Multi-detector row computed tomography angiography of peripheral arterial disease.
With the introduction of multi-detector row computed tomography (MDCT), scan speed and image quality has improved considerably. Since the longitudinal coverage is no longer a limitation, multi-detector row computed tomography angiography (MDCTA) is increasingly used to depict the peripheral arterial runoff. Hence, it is important to know the advantages and limitations of this new non-invasive alternative for the reference test, digital subtraction angiography. Optimization of the acquisition parameters and the contrast delivery is important to achieve a reliable enhancement of the entire arterial runoff in patients with peripheral arterial disease (PAD) using fast CT scanners. The purpose of this review is to discuss the different scanning and injection protocols using 4-, 16-, and 64-detector row CT scanners, to propose effective methods to evaluate and to present large data sets, to discuss its clinical value and major limitations, and to review the literature on the validity, reliability, and cost-effectiveness of multi-detector row CT in the evaluation of PAD.


Asymmetric formal synthesis of schulzeines A and C.
The asymmetric formal synthesis of schulzeines A and C is described. Key features of the synthesis include the efficient and stereoselective construction of the benzoquinolizidine skeleton via the aza-Claisen rearrangement-induced ring expansion of the 1-vinyl-N-glycyl-isoquinoline, which was prepared by the highly enantioselective asymmetric allylation of the 8-benzyloxy-substituted dihydroisoquinoline and by the acid-catalyzed transannulation of the resulting 10-membered lactam.


AMINO ACID LEVELS IN PRADER-WILLI SYNDROME AND OBESE INDIVIDUALS.
To determine if certain features (e.g., hypopigmentation) seen in persons with Prader-Willi syndrome (PWS) may be reflected in abnormalities of amino acid metabolism, fasting plasma amino acid levels were measured from 25 patients and compared with those in 17 obese individuals. Thirteen of the patients with PWS were previously identified by high-resolution analysis to have chromosome 15q deletion, while 12 had normal chromosomes. Compared with reference plasma levels, several amino acid levels were elevated in both patients and obese individuals. Aspartic acid, taurine, and glutamic acid levels were elevated (>2 Z score) in 44% of the patients with PWS but were increased in only one obese individual. The average phenylalanine and tyrosine levels were not different in the two groups. Significant differences in taurine, cystine, glutamic acid, citrulline, and aspartic acid levels were found. There was no correlation with age, degree of obesity (percentage of ideal body weight), and the degree of elevation of amino acids in either patients with PWS or obese individuals. Similarly, the degree of obesity in those with PWS was not associated with chromosome status. Several amino acid concentrations were abnormal in patients compared with our laboratory reference ranges, but many of these abnormalities were also present in obese individuals. Whether the amino acid changes simply reflect the altered eating habits of obese individuals or whether the altered profile may play a role in appetite or energy regulation is not known.


Half-sandwich bis(tetramethylaluminate) complexes of the rare-earth metals: synthesis, structural chemistry, and performance in isoprene polymerization.
The protonolysis reaction of [Ln(AlMe(4))(3)] with various substituted cyclopentadienyl derivatives HCp(R) gives access to a series of half-sandwich complexes [Ln(AlMe(4))(2)(Cp(R))]. Whereas bis(tetramethylaluminate) complexes with [1,3-(Me(3)Si)(2)C(5)H(3)] and [C(5)Me(4)SiMe(3)] ancillary ligands form easily at ambient temperature for the entire Ln(III) cation size range (Ln=Lu, Y, Sm, Nd, La), exchange with the less reactive [1,2,4-(Me(3)C)(3)C(5)H(3)] was only obtained at elevated temperatures and for the larger metal centers Sm, Nd, and La. X-ray structure analyses of seven representative complexes of the type [Ln(AlMe(4))(2)(Cp(R))] reveal a similar distinct [AlMe(4)] coordination (one eta(2), one bent eta(2)). Treatment with Me(2)AlCl leads to [AlMe(4)] --> [Cl] exchange and, depending on the Al/Ln ratio and the Cp(R) ligand, varying amounts of partially and fully exchanged products [{Ln(AlMe(4))(mu-Cl)(Cp(R))}(2)] and [{Ln(mu-Cl)(2)(Cp(R))}(n)], respectively, have been identified. Complexes [{Y(AlMe(4))(mu-Cl)(C(5)Me(4)SiMe(3))}(2)] and [{Nd(AlMe(4))(mu-Cl){1,2,4-(Me(3)C)(3)C(5)H(2)}}(2)] have been characterized by X-ray structure analysis. All of the chlorinated half-sandwich complexes are inactive in isoprene polymerization. However, activation of the complexes [Ln(AlMe(4))(2)(Cp(R))] with boron-containing cocatalysts, such as [Ph(3)C][B(C(6)F(5))(4)], [PhNMe(2)H][B(C(6)F(5))(4)], or B(C(6)F(5))(3), produces initiators for the fabrication of trans-1,4-polyisoprene. The choice of rare-earth metal cation size, Cp(R) ancillary ligand, and type of boron cocatalyst crucially affects the polymerization performance, including activity, catalyst efficiency, living character, and polymer stereoregularity. The highest stereoselectivities were observed for the precatalyst/cocatalyst systems [La(AlMe(4))(2)(C(5)Me(4)SiMe(3))]/B(C(6)F(5))(3) (trans-1,4 content: 95.6 %, M(w)/M(n)=1.26) and [La(AlMe(4))(2)(C(5)Me(5))]/B(C(6)F(5))(3) (trans-1,4 content: 99.5 %, M(w)/M(n)=1.18).


Carboxyhemoglobin levels in carbon monoxide poisoning: do they correlate with the clinical picture?
It is commonly written that carboxyhemoglobin (COHb) measurements correlate with the clinical presentation of patients poisoned with carbon monoxide (CO). However, the evidence supporting this concept is scanty. The present study was performed to analyze COHb measurements in a large population of patients with CO poisoning to determine whether clinically significant correlates exist. Records of all patients treated with hyperbaric oxygen for acute CO poisoning at a single private academic medical center from 1978 to 2005 were reviewed. The COHb measurements were analyzed with regard to sex, age, source of CO, loss of consciousness, endotracheal intubation, arterial pH, and death. Data from 1603 CO-poisoned patients were reviewed, and 1407 were included in the final analysis. Statistically higher COHb measurements were associated with male sex (24.2% +/- 11.2% vs 21.5% +/- 11.6), adult age range (24.0% +/- 11.0% vs 19.5% +/- 10.3%), poisoning by CO from fires (25.7% +/- 12.1%) or motor vehicles (22.7% +/- 24.7%), loss of consciousness (24.3% +/- 12.2% vs 22.3% +/- 9.4%), lower arterial pH, and death (32.1% +/- 12.8% vs 23.1% +/- 0.9%). Despite the fact that statistically significant differences in average COHb measurements were seen with regard to a number of variables, the clinical significance of these differences appeared to be minimal. Moreover, the utility of COHb measurements as predictors of clinical status in CO poisoning was not apparent. At least in part, this likely relates to delay and interval oxygen administration before obtaining COHb measurements.


A dual high-energy radiography platform with 15 μm resolution at the National Ignition Facility.
To study matter at extreme densities and pressures, we need mega laser facilities such as the National Ignition Facility as well as creative methods to make observations during timescales of a billionth of a second. To facilitate this, we developed a platform and diagnostic to characterize a new point-projection radiography configuration using two micro-wires irradiated by a short pulse laser system that provides a large field of view with up to 3.6 ns separation between images. We used tungsten-carbide solid spheres as reference objects and inferred characteristics of the back-lighter source using a forward-fitting algorithm. The resolution of the system is inferred to be 15 μm (using 12.5 μm diameter wires). The bremsstrahlung temperature of the source is 70-300 keV, depending on laser energy and coupling efficiency. By adding the images recorded on multiple stacked image plates, the signal-to-noise of the system is nearly doubled. The imaging characterization technique described here can be adapted to most point-projection platforms where the resolution, spectral contrast, and signal-to-noise are important.


Treatment of mild immersion hypothermia by direct body-to-body contact.
Body-to-body contact is often recommended for rewarming mildly hypothermic victims in the field. This procedure involves a euthermic individual donating heat to the recipient by direct contact in an insulated bag. However, this technique has not been critically evaluated and may not be beneficial because there is limited direct contact between recipient and donor, peripheral vasoconstriction may impair heat transfer to the core, skin warming may blunt the recipient's shivering response, and cold stress to the donor may be excessive. The present study was designed to evaluate whether donation of heat by a donor would be sufficient to enhance rewarming of a hypothermic subject (recipient). Six pairs of recipients (5 men, 1 woman) and donors (2 men, 4 women) participated in the study. Esophageal and skin temperatures, cutaneous heat flux, and oxygen consumption were measured. Recipients were immersed in 8 degrees C water until esophageal temperature decreased to a mean of 34.6 +/- 0.7 degrees C (SD). They then were rewarmed by one of three methods: rewarming by the endogenous heat generated by shivering only (SH), body-to-body rewarming (BB), or rewarming with a constant-heat source manikin (MAN). Mean afterdrop for the three conditions was 0.54 +/- 0.2, 0.54 +/- 0.2, and 0.57 +/- 0.2 degrees C for SH, BB, and MAN, respectively (NS), and the rate of rewarming was 2.40 +/- 0.8, 2.46 +/- 1.1 and 2.55 +/- 0.9 degrees C/h for SH, BB, and MAN, respectively (NS).(ABSTRACT TRUNCATED AT 250 WORDS)


Dye@bio-MOF-1 Composite as a Dual-Emitting Platform for Enhanced Detection of a Wide Range of Explosive Molecules.
By incorporating a cationic dye within a metal-organic framework (MOF) through an ion-exchange process, a responsive dye@bio-MOF-1 composite has been synthesized, serving as a dual-emitting platform for enhanced detection of different kinds of nitro-explosives, especially nitroalkanes, nitramines, and nitrate esters. The dye@bio-MOF-1 composite was constructed with free amines on their well-defined cavities, which is essential for the capture of explosives into their confined nanospace. It was observed that the encapsulation of explosives into the constructed dye@bio-MOF-1 composite could dramatically alter the luminescent properties of the dyes as well as the MOF skeletons owing to the size exclusivity and confinement-induced effect. For nitroaromatics, the dye@bio-MOF-1 composite exhibits turn-off responses via fluorescence quenching. Unexpectedly, the composite shows unique turn-on responses for aliphatic nitro-organics via confinement-induced enhancement, demonstrating enhanced ability to detecting different kinds of explosives selectively in aqueous solution. Furthermore, the dye@bio-MOF-1 film was facilely fabricated, making the chemical sensing more convenient and easier to realize the discrimination of the targeted explosives. The dual tunable responses indicate that dye@bio-MOF-1 composites are favorable materials for molecular sensing. On the basis of the host-guest properties of the constructed dye@bio-MOF-1 composite, our work can be further extended to sensing specific analytes with remarkable turn-on sensing properties, in particular those difficult to recognize with conventional methods.


