Memory technology-a primer for material scientists.

From our own experience, we know that there is a gap to bridge between the scientists focused on basic material research and their counterparts in a close-to-application community focused on identifying and solving final technological and engineering challenges. In this review, we try to provide an easy-to-grasp introduction to the field of memory technology for materials scientists. An understanding of the big picture is vital, so we first provide an overview of the development and architecture of memories as part of a computer and call attention to some basic limitations that all memories are subject to. As any new technology has to compete with mature existing solutions on the market, today's mainstream memories are explained, and the need for future solutions is highlighted. The most prominent contenders in the field of emerging memories are introduced and major challenges on their way to commercialization are elucidated. Based on these discussions, we derive some predictions for the memory market to conclude the paper.

Induction chemotherapy (IC) followed by radiotherapy (RT) versus cetuximab plus IC and RT in advanced laryngeal/hypopharyngeal cancer resectable only by total laryngectomy-final results of the larynx organ preservation trial DeLOS-II.

Background: The German multicenter randomized phase II larynx organ preservation (LOP) trial DeLOS-II was carried out to prove the hypothesis that cetuximab (E) added to induction chemotherapy (IC) and radiotherapy improves laryngectomy-free survival (LFS; survival with preserved larynx) in locally advanced laryngeal/hypopharyngeal cancer (LHSCC). Patients and methods: Treatment-naïve patients with stage III/IV LHSCC amenable to total laryngectomy (TL) were randomized to three cycles IC with TPF [docetaxel (T) and cisplatin (P) 75 mg/m2/day 1, 5-FU (F) 750 mg/m2/day days 1-5] followed by radiotherapy (69.6 Gy) without (A) or with (B) standard dose cetuximab for 16 weeks throughout IC and radiotherapy (TPFE). Response to first IC-cycle (IC-1) with ≥30% endoscopically estimated tumor surface shrinkage (ETSS) was used to define early responders; early salvage TL was recommended to non-responders. The primary objective was 24 months LFS above 35% in arm B. Results: Of 180 patients randomized (July 2007 to September 2012), 173 fulfilled eligibility criteria (A/B: larynx 44/42, hypopharynx 41/46). Because of 4 therapy-related deaths among the first 64 randomized patients, 5-FU was omitted from IC in the subsequent 112 patients reducing further fatal toxicities. Thus, IC was TPF in 61 patients and TP in 112 patients, respectively. The primary objective (24 months LFS above 35%) was equally met by arms A (40/85, 47.1%) as well as B (41/88, 46.6%). One hundred and twenty-three early responders completed IC+RT; their overall response rates (TPF/TP) were 94.7%/87.2% in A versus 80%/86.0% in B. The 24 months overall survival (OS) rates were 68.2% and 69.3%. Conclusions: Despite being accompanied by an elevated frequency in adverse events, the IC with TPF/TP plus cetuximab was feasible but showed no superiority to IC with TPF/TP regarding LFS and OS at 24 months. Both early response and 24 months LFS compare very well to previous LOP trials and recommend effective treatment selection and stratification by ETSS. Clinical trial information: NCT00508664.

[The value of supracricoid partial laryngectomy in moderately advanced laryngeal cancer (T3-T4a)]. / Stellenwert der suprakrikoidalen Teilresektion beim moderat fortgeschrittenen Glottiskarzinom (T3-T4a).

BACKGROUND: Transoral laser microsurgery (TLM) is the method of choice for partial laryngectomy in Germany. In advanced stages, chemoradiotherapy is increasingly indicated for organ preservation. OBJECTIVE: This report considers the indications for and outcomes of supracricoid partial laryngectomy (SPL), also known as crico-hyoido-(epiglotto)-pexy, as an option for surgical organ preservation in moderately advanced laryngeal cancer (T3-T4a), in the well-defined gap between TLM and chemoradiotherapy protocols in Germany. METHODS: Retrospective evaluation of functional and oncological outcomes of all SPLs conducted between 2008 and 2014. During this period, 17 SPLs with resection of rpT2 (n = 2), (r)pT3 (n = 11), and (r)pT4a (n = 4) were performed with resection of one arytenoid. Mean age was 58 years (range 47-75 years). In 5 patients, SPL was for a first or second local recurrence after TLM or open partial laryngectomy. Adjuvant radiotherapy was received by 7 patients staged pT4a or pN+. RESULTS: Salvage laryngectomy with adjuvant radiotherapy was required by 2 patients. The remaining patients (n = 15) had a mean tumor-free follow-up of 4 years with a functional intact larynx: these patients can eat and drink, have a closed tracheotomy, and a good voice. After 3 years tumor-free follow-up with a functional intact larynx, 2 patients died due to cardiac comorbidity at the age of 76 years. DISCUSSION: SPL is a rare but valuable option for surgical larynx preservation in stage pT3-4a laryngeal cancer.

