Valganciclovir as preemptive therapy for cytomegalovirus in cytomegalovirus-seronegative liver transplant recipients of cytomegalovirus-seropositive donor allografts.

The efficacy of valganciclovir as preemptive therapy for the prevention of cytomegalovirus (CMV) disease and its impact on indirect sequelae of CMV were assessed in recipient-negative/donor-positive (R-/D+) liver transplant recipients. Of 187 consecutive liver transplant recipients at our institution since July 2001, 36 (19.2%) belonged to the R-/D+ group. Surveillance tests for CMV were performed on all patients at weeks 2, 4, 6, 8, 10,12, and 16. In all, 27 patients with asymptomatic viremia received preemptive therapy with valganciclovir. At a total follow-up of 62.8 patient years (median: 19 months, range: 3 months to 5.6 years), no episodes of CMV disease were documented in these patients. The incidence of rejection, retransplantation, and bacterial or fungal infections and the probability of survival did not differ for R-/D+ patients and all non-R-/D+ patients treated preemptively with valganciclovir (P > 0.20 for all variables). Thus, preemptive therapy with valganciclovir in R-/D+ patients was not associated with CMV disease during the period of surveillance monitoring or at anytime thereafter (late-onset CMV disease). The indirect outcomes with the use of valganciclovir in R-/D+ patients were comparable to the outcomes of other subgroups of liver transplant recipients receiving preemptive therapy.     

Analysis of renal cell transformation following exposure to trichloroethene in vivo and its metabolite S-(dichlorovinyl)-L-cysteine in vitro

Trichloroethene (TCE) is classified as a potential human carcinogen although there is a significant debate regarding the mechanism of TCE induced renal tumor formation. This controversy stems in part from the extremely high doses of TCE required to induce renal tumors and the potential contribution of the associated nephrotoxicity to tumorigenesis. We have used Eker rats, which are uniquely susceptible to renal carcinogens, to determine if exposures to TCE in vivo or exposure to its metabolite S-(dichlorovinyl)-L-cysteine (DCVC) in vitro can transform kidney epithelial cells in the absence of cytotoxicity. Treatment with TCE (0, 100, 250, 500, 1000 mg/kg bw by gavage, 5 days a week) for 13 weeks resulted in a significant increase in cell proliferation in kidney tubule cells, but did not enhance formation of preneoplastic lesions or tumor incidence in Eker rat kidneys as compared to controls. In vitro, concentrations of DCVC, which reduced cell survival to 50%, were able to transform rat kidney epithelial cells. However, no carcinogen-specific mutations were identified in the VHL or Tsc-2 tumor suppressor genes in the transformants. Taken together, the inability of TCE to enhance formation of preneoplastic changes or neoplasia and the absence of carcinogen-specific alteration of genes accepted to be critical for renal tumor development suggest that TCE mediated carcinogenicity may occur secondary to continuous toxic injury and sustained regenerative cell proliferation.     

MEG biomarker of Alzheimer's disease: Absence of a prefrontal generator during auditory sensory gating

Magnetoencephalography (MEG), a direct measure of neuronal activity, is an underexplored tool in the search for biomarkers of Alzheimer's disease (AD). In this study, we used MEG source estimates of auditory gating generators, nonlinear correlations with neuropsychological results, and multivariate analyses to examine the sensitivity and specificity of gating topology modulation to detect AD. Our results demonstrated the use of MEG localization of a medial prefrontal (mPFC) gating generator as a discrete (binary) detector of AD at the individual level and resulted in recategorizing the participant categories in: (1) controls with mPFC generator localized in response to both the standard and deviant tones; (2) a possible preclinical stage of AD participants (a lower functioning group of controls) in which mPFC activation was localized to the deviant tone only; and (3) symptomatic AD in which mPFC activation was not localized to either the deviant or standard tones. This approach showed a large effect size (0.9) and high accuracy, sensitivity, and specificity (100%) in identifying symptomatic AD patients within a limited research sample. The present results demonstrate high potential of mPFC activation as a noninvasive biomarker of AD pathology during putative preclinical and clinical stages. Hum Brain Mapp 38:5180–5194, 2017. © 2017 Wiley Periodicals, Inc.     

