Transition-metal-catalyzed direct arylation of (hetero)arenes by C-H bond cleavage.
The area of transition-metal-catalyzed direct arylation through cleavage of C-H bonds has undergone rapid development in recent years, and is becoming an increasingly viable alternative to traditional cross-coupling reactions with organometallic reagents. In particular, palladium and ruthenium catalysts have been described that enable the direct arylation of (hetero)arenes with challenging coupling partners--including electrophilic aryl chlorides and tosylates as well as simple arenes in cross-dehydrogenative arylations. Furthermore, less expensive copper, iron, and nickel complexes were recently shown to be effective for economically attractive direct arylations.


[Purpura fulminans related to paroxysmal nocturnal haemoglobinuria: a case report and literatures review].
Objective: To improve the understanding of the rare clinical presentation and management of purpura fulminans (PF) in patients with paroxysmal nocturnal haemoglobinuria (PNH). Methods: A case of PF occurring in PNH is reported, while the related literature review is conducted. Results: A 49-year-old male patient suffered from one-week history of fever, greenish-brown colour urine, multiple well demarcated and painful purpura of the head and neck. He had been reported to have two thromboembolic events during the 22-year course of PNH. Skin biopsy displayed classic PF features. Laboratory testing showed a high PNH clone, intravascular hemolysis and coagulation system changes. After sufficient anticoagulation and short course of glucocorticoid therapy, the clinical conditions were improved correspondingly. During a follow-up period of 6 month, there was no recurrence of thrombosis. Conclusion: PF should be considered in PNH patients with unexplained, quickly developed painful purpura. Extensive work-up should be performed to find out other potential thrombophilic risk factors after diagnosis of PF. Early diagnosis, adequate anticoagulation therapy and control hemolysis were essential to PF treatment occurring in PNH. The survival of patients and the qualities of life can be improved. The PNH clone detection is needed to evaluate the status of procoagulation and predict the risk of recurrent thrombosis.


Interfaces in Heterogeneous Catalysts: Advancing Mechanistic Understanding through Atomic-Scale Measurements.
Developing novel catalysts with high efficiency and selectivity is critical for enabling future clean energy conversion technologies. Interfaces in catalyst systems have long been considered the most critical factor in controlling catalytic reaction mechanisms. Interfaces include not only the catalyst surface but also interfaces within catalyst particles and those formed by constructing heterogeneous catalysts. The atomic and electronic structures of catalytic surfaces govern the kinetics of binding and release of reactant molecules from surface atoms. Interfaces within catalysts are introduced to enhance the intrinsic activity and stability of the catalyst by tuning the surface atomic and chemical structures. Examples include interfaces between the core and shell, twin or domain boundaries, or phase boundaries within single catalyst particles. In supported catalyst nanoparticles (NPs), the interface between the metallic NP and support serves as a critical tuning factor for enhancing catalytic activity. Surface electronic structure can be indirectly tuned and catalytically active sites can be increased through the use of supporting oxides. Tuning interfaces in catalyst systems has been identified as an important strategy in the design of novel catalysts. However, the governing principle of how interfaces contribute to catalyst behavior, especially in terms of interactions with intermediates and their stability during electrochemical operation, are largely unknown. This is mainly due to the evolving nature of such interfaces. Small changes in the structural and chemical configuration of these interfaces may result in altering the catalytic performance. These interfacial arrangements evolve continuously during synthesis, processing, use, and even static operation. A technique that can probe the local atomic and electronic interfacial structures with high precision while monitoring the dynamic interfacial behavior in situ is essential for elucidating the role of interfaces and providing deeper insight for fine-tuning and optimizing catalyst properties. Scanning transmission electron microscopy (STEM) has long been a primary characterization technique used for studying nanomaterials because of its exceptional imaging resolution and simultaneous chemical analysis. Over the past decade, advances in STEM, that is, the commercialization of both aberration correctors and monochromators, have significantly improved the spatial and energy resolution. Imaging atomic structures with subangstrom resolution and identifying chemical species with single-atom sensitivity are now routine for STEM. These advancements have greatly benefitted catalytic research. For example, the roles of lattice strain and surface elemental distribution and their effect on catalytic stability and reactivity have been well documented in bimetallic catalysts. In addition, three-dimensional atomic structures revealed by STEM tomography have been integrated in theoretical modeling for predictive catalyst NP design. Recent developments in stable electronic and mechanical devices have opened opportunities to monitor the evolution of catalysts in operando under synthesis and reaction conditions; high-speed direct electron detectors have achieved sub-millisecond time resolutions and allow for rapid structural and chemical changes to be captured. Investigations of catalysts using these latest microscopy techniques have provided new insights into atomic-level catalytic mechanisms. Further integration of new microscopy methods is expected to provide multidimensional descriptions of interfaces under relevant synthesis and reaction conditions. In this Account, we discuss recent insights on understanding catalyst activity, selectivity, and stability using advanced STEM techniques, with an emphasis on how critical interfaces dictate the performance of precious metal-based heterogeneous catalysts. The role of extended interfacial structures, including those between core and shell, between separate phases and twinned grains, between the catalyst surface and gas, and between metal and support are discussed. We also provide an outlook on how emerging electron microscopy techniques, such as vibrational spectroscopy and electron ptychography, will impact future catalysis research.


Subchronic mild noise stress increases HRP permeability in rat small intestine in vitro.
Recently we reported an increased trans- and paracellular protein permeability in rat small intestine after acute cold restraint stress. In the present study, we applied randomized 95- or 105-dB white noise pulses during 45 min/h, 12 h/day, duration 8 days, as a milder, but more chronic stressor to male rats. At 8 days before the noise experiments, 50% of the animals were cannulated in the vena cava for blood sampling during the experimental period. The other 50% of the animals were sacrificed at Day 9, segments of ileum were mounted in Ussing chambers and perfused at 37 degrees C. Horseradish peroxidase (HRP) was added mucosally, serosal appearance was detected enzymatically and tissues were fixed for electron microscopy. In the animals exposed to 95-dB noise, plasma corticosterone levels were enhanced twofold compared to controls, and ileal HRP flux was enhanced twofold. Electron micrographs of tissue from stressed or control animals showed no detectable paracellular staining of HRP. Quantification of HRP-containing endosomes in enterocytes revealed a twofold increase in endosome number in the animals exposed to 95-db noise indicating that the increased HRP permeability was primarily due to increased endocytosis. In contrast to the animals exposed to 95-dB noise, rats exposed to 105-dB noise showed no increase in corticosterone levels and ileal HRP fluxes were not significantly different from controls. We conclude that mild subchronic noise stress may cause a decrease in intestinal barrier function by increased transcytosis of luminal antigens.


Preoperative staging of gastric cancer by endoscopic ultrasound: the prognostic usefulness of ascites detected by endoscopic ultrasound.
Endoscopic ultrasound (EUS) is the standard modality in local preoperative staging of gastric cancers and is reputedly able to detect ascites. However, the association between ascites detected by EUS and local tumor staging, peritoneal carcinomatosis, or survival after surgery is not well documented. To assess the accuracy, sensitivity, and specificity of EUS in the preoperative staging and detection of ascites in gastric cancers. We also try to correlate ascites with histologic staging, tumor differentiation, and survival rate of gastric carcinoma after surgery. The retrospective analysis was made in 57 consecutive patients with histologically confirmed gastric adenocarcinomas that underwent EUS before surgery. The accuracy of EUS was compared with the final surgical-pathologic findings. We estimated the prognostic usefulness by analyzing the clinicopathologic features of gastric adenocarcinomas and following up their survival rates. The overall T staging was 88% accurate by EUS. The accuracy for T staging was as follows: T1, 100%; T2, 33%; T3, 93%; and T4, 100%. About 50% of T2 cases were overstaged. The overall accuracy, sensitivity, and specificity of detecting lymph node metastasis by EUS were 79%, 79%, and 80%, respectively. One of the seven T1 cancers had regional lymph node metastasis, and it was missed by EUS, although the T classification was precisely staged based on finding submucosal invasion. A total of 22 patients (39%) had ascites detected by EUS; both the sensitivity and specificity of EUS in demonstrating ascites were 100% in our study. Ascites was significantly correlated with the depth of tumor invasion ( = 0.036), lymph node metastasis ( = 0.008), and poor cellular differentiation ( = 0.007), but it was not significantly correlated with macroscopic peritoneal carcinomatosis. The survival rate after surgical treatment was poor in those with gastric cancers with lymph node metastasis, ascites, or poorly differentiated tumors ( < 0.05). However, multivariate analysis showed that lymph node metastasis was the only significant prognostic predictor ( = 0.004). Endoscopic ultrasound is a valuable diagnostic tool in the local staging of gastric cancers and demonstration of ascites. Although the surgical treatment of gastric cancers with lymph node metastasis, ascites, or poor differentiation had poorer survival rate, only lymph node metastasis was proved to be a significant prognostic predictor in multivariate analysis.


The importance to including objective functional outcomes in the clinical follow up of total knee arthroplasty patients.
In clinical practice, it is increasingly important to assess patients' daily functionality routinely and objectively. Acceleration-based gait analysis (AGA) has shown to be reliable and technically suitable for routine clinical use outside the laboratory. This study investigated the suitability of AGA for measuring function in orthopaedic patients with symptomatic gonarthrosis listed for total knee arthroplasty (TKA) by investigating (a) the ability of AGA to distinguish patients from healthy subjects, (b) the sensitivity to gait changes of AGA in assessing recovery following total knee arthroplasty in a subpopulation, and (c) correlations between AGA parameters and clinical scales. Gait was assessed using AGA in 24 patients with symptomatic gonarthrosis listed for TKA, and in 24 healthy subjects. AGA parameters (e.g. speed, asymmetry) and clinical scales (e.g. KSS) were used to monitor progress in 12 patients 3 months after TKA. The Mann-Whitney-U test, Receiver Operating Characteristic (ROC) curves, repeated measurement ANOVA and Pearson correlations were performed. AGA differentiated pathological from healthy gait. The area under the ROC curve, sensitivity and specificity values were high for speed, step frequency and step length. Different recovery profiles were found, with clinical scales showing faster recovery rates. None or only weak correlations were found between AGA and clinical scores. AGA was found to be of clinical relevance in identifying and monitoring patients with symptomatic gonarthrosis in orthopaedic practice, providing objective and additional information about function beyond clinical scales. This, together with the fact that AGA can be applied routinely, suggests the suitability of AGA for use in rehabilitation programs.