A novel mutation in MCPH1 gene in an Iranian family with primary microcephaly.
Primary microcephaly (MCPH) is a genetic disorder in which affected individuals present with a head circumference 3 standard deviations (SDs) below the age- and sex-related mean and is accompanied by mental retardation without further associated malformations. Here we report a patient with sporadic MCPH from Northwest of Iran who was investigated for MCPH1 locus. Clinical examination and karyotype analyses were performed and microsatellite based mapping was done by using flanking and intragenic short tandem repeat (STR) markers for MCPH1 locus. For these markers the affected individual was homozygote and the parents were heterozygote. According to this pattern of allele sharing and also the cytogenetic findings, mutation screening of Microcephalin gene was performed and subsequent sequencing revealed a novel mutation in Microcephalin gene.


Theory for High-Throughput Genetic Interaction Screening.
Systematic, genome-scale genetic screens have been instrumental for elucidating genotype-phenotype relationships, but approaches for probing genetic interactions have been limited to at most ∼100 pre-selected gene combinations in mammalian cells. Here, we introduce a theory for high-throughput genetic interaction screens. The theory extends our recently developed Multiplexing using Spectral Imaging and Combinatorics (MuSIC) approach to propose ∼105 spectrally unique, genetically encoded MuSIC barcodes from 18 currently available fluorescent proteins. Simulation studies based on constraints imposed by spectral flow cytometry equipment suggest that genetic interaction screens at the human genome-scale may be possible if MuSIC barcodes can be paired to guide RNAs. While experimental testing of this theory awaits, it offers transformative potential for genetic perturbation technology and knowledge of genetic function. More broadly, the availability of a genome-scale spectral barcode library for non-destructive identification of single cells could find more widespread applications such as traditional genetic screening and high-dimensional lineage tracing.


Association of vitamin D receptor gene polymorphisms with serum 25(OH)D levels and metabolic syndrome in Thai population.
Metabolic syndrome (MetS) increases the risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). The vitamin D receptor gene (VDR) polymorphisms have been found associated with MetS and serum 25(OH)D levels but these associations remain controversial. The aim of this study was to investigate the relationship between the VDR polymorphisms and MetS, metabolic components, and serum 25(OH)D levels within the Thai population. A case-control study included 237 participants with MetS according to the MetS diagnostic criteria of NCEP ATPIII and 376 controls. Anthropometric data, blood pressure, lipid profiles, serum 25 (OH)D, and fasting blood glucose were measured. VDR FokI, BsmI, TaqI, and Cdx2 polymorphisms were genotyped by using PCR-HRM. There were no significant differences in the frequencies of VDR genotypes and alleles between MetS and the control groups. VDR TaqI TT, and BsmI BB + Bb genotypes were associated with lower 25(OH)D levels (p < 0.05) in comparison to TaqI Tt, and BsmI bb genotypes in the MetS group, respectively. In addition, the VDR Cdx2 GG genotype was associated with higher WC compared with the AG genotype in all subjects (p < 0.05). Logistic regression analysis revealed that BB + Bb genotypes of the VDR BsmI had significantly increased the odds ratio (OR) of hypertriglyceridemia when compared with the bb genotype (OR 1.87; 95% CI 1.10-3.19, p = 0.022). In conclusion, VDR BsmI variant was associated with hypertriglyceridemia and may be predisposed to developing MetS. VDR TaqI and BsmI polymorphisms seems to influence serum 25(OH)D levels in MetS subjects, while Cdx2 polymorphism may influence WC in all subjects.


APoc: large-scale identification of similar protein pockets.
Most proteins interact with small-molecule ligands such as metabolites or drug compounds. Over the past several decades, many of these interactions have been captured in high-resolution atomic structures. From a geometric point of view, most interaction sites for grasping these small-molecule ligands, as revealed in these structures, form concave shapes, or 'pockets', on the protein's surface. An efficient method for comparing these pockets could greatly assist the classification of ligand-binding sites, prediction of protein molecular function and design of novel drug compounds. We introduce a computational method, APoc (Alignment of Pockets), for the large-scale, sequence order-independent, structural comparison of protein pockets. A scoring function, the Pocket Similarity Score (PS-score), is derived to measure the level of similarity between pockets. Statistical models are used to estimate the significance of the PS-score based on millions of comparisons of randomly related pockets. APoc is a general robust method that may be applied to pockets identified by various approaches, such as ligand-binding sites as observed in experimental complex structures, or predicted pockets identified by a pocket-detection method. Finally, we curate large benchmark datasets to evaluate the performance of APoc and present interesting examples to demonstrate the usefulness of the method. We also demonstrate that APoc has better performance than the geometric hashing-based method SiteEngine. The APoc software package including the source code is freely available at http://cssb.biology.gatech.edu/APoc.


Mid-infrared HgTe Colloidal Quantum Dot LEDs.
Mid-infrared HgTe colloidal quantum dot electroluminescent devices are demonstrated. With emission at 4 μm, devices achieved an external quantum efficiency of ∼10-3 and power conversion efficiency of ∼10-4 under biases of a few volts. The power conversion efficiency benefited from lowering the transparent electrode resistance through the incorporation of a metal conductive grid. The average power emitted was about 16 μW at 2 V bias with 50% duty cycle and a 1 mm2 device. The room-temperature electroluminescence efficiency at low current was limited by the photoluminescence efficiency of the quantum dots, while the diode structure provided efficient electron-hole recombination.


Phosphorothioate modified oligonucleotide-protein interactions.
Antisense oligonucleotides (ASOs) interact with target RNAs via hybridization to modulate gene expression through different mechanisms. ASO therapeutics are chemically modified and include phosphorothioate (PS) backbone modifications and different ribose and base modifications to improve pharmacological properties. Modified PS ASOs display better binding affinity to the target RNAs and increased binding to proteins. Moreover, PS ASO protein interactions can affect many aspects of their performance, including distribution and tissue delivery, cellular uptake, intracellular trafficking, potency and toxicity. In this review, we summarize recent progress in understanding PS ASO protein interactions, highlighting the proteins with which PS ASOs interact, the influence of PS ASO protein interactions on ASO performance, and the structure activity relationships of PS ASO modification and protein interactions. A detailed understanding of these interactions can aid in the design of safer and more potent ASO drugs, as illustrated by recent findings that altering ASO chemical modifications dramatically improves therapeutic index.


[Abnormalities of the digestive system in autopsy material of children].
As a result of the autopsy reports of the Pathological Institute of M uhlhausen in a twenty-year-period from 1960 to 1979 there were 4.8 per cent (n = 219) malformations of the digestive tract among the 4,561 autopsies of stillborn children and live-born ones up to their 16th year of age. Lip, jaw and plate clefts, defects of diaphragm as well as oesophagus atresia and stenosis predominate among the various malformations. The malformations were classified and discussed according to nature, combinations, and sex differences as well as with respect to importance for mortality, territorial and time distribution.


Enabling functional genomics with genome engineering.
Advances in genome engineering technologies have made the precise control over genome sequence and regulation possible across a variety of disciplines. These tools can expand our understanding of fundamental biological processes and create new opportunities for therapeutic designs. The rapid evolution of these methods has also catalyzed a new era of genomics that includes multiple approaches to functionally characterize and manipulate the regulation of genomic information. Here, we review the recent advances of the most widely adopted genome engineering platforms and their application to functional genomics. This includes engineered zinc finger proteins, TALEs/TALENs, and the CRISPR/Cas9 system as nucleases for genome editing, transcription factors for epigenome editing, and other emerging applications. We also present current and potential future applications of these tools, as well as their current limitations and areas for future advances.


Effects of long-term oxygen therapy on the mental state of patients with chronic obstructive pulmonary disease: A systematic review.
This systematic review aimed to examine the effects of long-term oxygen therapy on the mental state of patients with chronic obstructive pulmonary disease. Web of Science, Medline, CINAHL, EMBASE, ProQuest, and Cochrane Library were selected to search for relevant studies. We followed the Cochrane Handbook for Systematic Reviews of Interventions, adopted the Cochrane risk-of-bias tool and Risk Of Bias In Non-randomized Studies of Interventions tool, and synthesized the outcomes narratively with Grading of Recommendations, Assessment, Development and Evaluations evidence profile. Six studies were included. Moderate quality of evidence supported no effects of long-term oxygen therapy on the mental state in patients with severe resting hypoxemia and moderate resting hypoxemia (or exertional desaturation) at follow-up of 6 to 12 months; however, adverse effects on mental state among patients with moderate resting or exertional desaturation were reported at the follow-up of 36 to 48 months. Nurses should focus on the mental state of patients treated with long-term oxygen therapy, especially those who use it for a prolonged time. Due to ethical constraints in this study, a quasi-experimental study with faithful consideration of internal validity can be commenced in the future.


Transmission of duck hepatitis B virus from Chinese carrier ducks to Japanese ducklings: a study of viral DNA in serum and tissue.
Human hepatitis B-like viruses have been found in several animal species, including Chinese ducks. Sera from Chinese carrier ducks which were positive for duck hepatitis B virus (DHBV) were inoculated in 33 Japanese one-day-old ducklings. The same sera were inoculated in four 3-week-old ducklings, and three 3-month-old ducks. Ten uninoculated ducklings served as controls. Hepatitis B e-antigen positive human sera and DNA polymerase-positive woodchuck sera were also inoculated into ducklings. DHBV was demonstrated in serum of all ducklings inoculated at one day of age and persisted for more than 6 months in 17 of 20 ducks. In the three ducks in which viremia disappeared, viral DNA was found in liver tissue. Southern hybridization revealed only free viral DNA in infected ducks. Only 1 of 7 ducklings inoculated at 3 weeks or later developed persistent infection. No cross-infectivity by hepatitis B virus or by woodchuck hepatitis virus was demonstrated. By inoculating DHBV-positive sera into 1-day-old ducklings of a virus-free Japanese flock, we were able to transmit DHBV in all of them and established a chronic carrier state in all ducks which were inoculated at 1 day of age.


