Neurons in the Human Left Amygdala Automatically Encode Subjective Value Irrespective of Task.

The amygdala plays an important role in the computation of internal reward signals. In animals it has been shown to enable a stimulus to indicate the current value of a reinforcer. However, the exact nature of the current value representations in humans remains unknown. Specifically, do neurons of the human amygdala represent current value signals only in tasks requiring valuation? We recorded from 406 neurons in the amygdala, orbitofrontal cortex, parahippocampal cortex, entorhinal cortex, and hippocampus of 6 neurosurgical patients while subjects repeatedly viewed 40 different pictures of sweet or salty "junk food" items in 2 different tasks. Neural activity during stimulus inspection in a valuation task reflected food preferences in the amygdala, orbitofrontal cortex, hippocampus, and entorhinal cortex. Notably, only left amygdala activity represented these food preferences even in a sweet-salty classification task. Valuation signals of the left amygdala thus appear to be stimulus-, not-task driven.

Non-fermentative Gram-negative rods bacteremia in children with cancer: a 14-year single-center experience.

PURPOSE: Data on non-fermentative Gram-negative rods (NFGNR) bacteremia in children with malignancies are limited. The aim of this study was to present clinical picture, antimicrobial susceptibility pattern, risk factors for resistance and outcome in NFGNR bacteremia in children with cancer. METHODS: All episodes of NFGNR bacteremia occurring during 2001-2014 in children with cancer in a tertiary-care hospital were retrospectively analyzed. Pseudomonas and Acinetobacter spp. resistant to three or more antibiotic classes and all Stenotrophomonas maltophilia (SM) were defined as multidrug-resistant bacteria (MDR). RESULTS: A total of 80 children (44 males, 0.8-18 years, median 5 years) developed 107 episodes (116 pathogens) of NFGNR bacteremia; Pseudomonas aeruginosa (PA) (51; 43.9%), Acinetobacter baumannii (AB) (21, 18.1%), SM (18, 15.5%); and others (27, 25.2%). The rate of NFGNR bacteremia in children with certain solid tumors (e.g. sarcoma, 12/134 (9.0%)) was comparable to that of hematological malignancies (52/429 (12.2%). Focal infection and septic shock occurred in 16 (14.9%) and four (3.7%) episodes, respectively. Thirty (25.8%) of 116 NFGNR were MDR. The most significant predictors of bacteremia with MDR PA or AB were severe neutropenia (<100 cells/mm3; OR 7.8, p = 0.002), hospital-acquired (OR 16.9, p < 0.0001) and breakthrough (OR 11.2, p < 0.0001) infection. Infection with MDR bacteria was associated with inappropriate empirical therapy. The 30-day mortality was 3/107 (2.8%), all in neutropenic patients with hematological malignancies. CONCLUSIONS: NFGNR bacteremia can present with nonspecific signs or symptoms. MDR NFGNRs are common and compromise treatment options, but mortality is relatively low. Knowledge of local epidemiology, pattern and risk factors for resistance is important to guide empirical therapy.

Assessing the fetal effects of maternal obesity via transcriptomic analysis of cord blood: a prospective case-control study.

OBJECTIVE: To analyse fetal gene expression at term using umbilical cord blood, in order to provide insights into the effects of maternal obesity on human development. DESIGN: Prospective case-control study. SETTING: Academic tertiary care centre. POPULATION: Eight obese (body mass index ≥30 kg/m(2)) and eight lean (body mass index <25 kg/m(2)) pregnant women undergoing prelabour caesarean delivery at term. METHODS: Women were matched for gestational age and fetal sex. Cord blood RNA was extracted and hybridised to gene expression arrays. Differentially regulated genes were identified using paired t-tests and the Benjamini-Hochberg correction. Functional analyses were performed using Ingenuity Pathway Analysis, BioGPS and Gene Set Enrichment Analysis with a fetal-specific annotation. Z-scores ≥2.0 or P-values <0.01 were considered significant. MAIN OUTCOME MEASURE: Functions of differentially regulated genes in fetuses of obese women. RESULTS: A total of 701 differentially regulated genes were identified, producing an expression profile implicating neurodegeneration, decreased survival of sensory neurons, and decreased neurogenesis in the fetuses of obese women. Upstream regulators related to inflammatory signalling were significantly activated; those related to insulin receptor signalling, lipid homeostasis, regulation of axonal guidance, and cellular response to oxidative stress were significantly inhibited. Of 26 tissue-specific genes that were differentially regulated in fetuses of obese women, six mapped to the fetal brain. CONCLUSION: Maternal obesity affects fetal gene expression at term, implicating dysregulated brain development, inflammatory and immune signalling, glucose and lipid homeostasis, and oxidative stress. This may have implications for postnatal neurodevelopment and metabolism.

