Contributions of Stereotactic EEG Electrodes in Grey and White Matter to Speech Activity Detection.

Recent studies have shown it is possible to decode and synthesize speech directly using brain activity recorded from implanted electrodes. While this activity has been extensively examined using electrocorticographic (ECoG) recordings from cortical surface grey matter, stereotactic electroen-cephalography (sEEG) provides comparatively broader coverage and access to deeper brain structures including both grey and white matter. The present study examines the relative and joint contributions of grey and white matter electrodes for speech activity detection in a brain-computer interface.

Roles of ventral versus dorsal pathways in language production: An awake language mapping study.

Human language is organized along two main processing streams connecting posterior temporal cortex and inferior frontal cortex in the left hemisphere, travelling dorsal and ventral to the Sylvian fissure. Some views propose a dorsal motor versus ventral semantic division. Others propose division by combinatorial mechanism, with the dorsal stream responsible for combining elements into a sequence and the ventral stream for forming semantic dependencies independent of sequential order. We acquired data from direct cortical stimulation in the left hemisphere in 17 neurosurgical patients and subcortical resection in a subset of 10 patients as part of awake language mapping. Two language tasks were employed: a sentence generation (SG) task tested the ability to form sequential and semantic dependencies, and a picture-word interference (PWI) task manipulated semantic interference. Results show increased error rates in the SG versus PWI task during subcortical testing in the dorsal stream territory, and high error rates in both tasks in the ventral stream territory. Connectivity maps derived from diffusion imaging and seeded in the tumor sites show that patients with more errors in the SG than in the PWI task had tumor locations associated with a dorsal stream connectivity pattern. Patients with the opposite pattern of results had tumor locations associated with a more ventral stream connectivity pattern. These findings provide initial evidence using fiber tract disruption with electrical stimulation that the dorsal pathways are critical for organizing words in a sequence necessary for sentence generation, and the ventral pathways are critical for processing semantic dependencies.

The Quest for more Research on Painful Diabetic Neuropathy.

A 62-year-old diabetologist diagnosed himself to have diabetes type-2, with an HbA1c of 9.5. Five months after lifestyle intervention and a multi-drug approach, HbA1c was 6.3, systolic blood pressure was below 135mmHg and BMI reduced to 27. But he suffered from severe painful diabetic neuropathy. Therefore he decided to visit his friend, a famous neuroscientist at an even more famous university. He asked him several plain questions: 1. What is the natural course of painful diabetic neuropathy? 2. Why do I have, despite almost normalizing HbA1c, more problems than before? 3. Are you sure my problems are due to diabetes or should we do a nerve biopsy? 4. Are there imaging techniques helpful for the diagnosis of this diabetic complication, starting in the distal nerve endings of the foot and slowly moving ahead? 5. Can you suggest any drug, specific and effective, for relieving painful diabetic neuropathy? This review will use the experts' answers to the questions of the diabetologist, not only to give a summary of the current knowledge, but even more to highlight areas of research needed for improving the fate of patients with painful diabetic neuropathy. Based on the unknowns, which exceed the knowns in diabetic neuropathy, a quest for more public support of research is made.

Evidence accumulation as a model for lexical selection.

We propose and demonstrate evidence accumulation as a plausible theoretical and/or empirical model for the lexical selection process of lexical retrieval. A number of current psycholinguistic theories consider lexical selection as a process related to selecting a lexical target from a number of alternatives, which each have varying activations (or signal supports), that are largely resultant of an initial stimulus recognition. We thoroughly present a case for how such a process may be theoretically explained by the evidence accumulation paradigm, and we demonstrate how this paradigm can be directly related or combined with conventional psycholinguistic theory and their simulatory instantiations (generally, neural network models). Then with a demonstrative application on a large new real data set, we establish how the empirical evidence accumulation approach is able to provide parameter results that are informative to leading psycholinguistic theory, and that motivate future theoretical development.

Specifying the role of the left prefrontal cortex in word selection.

