Background and Aims
Mutations in the disheveled, Egl‐10 and pleckstrin domain‐containing protein 5 (DEPDC5) gene have emerged as an important cause of various familial focal epilepsy syndromes. ...However, the significance of DEPDC5 mutations in patients with sporadic focal epilepsy has yet to be characterized.
Materials and Methods
We studied a kindred of familial focal epilepsy with variable foci using whole‐exome sequencing. We subsequently studied a cohort of 293 patients with focal epilepsy and sequenced all exons of DEPDC5 using targeted resequencing.
Results
We reported a Taiwanese family with a novel splice site mutation which affected mRNA splicing and activated the downstream mammalian target of rapamycin (mTOR) pathway. Among patients with focal epilepsies, the majority (220/293) of these patients had sporadic focal epilepsy without malformation of cortical development. Two (0.9%) of these patients had probably pathogenic mutations in the
DEPDC5 gene.
Discussion and Conclusions
Our finding suggests that DEPDC5 is not only the most common gene for familial focal epilepsy but also could be a significant gene for sporadic focal epilepsy. Since focal epilepsies account for more than 60% of all epilepsies, the effect of mTORC1 inhibitor on patients with focal epilepsy due to DEPDC5 mutations will be an important future direction of research.
The high rate of neuropsychologic sequelae in CM survivors indicates that initial antifungal therapy is far from being satisfactory. This prospective cross-sectional study applied DTI on HIV-negative ...CM patients to determine whether microstructural changes in brain tissue are associated with subsequent cognitive symptoms.
Fifteen patients with HIV-negative CM and 15 sex- and age-matched healthy volunteers were evaluated and compared. All underwent complete medical and neurologic examinations and neuropsychologic testing. Brain DTI was obtained to derive the FA and ADC of several brain regions. Correlations among DTI parameters, neuropsychologic rating scores, and cryptococcal-antigen titer in CSF were analyzed.
Significant ADC values increased and FA values decreased in HIV-negative CM patients in multiple selected regions of interest, including the genus of the corpus callosum and the frontal, parietal, orbito-frontal, and periventricular white matter and lentiform nucleus. Higher CSF cryptococcal-antigen titer on admission was associated with poorer DTI parameters (r = -0.666, P = .018), which were linearly related to worse cognitive performance during follow-up.
The decline in brain DTI parameters in the associated brain areas indicates an HIV-negative CM microstructural pathology that is related to neuropsychologic consequences.
Although treatment of brain abscess requires a combination of antimicrobials and surgical intervention for the infected foci, nonsurgical, empirical treatment is possible and efficient in selected ...groups of patients. A total of 31 patients were enrolled in this 22-year retrospective study. We describe our therapeutic experiences and attempt to analyze the risk factors that were predictive of therapeutic outcomes. Multiple logistic regression was used to evaluate the relationships between baseline clinical factors and therapeutic outcome during the study period. Of these 31 patients, 25 had community-acquired infections, whereas the other six had nosocomially-acquired infections. Thirteen cases (42%) had a single brain abscess and the other 18 cases (58%) had multiple brain abscesses. Furthermore, the association of bacterial meningitis and brain abscess was found in 81% (25/31) of cases. The overall case fatality rate was 48% (15/31). Significant risk factors for poor outcomes included Glasgow coma scale (GCS) at presentation, presence of septic shock and neck stiffness. In addition, each reduction of one point on the GCS increased the poor outcome rate by 28%. The findings of the study demonstrate that both a higher mortality rate (48%) and worse outcomes were found in this select group of patients. Among the significant prognostic factors, a lower mean GCS at presentation was a major determinant of poor outcome.
Background: Increased levels of cerebrospinal fluid (CSF) 14-3-3 proteins have been reported in acute bacterial meningitis. We tested the hypothesis that CSF 14-3-3 protein levels are substantially ...increased in acute bacterial meningitis and decreased after anti-microbial therapy, and that CSF 14-3-3 protein levels can predict treatment outcomes. Methods: We examined serial pan-CSF 14-3-3 (14-3-3-P) protein and five major isoform (β, γ, ε, η, ζ) levels in 29 adult community-acquired bacterial meningitis (ACABM) patients. The CSF 14-3-3 protein levels were also evaluated in 12 aseptic meningitis patients during the study period. Results: All of the meningitis patients had a positive result on admission. Levels of CSF 14-3-3 protein in ACABM cases were significantly increased initially, and substantially decreased thereafter. Most of those who survived (survivors = 25 and non-survivors = 4) had nearly cleared their 14-3-3 protein from the CSF before discharge. Conversely, patients who died never cleared their CSF 14-3-3 protein. The median value of CSF 14-3-3-P and 14-3-3 γ, 14-3-3 η and 14-3-3 ε isoforms on admission in the bacterial meningitis group were 173.7, 137.7, 42.2 and 9.1, respectively, which were statistically significant than those of the aseptic meningitis group (48.4, 39.6, 2.5 and 0, respectively). Stepwise logistic regression analysis showed only CSF 14-3-3 γ isoform on admission was independently associated with outcome (P = 0.05, OR = 0.991). Conclusions: Serial 14-3-3 protein γ isoform actually meets the major requirements for outcome prediction in the treatment of ACABM patients. Assay of the 14-3-3 protein γ isoform should be added as a neuro-pathologic marker among the panel of conventional CSF parameters.
