic findings (CSEF) in dyspepsia affects the initial management of this condition. With the changing epidemiology of organic upper gastrointestinal diseases in Asia, current data on CSEF remains uncertain.

Methods

A cross-sectional study of consecutive adult patients attending an open access endoscopy list for the primary indication of dyspepsia was conducted. Independent epidemiological and clinical factors for CSEF were determined prospectively.

Results

Data for 1167/1208 (96.6?%) adults (mean age 49.7?±?15.9?years, 42.4?% males, ethnic distribution: 30.5?% Malays, 36.9?% Chinese and 30.8?% Indians) were analysed between January 2007 and August 2008. Three-hundred and eight (26.4?%) patients were found to have CSEF, most often those with age ??45?years (30.3 vs 19?%, P?<?0.0001), male gender (34.1 vs 20.7?% female, P?<?0.0001), lower education levels (i.e. primary or no education), smoking (36.7 vs 24.9?%, P?=?0.003), H. pylori infection (40.6 vs 21.8?%, P?<?0.0001), and duration of dyspepsia ??5?months (32.8 vs 24.4?%, P?=?0.006). Age????45?years (OR 1.82, 95?% CI?=?1.38?C2.48), male gender (OR 1.84, 95?% CI?=?1.53?C2.59), H. pylori infection (OR 2.36, 95?% CI?=?1.83?C3.26), and duration of dyspepsia ??5?months (OR 1.44, 95?% CI?=?1.13?C2.03) were subsequently identified as independent risk factors for CSEF.

Conclusion

CSEF are found in 26.4?% of Asian adults with uninvestigated dyspepsia. Duration of symptoms <5?months, among other recognised factors, is predictive of CSEF.