Cerebellum in timing control: Evidence from contingent negative variation after cerebellar tDCS

Background and aims Timing control is defined as the ability to quantify time. The temporal estimation of supra-seconds range is generally seen as a conscious cognitive process, while the sub-seconds range is a more automatic cognitive process. It is accepted that cerebellum contributes to temporal processing, but its function is still debated. The aim of this research was to better explore the role of cerebellum in timing control. We transitorily inhibited cerebellar activity and studied the effects on CNV components in healthy subjects. Methods Sixteen healthy subjects underwent a S1-S2 duration discrimination motor task, prior and after cathodal and sham cerebellar tDCS, in two separate sessions. In S1-S2 task they had to judge whether the duration of a probe interval trial was shorter (Short-ISI-trial:800 ms), longer (long-ISI-trail:1600 ms), or equal to the Target interval of 1200 ms. For each interval trial for both tDCS sessions, we measured: total and W2-CNV areas, the RTs of correct responses and the absolute number of errors prior and after tDCS. Results After cathodal tDCS a significant reduction in total-CNV and W2-CNV amplitudes selectively emerged for Short (p < 0.001; p = 0.003 respectively) and Target-ISI-trial (total-CNV: p < 0.001; W2-CNV:p = 0.003); similarly, a significant higher number of errors emerged for Short (p = 0.004) and Target-ISI-trial (p = 0.07) alone. No differences were detected for Longer-ISI-trials and after sham stimulation. Conclusions These data indicate that cerebellar inhibition selectively altered the ability to make time estimations for second and sub-second intervals. We speculate that cerebellum regulates the attentional mechanisms of automatic timing control by making predictions of interval timing

Intra-articular injection of vitamin A: a rabbit model to study osteoarthrosis

An experimental model of osteoarthrosis (OA) induced by injection of vitamin A in knees of rabbits is presented.  This model represents a modification and improvement of a preexisting one (Boni et al., 1977;  Benazzo et al., 1982) based on a higher number of vitamin A injections. In our model, two vitamin A injections  were sufficient to induce OA without exposure of the subchondral bone. The advantages of this model  are: 1) the maintaining of articular cartilage could make the experimental joints suitable to test the reparative  efficiency of candidate intra-articular pharmacological treatments, 2) animal stress and the risk of  infections are strongly reduced in compliance with European legislation on laboratory animal welfare.

p27 and Skp2 immunoreactivity and its clinical significance with endocrine and chemo-endocrine treatments in node-negative early breast cancer

Background: Low p27 and high Skp2 immunoreactivity are associated with a poor prognosis and other poor prognostic features including resistant phenotypes and antiestrogen drug resistance. We investigated these proteins in two International Breast Cancer Study Group trials studying node-negative early breast cancer. Patients and methods: Trial VIII compared chemotherapy followed by goserelin with either modality alone in premenopausal patients. Trial IX compared chemotherapy followed by tamoxifen with tamoxifen alone in postmenopausal patients. Central Pathology Office assessed p27 and Skp2 expression in the primary tumor by immunohistochemistry among 1631 (60%) trial patients. Results: p27 and Skp2 were inversely related; 13% of tumors expressed low p27 and high Skp2. Low p27 and high Skp2 were associated with unfavorable prognostic factors including larger size and higher grade tumors, absence of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2 overexpression and high Ki-67 (each P < 0.05). Low p27 and high Skp2 were not associated with disease-free survival (P = 0.42 and P = 0.48, respectively). The relative effects of chemo-endocrine versus endocrine therapy were similar regardless of p27 or Skp2. Conclusions: We confirm the association of low p27 and high Skp2 with other poor prognostic features, but found no predictive or prognostic value, and therefore do not recommend routine determination of p27 and Skp2 for node-negative breast cance

The need to research refractory breathlessness

High-quality research is needed to improve quality of life for people with chronic refractory breathlessness in COP

Combining Nitrous Oxide with Carbon Dioxide Decreases the Time to Loss of Consciousness during Euthanasia in Mice — Refinement of Animal Welfare?

Carbon dioxide (CO2) is the most commonly used euthanasia agent for rodents despite potentially causing pain and distress. Nitrous oxide is used in man to speed induction of anaesthesia with volatile anaesthetics, via a mechanism referred to as the “second gas” effect. We therefore evaluated the addition of Nitrous Oxide (N2O) to a rising CO2 concentration could be used as a welfare refinement of the euthanasia process in mice, by shortening the duration of conscious exposure to CO2. Firstly, to assess the effect of N2O on the induction of anaesthesia in mice, 12 female C57Bl/6 mice were anaesthetized in a crossover protocol with the following combinations: Isoflurane (5%)+O2 (95%); Isoflurane (5%)+N2O (75%)+O2 (25%) and N2O (75%)+O2 (25%) with a total flow rate of 3l/min (into a 7l induction chamber). The addition of N2O to isoflurane reduced the time to loss of the righting reflex by 17.6%. Secondly, 18 C57Bl/6 and 18 CD1 mice were individually euthanized by gradually filling the induction chamber with either: CO2 (20% of the chamber volume.min−1); CO2+N2O (20 and 60% of the chamber volume.min−1 respectively); or CO2+Nitrogen (N2) (20 and 60% of the chamber volume.min−1). Arterial partial pressure (Pa) of O2 and CO2 were measured as well as blood pH and lactate. When compared to the gradually rising CO2 euthanasia, addition of a high concentration of N2O to CO2 lowered the time to loss of righting reflex by 10.3% (P<0.001), lead to a lower PaO2 (12.55±3.67 mmHg, P<0.001), a higher lactataemia (4.64±1.04 mmol.l−1, P = 0.026), without any behaviour indicative of distress. Nitrous oxide reduces the time of conscious exposure to gradually rising CO2 during euthanasia and hence may reduce the duration of any stress or distress to which mice are exposed during euthanasia