Abstract
Background
Although greater impairments in nerve functions parameters are most likely to occur with a lower kidney function, there is a paucity of information on the relationship between the ...kidney and peripheral nerve functions parameters in Type 2 diabetes.
Aim
To address the impact of peripheral nerve functions in Type 2 diabetes patients in different stages of chronic kidney diseases (CKD).
Design
This prospective study enrolled 238 patients with Type 2 diabetes at a tertiary medical center.
Method
We designed composite amplitude scores of nerve conductions (CAS) as a measure of severity of peripheral neuropathy (PN), and used estimated glomerular filtration rate (eGFR) and urine albumin-creatinine ratio (UACR) parameters to stage CKD in Type 2 diabetes patients. The intrapersonal mean, standard deviation and coefficient of variation of eGFR for 238 patients were obtained in the 3 years prior to the study.
Results
The patients who had lower eGFR and higher UACR were older, with longer diabetes duration, a greater percentage of retinopathy and PN and higher CAS. Multiple linear regression analysis revealed that diabetes duration and eGFR were independently associated with CAS, and a cut-off value of eGFR in the presence of PN was 65.3 ml/min/1.73 m2.
Conclusion
We observed a close relationship between the severity of kidney and peripheral nerve function in patients with diabetes. If a patient’s eGFR value is below 65.3 ml/min/1.73 m2 or the UACR value is above 98.6 mg/dl, caution is needed with the presence of PN even in diabetic patients who are asymptomatic.
To delineate the epidemiologic trend, clinical characteristics and therapeutic outcomes of bacterial meningitis in young adults in Southern Taiwan.
Over a period of 18 years, 329 cases of ...culture-proven adult bacterial meningitis were identified at our hospital. Among these 329 cases, 62 were identified as young adults (< or = 40 years) and their clinical features, laboratory data and therapeutic outcomes were reviewed. The prognostic factors between fatal and non-fatal groups were compared.
The 62 young adults were 48 men and 14 women, aged 17-40 years. Thirty of the 62 patients belonged to nosocomial infection, and the other 32 belonged to community-acquired infection. A total of 74% (46/62) of the patients had a post-neurosurgical state as the underlying condition. Alcoholism (n = 8) was the most common underlying condition of the other 16 patients with spontaneous meningitis. Of these 62 patients, Klebsiella pneumoniae and Pseudomonas aeruginosa were the most common implicated gram-negative pathogens. During the late study period, there was an increase in coagulase-negative staphylococcus and Staphylococcus aureus infections. The therapeutic results of this group of patients are as follows: 13 patients died, 18 had full recovery and 31 had varying degrees of neurologic deficits. Impaired consciousness and thrombocytopenia were significant prognostic factors.
A post-neurosurgical state is an important preceding event for young adults to develop bacterial meningitis. Of the implicated gram-negative pathogens, K. pneumoniae and P. aeruginosa are common; however, there has been an increase in staphylococcal infection in recent years. Therapeutic results of this specific group of patients showed that 20% (13/62) of the patients died, and 50% (31/61) of the patients in this study had neurologic deficits. However, the small case number and possible bias of case selection has limited the analytical conclusions of this study. Further large-scale studies are needed to delineate the clinical characteristics and therapeutic outcomes of bacterial meningitis in this specific group of patients.
