McLeod syndrome: Five new pedigrees with novel mutations.

OBJECTIVE: To present five new McLeod Syndrome (MLS) pedigrees with novel XK gene mutations, review the literature of this disorder, and discuss the typical and atypical clinical features noted with these new mutations. METHODS: This is a multi-center retrospective review of five MLS cases with novel gene mutations. Genotypic and phenotypic information has been obtained from each center. RESULTS: Five novel mutations are reported in this Case series. New clinical findings include prolonged asymptomatic elevated creatine kinase (CK) levels, vocal tics, presence of obstructive sleep apnea (OSA), and one patient of Vietnamese ethnicity. CONCLUSIONS: We expand on the clinical and genetic spectrum of MLS demonstrating the clinical variability of MLS.

Chemogenetic stimulation of the infralimbic cortex reverses alcohol-induced fear memory overgeneralization.

Post-traumatic stress disorder (PTSD) and alcohol use disorder (AUD) are often comorbid. Drinking tends to increase following trauma, which may exacerbate PTSD-related symptoms. Despite a clear relationship between excessive alcohol use and PTSD, how alcohol impacts the expression of traumatic fear remains unclear. This study aims to determine the neurobehavioral impact of chronic alcohol (ethanol; EtOH) on the expression of established fear memories in C57BL/6 N mice. We show that chronic EtOH selectively augments cued fear memory generalization and impairs fear extinction retrieval, leaving the expression of the original cued response intact. Immunohistochemistry for Arc/arg3.1 (Arc) revealed EtOH-induced decreases in Arc expression in the infralimbic cortex (IL) and basolateral amygdala complex (BLA) that were associated with cued fear memory overgeneralization. Chemogenetic stimulation of IL pyramidal neurons reversed EtOH-driven fear memory overgeneralization, identifying a role for the IL in cued fear memory precision. Considering the modulatory influence of the IL over conditioned fear expression, these data suggest a model whereby chronic EtOH-driven neuroadaptations in the IL promote fear memory overgeneralization. These findings provide new mechanistic insight into how excessive alcohol use, following exposure to a traumatic event, can exacerbate symptoms of traumatic fear.

A new multi-channel Mach probe measuring the radial ion flow velocity profile in the boundary plasma of the W7-X stellarator.

Ion flow velocity measurement in the edge and scraper-off layer region is beneficial to understand the confinement related phenomenon in fusion devices such as impurity transport and plays an important role in impurity control. During the Wendelstein 7-X (W7-X) operation phase 1.2a, a multi-channel (MC) Mach probe mounted on the multi-purpose manipulator has been used to measure radial profiles of edge ion flow velocity. This MC-Mach probe consists of two polar and two radial arrays of directional Langmuir pins (28 pins in total) serving for different aims, of which the polar arrays could obtain a polar distribution of ion saturation current, while the radial arrays can be used to study the dynamic process of a radially propagated event. In this paper, we report the observation of the radially outward propagation of a low frequency mode with a speed of around 200 m/s. The first measurement of the radial ion flow velocity profile using the MC-Mach probe in the boundary plasma of the W7-X with an island divertor will also be presented.

Operationalizing and validating disciplinary literacy in secondary education.

The goal of this study was to define the construct and establish the validity of disciplinary literacy, which has recently gained attention from the implementation of the Common Core State Standards (National Governors Association Center for Best Practices & Council of Chief State School Officers in Common Core State Standards for English language arts & literacy in history/social studies, science, and technical subjects [PDF]. Authors, Washington, DC, 2010). After defining disciplinary literacy in the four core disciplines of English language arts, science, history and social studies, and mathematics, scales were developed and administered to a snowball sample of professionals nationwide, with 857 respondents. The data showed evidence of disciplinary literacy as a multidimensional construct with three related factors: source literacy, analytic literacy, and expressive literacy. Based on EFA and CFA results, we can conclude that there are at least three types of literacy in operation among the four core disciplines. The three factors of literacy varied significantly by the four core disciplines of English/language arts (ELA), science, history and social studies, and mathematics, supporting the notion that each discipline uses literacy uniquely. This is the first study of its kind to attempt to define, quantify, and validate the construct of disciplinary literacy.

The performance of Bispectral Index in children during equi-MAC halothane vs. sevoflurane anaesthesia.

