Peripheral administration of lactate produces antidepressant-like effects.

This corrects the article DOI: 10.1038/mp.2016.179.

Peripheral administration of lactate produces antidepressant-like effects.

In addition to its role as metabolic substrate that can sustain neuronal function and viability, emerging evidence supports a role for l-lactate as an intercellular signaling molecule involved in synaptic plasticity. Clinical and basic research studies have shown that major depression and chronic stress are associated with alterations in structural and functional plasticity. These findings led us to investigate the role of l-lactate as a potential novel antidepressant. Here we show that peripheral administration of l-lactate produces antidepressant-like effects in different animal models of depression that respond to acute and chronic antidepressant treatment. The antidepressant-like effects of l-lactate are associated with increases in hippocampal lactate levels and with changes in the expression of target genes involved in serotonin receptor trafficking, astrocyte functions, neurogenesis, nitric oxide synthesis and cAMP signaling. Further elucidation of the mechanisms underlying the antidepressant effects of l-lactate may help to identify novel therapeutic targets for the treatment of depression.

[Renal cell carcinoma and exposure to trichloroethylene: are the French limits of occupational exposure relevant?]. / Cancer du rein et expositions au trichloroéthylène: les valeurs limites d'exposition professionnelle françaises en vigueur sont-elles adaptées ?

BACKGROUND: Several studies have investigated the association between trichloroethylene (TCE) exposure and renal cell cancer (RCC) but findings were inconsistent. The analysis of a case control study has shown an increased risk of RCC among subjects exposed to high cumulative exposure. The aim of this complementary analysis is to assess the relevance of current exposure limits regarding a potential carcinogenic effect of TCE on kidney. METHODS: Eighty-six cases and 316 controls matched for age and gender were included in the study. Successive jobs and working circumstances were described using a detailed occupational questionnaire. An average level of exposure to TCE was attributed to each job-period in turn. The main occupational exposures described in the literature as increasing the risk of RCC were assessed as well as non-occupational factors. A conditional logistic regression was performed to test the association between TCE and RCC risk. Three exposure levels were studied (average exposure during the eight-hour shift): 35ppm, 50ppm and 75ppm. Potential confounding factors identified were taken into account at the threshold limit of 10% (p=0.10) (body mass index [BMI], tobacco smoking, occupational exposures to cutting fluids and to other oils). RESULTS: Adjusted for tobacco smoking and BMI, the odd-ratios associated with exposure to TCE were respectively 1.62 [0.77-3.42], 2.80 [1.12-7.03] and 2.92 [0.85-10.09] at the thresholds of 35ppm, 50ppm and 75ppm. Among subjects exposed to cutting fluids and TCE over 50ppm, the OR adjusted for BMI, tobacco smoking and exposure to other oils was 2.70 [1.02-7.17]. CONCLUSION: Results from the present study as well as those provided in the international literature suggest that current French occupational exposure limits for TCE are too high regarding a possible risk of RCC.

Phosphorylation of neurofilament subunit NF-M is regulated by activation of NMDA receptors and modulates cytoskeleton stability and neuronal shape.

The cytoskeleton is essential for the structural organization of neurons and is influenced during development by excitatory stimuli such as activation of glutamate receptors. In particular, NMDA receptors are known to modulate the function of several cytoskeletal proteins and to influence cell morphology, but the underlying molecular and cellular mechanisms remain unclear. Here, we characterized the neurofilament subunit NF-M in cultures of developing mouse cortical neurons chronically exposed to NMDA receptor antagonists. Western blots analysis showed that treatment of cortical neurons with MK801 or AP5 shifted the size of NF-M towards higher molecular weights. Dephosphorylation assay revealed that this increased size of NF-M observed after chronic exposure to NMDA receptor antagonists was due to phosphorylation. Neurons treated with cyclosporin, an inhibitor of the Ca(2+)-dependent phosphatase calcineurin, also showed increased levels of phosphorylated NF-M. Moreover, analysis of neurofilament stability revealed that the phosphorylation of NF-M, resulting from NMDA receptor inhibition, enhanced the solubility of NF-M. Finally, cortical neurons cultured in the presence of the NMDA receptor antagonists MK801 and AP5 grew longer neurites. Together, these data indicate that a blockade of NMDA receptors during development of cortical neurons increases the phosphorylation state and the solubility of NF-M, thereby favoring neurite outgrowth. This also underlines that dynamics of the neurofilament and microtubule cytoskeleton is fundamental for growth processes.

