Genetic Variant in HK1 Is Associated With a Proanemic State and A1C but Not Other Glycemic Control�CRelated Traits

OBJECTIVE

A1C is widely considered the gold standard for monitoring effective blood glucose levels. Recently, a genome-wide association study reported an association between A1C and rs7072268 within HK1 (encoding hexokinase 1), which catalyzes the first step of glycolysis. HK1 deficiency in erythrocytes (red blood cells [RBCs]) causes severe nonspherocytic hemolytic anemia in both humans and mice.

RESEARCH DESIGN AND METHODS

The contribution of rs7072268 to A1C and the RBC-related traits was assessed in 6,953 nondiabetic European participants. We additionally analyzed the association with hematologic traits in 5,229 nondiabetic European individuals (in whom A1C was not measured) and 1,924 diabetic patients. Glucose control–related markers other than A1C were analyzed in 18,694 nondiabetic European individuals. A type 2 diabetes case-control study included 7,447 French diabetic patients.

RESULTS

Our study confirms a strong association between the rs7072268–T allele and increased A1C (β = 0.029%; P = 2.22 × 10⁻⁷). Surprisingly, despite adequate study power, rs7072268 showed no association with any other markers of glucose control (fasting- and 2-h post-OGTT–related parameters, n = 18,694). In contrast, rs7072268–T allele decreases hemoglobin levels (n = 13,416; β = −0.054 g/dl; P = 3.74 × 10⁻⁶) and hematocrit (n = 11,492; β = −0.13%; P = 2.26 × 10⁻⁴), suggesting a proanemic effect. The T allele also increases risk for anemia (836 cases; odds ratio 1.13; P = 0.018).

CONCLUSIONS

HK1 variation, although strongly associated with A1C, does not seem to be involved in blood glucose control. Since HK1 rs7072268 is associated with reduced hemoglobin levels and favors anemia, we propose that HK1 may influence A1C levels through its anemic effect or its effect on glucose metabolism in RBCs. These findings may have implications for type 2 diabetes diagnosis and clinical management because anemia is a frequent complication of the diabetes state.Type 2 diabetes is a major source of early excess morbidity and mortality, which result from lack of adequate blood glucose control in most diabetic patients (1). In the absence of widely available continuous glucose monitoring, the A1C assay has become the most popular index to evaluate the efficiency of type 2 diabetes treatments on long-term blood glucose control (2,3). A1C, which is formed through the nonenzymatic attachment of glucose to the NH₂-terminal of the β-chain of hemoglobin, is indeed commonly considered a surrogate marker of mean blood glucose concentration over the previous 8–12 weeks (i.e., a 120-day life span of erythrocytes) (4). Furthermore, the A1C assay is often used for confirming type 2 diabetes diagnosis when fasting plasma glucose (FPG) is in the pre-diabetes range (6.1 ≤ FPG <7.0 mmol/l, defining normal glycemia and overt diabetes, respectively [2]), as postprandial or post–glucose load measurements of blood glucose are difficult to widely apply in clinical practice. However, the A1C measurement displays well-known caveats, such as genetically inherited hemoglobin defects or erythrocyte (red blood cell [RBC]) life span heterogeneity in hematologically normal people, that would oblige the use of more complex measurement of glycated serum proteins or fructosamine as a surrogate of blood glucose levels (5,6).Thus far, several genome-wide association (GWA) studies have identified 22 genes or loci, increasing the risk for type 2 diabetes or modulating FPG levels (7–19). Recently, Pare et al. (20) reported a single nucleotide polymorphism (SNP), rs7072268, at the hexokinase 1 (HK1) locus (chr10q22) that strongly associates with increased A1C in a nondiabetic population. The four isozymes of the hexokinase family (HK1, HK2, HK3, and glucokinase) contribute to commit glucose to the glycolytic pathway. The predominant HK1 isozyme is expressed in the vast majority of cells and tissues, including cells that are strictly dependent on glucose uptake for their metabolic needs (21). Importantly, while most tissues express more than one HK isozyme, RBC glucose metabolism only depends on HK1 activity (22). In humans, mutations including nonsynonymous substitutions in the active site of HK1 and intragenic deletions have been shown to cause HK1 enzymatic deficiency associated with autosomal recessive severe nonspherocytic hemolytic anemia (21,23–25). A similar phenotype has been described in the Downeast Anemia (dea) mice displaying HK1 deficiency (22).Based on these observations, we postulated that HK1 genetic variation may modulate the maintenance of the RBC pool and thus indirectly alter A1C measurements independently of the ambient blood glucose concentration. We evaluated this hypothesis by assessing the impact of HK1 rs7072268 on A1C, other glucose control-related traits, type 2 diabetes risk, and RBC-related parameters in several prospective and case-control European cohorts. Our data suggest that HK1 variation through its anemic effect impairs A1C assays, which may have important clinical implications for both type 2 diabetes diagnosis and management because anemia is commonly associated with diabetes.     

