Time trends in incidence, mortality, and case-fatality after first episode of status epilepticus

PURPOSE: Status epilepticus (SE) is a medical emergency associated with a high mortality. Clinical series have suggested that mortality after SE has decreased. No studies have systematically examined trends in incidence, mortality, and case fatality after SE in a well-defined population. METHODS: All first episodes of SE receiving medical attention between January 1, 1935, and December 31, 1984, were ascertained through the Rochester Epidemiology Project Records-Linkage System and followed up until death or study termination (February 1, 1996). We calculated incidence rates in the 50-year period (1935-1984), while we considered mortality and case-fatality in the last 30-year period (1955-1984). RESULTS: Incidence of SE increased over time to 18.1/100,000 (1975 through 1984). The increase was related to an increased incidence in the elderly and to the advent of myoclonic SE after cardiac arrest, a condition not seen in the early decades. In the last decade, approximately 16% of the incidence was due to myoclonic SE. The mortality rates increased from 3.6 per year in the decade 1955-1965 to 4.0/100,000 per year between 1975 and 1984. The 30-day case-fatality (CF) was unchanged, although a trend toward improvement was shown after excluding myoclonic SE. CONCLUSIONS: Incidence and mortality rates of SE have increased in the last 30 years. Case fatality remained the same. The increased incidence and mortality are due to the occurrence in the last decade of myoclonic SE after cardiac arrest. The mortality in the elderly was twice that of the youngest age group, across all study periods. Changes in the age and cause distribution of SE over time are responsible for the stable survivorship. There is improvement in survivorship in the last decade when myoclonic SE is excluded.     

Molecular characterization of breakpoints in patients with holoprosencephaly and definition of the HPE2 critical region 2p21

Holoprosencephaly (HPE) is a common developmental defect involving the brain and face in humans. Cytogenetic deletions in patients with HPE have localized one of the HPE genes (HPE2) to the chromosomal region 2p21. Here we report the molecular genetic characterization of nine HPE patients with cytogenetic deletions or translocations involving 2p21. We have determined the parental origin of the deleted chromosomes and defined the HPE2 critical region between D2S119 and D2S88/D2S391. As a first step towards cloning the HPE2 gene which is crucial for normal brain development we have constructed a YAC contig which spans the smallest region of deletion overlap. Several of these YACs could be identified which span three different 2p21 breakpoints in HPE patients. These YACs narrow the HPE2 critical region to less than 1 Mb and are now being further analyzed to identify the gene causing holoprosencephaly on chromosome 2.      

Using Tree-Based Recursive Partitioning Methods to Group Haplotypes for Increased Power in Association Studies

Motivated by the increasing availability of high‐density single nucleotide polymorphism (SNP) markers across the genome, various haplotype‐based methods have been developed for candidate gene association studies, and even for genome‐wide association studies. Although haplotype approaches dramatically reduce the multiple comparisons problem (as compared to single SNP analysis), even the number of existing haplotypes is relatively large, which increases the degrees of freedom and decreases the power for the corresponding test statistic. Grouping haplotypes is a way to reduce the degrees of freedom. We propose a procedure that uses a tree‐based recursive partitioning algorithm to group haplotypes into a small number of clusters, and conducts the association test based on groups of haplotypes instead of individual haplotypes. The method can be used for both population‐based and family‐based association studies, with known or ambiguous phase information. Simulation studies suggest that the proposed method has the right type I error rate, and is more powerful than some existing haplotype‐based tests.     