Taxanes-induced cutaneous eruption: another histopathologic mimicker of malignancy.

BACKGROUND: Paclitaxel and docetaxel are antineoplastic drugs that bind the microtubules, producing the arrest of mitoses, which may be seen histopathologically. These histopathologic changes may simulate an intraepidermal keratinocytic malignant neoplasm, and an accurate diagnosis may be only established by clinicopathological correlation. OBJECTIVES: We report six cases of cutaneous eruptions by taxanes in which a striking cytotoxic effect was evident histopathologically. METHODS: Cutaneous biopsies were obtained in each patient. RESULTS: Atypical starburst-like or ring-like mitoses and dyskeratosis on basal and suprabasal layers of the epidermis. Areas of squamous syringometaplasia were also seen in one case. DISCUSSION: These findings were interpreted as expression of mitotic arrest due to taxanes. Similar changes have been described in association with other chemotherapeutic drugs such as vincristine, podophyllin and its derivative etoposide; colchicine, busulfan and maytansine, but cases like ours due to taxanes are exceptional or under-reported. CONCLUSION: Dermatopathologists should be aware of these effects in order to interpret carefully cutaneous biopsy specimens of patients receiving taxanes.

[Merkel cell carcinoma]. / Merkel-Zell-Karzinom.

Merkel cell carcinoma (MCC, cutaneous neuroendocrine carcinoma) is a rare form of tumor of unclear histogenesis which predominantly occurs in elderly patients on areas exposed to the sun. A higher incidence and occurrence in younger people is predominantly found in immunosuppressed persons which is why a pathogenetic role is also attributed to immunosuppression in addition to ultraviolet (UV) radiation. Additionally, in 80% of cases clonally integrated polyomavirus (Merkel cell polyomavirus, MCPyV) could be detected. Clinically MCC represents an uncharacteristic tumor. Histopathologically, monomorphic dermal and/or subcutaneous nodes are found consisting of round or oval medium sized cells with a vesicular nucleus and sparse cytoplasm. The neoplastic cells of MCC express cytokeratin (CK) 20 with a dot-like perinuclear accentuation. In addition, pan-CK, neuroendocrine markers (e.g. chromogranin A and synaptophysin), neurofilament proteins, CD56, CD57, Bcl-2, TdT and PAX-5 are immunohistochemically positive. In most cases CM2B4, an antibody against MCPyV is also positive. Expression of p63 has been observed in some of the cases and in some studies was associated with a favorable prognosis. The markers thyroid transcription factor 1, mammalian achaete scute complex like 1, vimentin, S-100 and CK7 are not normally expressed by MCC. The prognosis is primarily dependent on tumor size and the lymph node status. The presence of intralymphatic tumor complexes is associated with a higher rate of local recurrence and lymph node metastasis. A larger number of intratumoral cytotoxic T-lymphocytes is accompanied by a favorable prognosis and the presence of > 50% of K-67+ neoplastic cells with an unfavorable prognosis. Further morphological, phenotypical and genetic factors have not yet been validated in larger cohorts with respect to the prognostic relevance.

A revised intracarotid etomidate memory (Wada) procedure.

OBJECTIVES: To evaluate unilateral memory function by the means of a modified Montreal etomidate speech and memory procedure (e-SAM) in epilepsy patients who were candidates for standard anterior temporal lobectomy involving resection of mesial temporal lobe structures. MATERIALS AND METHODS: After the first three patients experienced significant side effects with the e-SAM procedure, we modified the procedure to a single bolus injection. The neuropsychological data of all 21 patients who underwent unilateral memory testing by means of intracarotid injection of etomidate were analyzed. RESULTS: There was a significant difference in memory scores when injections were on the side ipsilateral to the epileptogenic focus compared with when the injections were on the contralateral side (P < 0.01), supposedly reflecting unilateral hippocampal memory function and dysfunction. In addition, the procedural modification resulted in eradication of all major side effects in the ensuing 18 patients. CONCLUSIONS: The technical modification of the Montreal procedure from continuous to bolus injection effectively enabled the demonstration of the relative weakness of the memory function of the epileptogenic hemisphere. The revised etomidate procedure provided the clinical information on unilateral hippocampal memory function necessary for surgical decision.

