Internet-delivered Cognitive Behavioral Therapy for insomnia in youth with autism spectrum disorder: A pilot study.
Adolescents with ASD often suffer from sleep disorders affecting their development and quality of life. Research concerning psychological treatment of insomnia in this population is scarce. The objective of this pilot study was to examine the feasibility of internet-delivered CBT for insomnia (iCBT-I) and the participants' experiences after completing the treatment. Both quantitative and qualitative methods were used. Six adolescents with ASD and insomnia, aged 13 to 17, participated in the study. The results of the qualitative investigation showed general satisfaction with the iCBT-I. The participants experienced both better sleep and insights into their sleep patterns. Thematic analysis revealed five themes: experience of the structure of the treatment, treatment content, experienced outcomes, experienced difficulties, and suggested improvements. The results indicate the need for additional support for some participants and suggest distinct recommendations for further studies. The quantitative investigation showed large reductions in insomnia symptoms indicating the feasibility of the treatment in this population. The findings suggest promising results, but more studies are needed to define the efficacy of iCBT-I for adolescents with ASD.


Selective cytokine-inducing effects of low dose Echinacea.
Echinacea purpurea is a widely used plant immunomodulator with a selective immunomodulatory effect depending on the dilution of the initial preparation. In low doses, it causes selective induction of pro- and anti-inflammatory cytokines. The results recommend this preparation in a wide range of concentrations for adequate correction of the immune system work aimed at restoring the Th1/Th2 balance in various diseases.


Trends in osteoporosis and low bone mass in older US adults, 2005-2006 through 2013-2014.
This study examined trends in osteoporosis and low bone mass in older US adults between 2005 and 2014 using bone mineral density (BMD) data from the National Health and Nutrition Examination Survey (NHANES). Osteoporosis and low bone mass appear to have increased at the femur neck but not at the lumbar spine during this period. Recent preliminary data from Medicare suggest that the decline in hip fracture incidence among older US adults may have plateaued in 2013-2014, but comparable data on BMD trends for this time period are currently lacking. This study examined trends in the prevalence of osteoporosis and low bone mass since 2005 using BMD data from NHANES. The present study also updated prevalence estimates to 2013-2014 and included estimates for non-Hispanic Asians. Femur neck and lumbar spine BMD by DXA were available for 7954 adults aged 50 years and older from four NHANES survey cycles between 2005-2006 and 2013-2014. Significant trends (quadratic or linear) were observed for the femur neck (mean T-score and osteoporosis in both sexes; low bone mass in women) but not for the lumbar spine. The trend in femur neck status was somewhat U-shaped, with prevalences being most consistently significantly higher (by 1.1-6.6 percentage points) in 2013-2014 than 2007-2008. Adjusting for changes in body mass index, smoking, milk intake, and physician's diagnosis of osteoporosis between surveys did not change femur neck trends. In 2013-2014, the percent of older adults with osteoporosis was 6% at the femur neck, 8% at the lumbar spine, and 11% at either site. There was some evidence of a decline in femur neck BMD between 2005-2006 and 2013-2014, but not in lumbar spine BMD. Changes in the risk factors that could be examined did not explain the femur neck BMD trends.


[Carcinoembryonic antigen (CEA) in patients with lung cancer: correlation with tumour extent and response to treatment (author's transl)].
Carcinoembryonic antigen (CEA) was determined at the time of diagnosis in 90 patients with lung cancer. CEA levels were elevated in 47 (52%). High CEA levels were often associated with the presence of metastases. Serial CEA determinations in 40 patients, before and after radiotherapy and chemotherapy, revealed that patients who responded to treatment had a decreased CEA level, whereas those with progressive tumour growth had increased ones. CEA assay may, therefore, be useful in detecting metastases and in helping to assess the effect of treatment in patients with lung cancer.


In vitro demineralization prevention by fluoride and silver nanoparticles when applied to sound enamel and enamel caries-like lesions of varying severities.
To investigate the effect of fluoride and silver nanoparticles on the prevention of in vitro demineralization of sound enamel and enamel caries-like lesions of varying severities. Caries-like lesions of different severities (1/6/15 days) were created in bovine enamel specimens. One group remained sound. All specimens were demineralized again using a partially saturated acetic acid solution. Mimicking the intra-oral retention of fluoride and silver in vitro, this solution was supplemented with fluoride (0/1/10 ppm) and/or silver nanoparticles (0/10 ppm) in a factorial design. Changes in lesion depth (ΔL) and integrated mineral loss (ΔΔZ) were evaluated by digital transverse microradiography. Data was analyzed using three-way ANOVA. Lesion severity significantly affected ΔΔZ and ΔL, after no treatment and after the treatment of fluoride and silver independently (p = 0.012 and p = 0.037, respectively). Fluoride and the fluoride × lesion severity interaction were shown to be significant (p < 0.001) on ΔΔZ and ΔL. Silver nanoparticles significantly affected ΔΔZ (p = 0.041), but not ΔL (p = 0.15). The silver nanoparticles × lesion severity interaction was significant for ΔΔZ and ΔL (p = 0.032 and p = 0.024, respectively). No interaction was observed for ΔΔZ and ΔL between fluoride and silver (p = 0.962 and p = 0.971, respectively) as well as lesion severity and the use of fluoride and silver combined (p = 0.722 and p = 0.158, respectively). Fluoride and silver nanoparticles had a significant effect on the prevention of in vitro demineralization of sound enamel and enamel caries-like lesions of varying severities. Fluoride and silver nanoparticles may potentially allow for more tailored caries prevention.


Identification of Salmonella Typhimurium-specific DNA aptamers developed using whole-cell SELEX and FACS analysis.
Conventional methods for detection of infective organisms, such as Salmonella, are complicated and require multiple steps, and the need for rapid detection has increased. Biosensors show great potential for rapid detection of pathogens. In turn, aptamers have great potential for biosensor assay development, given their small size, ease of synthesis and labeling, lack of immunogenicity, a lower cost of production than antibodies, and high target specificity. In this study, ssDNA aptamers specific to Salmonella Typhimurium were obtained by a whole bacterium-based systematic evolution of ligands by exponential enrichment (SELEX) procedure and applied to probing S. Typhimurium. After 10 rounds of selection with S. Typhimurium as the target and Salmonella Enteritidis, Escherichia coli and Staphylococcus aureus as counter targets, the highly enriched oligonucleic acid pool was sorted using flow cytometry. In total, 12 aptamer candidates from different families were sequenced and grouped. Fluorescent analysis demonstrated that aptamer C4 had particularly high binding affinity and selectivity; this aptamer was then further characterized.


Noninvasive Imaging of Fluorescent Reporters in Small Rodent Models Using Fluorescence Molecular Tomography.
The capacity to combine noninvasive whole animal imaging of genetic reporters and exogenously added probes in a single animal makes fluorescence imaging a powerful tool for investigating molecular events in live animals in preclinical research. However, the adsorption and diffraction properties of light passing through tissues mean that the choice of reporters, models, and imaging systems needs to be carefully considered. Here, we describe approaches to design and run experiments incorporating noninvasive whole animal fluorescence imaging into small animal imaging studies.


Developmental changes of Islet-1 and its co-localization with pituitary hormones in the pituitary gland of chick embryo by immunohistochemistry.
Although Islet-1 expression in the pituitary gland of early mouse embryo has been previously described, there are no reports concerning the correlation of Islet-1 expression with lineage restrictions in cell types at the later stages of pituitary development. The role of Islet-1 in chickens is also unknown. The purpose of this study was to follow, by using immunohistochemistry, the ontogeny of pituitary Islet-1 and the various cell types that contain Islet-1 throughout chick embryo development. A few Islet-1-immunopositive (Islet-1(+)) cells were first detected in the pituitary primordium in two out of six embryos at embryonic day 5.5 (E5.5), most of the Islet-1(+) cells being ventrally located. As development progressed, many more Islet-1(+) cells were observed throughout the pars distalis. The relative percentage of Islet-1(+) cells amongst the total Rathke's pouch cells was 4.4% at E6.5. This increased significantly, reaching 11.1% by E10.5, followed by no significant change until hatching. Dual immunohistochemistry showed that adrenocorticotrophs, somatotrophs and lactotrophs did not express Islet-1. The cellular types expressing Islet-1 included luteinizing-hormone-positive (LH(+)) gonadotrophs and thyroid-stimulating-hormone-positive (TSH(+)) thyrotrophs. The cells co-expressing LH and Islet-1 were initially detected at E6.5, the proportion of LH(+) cells possessing Islet-1 being about 4%; this increased to 63% at E14.5, followed by no significant changes until hatching. TSH and Islet-1 co-localized cells were first observed at E10.5, with about 37% TSH(+) cell expressing Islet-1; this increased to about 50% by E16.5, after which there was no evident change until hatching. These results suggest that Islet-1 is involved in determining the cell lineages, proliferation, differentiation and maintenance of hormone-secreting functions of pituitary gonadotrophs and thyrotrophs of chick embryo.