Music perception with cochlear implants: a review.
The acceptance of cochlear implantation as an effective and safe treatment for deafness has increased steadily over the past quarter century. The earliest devices were the first implanted prostheses found to be successful in compensating partially for lost sensory function by direct electrical stimulation of nerves. Initially, the main intention was to provide limited auditory sensations to people with profound or total sensorineural hearing impairment in both ears. Although the first cochlear implants aimed to provide patients with little more than awareness of environmental sounds and some cues to assist visual speech-reading, the technology has advanced rapidly. Currently, most people with modern cochlear implant systems can understand speech using the device alone, at least in favorable listening conditions. In recent years, an increasing research effort has been directed towards implant users' perception of nonspeech sounds, especially music. This paper reviews that research, discusses the published experimental results in terms of both psychophysical observations and device function, and concludes with some practical suggestions about how perception of music might be enhanced for implant recipients in the future. The most significant findings of past research are: (1) On average, implant users perceive rhythm about as well as listeners with normal hearing; (2) Even with technically sophisticated multiple-channel sound processors, recognition of melodies, especially without rhythmic or verbal cues, is poor, with performance at little better than chance levels for many implant users; (3) Perception of timbre, which is usually evaluated by experimental procedures that require subjects to identify musical instrument sounds, is generally unsatisfactory; (4) Implant users tend to rate the quality of musical sounds as less pleasant than listeners with normal hearing; (5) Auditory training programs that have been devised specifically to provide implant users with structured musical listening experience may improve the subjective acceptability of music that is heard through a prosthesis; (6) Pitch perception might be improved by designing innovative sound processors that use both temporal and spatial patterns of electric stimulation more effectively and precisely to overcome the inherent limitations of signal coding in existing implant systems; (7) For the growing population of implant recipients who have usable acoustic hearing, at least for low-frequency sounds, perception of music is likely to be much better with combined acoustic and electric stimulation than is typical for deaf people who rely solely on the hearing provided by their prostheses.


[A case of generalized convulsion during induction with Diprivan].
The case report concerns a male patient presenting oligophrenia and epilepsy of long duration, adequately prepared for anesthesia with anticonvulsants, sustaining generalized convulsion during anesthesia induction with Diprivan. On deepening Diprivan anesthesia, the convulsion subsides. The patient runs an uneventful postoperative course, free of convulsions. The issue of small doses Diprivan giving rise to convulsions is comprehensively discussed.


Centralized national ethical review of clinical trials in Croatia.
To present the Croatian system of ethical review of clinical trials and assessment outcomes of the applications reviewed by the Croatian Central Ethics Committee. Clinical trial applications reviewed by the Croatian Central Ethics Committee, which has the legal mandate to review clinical trials of medicinal products and medical devices, were retrospectively analyzed from May 2004 to the end of 2008 according to the number, research area, and type of opinion issued. Applications from 2008 were analyzed separately according to the study phase, participants (adult trials vs pediatric trials), and sponsor (commercial trials vs academic trials). Data were analyzed by descriptive statistics. Since its establishment in 2004, the Croatian Central Ethics Committee has reviewed 407 trials. The greatest number of clinical trials was in the field of oncology (n = 69), mental and behavioral disorders (n = 52), and endocrine, nutritional, and metabolic diseases (n = 50). In the initial assessment of clinical trials, 60% applications received a conditionally positive opinion. In 28% of applications, the opinion had to be postponed because additional documentation or explanations were required. In 2008, the Croatian Central Ethics Committee reviewed 99 trials, most of which were phase III trials (n = 57). Five clinical trials included pediatric population and 3 were academic clinical trials. The model of centralized clinical trial review seems to be appropriate for the current number of clinical trials conducted in Croatia. The efficient and standardized review process of clinical trials by the Central Ethics Committee may positively affect the increasing number of clinical trials conducted in Croatia. Future development includes the transparency of the clinical trials through a publically available database and establishing the basis for conducting academic clinical trials.


Optimizing peptide inhibitors of SARS-Cov-2 nsp10/nsp16 methyltransferase predicted through molecular simulation and machine learning.
Coronaviruses, including the recent pandemic strain SARS-Cov-2, use a multifunctional 2'-O-methyltransferase (2'-O-MTase) to restrict the host defense mechanism and to methylate RNA. The nonstructural protein 16 2'-O-MTase (nsp16) becomes active when nonstructural protein 10 (nsp10) and nsp16 interact. Novel peptide drugs have shown promise in the treatment of numerous diseases and new research has established that nsp10 derived peptides can disrupt viral methyltransferase activity via interaction of nsp16. This study had the goal of optimizing new analogous nsp10 peptides that have the ability to bind nsp16 with equal to or higher affinity than those naturally occurring. The following research demonstrates that in silico molecular simulations can shed light on peptide structures and predict the potential of new peptides to interrupt methyltransferase activity via the nsp10/nsp16 interface. The simulations suggest that misalignments at residues F68, H80, I81, D94, and Y96 or rotation at H80 abrogate MTase function. We develop a new set of peptides based on conserved regions of the nsp10 protein in the Coronaviridae species and test these to known MTase variant values. This results in the prediction that the H80R variant is a solid new candidate for potential new testing. We envision that this new lead is the beginning of a reputable foundation of a new computational method that combats coronaviruses and that is beneficial for new peptide drug development.


Cardiac resynchronization therapy with special focus on patency of coronary sinus and its branches: conceptual viewpoint and semi-theoretical considerations on lead-induced obstruction.
Cardiac resynchronization therapy appears to be useful for patients with severe chronic congestive heart failure. However, many questions still arise concerning the effectiveness of this kind of therapy since hemodynamic improvement is not observed in all patients. Heterogeneity of conclusions reported by several multicenter clinical trials and prominent experts demonstrates that many uncertainties related to cardiac resynchronization therapy still exist. We tried to reveal some inadequacies in clinical results by focusing on cardiac venous blood return which is likely complicated by the presence of lead inside the coronary sinus and its branches. Downstream traversing lead may occlude (partially or completely) the ostia of minor tributaries and target vein of lead final positioning. Thrombosis may also be incited within the coronary sinus itself. Remaining lumen predetermined by the lead body and subsequent thrombosis may be insufficient to provide adequate blood flow. Resulting detrimental venous return presumably may slightly depress myocardial contractility which may be significant in very sensitive group of patients assigned to the New York Heart Association class III or IV. Cardiac venous blood pumping conditions (or venous drainage) are likely also complicated by abnormal activation of left ventricle. The contributory role of these two subtle causes unfavorably influencing venous drainage is still unknown. It may be treated as a hypothetical attempt to find the clue and needs future studies for verification.


[Liberation of potential local anesthetics from colloidal dispersions].
Evaluation of pharmaceutical availability of drugs from topical preparations is usually aimed to evaluate the capability of the dosage form to release the drug for its therapeutic action. Permeation cells have been used for this purpose, employing solid membranes including cellophane. Within a study of phenylcarbamic acid derivatives with local anaesthetic effect, the present paper evaluates the dosage form for topical administration containing potential drug XIX M, the chemical name N-[2-(2-heptyloxyphenylcarbamoyloxy)-ethyl]-morpholinium chloride and potential drug XXII B, the chemical name N-[2-(2-octyloxyphenylcarbamoyloxy)-ethyl]-dimethylammonium chloride. The selected auxiliary substance in the formulation of the dosage form was a cellulose derivative--methylcellulose in increasing concentrations from 0.5 to 1.5%. On the basis of the obtained results it can be stated that the examined polymer methylcellulose with increasing concentration decelerated the release of both potential drugs approximately in the same way and that it can be used in practice to prolong the local anaesthetic effect.


Illisimonin A, a Caged Sesquiterpenoid with a Tricyclo[5.2.1.01,6]decane Skeleton from the Fruits of Illicium simonsii.
Illisimonin A, an unprecedented sesquiterpenoid with a tricyclo[5.2.1.01,6]decane skeleton, was isolated from the fruits of Illicium simonsii. The structure and absolute configuration of 1 were determined using extensive spectroscopic evidence and electronic circular dichroism (ECD) calculations. It was determined that 1 possesses a caged 2-oxatricyclo[3,3,0,14,7]nonane ring system fused to a five-membered carbocyclic ring and a five-membered lactone ring. A plausible biogenetic pathway for 1 was proposed, and 1 showed neuroprotective effects against oxygen-glucose deprivation (OGD)-induced cell injury in SH-SY5Y cells with an EC50 value of 27.72 μM.


[Prehospital care of patients with acute ST elevation myocardial infarction].
Symptomatic prehospital therapy of patients suffering from an ST elevation myocardial infarction basically does not differ from in-hospital care regarding pain relief, beta-blockers, antiplatelets, and thrombin antagonists as well as therapy of elevated blood pressure and acute heart failure. Precondition of a targeted and adequate treatment, however, is the twelve-lead ECG whose reliability does not differ from the ECG in the hospital. Biomarkers have no role in the prehospital setting. Out-of-hospital thrombolysis, which has been proven to be superior to later in-hospital initiation, can be used as a safe strategy for reperfusion. Only the prehospital phase offers a chance to treat the majority of patients within the first 2 h after symptom onset, a time window where thrombolysis results in equal or even better outcomes with respect to mortality, if compared to percutaneous intervention. Therefore, prehospital thrombolysis should be routinely applied in areas with a weak infrastructure and few and less experienced facilities for intervention but should also be considered a principal way for earliest start of reperfusion therapy. There is increasing evidence supporting the "rescue PCI" concept in patients in whom thrombolysis has failed. By contrast, the role of "facilitated PCI" still has to be defined.