Word selection allows us to choose words during language production. This is often viewed as a competitive process wherein a lexical representation is retrieved among semantically-related alternatives. The left prefrontal cortex (LPFC) is thought to help overcome competition for word selection through top-down control. However, whether the LPFC is always necessary for word selection remains unclear. We tested 6 LPFC-injured patients and controls in two picture naming paradigms varying in terms of item repetition. Both paradigms elicited the expected semantic interference effects (SIE), reflecting interference caused by semantically-related representations in word selection. However, LPFC patients as a group showed a larger SIE than controls only in the paradigm involving item repetition. We argue that item repetition increases interference caused by semantically-related alternatives, resulting in increased LPFC-dependent cognitive control demands. The remaining network of brain regions associated with word selection appears to be sufficient when items are not repeated.

Double dissociation of the roles of the left and right prefrontal cortices in anticipatory regulation of action.

Recent actions can benefit or disrupt our current actions and the prefrontal cortex (PFC) is thought to play a major role in the regulation of these actions before they occur. The left PFC has been associated with overcoming interference from past events in the context of language production and working memory. The right PFC, and especially the right IFG, has been associated with preparatory inhibition processes. But damage to the right PFC has also been associated with impairment in sustaining actions in motor intentional disorders. Moreover, bilateral dorsolateral PFC has been associated with the ability to maintain task-sets, and improve the performance of current actions based on previous experience. However, potential hemispheric asymmetries in anticipatory regulation of action have not yet been delineated. In the present study, patients with left (n=7) vs. right (n=6) PFC damage due to stroke and 14 aged- and education-matched controls performed a picture naming and a verbal Simon task (participants had to say "right" or "left" depending on the color of the picture while ignoring its position). In both tasks, performance depended on the nature of the preceding trial, but in different ways. In the naming task, performance decreased if previous pictures were from the same rather than from different semantic categories (i.e., semantic interference effect). In the Simon task, performance was better for both compatible (i.e., response matching the position of the stimulus) and incompatible trials when preceded by a trial of the same compatibility (i.e. Gratton effect) relative to sequential trials of different compatibility. Left PFC patients were selectively impaired in picture naming; they had an increased semantic interference effect compared to both right PFC patients and aged-matched controls. Conversely, right PFC patients were selectively impaired in the Simon task compared to controls or left PFC patients; they showed no benefit when sequential trials were compatible (cC vs. iC trials) or a decreased Gratton effect. These results provide evidence for a double dissociation between left and right PFC in the anticipatory regulation of action. Our results are in agreement with a preponderant role of the left PFC in overcoming proactive interference from competing memory representations and provide evidence that the right PFC, plays a role in sustaining goal-directed actions consistent with clinical data in right PFC patients with motor intentional disorders.

Health care situation of patients with relapsing-remitting multiple sclerosis receiving immunomodulatory therapy: a retrospective survey of more than 9000 German patients with MS.

BACKGROUND AND PURPOSE: First-line immunomodulatory treatment with interferon-beta or glatiramer acetate is accepted as effective basic therapy in patients with relapsing-remitting multiple sclerosis (RRMS). However, a considerable portion of patients does not benefit from treatment. METHOD: To test basic immunomodulatory treatment under real-life conditions, we retrospectively analyzed clinical and subclinical disease activity within the last 12 months in a cohort of 9916 patients with RRMS, of which 7896 patients were receiving immunomodulatory treatment. In addition, factors associated with treating physicians' consideration of a switch of current treatment were assessed. RESULTS: The majority of treated patients (approximately 66%) experienced no relapse during the last 12 months. However, in line with common clinical study findings, about one-third (approximately 34%) of patients had relapses. When MRI data were taken into account, approximately one-quarter (24%) of patients would qualify for therapy escalation to monoclonal antibody natalizumab. Relapse rate in the preceding year (the year directly prior to the start of retrospective data collection) was strongly associated with considering a switch of current treatment. In addition, therapy switch was more often considered in younger patients. The relationship between MRI findings in the absence of clinical symptoms and consideration of a treatment switch was not as clear. CONCLUSIONS: This analysis confirms that disease progression occurs in a considerable proportion of patients with RRMS. These patients should be considered for therapy escalation.

Quality of life in 1000 patients with early relapsing-remitting multiple sclerosis.