BACKGROUND AND OBJECTIVE: The reliability of the Bispectral Index for evaluating and monitoring the depth of general anaesthesia in children is not as great as for that in adults. Therefore we analysed Bispectral Index performance in children by comparing changes in Bispectral Index values during a standardized and equipotent anaesthetic regimen using either halothane or sevoflurane for the induction and maintenance of general anaesthesia. Special interest was focussed on excitation during induction, and whether it was associated with simultaneous changes in Bispectral Index scores. METHODS: Twenty children (3-15 yr, ASA I-II) scheduled for general surgery were randomly allocated to either halothane (10 patients) or sevoflurane group (10 patients). Anaesthesia was induced by 3% halothane or 7% sevoflurane, either agent administered with 50% N2O in oxygen for 5 min, the period from the beginning of induction until intubation. Thereafter, anaesthesia was maintained by the respective volatile agent at 1 MAC (minimum alveolar concentration; in addition to 70% N2O in oxygen) and supplemented with remifentanil infusion adjusted to maintain the heart rate and mean arterial pressure to within 20% of the baseline values. Excitation at induction was defined as involuntary muscular movements. RESULTS: Sevoflurane induction produced a more rapid depression in Bispectral Index than halothane, the mean difference being greatest (47 Bispectral Index score) at 105 s. Excitation occurred in three patients during sevoflurane induction, which coincided with increases in Bispectral Index values in two of the three patients. During the maintenance phase at 1 MAC, the Bispectral Index (mean +/- SD) was 57+/-7 for halothane and 47+/-9 for sevoflurane (P < 0.05). The remifentanil doses did not differ between both groups. CONCLUSION: In children, halothane anaesthesia was associated with higher Bispectral Index values than sevoflurane when administered at 1 MAC. Large individual variation in Bispectral Index occurred within both groups. Due to these limitations, one should be cautious when interpreting paediatric Bispectral Index data.

Bilateral subthalamic stimulation in Parkin and PINK1 parkinsonism.

OBJECTIVES: To study the frequency of different gene mutations in patients with early-onset parkinsonism and bilateral subthalamic nucleus deep brain stimulation (STN-DBS) and the short- and long-term surgical outcome in mutation-positive (MUT+) and -negative (MUT-) patients. METHODS: Eighty patients with disease onset at age

Investigations to the synthesis of n.c.a. [18F]FClO3 as electrophilic fluorinating agent.

An approach to synthesize the electrophilic fluorinating agent no-carrier-added (n.c.a.) [18F]perchloryl fluoride ([18F]FClO3) in superacidic media in the presence of KClO4 or anhydrous perchloric acid starting from [18F]fluoride was demonstrated in this study. However, the radiochemical yields were low (1-6%) and poorly reproducible. Fluorosulphonic acid proved to be an essential intermediate as revealed by non-radioactive experiments. A key problem in the preparation of [18F]FClO3 is the assumed kinetic inhibition due to the unfavourable stoichiometric ratio of the ClO4 moiety to [18F]HSO3F.

Electrical high frequency stimulation of the caudate nucleus induces local GABA outflow in freely moving rats.

Electrical high frequency stimulation of the globus pallidus internus or the subthalamic nucleus has beneficial motor effects in advanced Parkinson's disease. The mechanisms underlying these clinical results remain, however, unclear. From previous in vitro studies it is proposed that the gamma-aminobutyric acid (GABA) system is involved in the effectiveness of electrical high frequency stimulation (HFS). In these experiments, we developed an in vivo model that allows for simultaneous and collocated microdialysis and HFS by electrical pulses of 124 Hz in the caudate nucleus of freely moving rats. GABA and glutamate outflow were sampled by microdialysis technique and quantified after pre-column o-phthaldialdehyde sulphite derivatization using HPLC with electrochemical detection. As the most outstanding result, we could demonstrate that high frequency stimulation significantly increased basal GABA outflow without affecting glutamate levels in freely moving rats.

A systemic route for drug loading to lymphatic phagocytes.

Lymph nodes are primary germination and proliferation sites for many types of pathogens. Maintaining therapeutic levels of appropriate chemotherapeutic agents in the lymph node tissue is critical for the treatment of both infection and cancer. This study was intended to develop a systemic route for loading lymph node phagocytes with drugs, using a lymph node specific nanocarrier. The latter is assembled as a 10-15 nm particle with a drug-carrying core and a phagocyte-homing poly(1-->6)-alpha-d-glucose based interface. Biokinetics and microdistribution of the model carrier were investigated in vivo. Nanocarrier accumulation in lymph nodes reached 30-35% dose/g in central lymph nodes, with deposition in various phagocytic cell populations. The latter included cells harboring inhaled microparticles translocated to lymph nodes from the lungs. In view of the nanocarrier ability to transport and release significant amounts of various drug substances, the data suggests feasibility of systemic drug loading to lymphatic phagocytes and, through drug release, to the neighboring cells.