Age-related changes in the cerebral substrates of cognitive procedural learning

Cognitive procedural learning occurs in three qualitatively different phases (cognitive, associative, and autonomous). At the beginning of this process, numerous cognitive functions are involved, subtended by distinct brain structures such as the prefrontal and parietal cortex and the cerebellum. As the learning progresses, these cognitive components are gradually replaced by psychomotor abilities, reflected by the increasing involvement of the cerebellum, thalamus, and occipital regions. In elderly subjects, although cognitive studies have revealed a learning effect, performance levels differ during the acquisition of a procedure. The effects of age on the learning of a cognitive procedure have not yet been examined using functional imaging. The aim of this study was therefore to characterize the cerebral substrates involved in the learning of a cognitive procedure, comparing a group of older subjects with young controls. For this purpose, we performed a positron emission tomography activation study using the Tower of Toronto task. A direct comparison of the two groups revealed the involvement of a similar network of brain regions at the beginning of learning (cognitive phase). However, the engagement of frontal and cingulate regions persisted in the older group as learning continued, whereas it ceased in the younger controls. We assume that this additional activation in the older group during the associative and autonomous phases reflected compensatory processes and the fact that some older subjects failed to fully automate the procedure.     

Current role of bloodless liver resection

Liver resections are demanding operations which can have life threatening complications although they are performed by experienced liver surgeons. Recently new technologies are applied in the field of liver surgery, having one goal： safer and easier liver operations. The aim of this article is to address the issue of bloodless liver resection using radiofrequency energy. Radionics, Cool-tip^TM System and Tissue Link are some of the devices which are using radiofrequency energy. All information included in this article, refers to these devices in which we have personal experience in our unit of liver surgery. These devices take advantage of its unique combination of radiofrequency current and internal electrode cooling to perform sealing of the small vessels and biliary radicals. Dissection is also feasible with the cool-tip probe. For the purposes of this study patient sex, age, type of disease and type of surgical procedure in association with the duration of parenchymal transection, blood loss, length of hospital stay, morbidity and mortality were analyzed. Cool-tip RF device may provide a unique, simple and rather safe method of bloodless liver resections if used properly. It is indicated mostly in cirrhotic patients with challenging hepatectomies （segment Ⅷ, central resections）. The total operative time is eliminated and the average blood loss is significantly decreased. It is important to note that this technique should not be applied near the hilum or the vena cava to avoid damage of these structures.     

Pharmacological inhibition of TRalpha1 receptor potentiates the thyroxine effect on body weight reduction in rats: potential therapeutic implications in controlling body weight

It has been previously reported that thyroid hormone receptor alpha1 (TRalpha1) is involved in the regulation of food intake and heart rhythm. Herein, we show that pharmacological inhibition of TRalpha1 by dronedarone, an amiodarone like compound (shown to antagonize thyroid hormone binding to TRalpha1), prevented the thyroid hormone induced increase in food intake and heart rate acceleration in rats. This resulted in a marked reduction in body weight. It is likely that thyroid analogs may prove potential therapeutic agents for controlling body weight.     