Vesical neck closure versus balloon catheter in suprapubic prostatectomy: a controlled clinical trial.
In a randomized trial comprising 102 cases of suprapubic prostatectomy a modified Hryntschak technique of vesical neck closure was compared to the balloon compression method. There were no statistically significant differences between the 2 groups in operative and postoperative blood loss, duration of operation or postoperative hospital stay. In the vesical neck closure group compared to the balloon catheter group more patients experienced catheters falling out prematurely, as well as more postoperative strictures and more cases of incontinence at followup 1 year later. Our data do not justify the adoption of the vesical neck closure technique in suprapubic prostatectomy.


[X-ray diagnosis for chronic osteomyelitis (author's transl)].
The basic programme of X-ray diagnosis consists of pictures in the a-p and lateral position in comparison with the healthy side. Tomography and toposcintigraphy give further information and can be completed by fistulography. Complementary information is possible by the use of ultrasonography.


Lateral cervical curve changes in patients receiving chiropractic care after a motor vehicle collision: a retrospective case series.
To examine radiological changes of the lateral cervical curve in patients who received chiropractic care after motor vehicle collisions. A retrospective case series. Thirteen patients who had received chiropractic care after motor vehicle collisions were selected from a northeastern Washington chiropractic office. Patients had a lateral cervical radiograph taken prior to the initiation of chiropractic treatment and a comparative lateral cervical radiograph subsequent to a period of care. Cases were included if they met the previously stated criteria and if the radiographs were of sufficient quality to determine the lateral cervical curve from C2-C7. Adjustments rendered using an Activator Adjusting Instrument. Eleven of the subjects were also instructed to perform stretching exercises. Compared to the initial lateral cervical radiograph, the comparative radiographs demonstrated a mean increase in cervical lordosis between C2 and C7 of 6.4 degrees (SD = 8.2). The standard error estimate of the population was 2.3 degrees, with a 95% confidence interval of 1.4 degrees to 11.4 degrees. There was a mean increase in the cervical lordosis of 6.4 degrees (SD = 8.2). The standard error estimate of the population was 2.3 degrees, with a 95% confidence interval of 1.4 degrees to 11.4 degrees. We were not able to determine the individual effects of adjustment, stretching, and natural progression of the condition. The results suggest that further study of this phenomenon should be undertaken.


20(S)-Ginsenoside Rh2 displays efficacy against T-cell acute lymphoblastic leukemia through the PI3K/Akt/mTOR signal pathway.
T-cell acute lymphoblastic leukemia (T-ALL) is a kind of aggressive hematological cancer, and the PI3K/Akt/mTOR signaling pathway is activated in most patients with T-ALL and responsible for poor prognosis. 20(S)-Ginsenoside Rh2 (20(S)-GRh2) is a major active compound extracted from ginseng, which exhibits anti-cancer effects. However, the underlying anticancer mechanisms of 20(S)-GRh2 targeting the PI3K/Akt/mTOR pathway in T-ALL have not been explored. Cell growth and cell cycle were determined to investigate the effect of 20(S)-GRh2 on ALL cells. PI3K/Akt/mTOR pathway-related proteins were detected in 20(S)-GRh2-treated Jurkat cells by immunoblotting. Antitumor effect of 20(S)-GRh2 against T-ALL was investigated in xenograft mice. The mechanisms of 20(S)-GRh2 against T-ALL were examined by cell proliferation, apoptosis, and autophagy. In the present study, the results showed that 20(S)-GRh2 decreased cell growth and arrested cell cycle at the G1 phase in ALL cells. 20(S)-GRh2 induced apoptosis through enhancing reactive oxygen species generation and upregulating apoptosis-related proteins. 20(S)-GRh2 significantly elevated the levels of pEGFP-LC3 and autophagy-related proteins in Jurkat cells. Furthermore, the PI3K/Akt/mTOR signaling pathway was effectively blocked by 20(S)-GRh2. 20(S)-GRh2 suppressed cell proliferation and promoted apoptosis and autophagy by suppressing the PI3K/Akt/mTOR pathway in Jurkat cells. Finally, 20(S)-GRh2 alleviated symptoms of leukemia and reduced the number of white blood cells and CD3 staining in the spleen of xenograft mice, indicating antitumor effects against T-ALL in vivo. These findings indicate that 20(S)-GRh2 exhibits beneficial effects against T-ALL through the PI3K/Akt/mTOR pathway and could be a natural product of novel target for T-ALL therapy.


Cerebral palsy and placental infection: a case-cohort study.
BACKGROUND: The association between cerebral palsy in very preterm infants and clinical, histopathologic and microbiological indicators of chorioamnionitis, including the identification of specific micro-organisms in the placenta, was evaluated in a case-cohort study. METHODS: Children with a diagnosis of cerebral palsy at five years of age were identified from amongst participants in a long-term follow-up program of preterm infants. The comparison group was a subcohort of infants randomly selected from all infants enrolled in the program. The placentas were examined histopathologically for chorioamnionitis and funisitis, and the chorioamnionic interface was aseptically swabbed and comprehensively cultured for aerobic and anaerobic bacteria, yeast and genital mycoplasmas. Associations between obstetric and demographic variables, indicators of chorioamnionitis and cerebral palsy status were examined by univariate analysis. RESULTS: Eighty-two infants with cerebral palsy were compared with the subcohort of 207 infants. Threatened preterm labor was nearly twice as common among the cases as in the subcohort (p < 0.01). Recorded clinical choroamnionitis was similar in the two groups and there was no difference in histopathologic evidence of infection between the two groups. E. coli was cultured from the placenta in 6/30 (20%) of cases as compared with 4/85 (5%) of subcohort (p = 0.01). Group B Streptococcus was more frequent among the cases, but the difference was not statistically significant. CONCLUSIONS: The association between E. coli in the chorioamnion and cerebral palsy in preterm infants identified in this study requires confirmation in larger multicenter studies which include microbiological study of placentas.


A modified method of vascular access system implantation using the subclavian vein.
A new method of implanting vascular access systems using the Arrow Percutaneous Sheath Introducer Kit is described. The surgeon who frequently inserts these systems may find this technique to be a useful alternative in those patients in whom cutdowns were unsuccessful or in whom the percutaneous technique with a peel-away sheath is found to be difficult.


Acellular Dermal Matrix, Osseoplastic Flap, and Transnasal Endoscopic Approach for Frontal Mucocele.
The primary objective of this study is to suggest the use of acellular dermal matrix through an osteoplastic flap and transnasal endoscopic treatment for the management of frontal mucoceles. The secondary objective is to propose the characteristics to choose this approach. A retrospective cohort study was carried out on patients with frontal mucoceles of different etiologies where an osteoplastic flap was made to address the sinus and subsequently obliterated with acellular dermal matrix. A cohort of 11 patients were included in the study, 6 (67%) were female and 5 (56%) were male, with a mean age of 56 years (range 35-71). The majority of patients (73%) with a history of trauma and all the patients were treated with frontal osteoplastic flap and obliteration with acellular dermal matrix. No evidence of recurrence in a follow-up period with a mean of 18 months and a low rate of complications. The frontal osteoplastic flap and obliteration with acellular dermal matrix is a simple and safe technique to perform with low morbidity. Also, an orbital reconstruction can be performed simultaneously.


Diagnostic yield of computed tomography-guided coaxial core biopsy of undetermined masses in the free retroperitoneal space: single-center experience.
The purpose of this study was to evaluate the diagnostic yield of core biopsy in coaxial technique under guidance of computed tomography (CT) for retroperitoneal masses. We performed a retrospective analysis of CT-guided coaxial core biopsies of undetermined masses in the non-organ-bound retroperitoneal space in 49 patients. In 37 cases a 15-G guidance needle with a 16-G semiautomated core biopsy system, and in 12 cases a 16-G guidance needle with an 18-G biopsy system, was used. All biopsies were technically successful. A small hematoma was seen in one case, but no relevant complication occurred. With the coaxial technique, up to 4 specimens were obtained from each lesion (mean, 2.8). Diagnostic accuracy in differentiation between malignant and benign diseases was 95.9%. A specific histological diagnosis could be established in 39 of 42 malignant lesions (92.9%). Correct subtyping of malignant lymphoma according to the WHO classification was possible in 87.0%. Benign lesions were correctly identified in seven cases, although a specific diagnosis could only be made in conjunction with clinical and radiological information. In conclusion, CT-guided coaxial core biopsy provides safe and accurate diagnosis of retroperitoneal masses. A specific histological diagnosis, which is essential for choosing the appropriate therapy, could be established in most cases of malignancy.


