Craniofacial morphology in ancient and modern Greeks through 4,000 years.
Multiple 20th century studies have speculated on the anthropological similarities of the modern inhabitants of Greece with their ancient predecessors. The present investigation attempts to add to this knowledge by comparing the craniofacial configuration of 141 ancient (dating around 2,000-500 BC) and 240 modern Greek skulls (the largest material among relevant national studies). Skulls were grouped in age at death, sex, era and geographical categories; lateral cephalograms were taken and 53 variables were measured and correlated statistically. The craniofacial measurements and measurements of the basic quadrilateral and cranial polygon were compared in various groups using basic statistical methods, one-way ANOVA and assessment of the correlation matrices. Most of the measurements for both sexes combined followed an akin pattern in ancient and modern Greek skulls. Moreover, sketching and comparing the outline of the skull and upper face, we observed a clock-wise movement. The present study confirms that the morphological pattern of Greek skulls, as it changed during thousands of years, kept some characteristics unchanged, with others undergoing logical modifications. The analysis of our results allows us to believe that the influence upon the craniofacial complex of the various known factors, including genetic or environmental alterations, is apt to alter its form to adapt to new conditions. Even though 4,000 years seems too narrow a span to provoke evolutionary insights using conventional geometric morphometrics, the full presentation of our results makes up a useful atlas of solid data. Interpreted with caution, the craniofacial morphology in modern and ancient Greeks indicates elements of ethnic group continuation within the unavoidable multicultural mixtures.


Polyfluoroarylation of oxazolones: access to non-natural fluorinated amino acids.
Herein, conditions are provided for the formation and use of the oxazolone enolate for the nucleophilic substitution of highly fluorinated (hetero)arenes, which after unmasking yield highly fluorinated non-natural amino acids and derivatives. In addition, the properties and chemical behavior of this new class of amino acids are explored. The utility is demonstrated in the one pot synthesis of medicinally relevant 2-aminohydantoins.


A simple and robust LC-MS/MS method for quantification of free 3-nitrotyrosine in human plasma from patients receiving on-pump CABG surgery.
We have developed a simple, sensitive, and robust liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS) method to determine free 3-nitrotyrosine concentrations in human plasma of patients receiving on-pump coronary artery bypass grafting surgery. A one-step solid-phase extraction protocol was optimized to enrich the analyte at low nanomolar concentrations. The processed samples were analyzed by LC-MS/MS with a 2.1 × 100 mm Kinetex PFP column and a triple quadrupole mass spectrometer. The method was validated for 3-nitrotyrosine concentrations close to real patient plasma levels. The relative standard deviations or relative errors of the intraday and interday determinations were all within 10%. Limit of detection and limit of quantitation were determined to be 0.034 nM and 0.112 nM, respectively, while lower limit of quantitation was below 0.625 nM. No deterioration of the column performance was noticed after running a large number of patient samples. The results showed that the 3-nitrotyrosine concentrations in coronary sinus plasma samples were elevated after cardiopulmonary bypass (CPB) procedure. The pre-CPB and post-CPB concentrations of 3-nitrotyrosine in patient plasmas were 1.494 ± 0.107 nM and 2.167 ± 0.177 nM (mean ± SEM), respectively. Application of this method to more patients in clinical studies may help validate 3-nitrotyrosine as a meaningful biomarker for nitrosative stress and link patient characteristics, clinical outcomes, and cardioprotective treatments to endogenous nitrosative stress levels.


Universal localization transition accompanying glass formation: insights from efficient molecular dynamics simulations of diverse supercooled liquids.
The origin of the precipitous dynamic arrest known as the glass transition is a grand open question of soft condensed matter physics. It has long been suspected that this transition is driven by an onset of particle localization and associated emergence of a glassy modulus. However, progress towards an accepted understanding of glass formation has been impeded by an inability to obtain data sufficient in chemical diversity, relaxation timescales, and spatial and temporal resolution to validate or falsify proposed theories for its physics. Here we first describe a strategy enabling facile high-throughput simulation of glass-forming liquids to nearly unprecedented relaxation times. We then perform simulations of 51 glass-forming liquids, spanning polymers, small organic molecules, inorganics, and metallic glass-formers, with longest relaxation times exceeding one microsecond. Results identify a universal particle-localization transition accompanying glass formation across all classes of glass-forming liquid. The onset temperature of non-Arrhenius dynamics is found to serve as a normalizing condition leading to a master collapse of localization data. This transition exhibits a non-universal relationship with dynamic arrest, suggesting that the nonuniversality of supercooled liquid dynamics enters via the dependence of relaxation times on local cage scale. These results suggest that a universal particle-localization transition may underpin the glass transition, and they emphasize the potential for recent theoretical developments connecting relaxation to localization and emergent elasticity to finally explain the origin of this phenomenon. More broadly, the capacity for high-throughput prediction of glass formation behavior may open the door to computational inverse design of glass-forming materials.


Crystal structures of the solute receptor GacH of Streptomyces glaucescens in complex with acarbose and an acarbose homolog: comparison with the acarbose-loaded maltose-binding protein of Salmonella typhimurium.
GacH is the solute binding protein (receptor) of the putative oligosaccharide ATP-binding cassette transporter GacFG, encoded in the acarbose biosynthetic gene cluster (gac) from Streptomyces glaucescens GLA.O. In the context of the proposed function of acarbose (acarviosyl-1,4-maltose) as a 'carbophor,' the transporter, in complex with a yet to be identified ATPase subunit, is supposed to mediate the uptake of longer acarbose homologs and acarbose for recycling purposes. Binding assays using isothermal titration calorimetry identified GacH as a maltose/maltodextrin-binding protein with a low affinity for acarbose but with considerable binding activity for its homolog, component 5C (acarviosyl-1,4-maltose-1,4-glucose-1,1-glucose). In contrast, the maltose-binding protein of Salmonella typhimurium (MalE) displays high-affinity acarbose binding. We determined the crystal structures of GacH in complex with acarbose, component 5C, and maltotetraose, as well as in unliganded form. As found for other solute receptors, the polypeptide chain of GacH is folded into two distinct domains (lobes) connected by a hinge, with the interface between the lobes forming the substrate-binding pocket. GacH does not specifically bind the acarviosyl group, but displays specificity for binding of the maltose moiety in the inner part of its binding pocket. The crystal structure of acarbose-loaded MalE showed that two glucose units of acarbose are bound at the same region and position as maltose. A comparative analysis revealed that in GacH, acarbose is buried deeper into the binding pocket than in MalE by exactly one glucose ring shift, resulting in a total of 18 hydrogen-bond interactions versus 21 hydrogen-bond interactions for MalE(acarbose). Since the substrate specificity of ATP-binding cassette import systems is determined by the cognate binding protein, our results provide the first biochemical and structural evidence for the proposed role of GacHFG in acarbose metabolism.


A survey of rationales for and against hand splinting in hemiplegia.
This study investigated rationales underlying splinting decisions involving patients with hemiplegia. The survey incorporated a limited-choice, multiple-option questionnaire based on the case study of a man with a left hemiparesis at three hypothetical stages of recovery. Ninety-three occupational therapists who answered indicated whether they would or would not recommend a splint at each stage, and selected one or more reasons for their decisions. The respondents fell into three major categories: those who would 1. never splint, 2. always splint, and 3. splint only in the presence of moderate to severe spasticity. Those with longer clinical experience reflected more tendency to splint. The results indicated conflicting practices in splinting and showed the need for further clinical research in this area.


Evolution in the supramolecular complexes between poly(phenylene ethynylene)-based polyelectrolytes and octadecyltrimethylammonium bromide as revealed by fluorescence correlation spectroscopy.
Poly(phenyleneethynylene)-based conjugated polyelectrolytes (PPE-SO(3)(-)) are a class of polyions with rigid backbones. This work uses fluorescence correlation spectroscopy to study how the diffusion of complexes, formed between a PPE-SO(3)(-) polyelectrolyte and octadecyltrimethylammonium bromide (OTAB) surfactant molecules, changes with OTAB concentration below its critical micelle concentration. The dependence of the hydrodynamic radius of the complexes on the OTAB concentration has three regimes. In the low concentration regime ( C(OTAB)/ C(monomer) < 6), the complex has a size comparable to that of the polymer in deionized water. In the intermediate concentration regime (6 < C(OTAB)/ C(monomer) < 400), the complexes have the largest size and substantial heterogeneity. In the high concentration regime (400 < C(OTAB)/ C(monomer) < 1800), the complexes have a size that is about three times larger than that in the low concentration regime. These results elucidate features of the self-assembly of a polyelectrolyte and an ionic surfactant and show that the C(OTAB)/ C(monomer) concentration ratio controls the composition of polyelectrolyte/surfactant complexes.


Correlation of Condylar Translation During Maximal Mouth Opening with Presence of Signs of Temporomandibular Joint Disorders in an Asymptomatic Population of 18-25 Years Age Group of Northern India.
The objective of this study was to determine the frequency of "subluxation" and presence of clinical signs of Temporomandibular Joint Disorder (TMD) in asymptomatic individuals and its distribution according to age and sex. The material investigated comprised of 200 asymptomatic subjects with 400 joints. The subjects were divided into two groups of 18-25 years and 50-60 years of age consisting of equal number of males and females. Clinical examination involved measurement of maximal inter-incisal distance, joint sounds and deviation. For radiological examination, Temporomandibular Joint (TMJ) open mouth close mouth view option (TMJ1/2) was used on a Digital Panoramic Machine. All the radiographs were traced to assess subluxation and anterior translation of the condyle. The statistical analysis was carried out using Statistical Package for Social Sciences (SPSS Inc., Chicago, IL, version 15.0 for Windows). The prevalence of the signs of TMDs in the asymptomatic population was found to be very high and more predominant in females as compared to males. Furthermore, the older age group had comparatively less signs of TMDs. It was of interest that the subjects presenting with clinical signs of TMD were significantly less as compared to the subjects presenting with subluxation. The value of anterior translation was found to be more in females in the younger age group as compared to the males. Similarly, it was more in males as compared to females in older age group. But the mean anterior translation difference in females in 18-25 years and 50-60 years showed a statistically significant difference with P-value 0.017. Subluxation is a very common feature found in almost all the subjects in this study with a high prevalence. Hence, we may assume that the increased incidence of TMDs could be a direct result of the phenomena of subluxation. The decrease in mandibular length could be the cause of decreased mouth opening and increased subluxation.