Prognostic threshold levels of NT-proBNP testing in primary care.
Chronic heart failure (HF) is a common condition with a poor prognosis. As delayed diagnosis and treatment of HF patients in primary care can be detrimental, risk-stratified waiting lists for echocardiography might optimize resource utilization. We investigated whether a prognostic threshold level of the cardiac peptide, NT-proBNP, could be identified. From 2003-2005, 5875 primary care patients with suspected HF (median age 73 years) had NT-proBNP analysed in the Copenhagen area. Eighteen percent died and 20% had a cardiovascular (CV) hospitalization (median follow-up time: 1127 and 1038 days, respectively). In Cox proportional hazards regression models regarding NT-proBNP levels, the fourth decile (range: 83-118 pg/mL) was associated with a 90% (95% CI: 30-190, P < 0.01) increased risk for CV hospitalization and the seventh decile (range: 229-363 pg/mL) was associated with an 80% (95% CI: 20-190, P = 0.01) increased mortality risk after adjustment for age, sex, previous hospitalization, CV diseases, and chronic diseases. We identified prognostic threshold levels for mortality and CV hospitalization for NT-proBNP in primary care patients suspected of HF. Our results have the potential to be used to risk-stratify waiting lists for echocardiography.


Legal requirements for human-health based appeals of wind energy projects in ontario.
In 2009, the government of the province of Ontario, Canada passed new legislation to promote the development of renewable energy facilities, including wind energy facilities in the province. Throughout the legislative process, concerns were raised with respect to the effect of wind energy facilities on human health. Ultimately, the government established setbacks and sound level limits for wind energy facilities and provided Ontario residents with the right to appeal the approval of a wind energy facility on the ground that engaging in the facility in accordance with its approval will cause serious harm to human health. The first approval of a wind facility under the new legislation was issued in 2010 and since then, Ontario's Environmental Review Tribunal as well as Ontario's courts has been considering evidence proffered by appellants seeking revocation of approvals on the basis of serious harm to human health. To date, the evidence has been insufficient to support the revocation of a wind facility approval. This article reviews the legal basis for the dismissal of human-health based appeals.


Nanoneedle formation via doughnut beam-induced Marangoni effects.
Recently, nanosecond pulsed optical vortices enables the production of a unique chiral and sharp needle-like nanostructure (nano-needle). However, the formation process of these structures has been unsolved although mass transport by angular momentum would contribute to the chirality. Here, we reveal that another key factor in the formation of a sharp nano-needle is the Marangoni effect during the melting condition at high temperature. Remarkably, the thickness and height of the nano-needle can be precisely controlled within 200 nm, corresponding to 1/25 of beam radius (5 µm) beyond the diffraction limit by ring-shaped inhomogeneous temperature rise. Our finding will facilitate the development of advanced nano-processing with a variety of structured light beams.


Diffusion-weighted MRI for quantification of liver fibrosis: preliminary experience.
The purpose of this study was to evaluate our preliminary experience using diffusion-weighted MRI for quantification of liver fibrosis. Diffusion-weighted MRI with single-shot echo-planar technique at b values of 50, 300, 500, 700, and 1,000 s/mm2 was prospectively performed on 23 patients with chronic hepatitis and on seven healthy volunteers. The apparent diffusion coefficient (ADC) was measured in four locations in the liver. Liver biopsy results (n = 19) were retrospectively reviewed by two hepatopathologists in consensus to determine stage of fibrosis and grade of inflammation. A Mann-Whitney test was used to compare the ADCs between patients classified with respect to having stage 2 or greater versus stage 1 or less fibrosis and stage 3 or greater versus stage or less 2 fibrosis. Receiver operating characteristics analysis was used to assess the performance of ADC in prediction of the presence of stage 2 or greater and stage 3 or greater fibrosis. Using a b value of 500 s/mm2 and all combined b values, we found significantly lower hepatic ADCs in stage 2 or greater versus stage 1 or less fibrosis and stage 3 or greater versus stage 2 or less fibrosis. The mean ADCs (x 10(-3) mm2/s) with all b values were 1.47 +/- 0.11 (SD) versus 1.65 +/- 0.10 for stage 2 or greater versus stage 1 or less fibrosis (p < 0.001) and 1.44 +/- 0.07 versus 1.66 +/- 0.10 for stage 3 or greater versus stage 2 or less fibrosis (p <0.001). Hepatic ADC was a significant predictor of stage 2 or greater and stage 3 or greater fibrosis, with areas under the curve of 0.896 and 0.896, sensitivity of 83.3% and 88.9%, and specificity of 83.3% and 80.0% (ADC with all b values, 1.54-1.53 x 10(-3) mm2/s or less). Diffusion-weighted MRI can be used for prediction of the presence of moderate and advanced liver fibrosis.


Role of Intravenous Thrombolytics Prior to Endovascular Thrombectomy.
Intravenous thrombolytics and endovascular thrombectomy for ischemic stroke have evolved in parallel. However, the best approach to combine these reperfusion therapies in patients eligible for both strategies remains uncertain. Initial randomized trials of endovascular thrombectomy included administration of intravenous thrombolytics to all eligible patients. However, whether that is of net benefit has been questioned and parallels drawn with treatment of ST-segment-elevation myocardial infarction, where intravenous thrombolytics are only given if first medical contact to percutaneous intervention is expected to be >90 minutes. Six randomized trials of a direct thrombectomy approach versus intravenous thrombolytics followed by endovascular thrombectomy have now reported their results. With exception of a minority of patients in one trial, the trials all used alteplase rather than potentially more effective tenecteplase. This review examines the current state of evidence and implications for clinical practice. Importantly, these trials only apply to patients who present to a hospital with immediate access to endovascular thrombectomy and are not relevant to patients who receive thrombolytic and are then transferred to an endovascular-capable hospital. Although 2 of the 6 randomized trials met their prespecified noninferiority margin, these margins were large compared with the absolute benefit of alteplase. Overall, functional outcome was similar, with slight trends favoring bridging thrombolytics and a significant increase in final reperfusion. Symptomatic hemorrhage was increased by ≈1.8% in the bridging group but death was nonsignificantly lower. The workflow in direct thrombectomy trials involved delaying thrombolytic administration until eligibility for thrombectomy and the trials was established and randomization completed. This reduced the time available for thrombolytics to occur prethrombectomy compared with standard practice. We conclude that, pending individual-patient data meta-analyses, intravenous thrombolytics retain an important role alongside endovascular thrombectomy. Further efforts to accelerate and enhance reperfusion with thrombolytics and perform individual patient-level pooled subgroup analyses are warranted.


Determination of adsorption affinity of nanoparticles for interleukin-8 secreted from A549 cells by in vitro cell-free and cell-based assays.
The evaluation of the potential of nanoparticles (NP) for adsorbing biomolecules and use of control approaches are important for accurate presentation of in vitro analytical data. In this study, seven types of NP including carbon black (CB), cerium dioxide (CeO2), copper oxide (CuO), indium trioxide (In2O3), nickel oxide (NiO), silicon dioxide (SiO2), and titanium dioxide (TiO2) were used for determining the adsorption ability of interleukin-8 (IL-8) under either (1) a cell-free condition where NP were incubated with supernatant of A549 cells, or (2) a cell-based condition, where cells were treated with NP. Under the cell-free condition, CB and TiO2 NP showed a high adsorption affinity for IL-8 in supernatants of both lipopolysaccharide (LPS)-stimulated and unstimulated A549 cells. In contrast, SiO2 and In2O3 NP displayed a relatively low adsorption affinity. Further, IL-8 adsorption was markedly reduced when NP were predispersed in fetal bovine serum. The results obtained under cell-based conditions using both stimulated and unstimulated cells were consistent with those of the cell-free condition. Data indicate that adsorption of IL-8 onto NP surface is variable depending on type of NP, preparation method of NP, and cellular inflammatory state. Thus, the cell-free adsorption assay may be utilized for reliable interpretation of data produced by in vitro cell-based methodology.


Annual review of selected scientific literature: Report of the committee on scientific investigation of the American Academy of Restorative Dentistry.
This review was conducted to assist the busy dentist in keeping abreast of the latest scientific information regarding the clinical practice of dentistry. Each of the authors, who are considered experts in their disciplines, was asked to peruse the scientific literature in their discipline published in 2016 and review the articles for important information that may affect treatment decisions. Comments on experimental methodology, statistical evaluation, and the overall validity of conclusions are included with many of the reviews. The reviews are not meant to stand alone but are intended to inform the interested reader about what has been discovered in the past year. The readers are then invited to go to the source, if they want more detail.


Refractory and relapsed hairy-cell leukemia (HCL): casting light on promising experimental drugs in clinical trials.
Hairy cell leukemia (HCL) is a rare subtype of indolent lymphoid leukemia originating from a mature B lymphocyte. The standard first-line treatment for classic HCL, and HCL variant (HCLv), consists of purine nucleoside analogs (PNA), with or without rituximab. However, almost half of patients relapse and require subsequent therapy. This article summarizes recent achievements in the treatment of relapsed and refractory HCL. A literature search was conducted of the PubMed and MEDLINE database for articles in English. Publications from 2010 through January 2023 were scrutinized. The search terms used were hairy cell leukemia in conjunction with BRAF inhibitors, Bruton's tyrosine kinase (BTK) inhibitors, CD20 monoclonal antibodies, relapsed, refractory and variant.The growing understanding of HCL biology has allowed the design of several new, chemotherapy-free targeted drugs which have demonstrated encouraging efficacy in early clinical trials. Novel drugs will soon be available to assist standard therapy for HCL and HCLv among patients with suboptimal results following PNA treatment. In particular, the BRAF inhibitors vemurafenib and dabrafenib, with or without rituximab, have revolutionized treatment of patients with relapsed or refractory disease.


"Ghost peaks" of olmesartan medoxomil: Two solution degradation products of olmesartan medoxomil via oxidation mediated by metal ions.
Two unknown solution degradants were found during the dissolution testing in 0.1-M HCl for olmesartan medoxomil (OLM) tablets. The structure of the degradants was identified and characterized by liquid chromatography-ultraviolet (LC-UV), liquid chromatography with tandem mass spectrometry (LC-MS/MS), and nuclear magnetic resonance (NMR) and demonstrated to be cyclization of tetrazole and benzene in the olmesartan (OL) and OLM structures. A series of studies including stress studies, simulation studies, and mechanism-based studies were performed to reveal the potential mechanisms that lead to the formation of the unknown degradants. The study results demonstrated that the degradation was catalyzed with radicals that originated from the metal ions leached from the inner surface of high-performance liquid chromatography (HPLC) glass vials with dissolved oxygen under acidic condition. Prerinsing the glass vials with acidic solution dissolved with EDTA can effectively avoid the generation of such oxidative impurities. The present work provides new insights into the understanding of degradation pathways of OLM, which might support the development of OLM tablets.