A novel interaction of CLN3 with nonmuscle myosin-IIB and defects in cell motility of Cln3(-/-) cells.
Juvenile neuronal ceroid lipofuscinosis (JNCL) is a pediatric lysosomal storage disorder characterized by accumulation of autofluorescent storage material and neurodegeneration, which result from mutations in CLN3. The function of CLN3, a lysosomal membrane protein, is currently unknown. We report that CLN3 interacts with cytoskeleton-associated nonmuscle myosin-IIB. Both CLN3 and myosin-IIB are ubiquitously expressed, yet mutations in either produce dramatic consequences in the CNS such as neurodegeneration in JNCL patients and Cln3(-/-) mouse models, or developmental deficiencies in Myh10(-/-) mice, respectively. A scratch assay revealed a migration defect associated with Cln3(-/-) cells. Inhibition of nonmuscle myosin-II with blebbistatin in WT cells resulted in a phenotype that mimics the Cln3(-/-) migration defect. Moreover, inhibiting lysosome function by treating cells with chloroquine exacerbated the migration defect in Cln3(-/-). Cln3(-/-) cells traversing a transwell filter under gradient trophic factor conditions displayed altered migration, further linking lysosomal function and cell migration. The myosin-IIB distribution in Cln3(-/-) cells is elongated, indicating a cytoskeleton defect caused by the loss of CLN3. In summary, cells lacking CLN3 have defects that suggest altered myosin-IIB activity, supporting a functional and physical interaction between CLN3 and myosin-IIB. We propose that the migration defect in Cln3(-/-) results, in part, from the loss of the CLN3-myosin-IIB interaction.


Evaluating deciduous tree leaves as biomonitors for ambient particulate matter pollution in Pittsburgh, PA, USA.
Fine particulate matter (PM2.5) air pollution varies spatially and temporally in concentration and composition and has been shown to cause or exacerbate adverse effects on human and ecological health. Biomonitoring using airborne tree leaf deposition as a proxy for particulate matter (PM) pollution has been explored using a variety of study designs, tree species, sampling strategies, and analytical methods. In the USA, relatively few have applied these methods using co-located fine particulate measurements for comparison and relying on one tree species with extensive spatial coverage, to capture spatial variation in ambient air pollution across an urban area. Here, we evaluate the utility of this approach, using a spatial saturation design and pairing tree leaf samples with filter-based PM2.5 across Pittsburgh, Pennsylvania, with the goal of distinguishing mobile and stationary sources using PM2.5 composition. Co-located filter and leaf-based measurements revealed some significant associations with traffic and roadway proximity indicators. We compared filter and leaf samples with differing protection from the elements (e.g., meteorology) and PM collection time, which may account for some variance in PM source and/or particle size capture between samples. To our knowledge, this study is among the first to use deciduous tree leaves from a single tree species as biomonitors for urban PM2.5 pollution in the northeastern USA.


Effect of hypertension on the closing dynamics and Lagrangian blood damage index measure of the b-datum regurgitant jet in a bileaflet mechanical heart valve.
We hypothesize that the formation of the closing vortex and subsequent b-datum regurgitation jet in bileaflet mechanical heart valves is governed by the magnitude of the driving mean aortic pressure (MAP), and that this sensitivity does impact the blood damage index (BDI) corresponding to platelet activation and lysis. High spatial resolution time resolved (1 kHz) as well as phase locked particle image velocimetry techniques captured the dynamic leaflet closure and regurgitation jet of a model 25 mm St. Jude Medical BMHV. Cell trajectories were estimated using Lagrangian particle tracking analysis while the leaflet kinematics was quantified by tracking the leaflet tip-position throughout closure. The non-principal as well as principal shear stress loading histories along each cell trajectory revealed BDI for platelet activation and lysis as a function of cell initial position, release time-point, and blood pressure. Results show that the leaflet closing time reduces by roughly 10 ms, in response to an increase in MAP by 40 mmHg. We report that higher MAP leads to a stronger b-datum vortex and jet formation. Platelet activation BDI lowers with a higher MAP due to reduction in exposure times despite an increase in principal shear stress experienced. Platelet lysis BDI however increases with higher MAP. Maximum BDI may occur for cells initially in the b-datum zone during the onset of leaflet closure. Our results provide a better understanding of BDI of the regurgitant b-datum jet and sheds light on the potential importance of blood damage testing under hypertensive conditions.


Development of antioxidant and smart NH3 -sensing packaging film by incorporating bilirubin into κ-carrageenan matrix.
Active and smart food packaging based on natural polymers and pH-sensitive dyes as indicators has attracted widespread attention. In the present study, an antioxidant and amine-response color indicator film was developed by incorporating bilirubin (BIL) into the κ-carrageenan (Carr) matrix. It was found that the introduction of BIL had no effect on the crystal/chemical structure, water sensitivity and mechanical performance of the Carr-based films. However, the barrier properties to light and the thermal stability were significantly improved after the addition BIL. The Carr/BIL composite films exhibited excellent 1,1-diphenyl-2-picryl-hydrazyl (i.e. DPPH)/2,2'-azino-bis-(3-ethylbenzothiazoline-6-sulfonic acid) (i.e. ABTS) free radical scavenging abilities and color responsiveness to different concentrations of ammonia. The application assay reflected that the Carr/BIL0.0075 film was effective in delaying the oxidative deterioration of shrimp during storage and realizing the color response of its freshness through the change of b* value. Active and smart packaging films were successfully prepared by incorporating different contents of BIL into the Carr matrix. The present study helps to further encourage the design and development of a multi-functional packaging material. © 2023 Society of Chemical Industry.


Switch between large hand-over-hand and small inchworm-like steps in myosin VI.
Many biological motor molecules move within cells using stepsizes predictable from their structures. Myosin VI, however, has much larger and more broadly distributed stepsizes than those predicted from its short lever arms. We explain the discrepancy by monitoring Qdots and gold nanoparticles attached to the myosin-VI motor domains using high-sensitivity nanoimaging. The large stepsizes were attributed to an extended and relatively rigid lever arm; their variability to two stepsizes, one large (72 nm) and one small (44 nm). These results suggest that there exist two tilt angles during myosin-VI stepping, which correspond to the pre- and postpowerstroke states and regulate the leading head. The large steps are consistent with the previously reported hand-over-hand mechanism, while the small steps follow an inchworm-like mechanism and increase in frequency with ADP. Switching between these two mechanisms in a strain-sensitive, ADP-dependent manner allows myosin VI to fulfill its multiple cellular tasks including vesicle transport and membrane anchoring.


The Emergency Department Systolic Blood Pressure Relationship After Traumatic Brain Injury.
Blood pressure alterations in patients with traumatic brain injury (TBI) have been shown to be associated with increased mortality. However, there is paucity of data describing the optimal emergency department (ED) systolic blood pressure (SBP) target during the initial evaluation. The aim of our study was to assess the association between SBP on presentation and mortality in patients with TBI. We performed a retrospective (2015-2016) review of the American College of Surgeons Trauma Quality Improvement Program database and included all adult (age ≥18y) trauma patients who had TBI on presentation. The outcome measure was in-hospital mortality at different ED-SBP values. A subanalysis by age and TBI severity in accordance with the Glasgow Coma Scale (GCS) was performed (mild (GCS ≥13), moderate (GCS 9-12), and severe (≤8)). Multivariate logistic regression analysis was performed. A total of 94,411 adult trauma patients with TBI were included. Mean age was 59 ± 21y, 62% were male, and median GCS was 15 [14-15]. Mean SBP was 147 ± 28 mmHg, and overall mortality was 8.6%. The lowest rate of mortality was noticed at ED SBP between 110 and 149 mmHg, whereas the highest mortality was at admission SBP <90 mmHg and SBP >190 mmHg. On regression analysis, SBP between 130 and 149 mmHg (odds ratio = 0.92; P = 0.68) was not associated with increased odds of mortality relative to SBP between 110 and 129 mmHg. On subanalysis based on severity of TBI (mild 80.9%, moderate 5.3%, and severe 13.8%), patients with SBP between 110 and 149 mmHg were less likely to die across all TBI groups. The optimal ED-SBP range for patients with TBI seems to be age and severity dependent. The optimum range might guide clinicians in developing resuscitation protocols for managing patients with TBI. Level III Prognostic.