Laryngomalacia and complicated, life-threatening mTOR-positive Kaposiform hemangioendothelioma cured by Supraglottoplasty and sirolimus.

The therapy of complicated Kaposiform hemangioendothelioma (KHE) is still difficult. We present the first case of laryngomalacia with simultaneous mammalian target of Rapamycin (mTOR)-positive KHE of the neck and thoracic inlet and concurrent Kasabach-Meritt Phenomenon (KMP) in an 11-month-old boy suffering life-threatening progress despite intravenous vincristine, corticosteroids, propranolol and local interstitial laser-application. The laryngomalacia restored after laser-supraglottoplasty. Successfully treatment of the prior fatal course of the KHE with KMP was initiated not till adding the mTOR inhibitor sirolimus to therapy. After 16 months single therapy of KHE with oral sirolimus the boy presented free of symptoms with minimal residual disease and excellent functional long-term results. Thus we stopped sirolimus therapy. The results are stable for 9 months without therapy. The special features including full report of histopathologic findings of this utmost complicated case are demonstrated in detail underlining the effectiveness of sirolimus for KHE.

Decline of lactate in tumor tissue after ketogenic diet: in vivo microdialysis study in patients with head and neck cancer.

In head and neck squamous cell carcinoma (HNSCC) aerobic glycolysis is the key feature for energy supply of the tumor. Quantitative microdialysis (µD) offers an online method to measure parameters of the carbohydrate metabolism in vivo. The aim was to standardize a quantitative µD-study in patients with HNSCC and to prove if a ketogenic diet would differently influence the carbohydrate metabolism of the tumor tissue. Commercially available 100 kDa-CMA71-µD- catheters were implanted in tumor-free and in tumor tissue in patients with HNSCC for simultaneous measurements up to 5 days. The metabolic pattern and circadian rhythm of urea, glucose, lactate, and pyruvate was monitored during 24 h of western diet and subsequent up to 4 days of ketogenic diet. After 3 days of ketogenic diet the mean lactate concentration declines to a greater extent in the tumor tissue than in the tumor-free mucosa, whereas the mean glucose and pyruvate concentrations rise. The in vivo glucose metabolism of the tumor tissue is clearly influenced by nutrition. The decline of mean lactate concentration in the tumor tissue after ketogenic diet supports the hypothesis that HNSCC tumor cells might use lactate as fuel for oxidative glucose metabolism.

[Dysplasia and laryngeal carcinoma in situ]. / Dysplasien und Carcinomata in situ des Larynx.

Although the glottis is amenable to chemotherapy, currently most lesions from stage I laryngeal dysplasia up to carcinoma in situ are excised. This literature review presents selected molecular biological aspects especially in relation to dysplasia of the larynx and its therapy, as well as currently preferred biomarkers for chemotherapeutic prevention of laryngeal dysplasia.

Hyperechogenicity of the substantia nigra in healthy controls is related to MRI changes and to neuronal loss as determined by F-Dopa PET.

Transcranial ultrasound (TCS) has been shown to reveal hyperechogenicity of the substantia nigra (SN) in Parkinsonian patients and in about 10% of healthy controls. It is hypothesized that SN hyperechogenicity in healthy subjects is a vulnerability marker for idiopathic Parkinson's disease (IPD). Although there is strong evidence that the echomarker results from increased local iron content, the exact pathophysiological mechanisms remain incompletely understood. Thus, prognostic impact can only be estimated. We examined 14 subjects with SN hyperechogenicity (SN+) (7 IPD patients and 7 controls) and 7 healthy controls without the echomarker (SN-) by a magnetic resonance imaging method (MRI; T2 relaxation times) known to reveal tissue inhomogeneity following abnormal iron content and by F-Dopa PET to assess nigrostriatal function.

Disgust in pre-clinical Huntington's disease: a longitudinal study.

Emotion recognition from both face and voice and experience of emotions were investigated in a group of non-symptomatic people at risk of carrying the Huntington's disease gene who presented for genetic testing. Based on the results of the DNA test, a group of people carrying the Huntington's disease gene (HD+), and a group of non-carriers (HD-) were formed. Since we were especially interested in the time course of possible deficits in emotion recognition, all people at risk were reassessed 6 and 12 months after the initial assessment. Recognising facial expressions of disgust was significantly impaired on all three assessments in the HD+ group, while recognition of vocal emotions and the experience of emotions were largely unaffected, confirming that deficits in recognition of facial expressions of disgust are an early correlate of carrying the gene for Huntington's disease. The inclusion of a healthy control group (n = 37) further allowed an estimate of the genetic and environmental contribution to deficits in facial emotion recognition.