Studies on the mechanism of decreased neutrophil adherence to postconfluent cultured endothelial cells.
The adherence of neutrophils (PMN) to endothelium is a crucial early step in neutrophil-mediated vascular injury. However, vascular injury is not a necessary event in inflammatory states, which suggests that endogenous mechanisms may protect endothelial cells from neutrophil-mediated injury. Previous studies suggested that leukocytes adhered in greater numbers to vascular endothelium in vivo and in vitro, where the contiguity of the cells was disrupted and where endothelial cells were actively migrating and proliferating. We studied the effect of development of a confluent monolayer on adherence of human PMN to cultured bovine calf aortic endothelial cells and investigated several mechanisms by which this effect might occur. We found that adherence of quiescent and activated PMN decreased with development of a confluent endothelial cell monolayer. A similar effect was found using human umbilical-vein endothelial cells. In contrast, adherence of nylon wool-nonadherent, thymus-derived lymphocytes increased. Variation in neutrophil adherence was not due to adherence of PMN to exposed tissue culture plastic or to exposed matrix components in preconfluent cultures, nor due to products released into culture supernatants. Diminished PMN adherence to postconfluent monolayers may have been related to changes in endothelial cell glycoproteins because neuraminidase or cycloheximide pretreatment augmented PMN adherence to postconfluent cultures more than to preconfluent cultures. However, the extent of total cell surface sialation, as assessed by neuraminidase-releasable [3H]glucosamine from metabolically labeled monolayers, did not differ between pre- and postconfluent cultures, suggesting that some specific sialated cell surface constituent is responsible for decreased PMN adherence to postconfluent monolayers.(ABSTRACT TRUNCATED AT 250 WORDS)


RENAL CELL CARCINOMA METASTASIS TO THE SINONASAL CAVITY: CASE REPORT.
Renal cell carcinoma accounts for 3% of all adult malignant tumors. Common sites of metastases are lungs, bone, liver, brain and adrenal glands. Metastatic disease to the head and neck ranges from 15% to 30%. The 5-year survival rate after nephrectomy is 60%-75%, but with multiorgan metastases the 5-year survival rate is significantly lower, 0-7%. A case is presented of a female patient diagnosed with renal cell carcinoma metastases to the paranasal sinuses, diagnosed and treated at the Department of ENT and Head and Neck Surgery, Zadar General Hospital, Zadar, Croatia. The tumor was surgically removed. Unfortunately, the patient died one year after the procedure due to multiorgan failure. Although metastases of renal cell carcinoma to the head and neck are very rare, it should be first suspected when investigating a metastatic tumor in this region. Surgical excision offers the best hope for long term survival. In case of unresectable tumor, other treatment options should be considered such as radiotherapy, immunotherapy and chemotherapy.


Kisspeptin and its Effect on Mammalian Spermatogensis.
Kisspeptin and its receptor, GPR54, are regarded as key regulators of and catalysts for male puberty onset, and also fundamental gatekeepers of spermatogenesis in mammals. Consequently, the loss function of kisspeptin or GPR54 leads to a symptom of Hypogonadotropic Hypogonadism (HH) in human and HH accompanied by lower gonadotrophic hormone levels, smaller testes, impaired spermatogenesis and abnormal sexual maturation in mice. Besides its well-recognized functions in hypothalamus before and during puberty, accumulating data strongly support kisspeptin production in testis, and participation in somatic and germ cell development and sperm functions as well. This review aims to summarize recent findings regarding kisspeptin activity in the testes and sperm function. We undertook a keyword search of peer-reviewed research literature including data from in vivo and in vitro studies in humans and genetically modified animal models to identify the roles of kisspeptins in male reproduction. A plethora of studies detail the role of kisspeptins and GPR54 in mammalian spermatogenesis in vivo and in vitro. This review identified recent findings regarding the kisspeptin system in male gonads, and regulation of kisspeptin in testicular physiology and male reproductive defects and disorders. The findings of this review confirm the importance role of kisspeptins in male fertility. Understanding their biphasic roles in testis may help to consider kisspeptins as potential pharmacological targets for treating human infertility.


An Orthopedic Performance Improvement Initiative at a Small Military Treatment Facility.
The scientific literature demonstrates a cost-benefit associated with early access to physical therapy. The purpose of this case study is to report the results of an orthopedic performance improvement initiative (OPII) at a small military treatment facility (approximately 4.5K active duty beneficiaries). The OPII was introduced to (1) limit variation by ensuring that all active duty orthopedic consults were audited ensuring proper timing of appropriate services and (2) establish contractual agreement for shared resources with the U.S. Naval Jacksonville Orthopedic Department. OPII was accomplished through consensus development and strong leadership support. All orthopedic referrals (n = 260) were audited for 6 months. Appropriate recommendations were provided to either continue with orthopedic care or to redirect to a physical therapy first approach. Orthopedic referrals decreased 27% with concomitant 32% increase in physical therapy referrals producing overall savings of $462K (33%). Meanwhile, surgical throughput improved 45%. Seventy percent of the savings were attributed to improved utilization translating to a relative value unit savings per beneficiary of $17.64 (23.7%). Our results support the value of a conservative physical therapy first approach for musculoskeletal conditions and shared mil-to-mil resourcing agreements. Success requires an iterative audit/feedback process balanced with stakeholder consensus.


Glycoconjugate expression of cells of human anagen hair follicles during keratinization.
Changes in the expression of glycoconjugates in cells of the inner root sheath (IRS) and outer root sheath (ORS) of human anagen hair follicles were investigated by lectin histochemistry. Concanavalin A (Con A) and Ricinus communis (RCA-I) stained hair follicle cells regardless of their differentiation stages. In IRS, Ulex europeaus-I (UEA-I) bound to the surface of the cells as soon as they were morphologically defined, and Glycine max (SBA) stained as their differentiation progressed. Innermost (IM) cells of ORS layers were reactive with UEA-I at the stage where Henle's cells were keratinized, while the reactivity of UEA-I was lost at the site of the completion of IRS keratinization where SBA reaction was detected. Staining of both UEA-I and SBA was prominent in other ORS cells at the levels where SBA binding in IM cells became strong. The staining intensity increased up to the position of the follicular isthmus. In addition, a sugar residue recognized by Dolichos biflorus (DBA) was detected in differentiated cells of ORS. In contrast, the DBA reaction was not found at all in cells of IRS, infundibulum, and epidermis. These findings identified a complexity of carbohydrate metabolism in the cells of different layers at various stages of keratinization. IM cells differentiate independently from other ORS cells but seem responsive to the degree of IRS keratinization. All ORS cells possess a unique sugar moiety not found in other keratinocytes either in the hair or epidermis.


Health-Associated Niche Inhabitants as Oral Probiotics: The Case of Streptococcus dentisani.
Oral diseases, including dental caries and periodontitis, are among the most prevalent diseases worldwide and develop as a consequence of a microbial dysbiosis. Several bacterial strains are being tested as potential oral health-promoting organisms, but usually they are species isolated from niches other than the site where they must exert its probiotic action, typically from fecal samples. We hypothesize that oral inhabitants associated to health conditions will be more effective than traditional, gut-associated probiotic species in key aspects such as colonization of the oral site where disease takes place or the possession of oral health promoting functions, as well as more practical issues like safety and toxicity, and establishing proper doses for administration. As an example of these active colonizers, we describe the case of Streptococcus dentisani, a new streptococcal species isolated from dental plaque of caries-free individuals. We have detected it in 98% of dental plaque samples from healthy individuals and, as expected, it does not produce any toxic secondary metabolite and does not survive a simulated stomach digestion, preventing potential secondary effects. Besides, this species has a double probiotic action, as it inhibits the growth of major oral pathogens through the production of bacteriocins, and also buffers acidic pH (the primary cause of dental caries) through an arginolytic pathway. We propose the use of S. dentisani as a promising probiotic against tooth decay.


Fibrillary Glomerulonephritis and DnaJ Homolog Subfamily B Member 9 (DNAJB9).
Fibrillary GN (FGN) is a rare glomerular disease that is diagnosed based on the presence of fibrils in glomeruli. The fibrils are typically noncongophilic, randomly oriented, and measure 12-24 nm. Traditionally, electron microscopy (EM) has been an important tool to aid in the diagnosis of FGN by identifying the fibrils and to distinguish it from other entities that could mimic FGN. However, recently DnaJ homolog subfamily B member 9 (DNAJB9) has emerged as both a specific and sensitive biomarker in patients with FGN. It allows prompt diagnosis and alleviates reliance on EM. DNAJB9 is a cochaperone of heat shock protein 70 and is involved in endoplasmic reticulum protein-folding pathways. But its role in the pathogenesis of FGN remains elusive. DNAJB9 may act as a putative antigen or alternatively it may secondarily bind to misfolded IgG in the glomeruli. These hypotheses need future studies to elucidate the role of DNAJB9 in the pathogenesis of FGN. The treatment regimen for FGN has been limited due to paucity of studies. Most patients receive combination immunosuppressive regimens. Rituximab has been studied the most in FGN and it may delay disease progression. Prognosis of FGN remains poor and 50% require dialysis within 2 years of diagnosis. Despite its poor prognosis in native kidneys, the rate of recurrence post-transplantation is low (20%) and patient as well as allograft outcomes are similar to patients without FGN.


Atrial natriuretic peptide in the preterm newborn.
Atrial natriuretic peptide (ANP), plasma renin and renin substrate concentrations (PRC and PRS) were measured in 31 preterm infants with idiopathic respiratory distress syndrome. Infants were studied at a mean of 1.4 days; 17 infants were also studied 2 days later. A 6-hour urine collection was made from 13 male infants on the first day of sampling to assess renal function. Both ANP and PRC were elevated and showed wide ranges of values (geometric means of 620 pg/ml and 18.4 ng/ml/h). Plasma ANP was significantly correlated with pH, PaCO2 and base excess. No correlations with parameters of cardiovascular or renal function were found. Plasma ANP rose in 13 of the 17 paired samples. We suggest that the very high ANP concentrations in these babies are a consequence of the pulmonary haemodynamic disturbances which accompany respiratory distress in the newborn.


