Abstract Adult hippocampal neurogenesis, a once unorthodox concept, has changed into one of the most rapidly growing fields in neuroscience. The present report results from the ECNP targeted expert ...meeting in 2007 during which cellular plasticity changes were addressed in the adult brain, focusing on neurogenesis and apoptosis in hippocampus and frontal cortex. We discuss recent studies investigating factors that regulate neurogenesis with special emphasis on effects of stress, sleep disruption, exercise and inflammation, a group of seemingly unrelated factors that share at least two unifying properties, namely that they all regulate adult hippocampal neurogenesis and have all been implicated in the pathophysiology of mood disorders. We conclude that although neurogenesis has been implicated in cognitive function and is stimulated by antidepressant drugs, its functional impact and contribution to the etiology of depression remains unclear. A lasting reduction in neurogenesis following severe or chronic stress exposure, either in adult or early life, may represent impaired hippocampal plasticity and can contribute to the cognitive symptoms of depression, but is, by itself, unlikely to produce the full mood disorder. Normalization of reductions in neurogenesis appears at least partly, implicated in antidepressant action.
It has long been known that cholera outbreaks can be initiated when Vibrio cholerae, the bacterium that causes cholera, is present in drinking water in sufficient numbers to constitute an infective ...dose, if ingested by humans. Outbreaks associated with drinking or bathing in unpurified river or brackish water may directly or indirectly depend on such conditions as water temperature, nutrient concentration, and plankton production that may be favorable for growth and reproduction of the bacterium. Although these environmental parameters have routinely been measured by using water samples collected aboard research ships, the available data sets are sparse and infrequent. Furthermore, shipboard data acquisition is both expensive and time-consuming. Interpolation to regional scales can also be problematic. Although the bacterium, V. cholerae, cannot be sensed directly, remotely sensed data can be used to infer its presence. In the study reported here, satellite data were used to monitor the timing and spread of cholera. Public domain remote sensing data for the Bay of Bengal were compared directly with cholera case data collected in Bangladesh from 1992-1995. The remote sensing data included sea surface temperature and sea surface height. It was discovered that sea surface temperature shows an annual cycle similar to the cholera case data. Sea surface height may be an indicator of incursion of plankton-laden water inland, e.g., tidal rivers, because it was also found to be correlated with cholera outbreaks. The extensive studies accomplished during the past 25 years, confirming the hypothesis that V. cholerae is autochthonous to the aquatic environment and is a commensal of zooplankton, i.e., copepods, when combined with the findings of the satellite data analyses, provide strong evidence that cholera epidemics are climate-linked.
The Geostationary Lightning Mapper (GLM) marks the first time that lightning observations at storm‐scale resolution are operationally available from geostationary orbit. We evaluate GLM detection ...efficiency (DE) for a special class of convective storms characterized by anomalous charge structures. These storms are anomalous as their internal layered charge structure departs from the tripole charge structure model, where midlevel negative charge is situated between upper and lower positive charge layers. Anomalous storms are characterized by extreme flash rates, low median flash heights, and intense precipitation. Ground truth information on lightning flash rates is provided by Lightning Mapping Arrays (LMA), which measure VHF radio frequency emissions produced by electrical breakdown. This study contrasts two regions: Colorado, where electrically “anomalous” storms are numerous, and Alabama, where they are rare. This study analyzes GLM DE as a function of the precipitation water path, cloud water path, and lightning properties from LMA. The GLM DE is found to vary with the geometric size of the flash and with cloud water path, the latter depending on flash height and cloud water content. Optical scattering (attenuation) by precipitation‐sized particles does not appear to be a factor since precipitation particles contain much less surface area than cloud particles. The size of the flash is correlated with its optical brightness, and the cloud water path is correlated with optical extinction. Regional differences in GLM DE remain that appear to be related to sensor viewing geometry and day versus night sensitivity differences.