Trends and determinants of severe morbidity in HIV-infected patients: the ANRS CO3 Aquitaine Cohort, 2000-2004

OBJECTIVE: The aim of the study was to characterize the causes, trends and determinants of severe morbidity in a large cohort of HIV-infected patients between 2000 and 2004. METHOD: Severe morbid events were defined as medical events associated with hospitalization or death. Epidemiological and biological data were recorded at the time of the morbid event. Trends were estimated using Poisson regression. RESULTS: Among 3863 individuals followed between 2000 and 2004, 1186 experienced one or more severe events, resulting in 1854 hospitalizations or deaths. The severe events recorded included bacterial infections (21%), AIDS events (20%), psychiatric events (10%), cardiovascular events (9%), digestive events including cirrhosis (7%), viral infections (6%) and non-AIDS cancers (5%). Between 2000 and 2004, the incidence rate of AIDS events decreased from 60 to 20 per 1000 person-years, that of bacterial infections decreased from 45 to 24 per 1000 person-years, and that of psychiatric events decreased from 26 to 14 per 1000 person-years (all P<0.01), whereas the incidences of cardiovascular events and of non-AIDS cancers remained stable at 14 and 10 per 1000 person-years, on average, respectively. CONCLUSION: Severe morbidity has shifted from AIDS-related to non-AIDS-related events during the course of HIV infection in developed countries. Limiting endpoints to AIDS events and death is insufficient to describe HIV disease progression in the era of combination antiretroviral therapy.     

Co-administration of C-Phycocyanin ameliorates thioacetamide-induced hepatic encephalopathy in Wistar rats

Fulminant hepatic failure (FHF) is a condition with a sudden onset of necrosis followed by degeneration of hepatocytes, without any previously established liver disease, generally occurring within hours or days. FHF is associated with a wide spectrum of neuropsychiatric alterations ranging from stupor to coma, culminating in death. In the present study FHF was induced in rats by the administration of thioacetamide (TAA). Oxidative stress is thought to play a prominent role in the pathophysiology of cerebral changes during FHF leading to the assumption that antioxidants might offer protection. Hence, in the present study the protective effect of C-Phycocyanin (C-PC), a natural antioxidant, was evaluated on TAA-induced tissue damage. C-Phycocyanin was administered intraperitoneally twice at 24 h interval (50 mg/kg body weight) along with the hepatotoxin TAA (300 mg/kg body weight). The animals were sacrificed 18 h after the second injection of TAA treatment and various biochemical parameters were analysed in liver, serum and brain tissues. These studies revealed significant prevention of TAA-induced liver damage by C-PC, as evidenced by a) increase in survival rate; b) the prevention of leakage of liver enzymes (AAT and AST) and ammonia into serum; c) increase in prothrombin time and d) liver histopathology. Ultrastructural studies of astrocytes of different regions of brain clearly showed a decrease in edema after C-PC treatment. TAA-induced histopathological lesions in different regions of the brain namely cerebral cortex, cerebellum and pons medulla were significantly reduced by the co-administration of C-PC with TAA. Further C-PC treatment resulted in a) decrease in the levels of tryptophan and markers of lipid peroxidation and b) elevation in the activity levels of catalase, glutathione peroxidase in different regions of brain. These studies reveal the potential of C-PC in ameliorating TAA-induced hepatic encephalopathy by improving antioxidant defenses.     

Thrombolytic therapy for acute ischaemic stroke in octogenarians: selection by magnetic resonance imaging improves safety but does not improve outcome

Background

Owing to the fear of an increased bleeding risk, thrombolytic therapy is withheld from many patients with acute stroke >80 years of age.

Objective

To analyse the risk for symptomatic intracranial haemorrhage (sICH), morbidity and mortality after thrombolytic therapy in octogenarians focusing, in particular, on whether patients selected using magnetic resonance imaging (MRI) had a better risk:benefit ratio.