Propacetamol and diclofenac alone and in combination for analgesia after elective tonsillectomy.

BACKGROUND: Diclofenac and paracetamol have different mechanisms and sites of action. Therefore, we tested if their combination is more effective for analgesia after tonsillectomy than either drug alone with respect to rescue analgesic consumption and visual analog scale values. METHODS: The analgesic effects of intravenously administered propacetamol (injectable pro-drug of paracetamol) and diclofenac or a combination on postoperative pain were compared in 71 adult elective tonsillectomy patients in a randomized, double-blind study. After induction of anesthesia the patients received monotherapy with 2 g propacetamol (n = 25) or 75 mg diclofenac (n = 25), or a combined treatment with 2 g propacetamol and 75 mg diclofenac (n = 21) in physiologic saline as an infusion. Postoperatively the propacetamol dosage was repeated twice and diclofenac once on the ward. Oxycodone (0.03 mg kg(-1)) was used as a rescue analgesic by patient-controlled analgesia. RESULTS: On average the patients needed oxycodone 15.3, 13.2 and 10.6 times in the propacetamol, diclofenac and combination groups, respectively (NS). A verbal rating scale and a visual analog scale were employed for assessing post-tonsillectomy pain, nausea and patient satisfaction in all groups. No statistically significant differences were found between the groups. Twelve of the 25 (48%) patients having received propacetamol complained of pain at the cannulation site. CONCLUSION: Combined treatment with propacetamol and diclofenac with the dosages used provided clinically only a minor advantage over monotherapy with propacetamol or diclofenac with respect to postoperative analgesia or the incidence of side-effects in adult tonsillectomy patients.

Synthesis of a macromolecular camptothecin conjugate with dual phase drug release.

A water soluble macromolecular conjugate of camptothecin (CPT) with a new, dual phase hydrolytic drug release mechanism was prepared on the basis of a 60 kDa biodegradable hydrophilic "stealth" polyacetal, poly(1-hydroxymethylethylene hydroxy-methyl formal). Succinamido-glycinate was used as a prodrug releasing group. A model preparation with 7.5% CPT content w/w was water soluble. The lipophilic camptothecin prodrug, camptothecin-(O20)-succinimidoglycinate, was released from the conjugate with t(1/2) = 2.2 +/- 0.1 h in rodent plasma. The blood clearance in a rodent model as measured by CPT was release limited, t(1/2) = 2.1 +/- 0.2 h, while the conjugate half-life was 14.2 +/- 1.7 h. In a xenograft tumor model, the conjugate demonstrated higher antineoplastic efficacy than CPT at a less than equitoxic dose. This improved therapeutic window is in line with the modified drug pharmacokinetics and with camptothecin release in a stabilized lipophilic prodrug form. Regulation of prodrug release and hydrolysis rates through linker structure modification will open the way to further improve both pharmacokinetics and pharmacodynamics.

New genes encoding subunits of a cytochrome bc1-analogous complex in the respiratory chain of the hyperthermoacidophilic crenarchaeon Sulfolobus acidocaldarius.

The soxL gene from Sulfolobus acidocaldarius (DSM 639) encodes a Rieske iron-sulfur protein. In this study we report the identification of two open reading frames in its downstream region. The first one, named soxN, codes for a membrane protein bearing a resemblance to the b-type cytochromes of the cytochrome bc1 and b6f complexes. The protein is predicted to contain at least 10 transmembrane helices and features the two conserved histidine pairs coordinating the heme groups of these cytochromes. The second open reading frame, named odsN, encodes a soluble protein of unknown function. The genomic region displays a complex transcription pattern. Northern blot and RT-PCR analyses revealed the presence of mono- and bi-cistronic transcripts as well as a tri-cistronic transcript of soxL and cbsAB, encoding the mono-heme cytochrome b558/566. Phylogenetic analyses of the genes of the soxLN pair and of other archaeal gene pairs encoding Rieske iron-sulfur proteins and b-type cytochromes revealed an identical branching patterns for both protein families, suggesting an evolutionary link of these genes provided by the functional interaction of the proteins. On the basis of the findings of this study and the previously studied properties of the soxL and cbsA proteins, we propose the occurrence of a novel cytochrome bc1-analogous complex in the membranes of Sulfolobus, consisting of the cytochrome b homolog soxN, the Rieske protein soxL, the high potential cytochrome cbsA, as well as the non-redox-active subunits cbsB and odsN.

[Applications for a robot in the lateral skull base. Evaluation of robot-assisted mastoidectomy in an anatomic specimen]. / Einsatz eines Roboters an der lateralen Schädelbasis. Evaluation einer robotergesteuerten Mastoidektomie am anatomischen Präparat.