Transmodal sensorimotor networks during action observation in professional pianists.

Audiovisual perception and imitation are essential for musical learning and skill acquisition. We compared professional pianists to musically naive controls with fMRI while observing piano playing finger-hand movements and serial finger-thumb opposition movements both with and without synchronous piano sound. Pianists showed stronger activations within a fronto-parieto-temporal network while observing piano playing compared to controls and contrasted to perception of serial finger-thumb opposition movements. Observation of silent piano playing additionally recruited auditory areas in pianists. Perception of piano sounds coupled with serial finger-thumb opposition movements evoked increased activation within the sensorimotor network. This indicates specialization of multimodal auditory-sensorimotor systems within a fronto-parieto-temporal network by professional musical training. Musical ''language,'' which is acquired by observation and imitation, seems to be tightly coupled to this network in accord with an observation-execution system linking visual and auditory perception to motor performance.

Neural correlates associated with impaired disgust processing in pre-symptomatic Huntington's disease.

Disturbances in recognizing facial expressions of disgust have been reported previously in pre-symptomatic and manifest Huntington's disease. Given the substantial role of the insula and basal ganglia in the perception of disgust as revealed by functional imaging, lesion studies and intracerebral recordings, we propose dysfunction within the insula and/or basal ganglia as the underlying neural substrate. Using functional MRI (fMRI), we studied a group of nine pre-symptomatic Huntington's disease gene carriers and nine healthy controls, matched for age, gender, intelligence and years of education, while they were viewing disgusted facial expressions. As control conditions, surprised and neutral expressions were presented. Compared with healthy controls, Huntington's disease gene carriers showed reduced responses within the left dorsal anterior insula during processing of disgusted facial expressions. Moreover, processing of disgust was associated with significant activation of the left dorsal anterior insula and putamen in healthy controls, but not in Huntington's disease gene carriers. Furthermore, behavioural assessment revealed a selective impairment in recognizing facial expressions displaying disgust in Huntington's disease gene carriers. Our finding of dysfunctional decreased insula activation in pre-symptomatic Huntington's disease provides an explanation for the clinical deficit in recognizing facial expression of disgust. Furthermore, it underscores the role of the insula in the emotion of disgust.

Facial expression recognition and subthalamic nucleus stimulation.

BACKGROUND: Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor signs in Parkinson's disease. However, clinical studies suggest that DBS of the STN may also affect cognitive and emotional functions. OBJECTIVE: To study the impact of STN stimulation in Parkinson's disease on perception of facial expressions. RESULTS: There was a selective reduction in recognition of angry faces, but not other expressions, during STN stimulation. CONCLUSIONS: The findings may have important implications for social adjustment in these patients.

A novel quality of life instrument for deep brain stimulation in movement disorders.

OBJECTIVE: To develop a short instrument to examine quality of life (QoL) which specifically addresses patients with movement disorders treated by deep brain stimulation (DBS). DESIGN: The instrument was developed within an existing concept of a modular questionnaire (questions on life satisfaction: "general life satisfaction" QLS(M)-A, and "satisfaction with health" QLS(M)-G), in which each item is weighted according to its relative importance to the individual. METHODS: Items were generated by interviews with 20 DBS patients, followed by item reduction and scale generation, factor analysis to determine relevant and final questionnaire items, estimation of reliability, and validation based on the medical outcome study 36 item short form health survey (SF-36) and the EuroQol (EQ-5D) (data from 152 patients with Parkinson's disease, essential tremor, or idiopathic torsion dystonia, including 75 patients with DBS). RESULTS: Initial questionnaires were reduced to 12 items for a "movement disorder module" (QLS(M)-MD), and five items for a "deep brain stimulation module" (QLS(M)-DBS). Psychometric analysis revealed Cronbach's alpha values of of 0.87 and 0.73, and satisfactory correlation coefficients for convergent validity with SF-36 and EQ-5D. CONCLUSIONS: QLS(M)-MD and QLS(M)-DBS can evaluate quality of life aspects of DBS in movement disorders. Psychometric evaluation showed the questionnaires to be reliable, valid, and well accepted by the patients.