Methods

The prospectively collected single‐centre data of all patients treated with systemic thrombolytic therapy for acute ischaemic stroke since 1998 (n = 468) were reviewed, and patients ⩾80 years (n = 90) were compared with those aged <80 years (n = 378). In addition, the group of octogenarians was analysed with respect to initial imaging modality.

Results

The overall rate of sICH in the octogenarians was 6.9%, compared with 5.3% in younger patients (p = 0.61). In older patients selected by computed tomography, the rate of sICH was 9.4%; no patient selected by MRI had sICH (p = 0.10). Mortality in the octogenarians selected by computed tomography was 29.7% after 3 months as compared with 26.9% in the patients selected by MRI (p = 1.0). 20.3% of the octogenarians selected by computed tomography and 15.4% of those selected by MRI had a favourable outcome (modified Rankin scale ⩽1) after 3 months (p = 0.77).

Conclusion

Compared with younger patients, octogenarians do not have an increased risk of sICH. The use of MRI to select octogenarians for thrombolytic therapy seemed to decrease the risk of sICH, but did not influence the overall outcome after 3 months.The incidence of stroke increases steeply with age. In a population‐based survey, incidence of a first‐ever stroke was around 0.8 per 1000 population per year in people aged <75 years as compared with 14 per 1000 population per year in those aged 75–84 years and 29 per 1000 population per year in those aged >85 years.¹ With respect to changes in the population''s age structure in the industrialised world, the number of acute vascular events in elderly people will almost double in the course of the next 25 years.¹ Furthermore, age is an independent predictor for poor outcome after ischaemic stroke. Older patients, especially those aged >80 years, have a higher in‐hospital mortality risk and a favourable functional outcome is less likely.² Intravenous thrombolysis with recombinant tissue‐type plasminogen activator (rt‐PA) is the only approved therapy for patients with acute ischaemic stroke. However, the European and Australian rt‐PA stroke trials excluded patients >80 years of age.^3,4,5 Older patients were only allowed to be enrolled in the National Institute of Neurological Disorders and Stroke (NINDS) rt‐PA stroke study, but a mean age of 69 years in this trial shows that few patients >80 years of age were actually included.⁶ Owing to the lack of knowledge about the safety and efficacy of thrombolysis in this age group from randomised trials, the European Medicines Evaluation Agency (EMEA) recommends that rt‐PA not be used in patients with ischaemic stroke aged >80 years.⁷In the past few years, it has become increasingly popular to select patients for thrombolytic therapy using multiparametric magnetic resonance imaging (MRI) techniques. Our objective was to analyse the morbidity, mortality and risk for symptomatic intracranial haemorrhage (sICH) after thrombolytic therapy in octogenarians, focusing in particular on whether the risk:benefit ratio was higher in patients selected by MRI.     

The antioxidant profiles of patients with recurrent acute and chronic pancreatitis

OBJECTIVE: It has been suggested that patients with chronic pancreatitis have antioxidant deficiencies. It is unclear whether these antioxidant deficiencies also occur in patients with recurrent acute pancreatitis and whether this condition represents an intermediate state between normality and chronic pancreatitis. The aim of this study was to determine the antioxidant profiles of patients with pancreatitis (recurrent acute and chronic) and to compare their profiles with a control population. METHODS: The antioxidant profiles of patients with chronic pancreatitis (n = 27) and recurrent acute pancreatitis (n = 11) were determined and compared with the antioxidant profiles of control subjects (n = 19). The following parameters were measured in blood: trace elements (selenium, copper, zinc), vitamins A and E, and carotenoids (alpha-carotene, beta-carotene, xanthine, beta-cryptoxanthine, lycopene). RESULTS: Patients with chronic pancreatitis had significantly lower plasma concentrations of selenium, vitamin A, vitamin E, beta-carotene, xanthine, beta-cryptoxanthine, and lycopene compared with both control subjects and patients with recurrent acute pancreatitis (p < 0.05). There were no significant differences between the antioxidant profiles of patients with chronic pancreatitis due to alcohol excess and patients with idiopathic chronic pancreatitis, or between the antioxidant profiles of patients with recurrent acute pancreatitis and control subjects. CONCLUSIONS: Patients with chronic pancreatitis had evidence of multiple antioxidant deficiencies. The antioxidant profiles of patients with recurrent acute pancreatitis did not differ from those of control subjects, discounting the hypothesis that recurrent acute pancreatitis represents an intermediate state between normality and chronic pancreatitis.     