The effects of task sequence on examinee performance.
If the sequence of administration of encounters in performance-based examinations has an appreciable impact on examinee performance, the validity of any associated assessment decisions could be compromised. The purpose of this article was to determine if the order in which encounters occurred in a multistation standardized patient assessment had an effect on examinee performance and, if so, could this be explained by examinee experience and familiarity with the assessment. Analysis of the scores of over 11,000 examinees who took a 10-station clinical skills assessment was performed to determine trends across the cases. The results showed that administration sequence does have significant, albeit small, impact on examinee performance. In general, examinees perform slightly better as they proceed through the assessment, especially in the first few encounters. The possible reasons for this effect were difficult to establish, but it is likely that comfort with the examination format plays a significant role. For a given assessment, all examinees saw the same cases in a fixed sequence. Therefore, as long as performance gains are relatively small and consistent, it is unlikely that sequence effects compromised the fairness of the assessment.


Ethnobotanical Study.
Ethnobotany is the study of interrelationships between human cultures and plants, animals, and other organisms in their environment. It also creates an awareness of the link between biodiversity and cultural diversity. From the beginning of civilization, people have been using plants for various purposes like food, shelter, medicines, etc. Ethnobotanists play a key role in exploring these kinds of information from indigenous people which creates a gateway for formulating a novel drug. The content in this chapter deals with these aspects in an approachable manner.


Very early onset inflammatory bowel disease in a South Asian country where inflammatory bowel disease is emerging: a distinct clinical phenotype from later onset disease.
Information on pediatric inflammatory bowel disease (PIBD) and very early onset IBD (VEOIBD) are sparse in India, where IBD is emerging. We aimed to evaluate characteristics of VEOIBD and later onset PIBD (LO-PIBD) in India. We performed retrospective analysis of a large, prospectively maintained IBD registry. PIBD was divided in to VEOIBD ( < 6 years) and LO-PIBD (6-17 years). Demographic data, disease characteristics and treatment were compared between the PIBD groups and with other Asian/Western studies as well as the adult patients of the registry. Of 3,752 IBD patients, 292 (7.8%) had PIBD (0-17 years) (175 Crohn's disease [CD], 113 ulcerative colitis [UC], 4 IBD-undifferentiated; 22 VEOIBD [7.5%], and 270 LO-PIBD [92.5%]). VEOIBD patients had more severe disease compared to LO-PIBD in both UC (P= 0.003) and CD (P< 0.001). Familial IBD was more common in VEOIBD (13.6%) compared to LO-PIBD (9.2%). Ileal disease (L1) was an independent risk factor for diagnostic delay in pediatric CD. Diagnostic delay ( > 6 months) was significantly lower in VEOIBD (40.9%) than in LO-PIBD (78.8%) (P< 0.001). Compared to other Asian and Western studies, extensive UC (72.5%) and complicated CD (stricturing/penetrating: 42.7%) were relatively more common. Perianal CD was relatively less frequent (7.4%). PIBD had a significantly higher number of complicated and ileal CD and extensive UC comparison to adult cohort of the registry. VEOIBD has more aggressive phenotype than LO-PIBD. Disease appears distinct from other Asian and Western studies and adult onset disease, with more complicated CD and extensive UC.


The Association Between Upper Disorders and Psychological Well-Being and its Implication in Text Neck Syndrome: A Systematic Review.
Non-specific/chronic musculoskeletal disorder in neck, head or low back (that we called Upper Disorders; UD) are widely common health problem in high-income, urban, and industrialized countries, especially for sedentary people who use electronic devices. This systematic review aims to analyse the association between UD and psychological disease. The database searches were conducted in 8 different databases, using relevant keywords. According to PRISMA Statements, full-text peer-reviewed articles in English which analysed the association between UD and indicators of psychological disease (i.e., mood disturbance, anxiety, depression, stress, social support, and alexithymia) in non-clinical sample were included. Of 8798 abstracts and titles, 10 full-text papers were included. The overall results showed a strong association between UD and mood disturbance, anxiety, depression, stress, alexithymia, and low social support. Thus, high levels of UD were associated with high levels of psychological disease. The results supported the assessment of physical and psychological symptoms in a holistic perspective. Their implications in terms of holistic care and text neck syndrome were discussed.


Sexually transmitted infections and adverse pregnancy outcomes among women attending inner city public sexually transmitted diseases clinics.
Studies in antenatal care clinics suggest that lower genital tract infections (LGTI) may be associated with adverse pregnancy outcomes (APO). We sought to characterize antenatal care patterns and determine whether LGTI are independently associated with preterm birth and/or low-birth weight among a high-risk public sexually transmitted diseases (STD) clinic population. Electronic STD clinic medical records and state birth records were matched for 730 pregnant women age 13 to 49 tested for 5 treatable LGTI (bacterial vaginosis, chlamydia, gonorrhea, early syphilis, and trichomoniasis) in a case-control analysis. Cases were women with preterm and/or low-birth weight newborns; controls were women without APO. The association between LGTI and APO was assessed using logistic regression. Although pregnant women attending STD clinics reported high risk behaviors and were found to have high rates of LGTI (55%), most of these women were engaged in antenatal care (85%). Of the pregnant women, 22% experienced an APO (7% preterm birth, 4% low birth weight, and 12% preterm birth and low birth weight). In multivariate analyses, chlamydia was associated with low-birth weight (adjusted odds ratio [aOR]: 2.07, 95% confidence interval [CI]: 1.01-4.24), and gonorrhea was associated with preterm birth (aOR: 2.01, 95% CI: 1.02-3.97), particularly when diagnosed during the first trimester (aOR: 2.95, 95% CI: 1.30-6.70). Our findings confirm the association of some LGTI with APO and suggest that timing of LGTI screening may affect outcomes. STD clinic visits represent a critical opportunity to target interventions aimed at improving pregnancy outcomes.


miR-16-5p/PDK4-Mediated Metabolic Reprogramming Is Involved in Chemoresistance of Cervical Cancer.
Cervical cancer is one of the most prevalent malignancies in women worldwide. Therefore, investigation about molecular pathogenesis and related therapy targets of cervical cancer is an emergency. The molecular mechanisms responsible for the chemoresistance of cervical cancer were investigated by the use of doxorubicin (Dox)-resistant HeLa/Dox and SiHa/Dox cells. Our data showed that chemoresistant cells exhibited significantly higher glucose consumption, lactate production rate, and ATP levels than that of their parental cells. Among metabolic and glycolytic related genes, the expression of PDK4 was upregulated in Dox-resistant cells. Knockdown of PDK4 can decrease glucose consumption, lactate production rate, and ATP levels and further sensitize resistant cervical cancer cells to Dox treatment. By screening microRNAs (miRNAs), which can regulate expression of PDK4, we found that miR-16-5p was downregulated in chemoresistant cells. Overexpression of miR-16-5p can decrease the expression of PDK4 and sensitize the resistant cells to Dox treatment. Xenograft models confirmed that knockdown of PDK4 can increase chemotherapy efficiency for in vivo tumor growth. Collectively, our data suggested that miR-16-5p/PDK4-mediated metabolic reprogramming is involved in chemoresistance of cervical cancer.


Evaluation of photoacoustic infrared spectroscopy for simultaneous measurement of N2 O and CO2 gas concentrations and fluxes at the soil surface.
Simultaneous measurement of N2 O and CO2 flux at the soil surface with photoacoustic infrared spectroscopy (PAS) is gaining popularity due to portability, low maintenance, and ease-of-operation. However, the ability of PAS to measure N2 O with accuracy and precision similar to gas chromatography (GC) is uncertain due to overlap in N2 O, CO2 , and H2 O absorbance spectra combined with the large range in analyte concentrations. We tested the ability of six PAS units to simultaneously measure N2 O and CO2 gas concentrations and fluxes with accuracy and precision similar to two GC units. We also evaluated H2 O vapor and CO2 interferences with N2 O measurement. The accuracy and precision of standard gas concentration measurements with PAS and GC were similar. High water vapor (~26 600 ppm) and CO2 concentrations (~4500 ppm) did not interfere with N2 O measurement across the concentration range typically observed in static flux chambers at the soil surface (~0.5-3.0 ppm N2 O). On average, N2 O fluxes measured with the six PAS were 4.7% higher than one GC and 9.9% lower than the second GC.


Agriculture increases the bioavailability of silicon, a beneficial element for crop, in temperate soils.
Crops may take benefits from silicon (Si) uptake in soil. Plant available Si (PAS) can be affected by natural weathering processes or by anthropogenic forces such as agriculture. The soil parameters that control the pool of PAS are still poorly documented, particularly in temperate climates. In this study, we documented PAS in France, based on statistical analysis of Si extracted by CaCl2 (SiCaCl2) and topsoil characteristics from an extensive dataset. We showed that cultivation increased SiCaCl2 for soils developed on sediments, that cover 73% of France. This increase is due to liming for non-carbonated soils on sediments that are slightly acidic to acidic when non-cultivated. The analysis performed on non-cultivated soils confirmed that SiCaCl2 increased with the < 2 µm fraction and pH but only for soils with a < 2 µm fraction ranging from 50 to 325 g kg-1. This increase may be explained by the < 2 µm fraction mineralogy, i.e. nature of the clay minerals and iron oxide content. Finally, we suggest that 4% of French soils used for wheat cultivation could be deficient in SiCaCl2.