Antiphospholipid antibodies and thrombosis.
Antiphospholipid antibodies (eg, anticardiolipin antibodies or the lupus anticoagulant) are a fascinating set of autoantibodies that have been linked to venous and arterial thrombosis, immune-mediated thrombocytopenia, and recurrent pregnancy loss. This review high-lights recent advances in the immunology of antiphospholipid antibodies and their target antigens, potential mechanisms of thrombosis and thrombocytopenia, and new methods for laboratory identification of these antibodies. Clinical syndromes associated with antiphospholipid antibodies are also covered, including ischemic neurological disorders, cardiac lesions, venous thromboembolism, and pregnancy loss. In each instance, recommendations for therapy are discussed.


Correlation Between Proprioceptive Impairment and Motor Deficits After Stroke: A Meta-Analysis Review.
Introduction: Proprioceptive impairment is a common symptom after stroke. Clarifying how proprioception correlates with motor function after stroke may be helpful in optimizing proprioception-augmented movement training. Previous studies have shown inconsistent findings. A meta-analysis is an optimal method to explore the correlation and identify the factors contributing to these inconsistencies. Objective: To explore the correlation between proprioception and motor function after stroke through a meta-analysis, taking into account characteristics of the measurements used in these studies. Methods: We searched multiple databases until November 2021 for eligible studies that measured both proprioception and motor functions in persons with stroke and reported their correlation or data for correlation analysis. A meta-analysis of the correlations was performed. The subgroup analysis and meta-regression were further conducted to investigate potential factors contributing to the heterogeneity of correlation strength, based on the participants' characteristics, proprioception, and motor function measures. Results: In total, 28 studies comprising of 1,829 participants with stroke were included in the meta-analysis. The overall correlation between proprioception and motor function was significant (r = 0.267, p < 0.05), but there was heterogeneity across studies (I 2 = 45%, p < 0.05). The results of the subgroup analysis showed proprioception of the axial segment in weight-bearing conditions (r = 0.443, p < 0.05) and upper limb without weight-bearing (r = 0.292, p < 0.05) had a stronger correlation with motor function than proprioception of the lower limb without weight-bearing. The proprioception measured through ipsilateral matching (r = 0.412, p < 0.05) showed a stronger correlation with motor function than through contralateral matching. The International Classification of Functioning, Disability, and Health (ICF) domains of motor function, movement function (r = 0.338, p < 0.05), activity performance (r = 0.239, p < 0.05), and independence (r = 0.319, p < 0.05) showed a stronger correlation with proprioception than with other domains. Conclusion: There is a significant correlation between proprioception and motor dysfunction after stroke. The proprioception measured in the axial segment under weight-bearing conditions or measured with ipsilateral matching, and motor function, specifically in the ICF domains of movement function, activity performance, and independence showed a positive contribution to the association between proprioception and motor function. The correlation does not imply causation and might be underestimated by attributes of current tests for proprioception and motor function. Further studies are needed to clarify the cause-effect relationship.


Tracking the Turn Maneuvering Target Using the Multi-Target Bayes Filter with an Adaptive Estimation of Turn Rate.
Tracking the target that maneuvers at a variable turn rate is a challenging problem. The traditional solution for this problem is the use of the switching multiple models technique, which includes several dynamic models with different turn rates for matching the motion mode of the target at each point in time. However, the actual motion mode of a target at any time may be different from all of the dynamic models, because these models are usually limited. To address this problem, we establish a formula for estimating the turn rate of a maneuvering target. By applying the estimation method of the turn rate to the multi-target Bayes (MB) filter, we develop a MB filter with an adaptive estimation of the turn rate, in order to track multiple maneuvering targets. Simulation results indicate that the MB filter with an adaptive estimation of the turn rate, is better than the existing filter at tracking the target that maneuvers at a variable turn rate.


A specific bacterial aminoacylase cleaves odorant precursors secreted in the human axilla.
Human axillary odor is known to be formed upon the action of Corynebacteria sp. on odorless axilla secretions. The known axilla odor determinant 3-methyl-2-hexenoic acid was identified in hydrolyzed axilla secretions along with a chemically related compound, 3-hydroxy-3-methylhexanoic acid. The natural precursors of both these acids were purified from non-hydrolyzed axilla secretions. From liquid chromatography/mass spectrometry analysis, it appeared that the acids are covalently linked to a glutamine residue in fresh axilla secretions, and the corresponding conjugates were synthesized for confirmation. Bacterial isolates obtained from the human axilla and belonging to the Corynebacteria were found to release the acids from these odorless precursors in vitro. A Zn(2+)-dependent aminoacylase mediating this cleavage was purified from Corynebacterium striatum Ax20, and the corresponding gene agaA was cloned and heterologously expressed in Escherichia coli. The enzyme is highly specific for the glutamine residue but has a low specificity for the acyl part of the substrate. agaA is closely related to many genes coding for enzymes involved in the cleavage of N-terminal acyl and aryl substituents from amino acids. This is the first report of the structure elucidation of precursors for human body odorants and the isolation of the bacterial enzyme involved in their cleavage.


Na(+)/K(+) pump interacts with the h-current to control bursting activity in central pattern generator neurons of leeches.
The dynamics of different ionic currents shape the bursting activity of neurons and networks that control motor output. Despite being ubiquitous in all animal cells, the contribution of the Na(+)/K(+) pump current to such bursting activity has not been well studied. We used monensin, a Na(+)/H(+) antiporter, to examine the role of the pump on the bursting activity of oscillator heart interneurons in leeches. When we stimulated the pump with monensin, the period of these neurons decreased significantly, an effect that was prevented or reversed when the h-current was blocked by Cs(+). The decreased period could also occur if the pump was inhibited with strophanthidin or K(+)-free saline. Our monensin results were reproduced in model, which explains the pump's contributions to bursting activity based on Na(+) dynamics. Our results indicate that a dynamically oscillating pump current that interacts with the h-current can regulate the bursting activity of neurons and networks.


Human Saliva-Mediated Hydrolysis of Eugenyl-β-D-Glucoside and Fluorescein-di-β-D-Glucoside in In Vivo and In Vitro Models.
Eugenyl-β-D-glucopyranoside, also referred to as Citrusin C, is a natural glucoside found among others in cloves, basil and cinnamon plants. Eugenol in a form of free aglycone is used in perfumeries, flavourings, essential oils and in medicinal products. Synthetic Citrusin C was incubated with human saliva in several in vitro models together with substrate-specific enzyme and antibiotics (clindamycin, ciprofloxacin, amoxicillin trihydrate and potassium clavulanate). Citrusin C was detected using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Citrusin C was completely degraded only when incubated with substrate-specific A. niger glucosidase E.C 22.214.171.124 (control sample) and when incubated with human saliva (tested sample). The addition of antibiotics to the above-described experimental setting, stopped Citrusin C degradation, indicating microbiologic origin of hydrolysis observed. Our results demonstrate that Citrusin C is subjected to complete degradation by salivary/oral cavity microorganisms. Extrapolation of our results allows to state that in the human oral cavity, virtually all β-D-glucosides would follow this type of hydrolysis. Additionally, a new method was developed for an in vivo rapid test of glucosidase activity in the human mouth on the tongue using fluorescein-di-β-D-glucoside as substrate. The results presented in this study serve as a proof of concept for the hypothesis that microbial hydrolysis path of β-D-glucosides begins immediately in the human mouth and releases the aglycone directly into the gastrointestinal tract.


A role for zinc in cerebellar synaptic transmission?
There is considerable evidence that the transition metal zinc plays an important role in mammalian neural development, physiology and pathology. The most compelling evidence for a synaptic role for zinc comes from hippocampal studies: zinc is concentrated in the synaptic vesicles of some glutamatergic neurons, zinc can be released during neural activity and zinc can modulate postsynaptic GABA and glutamate receptors. The possibility that zinc is involved in cerebellar synaptic transmission is supported by the expression of specific zinc transporters (ZnT, including the synaptic vesicle transporter ZnT-3) in the cerebellar cortex. Furthermore, some subtypes of neurotransmitter receptors, expressed by cerebellar neurones, are highly sensitive to low concentrations of exogenous zinc. However there appears to be little chelatable (synaptic) zinc in the cerebellum, deletion of the ZnT-3 gene has no effect on motor phenotype and there is currently no evidence that zinc is released from cerebellar neurones to have physiological actions. Thus it is possible that the different types of zinc transporter found in the cerebellum play a neuroprotective rather than a signalling role.


The immune response to the parasitic nematode Trichinella and the ways to escape it. From experimental studies to implications for human infection.
The review describes different aspects of the host immune response to Trichinella, not only at the intestinal level on which most of the studies have focused until now, but also in the muscles which represent the final target of host invasion. The role of antibodies, T cells, mast cells, eosinophils and neutrophils, respectively, in immune reaction to this nematode is considered, in the light of the recent data derived from experimental models, both "in vivo" and more recently "in vitro" and when available, from clinical observations. A section is also devoted to the principal escape mechanisms from host immune responses, described in Trichinella, which are in part common to other parasites, in part peculiar. Two groups of mechanisms are described: antigen-dependent, such as anatomic seclusion, antigen stage-specificity, shedding and renewal and molecular mimicry, and those directly affecting the host immune response. Of the latter, some act at central level like immune suppression, polyclonal activation and eosinophilia induction, others interfere with effector functions as in the case of host leukocyte modification, immune complex accumulation, blocking antibody production or complement assembly blocking. The antigenic composition of the different stages is the subject of another section which has the aim to give an overview of the principal antigens described up to now, without giving too many biochemical details, but just illustrating the candidates for possible vaccines. Finally, the perspectives for vaccination are described. Most of the results described are derived from the experimental studies, but their implications in human infection are relevant.


Cocaine induces cell death within the primate fetal cerebral wall.
Transferase dUTP nick-end labelling (TUNEL) analysis was used to compare the occurrence of cell death in the cerebral wall of cocaine-exposed and drug-naïve monkey fetuses. The rhesus monkeys providing the drug-exposed fetuses received 10 mg/kg of cocaine orally (in fruit treats) in the morning and in the evening between pregnancy days 50 and 65. The control pregnant animals received fruit treats only. The fetuses were removed for analysis by Caesarean section 10 h after the last cocaine treatment. The sections of the cerebral wall from the cocaine-exposed fetuses contained significantly higher numbers of TUNEL-positive nuclei (counted either per section area or per 1000 unlabeled nuclei) than the matching sections from the drug-naïve fetuses. This elevation in the number of TUNEL-positive cells was observed through the entire depth of the fetal cerebral wall including its proliferative and intermediate zones, cortical plate and the marginal zone. The present study demonstrates that consumption of cocaine during pregnancy can result in increased occurrence of cell death in the developing cerebrum.