Polaron melting and ordering as key mechanisms for colossal resistance effects in manganites

Polarons, the combined motion of electrons in a cloth of their lattice distortions, are a key transport feature in doped manganites. To develop a profound understanding of the colossal resistance effects induced by external fields, the study of polaron correlations and the resulting collective polaron behavior, i.e., polaron ordering and transition from polaronic transport to metallic transport is essential. We show that static long-range ordering of Jahn-Teller polarons forms a polaron solid which represents a new type of charge and orbital ordered state. The related noncentrosymmetric lattice distortions establish a connection between colossal resistance effects and multiferroic properties, i.e., the coexistence of ferroelectric and antiferromagnetic ordering. Colossal resistance effects due to an electrically induced polaron solid-liquid transition are directly observed in a transmission electron microscope with local electric stimulus applied in situ using a piezo-controlled tip. Our results shed light onto the colossal resistance effects in magnetic field and have a strong impact on the development of correlated electron-device applications such as resistive random access memory (RRAM).     

Effects of mycophenolate mofetil in ischemic acute renal failure in rats

Mycophenolate mofetil (MMF) is a purine synthesis inhibitor commonly used as immunosupresive agent in transplantation. Kidney grafts undergo more or less prolonged cold ischemia after harvesting which results in variable degrees of ischemia reperfusion injury. To determine whether the inhibition of early events of cellular infiltration may influence the severity of damage induced by ischemic acute renal failure, 45 Sprague Dawley rats were given MMF at a dose of 20mg/kg/day (MMF-rats) by gavage 2 days before (pre-MMF group, n=15) or after (post-MMF group, n=15) clamping the left renal artery for 40 minutes followed by rigt-sided nephrectomy. (control group, n=15) received vehicle. Serum Creatinine (Screat) was measured daily in all groups. On the 2nd post-ischemic day Screat was significantly lower (p=0.001) in pre-MMF group compared with post-MMF group and control group (4 +/- 2mg/dl post-MMF group vs 1.7 +/- 1.2 mg/dl pre-MMF group, control group 5+/-2, p< 0.05). Kidney biopsies shown that the histologic damage was 54 +/- 28% in post-MMF group vs 34+/- 22% in pre-MMF group and 61 +/- 25% in control group (pre-MMF vs post-MMF, p NS). On the 5th day post-ischemic, MMF-rats showed more severe tubulointerstitial necrosis (pre-MMF group: 17 +/- 20 %, post-MMF group: 33 +/- 27%) than controls (4 +/- 5%). The severity of ATN was significantly higher in post-MMF group compared with controls (p=0.01). Tubulointersticial T-lymphocyte (T CD 5) and monocyte (ED 1) infiltration evaluated on the 2nd post-ischemic day was less intense in group I (T CD5: 3 +/- 3, ED 1: 10 +/- 9, cel/mm2) compared to post-MMF group (T CD 5: 10 +/- 4, ED 1: 55 +/- 40) and to control group (T CD 5: 10+/- 4, ED 1: 64 +/- 46). However, on the 5th post-ischemia day, ED 1 infiltration was significantly higher in post-MMF group (24 +/- 18%) compared to pre-MMF group (5 +/- 5, p NS) and also in pre-MMF group vs control group (31 +/- 33, p< 0.05). Our results suggest that MMF given before a renal ischemic insult may reduce the severity of histologic damage resulting from ischemia reperfusion injury.