Helmet use and the risk of neck or cervical spine injury among users of motorized two-wheel vehicles.

OBJECTIVE: To quantify the effects of wearing a helmet on head and facial injury among users of motorized two-wheel vehicles and to determine if helmet use increases the risk of neck and cervical spine injury. DESIGN/METHOD: A population-based study involving injured riders from the Rhône Road Trauma Registry from 1996 to 2005. Victims were only included if they had an injury to a body region other than (or in addition to) the head, face, neck, or cervical spine. Thus, inclusion was not affected by helmet use by the rider. The risk of head, face, neck, and cervical spine injury was assessed, with helmet use as the exposure of interest using logistic regression analyses. Adjusted odds ratios and corresponding confidence intervals were calculated. RESULTS: Helmet use significantly decreased the risk of head and facial injuries. The adjusted odds ratios for non-helmeted riders were 2.43 (95% CI 2.05 to 2.87) and 3.02 (95% CI 2.48 to 3.67), respectively. There was no association between helmet use and the occurrence of neck or cervical spine injuries. The adjusted odds ratios for non-helmeted riders were 0.86 (95% CI 0.60 to 1.23) and 1.04 (95% CI 0.78 to 1.39), respectively. CONCLUSION: Helmets protect users of motorized two-wheel vehicles against head and facial injury without increasing the risk of neck or cervical spine injury.

Whiplash risk estimation based on linked hospital-police road crash data from France and Spain.

OBJECTIVES: To investigate potential risk factors for whiplash injury as a function of crash configuration and driver's characteristics, and to provide information on over-reporting and under-reporting of whiplash. DESIGN: A case-control study of drivers involved in two-car injury collisions. Cases were drivers who had a diagnosis of whiplash injury, with or without another injury. Controls were drivers without diagnosed whiplash injury. SETTING: Hospital registries linked to police crash databases for Barcelona (Spain) and the "Département du Rhône" (France). MAIN OUTCOME MEASURES: Relative risks of whiplash and 95% confidence intervals were estimated using a modified Poisson regression. RESULTS: Of the 8720 drivers involved in car-to-car crashes recorded in the French database, 12.2% were diagnosed with whiplash; the corresponding figure in the Spanish database was 12.0% of 7558 drivers. Female drivers and drivers in rear-impact collisions were most likely to have a whiplash diagnosis, although the absolute number of whiplash cases was greater in front and side impacts. Wearing a seatbelt, being in a heavier car, and age greater than 65 years were associated with a lower risk of whiplash injury. Drivers with other injuries were also more often diagnosed as having a whiplash injury, except the most severely injured. CONCLUSIONS: Devices aimed at reducing the occurrence of whiplash injuries, such as dynamic headrest systems, should be adapted to the characteristics of at-risk occupants, especially women, and should address the mechanics of front and side impacts in addition to rear impacts.

Road crash involvement and professional status: a prospective study using the French Gazel cohort.

OBJECTIVES: To assess professional status (PS) differences in the risk of road crash involvement (RCI) (irrespective of crash severity), and to examine the underlying mechanism by evaluating the role of exposure to road risk (ERR). METHOD: A total of 15,271 subjects selected from the French GAZEL cohort were studied. A proportional hazard model for recurrent events was used to calculate the relative risks (RR) of RCI associated with PS. The associations between RCI and PS were investigated by adjusting for ERR (kilometers travelled and risk behaviors on the road). RESULTS: In all, 1890 RCI were reported. Managers have greater crude RCI risk than unskilled workers (male, RR=1.30; female, RR=1.44). This difference was no longer statistically significant when adjusting for factors describing the drivers' behaviors. Female managers' risks were also insignificant when adjusted for vehicle kilometers travelled (VKT). Managers seemed at lower risk of injury when involved in a crash. CONCLUSION: Socially advantaged subjects have the greatest RCI risk. Qualitative and quantitative ERR factors explain these disparities. These results highlight the importance to focus on ERR when studying the effect of an individual characteristic on RCI. They also highlight the importance to analyse separately the "RCI" and the "susceptibility to injury".

