Neurotransmitter regulation of adult neurogenesis: putative therapeutic targets

The evidence that new neuron addition takes place in the mammalian brain throughout adult life has dramatically altered our perspective of the potential for plasticity in the adult CNS. Although several recent reports suggest a latent neurogenic capacity in multiple brain regions, the two major neurogenic niches that retain the ability to generate substantial numbers of new neurons in adult life are the subventricular zone (SVZ) lining the lateral ventricles and the subgranular zone (SGZ) in the hippocampal formation. The discovery of adult neurogenesis has also unveiled a novel therapeutic target for the repair of damaged neuronal circuits. In this regard, understanding the endogenous mechanisms that regulate adult neurogenesis holds promise both for a deeper understanding of this form of structural plasticity, as well as the identification of pathways that can serve as therapeutic targets to manipulate adult neurogenesis. The purpose of the present review is to discuss the regulation of adult neurogenesis by neurotransmitters and to highlight the relevance of these endogenous regulators as targets to modulate adult neurogenesis in a clinical context.     

Hippocampal mossy fiber sprouting induced by chronic electroconvulsive seizures

Stress, which can precipitate and exacerbate depression, causes atrophy and in severe cases death of hippocampal neurons. Atrophy of the hippocampus has also been observed in patients suffering from recurrent major depression. The present study examines the influence of electroconvulsive seizures, one of the most effective treatments for depression, on the morphology and survival of hippocampal neurons. The results demonstrate that chronic administration of electroconvulsive seizures induces sprouting of the granule cell mossy fiber pathway in the hippocampus. This sprouting is dependent on repeated administration of electroconvulsive seizures, reaches a maximum 12 days after the last treatment and is long lasting (i.e. up to six months). Electroconvulsive seizure-induced sprouting occurs in the absence of neuronal loss, indicating that sprouting is not a compensatory response to cell death. This is different from the sprouting induced by kindling or excitotoxin treatment, which induce cell death along with recurrent seizures. Electroconvulsive seizure-induced sprouting is significantly diminished in brain-derived neurotrophic factor heterozygote knockout mice, indicating that this neurotrophic factor contributes to mossy fiber sprouting. However, infusion of brain-derived neurotrophic factor into the hippocampus does not induce sprouting of the mossy fiber pathway. The results demonstrate that chronic administration of electroconvulsive seizures induces mossy fiber sprouting and suggest that increased expression of brain-derived neurotrophic factor is necessary, but not sufficient for the induction of this sprouting. Although the functional consequences remain unclear, sprouting of the mossy fiber pathway would appear to oppose the actions of stress and could thereby contribute to the therapeutic actions of electroconvulsive seizure therapy.     

Metastasis Suppressors and Their Roles in Breast Carcinoma

Metastasis remains the most deadly aspect of cancer and still evades direct treatment. Clinically and experimentally, primary tumor development and metastasis are distinct processes—locally growing tumors can progress without the development of metastases. The discovery of endogenous molecules that exclusively inhibit metastasis suggests that metastasis is an amenable therapeutic target. By definition, metastasis suppressors inhibit metastasis without inhibiting tumorigenicity and are thus distinct from tumor suppressors. As the biology underlying functional mechanisms of metastasis suppressors becomes clearer, it is evident that metastasis suppressors could be harnessed as direct drug targets, prognostic markers, and to understand the fundamental biology of the metastatic process. Metastasis suppressors vary widely in their cellular localization: they are found in every cellular compartment and some are secreted. In general, metastasis suppressors appear to regulate selectively how cells respond to exogenous signals, by affecting signaling cascades which regulate downstream gene expression. This review briefly summarizes current functional and biochemical data on metastasis suppressors implicated in breast cancer. We also present a schematic integrating known mechanisms for these metastasis suppressors highlighting potential targets for therapeutic intervention.     

Pattern of recurrence in paediatric malignant glioma: an institutional experience

Background: The purpose of this retrospective study was to investigate the pattern of recurrence in paediatric malignant gliomas. Material and methods: We reviewed the notes, diagnostic imaging and treatment charts of 30 consecutive paediatric patients (age less than 18 years at diagnosis, range 0.5–17 years) presenting with a malignant glioma presenting to the paediatric oncology unit at the Royal Marsden Hospital over a 10-year period. The imaging at the time of first relapse was compared with the initial diagnostic scans to define a relapse as local, marginal or distant. Results: Median follow-up was 13 months (range 1–99 months). Twenty-four of 30 patients (80%) showed evidence of progression with a median time to progression of 8.5 months (range 3–64 months). Thirteen out of 24 patients developed local or marginal recurrences while 11/24 patients recurred at distant sites as site of first relapse (46%). Conclusion: Our series suggests that the pattern of relapses in paediatric malignant gliomas could be different from that reported in adult studies as we observed a significant incidence of distant relapses. Larger prospective series need to be conducted to investigate the clinico-biological characteristics of the population at high risk for leptomeningeal dissemination.     