BACKGROUND AND PURPOSE: To examine the quality of life (QoL) in a large cohort of untreated patients with relapsing-remitting multiple sclerosis (RRMS) and to investigate the impact of intramuscular (IM) interferon beta-1a (IFNbeta-1a) treatment. METHODS: Prospective, observational, open-label, multicentre study conducted in Germany. Untreated patients with RRMS who initiated treatment with IM IFNbeta-1a were included and followed for 12 months. QoL was measured using the EQ-5D questionnaire. Clinical response was assessed by relapse rate and disability (Expanded Disability Status Scale; EDSS). RESULTS: A total of 1157 patients were included [mean age 37.6 years, median disease duration 13 months, mean relapse rate 1.7 (95%CI: 1.58-1.73), median EDSS score 2.0]. Relapse rate was reduced to 0.6 at 12 months (95%CI: 0.51-0.69, P < 0.0001). EDSS did not change significantly. At baseline, QoL was considerably lower in MS patients compared with the general German population, but was improved after treatment initiation [utilities of EQ-5D: 0.77 (95%CI: 0.75-0.78) vs. 0.75 (95%CI: 0.74-0.76) at baseline, 95%CI for difference: 0.01-0.03, P = 0.0046]. Higher disease activity and inability to work were negative predictors of QoL. 14.7% of patients were incapable of working for MS-related reasons. CONCLUSIONS: Quality of life is considerably impaired in early stages of MS. Treatment initiation with IM IFNbeta attenuates MS disease activity and improves QoL. Inability to work early during the disease is a major challenge for the social security systems.

Conservative surgical treatment of low-grade urothelial carcinoma in the renal allograft recipient: a case report.

Development of urothelial carcinoma in a renal allograft is rare. We report the case of 52-year-old male patient who developed chronic renal failure secondary to Balkan endemic nephropathy and underwent renal allotransplantation. The patient who developed low-grade pTa urothelial carcinoma in the left contracted kidney at 3 years after transplantation and underwent nephroureterectomy. Three years later, the same neoplastic process was observed in the renal allograft. Preoperative estimation for allograft tumor recurrence and progression included percutaneous tumor biopsy followed by cytopathological, histological, and cytogenetic analysis. Cytopathology revealed well-differentiated urothelial tumor cells. Histopathologic analysis showed low-grade urothelial carcinoma. Cytogenetic examination demonstrated that the tumor originated from the recipient suggesting a low malignant potential of carcinoma. Based on these findings, we decided to perform a right-side nephroureterectomy and graft-sparing procedure, which resulted in preservation of allograft function. In this report we discussed the prognostic factors, which are the basis for rational therapeutic approaches in these patients.

Malignant eccrine spiradenoma of the vulva: a case report and review of the literature.

Malignant eccrine spiradenoma is a rare skin tumor of sweat gland origin. We present the first reported case of this tumor in the female genitalia. Due to the rarity of this tumor, there has yet to be an established standard of care. The present case is that of a 41-year-old woman with malignant eccrine spiradenoma of the periclitoral region. She had an 18-month history of a recurrent, painful mass adjacent to the clitoris. Her diagnosis was made after excision of the cystic tumor. The patient then underwent a partial radical vulvectomy with bilateral sentinel lymph node sampling. As malignant eccrine spiradenoma is a rare tumor, no standard care exists for treatment and postoperative management. Based on our review of the literature, wide local excision appears to be the preferred initial treatment. Furthermore, adjuvant chemotherapy and/or radiation does not seem to improve survival in patients with advanced or recurrent cancer. Although lymph node sampling and/or lymphadenectomy is frequently reported in the treatment of this tumor, hematogenous metastasis can also occur. Therefore, these patients require close postoperative follow-up for recurrent disease.

Leaching of N-nitrosodimethylamine (NDMA) in turfgrass soils during wastewater irrigation.

N-nitrosodimethylamine (NDMA) is a carcinogenic by-product of chlorination that is frequently found in municipal wastewater effluent. NDMA is miscible in water and negligibly adsorbed to soil, and therefore may pose a threat to ground water when treated wastewater is used for landscape irrigation. A field study was performed in the summer months under arid Southern California weather conditions to evaluate the leaching potential of NDMA in turfgrass soils during wastewater irrigation. Wastewater was used to irrigate multiple turfgrass plots at 110 to 160% evapotranspiration rate for about 4 mo, and leachate was continuously collected and analyzed for NDMA. The treated wastewater contained relatively high levels of NDMA (114-1820 ng L(-1); mean 930 ng L(-1)). NDMA was detected infrequently in the leachate regardless of the soil type or irrigation schedule. At a method detection limit of 2 ng L(-1), NDMA was only detected in 9 out of 400 leachate samples and when it was detected, the NDMA concentration was less than 5 ng L(-1). NDMA was relatively persistent in the turfgrass soils during laboratory incubation, indicating that mechanisms other than biotransformation, likely volatilization and/or plant uptake, contributed to the rapid dissipation. Under conditions typical of turfgrass irrigation with wastewater effluent it is unlikely that NDMA will contaminate ground water.

