On the physiology of cognitive decline in type 1 diabetes

ObjectivesType 1 diabetes mellitus (T1DM) may be associated with cognitive impairment and notably a decline in psychomotor speed, information processing speed and attention. The mechanism for this decline is uncertain. Previous studies by our group and others have demonstrated a decline in EEG-power and event-related potential amplitude in T1DM. The objectives of the present study were to explore whether 1) the association between event-related potential (N100) amplitude and psychomotor speed is different between T1DM and healthy subjects, and 2) the decline in N100 amplitude depends on duration of diabetes.MethodsPatients with T1DM (N = 204) and healthy control subjects (N = 358) were included in a cross-sectional study. Event-related brain potentials were recorded with auditory reaction tasks. Psychomotor speed was evaluated with the Grooved Pegboard test in a subset of the patients (N = 70) and the healthy control subjects (N = 89).ResultsPatients with T1DM had a decrease in the N100 amplitude that correlated with a decline in psychomotor speed, longer duration of diabetes and increasing age. In healthy controls, the N100 amplitude did not decrease with age and the association between psychomotor speed and N100 amplitude was absent.ConclusionThe association between psychomotor speed and N100 amplitude is likely to be a specific trait for T1DM since it was not found in healthy controls and was dependent on diabetes duration. Our findings indicate that the pathogenesis of cognitive decline in T1DM may involve a disease-related factor with a long-term influence on the N100 amplitude.     

Association between SNPs in defined functional pathways and risk of early or late toxicity as well as individual radiosensitivity

Background and purpose

The aim of this study was to determine the impact of functional single nucleotide polymorphism (SNP) pathways involved in the ROS pathway, DNA repair, or TGFB1 signaling on acute or late normal toxicity as well as individual radiosensitivity.

Materials and methods

Patients receiving breast-conserving surgery and radiotherapy were examined either for erythema (n?=?83), fibrosis (n?=?123), or individual radiosensitivity (n?=?123). The 17 SNPs analyzed are involved in the ROS pathway (GSTP1, SOD2, NQO1, NOS3, XDH), DNA repair (XRCC1, XRCC3, XRCC6, ERCC2, LIG4, ATM) or TGFB signaling (SKIL, EP300, APC, AXIN1, TGFB1). Associations with biological and clinical endpoints were studied for single SNPs but especially for combinations of SNPs assuming that a SNP is either beneficial or deleterious and needs to be weighted.

Results

With one exception, no significant association was seen between a single SNP and the three endpoints studied. No significant associations were also observed when applying a multi-SNP model assuming that each SNP was deleterious. In contrast, significant associations were obtained when SNPs were suggested to be either beneficial or deleterious. These associations increased, when each SNP was weighted individually. Detailed analysis revealed that both erythema and individual radiosensitivity especially depend on SNPs affecting DNA repair and TGFB1 signaling, while SNPs in ROS pathway were of minor importance.

Conclusion

Functional pathways of SNPs may be used to form a risk score allowing to predict acute and late radiation-induced toxicity but also to unravel the underlying biological mechanisms.

     

pH Manipulation as a Novel Strategy for Treating Mucormycosis

Mucormycosis is a fatal fungal disease caused by several organisms within the order Mucorales. In recent years, traumatic injury has emerged as a novel risk factor for mucormycosis. Current antifungal therapy is ineffective, expensive, and typically requires extensive surgical debridement. There is thus a pressing need for safe prophylactic treatment that can be rapidly and easily applied to high-risk patients, such as those with major trauma injuries. Acetic acid has been used as a topical treatment for burn wounds for centuries and has proven activity against Gram-negative bacteria. Here, we demonstrate that acetic acid is also highly effective against major pathogenic groups of Mucorales, even at very low concentrations (0.3%). This antifungal effect is not seen with other acids, such as hydrochloric and lactic acid, suggesting that acetic acid activity against Mucorales spores is not solely evoked by low environmental pH. In agreement with this, we demonstrate that the antifungal activity of acetic acid arises from a combination of its ability to potently lower intracellular pH and from pH-independent toxicity. Thus, dilute acetic acid may offer a low-cost, safe, prophylactic treatment for patients at risk of invasive mucormycosis following traumatic injury.