54-year-old male with hepatic cirrhosis and therapy-associated torsade de pointes tachycardia

We present a case of a patient with newly diagnosed cirrhosis and kidney failure who underwent cardiopulmonary resuscitation twice after treatment with terlipressin. After the second application a QT interval prolongation and torsade de pointes were documented. Since other causes were excluded, we interpret both events as terlipressin-induced ventricular arrhythmia. Therefore, it seems important to consider this rare but potentially lethal side effect when administering this drug to patients.     

Anti-amyloid therapy protects against retinal pigmented epithelium damage and vision loss in a model of age-related macular degeneration

Age-related macular degeneration (AMD) is a leading cause of visual dysfunction worldwide. Amyloid β (Aβ) peptides, Aβ1-40 (Aβ40) and Aβ1-42 (Aβ42), have been implicated previously in the AMD disease process. Consistent with a pathogenic role for Aβ, we show here that a mouse model of AMD that invokes multiple factors that are known to modify AMD risk (aged human apolipoprotein E 4 targeted replacement mice on a high-fat, cholesterol-enriched diet) presents with Aβ-containing deposits basal to the retinal pigmented epithelium (RPE), histopathologic changes in the RPE, and a deficit in scotopic electroretinographic response, which is reflective of impaired visual function. Strikingly, these electroretinographic deficits are abrogated in a dose-dependent manner by systemic administration of an antibody targeting the C termini of Aβ40 and Aβ42. Concomitant reduction in the levels of Aβ and activated complement components in sub-RPE deposits and structural preservation of the RPE are associated with anti-Aβ40/42 antibody immunotherapy and visual protection. These observations are consistent with the reduction in amyloid plaques and improvement of cognitive function in mouse models of Alzheimer's disease treated with anti-Aβ antibodies. They also implicate Aβ in the pathogenesis of AMD and identify Aβ as a viable therapeutic target for its treatment.     

Maturation of obligatory auditory responses and their neural sources: evidence from EEG and MEG

Neural auditory responses are known to change from childhood to adulthood. The most prominent components of the event-related potentials (ERPs) found in children are the P1 and N2, while the P1 and N1 are strongest in adults. Previous dipole localizations showed regions of the auditory cortex (AC) underlying these responses. An N1 in children, however, has only been observed in older age or under certain experimental conditions different than commonly applied in adults. The current study aimed to further elucidate on auditory processing and related components in school-aged children. To do this, MEG and EEG was recorded in adults and 9 to 10year old children, while presenting pure tones either repetitively or randomly among tones of different pitch. Furthermore, the current paradigm was explicitly designed to not only investigate the P1 and N2 in children, but moreover to examine N1 modulations based on different refractory states caused by the two conditions. Our results are clear cut. In adults, P1(m) and N1(m) components were localized in AC regions, with the N1(m) largely attenuated for repetitive tones. The P1(m) and N2(m) components observed in children were also localized in AC regions. Most importantly, ERP modulations in the N1 time window (i.e., larger responses for random than repetitive tones) were remarkably similar for adults and children, both in amplitude and latency. This effect indicates that the N1 sub-component reflecting frequency-specific refractoriness is fully developed in 9 to 10year old children. Thus, previous interpretations on the function and maturation of the N1 need reconsideration.     

Medial prefrontal cortex activity during the extinction of conditioned fear: an investigation using functional near-infrared spectroscopy

The majority of fear conditioning studies in humans have focused on fear acquisition rather than fear extinction. For this reason only a few functional imaging studies on fear extinction are available. A large number of animal studies indicate the medial prefrontal cortex (mPFC) as neuronal substrate of extinction. We therefore determined mPFC contribution during extinction learning after a discriminative fear conditioning in 34 healthy human subjects by using functional near-infrared spectroscopy. During the extinction training, a previously conditioned neutral face (conditioned stimulus, CS+) no longer predicted an aversive scream (unconditioned stimulus, UCS). Considering differential valence and arousal ratings as well as skin conductance responses during the acquisition phase, we found a CS+ related increase in oxygenated haemoglobin concentration changes within the mPFC over the time course of extinction. Late CS+ trials further revealed higher activation than CS- trials in a cluster of probe set channels covering the mPFC. These results are in line with previous findings on extinction and further emphasize the mPFC as significant for associative learning processes. During extinction, the diminished fear association between a former CS+ and a UCS is inversely correlated with mPFC activity--a process presumably dysfunctional in anxiety disorders.     