Bacterial resistance to antimicrobial agents: an overview from Korea.
Antimicrobial resistance of bacteria has become a worldwide problem. Available data suggest that the resistance problem is comparatively more serious in Korea. In large hospitals, the proportion of methicillin-resistant Staphylococcus aureus (MRSA) has been reported at over 70%, and of penicillin-nonsusceptible Streptococcus pneumoniae at around 70%. Infection or colonization of vancomycin-resistant enterococci has started to increase. Extended-spectrum beta-lactamase producing Escherichia coli and Klebsiella pneumoniae has become widespread and even carbapenem-resistant Pseudomonas aeruginosa has been increasing. Community-acquired pathogens such as Salmonella, Shigella and Neisseria gonorrhoeae are often resistant to various antimicrobial agents. The prevalence of resistant bacteria can lead to erroneous empirical selection of either noneffective or expensive drugs, prolonging hospitalization and higher mortality. The emergence and spread of resistant bacteria are unavoidable unless antimicrobial agents are not used at all. The high prevalence of resistant bacteria in Korea seems to be related to antibiotic usage: 1) easy availability without prescription at drug stores, 2) injudicious use in hospitals, and 3) uncontrolled use in agriculture, animal husbandry, and fisheries. Nosocomial infection is an important factor in the spread of resistant bacteria. Antimicrobial resistance problems should be regarded as the major public health concern in Korea. It is urgently required to ban the sale of antibiotics without prescription, to use antibiotics more judiciously in hospitals by intensive teaching of the principles of the use of antibiotics, and to establish better control measures of nosocomial infections. Regulation of antimicrobials for other than human use should also be required. These issues are not easy to address and require the collective action of governments, the pharmaceutical industry, health care providers, and consumers.


Performance of an efficient image-registration algorithm in processing MR renography data.
To evaluate the performance of an edge-based registration technique in correcting for respiratory motion artifacts in magnetic resonance renographic (MRR) data and to examine the efficiency of a semiautomatic software package in processing renographic data from a cohort of clinical patients. The developed software incorporates an image-registration algorithm based on the generalized Hough transform of edge maps. It was used to estimate glomerular filtration rate (GFR), renal plasma flow (RPF), and mean transit time (MTT) from 36 patients who underwent free-breathing MRR at 3T using saturation-recovery turbo-FLASH. The processing time required for each patient was recorded. Renal parameter estimates and model-fitting residues from the software were compared to those from a previously reported technique. Interreader variability in the software was quantified by the standard deviation of parameter estimates among three readers. GFR estimates from our software were also compared to a reference standard from nuclear medicine. The time taken to process one patient's data with the software averaged 12 ± 4 minutes. The applied image registration effectively reduced motion artifacts in dynamic images by providing renal tracer-retention curves with significantly smaller fitting residues (P < 0.01) than unregistered data or data registered by the previously reported technique. Interreader variability was less than 10% for all parameters. GFR estimates from the proposed method showed greater concordance with reference values (P < 0.05). These results suggest that the proposed software can process MRR data efficiently and accurately. Its incorporated registration technique based on the generalized Hough transform effectively reduces respiratory motion artifacts in free-breathing renographic acquisitions.


Crystal Structure and Enzymology of Solanum tuberosum Inositol Tris/Tetrakisphosphate Kinase 1 (StITPK1).
Inositol phosphates and their pyrophosphorylated derivatives are responsive to the phosphate supply and are agents of phosphate homeostasis and other aspects of physiology. It seems likely that the enzymes that interconvert these signals work against the prevailing milieu of mixed populations of competing substrates and products. The synthesis of inositol pyrophosphates is mediated in plants by two classes of ATP-grasp fold kinase: PPIP5 kinases, known as VIH, and members of the inositol tris/tetrakisphosphate kinase (ITPK) family, specifically ITPK1/2. A molecular explanation of the contribution of ITPK1/2 to inositol pyrophosphate synthesis and turnover in plants is incomplete: the absence of nucleotide in published crystal structures limits the explanation of phosphotransfer reactions, and little is known of the affinity of potential substrates and competitors for ITPK1. Herein, we describe a complex of ADP and StITPK1 at 2.26 Å resolution and use a simple fluorescence polarization approach to compare the affinity of binding of diverse inositol phosphates, inositol pyrophosphates, and analogues. By simple HPLC, we reveal the novel catalytic capability of ITPK1 for different inositol pyrophosphates and show Ins(3,4,5,6)P4 to be a potent inhibitor of the inositol pyrophosphate-synthesizing activity of ITPK1. We further describe the exquisite specificity of ITPK1 for the myo-isomer among naturally occurring inositol hexakisphosphates.


Responsive photonic barcodes for sensitive multiplex bioassay.
Barcodes have a demonstrated value for multiplex high-throughput bioassays. The tendency of this technology is to pursue high sensitivity target screening. Herein, we presented a new type of inverse opal-structured poly(N-isopropylacrylamide) (pNIPAM) hydrogel photonic crystal (PhC) barcodes with the function of fluorescent signal self-amplification for the detection. During the bio-reaction process at body temperature, the pNIPAM hydrogel barcodes kept swelling, and their inverse opal structure with interconnected pores provided unblocked channels for the targets to diffuse into the voids of the barcodes and react. During the detection process, the barcodes were kept at a volume phase transition temperature (VPTT) to shrink their volume; this resulted in an obvious increase in the density of fluorescent molecules and signal amplification. It was demonstrated that the responsive barcodes could achieve the limits of detection (LOD) of α-fetoprotein (AFP) and carcinoembryonic antigen (CEA) at 0.623 ng mL-1 and 0.492 ng mL-1, respectively. In addition, the proposed barcodes showed good multiplex detection capacity with acceptable cross-reactivity, accuracy, and reproducibility, and the results were consistent with those of common clinical laboratory methods for the detection of clinical samples. These features of the inverse opal-structured responsive hydrogel barcodes indicate that they are ideal technology for high-sensitive multiplex bioassays.


Crystal structure of the MgtE Mg2+ transporter.
The magnesium ion Mg2+ is a vital element involved in numerous physiological processes. Mg2+ has the largest hydrated radius among all cations, whereas its ionic radius is the smallest. It remains obscure how Mg2+ transporters selectively recognize and dehydrate the large, fully hydrated Mg2+ cation for transport. Recently the crystal structures of the CorA Mg2+ transporter were reported. The MgtE family of Mg2+ transporters is ubiquitously distributed in all phylogenetic domains, and human homologues have been functionally characterized and suggested to be involved in magnesium homeostasis. However, the MgtE transporters have not been thoroughly characterized. Here we determine the crystal structures of the full-length Thermus thermophilus MgtE at 3.5 A resolution, and of the cytosolic domain in the presence and absence of Mg2+ at 2.3 A and 3.9 A resolutions, respectively. The transporter adopts a homodimeric architecture, consisting of the carboxy-terminal five transmembrane domains and the amino-terminal cytosolic domains, which are composed of the superhelical N domain and tandemly repeated cystathionine-beta-synthase domains. A solvent-accessible pore nearly traverses the transmembrane domains, with one potential Mg2+ bound to the conserved Asp 432 within the pore. The transmembrane (TM)5 helices from both subunits close the pore through interactions with the 'connecting helices', which connect the cystathionine-beta-synthase and transmembrane domains. Four putative Mg2+ ions are bound at the interface between the connecting helices and the other domains, and this may lock the closed conformation of the pore. A structural comparison of the two states of the cytosolic domains showed the Mg2+-dependent movement of the connecting helices, which might reorganize the transmembrane helices to open the pore. These findings suggest a homeostasis mechanism, in which Mg2+ bound between cytosolic domains regulates Mg2+ flux by sensing the intracellular Mg2+ concentration. Whether this presumed regulation controls gating of an ion channel or opening of a secondary active transporter remains to be determined.


Double-blind placebo-controlled trial of static magnets for the treatment of osteoarthritis of the knee: results of a pilot study.
Outpatient clinical studies of magnet therapy, a complementary therapy commonly used to treat osteoarthritis (OA), have been limited by the absence of a credible placebo control. Our objective was to assess the feasibility and promise of studying static magnetic therapy for knee OA and determine the ability of a new placebo-magnet device to provide concealment of group assignment. Randomized, double-blind, placebo-controlled clinical trial. Academic teaching hospital in Boston. We enrolled 29 subjects with idiopathic or post-traumatic OA of the knee. Subjects received either high-strength magnetic (active) or placebo-magnetic (placebo) knee sleeve treatment for 4 hours in a monitored setting and self-treatment 6 hours daily for 6 weeks. Primary outcomes were change in knee pain as measured by the WOMAC Osteoarthritis Index Pain Subscale at 6 weeks and extent of group concealment at study end. At 4 hours, VAS pain scores (+/- SE) on a 5-item scale (0-500, 500 worst) decreased 79 +/- 18 mm in the active group and 10 +/- 21 mm in the placebo group (P < 0.05). There were no significant differences in any primary or secondary measure of efficacy between the treatment groups at 6 weeks. Despite widespread testing for magnetic properties, at study end, 69% of the active group and 77% of the placebo group (P > 0.2) believed that they had been assigned to the active treatment group. Despite our small sample size, magnets showed statistically significant efficacy compared to placebo after 4 hours under rigorously controlled conditions. The sustained efficacy of magnetic therapy for knee osteoarthritis could be assessed in an adequately powered trial utilizing an appropriate control such our new placebo-magnet device.


Neutrophil elastase inhibitors, SC-37698 and SC-39026, reduce endotoxin-induced lung dysfunction in awake sheep.
Neutrophils have been implicated as important cellular mediators of the pulmonary dysfunction observed following endotoxemia in chronically instrumented awake sheep. Several areas of research suggest that neutrophil-derived proteases may be mediators of this dysfunction. We hypothesized that neutrophil elastase inhibitors would attenuate the effects of endotoxemia in sheep. To test this hypothesis, we studied the effects of two putative neutrophil elastase inhibitors, SC-37698 and SC-39026 (Searle, Skokie, IL), on endotoxin-induced lung dysfunction in awake sheep. Sheep were given intravenous neutrophil elastase inhibitor alone (20 mg/kg/h for 6 h), intravenous endotoxin (E. coli endotoxin, 0.5 microgram/kg over 20 min) 1 h after beginning the 6-h infusion of elastase inhibitor, or endotoxin 1 h after beginning a 6-h infusion of elastase inhibitor vehicle. SC-37698 attenuated the increase in lung lymph flow and lung lymph protein clearance, the alterations in lung mechanics, and the fall in white blood count. Qualitatively similar effects were seen with SC-39026. These data suggest the need for further research examining the role of protease-antiprotease interactions and the potential utility of neutrophil elastase inhibitors in acute lung injury like that observed in the adult respiratory distress syndrome (ARDS) in the human.