Interleukin-11 inhibits adipogenesis and stimulates myelopoiesis in human long-term marrow cultures

Interleukin-11 (IL-11) is a bone marrow (BM) stromal-derived growth factor that has been shown to stimulate murine myeloid and lymphoid cells both in vitro and in vivo and to inhibit adipogenesis in a murine fibroblast cell line. We have studied the effects of IL-11 on highly purified human BM stem and progenitor cells and on human long-term marrow cultures (LTMC). Adipocyte differentiation is an integral component of murine and human LTMC. IL-11 stimulates myeloid growth as a single cytokine when added to highly enriched CD34+, HLA-DR+ bone marrow cells. IL-11 stimulated no growth in the more primitive CD34+, HLA-DR- population even in the presence of additional cytokines. IL-11 addition to human LTMC resulted in the expansion of myeloid and mixed, but not erythroid, progenitor populations. IL-11 dramatically increased the adherent cell populations, including both stromal cells and macrophages. Treated cultures also showed marked inhibition of fat accumulation in the adherent cells due in part to a block in the differentiation of preadipocytes to adipocytes, as shown by RNA analysis using adipocyte-specific markers. These data show that IL-11 stimulates a more differentiated, although multipotential, progenitor cell in human BM and that LTMC provide a useful model for studying the effects of this cytokine in the context of the hematopoietic microenvironment.     

Pilot study of tandem high-dose chemotherapy and autologous stem cell transplantation with a novel combination of regimens in patients with poor risk lymphoma

In an effort to improve the outcome of poor-risk lymphoma patients, we evaluated a novel regimen of tandem high-dose chemotherapy (THDC) with autologous stem cell transplantation. A total of 41 patients (median age 40 years, range 15-68 years) with poor-risk non-Hodgkin's lymphoma and Hodgkin's disease were enrolled. THDC consisted of melphalan (180 mg/m2) and escalating dose mitoxantrone (30-50 mg/m2) (MMt) for the first conditioning regimen, and thiotepa (500 mg/m2), carboplatin (800 mg/m2), and escalating dose etoposide phosphate (400-850 mg/m2), (ETCb) as the second regimen. In all, 31 patients (76%) completed both transplants, with a median time between transplants of 55 days (range 26-120). The maximum tolerated dose was determined as 40 mg/m2 for mitoxantrone and 550 mg/m2 for etoposide phosphate. The overall toxic death rate was 12%. Following high-dose chemotherapy, 10 of 24 evaluable patients (42%) were in CR. The two-year overall survival and event-free survival is 67% (95% CI, 52-81%) and 45%, (95% CI, 29-61%) for the 41 patients enrolled; and 69% (95% CI, 525-586%) and 48% (95% CI, 30-67%) for the 31 patients completing both transplants. This THDC regimen is feasible but with notable toxicity in heavily pretreated patients; its role in the current treatment of high-risk lymphoma remains to be determined.     

High-intensity focused ultrasound extracorporeal ablation of liver tissues in rabbits

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The influence of purified recombinant human heavy-subunit and light- subunit ferritins on colony formation in vitro by granulocyte- macrophage and erythroid progenitor cells

Purified recombinant human heavy subunit (rHF, acidic) and recombinant human light subunit (rLF, basic) ferritins were assessed for their effects in vitro on colony formation by normal human granulocyte- macrophage (CFU-GM) and erythroid (BFU-E) progenitor cells. The purity of the samples was confirmed by electrophoresis in both nondenaturing and denaturing conditions and silver staining. Concentrations of 10(-8) to 10(-10) mol/L rHF caused an approximately 40% significant decrease in colony formation. Some significant activity was detected at 10(-11) mol/L, and activity was lost at 10(-12) mol/L. In contrast, rLF had no significant activity at 10(-8) to 10(-16) mol/L. rHF was significantly active against mouse bone marrow CFU-GM to concentrations as low as 10(- 8) to 10(-9) mol/L. The inhibitory activity of rHF was inactivated with three different monoclonal antibodies recognizing the heavy subunit of ferritin, but not with two monoclonal antibodies recognizing the light subunit of ferritin. The inhibitory activity of rHF was similar in the absence or presence of serum, monocytes, and T lymphocytes. We and others have shown an association of a glycosylated natural acidic isoferritin (AIF) with inhibitory activity, but since the rHF was expressed in Escherichia coli and did not bind to concanavalin A, glycosylation of AIF is not an absolute prerequisite for this activity. These results demonstrate that rHF has suppressive activity in vitro and substantiate our original observations using purified natural acidic isoferritins.