Even very low but sustained lithium intake can prevent suicide in the general population?

Although several meta-analyses have shown anti-suicidal properties of lithium in treating patients with mood disorders, these effects may be unrelated to the mood-stabilizing effects. Some epidemiological studies suggest that even very low lithium levels induced by routine consumption of lithium from tap water may have anti-suicidal effects both in patients with mood disorders and in the general population. We hypothesize that even very low but sustained lithium intake can prevent suicide in the general population. If this is the case, increasing lithium levels of drinking water could potentially reduce the risk of suicide, and justify administering lithium to tap water.     

Deletion of PIK3C3/Vps34 in sensory neurons causes rapid neurodegeneration by disrupting the endosomal but not the autophagic pathway

The lipid kinase PIK3C3 (also called Vps34) regulates both the endosomal and autophagic pathways. However, the effect of inactivating PIK3C3 on neuronal endosomal versus autophagic processes in vivo has not been studied. We generated mice in which Pik3c3 was conditionally deleted in differentiated sensory neurons. Within a few days after Pik3c3 deletion, mutant large-diameter myelinated neurons accumulated numerous enlarged vacuoles and ubiquitin-positive aggregates and underwent rapid degeneration. By contrast, Pik3c3-deficient small-diameter unmyelinated neurons accumulated excessive numbers of lysosome-like organelles and degenerated more slowly. These differential degenerative phenotypes are unlikely caused by a disruption in the autophagy pathway, because inhibiting autophagy alone by conditional deletion of Atg7 results in a completely distinct phenotype in all sensory neurons (i.e., formation of very large intracellular inclusion bodies and slow degeneration over a period of several months). More surprisingly, a noncanonical PIK3C3-independent LC3-positive autophagosome formation pathway was activated in Pik3c3-deficient small-diameter neurons. Analyses of Pik3c3/Atg7 double mutant neurons revealed that this unconventional initiation pathway still depends on ATG7. Our studies represent in vivo characterization of PIK3C3 functions in mammals and provide insights into the complexity of neuronal endo-lysosomal and autophagic pathways.PIK3C3 (also known as Vps34) is a class III phosphatidylinositol-3-kinase that specifically catalyzes the formation of phosphatidylinositol-3-phosphate (PI3P) (1). Studies in invertebrate organisms as well as in nonneuronal cells showed that PIK3C3/Vps34 regulates multiple aspects of both the endocytic/endosomal and autophagic pathways (2–5). In yeast, there are two distinct Vps34 complexes: complex I (Vps34, Vps15, Atg6, and Atg14) is involved in autophagy, and complex II (Vps34, Vps15, Atg6, and Vps38) functions in the vacuolar protein-sorting process (6). In mammals, homologs of Vps15 and Atg6 are p150 and Beclin1, respectively (7), and evidence exists for Beclin1-independent functions of PIK3C3 in the endocytic pathways (8). A mammalian homolog of complex I (PIK3C3, p150, Beclin1, and Atg14L) activates autophagy, and a homolog of complex II (PIK3C3, p150, Beclin1, and UVRAG/Vps38) regulates trafficking at late endosomes (7). Interestingly, Bif-1 and Rubicon can interact with complex II to promote autophagy (9, 10). The chemical inhibitor of PIK3C3 (3-MA or wortmanin) has been frequently used as an inhibitor for autophagy in numerous studies, including those studying autophagy in neurons (11–14). However, because of the lack of genetic studies on Pik3c3 in mammals, it is not clear how inactivating PIK3C3 in neurons in vivo differentially affects endosomal versus autophagic processes.Neurons are highly susceptible to disruptions in both endocytic and autophagic pathways. Genetic mutations in ubiquitously expressed proteins regulating the endocytic (15, 16) or autophagy pathways (17, 18) all resulted in various neuronal degeneration. Phosphoinositides play important roles in regulating diverse membrane-trafficking processes. Mutations in several enzymes regulating the metabolism of different phosphoinositides, such as MTMR2/MTMR13 (19), Fig4 (20), Vac14 (21), PIKfyve (22), and oculocerebrorenal syndrome of Lowe (23, 24), all cause various degenerations (25). Interestingly, polymorphism in the Pik3c3 promoter region was associated with schizophrenia and bipolar diseases (26), but no loss-of-function studies were carried out for this gene in mammals. We generated a conditional null allele of Pik3c3 gene and specifically deleted it in mature sensory neurons using the Cre-Lox strategy. Here, we describe our analyses of the Pik3c3-deficient neurons.Open in a separate windowFig. 4.Loss of Atg7 caused inclusion body formation and degeneration in aged sensory neurons. (A) Graphs of marker-expressing sensory neurons in control and Atg7-cKO mice (age = 9 months). (B) Sensory axon projection in control and Atg7-cKO mice (age = 9 months). Note the decrease of CGRP and vGluT1 levels in Atg7-cKO mice. (Scale bar: 100 μm.) (C) Representative EM images of a control (Left) and Atg7-cKO neuron (Right) at 9 months. Asterisks in Right point to large inclusion bodies. The three boxed areas (1, 2, and 3) are enlarged and shown in D. (Scale bar: 2 μm.) (D Left) Control neuron. (Center) An inclusion body of a mutant neuron. (Right) The cytosol of a mutant neuron showing electron-dense organelles with fibril-like materials. (Scale bar: 500 nm.)     

