Circulating peroxiredoxin 4 and type 2 diabetes risk: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study

Aims/hypothesis

Oxidative stress plays a key role in the development of type 2 diabetes mellitus. We previously showed that the circulating antioxidant peroxiredoxin 4 (Prx4) is associated with cardiometabolic risk factors. We aimed to evaluate the association of Prx4 with type 2 diabetes risk in the general population.

Methods

We analysed data on 7,972 individuals from the Prevention of Renal and Vascular End-stage Disease (PREVEND) study (49% men, aged 28–75 years) with no diabetes at baseline. Logistic regression models adjusted for age, sex, smoking, waist circumference, hypertension and family history of diabetes were used to estimate the ORs for type 2 diabetes.

Results

During a median follow up of 7.7 years, 496 individuals (288 men; 58%) developed type 2 diabetes. The median (Q1–Q3) Prx4 level was 0.84 (0.53–1.40) U/l in individuals who developed type 2 diabetes and 0.68 (0.43–1.08) U/l in individuals who did not develop type 2 diabetes. For every doubling of Prx4 levels, the adjusted OR (95% CI) for type 2 diabetes was 1.16 (1.05–1.29) in the whole population; by sex, it was 1.31 (1.14–1.50) for men and 1.03 (0.87–1.21) for women. Further adjustment for other clinical measures did not materially change the results. The addition of Prx4 to a validated diabetes risk score significantly improved the prediction of type 2 diabetes in men (p?=?0.002 for reclassification improvement).

Conclusions/interpretation

Our findings suggest that elevated serum Prx4 levels are associated with a higher risk of incident type 2 diabetes. For men, taking Prx4 into consideration can improve type 2 diabetes prediction over a validated diabetes risk score; in contrast, there is no improvement in risk prediction for women.     

Pancreatic beta cell function following liraglutide-augmented weight loss in individuals with prediabetes: analysis of a randomised,placebo-controlled study

Aims/hypothesis

Liraglutide can modulate insulin secretion by directly stimulating beta cells or indirectly through weight loss and enhanced insulin sensitivity. Recently, we showed that liraglutide treatment in overweight individuals with prediabetes (impaired fasting glucose and/or impaired glucose tolerance) led to greater weight loss (?7.7% vs ?3.9%) and improvement in insulin resistance compared with placebo. The current study evaluates the effects on beta cell function of weight loss augmented by liraglutide compared with weight loss alone.

Methods

This was a parallel, randomised study conducted in a single academic centre. Both participants and study administrators were blinded to treatment assignment. Individuals who were 40–70 years old, overweight (BMI 27–40 kg/m²) and with prediabetes were randomised (via a computerised system) to receive liraglutide (n?=?35) or matching placebo (n?=?33), and 49 participants were analysed. All were instructed to follow an energy-restricted diet. Primary outcome was insulin secretory function, which was evaluated in response to graded infusions of glucose and day-long mixed meals.

Results

Liraglutide treatment (n?=?24) significantly (p?≤?0.03) increased the insulin secretion rate (% mean change [95% CI]; 21% [12, 31] vs ?4% [?11, 3]) and pancreatic beta cell sensitivity to intravenous glucose (229% [161, 276] vs ?0.5% (?15, 14]), and decreased insulin clearance rate (?3.5% [?11, 4] vs 8.2 [0.2, 16]) as compared with placebo (n?=?25). The liraglutide-treated group also had significantly (p?≤?0.03) lower day-long glucose (?8.2% [?11, ?6] vs ?0.1 [?3, 2]) and NEFA concentrations (?14 [?20, ?8] vs ?2.1 [?10, 6]) following mixed meals, whereas day-long insulin concentrations did not significantly differ as compared with placebo. In a multivariate regression analysis, weight loss was associated with a decrease in insulin secretion rate and day-long glucose and insulin concentrations in the placebo group (p?≤?0.05), but there was no association with weight loss in the liraglutide group. The most common side effect of liraglutide was nausea.

Conclusions/interpretation

A direct stimulatory effect on beta cell function was the predominant change in liraglutide-augmented weight loss. These changes appear to be independent of weight loss.

Trial registration

ClinicalTrials.gov NCT01784965

Funding

The study was funded by the ADA.     