Selective up-regulation of type II inosine 5'-monophosphate dehydrogenase messenger RNA expression in human leukemias.
The discovery of isozymes (types I and II) of IMP dehydrogenase (IMPDH; EC 184.108.40.206), the rate-limiting enzyme of de novo GTP biosynthesis, has attracted attention as a possible novel approach to cancer diagnosis and selective tumor cell chemotherapy. To elucidate differences in expression and regulation of the two IMPDH isozymes, we examined the steady-state levels of these mRNAs in various types of leukemic cells from patients. Northern blot analysis revealed that type II IMPDH was more active transcriptionally (1.5- to 5.1-fold) in all the leukemic cells examined than in normal lymphocytes, whereas type I expression was similar. The increased expression of type II mRNA in leukemic cells was closely linked with the increase in total IMPDH activity (r = 0.92). When leukemic cells from a patient with chronic granulocytic leukemia in blast crisis were separated into blast-rich and mature leukocyte-rich fractions, the expression of type II mRNA correlated positively with the population of immature leukemic cells, whereas type I expression was unchanged. Treatment of leukemic blasts with 12-O-tetradecanoyl-phorbol-13-acetate for 5 days resulted in a 90% decrease in the expression of type II mRNA with macrophage-like differentiation, while the expression of type I mRNA was relatively stable. These observations suggest that expression of type II IMPDH is stringently linked with immature characteristics of leukemic cells; thus, it should be a selective target for antileukemic chemotherapy.


Roles of orf60a and orf61 in Development of Bacteriophages λ and Φ24B.
The exo-xis region of lambdoid bacteriophage genomes contains several established and potential genes that are evolutionarily conserved, but not essential for phage propagation under laboratory conditions. Nevertheless, deletion or overexpression of either the whole exo-xis region and important regulatory elements can significantly influence the regulation of phage development. This report defines specific roles for orf60a and orf61 in bacteriophage λ and Φ24B, a specific Shiga toxin-converting phage with clinical relevance. We observed that mutant phages bearing deletions of orf60a and orf61 impaired two central aspects of phage development: the lysis-versus-lysogenization decision and prophage induction. These effects were more pronounced for phage Φ24B than for λ. Surprisingly, adsorption of phage Φ24B on Escherichia coli host cells was less efficient in the absence of either orf60a or orf61. We conclude that these open reading frames (ORFs) play important, but not essential, roles in the regulation of lambdoid phage development. Although phages can propagate without these ORFs in nutrient media, we suggest that they may be involved in the regulatory network, ensuring optimization of phage development under various environmental conditions.


An interview with Christopher Wylie and Janet Heasman.
The 2014 Society for Developmental Biology (SDB) Lifetime Achievement Award was jointly awarded to Christopher Wylie and Janet Heasman in recognition of their outstanding and sustained contributions to the field. At the 73rd Annual SDB meeting, where they were presented with the award, we asked Chris and Janet about their careers and their advice for young researchers.


[Multifocal ischaemic stroke and myocardial infarction in a woman with occult lung cancer complicated with chronic DIC and thrombotic endocarditis].
Ischaemic stroke in thromboembolic mechanism may be a first sign of neoplastic disease, as in the presented case of a 56-year-old woman. Progressive trombocytopenia, anaemia with reticulocytosis and schistocytes in peripheral blood smear, elevated serum LDH activity as well as coexisting myocardial infarction initially suggested Moschcowitz syndrome. However, plasma exchange did not improve her neurological status and D-dimer values increase in subsequent evaluations indicated chronic DIC. At the same time, on transesophageal echocardiography, thrombotic endocarditis was diagnosed. Screening for cancer showed high CA 125 marker and chest computed tomography revealed lung tumor, not visible on earlier chest X-ray. In further treatment she underwent palliative radiotherapy and continued low molecular weight heparin. The neoplastic process had an unfavorable course and she died after four months. The authors point out that in case of multifocal ischaemic stroke and coexistent thrombocytopenia, neoplastic hypercoagulable state and thrombotic endocarditis should be considered.


Self-motion and the alpha relaxation in a simulated glass-forming polymer: crossover from Gaussian to non-Gaussian dynamic behavior.
We present fully atomistic molecular dynamics simulations for a realistic model of a glass-forming polymer: polyisoprene. The simulations are carried out at 363 K and extend until 20 ns. We calculate the self-part of the Van Hove correlation function G(s)(r,t), the mean-squared displacement <r(2)(t)>, the second-order non-Gaussian parameter alpha(2)(t), and the incoherent intermediate scattering function F(s)(Q,t) for the main chain protons. In addition, we also calculate the density-density correlation function F(Q,t)/F(Q,0) and the second-order autocorrelation function M2(t) for different C-H bonds of the main chain. alpha(2)(t) shows a broad maximum centered at a time t(*) approximately 4 ps, which corresponds to the intermediate region of <r(2)(t)> between microscopic dynamics and sublinear diffusion. The analysis of F(s)(Q,t), F(Q,t)/F(Q,0), and M2(t) focuses on the second slow step which is associated to the alpha relaxation. Following the usual experimental procedure this decay is described in terms of a Kohlrausch-Williams-Watts (KWW) function: A exp[-(t/tau)(beta)]. In the Q range below Q(max), where Q(max) is the value at which the static structure factor shows its first maximum, the Q dependence of the KWW relaxation time of F(s)(Q,t) follows a law tau approximately Q(-2/beta). This kind of Q dependence corresponds to a Gaussian behavior of G(s)(r,t) and F(s)(Q,t). This law has been experimentally found in this Q range for different polymers. In the higher Q range-not easily accessible experimentally-strong deviations from the Gaussian behavior manifest. This crossover from Gaussian to non-Gaussian behavior can be understood in the framework of the mode coupling theory as well as in terms of a crossover from homogeneous to heterogeneous dynamics. This last interpretation opens a possible way of rationalizing the apparent contradiction between the neutron scattering and relaxation techniques results concerning dynamical heterogeneity of the alpha relaxation.


Temperature- and light-responsive blends of pluronic F127 and poly(N,N-dimethylacrylamide-co-methacryloyloxyazobenzene).
Photoresponsive poly(N,N-dimethylacrylamide-co-methacryloyloxyazobenzene) (DMA-MOAB) and temperature-responsive Pluronic F127 (F127) copolymers were blended to obtain systems responsive to both stimuli that are potentially useful for pharmaceutical formulations. The random DMA-MOAB copolymer undergoes a trans to cis isomerization when irradiated by 366 nm light, which modifies both the air-water interfacial behavior and the self-associative properties of the copolymer. Under dark conditions the azobenzene groups of DMA-MOAB in the trans conformation self-associate and the interactions with F127 are minimal. The cis conformation of the azobenzene groups of the DMA-MOAB copolymer is relatively more hydrophilic than the trans conformation, which causes the copolymer micelles to dissociate upon irradiation, allowing the unimers to form mixed micelles with the F127. This causes the sol-gel transition temperature of the DMA-MOAB:F127 blend to be 10 degrees C lower upon irradiation at 366 nm compared to that for the dark conditions. It has been found that F127 (10-12 wt %):DMA-MOAB (5-6 wt %) aqueous solutions have at body temperature a low viscosity when equilibrated in the dark and undergo a sol-gel transition when irradiated. Such a transition strongly alters the diffusion of solutes such as methylene blue within the solutions. This light-induced interaction between the azobenzene moieties of DMA-MOAB and F127 micelles disappears when hydroxypropyl-beta-cyclodextrin (HPbetaCD) is added to the medium. In the presence of HPbetaCD, the cis-azobenzene groups are hosted in the cyclodextrin cavities and the mixed micelles are not formed. Therefore, changes in HPbetaCD concentration could be used to modulate the response of the copolymer blends to light.


Insulin lispro 25/75 and insulin lispro 50/50 as starter insulin in Japanese patients with type 2 diabetes: subanalysis of the CLASSIFY randomized trial.
In Japan, premixed insulins are commonly used as starter insulin for type 2 diabetes. This subpopulation analysis assessed the efficacy and safety of twice-daily LM25 (25% insulin lispro/75% insulin lispro protamine) and LM50 (50% insulin lispro/50% insulin lispro protamine) as starter insulin in Japanese subjects, and compared these results with the whole-trial populations of East Asian subjects. In this subpopulation analysis of an open-label, phase 4, randomized trial (CLASSIFY), Japanese subjects received LM25 (n = 88) or LM50 (n = 84) twice-daily for 26 weeks. The primary outcome was change from baseline at Week 26 in glycated hemoglobin (HbA1c). Results for Japanese subjects were generally similar to those for the whole-trial population. Similar changes from baseline in HbA1c were observed for LM25 and LM50 groups (least squares [LS] mean difference [95% confidence interval] of LM25 - LM50 = 0.13 [-0.16, 0.41]%, 1.42 [-1.75, 4.48] mmol/mol, p = 0.388). More LM50-treated subjects than LM25-treated subjects achieved HbA1c targets of <7.0% (59.5% versus 43.2%; p = 0.034) or ≤6.5% (45.2% versus 28.4%; p = 0.027). The reduction in postprandial blood glucose concentrations after morning and evening meals was statistically significantly greater for LM50 than for LM25. The incidence of both hypoglycemia and treatment-emergent adverse events were similar between treatment groups. Both LM25 and LM50 twice daily appear to be effective and well tolerated as starter insulin, although LM50 might be more effective for Japanese type 2 diabetes patients.


Meta-analysis and Harmonization of Life Cycle Assessment Studies for Algae Biofuels.
Algae biodiesel (BioD) and renewable diesel (RD) have been recognized as potential solutions to mitigating fossil-fuel consumption and the associated environmental issues. Life cycle assessment (LCA) has been used by many researchers to evaluate the potential environmental impacts of these algae-derived fuels, yielding a wide range of results and, in some cases, even differing on indicating whether these fuels are preferred to petroleum-derived fuels or not. This meta-analysis reviews the methodological preferences and results for energy consumption, greenhouse gas emissions, and water consumption for 54 LCA studies that considered algae BioD and RD. The significant variation in reported results can be primarily attributed to the difference in scope, assumptions, and data sources. To minimize the variation in life cycle inventory calculations, a harmonized inventory data set including both nominal and uncertainty data is calculated for each stage of the algae-derived fuel life cycle.


An enrichment selection for mutants resulting from oligonucleotide-directed mutagenesis of double-stranded DNA.
We report here a simple and rapid procedure for enrichment and selection of mutants from oligonucleotide-directed mutagenesis on double-stranded plasmid DNA. Mutagenic oligonucleotides were designed to insert or delete a unique restriction site with silent codon changes. After mutagenesis, plasmid DNA from all resulting colonies was pooled, restricted with the appropriate endonuclease, and the resulting unique form of DNA (linear or circular) was isolated and used for transformation of competent E. coli. These procedures provided an enrichment of mutant plasmid from the 4% obtained by more conventional techniques to greater than 65%.