Limits of the quasi-induced exposure method when compared with the standard case-control design. Application to the estimation of risks associated with driving under the influence of cannabis or alcohol.

The disparities between the quasi-induced exposure (QIE) method and a standard case-control approach with crash responsibility as disease of interest are studied. The 10,748 drivers who had been given compulsory cannabis and alcohol tests subsequent to involvement in a fatal crash in France between 2001 and 2003 were used to compare the two approaches. Odds ratios were assessed using conditional and unconditional logistic regressions. While both approaches found that drivers under the influence of alcohol or cannabis increased the risk of causing a fatal crash, the two approaches are not equivalent. They differ mainly with regards to the driver sample selected. The QIE method results in splitting the overall road safety issue into two sub-studies: a matched case-control study dealing with two-vehicle crashes and a case-control study dealing with single-vehicle crashes but with a specific control group. Using a specific generic term such as "QIE method" should not hide the real underlying epidemiological design. On the contrary, the standard case-control approach studies drivers involved in all type of crashes whatever the distribution of the responsibility in each crash. This method also known as "responsibility analysis" is the most relevant for assessing the overall road safety implications of a driver characteristic.

Second harmonic imaging and scoring of collagen in fibrotic tissues.

We compare second harmonic generation (SHG) to histological and immunohistochemical techniques for the visualization and scoring of collagen in biological tissues. We show that SHG microscopy is highly specific for fibrillar collagens and that combined SHG and two-photon excited fluorescence (2PEF) imaging can provide simultaneous three-dimensional visualization of collagen synthesis and assembly sites in transgenic animal models expressing GFP constructs. Finally, we propose several scores for characterizing collagen accumulation based on SHG images and appropriate for different types of collagen distributions. We illustrate the sensitivity of these scores in a murine model of renal fibrosis using a morphological segmentation of the tissue based on endogenous 2PEF signals.

HCV in serum, peripheral blood mononuclear cells and lymphocyte subpopulations in C-hepatitis patients.

To define the best marker for the follow-up and evaluation of HCV infections we determined anti-HCV antibodies, serum transaminases and HCV RNA in patients diagnosed with chronic hepatitis for C virus and treated with alpha-interferon. The presence/absence of HCV RNA was determined in serum, peripheral blood mononuclear cells (PBMC) and lymphocyte subpopulations. Samples were submitted to RT-PCR and subsequent nested PCR. Treatment with alpha-interferon induced a fall in the number of HCV RNA positive patients from an initial 88 to 25% at the end of the treatment. The withdrawal of treatment was associated with a significant increase in the number of HCV RNA positive patients (43% at the 12-month follow-up). In 61% of the patients the PCR analysis of the PBMC population detected the presence of HCV RNA. In 87% of cases the cell fraction identified as CD19 resulted positive in the PCR test and the viral genome was undetectable in PBMC subpopulations in only 13% of cases. In one third of the patients whose serum was negative for PCR the analysis demonstrated the presence of HCV RNA in PBMC. Conclusions: The disappearance of the viral genome in serum, a criterion of treatment response, is not necessarily followed by its disappearance in PBMC. The joint determination of HCV by PCR technique in serum and blood cells should be used as a particular instrument with each patient.

[Differences between males and females in traffic accident risk in France]. / Différences entre les hommes et les femmes face au risque routier.

BACKGROUND: In France 7,720 people were killed in traffic accidents in 2001, 75% of which were men; the number of injured people is estimated at 153,945, of which 65% were men. The objective of the study is to describe differences between males and females regarding accidents, and to explain the main reasons for these differences. METHODS: Analysis is conducted from both national police data (2001) and data from the Rhone medical road accident trauma Register (1996-2001). RESULTS: The male/female incidence rate is 3.1 for mortality (95% CI: 3.0-3.3) and 1.7 for morbidity (95% CI: 1.7-1.8). Two-wheel motorised vehicle accidents are very specific to males, which explains part of this overrepresentation. The fatality rate and the severe injuries rate among survivors are higher for males. This is true for every main user group (car users, motorised two-wheelers, cyclists, pedestrians) after adjusting for accident circumstances and age of casualties. Males are more severely injured for all body regions and have more often severe after-effects. CONCLUSIONS: This paper shows the mechanisms leading to this unfavourable outcome for men. They correspond to differences in the number of trips, in the choice of road transport types, and moreover to differences in risk-taking behaviours. Underlying these behaviours, deep-rooted, strong and rather invariant differences between genders are to be found in the values associated with risk-taking on the road.

