Report on the accident at Windscale No. 1 Pile on 10 October 1957.

A serious fire developed in the core of a nuclear reactor at Windscale Works, Sellafield, northwest England, which led to the release of significant quantities of radioactive material into the environment during 10-11th October, 1957. In 1957, Windscale Works was operated by the United Kingdom Atomic Energy Authority (UKAEA), and on 15th October it was announced by the Chairman of the UKAEA that a Committee of Inquiry had been established under the chairmanship of Sir William Penney to conduct an investigation into the accident. The Committee sat at Windscale Works during 17-25th October, interviewed 37 people (some more than once), and examined 73 technical exhibits. The Committee reported to the Chairman of the UKAEA on 26th October. The Report of the Committee formed the technical basis of a UK Government White Paper (Cmnd. 302) published on 8th November, 1957, but the Penney Report itself was not published, and was only made public (at what is now The National Archives, TNA, Kew) in January, 1988. The original Report of the Committee of Inquiry is reproduced here from a copy of the Report supplied by TNA from TNA File AB 86/25.

Ceramide is responsible for the failure of compensatory nerve sprouting in apolipoprotein E knock-out mice.

Apolipoprotein E (apoE) is a key transporter of the cholesterol and phospholipids required for membrane synthesis and nerve growth. We now report a virtual absence in apoE knock-out (KO) mice of normal nerve growth factor (NGF)-driven compensatory sprouting of undamaged cutaneous nociceptive nerves. In contrast, NGF-independent regeneration of crushed axons was unaffected. Essentially similar results came from aged wild-type mice. In apoE KO mice, the endogenous sprouting stimulus was suspect, because NGF administration induced normal sprouting; nevertheless, NGF increased normally in denervated skin, transported normally in the axons, and led to phosphorylation of trkA, erk1, and erk2. However, sprouting was restored in apoE KO mice (although not in aged mice) by fumonisin B1, an inhibitor of ceramide synthesis. A shotgun analysis revealed a wide array of changes in individual ceramide species in DRG neurons of apoE KO mice, and the changes for ceramide species OH_N15:0 made it a candidate inhibitor of sprouting (increased in apoE KO mice and normalized by fumonisin B1). Nevertheless, the unknown effects of individual ceramide species on sprouting, as well as the variability of their changed levels in apoE KO mice and how these were affected by fumonisin B1, support a different conclusion. We suggest that absence of apoE expression alters the balance among ceramide species to one that collectively inhibits compensatory sprouting, whereas fumonisin B1 establishes a new balance that allows sprouting. Nontoxic ceramide modulators might usefully promote sprouting and circuitry repair in neurodegenerative disorders in which ceramide species are perturbed, adding to the benefits of reducing ceramide-induced neuronal apoptosis.

Dual-action peptides: a new strategy in the treatment of diabetes-associated neuropathy.

Peripheral neuropathy is one of the most common and debilitating complications of type 1 and type 2 diabetes mellitus. Recent studies have shown that several small, non-neural peptides possess neurotrophic activity and exert beneficial effects on nervous system function in experimental and clinical diabetes. Two of these, C-peptide and islet neogenesis-associated protein peptide, are derived from pancreatic proteins and use related signal transduction mechanisms. Derivatives of erythropoietin possess similar properties in the nervous system. As a group, these peptides are of increasing interest as leads to potential new approaches in the treatment of diabetes-associated neuropathies and other neurodegenerative conditions. This review addresses the recent advances made with these peptides in the context of diabetic neuropathy, and highlights similarities and differences in their mechanisms of action from the perspective of combination therapy.

Pertussis toxin-sensitive G protein but not NO/cGMP pathway mediates the negative inotropic effect of carbachol in adult rat cardiomyocytes.

Previous studies have shown that muscarinic inhibition of cardiac contractility is mediated by either activation of nitric oxide (NO)/guanosine 3',5'-cyclic monophosphate (cGMP) pathway or stimulation of inhibitory G protein (G(i)). However, it still remains controversial as to whether NO/cGMP pathway or G(i) protein or both mediate(s) the negative inotropic effect of muscarinic agonists in adult ventricular myocytes. In the present study that involves the use of adult rat ventricular myocytes, the muscarinic agonist, carbachol, inhibited beta-adrenergic (isoproterenol) stimulation of contractility (cell shortening) by 82% and increased cGMP levels by 49% within 6 min. Pretreatment of myocytes with soluble guanylyl cyclase inhibitor (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ) or NO synthase inhibitor (N(G)-monomethyl-L-arginine, L-NMMA) for 30 min blocked carbachol-induced increases in cGMP levels. However, neither ODQ nor L-NMMA pretreatment had any effect on carbachol inhibition of isoproterenol-induced contractility. In addition, carbachol did not attenuate increases in myocyte contractility induced by forskolin (a direct activator of adenylyl cyclase) or 8-(4-chlorophenylthio)-adenosine 3',5'-cyclic monophosphate (a cell-permeable cAMP analog which activates cAMP-dependent protein kinase). Pretreatment of myocytes with G(i) protein inhibitor, pertussis toxin (PTX, 1 microg/ml), for 18-20 h abolished carbachol inhibition of isoproterenol-induced contractility. Furthermore, in ventricular myocytes isolated 3 days after in vivo treatment of rats with PTX (3 microg/100 g, i.p.), there was a complete loss of the negative inotropic effect of carbachol. These data indicate that pertussis toxin-sensitive G protein but not NO/cGMP pathway is required for muscarinic inhibition of beta-adrenoceptor-mediated increases in contractility in adult rat ventricular myocytes.

Neotrofin, a novel purine that induces NGF-dependent nociceptive nerve sprouting but not hyperalgesia in adult rat skin.

We report peripheral actions in rats of Neotrofin, a purine derivative of therapeutic interest. Systemic injections mimicked NGF in eliciting sprouting of nociceptive nerves without affecting their regeneration. The sprouting was prevented by anti-NGF treatment, implicating endogenous NGF. We detected no Neotrofin-induced increases in cutaneous NGF levels or in retrograde NGF transport. In contrast, both NGF and phosphorylation of trkA increased significantly in DRGs, with a marginal appearance of phosphorylated trkA in axons. We conclude that the DRG effects of Neotrofin are responsible for its induction of sprouting. Neotrofin also induced a striking phosphorylation of axonal erk 1 and 2, which was, however, unaffected by anti-NGF treatment. We suggest that this NGF-independent MAP kinase activation is involved in nonsprouting functions of Neotrofin such as neuroprotection. Unlike injected NGF, Neotrofin did not induce hyperalgesia, supporting its candidacy as a treatment for peripheral neuropathies like those induced by diabetes and anticancer chemotherapy.

An intact intermediate filament network is required for collateral sprouting of small diameter nerve fibers.

Expression of the intermediate filament (IF) protein peripherin is initiated during development at the time of axonal extension and increases during regeneration of nerve fibers. To test whether the IF network is essential for neuron process outgrowth in the mature organism in vivo, we disrupted endogenous peripherin IF in small-sized dorsal root ganglion (DRG) neurons in transgenic mice via expression of a mutant peripherin transgene under control of peripherin gene regulatory sequences. Anatomical and functional analyses showed that these neurons send peripheral and central axonal projections to correct targets, express correct neuropeptides, and mediate acute pain responses normally. However, disruption of IF significantly impaired the ability of uninjured small-sized DRG neurons to sprout collateral axons into adjacent denervated skin, indicating a critical role for intact IF in plasticity, specifically in compensatory nociceptive nerve sprouting.