Determination of procalcitonin concentration using the SphereLight 180 clinical auto-analyzer

BACKGROUND: Procalcitonin (PCT) is a biomarker for the diagnosis of sepsis and bacterial infection diseases. METHODS: A new fully automated SphereLight PCT (SL-PCT) assay system for PCT concentration in human serum or plasma by using SphereLight 180 (SL180, Olympus Corp.) analyzer was developed. The SL-PCT assay is based on chemiluminescent enzyme immunoassay. RESULTS: A linear dose response relationship was observed up to 200 ng/ml PCT concentration. The detection limit of PCT concentration was 0.06 ng/ml. Endogenous substances, anticoagulants, sodium fluoride and drugs did not interfere with assay results. There was a good correlation between the present method and the manual method in serum and plasma samples. CONCLUSIONS: These results indicate that the SL-PCT assay showed good performance in terms of the linearity, detection limit and precision. Use of this PCT measurement may improve the detection of sepsis and infectious disease.     

A case with a single liver metastasis from pancreatic cancer surviving for 29 months

We report a 62-year-old man with advanced pancreatic cancer who underwent pancreatoduodenectomy and was then found to have a single hepatic metastasis. Hepatic resection was performed after 19 months of systemic chemotherapy. The patient survived for 29 months after diagnosis of the hepatic metastasis without occurrence of further metastatic lesions. The patient was given a diagnosis of pancreatic head cancer and underwent pancreatoduodenectomy in September 2001. A single hepatic metastasis was found in July 2002. No local recurrence, lymph node metastasis, distant metastasis or peritoneal metastasis were noted on imaging studies. Chemotherapy with S-1 was performed. The hepatic metastasis remained single and there were no other metastatic lesions for 19 months. A metastasis was found in the right lung in May 2004. The patient died in December 2004 without local recurrence, lymph node metastasis or new hepatic metastasis.     

Structure-activity relationship of flavonoids for inhibition of epidermal growth factor-induced transformation of JB6 Cl 41 cells

We found that quercetin, myricetin, quercetagetin, fisetin, (-)-epigallocatechin gallate (EGCG), and theaflavins, among 24 flavonoids examined, markedly inhibited epidermal growth factor (EGF)-induced cell transformation of mouse epidermal JB6 Cl 41 cells. The six flavonoids suppressed the EGF-induced activation of activator protein 1 (AP-1). In addition, myricetin, quercetagetin, EGCG, and theaflavins directly inhibited EGF-induced phosphatidylinositol 3-kinase (PI3K) activation. The important structural features of flavonoids for cell transformation-inhibitory activity are 3'- and 4'-OH on the B-ring, 3-OH on the C-ring, C2=C3 double bond in the C-ring, and the phenylchromone (C6-C5-C6) skeleton in the flavonols, and the galloyl group in EGCG and theaflavins. Our results provide new insight into possible mechanisms of the anti-carcinogenic effects of flavonoids, and could help to provide a basis for the design of novel cancer chemopreventive agents.     

