Treatment gaps in the management of cardiovascular risk factors in patients with type 2 diabetes in Canada

OBJECTIVES:

To evaluate vascular protection treatment patterns and attainment of the 2003 Canadian Diabetes Association’s recommended targets in ambulatory patients with type 2 diabetes.

METHODS:

Between 2005 and 2006, 3002 outpatients with type 2 diabetes were enrolled by 229 primary health care settings across Canada. Baseline characteristics, therapeutic regimens and treatment success – defined as the achievement of a blood pressure (BP) of 130/80 mmHg or lower, glycosylated hemoglobin (A1C) of 7% or lower, low-density lipoprotein cholesterol (LDL-C) lower than 2.5 mmol/L and total cholesterol/high-density lipoprotein cholesterol ratio lower than 4.0 – are reported.

RESULTS:

Overall, 46% of individuals had a BP that was above the Canadian Diabetes Association’s recommended target. Of these, 11% were untreated, 28% were receiving monotherapy, 38% were not receiving an angiotensin-converting enzyme inhibitor and 16% were not receiving either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Optimal A1C levels were achieved in 53% of patients. Of those who did not attain A1C targets, 3% were not on glucose-lowering pharmacotherapy and 27% were receiving monotherapy. A total of 74% of patients were treated with statins. Overall, 64% and 62%, respectively, met the target LDL-C and the target total cholesterol/high-density lipoprotein cholesterol ratio. Statins were not prescribed to 43% of patients with LDL-C above target. Antiplatelet therapy was implemented in 81% of patients. In total, 21% achieved the combined targets for BP, A1C and LDL-C.

INTERPRETATION:

A substantial proportion of patients did not achieve guideline-recommended targets and were not receiving evidence-based therapy for vascular protection two years after publication of the Canadian guidelines. More research is warranted, and novel and effective strategies must be tested and implemented to correct this ongoing treatment gap.     

Harmaline and harmalol inhibit the carcinogen-activating enzyme CYP1A1 via transcriptional and posttranslational mechanisms

Dioxins are known to cause several human cancers through activation of the aryl hydrocarbon receptor (AhR). Harmaline and harmalol are dihydro-β-carboline compounds present in several medicinal plants such as Peganum harmala. We have previously demonstrated the ability of P. harmala extract to inhibit TCDD-mediated induction of Cyp1a1 in murine hepatoma Hepa 1c1c7 cells. Therefore, the aim of this study is to examine the effect of harmaline and its main metabolite, harmalol, on dioxin-mediated induction of CYP1A1 in human hepatoma HepG2 cells. Our results showed that harmaline and harmalol at concentrations of (0.5-12.5μM) significantly inhibited the dioxin-induced CYP1A1 at mRNA, protein and activity levels in a concentration-dependent manner. The role of AhR was determined by the inhibition of the TCDD-mediated induction of AhR-dependent luciferase activity and the AhR/ARNT/XRE formation by both harmaline and harmalol. In addition, harmaline significantly displaced [(3)H]TCDD in the competitive ligand binding assay. At posttranslational level, both harmaline and harmalol decreased the protein stability of CYP1A1, suggesting that posttranslational modifications are involved. Moreover, the posttranslational modifications of harmaline and harmalol involve ubiquitin-proteasomal pathway and direct inhibitory effects of both compounds on CYP1A1 enzyme. These data suggest that harmaline and harmalol are promising agents for preventing dioxin-mediated effects.     

Cytokines and C-reactive protein production in hip-fracture-operated elderly patients

BACKGROUND: The study aim was to determine the kinetics of serum pro- and anti-inflammatory cytokines and C-reactive protein (CRP) in hip-fracture patients over a month postfracture, and their relationship to postoperative (postop) complications and cognitive level. METHODS: Forty-one elderly hip-fracture patients were prospectively followed. Serum was obtained during the first 10 hours postfracture and presurgery, 48-60 hours postop, 7 and 30 days postop, measuring CRP, interleukin-1beta (IL-1beta), IL-6, IL-8, tumor necrosis factor-alpha (TNF-alpha), IL-10, and IL-1 receptor antagonist (IL-1RA). RESULTS: A significant increase was found postop for CRP, IL-6, TNF-alpha, IL-1RA (p <.001), IL-10 (p <.002), and IL-8 (p =.05). CRP kinetics curves were higher in patients with complications as a group, and in those suffering from infections, delirium, and cardiovascular complications (p <.05). IL-6 increase in patients with complications approached significance. Additional complications appeared in patients with impaired mental status (IMS) versus cognitively normal patients (p =.037). Higher kinetics curves in the IMS patients were found for CRP and IL-6 (p <.05). Analyzing the interaction effect of complications and IMS on CRP and cytokines production demonstrated that the increase in CRP was independently related to complications and IMS. IL-6, IL-8, and IL-10 were higher in IMS patients but not in patients with complications without IMS (p <.05). CONCLUSIONS: Serum CRP and cytokines increased drastically in postop hip-fracture elderly patients. Only CRP significantly and independently increased in IMS patients and in patients with complications, whereas cytokines significantly increased only in IMS patients. This study raises questions about possible effects that cytokine generation, after hip-fracture repair, might have on cognition and complications.     