Inhibition of endoplasmic reticulum chaperone protein glucose-regulated protein 78 potentiates anti-angiogenic therapy in renal cell carcinoma through inactivation of the PERK/eIF2α pathway.
Tumor microenvironments are characterized by decreased oxygen and nutrition due to the rapid and progressive nature of tumors and also stresses induced by several anti-tumor therapies. These intense cell stressors trigger a protective cell survival mechanism heralded by the unfolded protein response (UPR). The UPR is induced by an accumulation of unfolded proteins in the endoplasmic reticulum (ER) following cell starvation. Although the ER stress response is implicated in cytoprotection, its precise role during anti-angiogenic therapy remains unclear. One of the major proteins involved in ER stress is glucose-regulated protein 78 (GRP78), which binds to unfolded proteins and dissociates from membrane-bound ER stress sensors. To determine the role of ER stress responses during anti-angiogenic therapy and the potential role of GRP78 in combined therapy in renal cell carcinoma (RCC), we used GRP78 overexpressing or knockdown RCC cells under hypoxic or hypoglycemic conditions in vitro and in animal models treated with sunitinib. Here, we report that GRP78 plays a crucial role in protecting RCC cells from hypoxic and hypoglycemic stress induced by anti-angiogenic therapy. Knockdown of GRP78 using siRNA inhibited cancer cell survival and induced apoptosis in RCC cells in vitro and also resulted in ER stress-induced apoptosis and hypoxic/hypoglycemic stress-induced apoptosis by inactivating the PERK/eIF-2α pathway. Finally, GRP78 knockdown showed potent suppression of tumor growth and enhanced the antitumor effect of sunitinib in RCC xenografts. Our findings suggest that GRP78 may serve as a novel therapeutic target in combination with anti-angiogenic therapy for the management of RCC.


Lateral-drag propulsion forces induced by anisotropy.
We predict the existence of lateral drag forces near the flat surface of an absorbing slab made of an anisotropic material. The forces originate from the fluctuations of the electromagnetic field, when the anisotropy axis of the material forms a certain angle with the surface. In this situation, the spatial spectra of the fluctuating electromagnetic fields becomes asymmetric, different for positive and negative transverse wave vectors components. Differently from the case of van der Waals interactions in which the forward-backward symmetry is broken due to the particle movement, in our case the lateral motion results merely from the anisotropy of the slab. This new effect, of particular significance in hyperbolic materials, could be used for the manipulation of nanoparticles.


Psychological distress, coping behaviors, and preferences for support among New York healthcare workers during the COVID-19 pandemic.
The mental health toll of COVID-19 on healthcare workers (HCW) is not yet fully described. We characterized distress, coping, and preferences for support among NYC HCWs during the COVID-19 pandemic. This was a cross-sectional web survey of physicians, advanced practice providers, residents/fellows, and nurses, conducted during a peak of inpatient admissions for COVID-19 in NYC (April 9th-April 24th 2020) at a large medical center in NYC (n = 657). Positive screens for psychological symptoms were common; 57% for acute stress, 48% for depressive, and 33% for anxiety symptoms. For each, a higher percent of nurses/advanced practice providers screened positive vs. attending physicians, though housestaff's rates for acute stress and depression did not differ from either. Sixty-one percent of participants reported increased sense of meaning/purpose since the COVID-19 outbreak. Physical activity/exercise was the most common coping behavior (59%), and access to an individual therapist with online self-guided counseling (33%) garnered the most interest. NYC HCWs, especially nurses and advanced practice providers, are experiencing COVID-19-related psychological distress. Participants reported using empirically-supported coping behaviors, and endorsed indicators of resilience, but they also reported interest in additional wellness resources. Programs developed to mitigate stress among HCWs during the COVID-19 pandemic should integrate HCW preferences.


Susceptibility of glycans to beta-elimination in Fmoc-based O-glycopeptide synthesis.
In order to investigate the possible extent of beta-elimination occurring in Fmoc-based continuous-flow solid-phase glycopeptide synthesis, the influence of the pKb of the base used for N alpha-deprotection has been studied. A glycosylated pentapeptide was synthesized using 50% morpholine, 10% piperidine or 2% DBU, respectively, in DMF for deprotection. The dehydropentapeptide N alpha-Ac-Thr-Thr-delta Aba-Val-Thr-NH2, which would be formed in the case of beta-elimination, was prepared independently and used as a control in HPLC analysis; however, this product was not formed under any of the deprotection conditions applied. Furthermore, a 23 amino acid long glycopeptide from human intestinal mucin was prepared using 2% DBU as a base for Fmoc cleavage, and similarly no beta-elimination was observed. The glycopeptide products were subjected to a prolonged treatment with sodium hydroxide in methanol/water without significant formation of byproducts, and the pure glycopeptides were isolated and characterized by 1H-NMR spectroscopy.


Comparing traditional and computer-based training methods for standardized patients.
The use of computer-based training programs in medicine is widespread. To date, however, there has been little or no research conducted to explore how these self-delivered educational programs can be applied to the training of standardized patients (SPs). The purpose of this study was to compare a traditional SP training technique with one that was based on computer-based delivery of case materials and checklist-based scoring criteria. Ten SPs were trained to portray 1 of 5 cases. The SPs were paired by case and then randomly assigned to either an experimental (computer-based training) or control (traditional trainer-based training) group. Forty medical students completed a 5-station clinical skills assessment where they encountered both computer- and trainer-trained SPs. Portrayal fidelity and documentation accuracy was assessed via videotape review of the individual encounters. With reference to checklist scoring discrepancies, documentation accuracy was significantly greater for those SPs who were trained using the computer-based delivery method. Likewise, based on a summary measure of portrayal fidelity, the performances of traditionally trained SPs were quite realistic but, nevertheless, less dependable than those for the computer-trained group. The use of computer-assisted educational programs to train SPs is effective and can lead to performance fidelity gains as well as improved accuracy with respect to the documentation of history taking and physical examination skills.


Paediatric early warning systems for detecting and responding to clinical deterioration in children: a systematic review.
To systematically review the available evidence on paediatric early warning systems (PEWS) for use in acute paediatric healthcare settings for the detection of, and timely response to, clinical deterioration in children. The electronic databases PubMed, MEDLINE, CINAHL, EMBASE and Cochrane were searched systematically from inception up to August 2016. Eligible studies had to refer to PEWS, inclusive of rapid response systems and teams. Outcomes had to be specific to the identification of and/or response to clinical deterioration in children (including neonates) in paediatric hospital settings (including emergency departments). 2 review authors independently completed the screening and selection process, the quality appraisal of the retrieved evidence and data extraction; with a third reviewer resolving any discrepancies, as required. Results were narratively synthesised. From a total screening of 2742 papers, 90 papers, of varied designs, were identified as eligible for inclusion in the review. Findings revealed that PEWS are extensively used internationally in paediatric inpatient hospital settings. However, robust empirical evidence on which PEWS is most effective was limited. The studies examined did however highlight some evidence of positive directional trends in improving clinical and process-based outcomes for clinically deteriorating children. Favourable outcomes were also identified for enhanced multidisciplinary team work, communication and confidence in recognising, reporting and making decisions about child clinical deterioration. Despite many studies reporting on the complexity and multifaceted nature of PEWS, no evidence was sourced which examined PEWS as a complex healthcare intervention. Future research needs to investigate PEWS as a complex multifaceted sociotechnical system that is embedded in a wider safety culture influenced by many organisational and human factors. PEWS should be embraced as a part of a larger multifaceted safety framework that will develop and grow over time with strong governance and leadership, targeted training, ongoing support and continuous improvement.


Determination of elemental distribution in green micro-algae using synchrotron radiation nano X-ray fluorescence (SR-nXRF) and electron microscopy techniques--subcellular localization and quantitative imaging of silver and cobalt uptake by Coccomyxa actinabiotis.
The newly discovered unicellular micro-alga Coccomyxa actinabiotis proves to be highly radio-tolerant and strongly concentrates radionuclides, as well as large amounts of toxic metals. This study helps in the understanding of the mechanisms involved in the accumulation and detoxification of silver and cobalt. Elemental distribution inside Coccomyxa actinabiotis cells was determined using synchrotron nano X-ray fluorescence spectroscopy at the ID22 nano fluorescence imaging beamline of the European Synchrotron Radiation Facility. The high resolution and high sensitivity of this technique enabled the assessment of elemental associations and exclusions in subcellular micro-algae compartments. A quantitative treatment of the scans was implemented to yield absolute concentrations of each endogenous and exogenous element with a spatial resolution of 100 nm and compared to the macroscopic content in cobalt and silver determined using inductively coupled plasma-mass spectrometry. The nano X-ray fluorescence imaging was complemented by transmission electron microscopy coupled to X-ray microanalysis (TEM-EDS), yielding differential silver distribution in the cell wall, cytosol, nucleus, chloroplast and mitochondria with unique resolution. The analysis of endogenous elements in control cells revealed that iron had a unique distribution; zinc, potassium, manganese, molybdenum, and phosphate had their maxima co-localized in the same area; and sulfur, copper and chlorine were almost homogeneously distributed among the whole cell. The subcellular distribution and quantification of cobalt and silver in micro-alga, assessed after controlled exposure to various concentrations, revealed that exogenous metals were mainly sequestered inside the cell rather than on mucilage or the cell wall, with preferential compartmentalization. Cobalt was homogeneously distributed outside of the chloroplast. Silver was localized in the cytosol at low concentration and in the whole cell excluding the nucleus at high concentration. Exposure to low concentrations of cobalt or silver did not alter the localization nor the concentration of endogenous elements within the cells. To our knowledge, this is the first report on element co-localization and segregation at the sub-cellular level in micro-algae by means of synchrotron nano X-ray fluorescence spectroscopy.