Frequent loss of RAF kinase inhibitor protein expression in acute myeloid leukemia.

RAF kinase inhibitor protein (RKIP) is a negative regulator of the RAS-mitogen-activated protein kinase/extracellular signal-regulated kinase signaling cascade. We investigated its role in acute myeloid leukemia (AML), an aggressive malignancy arising from hematopoietic stem and progenitor cells (HSPCs). Western blot analysis revealed loss of RKIP expression in 19/103 (18%) primary AML samples and 4/17 (24%) AML cell lines but not in 10 CD34+ HSPC specimens. In in-vitro experiments with myeloid cell lines, RKIP overexpression inhibited cellular proliferation and colony formation in soft agar. Analysis of two cohorts with 103 and 285 AML patients, respectively, established a correlation of decreased RKIP expression with monocytic phenotypes. RKIP loss was associated with RAS mutations and in transformation assays, RKIP decreased the oncogenic potential of mutant RAS. Loss of RKIP further related to a significantly longer relapse-free survival and overall survival in uni- and multivariate analyses. Our data show that RKIP is frequently lost in AML and correlates with monocytic phenotypes and mutations in RAS. RKIP inhibits proliferation and transformation of myeloid cells and decreases transformation induced by mutant RAS. Finally, loss of RKIP seems to be a favorable prognostic parameter in patients with AML.

FDG-PET/MRI coregistration improves detection of cortical dysplasia in patients with epilepsy.

OBJECTIVE: Patients with cortical dysplasia (CD) are difficult to treat because the MRI abnormality may be undetectable. This study determined whether fluorodeoxyglucose (FDG)-PET/MRI coregistration enhanced the recognition of CD in epilepsy surgery patients. METHODS: Patients from 2004-2007 in whom FDG-PET/MRI coregistration was a component of the presurgical evaluation were compared with patients from 2000-2003 without this technique. For the 2004-2007 cohort, neuroimaging and clinical variables were compared between patients with mild Palmini type I and severe Palmini type II CD. RESULTS: Compared with the 2000-2003 cohort, from 2004-2007 more CD patients were detected, most had type I CD, and fewer cases required intracranial electrodes. From 2004-2007, 85% of type I CD cases had normal non-University of California, Los Angeles (UCLA) MRI scans. UCLA MRI identified CD in 78% of patients, and 37% of type I CD cases had normal UCLA scans. EEG and neuroimaging findings were concordant in 52% of type I CD patients, compared with 89% of type II CD patients. FDG-PET scans were positive in 71% of CD cases, and type I CD patients had less hypometabolism compared with type II CD patients. Postoperative seizure freedom occurred in 82% of patients, without differences between type I and type II CD cases. CONCLUSIONS: Incorporating fluorodeoxyglucose-PET/MRI coregistration into the multimodality presurgical evaluation enhanced the noninvasive identification and successful surgical treatment of patients with cortical dysplasia (CD), especially for the 33% of patients with nonconcordant findings and those with normal MRI scans from mild type I CD.

Sparse but not 'grandmother-cell' coding in the medial temporal lobe.

Although a large number of neuropsychological and imaging studies have demonstrated that the medial temporal lobe (MTL) plays an important role in human memory, there are few data regarding the activity of neurons involved in this process. The MTL receives massive inputs from visual cortical areas, and evidence over the last decade has consistently shown that MTL neurons respond selectively to complex visual stimuli. Here, we focus on how the activity patterns of these cells might reflect the transformation of visual percepts into long-term memories. Given the very sparse and abstract representation of visual information by these neurons, they could in principle be considered as 'grandmother cells'. However, we give several arguments that make such an extreme interpretation unlikely.

Human single-neuron responses at the threshold of conscious recognition.