Nitrogen-15 NMR spectroscopy of N-metallated nucleic acids: insights into 15N NMR parameters and N-metal bonds.
It was recently demonstrated spectroscopically that RNA/DNA nucleobases can bind to metal cations in aqueous solution through coordination bonds and covalent bonds. Nitrogen-15 (15N) NMR spectroscopy was employed and shown to be a powerful tool for determining the mode of metal ion binding to nitrogen atoms in RNA/DNA molecules. This review describes 15N NMR spectroscopic characteristics in accordance with the mode of metal ion binding to nitrogen atoms. The general rules for 15N chemical shift changes, which are applicable to the determination of the metal ion binding mode of N-metallated compounds, are also described.


The beneficial effects of adjunctive recombinant human interleukin-2 for multidrug resistant tuberculosis.
Multidrug-resistant tuberculosis (MDR-TB) is a hard-to-treat disease with a poor outcome of chemotherapy. In the present study, the efficacy and safety of recombinant human interleukin-2 (rhIL-2) were investigated in patients with MDR-TB. Fifty culture-confirmed patients with MDR-TB were included. Twenty-five patients were randomly assigned to the trial group (injection of 500 000 IU of rhIL-2 once every other day at the first, third, fifth and seventh months in addition to standard multidrug therapy) and another 25 patients to the control group with standard multidrug therapy. All patients were monitored clinically, and T-cell subsets were analyzed by flow cytometry. The rates of sputum negative conversion and X-ray resolution in the trial group were higher than those of the control, and the improvements were significant by completion of treatment. In addition, CD4(+)CD25(+) T cells in the controls rose gradually during treatment. The levels at the end of the seventh month were significantly higher than before, which were also significantly different when compared with those from the trial group at the same time. However, there were no such changes associated with treatment in the trial group. No significant differences appeared in other T cell subsets. Exogenous IL-2 in the present regimen improves immunity status. Adjunctive immunotherapy with a long period of rhIL-2 is a promising treatment modality for MDR-TB.


Molecular dosimetry of urinary aflatoxin-DNA adducts in people living in Guangxi Autonomous Region, People's Republic of China.
Hepatocellular carcinoma is one of the five leading human cancers causing at least 250,000 deaths each year. One of the major risk factors for this disease is exposure to dietary aflatoxins, and the development of appropriate molecular dosimetry biomarkers would facilitate the identification of individuals at risk. This study was undertaken to explore the relationship between dietary intake of aflatoxins and the excretion of the major aflatoxin-DNA adduct and other metabolites into the urine of chronically exposed people. The following protocol was developed for this investigation in Guangxi Autonomous Region, People's Republic of China, where the diets of 30 males and 12 females (ages, 25-64 years) were monitored for 1 week and aflatoxin intake levels determined each day. Starting on the fourth day, total urine volumes were obtained in consecutive 12-h fractions for 3 or 4 days. High performance liquid chromatography and competitive radioimmunoassay analyses were done on each of the urine samples, and the relationships between excretion of total aflatoxin metabolites, aflatoxin-N7-guanine, aflatoxin M1, aflatoxin P1, and aflatoxin B1, and aflatoxin B1 intake values were determined. The average intake of aflatoxin B1 by men was 48.4 micrograms/day, giving a total mean exposure during the study period of 276.8 micrograms. The average daily intake by women was 77.4 micrograms/day, resulting in a total average exposure during the 7-day period of 542.6 micrograms aflatoxin B1. Initial efforts to characterize aflatoxin metabolites in urine samples were with an analysis by competitive radioimmunoassay. The analysis by linear regression of the association between aflatoxin B1 intake/day and total aflatoxin metabolite excretion/day showed a correlation coefficient of only 0.26. These findings stimulated the immunoaffinity/analytical high performance liquid chromatography analysis for individual metabolites. When the data were analyzed by linear regression analysis, the aflatoxin N7-guanine excretion and aflatoxin B1 intake from the previous day showed a correlation coefficient of 0.65 and P less than 0.000001. Similar analysis for aflatoxin M1 resulted in a correlation coefficient of 0.55 and P less than 0.00001, whereas there was no positive statistical association between exposure in the diet and aflatoxin P1 excretion, despite aflatoxin P1 being quantitatively a major metabolite. Analysis of the total aflatoxin-N7-guanine excretion in the urine during the complete collection period plotted against the total aflatoxin B1 exposure in the diet for each of the individuals, smoothing the day to day variations, revealed a correlation coefficient of 0.80 and P less than 0.0000001.(ABSTRACT TRUNCATED AT 400 WORDS)


Heterotopic Ossification Encountered During a Complex Ventral Hernia Repair: Case Report and Literature Review.
Introduction: Heterotopic ossification involves the formation of trabecular bone outside of its usual anatomic location. While it is a well-known entity in orthopedic and spinal injury literature, it has also been observed after midline laparotomy and severe burns. Methods/Case Report: We present a case of a 69-year-old man who presented for ventral hernia repair after a prolonged postoperative course following colectomy involving an open abdomen with eventual closure with skin grafting. Results: Two large calcified objects were encountered during the excision of the skin graft from the small intestine and during the component separation. They had grown into the anterior fascia and rectus muscle and interdigitated between loops of the small bowel. After careful resection of the 2 calcified objects, a ventral hernia repair with a component separation was successfully performed. Pathology was consistent with heterotopic ossification. After 18 months, there was no clinical evidence of recurrence. Discussion: Heterotopic ossification is not frequently encountered during ventral hernia repairs, but its presence can complicate repair. Resection is the only option in the context of hernia repair. If recognized preoperatively, waiting up to a year for the bone to mature before excision has been suggested, but there is minimal data to support this. Consultation with a general surgeon is also advised in case the calcified tissue involves the underlying viscera.


Lowering the Radiation Dose in Dental Offices.
While the use of dental imaging continues to evolve into more advanced modalities such as 3-D cone beam computed tomography, in addition to conventional 2-D imaging (intraoral, panoramic and cephalometric), the public concern for radiation safety is also increasing. This article is a guide for how to reduce patients' exposure to the minimum with proper selection criteria (as needed only if it benefits the patient) and knowledge of effective doses, exposure parameters and proper collimation.


Differential regulation of murine Mesocestoides corti infection by bacterial lipopolysaccharide and interferon-gamma.
Many liver-invasive parasites cause extensive liver damage which may result in an impaired ability to catabolize endotoxin. The influence of endogenous endotoxin on the progress of liver-invasive parasitic diseases has been investigated in murine Mesocestoides corti infection. Invasion of liver tissue by tetrathyridia resulted in extensive parenchymal destruction with fibrosis. In association with this, undetoxified endotoxin, in potentially biologically active concentration, was found on peritoneal macrophages, 5 months post-M, corti infection. Host susceptibility was influenced by the Lps gene for responsiveness to lipopolysaccharide (LPS). The parasite burden of LPS-responsive (C3H/HeN) mice was significantly increased in the livers of these mice when compared to LPS-resistant (C3H/HeJ) mice. LPS reduced the ability of normal peritoneal macrophages to kill tetrathyridia, when co-cultured in vitro. LPS also abrogated the ability of recombinant interferon-gamma (r.IFN-gamma) to enhance macrophage larvicidal activity. These in vitro findings were confirmed in vivo. Daily intraperitoneal administration of LPS, at low concentration, caused a 4-fold increase in parasite burden in the liver, while r.IFN-gamma at optimal concentration reduced parasite burden by 57%. Post-infection macrophages have previously been shown to be refractory to cytokine-activation for larval killing. In this report, we conclude that (1) this refractoriness may be due to the presence of undetoxified endotoxin on post-infection macrophages and (2) endotoxin may reduce host resistance by abrogating effector macrophage response to IFN-gamma.


Evaluation of proprioceptive sense of the elbow joint with RehabRoby.
In recent years, robot-assisted rehabilitation systems have been an active research area that can quantitatively monitor and adapt to patient progress, and ensure consistency during rehabilitation. In this work, an exoskeleton type robot-assisted rehabilitation system called RehabRoby is developed. A control architecture, which contains a high level controller and a low level controller, is designed for RehabRoby. Proprioceptive sense of healthy subjects has been evaluated during the execution of a task with RehabRoby. Additionally, usability of RehabRoby has been evaluated using a questionnaire.


Multiple homologues of LuxR and LuxI control expression of virulence determinants and secondary metabolites through quorum sensing in Pseudomonas aeruginosa PAO1.
In Pseudomonas aeruginosa PAO1, expression of elastase is dependent upon an interaction between the positive transcriptional activator LasR and the auto-inducer molecule N-(3-oxododecanoyl)-L-homoserine lactone (OdDHL), the synthesis of which is directed by LasI. Previously we have shown that in PAN067, an elastase-negative mutant of PAO1, elastase production can be restored to some extent by addition of exogenous N-(3-oxohexanoyl)-L-homoserine lactone (OHHL). Here we report that PAN067 is also defective in the production of alkaline protease, haemolysin, cyanide, pyocyanin and autoinducer(s). As neither addition of exogenous OdDHL nor introduction of lasR restored PAN067 to the parental phenotype, we sought to complement PAN067 with PAO1 DNA. From a cosmid library, a 2 kb DNA fragment was identified which re-established production of autoinducer(s) and exoproducts in PAN067. From the nucleotide sequence of this fragment, two genes termed rhIR and rhII were identified. RhII is responsible for autoinducer synthesis and shares 31% homology with LasI; RhIR has been previously identified in P. aeruginosa strain DSM2659 as a regulator of rhamnolipid biosynthesis and shares 28% identity with LasR. These data provide clear evidence that multiple families of quorum-sensing modulons interactively regulate gene expression in P. aeruginosa.