Prevalence of tuberculosis, HIV and respiratory symptoms in two Zambian communities: implications for tuberculosis control in the era of HIV.
The Stop TB Partnership target for tuberculosis is to have reduced the prevalence of tuberculosis by 50% comparing 2015 to 1990. This target is challenging as few prevalence surveys have been conducted, especially in high burden tuberculosis and HIV countries. Current tuberculosis control strategies in high HIV prevalent settings are therefore based on limited epidemiological evidence and more evidence is needed from community-based surveys to inform improved policy formulation. 8044 adults were sampled from 2 sub-districts (wards) in Lusaka province, Zambia. Questionnaires were used to screen for symptoms, respiratory samples were obtained for culture and oral secretions collected for HIV testing. 79 individuals were found to have Mycobacterium tuberculosis in their sputum, giving an adjusted overall prevalence of tuberculosis of 870/100,000 (95% CI 570-1160/100,000). The adjusted overall prevalence of HIV was 28.61% (95% CI 26.04-31.19). HIV- infection was significantly associated with prevalent tuberculosis (Adj OR 2.3, 95% CI 1.42-3.74) and the population attributable fraction of HIV for prevalent tuberculosis was 36%. Symptoms such as prolonged cough (adj OR 12.72, 95% CI 7.05-22.94) and fever (Adj OR 2.04, 95%CI 1.23-3.39), were associated with prevalent tuberculosis, but 8 (10%) individuals with prevalent tuberculosis denied having any symptoms at all and only 34 (43%) would have been classified as a TB suspect by current guidelines. Undiagnosed tuberculosis is a challenge for tuberculosis control and new approaches are needed if we are to reach international targets. Epidemiological studies can inform screening algorithms for both detection and prevention of active tuberculosis.


BRCA2 mutation-associated breast cancers exhibit a distinguishing phenotype based on morphology and molecular profiles from tissue microarrays.
A distinct morphologic and molecular phenotype has been reported for BRCA1-associated breast cancers; however, the phenotype of BRCA2-associated breast cancers is less certain. To comprehensively characterize BRCA2-associated breast cancers we performed a retrospective case control study using tumors accrued through the Breast Cancer Family Registry. We examined the tumor morphology and hormone receptor status in 157 hereditary breast cancers with germline mutations in BRCA2 and 314 control tumors negative for BRCA1 and BRCA2 mutations that were matched for age and ethnicity. Tissue microarrays were constructed from 64 BRCA2-associated and 185 control tumors. Tissue microarray sections were examined for HER2/neu protein overexpression, p53 status and the expression of basal markers, luminal markers, cyclin D1, bcl2, and MIB1 by immunohistochemistry. The majority of BRCA2-associated tumors and control tumors were invasive ductal, no special-type tumors. In contrast to control tumors, BRCA2-associated cancers were more likely to be high grade (P<0.0001) and to have pushing tumor margins (P=0.0005). Adjusting for grade, BRCA2-associated tumors were more often estrogen receptor positive (P=0.008) and exhibited a luminal phenotype (P=0.003). They were less likely than controls to express the basal cytokeratin CK5 (P=0.03) or to overexpress HER2/neu protein (P=0.06). There was no difference in p53, bcl2, MIB1, or cyclin D1 expression between BRCA2-associated and control tumors. We have demonstrated, in the largest series of BRCA2-associated breast cancers studied to date, that these tumors are predominantly high-grade invasive ductal carcinomas of no special type and they demonstrate a luminal phenotype despite their high histologic grade.


Preliminary investigation of fungal bioprocessing of wheat straw for production of straw-thermoplastic composites.
Straw utilization for composites is limited by poor resin and polymer penetration, and excessive resin consumption owing to the straw cuticle, fines, and lignin-hemicellulose matrix. White-rot fungi degrade these components of straw and could, therefore, potentially be used to improve resin penetration and resin binding without the use of physical or chemical pretreatments. Although long treatment times and large footprints the limit use of fungal treatments on a large scale, distributed fungal pretreatments could alleviate land requirements. In this article, we present progress toward the development of a passive fungal straw upgrading system utilizing whiterot fungi.


[Lithium levels need to be monitored: discrepancies between guidelines and practice].
Since lithium can affect the thyroid gland and the kidneys, it is important to perform regular checks on levels of lithium, creatinine and thyroid-stimulating hormone (TSH). To investigate whether psychiatrists and general practitioners (GPs) perform the required checks twice a year on the levels of lithium, creatinine and tsh in accordance with the Dutch guidelines on bipolar disorder as laid down in 2001. The study was based on data that the clinical-chemical laboratory had regarding the lithium checks performed in 2004 in GPs' practices or by the mental health authority in Apeldoorn and the surrounding area. About 250,000 people live in this region. Some of the psychiatrists (11%) and GPs (about 25%) did not check lithium levels as frequently as recommended in the guidelines of 2001. The GPs checked significantly less frequently that the psychiatrists. Both the GPs and the psychiatrists monitored creatinine and TSH less frequently than recommended in the guidelines, creatinine was monitored in 65.8 and 61.2% and TSH in 68.3 and 58% respectively. CONCLUSION We recommend that a warning system be installed in the laboratory which will alert the doctor when a patient has missed a check. Another suggestion is that lithium should be prescribed only by psychiatrists, and not by GPs.


L-arginine improves wound healing after trauma-hemorrhage by increasing collagen synthesis.
Several studies indicate impaired wound healing after trauma and shock. Wound immune cell dysfunction seems to be responsible for altered wound healing after trauma-hemorrhage (T-H). In this respect, administration of the amino acid L-arginine normalized wound immune cell function under those conditions. It remains unknown, however, whether L-arginine improves impaired wound healing after T-H. To study this, male C3H/HeN mice were subjected to a midline laparotomy (i.e., soft tissue trauma induced), and polyvinyl sponges were implanted subcutaneously at the wound site before hemorrhage (35 +/- 5 mm Hg for 90 minutes) or were subjected to sham operation. During resuscitation, mice received 300 mg/kg body weight L-arginine or saline (vehicle). Seven days thereafter, hydroxyproline (OHP), a metabolite of collagen synthesis, was measured in the wound fluid using high-performance liquid chromatography. Collagen types I and III were determined in the wound by Western blot analysis. In addition, wound breaking strength was measured 10 days after T-H or sham operation. The results indicate that OHP was significantly decreased in T-H mice. L-arginine, however, restored depressed OHP in the wound fluid in the T-H animals. Similarly, L-arginine treatment prevented a significant depression of collagen I synthesis after T-H. Collagen III was not significantly affected by T-H or L-arginine. Most important, L-arginine increased maximal wound breaking strength after severe blood loss. Therefore, L-arginine improves wound healing after T-H by increasing collagen synthesis. Because L-arginine improves wound healing, the results suggest that L-arginine might represent a novel and useful adjunct to fluid resuscitation for decreasing wound complications after trauma and severe blood loss.


Mechanistic Investigations of the Asymmetric Hydrogenation of Enamides with Neutral Bis(phosphine) Cobalt Precatalysts.
The mechanism of the asymmetric hydrogenation of prochiral enamides by well-defined, neutral bis(phosphine) cobalt(0) and cobalt(II) precatalysts has been explored using(R,R)-iPrDuPhos ((R,R)-iPrDuPhos = (+)-1,2-bis[(2R,5R)-2,5-diisopropylphospholano]benzene) as a representative chiral bis(phosphine) ligand. A series of (R,R)-(iPrDuPhos)Co(enamide) (enamide = methyl-2-acetamidoacrylate (MAA), methyl(Z)-α-acetamidocinnamate (MAC), and methyl(Z)-acetamido(4-fluorophenyl)acrylate (4FMAC)) complexes (1-MAA, 1-MAC, and 1-4FMAC), as well as a dinuclear cobalt tetrahydride, [(R,R)-(iPrDuPhos)Co]2(μ2-H)3(H) (2), were independently synthesized, characterized, and evaluated in both stoichiometric and catalytic hydrogenation reactions. Characterization of (R,R)-(iPrDuPhos)Co(enamide) complexes by X-ray diffraction established the formation of the pro-(R) diastereomers in contrast to the (S)-alkane products obtained from the catalytic reaction. In situ monitoring of the cobalt-catalyzed hydrogenation reactions by UV-visible and freeze-quench electron paramagnetic resonance spectroscopies revealed (R,R)-(iPrDuPhos)Co(enamide) complexes as the catalyst resting state for all the three enamides studied. Variable time normalization analysis kinetic studies of the cobalt-catalyzed hydrogenation reactions in methanol established a rate law that is first order in (R,R)-(iPrDuPhos)Co(enamide) and H2 but independent of the enamide concentration. Deuterium-labeling studies, including measurement of an H2/D2 kinetic isotope effect and catalytic hydrogenations with HD, established an irreversible H2 addition step to the bound enamide. Density functional theory calculations support that this step is both rate and selectivity determining. Calculations, as well as HD-labeling studies, provide evidence for two-electron redox cycling involving cobalt(0) and cobalt(II) intermediates during the catalytic cycle. Taken together, these experiments support an unsaturated pathway for the [(R,R)-(iPrDuPhos)Co]-catalyzed hydrogenation of prochiral enamides.


Renal oxygenation during partial nephrectomy: a comparison between artery-only occlusion versus artery and vein occlusion.
During partial nephrectomy (PN), artery-only (AO) occlusion may mitigate ischemia/reperfusion injury because of retrograde venous flow. Using digital light processing-hyperspectral imaging (DLP(®)-HSI), we compared renal oxygenation during AO vs artery and vein (AV) occlusion in patients undergoing PN. Thirty-seven patients who were undergoing complex open PN (median R.E.N.A.L. nephrometry of 8) at our institution underwent renal oxygenation assessment using DLP-HSI. Percent renal parenchymal oxyhemoglobin (%HbO2) during AO vs AV occlusion was recorded and its correlation with postoperative estimated glomerular filtration rate (eGFR) was investigated using Pearson correlation. AO and AV occlusion was performed in 12 and 25 patients, respectively. Comparing AO vs AV, mean ischemia time was 41 vs 35 minutes (P=0.02). The %HbO2 at baseline was 73.6% vs 71% (P=0.23). After hilar occlusion, %HbO2 quickly reached an "ischemic plateau" in both groups, with mean ischemic %HbO2 measures of 59.7% vs 62.2% (P=0.19). In the AV group, a lower mean ischemic %HbO2 was associated with lower eGFR at the most recent follow-up (r=0.46, P=0.02) and remained significant on multivariable analysis (odds ratio 2.31; 95% confidence interval 0.29-4.32; P=0.03). In this pilot clinical study, renal oxygenation profiles during PN as assessed by DLP-HSI were similar for AO vs AV occlusion. Significant retrograde venous oxygen delivery using an AO occlusion technique could not be demonstrated. There was also no renal functional advantage for AO occlusion in this population of difficult PN where prolonged ischemia times may have mitigated any advantage. Further study in cases with shorter ischemia times is warranted.


