Treatment with K6PC-5, a selective stimulator of SPHK1, ameliorates intestinal homeostasis in an animal model of Huntington's disease.

Emerging evidence indicates that Huntington's disease (HD) may be described as multi-organ pathology. In this context, we and others have contributed to demonstrate that the disease is characterized by an impairment of the homeostasis of gastro-intestinal (GI) tract. Sphingolipids represent a class of molecules involved in the regulation and maintenance of different tissues and organs including GI system. In this study, we investigated whether the alteration of Sphingosine-1-phosphate (S1P) metabolism, previously described in human HD brains and animal models, is also detectable peripherally in R6/2 HD mice. Our findings indicate, for the first time, that sphingolipid metabolism is perturbed early in the disease in the intestinal tract of HD mice and, its modulation by K6PC-5, a selective activator of S1P synthesis, preserved intestinal integrity and homeostasis. These results further support the evidence that modulation of sphingolipid pathways may represent a potential therapeutic option in HD and suggest that it has also the potential to counteract the peripheral disturbances which may usually complicate the management of the disease and affect patient's quality of life.

Donepezil across the spectrum of Alzheimer's disease: dose optimization and clinical relevance.

Alzheimer's disease (AD) is an irreversible and progressive neurodegenerative disorder. AD is the most common cause of dementia worldwide, and its incidence is increasing in line with population aging. The primary feature of AD is progressive cognitive decline, and severe AD is characterized by reduced communication skills and mobility. However, successful treatment can substantially improve quality of life. Donepezil is an acetylcholinesterase inhibitor approved for use across the full spectrum of mild, moderate, and severe AD. Donepezil has been available at doses of 5 or 10 mg once daily for more than a decade and, more recently, a single high once-daily sustained-release 23-mg dose has been approved for treatment of patients with moderate to severe AD. The rationale for the higher dose formulation was the expected increase in acetylcholinesterase inhibition given the dose-response relationship of donepezil, with the benefits of the higher dose being most apparent in patients with more advanced AD. Donepezil 5 and 10 mg/day have been well studied in mild-to-moderate AD, and a clinical trial has confirmed the benefits of donepezil 23 mg/day in patients with moderate to severe AD, particularly for language and visuospatial ability. This review presents an overview of the evidence for donepezil across the spectrum of AD, with a focus on dose optimization for disease progression.

The sphingosine kinase activator K6PC-5 stimulates C2C12 myoblast differentiation.

Previously, K6PC-5, a synthetic derivative of ceramide, was demonstrated to activate sphingosine kinase (SK)-1 in keratinocytes. In this study its potential biological effect in mouse myoblasts was examined. The obtained results show that K6PC-5 promotes myogenic differentiation by enhancing myogenic marker expression, differentiation index and fusion index. Interestingly, its biological action was prevented by pharmacological inhibition of SK or S1P2 receptor, in full agreement with their recognized role in myoblast differentiation. This is the first evidence that pharmacological activation of SK accelerates myogenesis and suggests that this new therapeutic strategy could be possibly employed in skeletal muscle disorders where muscle regeneration is deficient.

Apicidin, the histone deacetylase inhibitor, suppresses Th1 polarization of murine bone marrow-derived dendritic cells.

Apicidin is a fungal metabolite shown to exhibit anti-proliferative, anti-invasive, and anti-inflammatory properties by the inhibition of histone deacetylase (HDAC). However, the effects of apicidin on the maturation and immunostimulatory function of dendritic cells (DCs) remain unknown. In this study, we investigated whether apicidin modulates surface molecule expression, cytokine production, endocytosis capacity, and underlying signaling pathways in murine bone marrow-derived DCs. We observed that apicidin significantly attenuated surface molecule expression in LPS-stimulated DCs, suppressed production of interleukin (IL)-12 and proinflammatory cytokines (IL-6 and TNF-alpha) by DCs, and reduced IFN-gama production by T cells. The apicidin-treated DCs were found to be highly efficient in antigen capture via mannose receptor-mediated endocytosis. Apicidin also inhibited LPS-induced MAPK activation and NF-kB nuclear translocation in DCs. Moreover, the apicidin-treated DCs were incapable of inducing Th1 responses and normal cell-mediated immune responses. These novel findings not only provide new insights into the immunopharmacological role of apicidin in terms of its effects on DCs, but also broaden current perspectives of the immunopharmacological functions of apicidin, and have implications for the development of therapeutic adjuvants for the treatment of DC-related acute and chronic diseases.