Expression of cyclooxygenase-2 in fine-needle aspirates from breast carcinoma and benign breast diseases.

Numerous studies have demonstrated that the levels of cyclooxygenase (COX), the enzyme that catalyzes the conversion of arachidonic acid to prostaglandin H(2), and of prostaglandins are higher in various tumors and cells during inflammation than in normal tissues. The aim of the present study was to analyze whether COX-2 isoform expression was noticeably higher in fine-needle aspirates (FNA) from breast carcinoma than in FNA from fibroadenoma and fibrocystic breast tissue. COX-2 expression was detected by immunocytochemical (IC) staining and was analyzed by microscopic scoring and computer gray-scale analysis. Evaluation of COX-2 IC positivity in FNA from three groups of patients (nine with breast carcinoma, nine with fibroadenoma, eight with fibrocystic breasts) revealed high COX-2 IC positivity in the majority of patients with breast carcinoma and low or absent COX-2 IC positivity in patients with fibrocystic breast changes. In addition, low or medium COX-2 IC positivity was found in the majority of patients with fibroadenoma, only three of these patients having high COX-2 IC positivity.

Precocial diving and patent foramen ovale in bearded seal (Erignathus barbatus) pups.

In this study we used a Doppler ultrasonic device, in combination with a sonographic contrast medium, to test whether free-living bearded seal (Erignathus barbatus) pups have a closed (anatomically or functionally) foramen ovale. A total of 17 examinations were performed on 12 individual pups with a body mass range of 29-103 kg (0-21 days old). These examinations showed that young bearded seal pups dive with a patent foramen ovale (PFO), and that this structure starts to close, at least functionally, during the 2nd week of life. The wide range in the timing of closure (one animal 21 days old still had a PFO) indicates that a closed foramen ovale is not crucial for the diving that these seals perform at this age. The primary function of diving during the 1st week of life is to avoid surface predation and only moderate diving ability is sufficient to achieve this goal. However, some of the diving performed by bearded seal pups with a PFO would likely be sufficient to create intravenous bubble formation during breath-hold diving in humans. Special adaptations in the seals, such as collapsible lungs and diving with minimal lung air volume, probably prevent this from happening.

ONYX-015: mechanisms of action and clinical potential of a replication-selective adenovirus.

Accumulated knowledge in the molecular processes of tumour development combined with the availability of genetically modified viruses resemble the basis for new promising cancer therapeutics. The main advantages of employing replication-competent viruses are achievement of tumour selective killing and amplification of their oncolytic potential within the tumour mass. In this review, we describe the development of ONYX-015, one of the first and most advanced replication-competent viruses for cancer therapy. We discuss the molecular biology of this therapeutic approach and the interesting results obtained with this virus in clinical trials.

Transcriptional activation of TRADD mediates p53-independent radiation-induced apoptosis of glioma cells.

Survival of patients with Glioblastoma Multiforme (GM), a highly malignant brain tumor, remains poor despite concerted efforts to improve therapy. The median survival of patients with GM has remained approximately 1 year regardless of the therapeutic approach. Since radiation therapy is the most effective adjuvant therapy for GM and nearly half of GM tumors harbor p53 mutations, we sought to identify genes that mediate p53-independent apoptosis of GM cells in response to ionizing radiation. Using broad-scale gene expression analysis we found that following radiation treatment, TRADD expression was induced in a uniquely radiosensitive GM cell line but not in radioresistant GM cell lines. TRADD over-expression killed GM cells and activated NF-kappa B. We found that blocking the TRADD-mediated pathway using a dominant-negative mutant of FADD (FADD-DN) enhanced radiation resistance of GM cells, as reflected in both susceptibility to apoptosis and clonogenic survival following irradiation. Conversely, stable expression of exogenous TRADD enhanced radiation-induced apoptosis of GM cell lines, reflecting the biological significance of TRADD regulation in p53-independent apoptosis. These findings generate interest in utilizing TRADD in gene therapy for GM tumors, particularly in light of its dual function of directly inducing rapid apoptosis and sensitizing GM cells to standard anti-neoplastic therapy.