A computer-aided drug design approach to discover tumour suppressor p53 protein activators for colorectal cancer therapy.
Colorectal cancer (CRC) is the third most detected cancer and the second foremost cause of cancer deaths in the world. Intervention targeting p53 provides potential therapeutic strategies, but thus far no p53-based therapy has been successfully translated into clinical cancer treatment. Here we developed a Quantitative Structure-Activity Relationships (QSAR) classification models using empirical molecular descriptors and fingerprints to predict the activity against the p53 protein, using the potency value with the active or inactive label, were developed. These models were built using in total 10,505 molecules that were extracted from the ChEMBL, ZINC and Reaxys® databases, and recent literature. Three machine learning (ML) techniques e.g., Random Forest, Support Vector Machine, Convolutional Neural Network were explored to build models for p53 inhibitor prediction. The performances of the models were successfully evaluated by internal and external validation. Moreover, based on the best in silico p53 model, a virtual screening campaign was carried out using 1443 FDA-approved drugs that were extracted from the ZINC database. A list of virtual screening hits was assented on base of some limits established in this approach, such as: (1) probability of being active against p53; (2) applicability domain; (3) prediction of the affinity between the p53, and ligands, through molecular docking. The most promising according to the limits established above was dihydroergocristine. This compound revealed cytotoxic activity against a p53-expressing CRC cell line with an IC50 of 56.8 µM. This study demonstrated that the computer-aided drug design approach can be used to identify previously unknown molecules for targeting p53 protein with anti-cancer activity and thus pave the way for the study of a therapeutic solution for CRC.


Experts' opinion about the pediatric secondary headaches diagnostic criteria of the ICHD-3 beta.
The 2013 International Classification of Headache Disorders-3 was published in a beta version to allow clinicians to confirm the validity of the criteria or suggest improvements based on field studies. The aim of this work was to review the Secondary Headache Disorders and Cranial Neuralgias and Other Headache Disorders sections of ICHD-3 beta data on children and adolescents (age 0-18 years) and to suggest changes, additions, and amendments. Several experts in childhood headache across the world applied different aspects of ICHD-3 beta in their normal clinical practice. Based on their personal experience and the available literature on pediatric headache, they made observations and proposed suggestions for the mentioned headache disorders on children and adolescents. Some headache disorders in children have specific features, which are different from adults that should be acknowledged and considered. Some features in children were found to be age-dependent: clinical characteristics, risks factors and etiologies have a strong bio psychosocial basis in children and adolescents making primary headache disorders in children distinct from those in adults. Several recommendations are presented in order to make ICHD-3 more appropriate for use in children.


Effect of acute plasma volume expansion on substrate turnover during prolonged low-intensity exercise.
We investigated the effect of acute, graded increases in plasma volume (PV) by use of dextran on substrate turnover and oxidation during exercise. Eight untrained males [peak aerobic power (VO2peak) = 45.2 +/- 2.2 (SE) ml.kg-1.min-1] performed 2 h of cycle ergometry at 46 +/- 4% of VO2peak on three occasions in a randomized order: 0% PV expansion (CON) and after 14% (LOW) and 21% (HIGH) PV expansion. Glucose and glycerol turnover were measured using primed continuous infusions of [6,6-2H2]glucose and [2H5]glycerol, respectively. Glycerol rate of appearance (Ra) was taken as a relative index of whole body lipolysis. Increases in PV had no effect on glucose Ra or disappearance (Rd) either at rest or during exercise. At the onset of exercise, both glucose Ra and Rd increased approximately 100% (P < 0.01). Glucose Ra and Rd continued to increase with exercise duration (P < 0.05) so that, at 120 min of exercise, they were > 330% higher than at rest (P < 0.01). Glycerol Ra also increased with exercise duration (P < 0.05). Total lipolysis during exercise, calculated as the area under the glycerol Ra vs. time curve, was reduced during LOW vs. CON (P < 0.01). Further expansion of PV (HIGH) had no additional effect on whole body lipolysis. No effect of hypervolemia was observed on whole body fat or carbohydrate oxidation. These results indicate that acute PV expansion can alter whole body lipolysis, possibly via a reduction in catecholamine secretion.


CyberKnife rhizotomy for facetogenic back pain: a pilot study.
By targeting the medial branches of the dorsal rami, radiofrequency ablation and facet joint injections can provide temporary amelioration of facet joint-producing (or facetogenic) back pain. The authors used CyberKnife radiosurgery to denervate affected facet joints with the goal of obtaining a less invasive yet more thorough and durable antinociceptive rhizotomy. Patients with refractory low-back pain, in whom symptoms are temporarily resolved by facet joint injections, were eligible. The patients were required to exhibit positron emission tomography-positive findings at the affected levels. Radiosurgical rhizotomy, targeting the facet joint, was performed in a single session with a marginal prescription dose of 40 Gy and a maximal dose of 60 Gy. Seven facet joints in 5 patients with presumptive facetogenic back pain underwent CyberKnife lesioning. The median follow-up was 9.8 months (range 3-16 months). The mean planning target volume was 1.7 cm(3) (range 0.9-2.7 cm(3)). A dose of 40 Gy was prescribed to a mean isodose line of 79% (range 75-80%). Within 1 month of radiosurgery, improvement in pain was observed in 3 of the 5 patients with durable responses at 16, 12, and 6 months, respectively, of follow-up. Two patients, after 12 and 3 months of follow-up, have neither improved nor worsened. No patient has experienced acute or late-onset toxicity. These preliminary results suggest that CyberKnife radiosurgery could be a safe, effective, and non-invasive alternative to radiofrequency ablation for managing facetogenic back pain. No patient suffered recurrent symptoms after radiosurgery. It is not yet known whether pain relief due to such lesions will be more durable than that produced by alternative procedures. A larger series of patients with long-term follow-up is ongoing.


Requirement of proline synthesis during Arabidopsis reproductive development.
Gamete and embryo development are crucial for successful reproduction and seed set in plants, which is often the determining factor for crop yield. Proline accumulation was largely viewed as a specific reaction to overcome stress conditions, while recent studies suggested important functions of proline metabolism also in reproductive development. Both the level of free proline and proline metabolism were proposed to influence the transition to flowering, as well as pollen and embryo development. In this study, we performed a detailed analysis of the contribution of individual proline biosynthetic enzymes to vegetative development and reproductive success in Arabidopsis. In contrast to previous reports, we found that pyrroline-5-carboxylate (P5C) synthetase 2 (P5CS2) is not essential for sexual reproduction although p5cs2 mutant plants were retarded in vegetative development and displayed reduced fertility under long-day conditions. Single mutant plants devoid of P5CS1 did not show any developmental defects. Simultaneous absence of both P5CS isoforms resulted in pollen sterility, while fertile egg cells could still be produced. Expression of P5C reductase (P5CR) was indispensable for embryo development but surprisingly not needed for pollen or egg cell fertility. The latter observation could be explained by an extreme stability of P5CR activity, which had a half-life time of greater than 3 weeks in vitro. Expression of P5CR-GFP under the control of the endogenous P5CR promoter was able to restore growth of homozygous p5cr mutant embryos. The analysis of P5CR-GFP-fluorescence in planta supported an exclusively cytoplasmatic localisation of P5CR. Our results demonstrate that potential alternative pathways for proline synthesis or inter-generation transfer of proline are not sufficient to overcome a defect in proline biosynthesis from glutamate during pollen development. Proline biosynthesis through P5CS2 and P5CR is limiting for vegetative and reproductive development in Arabidopsis, whereas disruption of P5CS1 alone does not affect development of non-stressed plants.


Early Intervention for Children With Autism Spectrum Disorder Under 3 Years of Age: Recommendations for Practice and Research.
This article reviews current evidence for autism spectrum disorder (ASD) interventions for children aged <3 years, based on peer-reviewed articles published up to December 2013. Several groups have adapted treatments initially designed for older, preschool-aged children with ASD, integrating best practice in behavioral teaching methods into a developmental framework based on current scientific understanding of how infants and toddlers learn. The central role of parents has been emphasized, and interventions are designed to incorporate learning opportunities into everyday activities, capitalize on "teachable moments," and facilitate the generalization of skills beyond the familiar home setting. Our review identified several comprehensive and targeted treatment models with evidence of clear benefits. Although some trials were limited to 8- to 12-week outcome data, enhanced outcomes associated with some interventions were evaluated over periods as long as 2 years. Based on this review, recommendations are proposed for clinical practice and future research.


Polysymptomatic distress in patients with rheumatoid arthritis: understanding disproportionate response and its spectrum.
Fibromyalgia (FM) in rheumatoid arthritis (RA) can cause consternation because symptoms are seen to be out of proportion to physician and laboratory assessments, and composite RA activity scores such as the 28 joint Disease Activity Score, Clinical Disease Activity Index, and Routine Assessment of Patient Index Data 3 (RAPID-3) can yield apparently "wrong" results. We explored the effect of polysymptomatic distress (PSD), a measure of fibromyalgianess and a quantity derived from the American College of Rheumatology 2010 FM diagnostic criteria, to explain the relationship of patient to physician variables. We obtained PSD scores on 300 RA patients prior to ordinary clinical care, and assessed the associations of PSD with tender and swollen joints, physician global estimate of RA activity, pain, Health Assessment Questionnaire score, and composite RA activity measures during routine clinic assessments. PSD scores greater than the sample mean (8.8) were associated with increased patient symptoms regardless of the presence or absence of FM, while scores below the mean were associated with better patient outcomes. PSD scores predicted all patient outcomes and less strongly predicted physician outcomes. The discrepancy between patient and physician measures was greatest at low levels of physician-estimated disease activity. PSD rather than FM diagnosis more usefully identifies and predicts disproportionate responses. Just as there are patients who lean disproportionately toward greater severity, there are also patients who disproportionately report milder symptoms. Composite measures used to assess RA are flawed, as they confound RA inflammation and patient distress, and more consideration should be given to disaggregated assessments. PSD also appears to be influenced weakly by RA disease activity.