The effects of lithium on renal function in older adults--a systematic review

Chronic renal failure (CRF) and nephrogenic diabetes insipidus (NDI) are potential consequences of chronic lithium use, while acute renal failure (ARF) has been described in lithium intoxication. We performed a systematic review of all studies pertaining to the effects of lithium on the kidney in older adults. The ARF incidence was 1.5% per person-year and concurrent loop diuretic and angiotensin-converting enzyme inhibitor use with lithium increased the risk. The CRF prevalence estimates varied from 1.2% to 34%, with risk factors including age, previous lithium intoxication, polyuria, previously impaired renal function, and decreased maximal urine osmolality. The prevalence of NDI varied widely from 1.8% to 85%. Risk factors included lithium duration, dose, level, slow-release formulation, and clinical nonresponse. Except for amiloride use in NDI, there is little evidence for treatment of other lithium-induced adverse renal effects. Currently, there is no compelling evidence to suggest that lithium should be avoided in elderly patients for fear of renal side effects.     

NOS1 ex1f-VNTR polymorphism affects prefrontal oxygenation during response inhibition tasks

Impulsivity is a trait shared by many psychiatric disorders and therefore a suitable intermediate phenotype for their underlying biological mechanisms. One of the molecular determinants involved is the NOS1 ex1f‐VNTR, whose short variants are associated with a variety of impulsive behaviors. Fifty‐six healthy controls were stratified into homozygous long (LL) (30 probands) and short (SS) (26 probands) allele groups. Subjects completed a combined stop‐signal go/nogo task, while the oxygenation in the prefrontal cortex was measured with functional near‐infrared spectroscopy. Electromyography was recorded to control for differences in muscle activity in the two inhibition tasks. Two questionnaires on impulsive traits were completed. Differences between the two tasks are shown by distinct activation patterns within the prefrontal cortex. The nogo task resulted mainly in the activation of the dorsolateral prefrontal cortex (dlPFC), whereas successful and unsuccessful inhibition in the stop‐signal task elicited the predicted activity in the inferior frontal cortex (IFC). Although significant differences were found in neither the scores obtained on impulsivity‐related questionnaires nor the behavioral data, the LL group displayed increased dlPFC activity during nogo trials and the predicted activation in the IFC during successful inhibition in the stop‐signal task, while no significant activation was found in the SS group. Our data confirm an influence of NOS1 ex1f‐VNTR on impulsivity, as carriers of the short risk allele exhibited diminished activity of (pre‐)frontal brain regions during the inhibition in a stop‐signal task. Impairment of prefrontal control with consecutive failure of inhibitory processes might underlie association findings reported previously. Hum Brain Mapp, 2012. © 2011 Wiley Periodicals, Inc.     

Finding the right control: The mismatch negativity under investigation

ObjectiveWhen investigating auditory perceptual regularity processing, mismatch negativity (MMN) is commonly used. MMN is computed as a difference signal between the event-related potentials (ERPs) elicited by repeated standard tones and rarely occurring deviant tones. This procedure leads to an underestimation of the N1 component elicited by standards compared to the N1 to deviants which might affect the MMN. Consequently, a random control design was previously introduced. This design, however, overestimates the N1 to the deviant. Here, we developed a new paradigm that avoids previous drawbacks.MethodsWe designed a regular cascadic sequence as a control to the deviant. ERPs were measured while presenting conventional oddball blocks (standards, deviants), random control blocks and a cascadic control block.ResultsMMN was observed in each difference signal. Regarding the N1, standards elicited smallest amplitudes. The N1 for the deviant and the cascadic control was comparable. The largest N1 was elicited by the random control.ConclusionStandards underestimate N1 refractoriness effects in the responses to deviants, while random control tones overestimate. Cascadic control tones, however, provide a reasonable estimation for the N1.SignificanceThe new cascadic control design is suitable to investigate auditory perceptual regularity processes while controlling for N1 refractoriness effects.     

Genetic evidence for a contribution of EphA:ephrinA reverse signaling to motor axon guidance

Repulsive Eph forward signaling from limb-derived ephrins guides the axons of lateral motor column (LMC) motor neurons. LMC axons also express ephrinAs, while their EphA receptors are expressed in the limb mesenchyme. In vitro studies have suggested that reverse signaling from limb-derived EphA4 to axonal ephrinAs might result in attraction of LMC axons. However, genetic evidence for this function is lacking. Here we use the Dunn chamber turning assay to show that EphA proteins are chemoattractants and elicit fast turning responses in LMC neurons in vitro. Moreover, ectopic expression of EphA4 in chick hindlimb changes the limb trajectory of LMC axons. Nervous system-specific deletion of EphA4 in mice resulted in fewer LMC axon projection errors than the ubiquitous deletion of EphA4. Additionally, a signaling-incompetent EphA4 mutant partially rescued guidance errors in the hindlimb, suggesting that limb-derived EphA4 contributes to the establishment of LMC projections. In summary, we provide evidence for a role of EphA:ephrinA attractive reverse signaling in motor axon guidance and in vivo evidence of in-parallel forward Eph and reverse ephrin signaling function in the same neuronal population.