Age-related differences in the functional connectivity of the hippocampus during memory encoding

The purpose of the current experiment was to examine the functional connectivity of the hippocampus during encoding in young and old adults, and the way in which this connectivity was related to recognition performance. Functional connectivity was defined as the correlation between activity in the hippocampus and activity in the rest of the brain, as measured by neuroimaging. During encoding of words and pictures of objects in young adults, hippocampal activity was correlated with activity in the ventral prefrontal and extrastriate regions, and increased activity in all these regions was associated with better recognition. In contrast, older adults showed correlations between hippocampal activity and the dorsolateral prefrontal and parietal regions, and positive correlations between activity in these regions and better memory performance. This ventral/dorsal distinction suggests a shift in the cognitive resources used with age from more perceptually based processes to those involved in executive and organizational functions. The results of this study provide evidence that aging is associated with alterations in hippocampal function, including how it is functionally connected with prefrontal cortex, and that these alterations have an impact on memory performance.     

Mechanisms underlying phase lag between systemic arterial blood pressure and cerebral blood flow velocity

To explore the mechanisms underlying the phase lag between oscillations in arterial blood pressure (ABP) and cerebral blood flow velocity (CBFV), ABP and CBFV signals were recorded noninvasively from normal volunteers who lay quietly in a supine position. Mean ABP (MAP) and CBFV (MFV) were calculated beat-to-beat by means of integration. Cerebral vascular resistance (CVR) was calculated by dividing MAP with MFV. Frequency domain analysis of MAP, MFV and CVR signals revealed very-low frequency (VLF, 0.016-0.04 Hz), low-frequency (LF, 0.04-0.15 Hz), and high-frequency (HF, 0.15-0.4 Hz) components. The transfer phase of MAP-CVR coupling in the LF and HF range was frequency-dependent, which is equivalent to a time delay of 2 s. However, the transfer phase differed in the CVR-MFV coupling in that the phase was distributed around 180 degrees across the LF and HF ranges. Cross-correlation analysis revealed a positive relationship between MAP-CVR coupling, with MAP leading by 2 s, and a negative relationship between CVR-MFV coupling, with CVR leading by 0.3 s. We concluded that the phase lag between oscillations in ABP and CBFV was chiefly contributed to by the starting latency of cerebral autoregulation (i.e. cerebral vasomotion, revealed by MAP-CVR coupling). Moreover, the negative correlation of the CVR-MFV coupling could offer a different explanation for the physiologic significance of the phase lead of CBFV-ABP oscillations.     

Maternal body burdens of methylmercury impair survival skills of offspring in Atlantic croaker (Micropogonias undulatus)

Methylmercury (MeHg), the organic form of mercury, bioaccumulates easily through the food chain. Fish in high trophic levels can accumulate substantial levels of MeHg and transfer it to their developing eggs. Here, the effects of maternally derived MeHg on the planktonic larval stage of Atlantic croaker were investigated. Adult Atlantic croaker were fed MeHg-contaminated food at three levels: 0, 0.05, and 0.1 mg kg⁻¹ day⁻¹ for 1 month. Fish were then induced to spawn and MeHg levels in the eggs were measured (0.04–4.6 ng g⁻¹). Behavioral performance of exposed and control larvae was measured at four developmental stages: end of yolk absorption (yolk), end of oil absorption (oil), and 4 and 11 days after oil absorption (oil + 4 and oil + 11). Behaviors analyzed included survival skills related to foraging and predator evasion: routine behavior (rate of travel, active swimming speed, net-to-gross displacement ratio, and activity) and startle response to a visual and a vibratory stimulus (responsiveness, reactive distance, response distance, response duration, average response speed, and maximum response speed). Maternally transferred MeHg induced concentration-dependent effects on survival skills. Statistical and simulation models applied to predict the ecological consequences of the behavioral effects suggested that maternal transfer of MeHg may substantially lower survival of planktonic stage larvae compared to unexposed larvae. These results also imply that larvae of top predatory fish species, such as blue marlin, may suffer mortality through maternal transfer of MeHg.