Failure to prevent cytomegalovirus infection by cytomegalovirus hyperimmune plasma: a randomized trial by the Nordic Bone Marrow Transplantation Group.
Bone marrow transplantation recipients who were cytomegalovirus (CMV) seropositive and/or had a CMV seropositive donor were randomized for treatment with CMV hyperimmune plasma (n = 27) or no treatment at all (n = 27). The CMV hyperimmune plasma had neutralization titers greater than 250 and enzyme-linked immunosorbent assay titers greater than 18,000. Plasma (200 mg/kg body weight) was given on four occasions (during 2 days) from day 3 to day 76 after transplantation. Patient characteristics were similar in the two groups. After transplantation, the median CMV titers increased with greater than 100% in the group receiving the CMV plasma and decreased to less than 50% in the controls (p less than 0.01). Asymptomatic CMV infections occurred in 26% of the patients in the plasma group and 33% of the controls. The frequency of patients with symptomatic CMV infections was also the same in the two groups (51% vs 33%). Three patients each in the two groups developed CMV-associated interstitial pneumonitis. Patient survival and causes of death were similar in the two groups. To conclude, no beneficial effect of CMV hyperimmune plasma was seen in patients at high risk of developing CMV infections.


Berberine behind the thriller of marked symptomatic bradycardia.
Patients with chronic aortic dissections are at high risk of catheter-induced complications. We report a Berberine is used in traditional Chinese medicine for the treatment of congestive heart failure, hypertension, diabetes, and dyslipidaemia and has a good safety profile. We report a case of a 53-year-old sportsman referred to our hospital for the onset of fatigue and dyspnoea upon exertion after he started berberine to treat hypercholesterolaemia. An electrocardiogram showed sinus bradycardia (45 bpm), first-degree atrioventricular block, and competitive junctional rhythm. An ergometric stress test showed slightly reduced chronotropic competence and the presence of runs of competitive junctional rhythm, atrial tachycardia, and sinus pauses in the recovery. After 10 d of wash-out from berberine, the patient experienced a complete resolution of symptoms, and an ergometric stress test showed good chronotropic competence. An electrocardiogram Holter showed a latent hypervagotonic state. This is the first case report that shows that berberine could present certain side effects in hypervagotonic people, even in the absence of a situation that could cause drug accumulation. Therefore, berberine's use should be carefully weighed in hypervagotonic people due to the drug's bradycardic and antiarrhythmic properties, which could became proarrhythmic, exposing patients to potential health risks.


Production and processing of a 59-kilodalton exochitinase during growth of Streptomyces lividans carrying pCHIO12 in soil microcosms amended with crab or fungal chitin.
Streptomyces lividans (pCHIO12), which carries the previously cloned Streptomyces olivaceoviridis exo-chiO1 gene on a multicopy vector, secretes a 59-kDa exochitinase, consisting of a catalytic domain (40 kDa), a central fibronectin type III-like module, and a chitin-binding domain (12 kDa). The propagation rate of S. lividans (pCHIO12) was higher in soil microcosms amended with fungal mycelia than in those containing crab chitin. Comparative biochemical and immunological studies allowed the following conclusions to be drawn. Within soil microcosm systems amended with crab shell chitin or chitin-containing Aspergillus proliferans mycelia, the strain expressed the clones exo-chiO1 gene and produced high quantities of a 59-kDa exochitinase. The enzyme was preferentially attached via its binding domain to the pellet from soil or liquid cultures. In contrast, truncated forms of 47, 40, and 25 kDa could be easily extracted from soil. The relative proportions of the 59-kDa enzyme and its truncated forms varied depending on the source of chitin and differed in soil and in liquid cultures.


Validation and clinical application of a targeted next-generation sequencing gene panel for solid and hematologic malignancies.
Next-generation sequencing (NGS) is a high-throughput technology that has become widely integrated in molecular diagnostics laboratories. Among the large diversity of NGS-based panels, the Trusight Tumor 26 (TsT26) enables the detection of low-frequency variants across 26 genes using the MiSeq platform. We describe the inter-laboratory validation and subsequent clinical application of the panel in 399 patients presenting a range of tumor types, including gastrointestinal (GI, 29%), hematologic (18%), lung (13%), gynecological and breast (8% each), among others. The panel is highly accurate with a test sensitivity of 92%, and demonstrated high specificity and positive predictive values (95% and 96%, respectively). Sequencing testing was successful in two-thirds of patients, while the remaining third failed due to unsuccessful quality-control filtering. Most detected variants were observed in the TP53 (28%), KRAS (16%), APC (10%) and PIK3CA (8%) genes. Overall, 372 variants were identified, primarily distributed as missense (81%), stop gain (9%) and frameshift (7%) altered sequences and mostly reported as pathogenic (78%) and variants of uncertain significance (19%). Only 14% of patients received targeted treatment based on the variant determined by the panel. The variants most frequently observed in GI and lung tumors were: KRAS c.35G > A (p.G12D), c.35G > T (p.G12V) and c.34G > T (p.G12C). Prior panel validation allowed its use in the laboratory daily practice by providing several relevant and potentially targetable variants across multiple tumors. However, this study is limited by high sample inadequacy rate, raising doubts as to continuity in the clinical setting.


Cryptogenic Pyogenic Liver Abscess Due to Fusobacterium nucleatum in an Immunocompetent Patient.
In this case, a 76-year-old female presented with 3-4 days of fever with no other localizing signs. Notably, she had had an untreated Fusobacterium bacteraemia approximately 8 weeks prior to admission. She underwent abdominal imaging which demonstrated a liver abscess and had percutaneous drainage of the same. Blood and pus cultures both grew Fusobacterium nucleatum, which is an unusual organism to be associated with a liver abscess, especially in an immunocompetent host with no risk factors for this condition. Interestingly, this patient did not have any history of dental work, instrumentation, liver function test (LFT) abnormalities and no extrahepatic source for the abscess. This case highlights the importance of having a high index of clinical suspicion for an occult source of infection and emphasizes the importance of following up on cultures even after discharge of a patient, since anaerobic infections such as those caused by Fusobacterium can have a largely indolent course. Fever of unknown aetiology with prior bacteraemia merits a thorough work-up for occult sources such as a localized abscess or malignancy, which can cause bacterial translocation.Fusobacterium and other anaerobic infectious agents should be considered in the context of an indolent disease course since they are slow-growing in cultures, and also, if the patient has risk factors such as immunosuppression, diabetes, poor oral hygiene and so on.It is important to have systems in place in hospitals to ensure follow-up for patients who may have a positive culture after discharge from hospital to confirm that the infection is adequately addressed.


Possible autosomal recessive inheritance of progressive hearing loss with stapes fixation.
Four sibs with progressive, bilateral conductive hearing loss are presented. Symmetrical hearing loss averaging 30-60 dB (0.125-8 kHz) became apparent between 8 and 24 years of age. Tympanotomy showed a fixed stapes either through ossified stapedius tendon or through ossified stapedius tendon or through a bony bridge from the stapes to the pyramidal eminence in all patients. After surgical removal of the bony tendon hearing was normal. Both parents, four other sibs, and all grandparents had normal hearing. This family and a further published case suggest a possibly recessive inheritance of this form of conductive hearing loss.


Green tea: nature's defense against malignancies.
The current practice of introducing phytochemicals to support the immune system or fight against diseases is based on centuries old traditions. Nutritional support is a recent advancement in the domain of diet-based therapies; green tea and its constituents are one of the important components of these strategies to prevent and cure various malignancies. The anti-carcinogenic and anti-mutagenic activities of green tea were highlighted some years ago suggesting that it could reduce the prevalence of cancer and even provide protection. The pharmacological actions of green tea are mainly attributed to polyphenols that includes epigallocatechin-3-gallate (EGCG), epicatechin, epicatechin-3-gallate, epigallocatechin. Green tea and its components effectively mitigate cellular damage arising due to oxidative stress. Green tea is supposed to enhance humoral and cell-mediated immunity, decreasing the risk of certain cancers, and may have certain advantage in treating inflammatory disorders. Much of the cancer chemopreventive properties of green tea are mediated by EGCG that induces apoptosis and promotes cell growth arrest, by altering the expression of cell cycle regulatory proteins, activating killer caspases, and suppressing nuclear factor kappa-B activation. Besides, it regulates and promotes IL-23 dependent DNA repair and stimulates cytotoxic T cells activities in a tumor microenvironment. It also blocks carcinogenesis by modulating the signal transduction pathways involved in cell proliferation, transformation, inflammation and metastasis. The review is intended to highlight the chemistry of green tea, its antioxidant potential, its immunopotentiating properties and mode of action against various cancer cell lines that showed its potential as a chemopreventive agent against colon, skin, lung, prostate, and breast cancer.


Bifidogenic effect of whole-grain wheat during a 12-week energy-restricted dietary intervention in postmenopausal women.
Consumption of whole-grain products is known to have beneficial effects on human health. The effects of whole-grain products on the intestinal microbiota and intestinal integrity have, however, only been studied limitedly. We investigate changes of the human gut microbiota composition after consumption of whole-grain (WW) or refined wheat (RW) and further study effects on gut wall integrity. Quantitative PCR was used to determine changes in the gut bacterial composition in postmenopausal women following a 12-week energy-restricted dietary intervention with WW (N=38) or RW (N=34). Intestinal integrity was determined by measuring trans-epithelial resistance (TER) across a Caco-2 cell monolayer, following exposure to faecal water. No significant differences in microbiota composition were observed between the two dietary groups; however, the whole-grain intervention increased the relative abundance of Bifidobacterium compared to baseline, supporting a prebiotic effect of whole-grain wheat. Faecal water increased TER independent of dietary intervention, indicating that commensal bacteria produce metabolites that generally provide a positive effect on intestinal integrity. Combining microbiota composition data from the run-in period with its effect on TER revealed a tendency for a negative correlation between the relative abundance of Bifidobacterium and TER (P=0.09). This contradicts previous findings but supports observations of increased Salmonella infection in animal models following treatment with bifidogenic prebiotics. The present study shows that whole-grain wheat consumption increases the abundance of bifidobacteria compared to baseline and may have indirect effects on the integrity of the intestinal wall.


