Distinguishing in-hospital and out-of-hospital status epilepticus: clinical implications from a 10-year cohort study.

BACKGROUND AND PURPOSE: The aim was to determine differences of clinical, treatment and outcome characteristics between patients with in-hospital and out-of-hospital status epilepticus (SE). METHODS: From 2005 to 2014, clinical data were assessed in adults with SE treated in an academic medical care centre. Clinical characteristics, treatment and outcomes were compared between patients with in-hospital and out-of-hospital SE. RESULTS: Amongst 352 patients, 213 were admitted with SE and 139 developed in-hospital SE. Patients with in-hospital SE had more acute/fatal aetiologies (60% vs. 35%, P < 0.001), fewer previous seizures (33% vs. 50%, P = 0.002), a higher median Charlson Comorbidity Index (3 vs. 2, P < 0.001), longer median SE duration (1 vs. 0.5 days, P = 0.001), more refractory SE (52% vs. 39%, P = 0.022), less return to functional baseline (38% vs. 54%, P = 0.006) and increased mortality (29% vs. 19%, P = 0.001). Whilst in multivariable analyses an increasing Status Epilepticus Severity Score (STESS) was an independent predictor for death in both groups, increased Charlson Comorbidity Index and treatment refractory SE were associated with death only in patients with in-hospital SE. Continuous anaesthesia for refractory SE was associated with increased mortality only in patients with out-of-hospital SE. The area under the receiver operating curve was 0.717 for prediction of death by STESS in patients with in-hospital SE and 0.811 in patients with out-of-hospital SE. CONCLUSIONS: Patients with in-hospital SE had more fatal aetiologies and comorbidities, refractory SE, less return to functional baseline, and increased mortality compared to patients with out-of-hospital SE. Whilst the STESS was a robust predictor for death in both groups, the association between continuous anaesthesia and death was limited to out-of-hospital SE.

Mouse cathepsin F: cDNA cloning, genomic organization and chromosomal assignment of the gene.

A murine cysteine protease of the papain family was identified by dbEST-database search. A 1.87kb full-length cDNA encoding a predicted polypeptide of 462 amino acids was sequenced. Since the encoded polypeptide shows more than 80% sequence identity with human cathepsin F, it is most likely that this cDNA represents the murine homologue of cathepsin F, and it was therefore named accordingly. Murine cathepsin F exhibits a domain structure typical for papain-like cysteine proteases, a 20 amino acid N-terminal hydrophobic signal sequence followed by an extraordinarily long propeptide of 228 amino acids and the domain of the mature protease comprising 214 amino acids. The mature region contains all features characteristic of a papain-like cysteine protease, including the highly conserved cysteine, histidine and asparagine residues of the 'catalytic triad'. Genomic clones covering the murine cathepsin F gene were isolated. The mouse cathepsin F gene consists of 14 exons and 13 introns and spans 5.8kb. Murine cathepsin F was mapped to chromosome 19, a region with synteny homology to a region of human chromosome 11 to which human cathepsin F has been mapped previously. Northern blot analysis of RNA from multiple tissues revealed a ubiquitous expression of cathepsin F in mouse and man.

Cathepsin J, a novel murine cysteine protease of the papain family with a placenta-restricted expression.

A novel mouse cysteine protease of the papain family was identified by searching the dbEST database. A 1.28 kb full-length cDNA was obtained which contains an open reading frame of 999 nucleotides and encodes a predicted polypeptide of 333 amino acids. The deduced polypeptide exhibits features characteristic of cysteine proteases of the papain type including the highly conserved residues of the catalytic triad, and was hence named cathepsin J. Cathepsin J represents the murine homologue of a previously described rat cathepsin L-related protein. Mature cathepsin J shows 59.3% identity to mouse cathepsin L and contains the characteristic ER(F/W)NIN motif within the propeptide indicating that this protease belongs to the subgroup of cathepsin L-like cysteine proteases. Northern blot analysis of various tissues revealed a placenta-restricted expression. This expression pattern may suggest a role of cathepsin J in embryo implantation and/or placental function. Ctsj was mapped to mouse chromosome 13 in the vicinity of cathepsin L suggesting that cathepsin J may have arisen by gene duplication from cathepsin L or a common ancestral gene.

Wilms' tumour gene (wt1) expression at diagnosis has no prognostic relevance in childhood acute lymphoblastic leukaemia treated by an intensive chemotherapy protocol.