Questions of scientific responsibility: the Baltimore case.
A number of cases of questionable behavior in science have been extensively reported in the media during the last two or three years. What standards are upheld by the scientific community affect the community internally, and also affect its relations with society at large, including Congress. Here I wish to address questions of scientific responsibility, using the Baltimore case as a concrete instance where they came up. The first part containing historical background is necessary to provide readers with documentation so that they can have some factual bases on which to evaluate respective positions and my conclusions that follow -- based on further but more succinctly summarized documentation. I have reproduced many quotes because I firmly believe people are entitled to be represented by their own wording. Conversely, I hold people accountable for their official positions. Some of these are reproduced in footnotes, and some longer ones are reproduced in appendices. I also do not ask to be trusted. By providing numerous references, I hope that readers who find my documentation insufficient can follow up by looking up these references.... The article is in six parts: Part I. Historical Background. This part gives mostly a historical background of the early phases of the Baltimore case. Part II. The First Issue of Responsibility. This part presents a discussion of certain scientific responsibilities based on that background, specifically: the responsibility of answering questions about one's work, and the responsibility whether to submit to authority. Part III. The NIH Investigations. This part summarizes the two NIH investigations. Part IV. The Dingell Subcommittee. This part deals with the responsibilities of a Congressional Committee vis-à-vis science. Part V. Further Issues of Responsibility. This part goes into an open ended discussion of many issues of responsibility facing scientists, vis-à-vis themselves and vis-à-vis society at large, including Congress. The list is long, and readers can look at the section and paragraph headings to get an idea of their content. Part VI. Personal Credibility, a Shift at the Grass Roots, and Baltimore's Persistence.


Gender differences in social anxiety disorder: A review.
Gender differences in social anxiety disorder (SAD) have not received much empirical attention despite the large body of research on the disorder, and in contrast to significant literature about gender differences in other disorders such as depression or posttraumatic stress disorder. To address this gap, we comprehensively reviewed the literature regarding gender differences in eight domains of SAD: prevalence, clinical presentation, functioning and impairment, comorbidity, course, treatment seeking, physiological arousal, and the oxytocin system. Findings from the present review indicate that women are more likely to have SAD and report greater clinical severity. Notwithstanding, men with the disorder may seek treatment to a greater extent. According to the present review, the course of SAD seems to be similar for men and women, and findings regarding gender differences in functional impairment and comorbidity are inconclusive. We highlight areas requiring future research and discuss the findings in the context of a number of theoretical perspectives. We believe that further research and integration of scientific findings with existing theories is essential in order to increase our understanding and awareness of gender differences in SAD, thus facilitating gender-sensitive and specifically-tailored interventions for both men and women with the disorder.


Floral anatomy and vegetative development in Ceratophyllum demersum: a morphological picture of an "unsolved" plant.
The phylogenetic position of Ceratophyllum is still controversial in recent molecular analyses of angiosperms, with various suggestions of a sister group relation to all other angiosperms, eudicots, monocots, eudicots + monocots, and magnoliids. Therefore, the morphological characters of Ceratophyllum are important for resolving the phylogeny of angiosperms. In this study, we observed the detailed developmental anatomy of all lateral organs and their configurations to elucidate the floral development and phyllotactic pattern of Ceratophyllum demersum. We observed fixed shoots of C. demersum with scanning electron microscopy and serial sections of the samples with light microscopy. Bract primordia arise first, followed by the stamen primordia in staminate flowers. Both bracts and stamens initiate unidirectionally, first on the abaxial side of the floral apex and later on the adaxial side, most likely due to the contact pressure imposed by the leaf primordium at the superior node. In pistillate flowers, bract primordia on the abaxial side were also initiated first. The configuration of buds at one node showed six patterns and each pattern included at least one vegetative bud, and flower buds were always accompanied by vegetative buds at the same node. The initiation pattern of organs in the outer whorls of C. demersum flowers is distorted by mechanical pressure, resulting in the phyllotactic variation of staminate flowers. Vegetative buds are the main axillary buds with floral buds as accessory buds, which suggests that the shoot of C. demersum has been modified from a decussate phyllotaxis.


Effect of sulfaphenazole on tolbutamide distribution in rabbits: analysis of interspecies differences in tissue distribution of tolbutamide.
The effect of sulfaphenazole on the distribution of tolbutamide was examined by comparing the change in the steady-state volume of distribution (Vdss) determined from in vivo plasma elimination with the tissue-to-plasma concentration ratio of various tissues (Kp) in rabbits; this effect was compared with that previously reported in rats. In rabbits, the Kp values of six tissues studied (i.e., brain, heart, spleen, small intestine, muscle, and skin) increased in the presence of sulfaphenazole ; except for brain, lung, and adipose tissue, the tissue-to-plasma unbound concentration ratio (Kp,f) of other tissues did show a significant decrease. This suggested that both the tissue and plasma protein binding of tolbutamide were affected by sulfaphenazole and that the increase in Kp was due mainly to the displacement of plasma protein binding of tolbutamide by sulfaphenazole , which was greater than that of tissue binding, while no change in Kp was due to a parallel change in both the plasma protein binding and tissue binding of tolbutamide. In both rabbits and rats, the Vdss calculated from plasma concentration versus time curve was very close to that calculated from the Kp values and volumes of various tissues in the presence and absence of sulfaphenazole , respectively. The interspecies difference of the effect of sulfaphenazole on the tissue distribution of tolbutamide between rabbits and rats was elucidated from both in vivo tissue distribution and in vitro plasma protein binding studies.


The solution structure of the CBM4-2 carbohydrate binding module from a thermostable Rhodothermus marinus xylanase.
The solution structure is presented for the second family 4 carbohydrate binding module (CBM4-2) of xylanase 10A from the thermophilic bacterium Rhodothermus marinus. CBM4-2, which binds xylan tightly, has a beta-sandwich structure formed by 11 strands, and contains a prominent cleft. From NMR titrations, it is shown that the cleft is the binding site for xylan, and that the main amino acids interacting with xylan are Asn31, Tyr69, Glu72, Phe110, Arg115, and His146. Key liganding residues are Tyr69 and Phe110, which form stacking interactions with the sugar. It is suggested that the loops on which the rings are displayed can alter their conformation on substrate binding, which may have functional importance. Comparison both with other family 4 cellulose binding modules and with the structurally similar family 22 xylan binding module shows that the key aromatic residues are in similar positions, and that the bottom of the cleft is much more hydrophobic in the cellulose binding modules than the xylan binding proteins. It is concluded that substrate specificity is determined by a combination of ring orientation and the nature of the residues lining the bottom of the binding cleft.


The internal carotid artery in the surgery of extensive oral cancer.
The selective sacrifice of the carotid arteries during extensive neck operative procedures, or their compulsory ligation after an exposure or hemorrhage postoperatively, are among the most serious problems in head and neck surgery. As the highest percentage of disastrous results, following ligation of the carotid vessels, occurs in those patients to whom ligation has been performed at a time when the blood pressure was low, due to preceding hemorrhage or shock, the selective ligation (or excision) of these vessels is not such a dangerous procedure. In 6 cases of selective ligation of carotid arteries, there was only one non-permanent, partial hemiplegia.


Ethnic sensitivity assessment - pharmacokinetic comparability between Japanese and non-Japanese healthy subjects on selected mAbs.
Ethnic sensitivity studies (ESSs), where safety and pharmacokinetics (PK) are assessed in Japanese subjects, are routinely conducted according to Japanese regulatory requirement before the subsequent clinical studies. The necessity of ESSs is questionable in case of mAbs, where inherent IgG characteristics are considered ethnically insensitive. This report investigated PK profiles and immunogenicity (IG) following a single administration of mAbs in Japanese and non-Japanese healthy subjects. PK and IG comparison between Japanese and non-Japanese healthy subjects was made on mAbs data available from public domain and unpublished internal reports. PK comparison was made based on statistical approach as well as assumed typical IgG profile using modeling and simulation. When compared directly, most mAbs showed no difference between ethnic groups. When profiles of various mAbs were fit to an assumed typical IgG PK model, the majority of mAbs follow the expected behavior regardless of ethnicities. Deviations from this behavior did not appear to be due to inherent ethnic differences. When the incidence of IG was assessed, only Adalimumab showed apparent ethnic difference. The overall lack of observational difference may facilitate discussion of mAbs' early clinical development in Japan, including the utility of dedicated ESSs.


Life cycle assessment of repurposing abandoned onshore oil and gas wells for geothermal power generation.
The annual global growth rate for geothermal power generation between 2021 and 2030 is targeted to be 13 % to meet net-zero emissions by 2050. Repurposing abandoned oil and gas wells (AOGWs) presents a strategic alternative to boost geothermal power by minimising the drilling requirements. This study performed the first cradle-to-grave life cycle assessment to evaluate the environmental performance of three options for geothermal power generation from repurposed oil and gas wells: i) two completely AOGWs (R-GEOdouble); ii) a single completely AOGW (R-GEOsingle); iii) two semi-AOGWs (R-GEOsemi - still in operation but with high water-cut). Their results are then compared with a business-as-usual geothermal power plant (GEObau). All 18 impact categories of the ReCiPe 2016 midpoint methodology plus cumulative energy demand have been analysed in detail, with background data from the Ecoinvent v3.8 database. R-GEOsemi is deemed the most promising repurposed system, exhibiting the lowest values in 11 impact categories. Specifically, R-GEOsemi produces 34 %, 23 %, and 14 % less CO2 eq./kWh when compared to GEObau, R-GEOdouble, and R-GEOsingle, respectively. Conversely, R-GEOdouble performed the worst in 12 impact categories, and the second worst in the rest of the indicators. Meanwhile, GEObau achieved the lowest impacts in nine categories when compared with repurposed systems, indicating the reduction of drilling and construction activities cannot always guarantee the mitigation of all environmental impacts. Sensitivity analyses showed that a longer lifetime could lower environmental impacts, but increasing annual power generation is constrained by site-specific factors. A 'breakeven' point analysis revealed that 85 % of repurposed systems' impact indicators could match GEObau if their lifetime reaches 30 years, but this remains uncertain. The findings of this study will be of interest to national and local governments developing future policies aimed at renewable energy transformation from oil and gas industries.


Living donor liver transplantation should be cautiously considered as initial treatment in recurrent hepatocellular carcinoma within the Milan criteria after curative liver resection.
Insufficient data are available about patient survival following different treatments for recurrent hepatocellular carcinoma (HCC) after primary hepatectomy. We retrospectively investigated the effectiveness of various treatment methods. From 2005 to 2011, 515 hepatectomy patients who developed recurrence within the Milan criteria (MC) were grouped by treatment modality into living donor liver transplantation (LDLT), hepatic re-resection (RR), radiofrequency ablation (RFA), transarterial chemoembolization (TACE), percutaneous ethanol injection (PEI), and combination of TACE and RFA (TACE-RFA) group. Disease-free survival and patient survival after first HCC recurrence were compared according to treatment strategies. TACE (n=230, 44.7%), RFA (n=171, 33.2%), PEI (n=35, 6.8%), RR (n=45, 8.7%), salvage LDLT (n=21, 4.1%), and TACE-RFA (n=13, 2.5%) were all used as the first treatment in recurrent HCC within the MC. The disease-free survival curve from 1st HCC recurrence in the PEI group was lower than in the other groups (P=0.004). The RR, salvage LDLT, and TACE-RFA groups showed good long-term prognosis. The patient survival rate at 3 years after 1st HCC recurrence was 45.2% in TACE, 51.7% in RFA, 39.8% in PEI, 38.2% in RR, 81.4% in salvage LDLT, and 80.8% in the TACE-RFA group. Thus, the patient survival curve in the salvage LDLT and TACE-RFA groups was higher than in the other groups (P<0.001). Long-term outcomes for patients with recurrent HCC within the MC do not differ with the first treatment strategies, except for PEI. Salvage LDLT does not prevent HCC recurrence, but it increases patient survival compared with the other treatment strategies.


