Inbred SJL mice recapitulate human resistance to Cryptococcus infection due to differential immune activation.

IMPORTANCE: Cryptococcosis studies often utilize the common C57BL/6J mouse model. Unfortunately, infection in these mice fails to replicate the basic course of human disease, particularly hampering immunological studies. This work demonstrates that SJL/J mice can recapitulate human infection better than other mouse strains. The immunological response to Cryptococcus infection in SJL/J mice was markedly different from C57BL/6J and much more productive in combating this infection. Characterization of infected mice demonstrated strain-specific genetic linkage and differential regulation of multiple important immune-relevant genes in response to Cryptococcus infection. While our results validate many of the previously identified immunological features of cryptococcosis, we also demonstrate limitations from previous mouse models as they may be less translatable to human disease. We concluded that SJL/J mice more faithfully recapitulate human cryptococcosis serving as an exciting new animal model for immunological and genetic studies.

Maintenance therapy with decitabine in younger adults with acute myeloid leukemia in first remission: a phase 2 Cancer and Leukemia Group B Study (CALGB 10503).

In this prospective phase 2 clinical trial conducted by Cancer and Leukemia Group B (CALGB, now the Alliance), we studied decitabine as maintenance therapy for younger adults with acute myeloid leukemia (AML) who remained in first complete remission (CR1) following intensive induction and consolidation. Given that decitabine is clinically active in AML and with hypomethylating activity distinct from cytotoxic chemotherapy, we hypothesized that 1 year of maintenance therapy would improve disease-free survival (DFS) for AML patients <60 years, who did not receive allogeneic stem cell transplantation in CR1. After blood count recovery from final consolidation, patients received decitabine at 20 mg/m2 intravenously daily for 4-5 days, every 6 weeks for eight cycles. One hundred and thirty-four patients received decitabine and 85 (63%) had favorable risk AML. The median number of cycles received was 7 (range: 1-8) and the primary reason for discontinuation was relapse. DFS at 1 year and 3 years was 79% and 54%, respectively. These results are similar to the outcomes in the historical control comprising similar patients treated on recent CALGB trials. Thus, maintenance with decitabine provided no benefit overall. Standard use of decitabine maintenance in younger AML patients in CR1 is not warranted. This trial was registered at www.clinicaltrials.gov as NCT00416598.

CH3NH3PbI3 perovskite single crystals: surface photophysics and their interaction with the environment.

Here we identify structural inhomogeneity on a micrometer scale across the surface of a CH3NH3PbI3 perovskite single crystal. At the crystal edge a local distortion of the crystal lattice is responsible for a widening of the optical bandgap and faster photo-carrier recombination. These effects are inherently present at the edge of the crystal, and further enhanced upon water intercalation, as a preliminary step in the hydration of the perovskite material.

Auditory afterimage: tonotopic representation in the auditory cortex.

The auditory afterimage is a sensation which occurs for several seconds after the exciting acoustic signal has been switched off, and which roughly corresponds to the inverse of the spectrum of the exciting signal. In contrast to the well-known visual afterimage, the physiological mechanism generating the auditory afterimage has been questionable so far. Neuromagnetic source imaging revealed that the source of cortical neural activity which coincides with the sensation of the afterimage is located in the auditory cortex and exhibits a tonotopic organization similar to that of the sustained response which occurs during continuous presentation of an acoustic stimulus. It is concluded that the neural processes leading to the generation of the two phenomena -sustained response and auditory afterimage - are similar.

Tinnitus and event-related activity of the auditory cortex.

A neuromagnetic study in tinnitus patients and normal-hearing controls was performed with a modified contingent negative variation (CNV) paradigm. While the warning stimulus S1 was a tone burst at an intensity well above threshold, the imperative stimulus S2 was presented at a near threshold intensity because, in the majority of cases, the perceived loudness of tinnitus is very close to the threshold for a pure tone of the same frequency. Subjects had to respond to S2 by pressing a button until its offset was detected. In this case, instead of the usual sudden cut-off of the CNV after the perception of S2, a slow negative deflection develops, the post-imperative negative variation (PINV). Its initial portion probably indicates the development of a second initial CNV because the subject had to attend also to the offset of S2. The neuromagnetic data were analysed both in the time domain and in the frequency domain (short-time spectral analysis of the classical EEG bands). The time domain waveform as well as the spectrotemporal patterns of the MEG bands exhibited deviations from the normal pattern in several tinnitus subgroups, depending on the characteristics of tinnitus (tonal vs. noisiform, monaural vs. binaural) and on the stimulation conditions (tinnitus side vs. non-tinnitus side).

Neurophysiological correlate of the auditory after-image ('Zwicker tone').

The 'Zwicker tone' (ZT) is an auditory after-image that can be evoked most effectively when a band-suppressed noise (relative width of gap 1/3 octave) presented for a certain period of time has been switched off. The sensation of this purely monaural phenomenon is that of a pure tone with a frequency corresponding to the center frequency of the gap and an equivalent level of 10-15 dB above auditory threshold. The sensation decays gradually; it may last as long as 10 s depending on how long the evoking noise was presented. The search for a physiological correlate has been futile so far, probably because the search was confined to more peripheral levels of the auditory system (inferior colliculus). A neuromagnetic study was performed in normal-hearing subjects in order to look for a neurophysiological correlate of the ZT in the auditory cortex. With a stimulation paradigm especially designed for this study, we have been able to isolate poststimulus activity which appears to be related to the ZT and which originates in the supratemporal auditory cortex. It is a sustained neuromagnetic activity that shows a clear-cut dipolar field distribution, and it appears that this activity has certain similarities with the tone-evoked auditory sustained response. The hypothesis is put forward that during the sensation of the ZT a process takes place in the auditory cortex which is similar to that underlying the sustained response, and which gives rise to the sensation of the ZT. In contrast to the sustained response, however, which is due to neural activity evoked by an external acoustic stimulus, the sustained activity associated with the ZT is due to a temporary absolute or relative reduction of neural activity originating from those regions in which the ZT exciting stimulus caused an adaptation. These differences in neural activity cannot be distinguished by the auditory system from a corresponding external acoustic signal. Preliminary studies in patients suffering from tonal tinnitus yielded results which exhibit a certain similarity with those obtained in the ZT experiment.

Electrocardiographic studies of developing rodents exposed in utero to trypan blue.

Techniques, based on computer-assisted analyses of ensembled ECG waveforms, have been developed in this laboratory to serve as a screening procedure for potentially cardiotoxic substances. This procedure was tested on fetal and neonatal rats exposed in utero to two levels of trypan blue, a known cardiovascular teratogen. The offspring of the treated animals exhibited decreased viability, as well as significant levels of both cardiac and noncardiac malformations. Qualitative assessment of ECG irregularities demonstrated an increased number of abnormalities in the treated groups. Correlations were also obtained between observed morphological defects and ECG irregularities in the trypan blue treated groups.