Unexplained gonad alterations in whitefish (Coregonus spp.) from Lake Thun, Switzerland: levels of persistent organic pollutants in different morphs

Since 2000, a surprisingly high number of macroscopical gonad alterations has been reported in whitefish (Coregonus spp.) from Lake Thun, Switzerland. This unique phenomenon is still unexplained and has received much public attention. As one possible trigger for these effects, the presence of persistent, bioaccumulative and toxic compounds acting as endocrine disruptors in the lake has been discussed. In this study, concentrations of selected persistent organic pollutants were examined in two morphs of whitefish from Lake Thun and their link to the observed abnormalities was investigated. Analyzed compound classes included polychlorinated biphenyls, polychlorinated dibenzo-p-dioxins and dibenzofurans, polychlorinated naphthalenes, polybrominated diphenyl ethers and hexabromocyclododecanes. The target substances were identified in all samples and concentrations of the analyzed compounds were highly correlated among each other. These correlations show that the analyzed substances have the same distribution pattern throughout the lake and that uptake, accumulation and elimination processes are similar. Significant differences in contaminant levels within the samples existed between the two analyzed morphs of whitefish, most likely due to different age, food patterns and growth rate. No difference in contaminant levels was observed between fish with abnormal gonads and fish with normal gonads, suggesting no causal link between the investigated lipophilic organohalogen compounds present in fish and the observed gonad abnormalities in whitefish from Lake Thun. A comparison to existing data shows that concentrations in Lake Thun whitefish are at the lower bound of contaminant levels in whitefish from Swiss lakes or from European waters.

Alterations of white matter integrity related to the season of birth in schizophrenia: a DTI study

In schizophrenia there is a consistent epidemiological finding of a birth excess in winter and spring. Season of birth is thought to act as a proxy indicator for harmful environmental factors during foetal maturation. There is evidence that prenatal exposure to harmful environmental factors may trigger pathologic processes in the neurodevelopment, which subsequently increase the risk of schizophrenia. Since brain white matter alterations have repeatedly been found in schizophrenia, the objective of this study was to investigate whether white matter integrity was related to the season of birth in patients with schizophrenia. Thirty-four patients with schizophrenia and 33 healthy controls underwent diffusion tensor imaging. Differences in the fractional anisotropy maps of schizophrenia patients and healthy controls born in different seasons were analysed with tract-based spatial statistics. A significant main effect of season of birth and an interaction of group and season of birth showed that patients born in summer had significantly lower fractional anisotropy in widespread white matter regions than those born in the remainder of the year. Additionally, later age of schizophrenia onset was found in patients born in winter months. The current findings indicate a relationship of season of birth and white matter alterations in schizophrenia and consequently support the neurodevelopmental hypothesis of early pathological mechanisms in schizophrenia.

White matter microstructure alterations of the medial forebrain bundle in melancholic depression

BACKGROUND The medial forebrain bundle (MFB) is a key structure of the reward system and connects the ventral tegmental area (VTA) with the nucleus accumbens (NAcc), the medial and lateral orbitofrontal cortex (mOFC, lOFC) and the dorsolateral prefrontal cortex (dlPFC). Previous diffusion tensor imaging (DTI) studies in major depressive disorder point to white matter alterations of regions which may be incorporated in the MFB. Therefore, it was the aim of our study to probe white matter integrity of the MFB using a DTI-based probabilistic fibre tracking approach. METHODS 22 patients with major depressive disorder (MDD) (12 melancholic-MDD patients, 10 non-melancholic-MDD patients) and 21 healthy controls underwent DTI scans. We used a bilateral probabilistic fibre tracking approach to extract pathways between the VTA and NACC, mOFC, lOFC, dlPFC respectively. Mean fractional anisotropy (FA) values were used to compare structural connectivity between groups. RESULTS Mean-FA did not differ between healthy controls and all MDD patients. Compared to healthy controls melancholic MDD-patients had reduced mean-FA in right VTA-lOFC and VTA-dlPFC connections. Furthermore, melancholic-MDD patients had lower mean-FA than non-melancholic MDD-patients in the right VTA-lOFC connection. Mean-FA of these pathways correlated negatively with depression scale rating scores. LIMITATIONS Due to the small sample size and heterogeneous age group comparisons between melancholic and non-melancholic MDD-patients should be regarded as preliminary. CONCLUSIONS Our results suggest that the melancholic subtype of MDD is characterized by white matter microstructure alterations of the MFB. White matter microstructure is associated with both depression severity and anhedonia.