Photodynamic therapy for lung cancer and malignant pleural mesothelioma.
Photodynamic therapy (PDT) is a form of non-ionizing radiation therapy that uses a drug, called a photosensitizer, combined with light to produce singlet oxygen ((1)O2) that can exert anti-cancer activity through apoptotic, necrotic, or autophagic tumor cell death. PDT is increasingly being used to treat thoracic malignancies. For early-stage non-small cell lung cancer (NSCLC), PDT is primarily employed as an endobronchial therapy to definitively treat endobronchial or roentgenographically occult tumors. Similarly, patients with multiple primary lung cancers may be definitively treated with PDT. For advanced or metastatic NSCLC and small cell lung cancer (SCLC), PDT is primarily employed to palliate symptoms from obstructing endobronchial lesions causing airway compromise or hemoptysis. PDT can be used in advanced NSCLC to attempt to increase operability or to reduce the extent of operation intervention required, and selectively to treat pleural dissemination intraoperatively following macroscopically complete surgical resection. Intraoperative PDT can be safely combined with macroscopically complete surgical resection and other treatment modalities for malignant pleural mesothelioma (MPM) to improve local control and prolong survival. This report reviews the mechanism of and rationale for using PDT to treat thoracic malignancies, details prospective and major retrospectives studies of PDT to treat NSCLC, SCLC, and MPM, and describes improvements in and future roles and directions of PDT.


GeneTrail--advanced gene set enrichment analysis.
We present a comprehensive and efficient gene set analysis tool, called 'GeneTrail' that offers a rich functionality and is easy to use. Our web-based application facilitates the statistical evaluation of high-throughput genomic or proteomic data sets with respect to enrichment of functional categories. GeneTrail covers a wide variety of biological categories and pathways, among others KEGG, TRANSPATH, TRANSFAC, and GO. Our web server provides two common statistical approaches, 'Over-Representation Analysis' (ORA) comparing a reference set of genes to a test set, and 'Gene Set Enrichment Analysis' (GSEA) scoring sorted lists of genes. Besides other newly developed features, GeneTrail's statistics module includes a novel dynamic-programming algorithm that improves the P-value computation of GSEA methods considerably. GeneTrail is freely accessible at http://genetrail.bioinf.uni-sb.de.


Bioenergetics and psychological profile of an ultra-endurance walker.
Ultra-endurance walking provides athletes with significant physiological and psychological challenges. In this study ultra-endurance walking races are intended as events where the participants have to cover the largest distance within a given time, usually 24, 36, 48 hours, or longer, keeping the pause time within 5% of the total walking time. The aim of the study was to evaluate the metabolic, bioenergetics, and psychological characteristics of a world record ultra-endurance walker during three different ultra-endurance events characterized by different durations (36 hours, 48 hours and 70 hours). The participant investigated in this study was an experienced male ultra-endurance walker (age 41 years; mass 69 kg; height 173 cm), who used always the Nordic walking technique. During the 70 hours event, our walker broke the "Longest Marathon Nordic Walking" Guinness World Record covering 274 km in 70 hours. An overall time-dependent increase of oxidative stress, as assessed by lipid hydroperoxide levels, was observed in 36 hours and 48 hours events. Speed and metabolic cost of walking decreased rather linearly with walking time over all the three events. The study shows how the walker was able to approach the three different ultra-endurance events characterized by different durations applying physiological, and psychological strategies allowing him to reach the goal of the completion of each ultra-endurance event.


Roles of the kinase TAK1 in CD40-mediated effects on vascular oxidative stress and neointima formation after vascular injury.
Although TAK1 has been implicated in inflammation and oxidative stress, its roles in vascular smooth muscle cells (VSMCs) and in response to vascular injury have not been investigated. The present study aimed to investigate the role of TAK1 in modulating oxidative stress in VSMCs and its involvement in neointima formation after vascular injury. Double immunostaining reveals that vascular injury induces a robust phosphorylation of TAK1 (Thr187) in the medial VSMCs of injured arteries in wildtype mice, but this effect is blocked in CD40-deficient mice. Upregulation of TAK1 in VSMCs is functionally important, as it is critically involved in pro-oxidative and pro-inflammatory effects on VSMCs and eventual neointima formation. In vivo, pharmacological inhibition of TAK1 with 5Z-7-oxozeaenol blocked the injury-induced phosphorylation of both TAK1 (Thr187) and NF-kB/p65 (Ser536), associated with marked inhibition of superoxide production, 3-nitrotyrosine, and MCP-1 in the injured arteries. Cell culture experiments demonstrated that either siRNA knockdown or 5Z-7-oxozeaenol inhibition of TAK1 significantly attenuated NADPH oxidase activation and superoxide production induced by CD40L/CD40 stimulation. Co-immunoprecipitation experiments indicate that blockade of TAK1 disrupted the CD40L-induced complex formation of p22phox with p47phox, p67phox, or Nox4. Blockade of TAK1 also inhibited CD40L-induced NF-kB activation by modulating IKKα/β and NF-kB p65 phosphorylation and this was related to reduced expression of proinflammatory genes (IL-6, MCP-1 and ICAM-1) in VSMCs. Lastly, treatment with 5Z-7-oxozeaenol attenuated neointimal formation in wire-injured femoral arteries. Our findings demonstrate previously uncharacterized roles of TAK1 in vascular oxidative stress and the contribution to neointima formation after vascular injury.


Submicron sized water-stable metal organic framework (bio-MOF-11) for catalytic degradation of pharmaceuticals and personal care products.
Water-stable and active metal organic frameworks (MOFs) are important materials for mitigation of water contaminants via adsorption and catalytic reactions. In this study, a highly water-stable Co-based MOF, namely bio-MOF-11-Co, was synthesized by a simplified benign method. Moreover, it was used as a catalyst in successful activation of peroxymonsulfate for catalytic degradation of sulfachloropyradazine (SCP) and para-hydroxybenzoic acid (p-HBA) as representatives of pharmaceuticals and personal care products, respectively. The bio-MOF-11-Co showed rapid degradation of both p-HBA and SCP and could be reused multiple times without losing the activity by simply water washing. The effects of catalyst and PMS loadings as well as temperature were further studied, showing that high catalyst and PMS loadings as well as temperature produced faster kinetic degradation of p-HBA and SCP. The generation of highly reactive and HO radicals during the degradation was investigated by quenching tests and electron paramagnetic resonance. A plausible degradation mechanism was proposed based on the functionalities in the bio-MOF-11-Co. The availability of electron rich nucleobase adenine reinforced the reaction kinetics by electron donation along with cobalt atoms in the bio-MOF-11-Co structure.


Hermansky-Pudlak syndrome type 3 in Ashkenazi Jews and other non-Puerto Rican patients with hypopigmentation and platelet storage-pool deficiency.
Hermansky-Pudlak syndrome (HPS), consisting of oculocutaneous albinism and a bleeding diathesis due to the absence of platelet dense granules, displays extensive locus heterogeneity. HPS1 mutations cause HPS-1 disease, and ADTB3A mutations cause HPS-2 disease, which is known to involve abnormal intracellular vesicle formation. A third HPS-causing gene, HPS3, was recently identified on the basis of homozygosity mapping of a genetic isolate of HPS in central Puerto Rico. We now describe the clinical and molecular characteristics of eight patients with HPS-3 who are of non-Puerto Rican heritage. Five are Ashkenazi Jews; three of these are homozygous for a 1303+1G-->A splice-site mutation that causes skipping of exon 5, deleting an RsaI restriction site and decreasing the amounts of mRNA found on northern blotting. The other two are heterozygous for the 1303+1G-->A mutation and for either an 1831+2T-->G or a 2621-2A-->G splicing mutation. Of 235 anonymous Ashkenazi Jewish DNA samples, one was heterozygous for the 1303+1G-->A mutation. One seven-year-old boy of German/Swiss extraction was compound heterozygous for a 2729+1G-->C mutation, causing skipping of exon 14, and resulting in a C1329T missense (R396W), with decreased mRNA production. A 15-year-old Irish/English boy was heterozygous for an 89-bp insertion between exons 16 and 17 resulting from abnormal splicing; his fibroblast HPS3 mRNA is normal in amount but is increased in size. A 12-year-old girl of Puerto Rican and Italian background has the 3,904-bp founder deletion from central Puerto Rico on one allele. All eight patients have mild symptoms of HPS; two Jewish patients had received the diagnosis of ocular, rather than oculocutaneous, albinism. These findings expand the molecular diagnosis of HPS, provide a screening method for a mutation common among Jews, and suggest that other patients with mild hypopigmentation and decreased vision should be examined for HPS.


[Tramadol in acute pain].
Tramadol has been in clinical use in Germany since the late 1970s and has proven effective in both experimental and clinical pain without causing serious cardiovascular or respiratory side effects. Moreover, the negligible abuse potential of tramadol has meant that it has never been a restricted drug, and it therefore very quickly became the most popular analgesic of its class in Germany. Although tramadol has been used in myocardial emergencies, in trauma and obstetric pain, or to supplement balanced anaesthesia, most studies have investigated postoperative patients. The focus of this article is to review clinical experience with tramadol in the treatment of acute postoperative pain. Tramadol, a synthetic opioid of the aminocyclohexanol group, is a centrally acting analgesic with weak opioid agonist properties, and effects on noradrenergic and serotonergic neurotransmission. In addition, these opioid and nonopioid modes of action appear to act synergistically. Tramadol has been shown to provide effective analgesia after both intramuscular and intravenous administration for the treatment of postoperative pain. The drug is available in formulations suitable for oral, rectal and parenteral administration. Clinically effective analgesic doses of tramadol were comparable to those of pethidine (meperidine) and about 10 times higher than those of morphine. While it is not recommended as a supplement to general anaesthesia because of its insufficient sedative activity, tramadol has been successful in the treatment of postoperative pain. A randomised double-blind study reported acceptable analgesia with postoperative intravenous tramadol 50mg, repeated once if required after 30 minutes. It produced an effect similar to that of morphine 5mg or the alpha 2 agonist, clonidine 150 micrograms. In another study, it was shown that the 50mg dose of tramadol fulfilled the requirements of an analgesic for the treatment of moderate postoperative pain, whereas for severe pain a higher dose was recommended. Tramadol is generally well tolerated, the most common adverse events being nausea and vomiting. In contrast to agents such as morphine and pethidine, clinically relevant respiratory depression is rarely observed during tramadol administration at equipotent doses and consequently it can be recommended for first-line management of postoperative pain instead of morphine. It is also associated with a low incidence of cardiac depression and significantly less dizziness and drowsiness than morphine. Finally, the dependence and abuse potential with tramadol is negligible. Comparative studies have generally shown that tramadol is more effective than NSAIDs for controlling post operative pain. Use of a combination of tramadol and NSAIDs allows the tramadol dose to be reduced and results in a lower incidence of adverse effects. Patient controlled analgesia (PCA) with tramadol has been frequently used and is well accepted by patients. Wide individual variations exist with regard to analgesic requirements and, nowadays, it is generally accepted that adequate pain management implies systematic individualisation of the therapy, i.e. titration of the analgesic effect to individual needs. Demand and loading doses play a decisive role in the success of PCA. Analgesic failures requiring rescue medication are rare, but it should be stressed that these can always occur with weak opioids. In conclusion, tramadol can be recommended as a basic analgesic for the treatment of moderate to severe pain. In the event of analgesic failure with tramadol, there is no reason not to switch to more potent opioids. Although no studies are available regarding its use in the management of postoperative pain after day case surgery, tramadol is frequently administered with good results in such patients. The most important side effects of tramadol are nausea and emesis, which can often be prevented by slow injection and administration of a prophylactic antiemetic such as metoclopramid


