Clinical picture of EPM1-Unverricht-Lundborg disease

Unverricht-Lundborg disease (ULD), progressive myoclonic epilepsy type 1 (EPM1, OMIM254800), is an autosomal recessively inherited neurodegenerative disorder characterized by age of onset from 6 to 16 years, stimulus-sensitive myoclonus, and tonic-clonic epileptic seizures. Some years after the onset ataxia, incoordination, intentional tremor, and dysarthria develop. Individuals with EPM1 are mentally alert but show emotional lability, depression, and mild decline in intellectual performance over time. The diagnosis of EPM1 can be confirmed by identifying disease-causing mutations in a cysteine protease inhibitor cystatin B (CSTB) gene. Symptomatic pharmacologic and rehabilitative management, including psychosocial support, are the mainstay of EPM1 patients' care. Valproic acid, the first drug of choice, diminishes myoclonus and the frequency of generalized seizures. Clonazepam and high-dose piracetam are used to treat myoclonus, whereas levetiracetam seems to be effective for both myoclonus and generalized seizures. There are a number of agents that aggravate clinical course of EPM1 such as phenytoin aggravating the associated neurologic symptoms or even accelerating cerebellar degeneration. Sodium channel blockers (carbamazepine, oxcarbazepine) and GABAergic drugs (tiagabine, vigabatrin) as well as gabapentin and pregabalin may aggravate myoclonus and myoclonic seizures. EPM1 patients need lifelong clinical follow-up, including evaluation of the drug-treatment and comprehensive rehabilitation.     

Restoration of hepatic glucokinase expression corrects hepatic glucose flux and normalizes plasma glucose in zucker diabetic fatty rats

OBJECTIVE—We examined in 20-week-old Zucker diabetic fatty (ZDF) rats whether restoration of hepatic glucokinase (GK) expression would alter hepatic glucose flux and improve hyperglycemia.RESEARCH DESIGN AND METHODS—ZDF rats were treated at various doses with an adenovirus that directs the expression of rat liver GK (AdvCMV-GKL) dose dependently, and various metabolic parameters were compared with those of nondiabetic lean littermates (ZCL rats) before and during a hyperglycemic clamp. Viral infection per se did not affect hepatic GK activity, since expression of a catalytically inactive form of GK did not alter endogenous hepatic GK activity.RESULTS—ZDF rats compared with ZCL rats have lower hepatic GK activity (11.6 ± 1.9 vs. 32.5 ± 3.2 mU/mg protein), marked hyperglycemia (23.9 ± 1.2 vs. 7.4 ± 0.3 mmol/l), higher endogenous glucose production (80 ± 3 vs. 38 ± 3 μmol · kg⁻¹ · min⁻¹), increased glucose-6-phosphatase flux (150 ± 11 vs. 58 ± 8 μmol · kg⁻¹ · min⁻¹), and during a hyperglycemic clamp, a failure to suppress endogenous glucose production (80 ± 7 vs. −7 ± 4 μmol · kg⁻¹ · min⁻¹) and promote glucose incorporation into glycogen (15 ± 5 vs. 43 ± 3 μmol/g liver). Treatment of ZDF rats with different doses of AdvCMV-GKL, which restored hepatic GK activity to one to two times that of ZCL rats, normalized plasma glucose levels and endogenous glucose production. During a hyperglycemic clamp, glucose production was suppressed and glucose incorporation into glycogen was normal.CONCLUSIONS—Alteration of hepatic GK activity in ZDF rats has profound effects on plasma glucose and hepatic glucose flux.In Western society, obesity is generally considered a primary risk for individuals with type 2 diabetes, since 60–90% of type 2 diabetic subjects are also obese (1). Initially, obese individuals have normal fasting glycemia with elevated plasma insulin, but become progressively more hyperglycemic and insulin resistant with a decline in plasma insulin levels associated with pancreatic β-cell dysfunction (2). Diabetic hyperglycemia results from a failure of insulin and elevated plasma glucose to increase glucose utilization and suppress endogenous glucose production (2). With >90% of endogenous glucose production derived from liver (3,4) and as much as 40% of alimentary glucose taken up by liver (5–7), for storage as glycogen (8–10), a progressive loss in these liver functions is associated with the deterioration of glycemic control and the eventual development of diabetes.Whether liver uses or produces glucose is mostly determined by the activity of the first and last enzymes of hepatic glucose utilization and production, respectively. Net hepatic glucose flux is therefore the balance between the rate of glucose phosphorylation catalyzed by glucokinase (GK), the first step of hepatic glucose utilization, and the rate of glucose-6-phosphate (G-6-P) dephosphorylation catalyzed by glucose-6-phosphatase (G-6-Pase), the last step of hepatic glucose production. In studies of nondiabetic rats, glucose-induced suppression of net hepatic glucose production was associated with increased glucose phosphorylation (11) and GK activity was required for a rise in plasma glucose to suppress hepatic glucose production (12).Male Zucker diabetic fatty (ZDF) rats are a widely used genetic model of obese type 2 diabetes, since many characteristic features of this model are common with human obese type 2 diabetes (13). Young ZDF rats exhibit normal fasting glycemia with slightly elevated plasma insulin levels and become progressively more hyperglycemic and insulin resistant as plasma insulin levels are decreased with pancreatic β-cell dysfunction (14). Previously, we reported that blunted hepatic glucose flux in response to a rise in plasma glucose and insulin, as seen in the early (10 weeks of age) and middle (14 weeks of age) phases of diabetes development in ZDF rats, is associated with impaired regulation of GK by GK regulatory protein (GKRP) (15–17). In our current study, we investigated GK expression in liver during the progressive development of diabetes in ZDF rats and examined what correlation altered GK expression may have with the development of defective hepatic glucose metabolism and hyperglycemia. We report here that GK expression in liver is progressively reduced with the development of hyperglycemia in ZDF rats and that normalizing liver GK expression restores plasma glucose to nearly normal levels by improving the responsiveness of hepatic glucose metabolism to alterations in blood glucose during this later phase of diabetes development in ZDF rats.     

Polymorphism of the C-reactive protein gene is associated with mortality in bacteraemia

C-reactive protein (CRP) is an important molecule in the defence against bacterial infections. To discover if variation in the CRP gene is associated with clinical outcome of bacteraemia, we investigated 147 microbiologically verified bacteraemia patients (mean age 59 y, range 19-93 y) and determined whether CRP -717A>G, +1059G>C or +1444C>T single nucleotide polymorphisms (SNPs) were associated with clinical outcome of bacteraemia and/or CRP concentration caused by Staphylococcus aureus, Streptococcus pneumoniae, beta-haemolytic streptococci or Escherichia coli. The patients were genotyped for CRP gene polymorphisms, CRP was measured and clinical outcomes were recorded. The CRP -717A>G, a promoter region polymorphism was strongly associated with mortality from Streptococcus pneumoniae but did not correlate with plasma CRP concentration. These results suggest that mortality from Streptococcus pneumoniae may be associated with polymorphism of the promoter region of the CRP gene.     

Mutant p53–associated myosin-X upregulation promotes breast cancer invasion and metastasis

Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53–driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport β₁ integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53–driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines.