Differential temporal profile of lowered blood glucose levels (3.5 to 6.5 mmol/l versus 5 to 8 mmol/l) in patients with severe traumatic brain injury.

INTRODUCTION: Hyperglycaemia is detrimental, but maintaining low blood glucose levels within tight limits is controversial in patients with severe traumatic brain injury, because decreased blood glucose levels can induce and aggravate underlying brain injury. METHODS: In 228 propensity matched patients (age, sex and injury severity) treated in our intensive care unit (ICU) from 2000 to 2004, we retrospectively evaluated the influence of different predefined blood glucose targets (3.5 to 6.5 versus 5 to 8 mmol/l) on frequency of hypoglycaemic and hyperglycaemic episodes, insulin and norepinephrine requirement, changes in intracranial pressure and cerebral perfusion pressure, mortality and length of stay on the ICU. RESULTS: Mortality and length of ICU stay were similar in both blood glucose target groups. Blood glucose values below and above the predefined levels were significantly increased in the 3.5 to 6.5 mmol/l group, predominantly during the first week. Insulin and norepinephrine requirements were markedly increased in this group. During the second week, the incidences of intracranial pressure exceeding 20 mmHg and infectious complications were significantly decreased in the 3.5 to 6.5 mmol/l group. CONCLUSION: Maintaining blood glucose within 5 to 8 mmol/l appears to yield greater benefit during the first week. During the second week, 3.5 to 6.5 mmol/l is associated with beneficial effects in terms of reduced intracranial hypertension and decreased rate of pneumonia, bacteraemia and urinary tract infections. It remains to be determined whether patients might profit from temporally adapted blood glucose limits, inducing lower values during the second week, and whether concomitant glucose infusion to prevent hypoglycaemia is safe in patients with post-traumatic oedema.

Low-dose formaldehyde delays DNA damage recognition and DNA excision repair in human cells.

OBJECTIVE: Formaldehyde is still widely employed as a universal crosslinking agent, preservative and disinfectant, despite its proven carcinogenicity in occupationally exposed workers. Therefore, it is of paramount importance to understand the possible impact of low-dose formaldehyde exposures in the general population. Due to the concomitant occurrence of multiple indoor and outdoor toxicants, we tested how formaldehyde, at micromolar concentrations, interferes with general DNA damage recognition and excision processes that remove some of the most frequently inflicted DNA lesions. METHODOLOGY/PRINCIPAL FINDINGS: The overall mobility of the DNA damage sensors UV-DDB (ultraviolet-damaged DNA-binding) and XPC (xeroderma pigmentosum group C) was analyzed by assessing real-time protein dynamics in the nucleus of cultured human cells exposed to non-cytotoxic (<100 µM) formaldehyde concentrations. The DNA lesion-specific recruitment of these damage sensors was tested by monitoring their accumulation at local irradiation spots. DNA repair activity was determined in host-cell reactivation assays and, more directly, by measuring the excision of DNA lesions from chromosomes. Taken together, these assays demonstrated that formaldehyde obstructs the rapid nuclear trafficking of DNA damage sensors and, consequently, slows down their relocation to DNA damage sites thus delaying the excision repair of target lesions. A concentration-dependent effect relationship established a threshold concentration of as low as 25 micromolar for the inhibition of DNA excision repair. CONCLUSIONS/SIGNIFICANCE: A main implication of the retarded repair activity is that low-dose formaldehyde may exert an adjuvant role in carcinogenesis by impeding the excision of multiple mutagenic base lesions. In view of this generally disruptive effect on DNA repair, we propose that formaldehyde exposures in the general population should be further decreased to help reducing cancer risks.