Sex differences in the association between plasma copeptin and incident type 2 diabetes: the Prevention of Renal and Vascular Endstage Disease (PREVEND) study

Aims/hypothesis

Vasopressin plays a role in osmoregulation, glucose homeostasis and inflammation. Therefore, plasma copeptin, the stable C-terminal portion of the precursor of vasopressin, has strong potential as a biomarker for the cardiometabolic syndrome and diabetes. Previous results were contradictory, which may be explained by differences between men and women in responsiveness of the vasopressin system. The aim of this study was to evaluate the usefulness of copeptin for prediction of future type 2 diabetes in men and women separately.

Methods

From the Prevention of Renal and Vascular Endstage Disease (PREVEND) study, 4,063 women and 3,909 men without diabetes at baseline were included. A total of 208 women and 288 men developed diabetes during a median follow-up of 7.7?years.

Results

In multivariable-adjusted models, we observed a stronger association of copeptin with risk of future diabetes in women (OR 1.49 [95% CI 1.24, 1.79]) than in men (OR 1.01 [95% CI 0.85, 1.19]) (p _interaction?p?=?0.02) and reclassification (integrated discrimination improvement [IDI] = 0.004, p?Conclusions/interpretation The association of plasma copeptin with the risk of developing diabetes was stronger in women than in men. Plasma copeptin alone, and along with existing biomarkers (glucose, hs-CRP and UAE), significantly improved the risk prediction for diabetes in women.     

INAUGURAL ARTICLE by a Recently Elected Academy Member:Impact of pyrethroid resistance on operational malaria control in Malawi

