FGF-21, a novel metabolic regulator, has a robust neuroprotective role and is markedly elevated in neurons by mood stabilizers.

Fibroblast growth factor-21 (FGF-21) is a new member of the FGF super-family and an important endogenous regulator of glucose and lipid metabolism. It has been proposed as a therapeutic target for diabetes and obesity. Its function in the central nervous system (CNS) remains unknown. Previous studies from our laboratory demonstrated that aging primary neurons are more vulnerable to glutamate-induced excitotoxicity, and that co-treatment with the mood stabilizers lithium and valproic acid (VPA) induces synergistic neuroprotective effects. This study sought to identify molecule(s) involved in these synergistic effects. We found that FGF-21 mRNA was selectively and markedly elevated by co-treatment with lithium and VPA in primary rat brain neurons. FGF-21 protein levels were also robustly increased in neuronal lysates and culture medium following lithium-VPA co-treatment. Combining glycogen synthase kinase-3 (GSK-3) inhibitors with VPA or histone deacetylase (HDAC) inhibitors with lithium synergistically increased FGF-21 mRNA levels, supporting that synergistic effects of lithium and VPA are mediated via GSK-3 and HDAC inhibition, respectively. Exogenous FGF-21 protein completely protected aging neurons from glutamate challenge. This neuroprotection was associated with enhanced Akt-1 activation and GSK-3 inhibition. Lithium-VPA co-treatment markedly prolonged lithium-induced Akt-1 activation and augmented GSK-3 inhibition. Akt-1 knockdown markedly decreased FGF-21 mRNA levels and reduced the neuroprotection induced by FGF-21 or lithium-VPA co-treatment. In addition, FGF-21 knockdown reduced lithium-VPA co-treatment-induced Akt-1 activation and neuroprotection against excitotoxicity. Together, our novel results suggest that FGF-21 is a key mediator of the effects of these mood stabilizers and a potential new therapeutic target for CNS disorders.

Orolingual angioedema after alteplase therapy of acute ischaemic stroke: incidence and risk of prior angiotensin-converting enzyme inhibitor use.

BACKGROUND AND PURPOSE: Orolingual angioedema (OA) is an uncommon but potentially life-threatening complication of treatment with recombinant tissue plasminogen activator (rt-PA; alteplase) during acute ischaemic stroke. This study aimed to determine the incidence of rt-PA-related OA in an Asian stroke population and the risk of pre-stroke anti-hypertensive drug use for development of this complication. METHODS: A multi-center stroke registry was used to identify the pre-stroke medications of acute ischaemic stroke patients receiving intravenous rt-PA from January 2002 to December 2013. The clinical manifestations of rt-PA-related OA were recorded and the incidence of this complication was determined. The risks of pre-stroke use of different anti-hypertensive agents for the occurrence of rt-PA-related OA were determined from this study and from a meta-analysis. RESULTS: A total of 559 patients received intravenous rt-PA over a 12-year period. Five patients (two males) developed OA after rt-PA administration. The incidence of OA amongst these patients was 0.89% (95% confidence interval 0.29%-2.09%), which was lower than that obtained by meta-analysis (1.9%). Amongst pre-stroke anti-hypertensive medications, angiotensin-converting enzyme (ACE) inhibitors were found in this study to have the highest relative risk for rt-PA-related OA (17.1; 95% confidence interval 3.0-96.9). Meta-analysis also revealed that pre-stroke use of ACE inhibitors was associated with a high relative risk of OA after intravenous rt-PA (12.9; 95% confidence interval 4.5-37.0). CONCLUSIONS: The incidence of rt-PA-related OA in the Asian population is lower than that in the Caucasian population. Pre-stroke use of ACE inhibitors significantly increases the risk of this complication.

Long-term efficacy of miglustat in paediatric patients with Niemann-Pick disease type C.