Leaf water potential, component potentials and relative water content in a xeric grass, Agropyron dasystachyum (Hook.) Scribn.
Leaf water potential (ψ l ), osmotic potential (ψ s ), pressure potential (ψ p , turgor pressure), relative water content (R) and their interrelationships were determined for a xeric grass (Agropyron dasystachyum) found in the grasslands of Canada. Thermocouple psychrometers were used to measure ψ l and ψ s ; ψ p was obtained by subtraction. ψ l dropped from near 0 bars to about-28 bars as R went from 90% to 75%. R greater than 90% was not observed, perhaps because of a systematic error in determination of turgid water content. R remained relatively high in A. dasystachyum, even at low ψ l . The slope of the ψ l -R relationship was similar to other species which are generally considered to be drought tolerant. ψ p as high as 14 bars was observed. Most of the decrease in ψ l was accounted for by a decline in ψ p . The ability of A. dasystachyum to adjust to fluctuating water stress over the growing season is probably as much related to changes in tissue structure and turgor relationships as to simple changes in osmotic potential.


Swept-source optical coherence tomography angiography in serpiginous choroiditis.
To analyse choroidal vascular density of affected and non-affected areas in active and inactive serpiginouschoroiditis (SC) by means of optical coherence tomography angiography (OCT-A). In this cross-sectional and observational study, 22 eyes of 11 patients diagnosed with SC were included. All patients underwent blue-light fundus autofluorescence (spectralis Heidelberg retinalangiography+OCT) and swept-source OCT-A (AngioPlex Elite 9000 SS-OCT, Carl Zeiss Meditech) to analyse qualitative features and choroidal vessel density of areas considered affected, and the inner and the outer border of the lesions. Unaffected areas of otherwise healthy retina have also been studied. All inactive inflammatory lesions were characterised by atrophy of choriocapillaris with an impairment of its detectable flow and greater visibility of choroidal vessels. On the other hand, all active inflammatory lesions showed an area of complete absence of decorrelation signal. The pathological border was characterised by a statistically significant lower choroidal vessel density compared with both the outer border and the unaffected area (0.650±0.113 vs 0.698±0.112, (p<0.001)). Although not statistically significant, vessel density of the outer border of inactive lesions was lower than vessel density of unaffected areas (0.650±0.113 vs 0.698±0.112, p=0.441). Active inflammatory lesions showed an area of complete absence of decorrelation signal at the level of the choriocapillaris and whole choroid. OCT-A represents a new imaging technique that provides useful information about the leading changes of choroidal vascular network in active and inactive lesions of SC.


Identical immunoreactivity of afferents to the rat suprachiasmatic nucleus with antisera against avian pancreatic polypeptide, molluscan cardioexcitatory peptide and neuropeptide Y.
Avian pancreatic polypeptide (APP)-like, molluscan cardioexcitatory peptide (FMRF)-like and neuropeptide Y (NPY)-like immunoreactivities were studied in a secondary visual pathway in rat brain. The cell bodies of this pathway are located in the lateral geniculate nucleus and its terminal plexus is found in the suprachiasmatic hypothalamic nucleus (SCN). The neurons and terminal plexus demonstrated by antiserum to each peptide are identical, and immunoreactivity is blocked by preabsorption of each antiserum with a low concentration of the antigen against which it was raised. Immunoreactivity is also blocked by preabsorption of each antiserum with either NPY or APP. In contrast, APP- and NPY-like immunoreactivities are blocked only partially when these antisera are preabsorbed with concentrations of FMRF as high as 100 microM. Since NPY is the only one of these peptides that has been isolated from mammalian brain, we conclude that NPY is the endogenous CNS peptide produced by neurons of the lateral geniculate-SCN projection.


Binding of ethylenediamine to phosphatidylserine is inhibitory to Na+/K(+)-ATPase.
Covalent linkage of ethylenediamine with the Na+/K(+)-ATPase complex from rabbit kidney outer medulla by the use of the water-soluble carbodiimide, N-ethyl,N'-(3-dimethylaminopropyl)carbodiimide, resulted in a 73% reaction with phosphatidylserine and only 27% with carboxylic groups in the proteic component of the enzyme. Condensation products from the reaction between phosphatidylserine and ethylenediamine, N-(O-phosphatidylseryl)ethylenediamine, N,N'-bis(O-phosphatidylseryl)ethylenediamine and its intermediary product O-phosphatidyl-[N,N'-bis(seryl)]ethylenediamine, were synthesised. Symmetrically substituted ethylenediamine was the most likely condensation product of ethylenediamine with endogenous phosphatidylserine. The synthesised lipids were incorporated in proteoliposomes containing Na+/K(+)-ATPase and only the addition of the phospholipid phosphatidylcholine. The ratio of phospholipid to protein was 52 (w/w). These proteoliposomes were perforated by the addition of 0.5% cholate and both the Na(+)-dependent phosphorylation level and its dependence on Na+, Mg2+ and ATP were measured. Phosphatidylcholine alone increased the half-maximal activation concentration for Na+ ([Na+]0.5) from 0.2 to 1-2 mM, for Mg2+ from 0.1 to 0.8 microM and for ATP from 0.02 to 0.3 microM. The Ki for K+ (in the absence of Na+) was unaffected: 12.8 microM vs. 12.5 microM in the non-reconstituted system. Replacing 10 mol% of phosphatidylcholine by phosphatidylethanolamine: or phosphatidylserine had no significant effect on [Na+]0.5: 1.1 and 0.7 mM, respectively. Replacing 5 mol% phosphatidylcholine by the bis(phosphatidylseryl) substituent of ethylenediamine further increased [Na+]0.5 to 13.7 mM, while half-maximal activation concentrations for Mg2+ and ATP were unaltered. The mono-phosphatidylseryl derivatives of ethylenediamine, each 5 mol%, also increased [Na+]0.5, but to a lesser extent (3.2-3.8 mM). In addition to their competitive effects, the phosphatidylseryl-substituted ethylenediamine compounds exerted a slowly-increasing non-competitive inhibition, not only in phosphorylation, but also in overall ATPase activity, which was reduced, although not abolished, by exogenous protein (bovine serum albumin). A detergent-like action in the usual sense is unlikely since liposomes containing these lipids remained intact. These studies prove that phospholipids are not only required for optimal activity of this transport enzyme, but in excess or in compositions deviating from the normal, may also be inhibitory.


Techno-Economic Assessment and Sensitivity Analysis of Glycerol Valorization to Biofuel Additives via Esterification.
Glycerol is a valuable feedstock, produced in biorefineries as a byproduct of biodiesel production. Esterification of glycerol with acetic acid yields a mixture of mono-, di-, and triacetins. The acetins are commercially important value-added products with a wide range of industrial applications as fuel additives and fine chemicals. Esterification of glycerol to acetins substantially increases the environmental sustainability and economic viability of the biorefinery concept. Among the acetins, diacetin (DA) and triacetin (TA) are considered high-energy-density fuel additives. Herein, we have studied the economic feasibility of a facility producing DA and TA by a two-stage process using 100,000 tons of glycerol per year using Aspen Plus. The capital costs were estimated by Aspen Process Economic Analyzer software. The analysis indicates that the capital costs are 71 M$, while the operating costs are 303 M$/year. The gross profit is 60.5 M$/year, while the NPV of the project is 235 M$ with a payback period of 1.7 years. Sensitivity analysis has indicated that the product price has the most impact on the NPV.


Ability of naloxone to enhance the colonoscopic appearance of normal colon vasculature and colon vascular ectasias.
Colon vascular ectasias are a common cause of lower intestinal bleeding among the elderly. The lesions may be difficult to diagnose at colonoscopy because they are small and their appearance may be influenced by the patient's blood pressure, blood volume, and narcotic sedation during the procedure. The purpose of this study was to determine whether naloxone influenced the appearance of colon vascular ectasias at colonoscopy. One hundred forty-four patients older than 60 years undergoing complete colonoscopy participated in the study. Medications were given in the usual doses. After a 2-minute inspection of the cecum and ascending colon, naloxone was given, followed by another 2-minute observation period. Photographic documentation of areas of interest was obtained before and after administration of naloxone. One hundred fourteen patients (79%) had no ectasias before or after administration of naloxone. Fourteen (9.7%) initially had normal vessels, and the vessels became more prominent; 4 (2.7%) initially had no ectasias, but ectasias later developed. Four patients (2.7%) had ectasias before administration of naloxone that did not change; 8 (5.4%) had ectasias before administration of naloxone that increased in size (3 patients), number (7 patients), or both (2 patients). Naloxone can enhance the appearance of normal colonic vasculature and ectasias. Naloxone is an important adjunctive medication for patients undergoing examinations for lower intestinal bleeding.