[Acute tongue and pharyngeal spasms during changeover from clozapine to amisulpride. A case example]. / Akute Zungen-Schlund-Krämpfe bei Umstellung von Clozapin auf Amisulprid. Ein Fallbeispiel.

With the advent of atypical antipsychotics, quality of life for patients with schizophrenia has improved significantly. The positive effects are based not only on the compliance-enhancing reduction of extrapyramidal side effects but also due to improved cognitive function and social integration, shorter duration, and overall reduction of hospital treatment. Numerous controlled studies have addressed the issue of switching patients from typical to atypical antipsychotics. However, published data on substituting one atypical antipsychotic for another are preliminary and very limited. This case report describes acute side effects which occurred when switching from clozapine to amisulpride and discusses mechanisms on the receptor level. Regarding these two agents, the clinical relevance of the knowledge of receptor profiles is outlined.

[Hemiparesis as a sequela of traumatic pseudoaneurysm of the carotid bifurcation]. / Hemiparese als Folge eines traumatischen Pseudoaneurysmas der Carotisbifurkation.

HISTORY AND CLINICAL FINDINGS: A 20-year-old patient was referred to our clinic after sudden onset of a left-sided hemiparesis. His past history revealed a severe trauma 4 years ago, including multiple bone fractures, rupture of the spleen, as well as renal failure, and an acute respiratory distress syndrome, from which he showed good recovery. At that time no central-nervous symptoms could be found. However, eighteen months ago, he complained about a transient weakness of his left arm and leg. INVESTIGATIONS: Examination of the cerebral arteries by duplex-sonography showed an aneurysm on the bifurcation of the right carotid artery with a peripheral flow-reduction. This could be confirmed by CT- and MR-based angiography, which also revealed a reopened embolic occlusion of the M1-segment of the right middle cerebral artery. On CT and diffusion weighted imaging there was evidence of an ischemic infarction pattern. TREATMENT AND COURSE: Under anticoagulation therapy with heparin the patient showed complete recovery from his symptoms. Duplex-sonography as well as MR-angiography documented a complete reopening of the primarily occluded middle cerebral artery. Finally, surgical reconstruction of the aneurysmatic part of the vessel was done. CONCLUSION: This case illustrates the potential risk of a traumatic aneurysm as a potential source of ischemic brain infarctions. We emphasize the importance of imaging the cerebral arteries in traumatic patients, even in the absence of initial neurological symptom.

Opposing effects of Ras on p53: transcriptional activation of mdm2 and induction of p19ARF.

Mdm2 acts as a major regulator of the tumor suppressor p53 by targeting its destruction. Here, we show that the mdm2 gene is also regulated by the Ras-driven Raf/MEK/MAP kinase pathway, in a p53-independent manner. Mdm2 induced by activated Raf degrades p53 in the absence of the Mdm2 inhibitor p19ARF. This regulatory pathway accounts for the observation that cells transformed by oncogenic Ras are more resistant to p53-dependent apoptosis following exposure to DNA damage. Activation of the Ras-induced Raf/MEK/MAP kinase may therefore play a key role in suppressing p53 during tumor development and treatment. In primary cells, Raf also activates the Mdm2 inhibitor p19ARF. Levels of p53 are therefore determined by opposing effects of Raf-induced p19ARF and Mdm2.

Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015).

The adenovirus mutant dl1520 (ONYX-015) does not express the E1B-55K protein that binds and inactivates p53. This virus replicates in tumor cells with mutant p53, but not in normal cells with functional p53. Although intra-tumoral injection of dl1520 shows promising responses in patients with solid tumors, previous in vitro studies have not established a close correlation between p53 status and dl1520 replication. Here we identify loss of p14ARF as a mechanism that allows dl1520 replication in tumor cells retaining wild-type p53. We demonstrate that the re-introduction of p14ARF into tumor cells with wild-type p53 suppresses replication of dl1520 in a p53-dependent manner. Our study supports the therapeutic use of dl1520 in tumors with lesions within the p53 pathway other than mutation of p53.