Epinephrine: the drug of choice for anaphylaxis. A statement of the World Allergy Organization.
Anaphylaxis is an acute and potentially lethal multi-system allergic reaction. Most consensus guidelines for the past 30 years have held that epinephrine is the drug of choice and the first drug that should be administered in acute anaphylaxis. Some state that properly administered epinephrine has no absolute contraindication in this clinical setting. A committee of anaphylaxis experts assembled by the World Allergy Organization has examined the evidence from the medical literature concerning the appropriate use of epinephrine for anaphylaxis. The Committee strongly believes that epinephrine is currently underutilized and often dosed suboptimally to treat anaphylaxis, is under-prescribed for potential future self-administration, that most of the reasons proposed to withhold its clinical use are flawed, and that the therapeutic benefits of epinephrine exceed the risk when given in appropriate i.m. doses.


Antidepressant-like effects of oxytocin in mice are dependent on the presence of insulin-regulated aminopeptidase.
Oxytocin is a neuromodulator with antidepressant-like effects. In vitro, oxytocin is rapidly cleaved by insulin-regulated aminopeptidase (IRAP). Oxytocin metabolites are known to exert strong central activities that are different from the effects of the parent molecule. Our goal is to investigate in vivo whether IRAP deletion modifies the antidepressant-like effects of oxytocin. Male and female C57Bl/6 mice, IRAP wild-type (IRAP(+/+)) and knock-out (IRAP(-/-)) mice were injected subcutaneously with saline, oxytocin or oxytocin combined with angiotensin IV. One hour after injection, immobility was timed during a 5 min forced swim that was preceded by an open field to study locomotor behaviour. Oxytocin induced antidepressant-like effects in male (0.25 mg/kg oxytocin) and female (0.15 mg/kg oxytocin) C57Bl/6 mice subjected to the forced swim test. Oxytocin did not influence locomotor behaviour in mice, as shown with the open field. These findings were reproduced in transgenic male (aged 3-6 months) and female (aged 12-18 months) IRAP(+/+) mice. However, the major findings of our study were that the antidepressant-like effect was reversed in angiotensin IV treated IRAP(+/+) mice and was completely absent in age- and gender-matched IRAP(-/-) mice. The lack of an antidepressant-like effect of oxytocin in young male and middle-aged female IRAP(-/-) mice attributes an important role to IRAP in mediating this effect.


Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls.
Multiple sclerosis (MS) is an immune-mediated disease, the etiology of which involves both genetic and environmental factors. The exact nature of the environmental factors responsible for predisposition to MS remains elusive; however, it's hypothesized that gastrointestinal microbiota might play an important role in pathogenesis of MS. Therefore, this study was designed to investigate whether gut microbiota are altered in MS by comparing the fecal microbiota in relapsing remitting MS (RRMS) (n = 31) patients to that of age- and gender-matched healthy controls (n = 36). Phylotype profiles of the gut microbial populations were generated using hypervariable tag sequencing of the V3-V5 region of the 16S ribosomal RNA gene. Detailed fecal microbiome analyses revealed that MS patients had distinct microbial community profile compared to healthy controls. We observed an increased abundance of Psuedomonas, Mycoplana, Haemophilus, Blautia, and Dorea genera in MS patients, whereas control group showed increased abundance of Parabacteroides, Adlercreutzia and Prevotella genera. Thus our study is consistent with the hypothesis that MS patients have gut microbial dysbiosis and further study is needed to better understand their role in the etiopathogenesis of MS.


Outcome of Men With Relapse After Adjuvant Carboplatin for Clinical Stage I Seminoma.
Purpose Adjuvant carboplatin is one of three management strategies that may follow inguinal orchiectomy in clinical stage I seminoma. However, little is known about the outcome of patients who experience a relapse after such treatment. Patients and Methods Data from 185 patients who relapsed after adjuvant carboplatin between January 1987 and August 2013 at 31 centers/groups from 20 countries were collected and retrospectively analyzed. Primary outcomes were disease-free survival and overall survival. Secondary outcomes were time to, stage at, and treatment of relapse as well as rate of subsequent relapses. Results With a median follow-up of 53 months (95% CI, 48 to 60 months) the 5-year disease-free survival was 82% (95% CI, 77% to 89%), and the 5-year overall survival was 98% (95% CI, 95% to 100%). The median time from orchiectomy to relapse was 19 months (95% CI, 17 to 23 months); 15% (95% CI, 10% to 21%) of relapses occurred > 3 years after treatment. The majority of relapses were detected by computed tomography scan during routine follow-up, 98% in the International Germ Cell Cancer Collaborative Group good prognosis group. Chemotherapy was administered to 92% of patients, mostly as standard first-line treatment corresponding to stage; 8% of patients had additional local treatments. Only 28 patients experienced a second relapse. At last follow-up, 174 (94%) of 185 patients were alive without disease, and four patients with disease. Seven patients died, three of whom due to progressive disease. Conclusion Within the limitations of a retrospective analysis, the results suggest that the majority of patients who experience a relapse after adjuvant carboplatin for clinical stage I seminoma can be successfully treated with a cisplatin-based chemotherapy regimen adequate for stage. Because 15% of the relapses occurred > 3 years after adjuvant treatment, a minimum of 5 years follow-up is recommended.


Treatment of an Unusual Non-Tooth Related Enamel Pearl (EP) and 3 Teeth-Related EPs with Localized Periodontal Disease Without Teeth Extractions: A Case Report.
Enamel may be found ectopically as enamel pearls (EPs), which are frequently associated with advanced localized periodontal (LP) destruction. This study presents a case in which an unusual non-tooth-related enamel pearl and three teeth-related enamel pearls with LP disease were found and treated without teeth extractions. A 47-year-old female patient presented at the New York University College of Dentistry with four EPs, three of which were associated with periodontal pockets and/or bleeding on probing (BOP), and one of them not related to any tooth. Periodontal therapy included scaling and root planing and open flap debridement with removal of the EPs. Two pearls were histologically analyzed by polarizing microscopy and scanning electron microscope (SEM). Clinical periodontal parameters, including probing depth and BOP, were measured. All enamel found in the pearls had the same general morphologic appearance when examined by a SEM. The non-tooth-related pearl could be classified as Rodriguez Ponte "adamantinóidea" pearl. Probing depths at 3 months and 9 months after EP removal diminished considerably. Only after the treatment was there no BOP. Before treatment it was in some areas, as shown in Table 1. The LP related to the EP was resolved. The authors conclude that early recognition of enamel pearls is important in the prevention of periodontal destruction, and removal of EPs by a surgical approach as an adjunct to mechanical periodontal treatment resulted in resolution of the LP. The authors state that this is the first time an "adamantinóideas" pearl is being reported on clinically in the literature.


Distribution of the anti-inflammatory and anti-depressant compounds: Incensole and incensole acetate in genus Boswellia.
Incensole and its acetate have shown anti-inflammatory and anti-depression activities due to their ability to activate ion channels in the brain to alleviate anxiety or depression. The natural occurrence of these two structurally and medicinally fascinating 14-membered diterpenoids was reported mainly from the genus Boswellia. Incensole and incensole acetate were detected in and isolated from both essential oils and resins of frankincense. One total synthesis was reported for incensole. Both incensole and its acetate served as precursors for several synthetic transformations. Given the fact that no specific enzymes were isolated from Boswellia trees, the major sources for incensole and incensole acetate, the biosynthetic pathway of these two compounds was only speculated. Recent studies on incensole and incensole acetate including ours have revealed another secret of the ancient drug. Understanding their mode of action will open a door in modern neurobiology and provides new insights on the mysterious diseases of the nervous system. This review interpretatively discusses the natural existence of incensole and incensole acetate, the variation of their percentages in different Boswellia species and other sources, their synthetic modifications, their biosynthesis and their therapeutic potential.


Kampo, A Japanese Traditional Medicinal System for Psychiatric Conditions: A Narrative Review.
Kampo is a Japanese traditional medicinal system and is represented by unity of mind and body. It is originally based upon Chinese traditional medicine but has uniquely developed in Japan. A narrative review on the use of Kampo for psychiatric conditions is provided. Kampo formula is a combination of several crude ingredients; most derive from natural plants and some from animals and minerals. These Kampo formulae are widely prescribed in almost all medical disciplines, including psychiatry, in Japan; they have been used for various psychiatric disorders such as dementia, schizophrenia spectrum disorders, mood disorders, anxiety disorders, and personality disorders. Kampo is a versatile traditional medicine with a variety of positive effects on mental states with relatively benign side effect profiles. Kampo formulae can be adjunctively combined with or substituted for the Western psychotropic drugs, which will provide more treatment options to patients with psychiatric conditions. This review summarizes the current knowledge on Kampo for psychiatric conditions, highlighting a paucity of data and a need for further good-quality evidence on these medications.


Intrarenal cells, not bone marrow-derived cells, are the major source for regeneration in postischemic kidney.
Ischemic injury to the kidney produces acute tubular necrosis and apoptosis followed by tubular regeneration and recovery of renal function. Although mitotic cells are present in the tubules of postischemic kidneys, the origins of the proliferating cells are not known. Bone marrow cells (BMCs) can differentiate across lineages to repair injured organs, including the kidney. However, the relative contribution of intrarenal cells and extrarenal cells to kidney regeneration is not clear. We produced transgenic mice that expressed enhanced GFP (EGFP) specifically and permanently in mature renal tubular epithelial cells. Following ischemia/reperfusion injury (IRI), EGFP-positive cells showed incorporation of BrdU and expression of vimentin, which provides direct evidence that the cells composing regenerating tubules are derived from renal tubular epithelial cells. In BMC-transplanted mice, 89% of proliferating epithelial cells originated from host cells, and 11% originated from donor BMCs. Twenty-eight days after IRI, the kidneys contained 8% donor-derived cells, of which 8.4% were epithelial cells, 10.6% were glomerular cells, and 81% were interstitial cells. No renal functional improvement was observed in mice that were transplanted with exogenous BMCs. These results show that intrarenal cells are the main source of renal repair, and a single injection of BMCs does not make a significant contribution to renal functional or structural recovery.