[Risk factors of small choroidal melanocytic lesions]. / Factores de riesgo en tumores melanocíticos coroideos de pequeño tamaño.

PURPOSE: To detect the possible predictive factors of tumor spread or future growth of the small choroidal melanocytic lesions. METHODS: Retrospective review of the clinical medical histories of fourteen patients with small choroidal melanocytic lesions --< or =3mm in thickness-, which due to these features could be confused with choroidal nevus. Few clinical parameters are assessed: tumor thickness, posterior tumor margin touching the optic disc, symptoms and documented tumor growth as main prognostic features. RESULTS: Tumor growth was seen in only one patient, whose tumor was treated with epiescleral iridium-192-wires, showing relapse later on. No other patient showed tumor growth, assessed by echography A-B and ocular fundus photography. One of those had symptoms with no other risk factor. Two patients had the tumor located beside the optic disc, one of which presented decreased vision and therefore we had to photocoagulate the tumor. A minimun of six months follow-up was performed in all the patients. CONCLUSIONS: With the criteria applied in our series of small choroidal melanocytic lesions, expectant observation is a valid treatment due to the small tumor growth risk. Thanks to echography and to the precise comparison between ocular fundus photographs to detect minimun growth, a simple follow-up is useful and early conservative treatment is still available.

[Vasoproliferative tumors of the ocular fundus]. / Tumores vasoproliferativos del fondo de ojo.

PURPOSE: To establish the differential diagnosis from choroidal melanoma and other malignant tumors. METHODS: We report 5 patients with vasoproliferative tumors studied in our Hospital since 1993; diagnosis was mainly based on clinic appearance of the lesions. Each patient had undergone indirect ophthalmoscopy and ocular echography. RESULTS: Three upon five cases (studied before 1995) were treated with brachytherapy with Ir(192) because they were suspected to be choroidal melanomas. Periodical observation and treatment of associated complications was the treatment of choice in two other cases in which these complications determined the final visual acuity. CONCLUSION: It is important to establish the differential diagnosis between choroidal melanoma and other malignant tumors, as their prognosis and treatment are different.

Linking deer browsing and terpene production among genetic identities in Chamaecyparis nootkatensis and Thuja plicata (Cupressaceae).

To investigate whether differential herbivore browsing reflects genetic variation in plant defense expression, variation in needle terpenes and damage caused by black-tailed deer (Odocoileus hemionus) was analyzed on yellow-cedar (Chamaecyparis nootkatensis) and western redcedar (Thuja plicata). In a 100-genet yellow-cedar population, three genets that were heavily browsed and had extremely low levels of monoterpenes (0-0.36% dry matter), sesquiterpenes, and diterpenes were compared to unbrowsed genets (0.85-3.83% monoterpenes in dry matter). These differences were maintained in individuals protected from browsing, suggesting genetically based variation in constitutive terpene production. In western redcedar, heavily browsed trees had significantly lower total monoterpene concentrations (1.69% dry matter) than lightly browsed trees (3.32% dry matter). One heavily browsed tree expressed no monoterpenes. No differences were found for diterpenes. In both species, the genotypes with extremely low monoterpene concentrations came from the same open-pollinated families.

CO vibration as a probe of ligand dissociation and transfer in myoglobin.

We report femtosecond visible pump, midinfrared probe, spectrally integrated experiments resolving the dynamics of CO in myoglobin upon photodissociation. Our results show a progressive change in absorption strength of the CO vibrational transition during its transfer from the heme to the docking site, whereas the vibrational frequency change is faster than our time resolution. A phenomenological model gives good qualitative agreement with our data for a time constant of 400 fs for the change in oscillator strength. Density-functional calculations demonstrate that indeed vibrational frequency and absorption strength are not linearly coupled and that the absorption strength varies in a slower manner due to charge transfer from the heme iron to CO.