Ridge alterations post-extraction in the esthetic zone: a 3D analysis with CBCT

Dimensional alterations of the facial bone wall following tooth extractions in the esthetic zone have a profound effect on treatment outcomes. This prospective study in 39 patients is the first to investigate three-dimensional (3D) alterations of facial bone in the esthetic zone during the initial 8 wks following flapless tooth extraction. A novel 3D analysis was carried out, based on 2 consecutive cone beam computed tomographies (CBCTs). A risk zone for significant bone resorption was identified in central areas, whereas proximal areas yielded only minor changes. Correlation analysis identified a facial bone wall thickness of ≤ 1 mm as a critical factor associated with the extent of bone resorption. Thin-wall phenotypes displayed pronounced vertical bone resorption, with a median bone loss of 7.5 mm, as compared with thick-wall phenotypes, which decreased by only 1.1 mm. For the first time, 3D analysis has allowed for documentation of dimensional alterations of the facial bone wall in the esthetic zone of humans following extraction. It also characterized a risk zone prone to pronounced bone resorption in thin-wall phenotypes. Vertical bone loss was 3.5 times more severe than findings reported in the existing literature.

Influence of platform switching on bone-level alterations: a three-year randomized clinical trial

The concept of platform switching has been introduced to implant dentistry based on clinical observations of reduced peri-implant crestal bone loss. However, published data are controversial, and most studies are limited to 12 months. The aim of the present randomized clinical trial was to test the hypothesis that platform switching has a positive impact on crestal bone-level changes after 3 years. Two implants with a diameter of 4 mm were inserted crestally in the posterior mandible of 25 patients. The intraindividual allocation of platform switching (3.3-mm platform) and the standard implant (4-mm platform) was randomized. After 3 months of submerged healing, single-tooth crowns were cemented. Patients were followed up at short intervals for monitoring of healing and oral hygiene. Statistical analysis for the influence of time and platform type on bone levels employed the Brunner-Langer model. At 3 years, the mean radiographic peri-implant bone loss was 0.69 ± 0.43 mm (platform switching) and 0.74 ± 0.57 mm (standard platform). The mean intraindividual difference was 0.05 ± 0.58 mm (95% confidence interval: -0.19, 0.29). Crestal bone-level alteration depended on time (p < .001) but not on platform type (p = .363). The present randomized clinical trial could not confirm the hypothesis of a reduced peri-implant crestal bone loss, when implants had been restored according to the concept of platform switching.

Bilateral posterior ischaemic optic neuropathy after severe diabetic ketoacidosis, cardiopulmonary resuscitation and respiratory failure

A 44-year-old male European with type I diabetes mellitus fell into diabetic ketoacidosis. In the emergency room, he developed an episode of asystole and respiratory failure requiring one cycle of cardiopulmonary resuscitation and extracorporeal membrane oxygenation (ECMO). Waking up 7 days later, he presented a bilateral complete loss of vision. Ophthalmological examination including funduscopy on days 1 and 10, after extubation, showed bilateral large round pupils non-reactive to light and a normal fundus. Neuroimaging studies, including MRI and MRA of the brain, were all within normal limits. A lumbar puncture and comprehensive serological testing excluded an infectious or rheumatic cause. An empirical high-dose intravenous steroid treatment administered for 5 days had no effect on his vision. His eye examination at 1.5 months follow-up showed a normal fundus except for progressive bilateral optic nerve disc pallor, which pointed towards the diagnosis of a posterior ischaemic optic neuropathy.

Impact of a stress coping strategy on perceived stress levels and performance during a simulated cardiopulmonary resuscitation: a randomized controlled trial

Background Cardiopulmonary resuscitation (CPR) causes significant stress, which may cause deficiencies in attention and increase distractibility. This may lead to misjudgements of priorities and delays in CPR performance, which may further increase mental stress (vicious cycle). This study assessed the impact of a task-focusing strategy on perceived stress levels and performance during a simulated CPR scenario. Methods This prospective, randomized-controlled trial was conducted at the simulator-center of the University Hospital Basel, Switzerland. A total of 124 volunteer medical students were randomized to receive a 10 minute instruction to cope with stress by loudly posing two taskfocusing questions (“what is the patient’s condition?”, “what immediate action is needed?”) when feeling overwhelmed by stress (intervention group) or a control group. The primary outcome was the perceived levels of stress and feeling overwhelmed (stress/overload); secondary outcomes were hands-on time, time to start CPR and number of leadership statements. Results Participants in the intervention group reported significantly less stress/overload levels compared to the control group (mean difference: -0.6 (95%CI −1.3, -0.1), p=0.04). Higher stress/overload was associated with less hands-on time. Leadership statements did not differ between groups, but the number of leadership statements did relate to performance. Hands-on time was longer in the intervention- group, but the difference was not statistically different (difference 5.5 (95%CI −3.1, 14.2), p=0.2); there were no differences in time to start CPR (difference −1.4 (95%CI −8.4, 5.7), p=0.71). Conclusions A brief stress-coping strategy moderately decreased perceived stress without significantly affecting performance in a simulated CPR. Further studies should investigate more intense interventions for reducing stress.