The density ratio of grey to white matter on computed tomography as an early predictor of vegetative state or death after cardiac arrest.

OBJECTIVES: To evaluate whether the ratio (in Hounsfield units; HU) of grey matter (GM) to white matter (WM) on computed tomography (CT) scans taken within 24 h of resuscitation can be used as a predictor of outcome. METHODS: 28 patients who resuscitated from cardiac arrest and had head CT performed within 24 h of resuscitation were retrospectively investigated. 27 subjects with normal head CT findings served as controls. Comatose patients were divided into two groups: those with a Glasgow outcome scale (GOS) score of 3-5 (good outcome subgroup) and those with a GOS score of 1-2 (poor outcome subgroup). HU were measured in GM and WM at the level of the basal ganglia on non-contrast CT scans. RESULTS: The density ratio of GM to WM was significantly lower in comatose patients than in controls (mean 1.21 vs 1.32, p<0.001). The GM:WM ratio was significantly lower in the poor subgroup than in the good subgroup (mean 1.19 vs 1.28, p<0.001). Receiver operating characteristic curve analysis determined a cutoff value of a GM:WM ratio of less than 1.22 for vegetative state or death. This value predicted vegetative state or death with a sensitivity of 63%, a specificity of 100%, a positive predictive value of 100%, and a negative predictive value of 56%. CONCLUSION: The GM/WM ratio correlates with the outcome of hypoxic ischaemic encephalopathy and may be useful as an objective early predictor of vegetative state or death in comatose patients after cardiac arrest.

A brief comparative review of primate posterior parietal cortex: A novel hypothesis on the human toolmaker.

The primate visual system contains two major cortical pathways: a ventral-temporal pathway that has been associated with object processing and recognition, and a dorsal-parietal pathway that has been associated with spatial processing and action guidance. Our understanding of the role of the dorsal pathway, in particular, has greatly evolved within the framework of the two-pathway hypothesis since its original conception. Here, we present a comparative review of the primate dorsal pathway in humans and monkeys based on electrophysiological, neuroimaging, neuropsychological, and neuroanatomical studies. We consider similarities and differences across species in terms of the topographic representation of visual space; specificity for eye, reaching, or grasping movements; multi-modal response properties; and the representation of objects and tools. We also review the relative anatomical location of functionally- and topographically-defined regions of the posterior parietal cortex. An emerging theme from this comparative analysis is that non-spatial information is represented to a greater degree, and with increased complexity, in the human dorsal visual system. We propose that non-spatial information in the primate parietal cortex contributes to the perception-to-action system aimed at manipulating objects in peripersonal space. In humans, this network has expanded in multiple ways, including the development of a dorsal object vision system mirroring the complexity of the ventral stream, the integration of object information with parietal working memory systems, and the emergence of tool-specific object representations in the anterior intraparietal sulcus and regions of the inferior parietal lobe. We propose that these evolutionary changes have enabled the emergence of human-specific behaviors, such as the sophisticated use of tools.

The characterization of molecular organization of multilamellar emulsions containing pseudoceramide and type III synthetic ceramide.

To investigate the molecular organization and phase behavior of physiologic lipid mixtures that contain either newly synthesized pseudoceramide or type III synthetic ceramide, various analytical techniques were used. The phase transition temperatures detected in differential scanning calorimetry analysis were 51.19 and 50.52 for the pseudoceramide-containing physiologic lipid mixture and synthetic type III ceramide-containing lipid mixture, respectively. From the small angle XRD patterns, the multilamellar emulsion-pseudoceramide showed 11.5 nm and 7.61 nm lamellar phases, while the multilamellar emulsion-synthetic ceramide showed only a 7.61 nm lamellar phase. The nonceramide containing lipid mixture did not show any distinct repeat pattern. Lateral packing distances of multilamellar emulsion-pseudoceramide and multilamellar emulsion-synthetic ceramide were measured as 0.4119 and 0.4110 nm at 30, respectively, which indicated the presence of hexagonal lattice. On the contrary, non-multilamellar emulsion did not show any definite repeat pattern. Transmission electron microscopy observation showed nearly comparable lamellar structures in all of the tested emulsions compared to the structure of human stratum corneum intercellular lipid. Decrease of water contents resulted in phase transition into liquid phase for all the tested emulsions, whereas phase transition into orthorhombic phase was observed only in multilamellar emulsion-pseudoceramide. From these results, we concluded that the molecular organization of multilamellar emulsion-pseudoceramide was characterized as the lateral hexagonal phase and both the long and short periodicity lamellar phases, which showed structural similarity with the native human stratum corneum intercellular lipid.