Niemann-Pick disease type C (NP-C) is a rare inherited neurovisceral disease characterized by progressive neurological manifestations. Oral miglustat was first approved for the treatment of children and adults with NP-C in Europe in 2009. There are still relatively few published data on the long-term efficacy and safety of miglustat in patients with NP-C in clinical practice. We report the effects of up to 6 years of treatment with miglustat 100 mg t.i.d. in five children. Overall, 3/5 patients displayed progressive dysphagia before starting miglustat, and 4/5 showed marked cognitive and/or motor impairment. The mean age at treatment start was 11.6 years, and the median (range) duration of therapy so far is 4 (4.1 to 6.1) years. No treatment dose alterations were required, but therapy was interrupted for 1-3 months at least once in all patients due to supply issues. Swallowing function was stabilised during miglustat therapy, with no significant increase in Han dysphagia scale or aspiration-penetration index scores among four evaluable patients (p > 0.05). Scores on the mini-mental state examination indicated an improvement in cognitive function during the first 3-6 months of miglustat therapy, followed by stabilisation up to 5 years. Ambulatory function remained stable for at least the first 2 years of treatment in most patients, but there was a trend towards deterioration thereafter, possibly related to treatment interruptions. The safety/tolerability profile of miglustat was similar to previous clinical studies, although reports of gastrointestinal disturbances were rare. Overall, miglustat appeared to stabilise key parameters of neurological disease progression.

Pre-ICH warfarin use, not antiplatelets, increased case fatality in spontaneous ICH patients.

BACKGROUND AND PURPOSE: Anticoagulant and antiplatelets for prevention of ischaemic stroke and cardiovascular diseases may increase the risk of intracerebral hemorrhage (ICH). This study aimed to investigate the influence of pre-ICH use of anticoagulant and antiplatelets on ICH patients. METHODS: Consecutive patients with acute spontaneous ICH registered in a single-center stroke registry during 2001 to 2010 were analyzed and categorized according to their pre-ICH use of warfarin (Group I), antiplatelets (Group II), or neither (Group III). Survival analysis and the Cox proportional hazard model were used to compare between the three groups and the predictors. RESULTS: Of 2021 ICH patients (male, 63.3%; mean age, 62.6 ± 14.4 years) included, there were 94 (4.7%) in Group I, 232 (11.4%) in Group II, and 1695 (83.9%) in Group III. Warfarin users had larger hematoma volume, more intraventricular extension, higher frequencies of lobar ICH, and higher case fatality than non-warfarin users (Groups II and III). The Cox proportional hazard model showed increased 6-month case fatality in pre-ICH warfarin users (adjusted hazard ratio 2.75, 95% confidence interval 2.04-3.72, P < 0.001), but not in pre-ICH antiplatelet users (adjusted hazard ratio 0.95, 95% confidence interval 0.72-1.26). CONCLUSIONS: Intracerebral hemorrhage patients with prior warfarin use, but not antiplatelet use, had significantly higher case fatality at 6 months.

Screen for intracranial dural arteriovenous fistulae with carotid duplex sonography.

OBJECTIVES: Early diagnosis and management of intracranial dural arteriovenous fistulae (DAVF) may prevent the occurrence of stroke. This study aimed to identify the best carotid duplex sonography (CDS) parameters for screening DAVF. METHODS: 63 DAVF patients and 170 non-DAVF patients received both CDS and conventional angiography. The use of seven CDS haemodynamic parameter sets related to the resistance index (RI) of the external carotid artery (ECA) for the diagnosis of DAVF was validated and the applicability of the best CDS parameter set in 20 400 patients was tested. RESULTS: The CDS parameter set (ECA RI (cut-off point = 0.7) and internal carotid artery (ICA) to ECA RI ratio (cut-off point = 0.9)) had the highest specificity (99%) for diagnosis of DAVF with moderate sensitivity (51%). Location of the DAVF was a significant determinant of sensitivity of detection, which was 70% for non-cavernous DAVF and 0% for cavernous sinus DAVF (p<0.001). The above parameter set detected abnormality in 92 of 20 400 patients. These abnormalities included DAVF (n = 25), carotid stenosis (n = 32), vertebral artery stenosis (n = 7), intracranial arterial stenosis (n = 6), head and neck tumour (n = 3) and unknown aetiology (n = 19). CONCLUSION: Combined CDS parameters of ECA RI and ICA to ECA RI ratio can be used as a screening tool for the diagnosis of DAVF.

Treatment of Niemann-Pick disease type C in two children with miglustat: initial responses and maintenance of effects over 1 year.