The impact of insecticide resistance on insect-borne disease programs is difficult to quantify. The possibility of eliminating malaria in high-transmission settings is heavily dependent on effective vector control reducing disease transmission rates. Pyrethroids are the dominant insecticides used for malaria control, with few options for their replacement. Their failure will adversely affect our ability to control malaria. Pyrethroid resistance has been selected in Malawi over the last 3 y in the two major malaria vectors Anopheles gambiae and Anopheles funestus, with a higher frequency of resistance in the latter. The resistance in An. funestus is metabolically based and involves the up-regulation of two duplicated P450s. The same genes confer resistance in Mozambican An. funestus, although the levels of up-regulation differ. The selection of resistance over 3 y has not increased malaria transmission, as judged by annual point prevalence surveys in 1- to 4-y-old children. This is true in areas with long-lasting insecticide-treated nets (LLINs) alone or LLINs plus pyrethroid-based insecticide residual spraying (IRS). However, in districts where IRS was scaled up, it did not produce the expected decrease in malaria prevalence. As resistance increases in frequency from this low initial level, there is the potential for vector population numbers to increase with a concomitant negative impact on control efficacy. This should be monitored carefully as part of the operational activities in country.The push for malaria elimination and eventual eradication will be heavily dependent on our ability to reduce disease transmission. A recent editorial suggests that we have the tools to take on this challenge in African malaria heartlands (1). This is predicated on ensuring that vector control prevention and drug treatment tools are fully deployed, reaching every person at risk. There will need to be improved delivery of these tools and better clinical management of malaria cases. In highly endemic areas our ability to reduce malaria transmission will be dependent on vector control, before the focus can shift to killing the parasite in infected people. Two forms of vector control, indoor residual spraying (IRS) and the distribution of long-lasting insecticide-treated nets (LLINs) have been demonstrated to reduce transmission when properly deployed against insecticide susceptible mosquito populations. The use of both interventions has dramatically increased since 2000 in many malaria endemic countries, with increased donor funding to attain the Roll Back Malaria targets and support the malaria elimination agenda (2).IRS and LLINs function by reducing the female mosquito daily survival rate and human biting frequency. Pyrethroids are the only insecticides recommended for use on LLINs, and only four chemical classes of insecticides that attack two target sites are available for IRS, and again pyrethroids dominate the IRS market. Resistance to pyrethroids has been selected in Anopheles gambiae and Anopheles funestus, the major African malaria vectors, although the frequency and level (fold) resistance conferred can vary dramatically. The impact of this resistance on the ability of either control intervention to reduce disease transmission is poorly understood, and current monitoring and evaluation practices are not sufficiently robust to assess this unless catastrophic failures occur. The perceived threat of pyrethroid resistance is now sufficiently high for the World Health Organization (WHO) to convene an international multidonor effort to counteract this.Operationally significant pyrethroid resistance has the potential to limit effective malaria control, owing to the small number of alternative public health insecticides. Pyrethroid resistance in malaria vectors has increased dramatically over the last decade (3, 4), particularly in Africa, where the bulk of malaria-related mortality occurs. Typically resistance is monitored by bioassays, for which the WHO has defined a diagnostic dosage for each insecticide that kills susceptible anopheline mosquitoes (5). Mosquitoes surviving the diagnostic dosage are an indication that resistance has been selected and that an operational problem may be developing, but bioassays alone do not signify control failure.Little operational monitoring of the underlying mechanisms of resistance occurs. Two mechanisms are predominantly responsible for insecticide resistance: changes in the insecticide target site, reducing binding of the insecticide, and increases in the rate at which the insecticide is metabolized (6). Information on the resistance mechanisms is more predictive than bioassays, providing information on the level of resistance and potential cross-resistance between insecticides. For example, two common mutations in the sodium channel convey low-level resistance to pyrethroids and higher-level resistance to dichlorodiphenyltrichloroethane (DDT) in An. gambiae (7, 8), whereas a cytochrome P450-based metabolic regulatory mechanism conveys very high-level pyrethroid and low-level carbamate resistance in An. funestus (9).Vector control interventions are being rapidly scaled up in Malawi, where malaria is highly endemic. Malaria accounts for 34% of all outpatient hospital visits and is the main cause of hospital admissions in children aged <5 y (10). Before 2007 sporadic WHO bioassays were undertaken, which indicated that the two major malaria vectors, An. gambiae and An. funestus, remained fully susceptible to pyrethroids. In 2007 pyrethroid-impregnated LLINs were distributed through antenatal and under-5 clinics at district and central hospitals countrywide. The numbers distributed were sufficient to achieve the Roll Back Malaria targets of 80% of pregnant women and children aged <5 y sleeping under a treated net. In 2008, a pilot study of IRS with the pyrethroid lambda cyhalothrin (ICON, Syngenta) was initiated in Nkhota Khota District, supported by the President’s Malaria Initiative (PMI). The initial program targeted 26,950 houses, and was expanded to 74,772 houses in 2009. Approximately 4 million LLINs were procured and ∼2 million distributed during this time. In 2010 the PMI-supported IRS was expanded to cover the whole of Nkohta Khota district, and the Malawian Ministry of Health supported IRS in a further six districts.A series of sentinel sites were established during this period to track the effect of this rapid increase in insecticide selection pressure on the local vectors and assess any impact on malaria transmission. This was particularly pertinent owing to the high levels of pyrethroid resistance reported in the southern part of neighboring Mozambique in An. funestus, which had prompted a switch from pyrethroids to carbamates or DDT for IRS in the Lubombo Spatial Development Initiative area of Mozambique (11, 12).     

Treatment and outcomes of acute coronary syndrome in the cancer population

Background:

Randomized trials have established the benefit of medical therapy and revascularization in the treatment of acute myocardial infarction (MI). Cancer and cardiovascular disease are the 2 most common diseases worldwide. In clinical practice, cancer patients are frequently afflicted with MI. The benefit of medical and/or revascularization therapy in the cancer population with MI is less well known.

Hypothesis:

Medical and revascularization therapy reduces mortality in cancer patients with MI.

Methods:

After approval by the institutional review board, we retrospectively reviewed all patients with a discharge diagnosis of acute MI who were admitted to the University of Texas MD Anderson Cancer Center between December 2000 and October 2006 and evaluated the association between cardiac treatments with survival outcomes.

