Lbx1 and Tlx3 are opposing switches in determining GABAergic versus glutamatergic transmitter phenotypes

Most neurons in vertebrates make a developmental choice between two principal neurotransmitter phenotypes (glutamatergic versus GABAergic). Here we show that the homeobox gene Lbx1 determines a GABAergic cell fate in the dorsal spinal cord at early embryonic stages. In Lbx1-/- mice, the presumptive GABAergic neurons are transformed into glutamatergic cells. Furthermore, overexpression of Lbx1 in the chick spinal cord is sufficient to induce GABAergic differentiation. Paradoxically, Lbx1 is also expressed in glutamatergic neurons. We previously reported that the homeobox genes Tlx1 and Tlx3 determine glutamatergic cell fate. Here we show that impaired glutamatergic differentiation, observed in Tlx3-/- mice, is restored in Tlx3-/-Lbx1-/- mice. These genetic studies suggest that Lbx1 expression defines a basal GABAergic differentiation state, and Tlx3 acts to antagonize Lbx1 to promote glutamatergic differentiation.     

Symptomatic hepatitis B virus (HBV) reactivation despite reduced viral fitness is associated with HBV test and immune escape mutations in an HIV-coinfected patient

Two sequential hepatitis B virus (HBV) strains obtained before and during an icteric flare-up of an occult HBV infection in a patient coinfected with human immunodeficiency virus revealed HBV surface antigen (HBsAg) test escape mutations, although the patient had never received hepatitis B-specific immunoglobulin. In contrast to the high HBV DNA loads, recurrence of HBsAg, and resulting icteric hepatitis, phenotypic analysis of the mutated HBV strains revealed significantly reduced replication efficacies in vitro, compared with wild-type HBV. Therefore, immune escape in the transiently anti-HBs-positive patient appeared to be crucial for persistence and reactivation. Immune escape mutants evolved even without exogenous selective pressure, hampered detection in HBsAg screening, and might be transmitted during reactivation with high HBV loads.     

Evaluation of alternative diagnostic techniques for diagnosis of cerebral malaria in a tertiary referral hospital in Bangladesh

Five alternative techniques for diagnosis of malaria were evaluated in 124 clinically diagnosed cerebral malaria cases admitted in a tertiary hospital in Bangladesh. Clinical diagnosis of cerebral malaria was done by WHO criteria. The tests were conventional routine malaria microscopy; prolonged microscopy; dipstick antigen capture assay (Para Sight TM-F test); pigments in peripheral leucocytes and routine microscopy repeated at 12 hours interval. First four tests were done at 0 hours of hospital admission and repeat routine microscopy was added at 12 hours interval. Diagnostic capability of the test was 64%, 65%, 69%, 27% and 63% respectively. None of the tests except pigments in peripheral leucocytes was superior at initial evaluation. Only the dipstick test added 5% more diagnostic possibility compared with routine microscopy as standard. Stratification of diagnostic capability in different ways improved diagnosis 15% and 11% in smear negative cases by dipstick and prolonged microscopy respectively. It was increased by 50% (5/10 patients) with dipstick test in the smear negative patients with history of anti-malarials prior to hospital admission.     

Comparative evaluation of mechanical and physical properties of a new bulk-fill alkasite with conventional restorative materials

PurposeThe physical and mechanical performance of a newly commercialized dental restorative material (alkasite) was compared with glass ionomer cement (GIC) and nano-hybrid composite.MethodologyHuman extracted premolars were used to investigate the shear bond strength. Restorative materials were placed on the dentine surface and were aged in deionized water for 14 days. The 3-D surface roughness was evaluated before and after chewing simulation cycles (50,000). The samples were fatigued mechanically using a chewing simulator and investigated with a scanning electron microscope (SEM).ResultsFor shear bond strength, alkasite showed significantly high values than GIC, whereas non-significant difference was observed between alkasite and nano-hybrid composite. After the chewing simulation (50,000 cycles), non-significant difference was found between GIC and nano-hybrid composite, where surface roughness values were highest for GIC and lowest for alkasite.ConclusionThe newly developed restorative material (alkasite) has shown better results than existing restorative materials.     