In the past decade, a great variety of robot systems have been applied in numerous areas of life. In the public health system, robots are increasingly used in the operating theater. The potential for reproducibility and predictability was one of the main arguments for the use of robots in orthopedic treatment of bones, especially the implantation of a cementless total hip replacement. In otorhinolaryngological surgery (ENT), different hearing aids were developed: the cochlea implant for the deaf or the totally implantable hearing aid for the hearing impaired. Their site of implantation is localized in the lateral skull base. Removal of the bone mass with the reamer requires both great precision and considerable physical effort on the part of the surgeon, which does not result in an ergonomic operating technique. The following project describes the evaluation of processing parameters for a robot-assisted mastoidectomy to expose an implantation bed. The goal was to establish different parameters for robot-controlled reaming in the calotte or mastoid. In addition, several parameters were tested for their influence on surface structure, procedure reliability, and quality as well as the ability of the Mayfield clip to stabilize the head during the operation.

Synthesis of novel 2-azabicyclo[2.2.0]- and [2.1.1]hexanols.

Methyl- and phenyl-substituted N-(ethoxycarbonyl)-2-azabicyclo[2.2.0]hex-5-enes 6 were reacted with NBS in wet DMSO to afford bromohydrins. Mixtures of unrearranged 6-exo-bromo-5-endo-hydroxy-2-azabicyclo[2.2.0]hexanes 7a,b and rearranged 5-anti-bromo-6-anti-hydroxy-2-azabicyclo[2.1.1]hexanes 8a,b were formed stereoselectively from the parent alkene 6a and 4-methyl alkene 6b. The 5-methyl alkene 6c affords only unrearranged bromohydrin 7c and dibromohydrin 9. By contrast, solely rearranged 3-endo-substituted-2-azabicyclo[2.1.1]hexane bromohydrins 8d-f result from additions to 3-endo-methyl alkene 6d, 3-endo-4-dimethyl alkene 6e, and 3-endo-phenyl alkene 6f. As an alternative route to bromohydrins, the parent 5,6-exo-epoxide 10a and 5-endo-methyl-5,6-exo-epoxide 10b were ring opened with bromine/triphenylphosphine to afford unrearranged 5-endo-bromo-6-exo-hydroxy-2-azabicyclo[2.2.0]hexanes 11a,b, while the 3-endo-methyl epoxide 10c afforded solely the rearranged 5-anti-bromo-6-anti-hydroxy-3-exo-methyl-2-azabicyclo[2.1.1]hexane isomer 8g. Tributyltin hydride reduction of bromohydrins 7a,b and 11a afforded novel 2-azabicyclo[2.2.0]hexan-5-ols 13a,b and -6-ol 14, and bromohydrins 8a,b, 8d-g afforded new 2-azabicyclo[2.1.1]-hexan-5-ols 15a,b and 15d-g.

Tracheal intubation after induction of anesthesia in children with propofol--remifentanil or propofol-rocuronium.

PURPOSE: To compare the intubating conditions after remifentanil-propofol with those after propofol-rocuronium combination with the aim of determining the optimal dose of remifentanil. METHODS: In a randomized, double-blind study 80 healthy children aged three to nine years were assigned to one of four groups (n=20): 2 or 4 microgxkg(-1) remifentanil (Re2 or Re4); 2 microgxkg(-1) remifentanil and 0.2 mgxkg(-1) rocuronium (Re2-Ro0.2); 0.4 mgxkg(-1) rocuronium (Ro0.4). After atropine, remifentanil was injected over 30 sec followed by 3.5 mgxkg(-1) propofol and rocuronium. After 60 sec, laryngoscopy and intubation were attempted. Intubating conditions were assessed as excellent, good or poor based on ease of ventilation, jaw relaxation, position of the vocal cords, and coughing to intubation. RESULTS: In all children intubation was successful. Overall intubating conditions were better (P < 0.01), and the frequency of excellent conditions, 85%, was higher (P < 0.01) in the Re4 group than in the Ro0.4 group. No child manifested signs of muscular rigidity. In the remifentanil groups, arterial pressure decreased 11-13% and heart rate 6-9% after anesthetic induction, and remained at that level throughout the study. CONCLUSION: The best intubating conditions were produced by the combination of 4 microgxkg(-1) remifentanil and 3.5 mgxkg(-1) propofol. It provided excellent or good intubating conditions in all children without causing undue cardiovascular depression.

A voice-controlled robotic assistant for neuroendoscopy.