Hoarseness after laryngeal blunt trauma: a differential diagnosis between an injury to the external branch of the superior laryngeal nerve and an arytenoid subluxation. A case report and literature review.

Arytenoid subluxation is a well-known cause of hoarseness due to incomplete glottic closure with intact inferior laryngeal nerves after severe laryngeal trauma. We report the case of a young man presenting after laryngeal blunt trauma with hoarseness, easy fatigue during phonation, marked difficulty with his high-pitch and singing voice and decreased phonation time, but intact function of both inferior laryngeal nerves, intact endolaryngeal mucosa sensibility and normal CT scans of the larynx and the neck. Due to the asymmetric anteromedial position of the right arytenoid with incomplete glottic closure, the primary diagnosis was arytenoid subluxation, and the patient was referred for instantaneous relocation therapy. The stroboscopic and electromyographic diagnosis of a unilateral paresis of the external branch of the right superior laryngeal nerve caused the therapy to be changed. Without repositioning, the patient had a total recovery of voice quality when the paresis receded 2 months later. In conclusion, the unilateral paresis of the external branch of the superior laryngeal nerve after laryngeal blunt trauma is reported here for the first time. Although the clinical findings are familiar sequelae of thyroid surgery, they may be misdiagnosed as arytenoid subluxation after laryngeal blunt trauma. Stroboscopy and electromyography permitted the correct diagnosis.

Neuroblastoma directed therapy by a rational prodrug design of etoposide as a substrate for tyrosine hydroxylase.

Tumor directed cytotoxic therapy is one of the major challenges for the success of chemotherapy. In order to accomplish this goal in neuroblastoma, we rationally designed a prodrug of etoposide as substrate for tyrosine hydroxylase, a well established neuroblastoma associated enzyme. Here, we report synthesis and characterization of a 3,4 dihydroxy-phenyl carbamate derivative of etoposide. In order to demonstrate activation by tyrosine hydroxylase, the coding sequence of murine tyrosine hydroxylase was generated by reverse transcriptase-polymerase chain reaction from NXS2 neuroblastoma cells and cloned into the pRSET-A bacterial expression vector. The enzyme was expressed in Escherichia coli, characterized by Western blot and enzymatic activity was demonstrated by conversion of tyrosine into DOPA in the presence of cofactors using reversed phase high-performance liquid chromatography. Under these enzymatic conditions, we demonstrate conversion of 3,4 dihydroxy-phenyl carbamate prodrug into free etoposide. This effect was clearly mediated by the enzyme since bacteria transformed with the empty vector were ineffective of prodrug activation. Furthermore, tyrosine hydroxylase positive cells exposed to the etoposide prodrug were effectively killed in contrast to tyrosine hydroxylase negative controls. These findings demonstrate that etoposide can be designed as a prodrug substrate for tyrosine hydroxylase and thereby establish proof of concept for neuroblastoma directed enzyme prodrug therapy.

Rationally designed hydrolytically activated etoposide prodrugs, a novel strategy for the treatment of neuroblastoma.

Effective chemotherapy in neuroblastoma is limited by poor anti-tumor efficacy, systemic toxicity and the induction of drug resistance. Here, we provide further evidence that a hydrolytic activated prodrug design may overcome these problems. For this purpose, VP-16 was functionally blocked by a carbonate linker to generate two novel chemically stable prodrugs of VP-16, ProVP-16 I and II. We demonstrate profoundly different biological effects in vitro and in vivo of the prodrugs compared to parental VP-16. First, we established an up to >2 log higher in vitro toxicity of the two prodrugs compared to VP-16 on a panel of neuroblastoma cell lines. The highest increase of prodrug mediated cytotoxicity was observed in multi drug resistant cell lines. Second, in vivo studies showed a maximum tolerated dose (MTD) of ProVP-16 II (60 mg/kg), which was at least threefold higher than that of VP-16 (20 mg/kg). Tests of ProVP-16 II in a syngeneic NXS2 neuroblastoma model indicated that mice treated with this prodrug at 1/3 of the MTD was as effective as VP-16 parental compound used at the MTD in suppression of tumor growth. In summary, the etoposide prodrugs proved effective and less toxic and are therefore highly promising new anti-neuroblastoma compounds.

Facial expression recognition in people with medicated and unmedicated Parkinson's disease.