We studied the responses of single neurons in the human medial temporal lobe while subjects viewed familiar faces, animals, and landmarks. By progressively shortening the duration of stimulus presentation, coupled with backward masking, we show two striking properties of these neurons. (i) Their responses are not statistically different for the 33-ms, 66-ms, and 132-ms stimulus durations, and only for the 264-ms presentations there is a significantly higher firing. (ii) These responses follow conscious perception, as indicated by the subjects' recognition report. Remarkably, when recognized, a single snapshot as brief as 33 ms was sufficient to trigger strong single-unit responses far outlasting stimulus presentation. These results suggest that neurons in the medial temporal lobe can reflect conscious recognition by "all-or-none" responses.

Ultra-fine frequency tuning revealed in single neurons of human auditory cortex.

Just-noticeable differences of physical parameters are often limited by the resolution of the peripheral sensory apparatus. Thus, two-point discrimination in vision is limited by the size of individual photoreceptors. Frequency selectivity is a basic property of neurons in the mammalian auditory pathway. However, just-noticeable differences of frequency are substantially smaller than the bandwidth of the peripheral sensors. Here we report that frequency tuning in single neurons recorded from human auditory cortex in response to random-chord stimuli is far narrower than that typically described in any other mammalian species (besides bats), and substantially exceeds that attributed to the human auditory periphery. Interestingly, simple spectral filter models failed to predict the neuronal responses to natural stimuli, including speech and music. Thus, natural sounds engage additional processing mechanisms beyond the exquisite frequency tuning probed by the random-chord stimuli.

Possible remote functional reorganization in left temporal lobe epilepsy.

OBJECTIVE: To provide functional magnetic resonance imaging-based insight into the impact of left temporal lobe epilepsy (TLE) on language-related functional re-organization. MATERIALS AND METHODS: Ten right-handed patients with left TLE were compared with 10 matched healthy controls. Regional brain activation during the language task was measured in the inferior frontal gyrus (IFG) and in the superior temporal gyrus (STG), and the regional inter-hemispheric lateralization index (LI) was calculated. RESULTS: Left language lateralization was documented in all the patients and controls. Reduced lateralization in the IFG was due to decreased activity in the left frontal region rather than to increased activity in the right frontal region. The LI values in the STG correlated with the LI values in the IFG in the controls but not in the patients. CONCLUSIONS: The left IFG was most probably involved in the epileptogenesis and concomitant language-related cortical plasticity in patients with left TLE.

Decoding visual inputs from multiple neurons in the human temporal lobe.

We investigated the representation of visual inputs by multiple simultaneously recorded single neurons in the human medial temporal lobe, using their firing rates to infer which images were shown to subjects. The selectivity of these neurons was quantified with a novel measure. About four spikes per neuron, triggered between 300 and 600 ms after image onset in a handful of units (7.8 on average), predicted the identity of images far above chance. Decoding performance increased linearly with the number of units considered, peaked between 400 and 500 ms, did not improve when considering correlations among simultaneously recorded units, and generalized to very different images. The feasibility of decoding sensory information from human extracellular recordings has implications for the development of brain-machine interfaces.

Electrical conductivities of the freshly excised cerebral cortex in epilepsy surgery patients; correlation with pathology, seizure duration, and diffusion tensor imaging.

The electrical conductivities (sigma) of freshly excised neocortex and subcortical white matter were studied in the frequency range of physiological relevance for EEG (5-1005 Hz) in 21 patients (ages 0.67 to 55 years) undergoing epilepsy neurosurgery. Surgical patients were classified as having cortical dysplasia (CD) or non-CD pathologies. Diffusion tensor imaging (DTI) for apparent diffusion coefficient (ADC) and fractional anisotropy (FA) was obtained in 9 patients. Results found that electrical conductivities in freshly excised neocortex vary significantly from patient to patient (sigma = 0.0660-0.156 S/m). Cerebral cortex from CD patients had increased conductivities compared with non-CD cases. In addition, longer seizure durations positively correlated with conductivities for CD tissue, while they negatively correlated for non-CD tissue. DTI ADC eigenvalues inversely correlated with electrical conductivity in CD and non-CD tissue. These results in a small initial cohort indicate that electrical conductivity of freshly excised neocortex from epilepsy surgery patients varies as a consequence of clinical variables, such as underlying pathology and seizure duration, and inversely correlates with DTI ADC values. Understanding how disease affects cortical electrical conductivity and ways to non-invasively measure it, perhaps through DTI, could enhance the ability to localize EEG dipoles and other relevant information in the treatment of epilepsy surgery patients.