Mutagenicity of cidial (phenthoate). I: Effect on maternal and fetal somatic cells

Cidial, an organophosphorous insecticide (also known as phenthoate), was tested for its genotoxic effect on both maternal and fetal cells. Cidial was administered at three different dose levels (53.5, 106.9, and 171 mg/kg) to pregnant mice on day 16 of gestation. Maternal bone marrow and embryonic liver cells were examined for chromosomal aberrations and cellular proliferation. Cidial was found to increase the percentage of cells with chromosomal aberrations in both mothers and fetuses. It also significantly inhibited the rate of mitotic activity of both maternal and fetal cells, with the inhibitory effect being more appreciable in fetal cells than in maternal cells. The data indicate that cidial, which is widely used in rural areas, is hazardous to both mothers and their transplacentally exposed babies. Environ. Mol. Mutagen. 29:53–57, 1997 © 1997 Wiley-Liss, Inc.     

TRPV1 signaling: mechanistic understanding and therapeutic potential

Transient receptor potential vanilloid 1 (TRPV1) is a non-selective cation channel gated by noxious heat, vanilloids and extracellular protons. TRPV1 is acting as an important signal integrator in sensory nociceptors under physiological and pathological conditions including inflammation and neuropathy. Because of its integrative signaling properties in response to inflammatory stimuli, TRPV1 agonists and antagonists are predicted to inhibit the sensation of ongoing or burning pain that is reported by patients suffering from chronic pain, therefore offering an unprecedented advantage in selectively inhibiting painful signaling from where it is initiated. In this article, we firstly summarize recent advances in the understanding of the role of TRPV1 in pain signaling, including a overview of clinical pharmacological trials using TRPV1 agonists and antagonists. Finally, we also present an update on the mechanistic understanding and controlling of hyperthermia caused by TRPU1 antagonists, and provide perspective for future study.     

Post-injury repeated administrations of minocycline improve the antinociceptive effect of morphine in chronic constriction injury model of neuropathic pain in rat

It is confirmed that pharmacological attenuation of glial cells can alleviate neuropathic pain by lowering proinflammatory cytokine expression. The present study tries to confirm that post-injury administration of glia inhibitor, minocycline, can attenuate the neuropathic pain symptoms and improves the efficacy of morphine anti-nociception in chronic constriction injury (CCI). Male Wistar rats (230-270 g) underwent surgery for induction CCI model of neuropathy. For assessment of the thermal hyperalgesia and mechanical allodynia after CCI induction, morphine (2.5, 5, 7.5, 10 and 15 mg/kg; s.c.) and saline were administered on post-operative days (PODs) 0, 6 and 14. Hargreaves and Von-Frey tests were performed before and 30 min after morphine administration, respectively. The results showed significant decrease in antinociceptive effect of morphine on POD 6 compared to POD 0 only at the dose of 5 mg/kg. On the other hand, on POD 14 the antinociceptive effect of morphine (5, 7.5, 10 and 15 mg/kg) significantly decreased in comparison with POD 0. In another set of experiments, animals received minocycline (10, 20 and 40 mg/kg; i.p.) for eight days from POD 6 to 13 and then the antinociceptive effect of single dose of morphine 5 mg/kg was tested on POD 14. Behavioral tests showed that minocycline (40 mg/kg) could effectively attenuate the thermal hyperalgesia and mechanical allodynia on POD 13. Moreover, minocycline (40, 20 mg/kg) improved the anti-hyperalgesic, and minocycline (40 mg/kg) improved the anti-allodynic effects of morphine 5 mg/kg on POD 14. It seems that the reduction of antinociceptive effect of morphine after CCI may be mediated through glia activation. Modulation of glial activity by minocycline can attenuate CCI-induced neuropathic pain. It is also shown that repeated post-injury administration of minocycline improves the antinociceptive effect of morphine in neuropathic pain.