Expression of the Wilms' tumour gene (wt1) has been demonstrated in a large proportion of human acute leukaemias and is thought to play a role in leukaemogenesis. Recent observations in adult patients with acute leukaemia suggest that wt1 gene expression is a poor prognostic factor. In childhood acute leukaemia, the clinical role of wt1 gene expression has not been established. We have therefore investigated bone marrow samples from 50 children with acute lymphocytic leukaemia at the time of diagnosis for the presence of wt1 transcripts to determine whether wt1 gene expression is associated with specific characteristics of leukaemic cells and whether it is predictive of response to treatment. All patients were treated according to the ALL-BFM 90 protocol. The median observation time was 30 months. Wt1 transcripts were detected by RT-PCR in 60% of the diagnostic samples. Wt1 PCR positive patients showed a higher median leukocyte and peripheral blast cell count than wt1 negative patients. High and intermediate risk patients more frequently displayed wt1 transcripts than low risk patients. No correlation between wtl gene expression and FAB type, immunophenotype, co-expression of myeloid antigens or karyotype has been observed. Furthermore, there was no correlation between wt1 gene expression at diagnosis and achievement of complete remission (CR) and no difference in disease-free survival (DFS) or overall survival (OS) between wt1 positive and negative patients (p > 0.1). These data indicate that (1) wt1 gene expression at diagnosis is detected more frequently in patients with high leukocyte and peripheral blast cell counts, but is not associated with specific characteristics of leukaemic cells, (2) wt1 gene expression is not an independent prognostic factor for CR, DFS or OS in childhood ALL treated by an intensive therapy protocol.

Detection of the WT1 transcript by RT-PCR in complete remission has no prognostic relevance in de novo acute myeloid leukemia.

The WT1 gene is expressed in 73-100% of patients with acute myelogenous leukemia (AML) and is thought to play a role in maintaining the viability of leukemic cells. WT1 has been proposed as a marker for minimal residual disease in leukemia. We obtained serial blood or bone marrow samples from patients with de novo AML at diagnosis, during therapy, and up to 95 months after diagnosis and analyzed for WT1 gene expression by RT-PCR to determine whether gene expression was predictive of relapse. Forty-four patients had WT1-positive AML and achieved a complete remission (CR) following chemotherapy and 24 patients underwent unrelated donor (n = 4), sibling donor (n = 13) or autologous (n = 7) marrow transplantation. After achieving CR 62% of the patients became WT1-negative, while 38% remained WT1-positive. There was no difference in the disease-free survival (DFS) and survival from remission between WT1-positive and -negative patients (P > 0.1). Following BMT, 32% of the patients analyzed in CR within the first 100 days after transplantation were WT1 PCR positive. Detection of WT1 transcripts within 100 days following BMT did not affect DFS and overall survival (OS) after transplantation (P > 0.1). Ten of 11 patients who are in continuous CR following chemotherapy or BMT for more than 3 years were transiently WT1-positive during the observation period. Four of these patients displayed the WT1 transcript at the last examination. Thirteen of 39 patients were WT1 PCR negative within 4 months before clinical onset of relapse and eight patients were WT1 PCR negative at time of relapse. These data indicate that: (1) achievement of WT1 negativity is not associated with longer DFS, survival from remission, or OS after transplantation; (2) not all patients who relapse become WT1 positive again; (3) long-term remitters frequently display the WT1 transcript. Thus, we conclude that the monitoring of WT1 gene expression by qualitative RT-PCR during treatment and CR is of very limited value.

Prognostic significance of WT1 gene expression at diagnosis in adult de novo acute myeloid leukemia.

We examined the presence of WT1-specific mRNA in bone marrow samples of 125 patients with de novo acute myeloid leukemia at diagnosis by two-step RT-PCR. The sensitivity of the assay was 1:100 (first step) and 1:10000 (second step), respectively. WT1-specific mRNA was detected in 73% of patients. No correlation was found between WT1 gene expression and age, FAB type, LDH and karyotype at diagnosis. All patients were treated with standard induction chemotherapy. There was no difference in the CR rate between WT1-positive and -negative patients. Using Kaplan and Meier plot analysis we found no difference in disease-free survival (DFS) and overall survival (OS) between patients displaying the WT1 transcript and WT1-negative patients. Furthermore, no significant interactions between WT1 PCR results and age, FAB type, LDH and karyotype on DFS and OS were demonstrable using Cox regression analysis. Eight patients who were WT1 PCR positive at diagnosis and achieved complete hematological remission following chemotherapy were monitored during the course of the disease. Based on our limited data demonstrating a heterogeneity of WT1 PCR results in CR we cannot draw any conclusions regarding the usefulness of WT1 PCR analysis for the early detection of relapse. We conclude that WT1 gene expression at diagnosis is not associated with specific characteristics of AML blast cells and is not a prognostic factor for CR, remission duration and overall survival in acute myeloid leukemia.