A microfluidic device for quantitative investigation of zebrafish larvae’s rheotaxis

Zebrafish is a model organism for various sensory-motor biological studies. Rheotaxis, or the ability of zebrafish to orient and swim against the water stream, is a common behavior that involves multiple sensory-motor processes such as their lateral line and visual systems. Due to the lack of a controllable and easy-to-use assay, zebrafish rheotaxis at larval stages is not well-understood. In this paper, we report a microfluidic device that can be used to apply the flow stimulus precisely and repeatedly along the longitudinal axis of individual zebrafish larvae to study their coaxial rheotaxis. We quantified rheotaxis in terms of the response rate and location along the channel at various flow velocities (9.5–38 mm.sec^?1). The larvae effectively exhibited a similarly high rheotactic response at low and medium velocities (9.5 and 19 mm.sec^?1); however, at high velocity of 38 mm.sec^?1, despite sensing the flow, their rheotactic response decreased significantly. The flow velocity also affected the response location along the channel. At 9.5 mm.sec^?1, responses were distributed evenly along the channel length while, at 19 and 38 mm.sec^?1, the larvae demonstrated higher rheotaxis responses at the anterior and posterior ends of the channel, respectively. This result shows that although the response is similarly high at low and medium flow velocities, zebrafish larvae become more sensitive to the flow at medium velocity, demonstrating a modulated rheotactic behavior. Employing our device, further investigations can be conducted to study the sensory-motor systems involved in rheotaxis of zebrafish larvae and other fish species.     

Amyotrophic lateral sclerosis affects cortical and subcortical activity underlying motor inhibition and action monitoring

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder characterized by muscular atrophy, spasticity, and bulbar signs caused by loss of upper and lower motor neurons. Evidence suggests that ALS additionally affects other brain areas including premotor cortex and supplementary motor area. Here, we studied movement execution and inhibition in ALS patients using a stop‐signal paradigm and functional magnetic resonance imaging. Seventeen ALS patients and 17 age‐matched healthy controls performed a stop‐signal task that required responding with a button press to a right‐ or left‐pointing black arrow (go‐stimuli). In stop‐trials, a red arrow (stop‐stimulus) was presented shortly after the black arrow indicating to withhold the prepared movement. Patients had by trend higher reaction times in go‐trials but did not differ significantly in their inhibition performance. Patients showed stronger inhibition‐related activity in inferior, superior, and middle frontal gyri as well as in putamen and pallidum. Error‐related activity, conversely, was found to be stronger in healthy controls, particularly in the insula bilaterally. Patients also showed increased activity in the motor cortex during button presses. The results provide evidence for altered prefrontal and subcortical networks underlying motor execution, motor inhibition, and error monitoring in ALS. Hum Brain Mapp 36:2878–2889, 2015. © 2015 Wiley Periodicals, Inc.     

The Granuloma Response Controlling Cryptococcosis in Mice Depends on the Sphingosine Kinase 1–Sphingosine 1-Phosphate Pathway

Cryptococcus neoformans is a fungal pathogen that causes pulmonary infections, which may progress into life-threatening meningitis. In commonly used mouse models of C. neoformans infections, fungal cells are not contained in the lungs, resulting in dissemination to the brain. We have previously reported the generation of an engineered C. neoformans strain (C. neoformans Δgcs1) which can be contained in lung granulomas in the mouse model and have shown that granuloma formation is dependent upon the enzyme sphingosine kinase 1 (SK1) and its product, sphingosine 1-phosphate (S1P). In this study, we have used four mouse models, CBA/J and C57BL6/J (both immunocompetent), Tgε26 (an isogenic strain of strain CBA/J lacking T and NK cells), and SK^−/− (an isogenic strain of strain C57BL6/J lacking SK1), to investigate how the granulomatous response and SK1-S1P pathway are interrelated during C. neoformans infections. S1P and monocyte chemotactic protein-1 (MCP-1) levels were significantly elevated in the bronchoalveolar lavage fluid of all mice infected with C. neoformans Δgcs1 but not in mice infected with the C. neoformans wild type. SK1^−/− mice did not show elevated levels of S1P or MCP-1. Primary neutrophils isolated from SK1^−/− mice showed impaired antifungal activity that could be restored by the addition of extracellular S1P. In addition, high levels of tumor necrosis factor alpha were found in the mice infected with C. neoformans Δgcs1 in comparison to the levels found in mice infected with the C. neoformans wild type, and their levels were also dependent on the SK1-S1P pathway. Taken together, these results suggest that the SK1-S1P pathway promotes host defense against C. neoformans infections by regulating cytokine levels, promoting extracellular killing by phagocytes, and generating a granulomatous response.     

Medullary thyroid carcinoma associated with hyperthyroidism: a case report and review of the literature.