Continuous infusion of insulin-like growth factor-I into the epiphysis of the tibia

We have developed a method to promote longitudinal bone growth at the level of a specific growth-plate (GP) in young rabbits. Insulin-like growth factor-I (IGF-I) was continuously infused by means of an osmotic pump into the bone marrow cavity of the proximal epiphysis of the tibia. Radiological measurement showed a 2-mm overgrowth of the tibia after 4 weeks of treatment, while histological analysis demonstrated a 15% increase in the thickness of the selected GP. The local infusion of IGF-I increased the numbers of both proliferative and hypertrophic chondrocytes and promoted hyperplasia of bony trabeculae within the epiphysis. The distribution of material infused locally into the epiphysis was simulated by the infusion of Indian ink using the same methodology (osmotic pump) as that for IGF-I. Most of the dye remained within the bone marrow cavity of the epiphysis, but a portion infiltrated into the GP, reaching the deep layer of the physeal chondrocytes and primary spongiosa of the metaphysis. These results suggest that the method reported here is a valid one for delivering cytokines or growth factors to the selected GP and for controlling the growth and differentiation of physeal chondrocytes.     

T helper type 2 differentiation and intracellular trafficking of the interleukin 4 receptor-alpha subunit controlled by the Rac activator Dock2

The lineage commitment of CD4+ T cells is coordinately regulated by signals through the T cell receptor and cytokine receptors, yet how these signals are integrated remains elusive. Here we find that mice lacking Dock2, a Rac activator in lymphocytes, developed allergic disease through a mechanism dependent on CD4+ T cells and the interleukin 4 receptor (IL-4R). Dock2-deficient CD4+ T cells showed impaired antigen-driven downregulation of IL-4Ralpha surface expression, resulting in sustained IL-4R signaling and excessive T helper type 2 responses. Dock2 was required for T cell receptor-mediated phosphorylation of the microtubule-destabilizing protein stathmin and for lysosomal trafficking and the degradation of IL-4Ralpha. Thus, Dock2 links T cell receptor signals to downregulation of IL-4Ralpha to control the lineage commitment of CD4+ T cells.     

WSX-1 plays a significant role for the initiation of experimental autoimmune uveitis

WSX-1 is a subunit of the IL-27R, which plays a critical role in the initiation of T(h)1 responses. Murine experimental autoimmune uveitis (EAU) is a model of human autoimmune uveitis, in which a T(h)1 response predominates in the pathogenetic process. To explore the role of WSX-1 in this model, WSX-1(-/-) mice were immunized with interphotoreceptor retinoid-binding protein peptide 1-20 to induce EAU. We found that the EAU clinical and histological scores were lower in the WSX-1(-/-) mice up to day 21, whereas after day 21, the EAU scores were the same between the wild-type (WT) and WSX-1(-/-) mice with both declining at the same rate. In contrast to T lymphocytes from WT mice, WSX-1(-/-) T lymphocytes on day 9 after immunization failed to produce IFN-gamma. Similarly, expression of T(h)1-related chemokines, such as regulated on activation, normal T cell expressed and secreted and IP-10, in the eye was reduced in WSX-1(-/-) mice compared with WT mice on day 13 after immunization. In addition, sub-retinal transfer of lymphocytes from WSX-1(-/-) mice on day 9 after immunization did not induce EAU in the recipient mice. Importantly, IFN-gamma production, chemokine expression and the transferability of disease by lymphocytes became comparable for WSX-1(-/-) and WT mice at later stages. Thus, IL-27/WSX-1 affects the early development of EAU, and might be a target for therapy during the onset of autoimmune uveitis in humans.