Results:

A total of 456 patients with a discharge diagnosis of acute MI were identified and included in the study, of which 386 had non–ST‐segment elevation MI (NSTEMI) and 70 had ST‐segment elevation MI (STEMI). Compared with patients with NSTEMI, patients who had STEMI were more often prescribed aspirin (66% vs 43%; P = 0.004), β‐blockers (61% vs 46%; P = 0.018), and thrombolytic therapy (9% vs 0.3%; P = 0.0001). In the multivariable analysis, aspirin use was associated with a 23% decreased risk of death (hazard ratio [HR]: 0.77, 95% confidence interval [CI]: 0.60‐0.98, P = 0.033) and β‐blocker use was associated with a 36% decreased risk of death (HR: 0.64, 95% CI: 0.51–0.81, P = 0.0002). Statins (HR: 0.82, P = 0.18) and catheter‐based revascularization (HR: 0.57, P = 0.09) did not have an impact on the risk of death. Compared with patients with limited cancer, advanced cancer patients were twice as likely to die (HR: 2.12, 95 CI: 1.47–3.04, P < 0.0001). Previous chemotherapy (P = 0.005) and chest radiotherapy (P = 0.017) were associated with increased 1‐year mortality, whereas hyperlipidemia (P = 0.018) was protective.

Conclusions:

In this study of cancer patients with MI, medical therapy with aspirin and β‐blockers was associated with improved survival. The authors have no funding, financial relationships, or conflicts of interest to disclose.     

Ultrasound-guided simultaneous irrigation and drainage of facial abscess

The establishment of drainage and the elimination of the origin of infection are essential procedures for successful management of odontogenic infections. Irrigation and aspiration are considered as the 2 main procedures for the treatment of facial space infections; we invented a new method named simultaneous irrigation and aspiration. The simultaneous irrigation and aspiration method is significantly less painful and less invasive compared with the standard surgical incision and drainage. This method was thought to be useful for managing facial infections if proper patient selection is performed.     

Spatiotemporal distribution of cortical processing of first and second languages in bilinguals. I. Effects of proficiency and linguistic setting

The study determined how spatiotemporal distribution of cortical activity to words in first and second language is affected by language, proficiency, and linguistic setting. Ten early bilinguals and 14 late adult bilinguals listened to pairs of words presented in Arabic (L1), Hebrew (L2), or in mixed pairs and indicated whether both words had the same meaning or not. Source current densities of event‐related potentials were estimated. Activity to first words in the pair lateralized to right hemisphere, higher to L1 than L2 during early processing (<300 ms) among both groups but only among late bilinguals during late processing (>300 ms). During early and late processing, activities were larger in mixed than monolinguistic settings among early bilinguals but lower in mixed than in monolinguistic settings among late bilinguals. Late processing in auditory regions was of larger magnitude in left than right hemispheres among both groups. Activity to second words in the pair was larger in mixed than in monolinguistic settings during both early and late processing among both groups. Early processing of second words in auditory regions lateralized to the right among early bilinguals and to the left among late bilinguals, whereas late processing did not differ between groups. Wernicke's area activity during late processing of L2 was larger on the right, while on the left no significant differences between languages were found. The results show that cortical language processing in bilinguals differs between early and late processing and these differences are modulated by linguistic proficiency and setting. Hum Brain Mapp 34:2863–2881, 2013. © 2012 Wiley Periodicals, Inc.     

Biomechanical comparison of locked plating and spiral blade retrograde nailing of supracondylar femur fractures

Objective

Biomechanical comparison between locked plating and retrograde nailing of supracondylar femur fractures with simulated postoperative weight-bearing.

Methods

The Locking Condylar Plate (LCP) and Retrograde/Antegrade EX Femoral Nail (RAFN) were tested using 10 paired elderly cadaveric femurs, divided into Normal and Low Bone Mineral Density (BMD) groups, with a simulated AO/OTA type 33-A3 supracondylar femur fracture. Each specimen was subjected to 200,000 loading cycles in an attempt to simulate six weeks of postoperative recovery with full weight-bearing for an average individual. The construct's subsidence due to cyclic loading, and axial stiffness before and after the cyclic loading were measured and their correlation with BMD was studied. The two implants were compared in a paired study within each BMD group.

Results

LCP constructs showed higher axial stiffness compared to RAFN for both Normal and Low BMD groups (80% and 57%, respectively). After cyclic loading, axial stiffness of both constructs decreased by 20% and RAFN constructs resulted in twice as much subsidence (1.9 ± 0.6 mm). Two RAFN constructs with Low BMD failed after a few cycles whereas the matched pairs fixed with LCP failed after 70,000 cycles.

Conclusions

The RAFN constructs experienced greater subsidence and reduced axial stiffness compared to the LCP constructs. In Low BMD specimens, the RAFN constructs had a higher risk of failure.