Synthesis, structural characterization and in vitro antitumor activity of novel 6-chloro-1,1-dioxo-1,4,2-benzodithiazie derivatives.
A series of nonconventional aminium N-(6-chloro-7-R-1,1-dioxo-1,4,2-benzodithiazin-3-yl)arylsulfonamidates 7-15 have been synthesized by the reactions of 6-chloro-7-R-3-methylthio-1,4,2-benzodithiazine 1,1-dioxides with 4-dimethylaminopyridine or Et(3)N and some arylsulfonamides. The free N-(6-chloro-7-methyl-1,1-dioxo-1,4,2-benzodithiazin-3-yl)benzenesulfonamides 16-18 were obtained by treatment of their aminium salts with H(2)SO(4) in boiling acetic acid. The in vitro antitumor activity of the compounds 9, 11-14 and 16-18 has been tested in the antitumor screening of the National Cancer Institute (NCI), and relationships between structure and antitumor activity are discussed. 4-Dimethylaminopyridinium 4-chloro-N-(6-chloro-7-methyl-1,1-dioxo-1,4,2-benzodithiazin-3-yl)benzenesulfonamidate 9 is the prominent of the compounds due to its remarkable activity (log GI(50)<-8.00, log TGI=-5.50) and selectivity for the leukemia SR cell line. For that reason experimental and theoretical analysis of the geometric and electronic properties of 9 was carried out.


Discovery of a rhamnose utilization pathway and rhamnose-inducible promoters in Pichia pastoris.
The rhamnose utilization pathway in Pichia pastoris has not been clarified although this strain can grow well on rhamnose as a sole carbon source. In this study, four genes, PAS_chr4_0338, PAS_chr4_0339, PAS_chr4_0340, and PAS_chr4_0341, were, for the first time, predicted to be involved in rhamnose metabolism along with the previously identified gene PAS_chr1_4-0075. Moreover, expression of these genes, especially PAS_chr4_0341 and PAS_chr1_4-0075 designated as LRA4 and LRA3, was confirmed to significantly increase and clearly decrease in the presences of rhamnose and glucose, respectively. LRA4 encoding a putative L-2-keto-3-deoxyrhamnonate aldolase, was further confirmed via gene disruption and gene complementation to participate in rhamnose metabolism. Using β-galactosidase and green fluorescent protein as reporters, the promoters of LRA4 and LRA3 performed well in driving efficient production of heterologous proteins. By using food grade rhamnose instead of the toxic compound methanol as the inducer, the two promoters would be excellent candidates for driving the production of food-grade and therapeutically important recombinant proteins.


Effects of the antiestrogen LY 117018 on the modulation by ethinyl estradiol of the metabolism of [1-14C]oleic acid by perfused livers from normal and ovariectomized rats.
Intact female Sprague-Dawley rats (195-249 g) and rats that had been ovariectomized (210-285 g) were injected subcutaneously for 14 days with ethinyl estradiol (15 micrograms/kg), the antiestrogen LY 117018 (500 micrograms/kg), both drugs simultaneously, or the vehicle (sesame oil) alone. Livers were removed and perfused in vitro in a recycling system. The administration of LY 117018 alone did not affect the secretion of triacylglycerol by livers from normal rats but decreased the secretion of triacylglycerol by livers from ovariectomized rats. When the drugs were administered concurrently to either normal or ovariectomized animals, the increase in the concentration of triacylglycerol and the decrease in the concentration of cholesteryl esters in the plasma produced by ethinyl estradiol were prevented. When administered to either intact or ovariectomized rats, ethinyl estradiol alone stimulated the synthesis and secretion of triacylglycerol and cholesteryl esters by perfused livers isolated from these animals. The simultaneous administration of LY 117018 with ethinyl estradiol prevented this stimulation of the hepatic synthesis and secretion of triacylglycerol and cholesteryl esters. The depression of ketogenesis observed with livers from rats administered ethinyl estradiol alone was reversed by concurrent administration of LY 117018. The concurrent administration of the estrogen and antiestrogen did not result, however, in a complete blockade of the estrogen-induced elevation of hepatic triacylglycerol synthesis and depression of ketogenesis. The incorporation of [1-14C]oleic acid into the triacylglycerol and ketone bodies by livers from ovariectomized rats was less than that of livers from normal rats. It is clear that the antiestrogen antagonizes the actions of ethinyl estradiol on hepatic lipid metabolism. Furthermore, the use of the antiestrogen LY 117018 in these experiments allows the probable conclusion that the modulation of hepatic metabolism of fatty acid by estrogen is mediated by conventional estrogenic receptors.


Is surveillance imaging in pediatric patients treated for localized rhabdomyosarcoma useful? The European experience.
After the completion of therapy, patients with localized rhabdomyosarcoma (RMS) are subjected to intensive radiological tumor surveillance. However, the clinical benefit of this surveillance is unclear. This study retrospectively analyzed the value of off-therapy surveillance by comparing the survival of patients in whom relapse was detected by routine imaging (the imaging group) and patients in whom relapse was first suspected by symptoms (the symptom group). This study included patients with relapsed RMS after the completion of therapy for localized RMS who were treated in large pediatric oncology hospitals in France, the United Kingdom, Italy, and the Netherlands and who were enrolled in the International Society of Paediatric Oncology Malignant Mesenchymal Tumor 95 (1995-2004) study, the Italian Paediatric Soft Tissue Sarcoma Committee Rhabdomyosarcoma 96 (1996-2004) study, or the European Paediatric Soft Tissue Sarcoma Study Group Rhabdomyosarcoma 2005 (2005-2013) study. The survival times after relapse were compared with a log-rank test between patients in the imaging group and patients in the symptom group. In total, 199 patients with relapsed RMS were included: 78 patients (39.2%) in the imaging group and 121 patients (60.8%) in the symptom group. The median follow-up time after relapse was 7.4 years (interquartile range, 3.9-11.5 years) for survivors (n = 86); the 3-year postrelapse survival rate was 50% (95% confidence interval [CI], 38%-61%) for the imaging group and 46% (95% CI, 37%-55%) for the symptom group (P = .7). Although systematic routine imaging is the standard of care after RMS therapy, the majority of relapses were detected as a result of clinical symptoms. This study found no survival advantage for patients whose relapse was detected before the emergence of clinical symptoms. These results show that the value of off-therapy surveillance is controversial, particularly because repeated imaging may also entail potential harm.


PKPD and cardiac single cell modeling of a DDI study with a CYP3A4 substrate and itraconazole to quantify the effects on QT interval duration.
Plasma drug concentration and electrocardiogram (ECG) data from a drug-drug interaction (DDI) study employing the metabolic inhibitor itraconazole have been used as part of a prospectively defined pharmacokinetic/pharmacodynamic modelling strategy to quantify the potential for QT interval prolongation from basmisanil, an investigational compound. ECG data were collected on multiple days during repeat dosing treatment regimens, thereby allowing the capture of QT data across a wide range of drug concentrations in each study participant and encompassing both "therapeutic" and "supra-therapeutic" exposures. The data were used to develop a non-linear mixed effect concentration-QT (C-QT) model that differentiated drug-induced QT prolongation from other factors altering QT interval duration. Food effects were accounted by quantitating their influences on the parameters describing the diurnal variation of QT. The final model demonstrated that itraconazole does not cause QT prolongation, while for basmisanil, the 1-sided upper 95% CI of the QT interval at 240 mg (the highest dose tested in ongoing phase 2 studies) with DDI, was below the 10 ms threshold considered to be of clinical significance by regulatory authorities. The empirical modelling was complemented with a human mechanistic cardiac single cell model that was used to simulate the change in action potential duration as a function of drug concentration. The results of the two approaches were in agreement, suggesting that the effect of basmisanil on QT interval duration can be attributed to the effect on hERG alone. The C-QT model for basmisanil can be used to derive the QT interval corrected changes in heart rate (QTc) and thus inform cardiac safety strategy in later development without the need for a separate, dedicated study.


