Pharmacological doses of melatonin impede cognitive decline in tau‐related Alzheimer models,once tauopathy is initiated,by restoring the autophagic flux

Alterations in autophagy are increasingly being recognized in the pathogenesis of proteinopathies like Alzheimer's disease (AD). This study was conducted to evaluate whether melatonin treatment could provide beneficial effects in an Alzheimer model related to tauopathy by improving the autophagic flux and, thereby, prevent cognitive decline. The injection of AAV‐hTau^P301L viral vectors and treatment/injection with okadaic acid were used to achieve mouse and human ex vivo, and in vivo tau‐related models. Melatonin (10 μmol/L) impeded oxidative stress, tau hyperphosphorylation, and cell death by restoring autophagy flux in the ex vivo models. In the in vivo studies, intracerebroventricular injection of AAV‐hTau^P301L increased oxidative stress, neuroinflammation, and tau hyperphosphorylation in the hippocampus 7 days after the injection, without inducing cognitive impairment; however, when animals were maintained for 28 days, cognitive decline was apparent. Interestingly, late melatonin treatment (10 mg/kg), starting once the alterations mentioned above were established (from day 7 to day 28), reduced oxidative stress, neuroinflammation, tau hyperphosphorylation, and caspase‐3 activation; these observations correlated with restoration of the autophagy flux and memory improvement. This study highlights the importance of autophagic dysregulation in tauopathy and how administration of pharmacological doses of melatonin, once tauopathy is initiated, can restore the autophagy flux, reduce proteinopathy, and prevent cognitive decline. We therefore propose exogenous melatonin supplementation or the development of melatonin derivatives to improve autophagy flux for the treatment of proteinopathies like AD.     

Properties of polyacetylene obtained with (η-Cp)2Ti(PMe3)2

Acetylene was polymerized by (η-Cp)₂Ti(PMe₃)₂ at room temperature to give predominantly trans-polyacetylene. All properties are within the ranges reported for polyacetylene produced with Ti(OBu)₄/AlEt₃ as catalyst.     

A Decision Rule for Predicting Bacterial Meningitis in Children with Cerebrospinal Fluid Pleocytosis When Gram Stain Is Negative or Unavailable

Objectives:  Among children with cerebrospinal fluid (CSF) pleocytosis, the task of separating aseptic from bacterial meningitis is hampered when the CSF Gram stain result is unavailable, delayed, or negative. In this study, the authors derive and validate a clinical decision rule for use in this setting.
Methods:  This was a review of peripheral blood and CSF test results from 78 children (<19 years) presenting to Children's Hospital Columbus from 1998 to 2002. For those with a CSF leukocyte count of >7/μL, a rule was created for separating bacterial from viral meningitis that was based on routine laboratory tests, but excluded Gram stain. The rule was validated in 158 subjects seen at the same site (Columbus, 2002–2004) and in 871 subjects selected from a separate site (Boston, 1993–1999).
Results:  One point each (maximum, 6 points) was assigned for leukocytes >597/μL, neutrophils >74%, glucose <38 mg/dL, and protein >97 mg/dL in CSF and for leukocytes >17,000/mL and bands to neutrophils >11% in peripheral blood. Areas under receiver-operator-characteristic curves (AROCs) for the resultant score were 0.98 for the derivation set and 0.90 and 0.97, respectively, for validation sets from Columbus and Boston. Sensitivity and specificity pairs for the Boston data set were 100 and 44%, respectively, at a score of 0 and 97 and 81% at a score of 1. Likelihood ratios (LRs) increased from 0 at a score of 0 to 40 at a score of ≥4.
Conclusions:  Among children with CSF pleocytosis, a prediction score based on common tests of CSF and peripheral blood and intended for children with unavailable, negative, or delayed CSF Gram stain results has value for diagnosing bacterial meningitis.     