Current surgical results of retrosigmoid approach in extralarge vestibular schwannomas.

BACKGROUND: Vestibular schwannomas (VS) are common tumors that can be cured; they are reported to comprise 6 approximately 8% of all intracranial tumors. The primary objective in the surgery of extralarge VS is total removal of the tumor mass while preserving the facial nerve. In extralarge tumors, complete excision of the tumor carries a significant risk of injuring the facial nerve and adjacent vital brain structures. The authors are reporting the techniques and results of operation on extralarge VS. METHODS: The material consisted of 30 patients during the last 6 years with surgically treated VS that had a maximal extrameatal diameter exceeding 4 cm. Suboccipital craniotomy and tumor removal was performed with patients in the lateral position. Results and complications of the surgical technique will be reviewed. RESULTS: Average age of patients was 45.2 years; there was a slight female predominance (1.5:1). Size of the mass ranged from 41 to 70 mm; all were removed by the retrosigmoid transmeatal approach. Peritumoral edema on MRI was seen in 50% (15/30). Total removal was achieved in 73.3% (22/30) with no significant relationship to peritumoral edema. In the cases of total removal, the facial nerve preservation rate was 86.4% (19/22). There was no mortality. Surgical complications were hemorrhage and CSF leakage in 1 case (3%) and 8 cases (26.7%), respectively, but in most of these cases, conservative treatment was adequate. In patients in whom anatomic preservation of the facial nerve was achieved, facial nerve function improved progressively within a year. In all cases except for one with gait disturbance, a good outcome was achieved. CONCLUSIONS: Our surgical techniques, including the prediction of facial nerve displacement, not using retractors, and replacement of bone, contributed to good surgical results in a series of extralarge VS.

Recurrent unilateral frosted branch angiitis.

In the left eye of a 27-year-old man we found perivascular creamy sheathing of retinal veins with retinal hemorrhages and, on fluorescein angiography, delayed filling of veins with late leakage. Dramatic recovery of visual acuity and healing of retinal lesions followed intravenous corticosteroid therapy. However, the condition recurred several times within a few months. Fluorescein angiography showed delayed filling of arteries and veins and arteriovenous anastomoses with a widespread capillary nonperfusion area. Eventually, neovascular glaucoma resulted. It is suggested that frosted branch angiitis is related to vascular occlusion. Systemic corticosteroid therapy seems to affect the course of this disease.

An outbreak of highly pathogenic avian influenza at a public animal exhibit in seoul, Korea, during 2008.

This study describes the first recorded outbreak of HPAI in the city of Seoul, in captive birds held in an exhibition for public viewing at a local district office. The index cases were two pheasants, which had been introduced into the exhibit on 24 April, 4 days prior to death, from a store in a local market in Gyeonggi-do. Ducks and chickens from an HPAI outbreak farm, subsequently confirmed on 4 May, had also been held in this store. This outbreak highlights the potential role of local markets in AIV transmission. This outbreak led to considerable public health concern in Korea, however, no human cases were reported. The non-commercial poultry sector needs to be considered in national plans for preparedness and response.

Metabolic syndrome and ALT: a community study in adult Koreans.

OBJECTIVE: To investigate an association between the metabolic syndrome (MS) and alanine aminotransferase (ALT) of normal ranges. DESIGN: A population-based cross-sectional survey in three rural communities, South Korea. SUBJECTS: A total of 1248 men and 2157 women aged 30 y and older. MEASUREMENTS: Body mass index (BMI), waist circumference, fasting blood lipid and glucose, resting blood pressure, and ALT. RESULTS: ALT and BMI increased with an addition of the MS components. A consistent association between ALT more than 15 IU/l and the MS was found in both sexes, independently of age, education, BMI, smoking, alcohol drinking, and sedentary life style. The odds ratios for the MS in the highest quintiles of ALT were 7.1-fold higher than the reference quintile in men and 2.1-fold higher in women. The likelihood ratio tests for trend were also significant with ALT increments (P<0.001 for trend). CONCLUSION: The MS is significantly associated with the higher quintiles of normal ALT in both genders. ALT could be a sensitive marker of hepatic dysfunction associated with the MS, even in the range below the current limit.