Pharmacokinetics of a controlled release preparation of naproxen.
The pharmacokinetics of a controlled release preparation of naproxen (750 mg) was compared with that of standard release naproxen, in 12 healthy volunteers. The plasma levels of naproxen and urinary recoveries of naproxen and metabolites were determined both after single doses and chronic administration. The experimental data show that the bioavailability of the controlled release preparation is equal to that of standard release naproxen; however, the controlled release preparation allows more constant plasma levels of naproxen and, when administered once a day for prolonged periods, is capable of maintaining effective concentrations for most of the dosing period.


The joint development of externalizing and internalizing behaviors in black and Hispanic youth and the link to late adolescent substance use.
There is a need to understand how the joint development of externalizing and internalizing behaviors is related to substance use, particularly among historically understudied and often disadvantaged populations. Latent class models were used to estimate patterns of externalizing behaviors and internalizing behaviors in the form of depressive and anxious symptoms from age 6 to 14 among 390 Black and Hispanic youth. Then, growth curve models of substance use between the ages of 15 and 19 were estimated as a function of joint latent class membership. Only elevated levels of externalizing behaviors were associated with higher levels of substance use through age 18. Internalizing behaviors appeared to serve as a protective factor among those with moderate displays of externalizing behavior only. Additionally, growth in substance use from ages 15 to 19 was slower among those who displayed the highest level of externalizing behaviors, and internalizing behaviors appeared to moderate growth (and serve as protective factor) among those who displayed moderate levels of externalizing behaviors. The findings underscore the importance of pattern profiles based on observations of the joint development of problem behaviors to assess risk for substance use, particularly in understudied populations where risk/protective factors may operate in a unique manner.


Automating phase singularity localization in mathematical models of cardiac tissue dynamics.
Electrical wave-fronts are responsible for contraction in heart tissue. Rotary wave-fronts break up into daughter waves and it is this break up that is believed to underlie ventricular fibrillation. Mathematical methods abound for simulation of fibrillation, and localizing the core of rotary wave-fronts (the phase singularities) is key to characterizing the state of fibrillation and effectiveness of defibrillation in these models. We present a formal method for automating this process in these various models. Automation will allow for side-by-side comparisons of suggested mechanisms of fibrillation, comparison of various models of these mechanisms and faster evaluation of defibrillation strategies making use of these models.


Venous disease: the missing link in cardiovascular medicine.
Until recently, medical literature and the practice of vascular medicine focused on the cosmetic aspects of venous disease and the advanced stages of venous insufficiency such as painful varicose veins and venous ulcers. The systemic effects of venous insufficiency resulting from a reduction of venous return and increased transit time of blood from the lower extremities that can mimic heart failure are only recently being recognized. This article reviews the diagnosis and treatment options for the patients with venous insufficiency, and increases awareness about the systemic effects of venous disease and its role in the practice of cardiovascular medicine.


An inventory and update of jealousy-evoking partner behaviours in modern society.
The goal of the present study was to identify the most important jealousy-evoking partner behaviours and to examine the extent to which these behaviours evoke jealousy. Based on the literature, a questionnaire was constructed containing 42 jealousy-evoking partner behaviours, including a partner's extra-dyadic involvement with someone else by means of modern communication devices, such as the Internet. A second study examined the extent to which undergraduates and a community sample experienced jealousy in response to these partner behaviours. Results showed that explicit unfaithful behaviours evoked most feelings of jealousy, followed by a partner's emotional or romantic involvement with someone else by means of modern communication devices. In general, older individuals responded with less jealousy in response to a partner's unfaithful and suspicious behaviours. Clinical implications are discussed.


Total parenteral nutrition: a concurrent drug utilization review.
University Hospital, a 428-bed tertiary care teaching hospital, treats approximately 150 patients annually with TPN. Currently used are three standard TPN base formulae which are ordered by physicians using preprinted TPN order forms. A concurrent Drug Utilization Review (DUR) was conducted on TPN treatment of 30 patients, to examine adherence to the current TPN protocol. Criteria for evaluation included ruling out enteral feeding, indications for TPN use, duration of therapy, monitoring of laboratory values, and caloric delivery. Physician and dietician estimation of caloric needs were compared to calories actually ordered by the physician. The number of pharmacist interventions and TPN bags wasted were also determined. Results could not be obtained with respect to ruling out enteral feeding and indications for TPN therapy due to inadequate information. The five-day minimum for duration of TPN therapy established in the DUR criteria was not attained in 23 percent (7/30) of patients. Seventy-seven percent of laboratory monitoring tests were completed. Results indicate wide disparities in caloric calculation and delivery; only 45 percent (10/22) of the patients who were ordered TPN met the physician's caloric goal. A number of recommendations were made to improve the TPN protocol and TPN therapy.


Ocular manifestations as key features for diagnosing mucopolysaccharidoses.
Diagnosis of mucopolysaccharidosis (MPS) requires awareness of the multisystem disease manifestations and their diverse presentation in terms of time of onset and severity. Many patients with MPS remain undiagnosed for years and progressively develop irreversible pathologies, which ultimately lead to premature death. To foster timely treatment and ensure a better outcome, it is of utmost importance to recognize and evaluate the typical ocular features that present fairly early in the course of the disease in many children with MPS. These include corneal clouding, ocular hypertension/glaucoma, retinal degeneration, optic disc swelling and optic nerve atrophy. Other associations include pseudo-exophthalmos, amblyopia, strabismus and large refractive errors requiring spectacle correction. While some ocular manifestations require specialized equipment for detecting abnormalities, light sensitivity, pseudo-exophthalmos and strabismus are often apparent on a routine physical examination. In addition, patients may be symptomatic from vision impairment, photosensitivity, night blindness and visual field constriction. Combined with the skeletal/joint complications and other manifestations, these ocular features are key in the differential diagnosis of children with joint abnormalities. Rheumatologists should have a high index of suspicion for MPS to facilitate early diagnosis. Referral to a geneticist, a metabolic specialist or physician who specializes in MPS can confirm the diagnosis and provide disease management. Consultation with an ophthalmologist who has expertise in MPS is also needed for thorough examination of the eyes and regular follow-up care.


Microbial community dynamics based on 16S rRNA gene profiles in a Pacific Northwest estuary and its tributaries.
We analyzed bacterioplankton community structure in Tillamook Bay, Oregon and its tributaries to evaluate phylogenetic variability and its relation to changes in environmental conditions along an estuarine gradient. Using eubacterial primers, we amplified 16S rRNA genes from environmental DNA and analyzed the PCR products by length heterogeneity polymerase chain reaction (LH-PCR), which discriminates products based on naturally occurring length differences. Analysis of LH-PCR profiles by multivariate ordination methods revealed differences in community composition along the estuarine gradient that were correlated with changes in environmental variables. Microbial community differences were also detected among different rivers. Using partial 16S rRNA sequences, we identified members of dominant or unique gene fragment size classes distributed along the estuarine gradient. Gammaproteobacteria and Betaproteobacteria and members of the Bacteroidetes dominated in freshwater samples, while Alphaproteobacteria, Cyanobacteria and chloroplast genes dominated in marine samples. Changes in the microbial communities correlated most strongly with salinity and dissolved silicon, but were also strongly correlated with precipitation. We also identified specific gene fragments that were correlated with inorganic nutrients. Our data suggest that there is a significant and predictable change in microbial species composition along an estuarine gradient, shifting from a more complex community structure in freshwater habitats to a community more typical of open ocean samples in the marine-influenced sites. We also demonstrate the resolution and power of LH-PCR and multivariate analyses to provide a rapid assessment of major community shifts, and show how these shifts correlate with environmental variables.


Multivariate analyses of the risk of insulin-dependent diabetes mellitus for siblings of insulin-dependent diabetic patients.
Multivariate models for the risk of insulin-dependent diabetes mellitus for siblings of patients with insulin-dependent diabetes were developed using logistic regression analysis. The individuals studied in this report are full siblings of the insulin-dependent diabetic patients diagnosed at Children's Hospital of Pittsburgh between 1964 and 1982. For all siblings considered together, the sharing of two (but not one) HLA haplotypes, the presence of insulin-dependent diabetes in a parent, and being relatively young at the time the proband in the family was diagnosed were significantly associated with increased risk. On the other hand, B7 + siblings had a significantly decreased risk compared to B7--siblings, indicating the presence of an HLA-linked protective gene for the development of the disease. There was a significant interaction between sharing two HLA haplotypes and maternal age at the time of birth; for non-HLA-identical siblings, risk increased with increased maternal age, but maternal age had little or no effect on the risk for HLA-identical siblings. When non-HLA-identical siblings (0 or 1 HLA haplotypes shared) were analyzed separately, only the presence of insulin-dependent diabetes in one of the parents and increased maternal age at the time of birth of the sibling were found to be significantly associated with increased risk. Both of the totally non-HLA-identical diabetic siblings (neither HLA haplotype shared) in this data set had a parent with insulin-dependent diabetes, indicating that at least one HLA haplotype must be inherited in common with an affected family member for diabetes to develop. For HLA-identical siblings, the significant variables were the age of the sibling when the proband was diagnosed, the possession of B7, and maternal age at the time of birth of the sibling, and all three were negatively associated with risk.


Enhanced Electroplasticity through Room-Temperature Dynamic Recrystallization in a Mg-3Al-1Sn-1Zn Alloy.
It has been well known that electric pulse can be utilized to enhance the plasticity of metals, which is attributed to the change of dislocation dynamics, e.g., localized planar slip to homogeneous wavy slip. Here, we show another effect of pulse current, which facilitates texture weakening through room-temperature dynamic recrystallization and additionally improve the plasticity of a polycrystalline Mg-3Al-1Sn-1Zn alloy. By conducting a tensile test under electrical pulse, we found that the peak flow stress and fracture strain depend strongly on current density. As peak current densities increases, the flow stress drops and the fracture strain increases. Our Electron Backscatter Diffraction results suggest that dynamic recrystallization occurs at room temperature, which develops a weakened texture. Our work provides a new insight into electroplasticity mechanism in Mg alloys.


Anisotropic constitutive equations and experimental tensile behavior of brain tissue.
The present study deals with the experimental analysis and mechanical modeling of tensile behavior of brain soft tissue. A transversely isotropic hyperelastic model recently proposed by Meaney (2003) is adopted and mathematically studied under uniaxial loading conditions. Material parameter estimates are obtained through tensile tests on porcine brain materials accounting for regional and directional differences. Attention is focused on the short-term response. An extrapolation of tensile test data to the compression range is performed theoretically, to study the effect of the heterogeneity in the tensile/compressive response on the material parameters. Experimental and numerical results highlight the sensitivity of the adopted model to the test direction.