Niemann-Pick disease type C (NP-C) is a lipid storage disorder characterized by the accumulation of unesterified cholesterol and glycolipids in the lysosomal/late endosomal system of certain cells in the central nervous system (CNS) and visceral organs. Clinical symptoms include progressive neurological deterioration and visceral organomegaly. Miglustat, a small iminosugar molecule approved for the treatment of Gaucher disease, reversibly inhibits glucosylceramide synthase, which catalyses the first committed step in glycosphingolipid synthesis. The physicochemical properties of miglustat allow it to cross the blood-brain barrier and suggest possible benefits in lysosomal storage diseases affecting the CNS. Here, we present findings in two children with NP-C, aged 14 years (patient 1) and 9 years (patient 2), treated with miglustat for 1 year. Before treatment, patient 1 presented with severe difficulties in swallowing and walking, and patient 2 with problems mostly affecting communication and social interaction. Videofluoroscopic studies in patient 1 demonstrated a substantial improvement in swallowing by month 6 of treatment, and ambulation index measurements indicated improved walking. Mini Mental-State Examination (MMSE) assessments in patient 2 showed cognitive improvement by month 6, which was sustained up to month 12. Liver/spleen volume and plasma chitotriosidase activities were stabilized in both cases. There was no weight loss during treatment. Patient 1 experienced severe but self-limiting paresthesia, which was not associated with peripheral neuropathy. We conclude that miglustat can provide therapeutic benefits in CNS symptoms and allows stabilization of systemic disease in childhood-onset NP-C. Further follow-up is crucial to determine the long-term maintenance of these effects.

The role of the occipital artery in the diagnosis of intracranial dural arteriovenous fistula using duplex sonography.

BACKGROUND AND PURPOSE: The occipital artery is usually a main feeding artery of an intracranial dural arteriovenous fistula. The aim of this study was to establish the role of the OA in the diagnosis of DAVFs by using duplex sonography. MATERIALS AND METHODS: We first compared the clinical features between patients with DAVFs having and not having the OA as one of feeding arteries in 181 consecutive patients with DAVFs. Second, we investigated the OA by using duplex sonography in 60 control subjects to test the accessibility. Finally, we studied 24 DAVF and 60 non-DAVF patients to validate the diagnostic performances of duplex sonography. Hemodynamic parameters, including the resistance index and flow velocity, were analyzed. RESULTS: Half of the DAVFs (51%) had the OA as one of feeding arteries. DAVFs with the OA as one of the feeders were more likely located at noncavernous sinuses; to belong to types IIb, IIa+b, III, IV, or V; and to be associated with aggressive manifestations compared with DAVFs without the OA as a feeder (P < .05). Accessibility of the OA by using duplex sonography was 100%. The resistance index was lower and flow velocity was higher in the OA among patients with DAVFs compared with control subjects (P < .001). An OA resistance index <0.76 yielded a sensitivity and specificity of 96% and 97%, respectively, for the diagnosis of a DAVF. CONCLUSIONS: The OA resistance index can be used to screen for DAVFs having the OA as one of feeding arteries, and this kind of DAVF was usually associated with nonbenign clinical courses.

Serum calcium concentration affects signal changes on diffusion-weighted imaging in hypoglycemic encephalopathy.

BACKGROUND AND PURPOSE: Abnormal signals in brain DWI may appear in patients with HE. The aim of this study was to compare the clinical condition and various physiologic factors between patients with HE with and without abnormal signal intensity changes on DWI. MATERIALS AND METHODS: We retrospectively enrolled patients with HE who underwent brain DWI studies from January 2002 to November 2010. A diagnosis of HE was defined as low serum glucose levels (<50 mg/dL) with alteration of consciousness. Several clinical conditions and physiologic parameters were compared between patients with and without abnormal signals on DWI, including consciousness levels; outcome; body temperature; blood pressure; and serum levels of glucose, calcium, sodium, blood urea nitrogen, and creatinine. RESULTS: Nine patients with HE were included, and 3 of them (33%) had abnormal signals on brain DWI. There was a trend toward serum calcium concentrations being lower in patients with normal findings on DWI studies compared with patients with abnormal DWI signals (7.6 ± 1.7 versus 9.4 ± 0.7 mg/dL, P = .07). Serum glucose concentration, duration of hypoglycemia, consciousness levels, other physiologic parameters, and clinical outcome did not reveal any differences between the 2 groups. CONCLUSIONS: One-third of patients with HE had abnormal signals on brain DWI, and patients with low serum calcium levels may be less likely to present with abnormal DWI signals.

The WH11 gene of Candida albicans is regulated in two distinct developmental programs through the same transcription activation sequences.