Basic control of reperfusion effectively protects against reperfusion injury in a realistic rodent model of acute limb ischemia.
Reperfusion injury is insufficiently addressed in current clinical management of acute limb ischemia. Controlled reperfusion carries an enormous clinical potential and was tested in a new reality-driven rodent model. Acute hind-limb ischemia was induced in Wistar rats and maintained for 4 hours. Unlike previous tourniquets models, femoral vessels were surgically prepared to facilitate controlled reperfusion and to prevent venous stasis. Rats were randomized into an experimental group (n=7), in which limbs were selectively perfused with a cooled isotone heparin solution at a limited flow rate before blood flow was restored, and a conventional group (n=7; uncontrolled blood reperfusion). Rats were killed 4 hours after blood reperfusion. Nonischemic limbs served as controls. Ischemia/reperfusion injury was significant in both groups; total wet-to-dry ratio was 159+/-44% of normal (P=0.016), whereas muscle viability and contraction force were reduced to 65+/-13% (P=0.016) and 45+/-34% (P=0.045), respectively. Controlled reperfusion, however, attenuated reperfusion injury significantly. Tissue edema was less pronounced (132+/-16% versus 185+/-42%; P=0.011) and muscle viability (74+/-11% versus 57+/-9%; P=0.004) and contraction force (68+/-40% versus 26+/-7%; P=0.045) were better preserved than after uncontrolled reperfusion. Moreover, subsequent blood circulation as assessed by laser Doppler recovered completely after controlled reperfusion but stayed durably impaired after uncontrolled reperfusion (P=0.027). Reperfusion injury was significantly alleviated by basic modifications of the initial reperfusion period in a new in vivo model of acute limb ischemia. With this model, systematic optimizations of according protocols may eventually translate into improved clinical management of acute limb ischemia.


Preoperative oral immunonutrition versus standard preoperative oral diet in well nourished patients undergoing pancreaticoduodenectomy.
Pancreaticoduodenectomy is still associated to high morbility, especially due to pancreatic surgery related and infectious complications: many risk factors have already been advocated. Aim of this study is to evaluate the role of preoperative oral immunonutrition in well nourished patients scheduled for pancreaticoduodenectomy. From February 2014 to June 2015, 54 well nourished patients undergoing pancreaticoduodenectomy were enrolled for 5 days preoperative oral immunonutrition. A series of consecutive patients submitted to the same intervention in the same department, with preoperative standard oral diet, was matched 1:1. For analysis demographic, pathological and surgical variables were considered. Mortality rate, overall postoperative morbility, pancreatic fistula, post pancreatectomy haemorrhage, delayed gastric emptying, infectious complications and length of hospital stay were described for each groups. Chi squared test, Fisher's Exact test and Student's T test were used for comparison. Differences were considered statistically significant at p < 0.05. Statistics was performed using a freeware Microsoft Excel (®) based program and SPSS v 10.00. No statistical differences in term of mortality (2.1% in each groups) and overall morbility rate (41.6% vs 47.9%) occurred between the groups as well as for pancreatic surgery related complications. Conversely, statistical differences were found for infectious complications (22.9% vs 43.7%, p = 0.034) and length of hospital stay (18.3 ± 6.8 days vs 21.7 ± 8.3, p = 0.035) in immunonutrition group. Preoperative oral immunonutrition is effective for well nourished patients scheduled for pancreaticoduodenectomy; it helps to reduce the risk of postoperative infectious complications and length of hospital stays.


Exploring cellular senescence in the musculoskeletal system: Any insights for biomarkers discovery?
The locomotor system comprises skeletal muscles and bones with active metabolism and cellular turnover. Chronic locomotor system disorders gradually arising with aging are inversely associated with the correct function of bone and muscles. Senescent cells appear more frequently in advanced ages or pathological conditions, and the accumulation of senescent cells in muscle tissue negatively correlates with muscle regeneration, which is crucial for maintaining strength and preventing frailty. Senescence in the bone microenvironment, osteoblasts, and osteocytes affects bone turnover favoring osteoporosis. It is likely that in response to injury and age-related damage over the lifetime, a subset of niche cells accumulates oxidative stress and DNA damage beyond the threshold that primes the onset of cellular senescence. These senescent cells may acquire resistance to apoptosis that, combined with the weakened immune system, results in impaired clearance of senescent cells and their accumulation. The secretory profile of senescent cells causes local inflammation, further spreading senescence in neighboring niche cells and impairing tissue homeostasis. The resulting impairment of turnover/tissue repair in the musculoskeletal system reduces the efficiency of the organ in response to environmental needs that finally lead to functional decline. Management of the musculoskeletal system at the cellular level can benefit the quality of life and reduce early aging. This work discusses current knowledge of cellular senescence of musculoskeletal tissues to conclude with biologically active biomarkers effective enough to reveal the underlying mechanisms of tissue flaws at the earliest possible.


Pharmacology of locomotion: an account of studies in spinal cats and spinal cord injured subjects.
This paper summarizes a research approach which started with experiments in cats and eventually led to the successful use of drugs in spinal cord injured (SCI) patients to improve their walking. In such a short paper, it is impossible to cover the details of this approach but we will establish important landmarks and give a bibliography to guide further reading.


Congenital cartilaginous rests of the neck (wattles).
Congenital cartilaginous rests of the neck (wattles) are very rare, probably branchiogenic malformations. To discuss the clinical and histologic features and the therapy of wattles. We report a 4-year-old patient with symmetric exophytic nodules of the neck that had been present since birth. The two lesions, 0.5 3 0.5 cm, were removed. The histopathologic examination confirmed ectopic cartilaginous tissue. Wattles must be excised, including their cartilaginous core, after having sonographically excluded fistulae or sinuses.


Seminal plasma biochemistry. IV: Enzymes involved in the liquefaction of human seminal plasma.
A significant positive correlation was found between the liquefaction time of human seminal coagula and bound sialic acid. There was also a similar relationship between bound sialic acid and the enzyme sialyl-transferase. This suggests that the degree of sialylation of the components of seminal coagulum are important in determining the liquefaction time of the coagulum. These results support previous findings. The coagulum is considered to be composed of glycoprotein-metal ion complexes, and the initial stage of liquefaction results from the reduction of these metal ions by L-ascorbic acid. The removal of hydrogen peroxide, generated by the oxidation of L-ascorbic acid, requires the presence of glutathione peroxidase and glutathione reductase. These enzymes have been identified in human seminal plasma and their possible physiological importance is discussed.


An overview of substrate stiffness guided cellular response and its applications in tissue regeneration.
Cell-matrix interactions play a critical role in tissue repair and regeneration. With gradual uncovering of substrate mechanical characteristics that can affect cell-matrix interactions, much progress has been made to unravel substrate stiffness-mediated cellular response as well as its underlying mechanisms. Yet, as a part of cell-matrix interaction biology, this field remains in its infancy, and the detailed molecular mechanisms are still elusive regarding scaffold-modulated tissue regeneration. This review provides an overview of recent progress in the area of the substrate stiffness-mediated cellular responses, including 1) the physical determination of substrate stiffness on cell fate and tissue development; 2) the current exploited approaches to manipulate the stiffness of scaffolds; 3) the progress of recent researches to reveal the role of substrate stiffness in cellular responses in some representative tissue-engineered regeneration varying from stiff tissue to soft tissue. This article aims to provide an up-to-date overview of cell mechanobiology research in substrate stiffness mediated cellular response and tissue regeneration with insightful information to facilitate interdisciplinary knowledge transfer and enable the establishment of prognostic markers for the design of suitable biomaterials.


Interplay between transglutaminase treatment and changes in digestibility of dietary proteins.
The changes in digestibility of TG-treated myofibrillar protein (MP), soybean protein isolate (SPI) and mixed proteins were evaluated by measuring liberation of primary amino groups, monitoring structural changes and investigating peptide fingerprints. TG treatment generally increased gastric digestion of treated proteins, possibly due to the structural changes occurred during TG treatment. In contrast, the initial intestinal digestion was suppressed by TG treatment. Compared with MP, the digestibility and peptide composition of SPI were affected by TG treatment to a larger degree, possibly due to the higher level of glutamine in SPI. Peptidomics analysis indicated that the changes in peptide composition of digests of TG-treated samples were related with the loss of Lys residues during TG treatment. Larger quantities of bioactive peptides KIEFEQFLPM, EVHEPEEKPRPK and TVKEDQVFPMNPPK were released after digestion of TG-treated MP. These results highlighted the complex and substantial influence of TG treatment on the digestibility of dietary proteins.