Communicating with patients: what happens in practice?
Communication is the most important aspect of practice that health care professionals have to master. The purpose of this study was to measure the content and prevalence of verbal and nonverbal communications between physical therapists and patients with back pain. Seven physical therapists and 21 patients with back pain participated in this study. The first interaction following the initial assessment was recorded with a video camera. The outcome measures were the Medical Communications Behavior System (verbal communication) and frequencies of nonverbal behaviors (affirmative head nodding, smiling, eye gaze, forward leaning, and touch). Semistructured interviews were undertaken with the physical therapists to determine the perceived influence of the video camera. A total of 2,055 verbal statements were made. Physical therapists spent approximately twice as much time talking as patients, with content behaviors (such as taking history and giving advice) comprising 52% of verbal communications. The most prevalent nonverbal behaviors were touch by physical therapists (54%) and eye gaze by patients (84%). The prevalence and content of communication can be measured with video analysis and validated tools. Communication is an extremely important but underexplored dimension of the patient-therapist relationship, and the methods described here could provide a useful model for further research and reflective practice.


Automated detection of Antarctic blue whale calls.
This paper addresses the problem of automated detection of Z-calls emitted by Antarctic blue whales (B. m. intermedia). The proposed solution is based on a subspace detector of sigmoidal-frequency signals with unknown time-varying amplitude. This detection strategy takes into account frequency variations of blue whale calls as well as the presence of other transient sounds that can interfere with Z-calls (such as airguns or other whale calls). The proposed method has been tested on more than 105 h of acoustic data containing about 2200 Z-calls (as found by an experienced human operator). This method is shown to have a correct-detection rate of up to more than 15% better than the extensible bioacoustic tool package, a spectrogram-based correlation detector commonly used to study blue whales. Because the proposed method relies on subspace detection, it does not suffer from some drawbacks of correlation-based detectors. In particular, it does not require the choice of an a priori fixed and subjective template. The analytic expression of the detection performance is also derived, which provides crucial information for higher level analyses such as animal density estimation from acoustic data. Finally, the detection threshold automatically adapts to the soundscape in order not to violate a user-specified false alarm rate.


HIV-1 reverse transcriptase: inhibition by 2',5'-oligoadenylates.
2',5'-Oligoadenylates (2-5A) and derivatives are noncompetitive inhibitors of primer/HIV-1 reverse transcriptase complex formation. The mechanism and specificity of this inhibitory action of 2-5A and 2-5A derivatives have been evaluated with 2-5A molecules modified in ribosyl moiety, chain length, extent of 5'-phosphorylation, and 2',5'-phosphodiester linkage. UV covalent cross-linking of preformed complexes of p66/p66 homodimer or p66/p51 heterodimer recombinant HIV-1 reverse transcriptase and the primer analog pd(T)16 allowed analysis of the initial step in HIV-1 reverse transcriptase-catalyzed DNA synthesis. Utilizing this primer binding assay, it is demonstrated that 2-5A and 2-5A derivatives inhibit the binding of pd(T)16 to HIV-1 reverse transcriptase. This inhibition is specific for the 2',5'-internucleotide linkage in that the corresponding 3',5'-adenylate derivatives do not exhibit inhibitory activity. Enhanced inhibitory properties were observed following modifications of the 2-5A molecule which result in an increase in hydrophobicity. Replacement of the D-ribosyl moiety of 2-5A with the 3'-deoxyribosyl moiety increased the inhibition of primer/HIV-1 reverse transcriptase complex formation 15-20%. 2',5'-Phosphorothioate substitution yielded the most effective inhibitors, with Ki's of 7-13 microM. In all cases, inhibition of primer/HIV-1 reverse transcriptase complex formation showed a preference for the 5'-triphosphate moiety. Nonphosphorylated derivatives were not inhibitory; 5'-monophosphate derivatives exhibited little or no inhibition. The inhibition of primer binding to HIV-1 reverse transcriptase correlated well with the inhibition of DNA-directed DNA synthesis.(ABSTRACT TRUNCATED AT 250 WORDS)


Factors distinguishing youth who report self-injurious behavior: a population-based sample.
To identify factors distinguishing adolescents across 3 groups: no self-harm, nonsuicidal self-injury (NSSI) only, and NSSI and suicide attempt (NSSI + SA). Data were from the 2007 Minnesota Student Survey. The sample included 61,330 students in grades 9 and 12. Logistic regression analysis determined factors that best distinguished adolescents who reported NSSI from those who reported no self-harm, and adolescents who reported NSSI + SA. Final models were developed over 3 stages of analysis that tested the importance of variables within risk factor, protective factor, and co-occurring health-risk behavior domains. For male and female subjects, factors that consistently distinguished youth who reported NSSI from those who reported no self-harm included depressive symptoms, hopelessness, physical abuse, less parent connectedness, running away from home, and maladaptive dieting behavior. Factors that distinguished the NSSI + SA group from the NSSI only group for both sexes were a mental health problem, depressive symptoms, hopelessness, physical abuse, and running away from home. Other factors, such as sexual abuse, were significant in models for males or females only. Hopelessness constituted the leading factor to increase the likelihood that youth who self-injured also attempted suicide. Youth engaging in NSSI experience diverse psychosocial stressors and significant distress. Clinicians and school personnel are well-positioned to offer support to these youth. Furthermore, they can help address NSSI among youth by identifying those who self-injure early, assessing for hopelessness and suicidality, facilitating connections to prosocial adults, addressing maladaptive dieting behavior, and supporting runaway youth.


Cognitive reserve impacts on inter-individual variability in resting-state cerebral metabolism in normal aging.
There is a great deal of heterogeneity in the impact of aging on cognition and cerebral functioning. One potential factor contributing to individual differences among the elderly is the cognitive reserve, which designates the partial protection from the deleterious effects of aging that lifetime experience provides. Neuroimaging studies examining task-related activation in elderly people suggested that cognitive reserve takes the form of more efficient use of brain networks and/or greater ability to recruit alternative networks to compensate for age-related cerebral changes. In this exploratory multi-center study, we examined the relationships between cognitive reserve, as measured by education and verbal intelligence, and cerebral metabolism at rest (FDG-PET) in a sample of 74 healthy older participants. Higher degree of education and verbal intelligence was associated with less metabolic activity in the right posterior temporoparietal cortex and the left anterior intraparietal sulcus. Functional connectivity analyses of resting-state fMRI images in a subset of 41 participants indicated that these regions belong to the default mode network and the dorsal attention network respectively. Lower metabolism in the temporoparietal cortex was also associated with better memory abilities. The findings provide evidence for an inverse relationship between cognitive reserve and resting-state activity in key regions of two functional networks respectively involved in internal mentation and goal-directed attention.


Antenatal Betamethasone for Women at Risk for Late Preterm Delivery.
Infants who are born at 34 to 36 weeks of gestation (late preterm) are at greater risk for adverse respiratory and other outcomes than those born at 37 weeks of gestation or later. It is not known whether betamethasone administered to women at risk for late preterm delivery decreases the risks of neonatal morbidities. We conducted a multicenter, randomized trial involving women with a singleton pregnancy at 34 weeks 0 days to 36 weeks 5 days of gestation who were at high risk for delivery during the late preterm period (up to 36 weeks 6 days). The participants were assigned to receive two injections of betamethasone or matching placebo 24 hours apart. The primary outcome was a neonatal composite of treatment in the first 72 hours (the use of continuous positive airway pressure or high-flow nasal cannula for at least 2 hours, supplemental oxygen with a fraction of inspired oxygen of at least 0.30 for at least 4 hours, extracorporeal membrane oxygenation, or mechanical ventilation) or stillbirth or neonatal death within 72 hours after delivery. The primary outcome occurred in 165 of 1427 infants (11.6%) in the betamethasone group and 202 of 1400 (14.4%) in the placebo group (relative risk in the betamethasone group, 0.80; 95% confidence interval [CI], 0.66 to 0.97; P=0.02). Severe respiratory complications, transient tachypnea of the newborn, surfactant use, and bronchopulmonary dysplasia also occurred significantly less frequently in the betamethasone group. There were no significant between-group differences in the incidence of chorioamnionitis or neonatal sepsis. Neonatal hypoglycemia was more common in the betamethasone group than in the placebo group (24.0% vs. 15.0%; relative risk, 1.60; 95% CI, 1.37 to 1.87; P<0.001). Administration of betamethasone to women at risk for late preterm delivery significantly reduced the rate of neonatal respiratory complications. (Funded by the National Heart, Lung, and Blood Institute and the Eunice Kennedy Shriver National Institute of Child Health and Human Development; ClinicalTrials.gov number, NCT01222247.).


Complete Genome Sequences of Zika Virus Strains Isolated from the Blood of Patients in Thailand in 2014 and the Philippines in 2012.
Here, we present the complete genome sequences of two Zika virus (ZIKV) strains, Zika virus/Homo sapiens-tc/THA/2014/SV0127-14 and Zika virus/H. sapiens-tc/PHL/2012/CPC-0740, isolated from the blood of patients collected in Thailand, 2014, and the Philippines, 2012, respectively. Sequencing and phylogenetic analysis showed that both strains belong to the Asian lineage.


Tyrosine transaminase: development of daily rhythm in liver of neonatal rat.
The development of the 24-hour rhythm in tyrosine transaminase activity was studied in the liver of the neonatal rat. A recognizable rhythm appears within 48 hours after birth, but it is opposite in phase to that observed in the adult rat. The reversal of the adult pattern occurs 21 to 23 days after birth and may represent a response to a change both in the eating pattern and in the amount of protein eaten.