General distance geometry three-dimensional receptor model for diverse dihydrofolate reductase inhibitors.
A common three-dimensional receptor model has been formulated for six different classes of rat liver dihydrofolate reductase inhibits using the distance geometry approach. Altogether, 62 molecules of five different classes were used to generate the receptor model, which has 11 attractive site points and 5 repulsive ones. It gave a fit having a correlation coefficient of 0.949 and root mean square (rms) deviation of 0.527. The attractive site points of the model closely correspond to the one we reported earlier. The model successfully predicted the biological data of 33 molecules of 5 different classes, one molecule of which was a member of a new class not included in the original data set. Guidelines are put forth for the synthesis of improved inhibitors.


Capsaicin-sensitive nerve fibres induce epithelial cell proliferation, inflammatory cell immigration and transforming growth factor-alpha expression in the rat colonic mucosa in vivo.
Capsaicin-sensitive nerve fibres protect gastrointestinal mucosa in animal models of mucosal injury by modulation of mucosal blood flow and mucus secretion. The aim of our study was to evaluate the effects of capsaicin-sensitive nerve fibres in rat colonic mucosa on epithelial cell proliferation and transforming growth factor-alpha (TGFalpha) expression, which is important in mucosal defence, protection and repair. Male Wistar rats received either a capsaicin enema with or without giving antagonists to calcitonin-gene-related-peptide (CGRP) or substance P (SP) i.v. immediately prior to the capsaicin enemas; a capsaicin enema after sensory desensitization as described previously; or a vehicle enema. In all experiments, animals received 50 mg/kg BrdU i.v. and were killed at 2, 4, 8, 12, 24 and 48 h after the various treatments. Colonic mucosal specimens were evaluated microscopically for mucosal damage, changes in the numbers of inflammatory cells and BrdU-immunoreactive epithelial cell nuclei. In the same specimens, TGFalpha-mRNA and -protein expression were evaluated by RT-PCR and Western blot analysis using standardized procedures. A significant increase in the number of mucosal inflammatory cells and an increase in BrdU-immunoreactive nuclei were detected following mucosal exposure to capsaicin. A 2-fold increase of TGFalpha mRNA and a 10-fold increase of TGFalpha protein expression were obtained 2-12 h after capsaicin enemas. The effects on the invading number of inflammatory cells and on the increase in BrdU immunoreactive epithelial cell nuclei were significantly reduced by both CGRP and SP antagonists and were abolished in rats previously sensory-desensitized. Capsaicin-sensitive nerve fibres modulate epithelial cell proliferation and TGFalpha expression in colonic mucosa as well as a migration of inflammatory cells into the colonic mucosa. These effects are mediated by the neurotransmitters CGRP and SP.


Capsule endoscopy in the evaluation of gastrointestinal disease.
The small bowel has been a technically difficult area to examine. Indirect modalities such as barium follow-through have the disadvantage of attendant radiation exposure. Capsule endoscopy, a novel wireless method of investigation of the small bowel, has acquired an important role in both adult and paediatric medicine. The clinical utility of capsule endoscopy has rapidly expanded since its approval by the Food & Drug Administration in the USA in 2001. It has developed an established role in adults, in the investigation of obscure gastrointestinal bleeding, small bowel Crohn's disease, complications of coeliac disease and surveillance of polyposis syndromes. Despite a lag in its use in paediatrics, capsule endoscopy offers an accurate and effective means of investigating the small bowel in children. It has opened up new horizons and permitted a noninvasive approach to identifying occult lesions in the small bowel of children when conventional imaging has been unhelpful. This review appraises the current literature to define the clinical indications and practical aspects of capsule endoscopy that are of interest to the paediatrician.


Findings of the International Nosocomial Infection Control Consortium (INICC), Part I: Effectiveness of a multidimensional infection control approach on catheter-associated urinary tract infection rates in pediatric intensive care units of 6 developing countries.
A before-after prospective surveillance study to assess the impact of a multidimensional infection control approach for the reduction of catheter-associated urinary tract infection (CAUTI) rates. Pediatric intensive care units (PICUs) of hospital members of the International Nosocomial Infection Control Consortium (INICC) from 10 cities of the following 6 developing countries: Colombia, El Salvador, India, Mexico, Philippines, and Turkey. PICU inpatients. We performed a prospective active surveillance to determine rates of CAUTI among 3,877 patients hospitalized in 10 PICUs for a total of 27,345 bed-days. The study was divided into a baseline period (phase 1) and an intervention period (phase 2). In phase 1, surveillance was performed without the implementation of the multidimensional approach. In phase 2, we implemented a multidimensional infection control approach that included outcome surveillance, process surveillance, feedback on CAUTI rates, feedback on performance, education, and a bundle of preventive measures. The rates of CAUTI obtained in phase 1 were compared with the rates obtained in phase 2, after interventions were implemented. During the study period, we recorded 8,513 urinary catheter (UC) days, including 1,513 UC-days in phase 1 and 7,000 UC-days in phase 2. In phase 1, the CAUTI rate was 5.9 cases per 1,000 UC-days, and in phase 2, after implementing the multidimensional infection control approach for CAUTI prevention, the rate of CAUTI decreased to 2.6 cases per 1,000 UC-days (relative risk, 0.43 [95% confidence interval, 0.21-1.0]), indicating a rate reduction of 57%. Our findings demonstrated that implementing a multidimensional infection control approach is associated with a significant reduction in the CAUTI rate of PICUs in developing countries.


Atrial Fibrillation Due to Over The Counter Stimulant Drugs in A Young Adult.
The usage of over the counter stimulant drugs and energy drinks is increasing on a day to day basis for various purposes including work, sports and leisure among individuals in all age groups. Multiple formulations are available in the market including pills, liquid capsules and drinks in various flavours. Many of them contain excessively high doses of caffeine along with a variety of stimulant compounds that have multiple effects in different parts of the human body. The consumption of such high amounts of caffeine itself has shown to have caused cardiac arrhythmias in healthy individuals and when it is mixed with a number of stimulant compounds can be associated with a number of adverse effects in the human body. However, the awareness of such life threatening complications associated with these energy drinks does not exist among people who consume it on a day to day basis. We report a case of 25-year-old Caucasian male with no significant past medical history for cardiac diseases, no risk factors for atrial fibrillation, non smoker, occasional alcohol drinker who presents with new onset atrial fibrillation with rapid ventricular response due to the consumption of over the counter stimulant energy capsule which had high doses of caffeine.


Influence of electric dichroism on the temperature-jump relaxation study of proflavine-DNA complexes.
The temperature-jump relaxation kinetics of proflavine-DNA complexes has been reinvestigated with a standard apparatus equipped for absorption detection of plane-polarized light in order to discriminate between chemical relaxation and transient orientation effects. Under low ionic strength conditions (0.015 M Na+), these effects may represent the major contribution to the signal when the T-jump apparatus is used without a polarizer. They have been improperly assigned to chemical relaxation in previous work. The actual relaxation times are smaller than 30 musec at 10 degrees C. Under medium ionic strength conditions (0.2 M Na+) it is shown that: (i) the "instantaneous" change of transmission reported in earlier work (Li, H. J., and Crothers, D. M. (1969), J. Mol. Biol. 39, 461-477; Schmechel, D. E. V., and Crothers, D. M. (1971), Biopolymers 10, 465-480) is due to orientation effects; (ii) an intermediate exists whose absorption spectrum resembles somewhat that of proflavine aggregates on a linear polyanion; (iii) the rate constants for outside binding may be significantly larger than previously reported. The new kinetic data are consistent with a modified mechanism derived from equilibrium studies (Ramstein, J., Hogrel, J. F., Dourlent, M., Leng, M., an Hélène, C. 1973), in Dynamic Aspects of Conformation Changes in Biological Macromolecules, Sadron, C., Ed., Dordrecht, Holland, Reidel Publisher, pp 333-347; Dourlent, M., and Hogrel, J. F. (1976), Biopolymers (in press)), but, however, do not unambiguously prove it. From these studies, it is inferred that orientation effects can perturb relaxation data on systems containing linear polymers in many cases.


[Effects of cisplatin and sodium selenite on transformation and rRNA gene transcription activity of human T lymphocytes].
In order to investigate the effect of sodium selenite on the action of cisplatin inhibiting transformation of human T lymphocytes, explore the influence of cisplatin and sodium selenite on rRNA gene transcription activity of lymphocytes and to explore the relationship between transformation of T cells and rRNA gene transcription activity, cisplatin was administered to the culture of lymphocytes after incubation for 24 hours with three different dosages (0.05, 0.2, and 0.5 mg/L). The culture was also supplemented with sodium selenite (0.05 mg/L) at the beginning of the cell culture or at the same time as cisplatin was administered for different treatment. The slide specimens were prepared using cytogenetical method after the cells were cultured for 72 hours, and then, the changes of the transformation rate of T lymphocytes and frequencies of Ag-NORs that reflect rRNA gene transcription activity were investigated. The results showed that the rate of T lymphocyte transformation in the groups treated with both sodium selenite and cisplatin were significantly increased (p < 0.01) as compared with that in the groups without sodium selenite supplementation and suffering exposures to cisplatin alone at corresponding dose, up to or over the rate of negative control group. There were no significant differences in the ratios of lymphocyte transformation between the groups pre-treated by sodium selenite and the groups treated by both sodium selenite and cisplatin on the condition that the other treatments were the same. There were no remarkable differences (p > 0.05) in the frequencies of Ag-NOR and satellite association among the all groups. This study indicated that sodium selenite supplementation can preclude the inhibition of transformation of T lymphocytes in vitro by cisplatin, regardless the pre-treatment by sodium selenite or co-treatment with cisplatin.