To determine the factors predictive of fatality in massive middle cerebral artery (MCA) territory infarction and outcome of decompressive hemicraniectomy, 62 patients who were retrospectively ...verified with first event massive MCA infarctions were enrolled in this study. Amongst them, 21 received decompressive hemicraniectomy during hospitalization. Clinical data between early and late hemicraniectomy groups were also compared. Significant deterioration occurred in 40 cases, 21 of whom received decompressive hemicraniectomy. The other 19 received conservative treatment. The mortality rate of these 40 cases between decompressive hemicraniectomy and conservative treatment was 29% (six of 21) and 42% (eight of 19), respectively. Factors that predicted fatalities in our massive MCA infarction patients with or without decompressive hemicraniectomy were total scores of baseline GCS at the time of admission, associated with coronary artery diseases, and significant deterioration during hospitalization. This study confirms the lifesaving procedure of hemicraniectomy that prevents death in patients deteriorating because of cerebral edema after infarction, although it may produce severe disability with an unacceptably poor quality of life in survival. Despite high mortality and morbidity, decompressive hemicraniectomy to prevent cerebral herniation when significant deterioration is demonstrated are essential for maximizing the potential for survival.
The expression of both high-mobility group box 1 (HMGB1) and receptor for advanced glycation end-products (RAGE) is upregulated in degenerated discs. HMGB1 is known to function as a coupling factor ...between hypoxia and inflammation in arthritis, and this inflammatory response is modulated by microRNAs (miRNAs), with miR-107 expression downregulated during hypoxia. In this study, we investigated the regulation of the miR-107/HMGB1/RAGE pathway in degenerated nucleus pulposus cells (NPCs) after hyperbaric oxygen (HBO) treatment.
NPCs were separated from human degenerated intervertebral disc tissues. The control cells were maintained in 5% CO
/95% air, and the hyperoxic cells were exposed to 100% O
at 2.5 atmospheres absolute. MiRNA expression profiling was performed via microarray and confirmed by real-time PCR, and miRNA target genes were identified using bioinformatics and luciferase reporter assays. The cellular protein and mRNA levels of HMGB1, RAGE, and inducible nitric oxide synthase (iNOS) were assessed, and the phosphorylation of MAPK (p38MAPK, ERK, and JNK) was evaluated. Additionally, cytosolic and nuclear fractions of the IκBα and NF-κB p65 proteins were analyzed, and secreted HMGB1 and metalloprotease (MMP) levels in the conditioned media were quantified.
Using microarray analyses, 96 miRNAs were identified as upregulated and 66 downregulated following HBO treatment. Based on these results, miR-107 was selected for further investigation. Bioinformatics analyses indicated that the 3' untranslated region of the HMGB1 mRNA contained the "seed-matched-sequence" for hsa-miR-107, which was validated via dual-luciferase reporter assays. MiR-107 was markedly induced by HBO, and simultaneous suppression of HMGB1 was observed in NPCs. Knockdown of miR-107 resulted in upregulation of HMGB1 expression in HBO-treated cells, and HBO treatment downregulated the mRNA and protein levels of HMGB1, RAGE, and iNOS and the secretion of HMGB1. In addition, HBO treatment upregulated the protein levels of cytosolic IκBα and decreased the nuclear translocation of NF-κB in NPCs. Moreover, HBO treatment downregulated the phosphorylation of p38MAPK, ERK, and JNK and significantly decreased the secretion of MMP-3, MMP-9, and MMP-13.
HBO inhibits pathways related to HMGB1/RAGE signaling via upregulation of miR-107 expression in degenerated human NPCs.
Background: Increased levels of plasma nuclear and mitochondrial DNA have been reported in critically ill patients. We tested the hypothesis that plasma nuclear and mitochondrial DNA are ...substantially increased in acute bacterial meningitis and decrease after antimicrobial therapy, and that plasma nuclear and mitochondrial DNA levels can predict treatment outcomes. Methods: We examined serial plasma nuclear and mitochondrial DNA levels in 22 adult community-acquired bacterial meningitis (ACABM) patients. The plasma nuclear and mitochondrial DNA levels were also evaluated in 11 aseptic meningitis patients and 22 volunteer subjects during the study period. Results: All of the both bacterial and aseptic meningitis groups had a higher plasma DNA levels on admission as compared with those of volunteer groups. Levels of plasma nuclear and mitochondrial DNA in ACABM cases were significantly increased initially and substantially decreased thereafter. Both plasma nuclear DNA and plasma mitochondrial DNA levels at presentation are significantly negative correlate with modified Barthel Index (average) (r = −0.639, P = 0.004 and r = −0.551, P = 0.018) at 3 months after discharge (average), respectively, in this study. Both higher plasma nuclear (cutoff value of >169 ng/ml) and mitochondrial DNA levels (cutoff value of >58.9 ng/ml) at presentation were associated with poor outcome in ACABM patients. Conclusions: Based on our results, the higher plasma DNA levels were associated with a poorer outcome. Therefore, we look forward to more prospective multicenter investigations specifically to confirm the predictive value of plasma DNA levels in outcome prediction.