ABC versus CAB for cardiopulmonary resuscitation: a prospective, randomized simulator-based trial

QUESTIONS UNDER STUDY: After years of advocating ABC (Airway-Breathing-Circulation), current guidelines of cardiopulmonary resuscitation (CPR) recommend CAB (Circulation-Airway-Breathing). This trial compared ABC with CAB as initial approach to CPR from the arrival of rescuers until the completion of the first resuscitation cycle. METHODS: 108 teams, consisting of two physicians each, were randomized to receive a graphical display of either the ABC algorithm or the CAB algorithm. Subsequently teams had to treat a simulated cardiac arrest. Data analysis was performed using video recordings obtained during simulations. The primary endpoint was the time to completion of the first resuscitation cycle of 30 compressions and two ventilations. RESULTS: The time to execution of the first resuscitation measure was 32 ± 12 seconds in ABC teams and 25 ± 10 seconds in CAB teams (P = 0.002). 18/53 ABC teams (34%) and none of the 55 CAB teams (P = 0.006) applied more than the recommended two initial rescue breaths which caused a longer duration of the first cycle of 30 compressions and two ventilations in ABC teams (31 ± 13 vs.23 ± 6 sec; P = 0.001). Overall, the time to completion of the first resuscitation cycle was longer in ABC teams (63 ± 17 vs. 48 ± 10 sec; P <0.0001).CONCLUSIONS: This randomized controlled trial found CAB superior to ABC with an earlier start of CPR and a shorter time to completion of the first 30:2 resuscitation cycle. These findings endorse the change from ABC to CAB in international resuscitation guidelines.

Angiopoietin 2 mediates microvascular and hemodynamic alterations in sepsis

Septic shock is characterized by increased vascular permeability and hypotension despite increased cardiac output. Numerous vasoactive cytokines are upregulated during sepsis, including angiopoietin 2 (ANG2), which increases vascular permeability. Here we report that mice engineered to inducibly overexpress ANG2 in the endothelium developed sepsis-like hemodynamic alterations, including systemic hypotension, increased cardiac output, and dilatory cardiomyopathy. Conversely, mice with cardiomyocyte-restricted ANG2 overexpression failed to develop hemodynamic alterations. Interestingly, the hemodynamic alterations associated with endothelial-specific overexpression of ANG2 and the loss of capillary-associated pericytes were reversed by intravenous injections of adeno-associated viruses (AAVs) transducing cDNA for angiopoietin 1, a TIE2 ligand that antagonizes ANG2, or AAVs encoding PDGFB, a chemoattractant for pericytes. To confirm the role of ANG2 in sepsis, we i.p. injected LPS into C57BL/6J mice, which rapidly developed hypotension, acute pericyte loss, and increased vascular permeability. Importantly, ANG2 antibody treatment attenuated LPS-induced hemodynamic alterations and reduced the mortality rate at 36 hours from 95% to 61%. These data indicate that ANG2-mediated microvascular disintegration contributes to septic shock and that inhibition of the ANG2/TIE2 interaction during sepsis is a potential therapeutic target.

The craniosacral progression of muscle development influences the emergence of neuromuscular junction alterations in a severe murine model for spinal muscular atrophy.