Epilepsy in phenylketonuria: a complex dependence on serum phenylalanine levels

PURPOSE: Phenylketonuria (PKU) is a disorder of phenylalanine (Phe) metabolism that frequently results in epilepsy if a low Phe diet was not implemented at birth. The mechanisms by which Phe affects the brain are poorly understood. METHODS: Audiogenic seizures (AGS) were studied in female homozygous Pah(enu2) BTBR (PKU) mice. RESULTS: Adult PKU mice, 18-20 weeks of age, in contrast to wild-type and heterozygous counterparts, exhibited a full range of AGS. Younger PKU mice, 5-7 weeks of age, had higher serum Phe levels (2.22 +/- 0.20 mM) in comparison with the adult animals (1.72 +/- 0.05 mM) and were not susceptible to AGS. Among adult mice, animals susceptible to AGS had significantly lower serum Phe levels (1.62 +/- 0.06 mM) in comparison with those resistant to AGS (1.86 +/- 0.07 mM). Susceptibility to AGS tended to increase in the afternoon when serum Phe concentration decreased in comparison to evening and morning. Normalization of serum Phe level by instituting a low Phe diet generally prevented susceptibility to AGS within 12 h. Although return to a standard diet raised Phe levels to hyperphenylalaninemic within 12 h in animals treated with a low Phe diet for 2 weeks, more than 7 weeks were needed for a complete resumption of AGS. CONCLUSIONS: Transient decrease in Phe levels within hyperphenylalaninemic range may be a necessary condition for PKU-related seizures to occur. A low Phe diet prevents susceptibility to seizures, which can resume with the significant delay after termination of dietary treatment.     

The effectiveness of ziprasidone in treating impaired quality of life in schizophrenia: a 12-month, open-label, flexible-dose, naturalistic observational study of patients undergoing usual care

OBJECTIVE: Health related quality of life (HRQL) has become an important outcome measure in the treatment of psychiatric disorders. This long-term observational study examined ziprasidone-induced improvement in satisfaction with HRQL in schizophrenia patients treated under real-world conditions. METHOD: Seventy schizophrenia patients with persistent symptoms or troublesome side effects were assigned to a 12-month, open-label, flexible-dose (40-160 mg/d), large-scale, naturalistic trial. Outcome measures were taken at baseline, 6, and 12 months, and included the Quality of Life Enjoyment and Satisfaction Questionnaire (Q-LES-Q), severity of symptoms, distress, and side effects. RESULTS: Thirty-two patients fully completed the study protocol. Patients reported poorer general HRQL compared with healthy subjects. At the end of the study, significant improvement in general activity, and satisfaction with life was observed. The effect sizes for these changes were moderate (0.55, and 0.72, respectively). After Bonferroni correction for multiple comparisons improvement in satisfaction with general activity remained significant. No significant changes were noted in other Q-LES-Q dimensions. Improvement in general activity was associated with a reduction in the severity of symptoms and emotional distress, but was unrelated to the ziprasidone daily dose, side effect scores, and concomitantly prescribed antidepressants, anxiolytics, mood stabilizers, or antiparkinson drugs. CONCLUSION: This study indicates that ziprasidone treatment resulted in the improvement of the satisfaction with general activity that tended to increase over time, from month 6 onwards. This effect was associated with reduction in the severity of clinical symptoms, and emotional distress.     

Protection against mouse and avian influenza A strains via vaccination with a combination of conserved proteins NP, M1 and NS1

Background Experimental data accumulated over more than a decade indicate that cross‐strain protection against influenza may be achieved by immunization with conserved influenza proteins. At the same time, the efficacy of immunization schemes designed along these lines and involving internal influenza proteins, mostly NP and M1, has not been sufficient. Objective To test the immunogenicity and protective efficacy of DNA vaccination with a combination of NP, M1 and NS1 genes of influenza virus. Methods The immunogenicity and protective efficacy of DNA vaccination with NP, M1 and NS1 was tested in mice and chickens. Mice were challenged with mouse‐adapted viral strains H3N2 and H5N2 and chicken challenged with avian H5N3 virus. Results In these settings, wild‐type NS1 did not impede the cellular and humoral response to NP/M1 immunization in vivo. Moreover, addition of NS1‐encoding plasmid to the NP/M1 immunization protocol resulted in a significantly increased protective efficacy in vivo. Conclusions The addition of NS1 to an influenza immunization regimen based on conserved proteins bears promise. It is feasible that upon further genetic modification of these and additional conserved influenza proteins, providing for their higher safety, expression and immunogenicity, a recombinant vaccine based on several structural and non‐structural proteins or their epitopes will offer broad anti‐influenza protection in a wide range of species.     

Stabilization of neurotoxic Alzheimer amyloid-β oligomers by protein engineering

Soluble oligomeric aggregates of the amyloid-β peptide (Aβ) have been implicated in the pathogenesis of Alzheimer’s disease (AD). Although the conformation adopted by Aβ within these aggregates is not known, a β-hairpin conformation is known to be accessible to monomeric Aβ. Here we show that this β-hairpin is a building block of toxic Aβ oligomers by engineering a double-cysteine mutant (called Aβcc) in which the β-hairpin is stabilized by an intramolecular disulfide bond. Aβ₄₀cc and Aβ₄₂cc both spontaneously form stable oligomeric species with distinct molecular weights and secondary-structure content, but both are unable to convert into amyloid fibrils. Biochemical and biophysical experiments and assays with conformation-specific antibodies used to detect Aβ aggregates in vivo indicate that the wild-type oligomer structure is preserved and stabilized in Aβcc oligomers. Stable oligomers are expected to become highly toxic and, accordingly, we find that β-sheet-containing Aβ₄₂cc oligomers or protofibrillar species formed by these oligomers are 50 times more potent inducers of neuronal apoptosis than amyloid fibrils or samples of monomeric wild-type Aβ₄₂, in which toxic aggregates are only transiently formed. The possibility of obtaining completely stable and physiologically relevant neurotoxic Aβ oligomer preparations will facilitate studies of their structure and role in the pathogenesis of AD. For example, here we show how kinetic partitioning into different aggregation pathways can explain why Aβ₄₂ is more toxic than the shorter Aβ₄₀, and why certain inherited mutations are linked to protofibril formation and early-onset AD.