Orthotopic placement of the dunning R3327 AT-3 prostate tumor in the copenhagen X fischer rat

Orthotopic placement of in vitro propagated Dunning R3327 AT-3 tumor cells resulted in a greater percentage of tumor takes and a two-fold shift in the exponential growth curve compared to flank implantation. The orthotopic tumor appeared to disseminate preferentially to regional lymph nodes, rather than to the lungs which is characteristic of flank tumors. The results suggest an important role of stromal-epithelial interactions in the growth of this tumor. © 1995 Wiley-Liss, Inc.     

Effects of tamoxifen and somatostatin analogue on growth of human medullary, follicular, and papillary thyroid carcinoma cell lines: tissue culture and nude mouse xenograft studies

The knowledge that (1) the normal thyroid contains somatostatin, (2) polypeptide growth factors influence thyroid cell function, and (3) thyroid cells contain steroid hormone receptors prompted us to add somatostatin analogue No. 201-995 (SMS) (5 ng/ml) and/or tamoxifen citrate (TAM) (5 mumol/L) to 7-day monolayer cultures (50,000 cells/well) of three separate human thyroid carcinoma cell lines: DR081 (medullary), WR082 (follicular), and NPA'87 (papillary). Results, tabulated as cell numbers/well (X10(5) on day 7, revealed that TAM inhibited growth of medullary and follicular cells and that TAM plus SMS inhibited growth of papillary cells. In vivo studies of subcutaneous tumor cell xenografts in nude mice have documented that TAM (5 mg subcutaneous pellet) significantly inhibits the growth of medullary implants. Flow cytometric DNA studies of medullary cell cultures demonstrated a reduced G2 + M phase with TAM treatment. For papillary cell implants, TAM plus SMS (5 micrograms subcutaneously, twice daily) did not suppress tumor growth. All three cell lines were negative for estrogen receptor; addition of estradiol (5 ng/ml) to medullary cell cultures neither stimulated replication nor reversed the inhibitory effects of TAM in vitro. We conclude that (1) TAM slowed the growth of a cell line of human medullary carcinoma, both in vitro and in vivo; (2) this effect was not reversed by estradiol; (3) TAM plus SMS inhibited replication of a papillary carcinoma cell line in vitro, but not in vivo; and (4) TAM alone and TAM plus SMS inhibited replication of cultures of a human follicular thyroid carcinoma cell line. TAM and SMS may be useful in treatment of some human thyroid carcinomas.     

Autoantibodies and levels of polychlorinated biphenyls in persons living near a hazardous waste treatment facility.

BACKGROUND: Increased autoantibody prevalence has been described in instances of high-dose exposure to polychlorinated biphenyls (PCBs). In 1996, an equipment malfunction at the Swan Hills Treatment Centre in Alberta, Canada, caused the release of gases containing PCBs into the ambient air. In view of the immune effects of PCBs and their potential as endocrine disruptors, we assessed autoantibody prevalence and looked for correlations with PCB levels. METHODS: Fifty-seven persons living within a 100 km radius of the waste treatment facility were assessed. Autoantibodies were measured by indirect immunofluorescence, double immunodiffusion, and immunoblotting. The levels of 26 congeners of PCBs were measured by gas chromatography and mass spectrometry. Provincial health records for physician visits and hospitalizations were reviewed for diagnoses of autoimmune disease. RESULTS: The prevalence of autoantibodies was 11% in the study participants and 0% in healthy controls. There was no correlation of PCB levels with autoantibody results. There was no associated increase in autoimmune disease noted on physician visits or hospitalizations. PCB levels were comparable to background levels reported for other populations. CONCLUSION: A correlation of titers of autoantibodies in the sera of individuals at risk and the blood levels of PCBs was not found, and the prevalence of autoantibodies in the at-risk group was not statistically different (p > .05) from that of an unexposed control group. The study group had higher titers of autoantibodies and some strong reactivity with intracellular antigens, but the significance of this observation may be understood only after long-term clinical assessments and follow-up.