Adherence to a plant-based, high-fibre dietary pattern is related to regression of non-alcoholic fatty liver disease in an elderly population.
Dietary lifestyle intervention is key in treating non-alcoholic fatty liver disease (NAFLD). We aimed to examine the longitudinal relation between well-established dietary patterns as well as population-specific dietary patterns and NAFLD. Participants from two subsequent visits of the Rotterdam Study were included. All underwent serial abdominal ultrasonography (median follow-up: 4.4 years) and filled in a food frequency questionnaire. Secondary causes of steatosis were excluded. Dietary data from 389 items were collapsed into 28 food groups and a posteriori dietary patterns were identified using factor analysis. Additionally, we scored three a priori dietary patterns (Mediterranean Diet Score, Dutch Dietary Guidelines and WHO-score). Logistic mixed regression models were used to examine the relation between dietary patterns and NAFLD. Analyses were adjusted for demographic, lifestyle and metabolic factors. We included 963 participants of whom 343 had NAFLD. Follow-up data was available in 737 participants. Incident NAFLD was 5% and regressed NAFLD was 30%. We identified five a posteriori dietary patterns (cumulative explained variation [R2] = 20%). The patterns were characterised as: vegetable and fish, red meat and alcohol, traditional, salty snacks and sauces, high fat dairy & refined grains pattern. Adherence to the traditional pattern (i.e. high intake of vegetable oils/stanols, margarines/butters, potatoes, whole grains and sweets/desserts) was associated with regression of NAFLD per SD increase in Z-score (0.40, 95% CI 0.15-1.00). Adherence to the three a priori patterns all showed regression of NAFLD, but only the WHO-score showed a distinct association (0.73, 95% CI 0.53-1.00). Hence, in this large elderly population, adherence to a plant-based, high-fibre and low-fat diet was related to regression of NAFLD.


Spatial variability during gait initiation while dual tasking is increased in individuals with mild cognitive impairment.
Gait initiation (GI) is a complex transition phase of gait that can induce postural instability. Gait impairment has been well documented in people with Alzheimer's disease, but it is still inconclusive in individuals with Mild Cognitive Impairment (MCI). Previous studies have usually investigated gait performance of cognitive impaired persons under steady state walking. This study aimed to examine spatiotemporal variability during GI under single- and dual-task conditions in people with and without MCI. Spatiotemporal stepping characteristics and variability under single- and dual-task conditions (counting backwards by 3s) were assessed in 30 older adults with MCI and 30 cognitively intact controls. Mean and coefficients of variation (COV) of swing time, step time, step length and step width were compared between the two groups. Mixed-model repeated measures ANOVA revealed a significant Group x Walking condition interaction for COV of step length and step width (P<0.05). Post-hoc analysis revealed that variability for these measures were significantly larger in the MCI group compared with the control group under the dual-task condition (P<0.05). Step length and step width variability is increased in people with MCI during GI, particularly in a condition involving a secondary cognitive task. These findings suggest that individuals with MCI have reduced balance control when undertaking a challenging walking task such as gait initiation, and this is exacerbated with an added cognitive task. Future studies should prospectively investigate the relationship between GI variability and fall risk in this population.


In vivo-to-in silico iterations to investigate aeroallergen-host interactions.
Allergic asthma is a complex process arising out of the interaction between the immune system and aeroallergens. Yet, the relationship between aeroallergen exposure, allergic sensitization and disease remains unclear. This knowledge is essential to gain further insight into the origin and evolution of allergic diseases. The objective of this research is to develop a computational view of the interaction between aeroallergens and the host by investigating the impact of dose and length of aeroallergen exposure on allergic sensitization and allergic disease outcomes, mainly airway inflammation and to a lesser extent lung dysfunction and airway remodeling. BALB/C mice were exposed intranasally to a range of concentrations of the most pervasive aeroallergen worldwide, house dust mite (HDM), for up to a quarter of their lifespan (20 weeks). Actual biological data delineating the kinetics, nature and extent of responses for local (airway inflammation) and systemic (HDM-specific immunoglobulins) events were obtained. Mathematical equations for each outcome were developed, evaluated, refined through several iterations involving in vivo experimentation, and validated. The models accurately predicted the original biological data and simulated an extensive array of previously unknown responses, eliciting two- and three-dimensional models. Our data demonstrate the non-linearity of the relationship between aeroallergen exposure and either allergic sensitization or airway inflammation, identify thresholds, behaviours and maximal responsiveness for each outcome, and examine inter-variable relationships. This research provides a novel way to visualize allergic responses in vivo and establishes a basic experimental platform upon which additional variables and perturbations can be incorporated into the system.


TRAIL-mediated apoptosis in HIV-1-infected macrophages is dependent on the inhibition of Akt-1 phosphorylation.
HIV-1 uses mononuclear phagocytes (monocytes, tissue macrophages, and dendritic cells) as a vehicle for its own dissemination and as a reservoir for continuous viral replication. The mechanism by which the host immune system clears HIV-1-infected macrophages is not understood. TRAIL may play a role in this process. TRAIL is expressed on the cell membrane of peripheral immune cells and can be cleaved into a soluble, secreted form. The plasma level of TRAIL is increased in HIV-1-infected patients, particularly those with high viral loads. To study the effect of elevated TRAIL on mononuclear phagocytes, we used recombinant human (rh) TRAIL and human monocyte-derived macrophages (MDM) as an in vitro model. Our results demonstrated rhTRAIL-induced apoptosis in HIV-1-infected MDM and inhibited viral replication, while having a reduced effect on uninfected MDM. HIV-1 infection significantly decreased Akt-1 phosphorylation; rhTRAIL exposure further decreased Akt-1 phosphorylation. Infection with a dominant-negative Akt-1 adenovirus potentiated rhTRAIL-induced apoptosis, while constitutively active Akt-1 blocked rhTRAIL-induced apoptosis in HIV-1-infected MDM. From this data we conclude the death ligand TRAIL preferentially provokes apoptosis of HIV-1-infected MDM, and the mechanism is reliant upon the inhibition of Akt-1 phosphorylation. Understanding this mechanism may facilitate the elimination of HIV-1-infected macrophages and lead to new therapeutic avenues for treatment of HIV-1 infection.


Parkinson's disease and REM sleep behavior disorder result in increased non-motor symptoms.
Rapid eye movement (REM)-sleep behavior disorder (RBD) is often comorbid with Parkinson's disease (PD). The current study aimed to provide a detailed understanding of the impact of having RBD on multiple non-motor symptoms (NMS) in patients with PD. A total of 86 participants were evaluated for RBD and assessed for multiple NMS of PD. Principal component analysis was utilized to model multiple measures of NMS in PD, and a multivariate analysis of variance was used to assess the relationship between RBD and the multiple NMS measures. Seven NMS measures were assessed: cognition, quality of life, fatigue, sleepiness, overall sleep, mood, and overall NMS of PD. Among the PD patients, 36 were classified as having RBD (objective polysomnography and subjective findings), 26 as not having RBD (neither objective nor subjective findings), and 24 as probably having RBD (either subjective or objective findings). RBD was a significant predictor of increased NMS in PD while controlling for dopaminergic therapy and age (p=0.01). The RBD group reported more NMS of depression (p=0.012), fatigue (p=0.036), overall sleep (p=0.018), and overall NMS (p=0.002). In PD, RBD is associated with more NMS, particularly increased depressive symptoms, sleep disturbances, and fatigue. More research is needed to assess whether PD patients with RBD represent a subtype of PD with different disease progression and phenomenological presentation.


Spontaneous resolution of bone mineral depletion in preterm infants.
Fifteen preterm infants and 17 born at full term whose gestational ages ranged from 25 to 34 weeks and 38 to 42 weeks, respectively, were examined initially at postconceptional ages ranging from 38 to 44 weeks and subsequently at 46 to 71 weeks. Each examination included measurement of bone mineral content of the mid-forearm by single photon absorptiometry. For the preterm group, the mean (SD) value of bone mineral content at the first examination was 109.0 (27.6) mg/cm and was significantly lower than the corresponding value of 194.4 (19.6) mg/cm for the whole full term group. The mean subsequent rate of mineral accretion in the preterm group was 8.70 (4.60) mg/cm/week, the mean individual duration of observation being 9.7 weeks. Rate of mineral accretion for the full term group was independent of the duration of observation and averaged 1.60 (2.20) mg/cm/week. The difference between mean values of rate of mineral accretion in the preterm and full term groups was highly significant. Our results show that there is a phase of rapid mineral accretion starting at 40 weeks' postconception in preterm infants that substantially reduces the perinatal mineralisation deficit.


Hand function and its prognostic factors of very low birth weight preterm children up to a corrected age of 24 months.
A delay in functional hand performance broadly affects a child's successful participation in daily activities as well as later academic performance. Despite its high prevalence, hand function has received much less attention than other developmental domains, especially for young children. The aims of this study, therefore, were to examine hand function in preterm children up to a corrected age of 24 months; to establish predictive models for estimating preterm children's hand function; and to identify the contribution of early neuromotor assessments. This study included 230 preterm children (69, 76, and 85 children at corrected ages of 6-, 12-, and 24-months, respectively) who were recruited from the database of the preemie follow-up clinic at the National Cheng Kung University Hospital in Tainan, Taiwan. Hand function was evaluated using the Peabody Developmental Motor Scales II. Demographic information, birth history, and developmental documents were obtained from the medical records of routine preemie clinic follow-ups. Approximately half of healthy preterm children demonstrate hand function deficits at 12 and 24 months of corrected age. The Neonatal Medical Index, representing an infant's history of medical complication, was the best predictor of hand function at 12 and 24 months of corrected age. The social factor, represented by maternal educational year, was found to have influence on hand function only in preterm children at corrected age of 24 months old. Finally, early neuromotor performance demonstrated significant predictability of later hand function that supports the importance of continuous follow-up examinations in children with a history of prematurity. An understanding of a preterm child's early hand function as well as how its risk factors evolve helps clinicians both target children who might benefit from early intervention and ensure that children reach their full developmental potential.


Effect of verification bias on screening for prostate cancer by measurement of prostate-specific antigen.
The sensitivity and specificity of a screening test are biased when disease status is not verified in all subjects and when the likelihood of confirmation depends on the test result itself. We assessed the screening characteristics of the prostate-specific antigen (PSA) measurement after correction for verification bias. Between 1995 and 2001, 6691 men underwent PSA-based screening for prostate cancer. Of these men, 705 (11 percent) subsequently underwent biopsy of the prostate. Under the assumption that the chance of undergoing a biopsy depends only on the PSA-test result and other observed clinical variables, we used a mathematical model to estimate adjusted receiver-operating-characteristic (ROC) curves. Adjusting for verification bias significantly increased the area under the ROC curve (i.e., the overall diagnostic performance) of the PSA test, as compared with an unadjusted analysis (0.86 vs. 0.69, P<0.001, for men less than 60 years of age; 0.72 vs. 0.62, P=0.008, for men 60 years of age or older). If the threshold PSA value for undergoing biopsy were set at 4.1 ng per milliliter, 82 percent of cancers in younger men and 65 percent of cancers in older men would be missed. A digital rectal examination that is abnormal but not suspicious for cancer does not affect the overall performance characteristics of the test. A lower threshold level of PSA for recommending prostate biopsy, particularly in younger men, may improve the clinical value of the PSA test.