The impact of obesity on the outcome of emergency intubation in trauma patients.
Emergency intubation of trauma patients is a complex intervention, which can be safely and successfully performed in most trauma centers. This, however, has never been validated in the obese trauma population. Obese patients have anatomic and physiologic characteristics that make their intubation more challenging. We therefore hypothesize that obese trauma patients requiring emergency intubation are at increased risk for unsuccessful intubation and airway-related complications. Retrospective review of prospectively collected data from an airway surveillance database at an urban Level I trauma center between 2001 and 2004 was analyzed. The study population included all adult patients admitted to the trauma center, who required urgent airway management. The patients were stratified into four groups according to their body mass index (BMI): lean (BMI < 25), overweight (25 < or = BMI < 30), obese (30 < or = BMI < or = 40), and morbid obesity (BMI > 40). Demographic parameters and outcome measures including field intubation success, airway complications, early respiratory complications, and mortality were collected. Logistic regression was performed to determine predictors of these outcome measures. Of the 9,980 patients evaluated during the three-year study period, 1,435 (14%) were emergently intubated and made up the study population. About 92% of ED intubations were performed by the anesthesia team. Of all emergently intubated patients, 46% were lean, 37% were overweight, 15% were obese, and 2% were morbidly obese. There were no significant differences in demographic parameters between the lean, overweight, and obese groups. The morbidly obese patients were however older, composed of more female patients and more likely to have suffered a blunt injury. Logistic regression analysis revealed that BMI was not an independent risk factor for failed intubations in the field or in the ED, postintubation airway complications, or death. Only early respiratory complications demonstrated a statistically significant (p = 0.02), but unlikely clinically relevant (OR = 1.04; 95% CI, 0.99-1.07) association with a higher BMI. Emergency intubation of obese trauma patients can be safely and successfully performed in a high volume Level I trauma center. Obesity is not a predictor of postintubation airway complications or mortality. Larger studies are needed to validate these finding in the morbidly obese patients.


[Inflammatory Myofibroblastic Tumor Misdiagnosed as Intrahepatic Cholangiocarcinoma].
An inflammatory myofibroblastic tumor (IMT) is a rare tumor that is currently classified as an intermediate cancer according to the World Health Organization classification system. The pathophysiology of its occurrence is still unknown. Imaging tests, such as CT or MRI, can be helpful in diagnosis, but the final diagnosis is confirmed by a pathological examination through a biopsy and immunohistochemistry stain. The patient, in this case, presented an asymptomatic intrahepatic mass discovered incidentally on an imaging examination. Initially, intrahepatic cholangiocarcinoma was suspected, but she was finally diagnosed with IMT through a histological examination after a liver resection.


Town population change in the Republic of Ireland: the need for an urban policy review.
"This article argues for the adoption of a co-ordinated urban planning policy in the Republic of Ireland where towns now accommodate 64% of the total population. A review of trends in town population change for the years 1986-91 suggests that the ad hoc approach to planning urban employment and service provision that exists currently is inadequate to prevent major disparities in population distribution becoming exacerbated between large and small settlements and between regions within the state. These disparities are the result in part of fundamental economic restructuring which is related to international trends but they also reflect the gradual withdrawal by the Irish Government from regional planning from the mid-1980s on. By way of introduction to the discussion of the empirical evidence, an earlier phase of Irish urban and employment planning is reviewed briefly."


Angiotensin II and IGF-I may interact to regulate tubulointerstitial cell kinetics and phenotypic changes in hypertensive rats.
Angiotensin II and insulin-like growth factor-I (IGF-I) are known to be actively involved in the pathogenesis of progressive renal injury, particularly in cell proliferation and phenotypic changes that contribute to tubulointerstitial injury. To investigate the possible mechanisms by which angiotensin II type 1 receptor antagonist (AIIA) ameliorates renal injury in a renal ablation model and to determine the contribution of phenotypic changes and IGF-I to morphological changes, we examined 1) whether AIIA attenuated phenotypic changes as markers of alpha-smooth muscle actin (SMA) and vimentin, 2) whether AIIA altered renal IGF-I expression, and 3) the changes of tubulointerstitial cell kinetics between apoptosis (tested via terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end labeling, TUNEL) and cell proliferation (a test of proliferating cell nuclear antigen, PCNA). Following a sham operation (sham) or 5/6 nephrectomy (Nx), we administered E4177, a potent, selective competitive angiotensin II type 1 receptor antagonist (AIIA), for 10 weeks. In Nx rats, SMA and vimentin expressions developed in injured tubulointerstitium, particularly in hypoperfused scar-adjacent areas, and there was an increase in renal IGF-I expressions. The TUNEL score increased 5-fold and PCNA increased 8-fold, compared with TUNEL and PCNA measurements in sham-operated rats. Renin expression in the juxtaglomerular apparatus was markedly suppressed in the Nx group, although de novo tubular renin expression appeared in Nx, compared with that in the sham group. E4177, both 10 mg/kg (AIIA 10) and 1 mg/kg (AIIA 1), markedly ameliorated renal injury, although blood pressure was less affected in AIIA 1. Both AIIA 10 and AIIA 1 suppressed the neoexpressions of SMA and vimentin in an association with decreased IGF-I expression. Regarding cell kinetics, neither AIIA 10 nor AIIA 1 decreased the TUNEL score; rather, tended to increase, while PCNA was significantly suppressed by AIIA. In conclusion, one of the underlying protective mechanisms of AIIA in this model may be related to the modulations of angiotensin II-induced phenotypic changes and tubulointerstitial cell kinetics through IGF-I.


Notes on voice and speech disorders in ancient and Byzantine Greece.
Voice and speech were considered important by the Ancient and Byzantine Greeks and their disorders were examined and treated on a reasoned basis, without prejudice, by such famous doctors and practitioners of these periods as Hippocrates, Aristotle, Galen, Orebassius and Paul the Aeginitian. In this article, we present the voice and speech disorders which were described and analysed in the texts of Ancient and Byzantine Greek doctors and historians.


Hormonal influence on the central nervous system.
Sex steroids play a very important role in female neurobiology. Postmenopausal gonadal hormone withdrawal seem to be of critical importance in mood disorders, reduced libido and cognitive disturbances, which accompany this phase of a woman's life. Clinical studies have demonstrated that central nervous system (CNS) effects of estrogens are not only limited to resolution of vasomotor instability, they are extended to psychological disturbances like depression, behavioral changes and cognitive dysfunction. Progestins, on the other hand, may have variable effects on the brain, occasionally inducing dysphoric mood and altered behavior. Although their use in hormone replacement therapy (HRT) is widely debated, androgens may help resolve changes in libido experienced by many women after the menopause. It is still, however, difficult to draw guidelines on the use of HRT and postmenopausal CNS disorders as studies present up to date have been carried out with different kinds of molecules and routes of administration. Further studies are required in order to explain the specific role of endogenous and exogenous sex steroids on the CNS.


[Involuntary movement complicated with the postoperative stage of ruptured aneurysm: a case report].
Involuntary movement complicated with the postoperative stage of the ruptured cerebral aneurysm is extremely rare. And, the pathophysiology of the involuntary movement has not been established yet. The authors report such a case because of its rarity and to make the mechanism of its appearance clear. The case was a 45-year-old female who was transported to our clinic after the onset of sudden headache. On admission, she had no neurological deficits without severe headache. CT scan revealed subarachnoid hemorrhage, and left carotid angiogram showed an aneurysm at the bifurcation of the left internal carotid artery. On the day of admission, neck clipping for the aneurysm was successfully performed. Postoperative course was uneventful without mild right hemiparesis which diminished until two weeks after operation. Since the 24th day from operation, athetoid involuntary movement occurred to her four toes. 123I-IMP SPECT revealed low perfusion from left frontal base to caudate, and CT scan showed atrophy of the left caudate. Athetoid involuntary movement as postoperative complication of ruptured cerebral aneurysm has not been reported without our case. We suppose it was caused by the ischemic effect of the left caudate due to the operative retraction or the delayed vasospasm after subarachnoid hemorrhage.


Adverse reactions to sulfa drugs: implications for malaria chemotherapy.
National adverse drug reaction registers in Sweden and the United Kingdom provided data on the type, severity and frequency of reported adverse reactions attributed to sulfa drugs. Reactions to the ten principal drugs were examined in terms of their half-lives and usual indications for use. Of 8339 reactions reported between 1968 and 1988, 1272 (15%) were blood dyscrasias, 3737 (45%) were skin disorders, and 578 (7%) involved the liver. These side-effects occurred with all types of sulfa drugs investigated, although at different relative rates, and 3525 (42%) of them were classified as serious. The overall case fatality rate (CFR) was 1:15 serious reactions, and was highest in patients with white blood cell dyscrasias (1:7). Drugs with longer elimination half-lives had higher CFRs, particularly for fatalities after skin reactions. In Sweden, the estimated incidences of serious reactions were between 9 and 33 per 100,000 short-term users of sulfa drugs (two weeks), between 53 and 111 among those on malaria prophylaxis, and between 1744 and 2031 in patients on continuous therapy. For dapsone, the incidence appeared to increase with higher doses. Our results indicate that sulfa drugs with short elimination half-lives deserve to be considered for use in combination with proguanil or chlorproguanil for malaria chemotherapy and possibly prophylaxis. The smaller risk of adverse reactions associated with lower-dose dapsone suggests that it should also be evaluated as a potentially safe alternative.