Is there any correlation between severity of epilepsy and cognitive abilities in patients with temporal lobe epilepsy?

Frequent refractory seizures may cause cognitive deterioration when they present at an early age, especially in infants. The findings of previous studies designed to examine the impact of repetitive seizures on cognition in adolescents and adults, however, have shown wide variation. We analyzed the data of neuropsychological evaluations of patients before they underwent temporal lobe resection because of refractory seizure disorder in our institution from 1998 to 2001. Forty-four consecutive patients aged 12-48 years underwent a comprehensive neuropsychological evaluation that included a battery of selected visual and verbal memory tests. Statistical analysis revealed no significant correlation between disease-related parameters, such as age of onset, duration of active disease, estimated cumulative number of complex partial seizures and secondarily generalized seizures, and the results of neuropsychological tests. These findings support the hypothesis that factors other than repetitive seizures are responsible for cognitive dysfunction among adolescents and adults.

Invariant visual representation by single neurons in the human brain.

It takes a fraction of a second to recognize a person or an object even when seen under strikingly different conditions. How such a robust, high-level representation is achieved by neurons in the human brain is still unclear. In monkeys, neurons in the upper stages of the ventral visual pathway respond to complex images such as faces and objects and show some degree of invariance to metric properties such as the stimulus size, position and viewing angle. We have previously shown that neurons in the human medial temporal lobe (MTL) fire selectively to images of faces, animals, objects or scenes. Here we report on a remarkable subset of MTL neurons that are selectively activated by strikingly different pictures of given individuals, landmarks or objects and in some cases even by letter strings with their names. These results suggest an invariant, sparse and explicit code, which might be important in the transformation of complex visual percepts into long-term and more abstract memories.

Cortical lesions associated with transient neurological symptoms - not always a matter of cause and effect.

The occurrence of transient recurrent stereotypical neurological events mandates the exclusion of an underlying brain lesion. When imaging studies demonstrate the presence of a structural brain lesion, a cause and effect relationship between the two entities is assumed, and the decision for surgical intervention may then follow almost automatically. We describe five patients with transient neurological events suspected as being seizures that were referred for surgery because of an associated structural brain lesion. Video electroencephalographic recordings revealed that the events that brought these patients to neurosurgical attention were non-epileptic seizures. None of these patients underwent surgical intervention, and all were referred for behavioral therapy. Therefore, even in the presence of a confirmed brain lesion, the presenting paroxysmal events may be of a non-organic origin and should not necessarily be assumed to be caused by the concomitantly existing structural abnormality.

Ictal magnetic source imaging as a localizing tool in partial epilepsy.

OBJECTIVE: To determine the feasibility and usefulness of ictal magnetoencephalography (MEG) recordings in the presurgical evaluation of patients with epilepsy. METHODS: Twenty patients with frequent or predictable seizures were studied with the intent to capture seizures using a large array single-probe 37-channel or dual-probe 74-channel biomagnetometer. RESULTS: Successful ictal MEG recordings were made in 6 of 20 patients with neocortical epilepsy. In one other patient, a seizure was captured but movement artifact made MEG recordings impossible. As determined by invasive EEG recording and postsurgical outcome, ictal MEG provided localizing information that was superior to interictal MEG in three of the six patients. Localization of ictal onset by MEG was at least equivalent to invasive EEG in five of the six patients, and was superior in two patients as determined by postsurgical outcome. CONCLUSION: Larger studies are necessary to confirm that ictal MEG recordings in patients with frequent or easily provoked neocortical seizures can contribute localizing information equivalent or superior to invasive EEG recording.

Ultradian sleep-cycle variation of serotonin in the human lateral ventricle.

Serotonin is thought to be intimately involved in the regulation of sleep and waking in humans, though the evidence for such is indirect. Using in vivo microdialysis, the authors show that serotonin in human ventricular CSF covaries with the state of consciousness. They hypothesize that CSF serotonin may be acting in an endocrine-like manner through activation of known leptomeningeal serotonin receptors and possibly participating in modulation of choroidal production of CSF.