Thyroid cancer is occasionally associated with hyperthyroidism. Papillary thyroid carcinoma is the most frequently reported histologic type followed by follicular thyroid carcinoma. Medullary thyroid carcinoma (MTC) has been rarely described in association with Graves' disease or other forms of hyperthyroidism. To our knowledge, only 14 cases have been described in which MTC was associated with hyperthyroidism. We report a 70-year-old male who had a clinically significant MTC discovered in the course of diagnostic work-up for hyperthyroidism. We also summarize the clinical features of the other 14 reported cases.     

Rescue angioplasty or repeat fibrinolysis after failed fibrinolytic therapy for ST-segment myocardial infarction: a meta-analysis of randomized trials.

OBJECTIVES: We sought to best estimate the benefits and risks associated with rescue percutaneous coronary intervention (PCI) and repeat fibrinolytic therapy as compared with conservative management in patients with failed fibrinolytic therapy for ST-segment myocardial infarction (STEMI). BACKGROUND: Fibrinolytic therapy is the most common treatment for STEMI; however, the best therapy in patients who fail to achieve reperfusion after fibrinolytic therapy remains uncertain. METHODS: We performed a meta-analysis of randomized trials using a fixed-effects model. We included 8 trials enrolling 1,177 patients with follow-up duration ranging from hospital discharge to 6 months. RESULTS: Rescue PCI was associated with no significant reduction in all-cause mortality (relative risk [RR] 0.69; 95% confidence interval [CI] 0.46 to 1.05), but was associated with significant risk reductions in heart failure (RR 0.73; 95% CI 0.54 to 1.00) and reinfarction (RR 0.58; 95% CI 0.35 to 0.97) when compared with conservative treatment. Rescue PCI was associated with an increased risk of stroke (RR 4.98; 95% CI 1.10 to 22.5) and minor bleeding (RR 4.58; 95% CI 2.46 to 8.55). Repeat fibrinolytic therapy was not associated with significant improvements in all-cause mortality (RR 0.68; 95% CI 0.41 to 1.14) or reinfarction (RR 1.79; 95% CI 0.92 to 3.48), but was associated with an increased risk for minor bleeding (RR 1.84; 95% CI 1.06 to 3.18). CONCLUSIONS: Rescue PCI is associated with improved clinical outcomes for STEMI patients after failed fibrinolytic therapy, but these benefits must be interpreted in the context of potential risks. On the other hand, repeat fibrinolytic therapy is not associated with significant clinical improvement and may be associated with increased harm.     

Oxygen - a limiting factor for brain recovery

Effective brain metabolism is highly dependent on a narrow therapeutic window of oxygen. In major insults to the brain (e.g., intracerebral hemorrhage), a slight decrease in oxygen supply, as occurs in a hypobaric environment at high altitude, has devastating effects on the injured brain tissue. Conversely, increasing brain oxygenation, by the use of hyperbaric oxygen therapy, can improve brain metabolism and its dependent regenerative processes.     

The role of previously unmeasured organic acids in the pathogenesis of severe malaria

IntroductionSevere falciparum malaria is commonly complicated by metabolic acidosis. Together with lactic acid (LA), other previously unmeasured acids have been implicated in the pathogenesis of falciparum malaria.MethodsIn this prospective study, we characterised organic acids in adults with severe falciparum malaria in India and Bangladesh. Liquid chromatography-mass spectrometry was used to measure organic acids in plasma and urine. Patients were followed until recovery or death.ResultsPatients with severe malaria (n=138), uncomplicated malaria (n=102), sepsis (n=32) and febrile encephalopathy (n=35) were included. Strong ion gap (mean±SD) was elevated in severe malaria (8.2 mEq/L±4.5) and severe sepsis (8.6 mEq/L±7.7) compared with uncomplicated malaria (6.0 mEq/L±5.1) and encephalopathy (6.6 mEq/L±4.7). Compared with uncomplicated malaria, severe malaria was characterised by elevated plasma LA, hydroxyphenyllactic acid (HPLA), α-hydroxybutyric acid and β-hydroxybutyric acid (all P<0.05). In urine, concentrations of methylmalonic, ethylmalonic and α-ketoglutaric acids were also elevated. Multivariate logistic regression showed that plasma HPLA was a strong independent predictor of death (odds ratio [OR] 3.5, 95 % confidence interval [CI] 1.6–7.5, P=0.001), comparable to LA (OR 3.5, 95 % CI 1.5–7.8, P=0.003) (combined area under the receiver operating characteristic curve 0.81).ConclusionsNewly identified acids, in addition to LA, are elevated in patients with severe malaria and are highly predictive of fatal outcome. Further characterisation of their sources and metabolic pathways is now needed.

Electronic supplementary material

The online version of this article (doi:10.1186/s13054-015-1023-5) contains supplementary material, which is available to authorized users.