Diffuse intrinsic pontine gliomas (DIPGs) are highly aggressive tumors of childhood that are almost universally fatal. Our understanding of this devastating cancer is limited by a dearth of available tissue for study and by the lack of a faithful animal model. Intriguingly, DIPGs are restricted to the ventral pons and occur during a narrow window of middle childhood, suggesting dysregulation of a postnatal neurodevelopmental process. Here, we report the identification of a previously undescribed population of immunophenotypic neural precursor cells in the human and murine brainstem whose temporal and spatial distributions correlate closely with the incidence of DIPG and highlight a candidate cell of origin. Using early postmortem DIPG tumor tissue, we have established in vitro and xenograft models and find that the Hedgehog (Hh) signaling pathway implicated in many developmental and oncogenic processes is active in DIPG tumor cells. Modulation of Hh pathway activity has functional consequences for DIPG selfrenewal capacity in neurosphere culture. The Hh pathway also appears to be active in normal ventral pontine precursor-like cells of the mouse, and unregulated pathway activity results in hypertrophy of the ventral pons. Together, these findings provide a foundation for understanding the cellular and molecular origins of DIPG, and suggest that the Hh pathway represents a potential therapeutic target in this devastating pediatric tumor.Hedgehog pathway | cancer stem cells | brainstem glioma

We reviewed a series of deaths in which methamphetamine was detected in the decedent's blood. Analysis of postmortem whole blood was performed by gas chromatography/mass spectrometry with a limit of quantitation of 0.05 mg/L. Methamphetamine was detected in 146 cases; 52 were drug caused, i.e., a death in which the direct toxic effects of the drug caused or contributed to the death, 92 were classified as drug related, i.e., a death in which the drug was demonstrated in the blood, but did not directly cause death. A large proportion of the deaths resulted from homicidal (27%) or suicidal (15%) violence. An examination of methamphetamine concentrations in drug related deaths (n = 92), suggests that the range of concentrations in the recreational abusing population is substantial (0.05–9.30 mg/L) but with a median concentration of 0.42 mg/L, and with 90% of that population having concentrations less than 2.20 mg/L. There was substantial overlap in methamphetamine concentration between drug related deaths and drug caused deaths, although the highest concentrations were seen in the unintentional (accidental or undetermined) drug caused deaths. Methamphetamine related traffic deaths (n = 17) showed patterns of driving behavior consistent with reports elsewhere, and showed blood methamphetamine concentrations ranging from 0.05–2.60 mg/L (median 0.35 mg/L). The data show that most methamphetamine deaths occur with blood concentrations greater than 0.5 mg/L, but can occur with levels as low as 0.05 mg/L, though usually in conjunction with other drugs or significant natural disease. Neither apparently toxic nor therapeutic concentrations should be used in isolation to establish conclusively whether a death was caused by methamphetamine; proper classification of deaths involving methamphetamine requires complete death investigation, including investigation of the scene and circumstances of death, and a complete autopsy.

The role of protein kinase C (PKC) in interleukin‐1β‐ (II‐ 1β)‐, tumor necrosis factor‐α‐ (TNF‐α)‐, and lipopolysaccharide‐(LPS)‐induced vascular cell adhesion molecule‐1 (VCAM‐1) expression on human umbilical vein endothelial cells (HUVEC) was studied. PKC inhibition or downregulation diminished VCAM‐1 mRNA accumulation and protein expression. Interleukin‐1β, TNF‐α, and LPS induce nuclear factor (NF)‐kB‐like binding activity, which precedes VCAM‐1 transcription. PKC inhibition did not prevent NF‐xB‐like binding activity, indicating that this is PKC‐independent, and NF‐kB‐like binding activity is insufficient for transcription of VCAM‐1.

Fifty-three suicides using plastic bags were identified in a review of cases within the jurisdiction of the King County Medical Examiner's Office, Seattle, Washington from 1984 to 1993. We found that this method was used at a greater frequency by individuals older than 50 in comparison with other methods. The most commonly identified stressor leading to the suicide in this population was failing health. The use of this method as a means of "self deliverance," as advocated by the Hemlock Society, could be inferred in only a small minority of cases where terminal illnesses were identified. This method may be preferred by those older than 50 years because of the ready availability of plastic bags and the relative nonviolence of the death. Analysis of the autopsy findings showed no specific features for this method of suicide. In particular, petechiae, which are often considered a marker of asphyxia, were present in only a small minority of cases (3%). Furthermore, the scene investigation rarely revealed specific features, other than the plastic bag in place. Thus, if the plastic bag were removed after death, the cause and manner of death would be obscure.

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