AIMS As 4-day-old mice of the severe spinal muscular atrophy (SMA) model (dying at 5-8 days) display pronounced neuromuscular changes in the diaphragm but not the soleus muscle, we wanted to gain more insight into the relationship between muscle development and the emergence of pathological changes and additionally to analyse intercostal muscles which are affected in human SMA. METHODS Structures of muscle fibres and neuromuscular junctions (NMJs) of the diaphragm, intercostal and calf muscles of prenatal (E21) and postnatal (P0 and P4) healthy and SMA mice were analysed by light and transmission electron microscopy. NMJ innervation was studied by whole mount immunofluorescence in diaphragms of P4 mice. RESULTS During this period, the investigated muscles still show a significant neck-to-tail developmental gradient. The diaphragm and calf muscles are most and least advanced, respectively, with respect to muscle fibre fusion and differentiation. The number and depth of subsynaptic folds increases, and perisynaptic Schwann cells (PSCs) acquire a basal lamina on their outer surface. Subsynaptic folds are connected to an extensive network of tubules and beaded caveolae, reminiscent of the T system in adult muscle. Interestingly, intercostal muscles from P4 SMA mice show weaker pathological involvement (that is, vacuolization of PSCs and perineurial cells) than those previously described by us for the diaphragm, whereas calf muscles show no pathological changes. CONCLUSION SMA-related alterations appear to occur only when the muscles have reached a certain developmental maturity. Moreover, glial cells, in particular PSCs, play an important role in SMA pathogenesis.

Metabolomics reveals trichloroacetate as a major contributor to trichloroethylene-induced metabolic alterations in mouse urine and serum

Trichloroethylene (TCE)-induced liver toxicity and carcinogenesis is believed to be mediated in part by activation of the peroxisome proliferator-activated receptor α (PPARα). However, the contribution of the two TCE metabolites, dichloroacetate (DCA) and trichloroacetate (TCA) to the toxicity of TCE, remains unclear. The aim of the present study was to determine the metabolite profiles in serum and urine upon exposure of mice to TCE, to aid in determining the metabolic response to TCE exposure and the contribution of DCA and TCA to TCE toxicity. C57BL/6 mice were administered TCE, TCA, or DCA, and urine and serum subjected to ultra-performance liquid chromatography coupled with electrospray ionization quadrupole time-of-flight mass spectrometry (UPLC-ESI-QTOFMS)-based global metabolomics analysis. The ions were identified through searching metabolomics databases and by comparison with authentic standards, and quantitated using multiple reactions monitoring. Quantitative polymerase chain reaction of mRNA, biochemical analysis, and liver histology were also performed. TCE exposure resulted in a decrease in urine of metabolites involved in fatty acid metabolism, resulting from altered expression of PPARα target genes. TCE treatment also induced altered phospholipid homeostasis in serum, as revealed by increased serum lysophosphatidylcholine 18:0 and 18:1, and phosphatidylcholine metabolites. TCA administration revealed similar metabolite profiles in urine and serum upon TCE exposure, which correlated with a more robust induction of PPARα target gene expression associated with TCA than DCA treatment. These data show the metabolic response to TCE exposure and demonstrate that TCA is the major contributor to TCE-induced metabolite alterations observed in urine and serum.

Cardiopulmonary performance testing using a robotics-assisted tilt table: Feasibility assessment in able-bodied subjects

BACKGROUND: Robotics-assisted tilt table technology was introduced for early rehabilitation of neurological patients. It provides cyclical stepping movement and physiological loading of the legs. The aim of the present study was to assess the feasibility of this type of device for peak cardiopulmonary performance testing using able-bodied subjects. METHODS: A robotics-assisted tilt table was augmented with force sensors in the thigh cuffs and a work rate estimation algorithm. A custom visual feedback system was employed to guide the subjects' work rate and to provide real time feedback of actual work rate. Feasibility assessment focused on: (i) implementation (technical feasibility), and (ii) responsiveness (was there a measurable, high-level cardiopulmonary reaction?). For responsiveness testing, each subject carried out an incremental exercise test to the limit of functional capacity with a work rate increment of 5 W/min in female subjects and 8 W/min in males. RESULTS: 11 able-bodied subjects were included (9 male, 2 female; age 29.6 ± 7.1 years: mean ± SD). Resting oxygen uptake (O_{2}) was 4.6 ± 0.7 mL/min/kg and O_{2}peak was 32.4 ± 5.1 mL/min/kg; this mean O_{2}peak was 81.1% of the predicted peak value for cycle ergometry. Peak heart rate (HRpeak) was 177.5 ± 9.7 beats/min; all subjects reached at least 85% of their predicted HRpeak value. Respiratory exchange ratio (RER) at O_{2}peak was 1.02 ± 0.07. Peak work rate) was 61.3 ± 15.1 W. All subjects reported a Borg CR10 value for exertion and leg fatigue of 7 or more. CONCLUSIONS: The robotics-assisted tilt table is deemed feasible for peak cardiopulmonary performance testing: the approach was found to be technically implementable and substantial cardiopulmonary responses were observed. Further testing in neurologically-impaired subjects is warranted.