Candida albicans strain WO-1 undergoes two developmental programs, the bud-hypha transition and high-frequency phenotypic switching in the form of the white-opaque transition. The WH11 gene is expressed in the white budding phase but is inactive in the white hyphal phase and in the opaque budding phase. WH11 expression, therefore, is regulated in the two developmental programs. Through fusions between deletion derivatives of the WH11 promoter and the newly developed Renilla reniformis luciferase, the WH11 promoter has been characterized in the two developmental programs. Three transcription activation sequences, two strong and one weak, are necessary for the full expression of WH11 in the white budding phase, but no negative regulatory sequences were revealed as playing a role in either the white hyphal phase or the opaque budding phase. These results suggest that regulation is solely through activation in the white budding phase and the same mechanism, therefore, is involved in regulating the differential expression of WH11 in the alternative white and opaque phases of switching and the budding and hyphal phases of dimorphism.

Phenotypic switching in Candida glabrata involves phase-specific regulation of the metallothionein gene MT-II and the newly discovered hemolysin gene HLP.

Although Candida glabrata has emerged in recent years as a major fungal pathogen, there have been no reports demonstrating that it undergoes either the bud-hypha transition or high-frequency phenotypic switching, two developmental programs believed to contribute to the pathogenic success of other Candida species. Here it is demonstrated that C. glabrata undergoes reversible, high-frequency phenotypic switching between a white (Wh), light brown (LB), and dark brown (DB) colony phenotype discriminated on an indicator agar containing 1 mM CuSO(4). Switching regulates the transcript level of the MT-II metallothionein gene(s) and a newly discovered gene for a hemolysin-like protein, HLP. The relative MT-II transcript levels in Wh, LB, and DB cells grown in the presence of CuSO(4) are 1:27:81, and the relative transcript levels of HLP are 1:20:35. The relative MT-II and HLP transcript levels in cells grown in the absence of CuSO(4) are 1:20:30 and 1:20:25, respectively. In contrast, switching has little or no effect on the transcript levels of the genes MT-I, AMT-I, TRPI, HIS3, EPAI, and PDHI. Switching of C. glabrata is not associated with microevolutionary changes identified by the DNA fingerprinting probe Cg6 and does not involve tandem amplification of the MT-IIa gene, which has been shown to occur in response to elevated levels of copper. Finally, switching between Wh, LB, and DB occurred in all four clinical isolates examined in this study. As in Candida albicans, switching in C. glabrata may provide colonizing populations with phenotypic plasticity for rapid responses to the changing physiology of the host, antibiotic treatment, and the immune response, through the differential regulation of genes involved in pathogenesis. More importantly, because C. glabrata is haploid, a mutational analysis of switching is now feasible.

EFG1 null mutants of Candida albicans switch but cannot express the complete phenotype of white-phase budding cells.

The Candida albicans gene EFG1 encodes a putative trans-acting factor. In strain WO-1, which undergoes the white-opaque transition, EFG1 is transcribed as a 3.2-kb mRNA in white-phase cells and a less-abundant 2.2-kb mRNA in opaque-phase cells. cDNA sequencing and 5' rapid amplification of cDNA ends analysis demonstrate that the major difference in molecular mass of the two transcripts is due to different transcription start sites. EFG1 null mutants form opaque-phase colonies and express the opaque-phase cell phenotype at 25 degrees C. When shifted from 25 to 42 degrees C, mutant opaque-phase cells undergo phenotypic commitment to the white phase, which includes deactivation of the opaque-phase-specific gene OP4 and activation of the white-phase-specific gene WH11, as do wild-type opaque-phase cells. After the commitment event, EFG1 null mutant cells form daughter cells which have the smooth (pimpleless) surface of white-phase cells but the elongate morphology of opaque-phase cells. Taken together, these results demonstrate that EFG1 expression is not essential for the switch event per se, but is essential for a subset of phenotypic characteristics necessary for the full expression of the phenotype of white-phase cells. These results demonstrate that EFG1 is not the site of the switch event, but is, rather, downstream of the switch event.

Intracranial dural arteriovenous fistulas with or without cerebral sinus thrombosis: analysis of 69 patients.