Key Points
Geostationary Lightning Mapper (GLM) detection efficiency (DE) is characterized using Lightning Mapping Arrays
Reduced detection efficiency (DE) is found for storms with anomalous charge structures
Additional factors related to viewing geometry and day‐night effects are likely required to explain regional differences in DE
Mutational activation of BRAF is a frequent event in human malignant melanomas suggesting that BRAF-dependent signaling is conducive to melanoma cell growth and survival. Previously published work ...reported that melanoma cells exhibit constitutive anti-apoptotic nuclear factor κB (NF-κB) transcription factor activation triggered by proteolysis of its inhibitor IκB. IκB degradation is dependent upon its phosphorylation by the IκB kinase (IKK) complex and subsequent ubiquitination facilitated by β-Trcp E3 ubiquitin ligase. Here, we report that melanocytes expressing a conditionally oncogenic form of BRAFV600E exhibit enhanced β-Trcp expression, increased IKK activity and a concomitant increase in the rate of IκBα degradation. Conversely, inhibition of BRAF signaling using either a broad-spectrum Raf inhibitor (BAY 43-9006) or by selective knock-down of BRAFV600E expression by RNA interference in human melanoma cells leads to decreased IKK activity and β-Trcp expression, stabilization of IκB, inhibition of NF-κB transcriptional activity and sensitization of these cells to apoptosis. Taken together, these data support a model in which mutational activation of BRAF in human melanomas contributes to constitutive induction of NF-κB activity and to increased survival of melanoma cells.
We present here quantitative evidence for an increased role of interannual climate variability on the temporal dynamics of an infectious disease. The evidence is based on time-series analyses of the ...relationship between El Niño/Southern Oscillation (ENSO) and cholera prevalence in Bangladesh (formerly Bengal) during two different time periods. A strong and consistent signature of ENSO is apparent in the last two decades (1980-2001), while it is weaker and eventually uncorrelated during the first parts of the last century (1893-1920 and 1920-1940, respectively). Concomitant with these changes, the Southern Oscillation Index (SOI) undergoes shifts in its frequency spectrum. These changes include an intensification of the approximately 4-yr cycle during the recent interval as a response to the well documented Pacific basin regime shift of 1976. This change in remote ENSO modulation alone can only partially serve to substantiate the differences observed in cholera. Regional or basin-wide changes possibly linked to global warming must be invoked that seem to facilitate ENSO transmission. For the recent cholera series and during specific time intervals corresponding to local maxima in ENSO, this climate phenomenon accounts for over 70% of disease variance. This strong association is discontinuous in time and can only be captured with a technique designed to isolate transient couplings.
Experimental and analytical studies of the effects of voltage and current harmonics on induction machines, transformers, appliances, and relays show that the present versions of IEEE and IEC are too ...restrictive for low-frequency voltage and current (integer) harmonics, as they apply to residential power systems. It is recommended that not rigid but flexible guidelines are established so that different harmonic spectra are permitted which result in the same additional temperature rise in transformers and induction machines. Very restrictive amplitude limits for inter-harmonics and subharmonics should be included in the revision of the above standards due to their detrimental effects on under-frequency relays (malfunctioning), lighting equipment (flicker) and rotating machines (harmonic torques).
Persisting cancer-related fatigue impairs health-related quality of life (HRQoL) and social reintegration in patients with Hodgkin’s lymphoma (HL). The GHSG HD18 trial established treatment ...de-escalation for advanced-stage HL guided by positron emission tomography after two cycles (PET-2) as new standard. Here, we investigate the impact of treatment de-escalation on long-term HRQoL, time to recovery from fatigue (TTR-F), and time to return to work (TTR-W).
Patients received European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) and life situation questionnaires at baseline, interim, end of treatment, and yearly follow-up. TTR-F was defined as time from the end of chemotherapy until the first fatigue score <30. TTR-W was analyzed in previously working or studying patients and measured from the end of treatment until the first documented work or education. We compared duration of treatment on TTR-F and TTR-W using Cox proportional hazards regression adjusted for confounding variables.