This paper describes experiments with a voice-controlled robot system to be used in endoscopic neurosurgery. The robot was a modified version of the robot described in previous publications of the group at Fraunhofer IPA and HSK. To control the robot a voice-controlled user interface was developed. The experiments were conducted on cadavers for three standard approaches in neuroendoscopy. The goal was to gain experience with a voice-controlled user interface and also with the set-up and use of the robotic system under clinical conditions. The results indicate that modifications to the robot and user interface are necessary. However the overall feasibility of the application was demonstrated.

Transient neurological symptoms after spinal anaesthesia with hyperbaric 5% lidocaine or general anaesthesia.

Transient neurotoxicity of concentrated local anaesthetics has been thought to be the main reason for transient neurological symptoms after spinal anaesthesia. Profound musculoligamental relaxation by high doses of local anaesthetics may contribute to the development of postoperative musculoskeletal pain. In order to evaluate the role of the loss of strength of the supportive structures of the spine in the development of transient neurological symptoms, 60 patients (ASA I-II) undergoing minor orthopaedic, varicose vein or inguinal hernia operations were allocated randomly to receive spinal anaesthesia with hyperbaric lidocaine 50 mg ml-1 (85-100 mg) or balanced general anaesthesia with neuromuscular block. Patients were interviewed 24 h later and after 1 week they returned a written questionnaire. Transient neurological symptoms, consisting of pain in the buttocks or pain radiating symmetrically to the lower extremities, occurred in eight patients (27%) receiving spinal anaesthesia and in one patient (3%) receiving general anaesthesia (P < 0.05). We conclude that a transient neurotoxic effect of hyperbaric lidocaine 50 mg ml-1 is probably the main reason for transient neurological symptoms after spinal anaesthesia but musculoligamental relaxation may contribute to the development of low back or leg pain after both anaesthetic techniques.

Retigabine N-glucuronidation and its potential role in enterohepatic circulation.

The metabolism of retigabine in humans and dogs is dominated by N-glucuronidation (), whereas in rats, a multitude of metabolites of this new anticonvulsant is observed (). The comparison of the in vivo and in vitro kinetics of retigabine N-glucuronidation in these species identified a constant ratio between retigabine and retigabine N-glucuronide in vivo in humans and dog. An enterohepatic circulation of retigabine in these species is likely to be the result of reversible glucuronidation-deglucuronidation reactions. Rats did not show such a phenomenon, indicating that enterohepatic circulation of retigabine via retigabine N-glucuronide does not occur in this species. In the rat, 90% of retigabine N-glucuronidation is catalyzed by UDP-glucuronosyltransferase (UGT)1A1 and UGT1A2, whereas family 2 UGT enzymes contribute also. Of ten recombinant human UGTs, only UGTs 1A1, 1A3, 1A4, and 1A9 catalyzed the N-glucuronidation of retigabine. From the known substrate specificities of UGT1A4 toward lamotrigine and bilirubin and our activity and inhibition data, we conclude that UGT1A4 is a major retigabine N-glucuronosyl transferase in vivo and significantly contributes to the enterohepatic cycling of the drug.

Antitumor activity of Herceptin in combination with STEALTH liposomal cisplatin or nonliposomal cisplatin in a HER2 positive human breast cancer model.

Single agent antitumor activity of Herceptin, a humanized monoclonal antibody directed against HER2, has been demonstrated in numerous preclinical and clinical studies. Additionally, combination therapy with Herceptin and chemotherapy (CRx) has demonstrated additive antitumor activity in both preclinical models and early clinical trials. STEALTH (pegylated) liposomal (PL) cisplatin, also known as SPI-077, is currently in clinical trials for a variety of solid tumors. The three studies reported here discuss the antitumor activity of the combination of Herceptin and nonliposomal cisplatin or PL-cisplatin in two xenograft tumor models, initiated from the cell lines, BT474 and MDA453, that overexpress the oncogene, HER2. Herceptin alone had significant antitumor activity in all three experiments (p < 0.0001). Nonliposomal cisplatin and PL-cisplatin were both effective antitumor agents but, at tolerable dose levels, PL-cisplatin was superior to nonliposomal cisplatin (p < 0.0003). The effect of combining Herceptin with the chemotherapeutic cisplatin or PL-cisplatin, was most significant at moderate doses of H (0.5 mg/kg, p < 0.0001), but tended to be greater than either agent alone in all experiments. The combination of PL-cisplatin with Herceptin had statistically similar antitumor activity to that of nonliposomal cisplatin with Herceptin in all experiments. We conclude that combination therapy with PL-cisplatin and Herceptin results in significant antitumor activity with the potential for reducing toxicity in metastatic breast cancer patients.