OBJECTIVES: To compare the characteristics of dural arteriovenous fistulas (AVFs) with or without cerebral sinus thrombosis (CST), and to analyse the determinants of aggressive manifestations in patients with dural AVF. METHODS: We investigated 69 patients aged 51.4 (SD 15) years who were diagnosed as having dural AVF. According to the location of the lesion and venous drainage pattern, dural AVF was classified into three sites (cavernous sinus, large sinus, and other) and five types (by Cognard's method). Aggressive manifestations of dural AVF were defined as intracranial haemorrhage, venous infarction, seizure, altered mental status, and intracranial hypertension. The diagnosis of CST was based on cerebral angiography. Logistic regression methods were used to analyse the determinants of aggressive manifestation in patients with dural AVF. RESULTS: CST was found in 39% of the patients with dural AVF. It was located at almost either the sinus around the dural AVF or the downstream venous flow pathways of the dural AVF. There was no significant difference with regard to sex, location, or type of dural AVF between patients with dural AVF with and without CST. The location "other sinuses" and the type of dural AVF "IIb/IIa+b/III/IV/V" were significantly related to aggressive manifestations of dural AVF (odds ratio 19 (p = 0.001) and 5.63 (p = 0.033), respectively). Presence of CST in patients with dural AVF had an odds ratio of 4.25 (p = 0.12) for development of aggressive manifestations. CONCLUSIONS: CST affects two fifths of patients with dural AVF. The location and type of dural AVF are major determinants of aggressive manifestations in patients with dural AVF.

The sea pansy Renilla reniformis luciferase serves as a sensitive bioluminescent reporter for differential gene expression in Candida albicans.

The infectious yeast Candida albicans progresses through two developmental programs which involve differential gene expression, the bud-hypha transition and high-frequency phenotypic switching. To understand how differentially expressed genes are regulated in this organism, the promoters of phase-specific genes must be functionally characterized, and a bioluminescent reporter system would facilitate such characterization. However, C. albicans has adopted a nontraditional codon strategy that involves a tRNA with a CAG anticodon to decode the codon CUG as serine rather than leucine. Since the luciferase gene of the sea pansy Renilla reinformis contains no CUGs, we have used it to develop a highly sensitive bioluminescent reporter system for C. albicans. When fused to the galactose-inducible promoter of GAL1, luciferase activity is inducible; when fused to the constitutive EF1 alpha 2 promoter, luciferase activity is constitutive; and when fused to the promoter of the white-phase-specific gene WH11 or the opaque-phase-specific gene OP4, luciferase activity is phase specific. The Renilla luciferase system can, therefore, be used as a bioluminescent reporter to analyze the strength and developmental regulation of C. albicans promoters.

[The hemodynamic and ventilatory effects between Trendelenburg and reverse Trendelenburg position during laparoscopy with CO2-insufflation].

Thirty ASA class I female patients underwent gynecologic pelvioscopy and laparoscopic cholecystectomy were included in this study. All of them received general anesthesia and certain volume of CO2 pneumoperitoneum. We evaluated the effect of positioning (Trendelenburg as group I and reverse Trendelenburg as group II) on hemodynamic parameters and ventilation. The hemodynamic parameters, ventilation, and arterial blood gas were determined at the following stages: (1) after 10 minutes of normoventilation and before CO2 pneumoperitoneum (as control), (2) 5 minutes after CO2 pneumoperitoneum and positioning, (3) 25 minutes after positioning, (4) 50 minutes after positioning, (5) 10 minutes after resumption of supine position and decompression of abdomen. Arterial blood pressure, heart rate, minute volume, end-tidal CO2, oxygen saturation and blood gas analysis were taken during normoventilation. We found that there was no statistical difference between either group in respect to hemodynamic parameters. For the ventilation, both groups had appropriate SpO2 during the period of CO2 pneumoperitoneum, but PaCO2 was significantly increased in group I 25 min after CO2 pneumoperitoneum and Trendelenburg positioning. Nonetheless, end-tidal CO2 was not significantly increased. pH value and PaCO2 did respectively decrease and increase significantly in group I 50 min after Trendelenburg position. However, no change was found in end-tidal CO2. All data were not significantly different after resumption of supine position and decompression of abdomen. Conclusively, except that pH and PaCO2 had changed after a period of Trendelenburg positioning with CO2 pneumoperitoneum, the patients who underwent laparoscopic surgery with normoventilation have no hemodynamic and respiratory change.(ABSTRACT TRUNCATED AT 250 WORDS)