Regioselective haloaromatization of 1,2-bis(ethynyl)benzene via halogen acids and PtCl2. Platinum-catalyzed 6-pi electrocyclization of 1,2-bis(1'-haloethenyl)benzene intermediates.
[reaction: see text] Treatment of 1,2-bis(ethynyl)benzene (1) with aqueous HX (X = Br, I) in hot 3-pentanone (100-105 degrees C, 2 h) afforded 1,2-bis(1'-haloethenyl)benzene species 2-Br and 2-I in 98% and 95% yields, respectively. The hydrochlorination of endiyne 1 failed to proceed at elevated temperature but was implemented efficiently by PtCl2 (5 mol %) in hot 3-pentanone (100 degrees C, 2 h) to give 1,2-bis(1'-chloroethenyl)benzene 2-Cl in 80% yield. In the presence of PtCl2 (5 mol %), these halides 2-Cl,2-Br, and 2-I were subsequently converted to 1-halonaphthalenes 3-Cl, 3-Br, and 3-I in the mother solution via sequential 6-pi electrocyclization and dehalogenation reactions. PtCl2 (5 mol %) also effected direct haloaromatization of endiyne 1 with HX (X = Cl, Br, I) and gave 1-halonaphthalenes 3-Cl, 3-Br, and 3-I in 64-71% yields. This investigation reports the scope and the regioselectivity of haloaromatization of various enediynes catalyzed by PtCl2.


PaDef (Persea americana var. drymifolia), a Plant Antimicrobial Peptide, Triggers Apoptosis, and Induces Global Epigenetic Modifications on Histone 3 in an Acute Lymphoid Leukemia Cell Line.
In recent years, it has been recognized that epigenetic alterations play an important role in the development and maintenance of cancer, including leukemias. Furthermore, it is known that these alterations are involved in the emergence of resistance to conventional chemotherapeutics. Consequently, molecules with an anticancer activity whose activity is ruled by epigenetic modifications are attractive to search for new therapies against cancer. The plant antimicrobial peptides have been widely evaluated as molecules with anticancer activity; however, the analysis of the epigenetic regulation induced by these molecules associated with this activity is scarce and still is an unexplored field. In this work, we show that the PaDef defensin, a plant antimicrobial peptide from Mexican avocado fruit (Persea americana var. drymifolia) is cytotoxic for Jurkat cell line from acute lymphoid leukemia cells, through an apoptotic process. PaDef inhibited cell viability in a concentration-dependent manner, with an IC50 = 47.3 μM. Treatment of Jurkat cells with PaDef (IC50) induced cell death by apoptosis dependent on caspases 8 and 9; besides, it was related to an increase in the production of reactive oxygen species and the loss of mitochondrial membrane potential. Interestingly, the inhibition of caspase activation by inhibitors of caspases 8 and 9 does not revert the reduction in viability, suggesting that other mechanisms, in addition to caspase activity, could be participating in the PaDef cytotoxic effect. Also, the modifications in the histone 3 tails induced by PaDef in Jurkat cells were evaluated, specifically acetylation and methylation. PaDef increased global histone 3 acetylation and lysine 9 specific marks (2-fold and up to 4-fold, respectively). These effects correlated with the reduction of the Histone Deacetylase activity (HDAC, ∼50%). Based on methylation marks, PaDef treatment increased lysine 9 di- and tri-methylation tags (2-fold in both cases). The epigenetic modulation induced by PaDef on Jurkat cells could be related to the chromatin compaction-decompaction promoting gene expression or repression; however, further studies are necessary to correlate these marks with the transcription of specific genes. Therefore, the study of new molecules that may have anticancer activity through epigenetic modulation is interesting.


Incidence of myocardial infarction or stroke or death at 47-month follow-up in patients with diabetes and a predicted exercise capacity <or=85% vs >85% during an exercise treadmill sestamibi stress test.
A treadmill exercise sestamibi stress test (TESST) was performed in 609 consecutive diabetic persons with a mean age of 70 years and no history of coronary artery disease (CAD) who were referred for a TESST because of chest pain or dyspnea. Of 609 patients, 301 (49%) had a predicted exercise capacity <or=85% (group A) and 308 (51%) had a predicted exercise capacity >85% (group B). Group A patients had a higher prevalence of myocardial ischemia (43% vs 30%, P=.0005), 2- or 3-vessel obstructive CAD (38% vs 18%, P=.001), myocardial infarction (17% vs 9%, P=.004), death (10% vs 4%, P=.008), and myocardial infarction or stroke or death at 47-month follow-up (21% vs 12%, P=.001). Stepwise Cox regression analysis showed that the only significant independent predictor for the time to development of myocardial infarction or stroke or death was a predicted exercise capacity >85% (hazard ratio, 0.52; 95% confidence interval, 0.34-0.78; P=.002). Diabetic persons with a predicted exercise capacity >85% had a 48% lower chance of myocardial infarction, stroke, or death than those with a predicted exercise capacity <or=85%.


Plasma amino acid and urine organic acid analyses of methylmalonic acidemia in a Thai infant.
Methylmalonic acidemia is an inborn error of organic acid metabolism resulting from defects in methylmalonyl CoA mutase. Analysis of plasma free amino acids in a 15-month-old Thai infant by HPLC showed marked elevation of glycine. HPLC analysis of urinary organic acids showed high levels of methylmalonic acid.


Design and Fabrication of Bilayer Hydrogel System with Self-Healing and Detachment Properties Achieved by Near-Infrared Irradiation.
A novel kind of graphene oxide (GO)-containing bilayer hydrogel system with excellent self-healing and detachment properties stimulated by near-infrared irradiation is successively fabricated via a two-step in situ free radical polymerization. In addition to high mechanical strength, as components of a bilayer hydrogel system, a poly N,N-dimethylacrylamide (PDMAA) layer with 3 mg/mL GO and a poly N-isopropylacrylamide (PNIPAm) layer with 3 mg/mL GO exhibits firm interface bonding. GO in a PDMAA layer transforms under a near-infrared laser into heat, which promotes mutual diffusion of hydrogen bonds and realizes a self-healing property. The irradiation of near infrared laser results in the temperature of PNIPAm layer being higher than the volume phase transition temperature, reducing the corresponding biological viscidity and achieving detachment property. The increase of GO content enhances the self-healing degree and detachment rate. The bilayer hydrogel system fabricated via mold design combines characteristics of PDMAA layer and PNIPAm layer, which can be treated as materials for medical dressings, soft actuators, and robots.


Physicochemical Characteristics and Microbial Communities in Gochujang, a Traditional Korean Fermented Hot Pepper Paste.
Gochujang is a Korean fermented hot pepper paste beneficial to human health by providing various nutrients. In this study, its physicochemical characteristics were identified, and its microbial communities were analyzed by high-throughput sequencing. The interrelationship between physicochemical characteristics and microbial composition was investigated to reveal the properties of gochujang before and after fermentation. After fermentation, all samples showed decreased salt concentration, pH, and reducing sugar content, while the acidity and amino-type nitrogen increased. The water content, salt concentration, amino-type nitrogen, and reducing sugar differed according to the batches of samples. Bacillus, Aerosakkonema, and Enterococcus were identified as the predominant bacterial genera. Furthermore, Aerosakkonema was the most abundant genus before fermentation; however, it was replaced by Bacillus as it decreased after fermentation. For the fungi, Aspergillus dominated before fermentation, whereas Zygosaccharomyces and Millerozyma dominated after fermentation. The high level of amino-type nitrogen in gochujang was related to the relative abundance of B. haynesii/B. licheniformis before fermentation. Additionally, the high abundance of Z. rouxii after fermentation was related to the flavor of gochujang. This comprehensive analysis of the microbial community associated with the physicochemical properties of gochujang could help in understanding the factors affecting the quality of the product.


Disconnection-Mediated Transition in Segregation Structures at Twin Boundaries.
Twin boundaries play an important role in the thermodynamics, stability, and mechanical properties of nanocrystalline metals. Understanding their structure and chemistry at the atomic scale is key to guide strategies for fabricating nanocrystalline materials with improved properties. We report an unusual segregation phenomenon at gold-doped platinum twin boundaries, which is arbitrated by the presence of disconnections, a type of interfacial line defect. By using atomistic simulations, we show that disconnections containing a stacking fault can induce an unexpected transition in the interfacial-segregation structure at the atomic scale, from a bilayer, alternating-segregation structure to a trilayer, segregation-only structure. This behavior is found for faulted disconnections of varying step heights and dislocation characters. Supported by a structural analysis and the classical Langmuir-McLean segregation model, we reveal that this phenomenon is driven by a structurally induced drop of the local pressure across the faulted disconnection accompanied by an increase in the segregation volume.


Usability Evaluation of a VibroTactile Feedback System in Stroke Subjects.
To increase the functional capabilities of stroke subjects during activities of daily living, patients receive rehabilitative training to recover adequate motor control. With the goal to motivate self-training by use of the arm in daily life tasks, a sensor system (Arm Usage Coach, AUC) was developed that provides VibroTactile (VT) feedback if the patient does not move the affected arm above a certain threshold level. The objective of this study is to investigate the usability of this system in stroke subjects. The study was designed as a usability and user acceptance study of feedback modalities. Stroke subjects with mild to moderate arm impairments were enrolled. The subjects wore two AUC devices one on each wrist. VT feedback was given by the device on the affected arm. A semi-structured interview was performed before and after a measurement session with the AUC. In addition, the System Usability Scale (SUS) questionnaire was given. Ten ischemic chronic stroke patients (39 ± 38 months after stroke) were recruited. Four out of 10 subjects have worn the VT feedback on their dominant, affected arm. In the pre-measurement interview, eight participants indicated a preference for acoustic or visual over VT feedback. In the post evaluation interview, nine of 10 participants preferred VT over visual and acoustic feedback. On average, the AUC gave VT feedback six times during the measurement session. All participants, with the exception of one, used their dominant arm more then the non-dominant. For the SUS, eight participants responded above 80%, one between 70 and 80%, and one participant responded below 50%. More patients accepted and valued VT feedback after the test period, hence VT is a feasible feedback modality. The AUC can be used as a telerehabilitation device to train and maintain upper extremity use in daily life tasks.


Molecular markers in gliomas: impact for the clinician.
Over the last decade, understanding of glioma on a molecular level has greatly expanded. However, optimal incorporation of molecular markers into clinical care is controversial. We briefly review the potential utility of molecular stratification in refining histologic diagnosis, prognosis, and treatment decisions, focussing on 1p/19q co-deletion, MGMT promoter methylation, EGFR mutations, and IDH mutation. The most recently discovered IDH mutation is a striking example of a rapid implementation of a molecular marker for prognostication into common clinical use.