Background: During sepsis progression microcirculatory dysfunction precedes macrocirculatory failure, partly explaining the occurrence of early organ dysfunction. The matter concerning microcirculatory dysfunction in the brain under septic conditions is less clear. We investigated the integrity of the activation flow coupling during sepsis progression in a rat model of septic shock. Methods: Chloralose-anesthetized rats (n = 30) were subjected to electric forepaw stimulation. Over the somatosensory cortex electrical activity and hemodynamic responses were recorded with surface electrodes and laser Doppler. After baseline recordings, vehicle, 1 or 5 mg/kg lipopolysaccharide (LPS) from Escherichia coli was given intravenously, and activation flow coupling, blood pressure and blood gases were investigated at regular time points up to 270 min. In the end lactate, glucose, neuron-specific enolase (NSE) and S-100B protein levels were measured. Results: Besides stable data from the control group, all LPS-treated rats developed signs of septic shock, which were more pronounced in the 5 mg/kg LPS group. Cerebral hyperemia occurred and was similar between the sepsis groups despite lower blood pressure levels in the 5 mg/kg LPS group. While the activation flow coupling remained intact in the 1 mg/kg LPS group, an uncoupling occurred in the 5 mg/kg group. First, the evoked flow velocity responses dropped 60 min after sepsis induction before the somatosensory amplitudes also decreased 120 min later. From similar NSE levels we suggest a functional rather than structural deficit explaining the difference in evoked potentials. Conclusions: For the first time we demonstrate microcirculatory dysfunction in the activation flow coupling of the brain. Inappropriate blood supply of neurons might explain the disturbance of neuronal function.

No abstract

Type 1 diabetic individuals are known to develop disorders of bone metabolism resulting in osteopenia. Previous studies have suggested an influence of vitamin D receptor alleles on bone metabolism and susceptibility for type 1 diabetes mellitus. The present study was initiated to investigate the distribution of vitamin D receptor alleles in Caucasian type 1 diabetic patients and their relation to bone turnover parameters. 75 patients were included and compared to 57 healthy controls. Three vitamin D receptor alleles were examined (BsmI, TaqI and FokI); serum levels of intact osteocalcin, parathyroid hormone, bone specific alkaline phosphatase, the carboxy terminal extension peptide of type I procollagen, 25-OH-vitamin D levels, HbA1c and urinary deoxypyridinoline excretion were measured. We observed a higher frequency of the TT genotype in diabetic patients, but no difference in markers of bone turnover between diabetics and non-diabetics in either sex. Bone turnover was different in men and in women without any association with vitamin D receptor genotype. No association was found between diabetes duration, age of onset or metabolic control and bone turnover parameters. In summary, our results show an association between the TT genotype and diabetes in Germans, but no difference in bone turnover markers between diabetics and non-diabetics.

Reduction in evoked flow velocity responses reflects reduced nitric oxide bioavailability and therefore supports molecular findings of acute statin withdrawal. Questions arise if the present data might give a link to reports of increased vascular events in patients at vascular risk after acute statin withdrawal.

Background and Purpose-Hyperhomocysteinemia is a vascular risk factor that infers with the nitric oxide signaling pathway of endothelial vasoregulation. Most investigations in young healthy humans on the peripheral vasculature using a standardized methionine challenge demonstrated altered vascular reactivity. In contrast, the cerebral autoregulation mechanism was shown to be unaffected by the same methionine load. To obtain additional insight into the compensatory range of the cerebral vasculature during a methionine challenge, we tested the neurovascular coupling mechanism that adjusts cerebral blood flow in accordance with cortical activity. Methods-Fifteen healthy young adults (age, 24.7Ϯ2.3 years; 7 men) were tested with a functional transcranial Doppler test before and 3, 8, and 24 hours after administration of placebo, 20 mg folic acid, 20 mg folic acid and 0.1 g/kg body weight L-methionine, or L-methionine alone. Evoked blood flow response was evaluated according to a control system approach. Plasma concentrations of homocysteine, resting blood flow velocities, and control system parameters of flow velocity change were compared for each time point using a multiple analysis of variance test. Results-Homocysteine levels increased significantly compared with baseline (before, 7.6Ϯ1.9 mol/L; 3 hours, 22 Key Words: endothelium Ⅲ homocyst(e)ine Ⅲ ultrasonography, Doppler Ⅲ vasodilation T he neurovascular coupling (NC) mechanism adjusts local cerebral blood flow in accordance with the underlying cortical activity. [1][2][3][4] Whereas the detailed mechanisms remain to be resolved, there is good evidence that the biological elements of the NC mechanism functionally resemble a complex and cascaded control system. 1,2,4 -8 The vascular endothelium and its nitric oxide system play a crucial role in the NC-related vasoregulation. 4,9 -13 Hyperhomocysteinemia is an emerging vascular risk factor leading to endothelial dysfunction, atherosclerosis, and consequently parenchymal ischemia. 10 -13 The term "endothelial dysfunction" is assumed to describe in general a functional alteration of the vasculature, depending on some vasoregulative mechanism. 14,15 Under acute hyperhomocysteinemia, it is hypothesized to be caused by a decrease in availability of nitric oxide. 16 -19 Several studies in healthy young volunteers undergoing an oral methionine loading of 0.1 g/kg body weight demonstrated an impaired peripheral vascular reactivity. 20 -24 However, some reports found neither an altered peripheral vascular reactivity 25,26 nor a change in arterial rigidity under the same homocysteine challenge. 27 Similarly, for the cerebral autoregulation (CA) mechanism that maintains constant cerebral perfusion despite changes in arterial blood pressure, it was demonstrated that vascular reactivity was affected only in aged but not in young healthy subjects. 28 An attenuation of the endothelium-dependent cerebrovascular reactivity was found consistently only in animal experiments using high concentrations of homocysteine (1 mmol/L)...