HRQoL questionnaires at baseline were available in 1632 (83.9%) of all randomized patients. Overall, higher baseline fatigue and age were significantly associated with longer TTR-F and TTR-W and male sex with shorter TTR-W. Treatment reduction from eight to four chemotherapy cycles led to a significantly shorter TTR-F hazard ratio (HR) 1.41, P = 0.008 and descriptively shorter TTR-W (HR 1.24, P = 0.084) in PET-2-negative patients. Reduction from six to four cycles led to non-significant but plausible intermediate accelerations. The addition of rituximab caused significantly slower TTR-F (HR 0.70, P = 0.0163) and TTR-W (HR 0.64, P = 0.0017) in PET-2-positive patients. HRQoL at baseline and age were the main determinants of 2-year HRQoL.
Individualized first-line treatment in patients with advanced-stage HL considerably shortens TTR-F and TTR-W in PET-2-negative patients. Our results support the use of response-adapted shortened treatment duration for patients with HL.
•We used time-to-event methods to compare treatment effects on fatigue and social reintegration in patients with HL.•Addition of rituximab prolonged time to recovery from fatigue (TTR-F) and time to return to work (TTR-W) in positron emission tomography (PET-2)-positive patients.•Shorter treatment considerably shortens TTR-F and TTR-W in PET-2-negative patients.
Recent evidence has shown that
d-amino acids are present in animals and humans in high concentrations and fulfill specific biological functions. In the central nervous system, two
d-amino acids,
...d-serine and
d-aspartate, occur in considerable concentrations.
d-Serine is synthesized and metabolized endogenously and the same might account for
d-aspartate.
d-Serine has been studied most extensively and was shown to play a role in excitatory amino acid metabolism, being a co-agonist of the
N-methyl-
d-aspartate (NMDA) receptor. Insight into
d-serine metabolism is relevant for physiological NMDA receptor (NMDAr) activation and for all the disorders associated with an altered function of the NMDAr, such as schizophrenia, ischemia, epilepsy, and neurodegenerative disorders.
d-Aspartate appears to play a role in development and endocrine function, but the precise function of
d-aspartate and other
d-amino acids in animals and humans requires further investigation. As
d-amino acids play biological roles, alterations in the concentrations of
d-amino acids might occur in some disorders and relate to the pathogenesis of these disorders.
d-Amino acid concentrations may then not only help in the diagnostic process, but also provide novel therapeutic targets. Consequently, the presence and important roles of
d-amino acids in higher organisms do not only challenge former theories on mammalian physiology, but also contribute to exciting new insights in human disease.
Mitochondrial trifunctional protein (MTP) is involved in long‐chain fatty acid β‐oxidation (lcFAO). Deficiency of one or more of the enzyme activities as catalyzed by MTP causes generalized MTP ...deficiency (MTPD), long‐chain hydroxyacyl‐CoA dehydrogenase deficiency (LCHADD), or long‐chain ketoacyl‐CoA thiolase deficiency (LCKATD). When genetic variants result in thermo‐sensitive enzymes, increased body temperature (e.g. fever) can reduce enzyme activity and be a risk factor for clinical decompensation. This is the first description of five patients with a thermo‐sensitive MTP deficiency. Clinical and genetic information was obtained from clinical files. Measurement of LCHAD and LCKAT activities, lcFAO‐flux studies and palmitate loading tests were performed in skin fibroblasts cultured at 37°C and 40°C. In all patients (four MTPD, one LCKATD), disease manifested during childhood (manifestation age: 2–10 years) with myopathic symptoms triggered by fever or exercise. In four patients, signs of retinopathy or neuropathy were present. Plasma long‐chain acylcarnitines were normal or slightly increased. HADHB variants were identified (at age: 6–18 years) by whole exome sequencing or gene panel analyses. At 37°C, LCHAD and LCKAT activities were mildly impaired and lcFAO‐fluxes were normal. Remarkably, enzyme activities and lcFAO‐fluxes were markedly diminished at 40°C. Preventive (dietary) measures improved symptoms for most. In conclusion, all patients with thermo‐sensitive MTP deficiency had a long diagnostic trajectory and both genetic and enzymatic testing were required for diagnosis. The frequent absence of characteristic acylcarnitine abnormalities poses a risk for a diagnostic delay. Given the positive treatment effects, upfront genetic screening may be beneficial to enhance early recognition.
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