Recognition of facial expressions of emotion was investigated in people with medicated and unmedicated Parkinson's disease (PD) and matched controls (unmedicated PD, n=16; medicated PD, n=20; controls, n=40). Participants in the medicated group showed some visual impairment (impaired contrast sensitivity) and performed less well on perception of unfamiliar face identity, but did not show significant deficits in the perception of sex, gaze direction, or familiar identity from the face. For both Parkinson's disease groups, there was evidence of impaired recognition of facial expressions in comparison to controls. These deficits were more consistently noted in the unmedicated group, who were also found to perform worse than the medicated group at recognising disgust from prototypical facial expressions, and at recognising anger and disgust in computer-manipulated images. Although both Parkinson's disease groups showed impairments of facial expression recognition, the consistently worse recognition of disgust in the unmedicated group is consistent with the hypothesis from previous studies that brain regions modulated by dopaminergic neurons are involved in the recognition of disgust.

Subthalamic nucleus stimulation affects striato-anterior cingulate cortex circuit in a response conflict task: a PET study.

The subthalamic nucleus (STN) has generally been considered as a relay station within frontal-subcortical motor control circuitry. Little is known about the influence of the STN on cognitive networks. Clinical observations and studies in animals suggest that the STN participates in non-motor functions which can now be probed in Parkinson's disease patients with deep brain stimulation of the STN, allowing selective and reversible modulation of this nucleus. Using PET, we studied changes in regional cerebral blood flow (rCBF) associated with a response conflict task (Stroop task) in Parkinson's disease patients ON and OFF bilateral STN stimulation. The Stroop task requires subjects to name the font colour of colour words (e.g. "blue") printed in an incongruent colour ink (e.g. yellow). During STN stimulation, impaired task performance (prolonged reaction times) was associated with decreased activation in both right anterior cingulate cortex (ACC) and right ventral striatum. Concomitant increased activation in left angular gyrus indicative of ongoing word processing during stimulation is consistent with an impairment to inhibit habitual responses. ACC and ventral striatum are part of the ACC circuit associated with response conflict tasks. The decreased activation during STN stimulation in the ACC circuit, while response conflict processing worsened, provides direct evidence of STN modulating non-motor basal ganglia-thalamocortical circuitry. Impairment in ACC circuit function could account for the subtle negative effects on cognition induced by STN stimulation.

Influence of nanoparticles on the brain-to-serum distribution and the metabolism of valproic acid in mice.

The suitability of nanoparticles as a drug-carrier system for the antiepileptic valproic acid has been studied in mice. The aim of the study was to increase the brain-to-serum ratio of the drug to reduce dose-related side effects in the periphery. The influence of nanoparticles on the metabolism of valproic acid was also investigated. The serum kinetics and the brain tissue levels of valproic acid were not altered by administration with nanoparticles. However, the nanoparticles did inhibit the metabolic degradation of valproic acid via mitochondrial beta-oxidation but did not influence any other metabolic pathway. It can be concluded that nanoparticles loaded with valproic acid may help to reduce the toxic side effects of valproate therapy, not by reducing the therapeutically necessary dosage but by inhibition of formation of toxic metabolites. Using their ability to selectively block a pathway nanoparticles may serve as a tool to investigate the metabolic origin of metabolites and their contribution to therapeutic efficacy and side effects.

Quinolinic acid released from polymeric brain implants causes behavioral and neuroanatomical alterations in a rodent model of Huntington's disease.

Quinolinic acid (QA) is an N-methyl-d-aspartate agonist that has been shown to produce neurotoxic effects that mimic certain neurodegenerative diseases when administered to laboratory animals. Intrastriatal injections of QA in rats have been used extensively to produce some of the neuropathological and behavioral deficits that are analogous to Huntington's disease (HD). However, acute intrastriatal injections of QA produce symptoms that are not analogous to the progressive nature of HD. Thus far, models using chronic administration of QA that produce HD-like behavioral and neuroanatomical changes have necessitated the use of a relatively bulky and fragile microdialytic pump apparatus. The present study tested an alternative way of chronically administering QA. Specifically, this study tested whether gradual release of QA from ethylene vinylacetate (EVA) polymers could produce symptoms analogous to HD. Rats received either no implants or bilateral intrastriatal implants of polymers with or without QA. Subsequent tests for spontaneous motor activity (SMA), grip strength, balance, and learning ability in a radial-arm-water-maze task revealed QA-induced impairments in balance and learning ability, but did not affect grip strength or SMA. Histological analysis revealed QA-induced enlargement of lateral ventricles, striatal atrophy, and striatal neuronal loss, with relative sparing of NADPH-diaphorase-positive neurons. These results suggest that QA released from polymers can produce behavioral and neuropathological profiles analogous to early stages of HD and that EVA polymers offer a useful means of chronically delivering QA in rodent models of neurodegeneration.