Comparison of PCR, immunofluorescence assay, and pathogen isolation for diagnosis of q fever in humans with spontaneous abortions

Coxiella burnetii, an obligate intracellular parasite with a worldwide distribution, is the causative agent of Q fever in humans. We tested a total of 368 samples (placental bits, genital swabs, fecal swabs, and urine and serum samples) collected from women (n = 74) with spontaneous abortions for C. burnetii by a PCR assay targeting IS1111, the repetitive transposon-like region of C. burnetii (trans-PCR); real-time PCR; an indirect immunofluorescence assay (IFA); and the isolation of the pathogen. The IFA showed seropositivity for 25.68% of the women with spontaneous abortions, whereas trans-PCR and real-time PCR each detected the pathogen in 21.62% of cases. Overall, 25.68% of the subjects were positive by one or more assays. Real-time PCR showed a slightly higher level of sensitivity than trans-PCR. With the IFA as the reference, the two PCR assays showed a higher level of sensitivity (84.21%) than pathogen isolation (26.31%), while both the PCR assays and pathogen isolation were specific (100%). The detection of high numbers of C. burnetii cells in clinical samples and the frequent association of the pathogen with cases of spontaneous abortions observed in this study revealed that Q fever remains underdiagnosed and that the prevalence in India is underestimated.     

The impact of premium subsidies on health plan choices in Switzerland: Who responds to the incentives set by in-kind as opposed to cash transfers?

Mandatory health insurance in Switzerland operates on a community-based premium scheme. This can lead to a high financial burden on lower income individuals. Until 2014, premium subsidies were paid as cash transfer or in-kind transfer, providing different incentives to individuals for choosing their health plans. Using a difference-in-differences strategy, the impact of in-kind subsidy transfers on deductible choice and the choice of a cost-saving health plan was evaluated to understand effect heterogeneity based on individual background characteristics. The results indicate that eligible individuals from in-kind transfer cantons in general are incentivized to choose a low deductible plan compared to eligible individuals from cash transfer cantons. This effect is found strongest among female, middle-aged and healthy individuals who have most flexibility in adjusting their health plan choices in response to the financial incentives. Additionally, eligible individuals are less likely to choose a cost-saving health plan compared to a cash transfer canton.     

Synthesis and characterization of a catechol-terminated alkanethiolate monolayer adsorbed on gold

Structural, redox, and metal ion binding characterizations of the monolayer formed by the chemisorption of 3,4-dihydroxyphenethyl mercaptan (DHPM) on gold are described. This system was explored as a model for investigations of surface-immobilized molecules that contain redox-transformable coordination sites for binding metal ions from solution. The characterizations were carried out using infrared reflection spectroscopy, X-ray photoelectron spectroscopy, cyclic voltammetry, and long optical pathlength thin-layer spectroscopy. The XPS data show that this monolayer adsorbs as a thiolate, and the IRS results indicate that the average orientation of the aromatic ring plane is close to the surface normal. Cyclic voltammetry reveals that the pendant catechol/quinone undergoes the expected two-electron, two-proton redox transformation; however, the oxidized form of the couple is unstable, particularly in alkaline aqueous solutions. A determination of Cu(II) binding ability to the surface-immobilized catechol moieties, using a long optical pathlength thin-layer cell to follow the depletion of Cu(II) from solution, indicated that the complexation of the metal was not substantially different from that for the solution form of catechol. The instability of the oxidized form of the ligand, nevertheless, precluded an assessment of its metal ion binding ability. An approach using these data for estimating the conditional formation constant for the surface complexation reaction is also developed.     

Transforaminal lumbar interbody fusion using unilateral pedicle screws and a translaminar screw

Lumbar spinal fusion is advancing with minimally invasive techniques, bone graft alternatives, and new implants. This has resulted in significant reductions of operative time, duration of hospitalization, and higher success in fusion rates. However, costs have increased as many new technologies are expensive. This study was carried out to investigate the clinical outcomes and fusion rates of a low implant load construct of unilateral pedicle screws and a translaminar screw in transforaminal lumbar interbody fusion (TLIF) which reduced the cost of the posterior implants by almost 50%. Nineteen consecutive patients who underwent single level TLIF with this construct were included in the study. Sixteen patients had a TLIF allograft interbody spacer placed, while in three a polyetheretherketone (PEEK) cage was used. Follow-up ranged from 15 to 54 months with a mean of 32 months. A clinical and radiographic evaluation was carried out preoperatively and at multiple time points following surgery. An overall improvement in Oswestry scores and visual analogue scales for leg and back pain (VAS) was observed. Three patients underwent revision surgery due to recurrence of back pain. All patients showed radiographic evidence of fusion from 9 to 26 months (mean 19) following surgery. This study suggests that unilateral pedicle screws and a contralateral translaminar screw are a cheaper and viable option for single level lumbar fusion.