Chemical Hybridization of Vizantin and Lipid A to Generate a Novel LPS Antagonist.

Lipopolysaccharide (LPS) antagonists have attracted considerable interest as promising candidates for the treatment of severe sepsis triggered by Gram-negative bacteria. In this article, we describe the development of a novel LPS antagonist based on chemical hybridization of vizantin and the hydrophobic molecular unit of LPS (lipid A). Vizantin, 6,6'-bis-O-(3-nonyldodecanoyl)-α,α'-trehalose, was designed as an immunostimulator from a structure-activity relationship (SAR) study with trehalose 6,6'-dicorynomycolate (TDCM). Our recent study indicated that vizantin displays adjuvant activity by specifically binding to the Toll-like receptor 4 (TLR4)/MD2 protein complex. Because lipid A unit (or LPS) is also known to trigger an inflammatory response via the same TLR4/MD2 complex as vizantin, we designed a hybrid compound of vizantin and lipid A with the aim of developing a novel biofunctional glycolipid. Focusing on the antagonism to Escherichia coli LPS in an in vitro model with human macrophages (THP-1 cells), we identified a potent LPS antagonist among the synthesized hybrid compounds. The novel LPS antagonist effectively inhibited LPS-induced release of tumor necrosis factor-alpha (TNF-α) in a dose-dependent manner with an IC50 value of 3.8 nM, making it a candidate for the treatment drug of Gram-negative sepsis and/or septic shock.

Intralimb incoordination in patients with ataxia.

Intralimb incoordination needs to be distinguished from interlimb incoordination, which is observed in Parkinson's disease (PD). With this aim, intra and inter-limb coordination impairment in the lower limbs were measured in 13 patients with cerebellar ataxia during pedaling of an ergometer with left and right pedals that can be rotated independently. Intralimb incoordination in patients with cerebellar ataxia was compared with interlimb incoordiation in patients with PD. We concluded that impairment of intralimb coordination in ataxia patients leads to inability to maintain pedaling amplitude and speed, but unlike in PD, right and left coordination was roughly preserved. Our method may be useful for assessing the severity of ataxia and detecting hidden parkinsonism in ataxic patients.

Overestimation of stability limits leads to a high frequency of falls in patients with Parkinson's disease.

OBJECTIVES: To test a hypothesis that patients with Parkinson's disease may not notice discrepancies between their perceived and actual stability limits and cannot keep their centre of gravity within the stability region. SETTINGS: Outpatients with neurological disorders in rehabilitation service. SUBJECTS: Twenty-one patients with Parkinson's disease (11 men, 10 women; mean duration 5.9 +/- 3.9 years) and age- and sex-matched healthy volunteers were recruited. METHODS: Each subject's right arm length was subtracted from the distance between the right acromion and the perceived reachable boundary. This was called 'perceived reach'. The figure given by subtracting the right arm length from the maximum forward reach length measured by the Functional Reach Test was named 'actual reach', and is an index of actual stability limits in each subject. The difference between actual and perceived stability limits (DAP) is given by actual reach minus perceived reach. The motor score of the Unified Parkinson's Disease Rating Scale were used to evaluate disease severity. RESULTS: The mean DAP for the Parkinson's disease group was negative (-1.8 +/- 5.7 cm) and significantly different from that of controls (3.3 +/- 9.2 cm) (P < 0.05). In Parkinson's disease, DAP was significantly correlated with the Unified Parkinson's Disease Rating Scale score (correlation coefficient = -0.39, P < 0.05). CONCLUSIONS: These results indicated that patients with Parkinson's disease overestimated their stability limits, which may result in falls. In addition, the results demonstrate that patients with Parkinson's disease develop overestimation of stability limits in parallel with their disease progression.

Intralimb and Interlimb Incoordination: Comparative Study between Patients with Parkinsonism and with Cerebellar Ataxia.

Dysfunction of limb coordination may be divided into two categories; intra and inter-limb incoordination. To make clear differential character in these two limb incoordination, we measured 13 patients mainly with cerebellar ataxia and 27 patients mainly with parkinsonism during pedaling of an ergometer with left and right pedals that can be rotated independently. As a result, interlimb incoordination was predominantly observed in patients with parkinsonism, while patients with cerebellar ataxia showed relatively preserved interlimb coordination but intralimb incoordination. We concluded that impairment of intralimb coordination was a character in patients with cerebellar ataxia, while impairment of interlimb coordination was a character in patients with parkinsonism.