Neural correlates of reward-directed action and inhibition of action.
Human and non-human primate studies have examined neural responses to action and inhibition of action. However, it remains unclear whether the cerebral processes supporting these two distinct responses are differentially modulated by reward. In a sample of 35 healthy human adults, we examined brain activations to action and inhibition of action in a reward go/no-go task, with approximately ⅔ go and ⅓ no-go trials. Correct go and no-go trials were rewarded with $1 or ¢5 in reward sessions. Behaviorally, reward facilitated go and impeded no-go. A conjunction analysis showed shared activation to rewarded go and no-go responses in the rostral anterior cingulate cortex (rACC) and inferior parietal cortex. A whole-brain two-way ANOVA of response (go vs no-go) and reward (dollar vs nickel) revealed a significant main effect of response, with greater activity for no-go vs go success in the middle frontal cortex and the reversed pattern in the dorsal ACC, insula, thalamus, and caudate. The thalamus and caudate also responded preferentially to dollar relative to nickel reward during go trials. The main effect of reward (dollar > nickel) involved not only regions associated with reward valuation (e.g., medial orbitofrontal cortex - mOFC) but also those implicated in motor control, saliency, and visual attention including the rACC, ventral striatum, insula, and occipital cortex. Finally, the mOFC distinguished go and no-go responses in the dollar but not nickel trials, suggesting a functional bias toward response execution that leads to larger rewards. Together, these findings identified both shared and non-overlapping neural processes underlying goal-directed action and inhibition of action as well as delineated the effects of reward magnitude on such processes.


Aquaglyceroporins: channel proteins with a conserved core, multiple functions, and variable surfaces.
Membrane channels for water and small nonionic solutes are required for osmoregulation in bacteria, plants, and animals. Aquaporin-1, the water channel of human erythrocytes, is the first channel demonstrated to conduct water, by expression in Xenopus oocytes. Phylogenetic analyses reveal the existence of two clusters of subfamilies, the aquaporins (AQPs) and glycerol facilitators (GLPs). Sequence-based structure prediction provided a model comprising six membrane-spanning helices, while sequence analyses suggested strategic residues that are important for structure and function. The surface topography of several AQPs has been mapped by atomic force microscopy, revealing different features that correlate with differences in the loops connecting transmembrane helices. The 3D structures of AQP1 and GlpF have been determined by electron cryomicroscopy. The 3.8-A density map allowed the first atomic model of AQP1 to be built, taking into account data from sequence analyses. This model provides some insight into the permeation of water through a channel that blocks the passage of protons. GIpF has been resolved to 6.9 A, revealing helices that are similar to those of AQP1. Homology modeling shows the channel region of these distant aquaglyceroporins to be similar, as confirmed by the 2.2-A structure of GlpF from X-ray crystallography.


Cerebrospinal fluid biomarkers and apolipoprotein E genotype in cerebral amyloid angiopathy. A narrative review.
Sporadic cerebral amyloid angiopathy (CAA) is a cerebral small vessel disease, characterized by the deposition of β-amyloid within the cortical and leptomeningeal blood vessel walls. It has attracted interest concerning new therapeutic perspectives. However, there are scarce data regarding the cerebrospinal fluid biomarkers (CSF) and genetic factors in sporadic CAA. In this narrative review, we investigated the literature regarding the cerebrospinal fluid core biomarkers profile of patients with probable or possible CAA and its subtype, the CAA- related inflammation (CAA-ri), taking into account the clinical and radiological characteristics of the patients. We also analyzed the Apolipoprotein E (APOE) genotype differentiations among the different subtypes of cerebral amyloid angiopathy. Our results demonstrate specific CSF patterns of β-amyloid (Aβ42 and Aβ40) and tau-proteins (t-tau and p-tau) which may serve as molecular biomarkers for CAA/ CAA-ri and could prove helpful for novel therapeutic procedures. Specifically, decreased levels of Aβ40 and Aβ42 in both CAA and CAA-ri, mildly increased concentrations of tau protein in patients with CAA-ri and a strong association between APOE ε4/ε4 genotype and CAA-ri are the main findings.


α-Synuclein Overexpression in SH-SY5Y Human Neuroblastoma Cells Leads to the Accumulation of Thioflavin S-positive Aggregates and Impairment of Glycolysis.
Deterioration of energy metabolism in affected cells is an important feature of synucleinopathies, including Parkinson's disease. Here, we studied the association between α-synuclein accumulation and glycolysis using SH-SY5Y neuroblastoma cell lines stably expressing wild-type α-synuclein or its A53T mutant linked to the autosomal dominant form of the disease. Overexpression of both proteins led to the accumulation of thioflavin S-positive aggregates, more pronounced for α-synuclein A53T. It also caused changes in the cell energy metabolism manifested as a decrease in the lactate accumulation and glucose uptake. Impairments in glycolysis were also accompanied by a decrease in the activity of the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase (GAPDH). In vitro experiments with purified proteins indicated that GAPDH inactivation might be caused by its binding to the monomeric and oligomeric forms of α-synuclein. Therefore, a decrease in the GAPDH activity induced by its interaction with α-synuclein, might be one of the causes of glucose metabolism deterioration in synucleinopathies.


Characteristics of a low-molecular-weight factor extracted from mouse tumors that affects in vitro properties of macrophages.
A dialysable low-molecular-weight factor capable of affecting in vitro properties of macrophages was extracted from four different mouse tumors. This factor not only modulates closely related properties of peritoneal macrophages such as spreading and migration but also inhibits lipopolysaccharde-induced tumoricidal activity of these cells. It can be extracted not only from tumor tissues but also from tumor cells grown in vitro. The appearance of this factor is unique to tumors and it is not present in detectable quantities in normal tissues. The factor from one of the tumors, Lewis lung carcinoma, was purified extensively and the partially purified factor retains all the above effects on macrophages. It is not sensitive to pronase or a mixture of bovine spleen phosphodiesterase II, E. coli alkaline phosphatase and pancreatic ribonuclease. The factor is lipid-like in character and it is soluble in both organic solvents and aqueous media. It has ionizable group(s) and is anionic at neutral pH but non-ionic under acidic conditions.


St John's wort induces both cytochrome P450 3A4-catalyzed sulfoxidation and 2C19-dependent hydroxylation of omeprazole.
St John's wort, an extract of the medicinal plant Hypericum perforatum, is widely used as an herbal antidepressant. Although the ability of St John's wort to induce cytochrome P450 (CYP) 3A4-mediated reaction has been well established, the effect on CYP2C19 is still not determined. Thus the objective of this study was to determine the impact of St John's wort on the pharmacokinetic profiles of omeprazole and its metabolites. Twelve healthy adult men (6 CYP2C19*1/CYP2C19*1, 4 CYP2C19*2/CYP2C19*2 and 2 CYP2C19*2/CYP2C19*3) were enrolled in a 2-phase randomized crossover design. In each phase the volunteers received placebo or a 300-mg St John's wort tablet 3 times daily for 14 days. Then all subjects took a 20-mg omeprazole capsule orally. Blood samples were collected up to 12 hours after omeprazole administration. Omeprazole and its metabolites were quantified by use of HPLC with ultraviolet detection. Omeprazole and its metabolites all exhibit CYP2C19 genotype-dependent pharmacokinetic profiles. After a 14-day treatment with St John's wort, substantial decreases in plasma concentrations of omeprazole were observed. The peak plasma concentration (C(max)) significantly decreased by 37.5% +/- 13.3% (P =.001) in CYP2C19*2/CYP2C19*2 or *3 and by 49.6% +/- 20.7% (P =.017) in CYP2C19*1/CYP2C19*1; the area under the concentration-time curve extrapolated to infinity [AUC(0- infinity )] decreased by 37.9% +/- 21.3% (P =.014) and 43.9% +/- 23.7% (P =.011) in CYP2C19 mutant and wild genotypes, respectively. Moreover, the C(max) and AUC(0- infinity ) of omeprazole sulfone increased by 160.3% +/- 45.5% (P =.001) and by 136.6% +/- 84.6% (P =.014), 155.5% +/- 58.8% (P =.001), and 158.7% +/- 101.4% (P =.017) in mutant and wild genotypes, respectively. St John's wort increased the C(max) of 5-hydroxyomeprazole by 38.1% +/- 30.5% (P =.028) and the AUC(0- infinity ) by 37.2% +/- 26% (P =.005) in CYP2C19 wild-type subjects, whereas it did not produce any significant alterations to the corresponding pharmacokinetic parameters in subjects with variant genotypes. St John's wort induces both CYP3A4-catalyzed sulfoxidation and CYP2C19-dependent hydroxylation of omeprazole and enormously decreases the plasma concentrations of omeprazole. Clinically relevant interactions with other drugs may occur and must be taken into account when St John's wort is being taken.


Identification of a Mycobacterium tuberculosis strain with stable, low-level resistance to isoniazid.
We have identified a potential quality control strain of Mycobacterium tuberculosis to monitor isoniazid susceptibility testing. This strain (strain A) has a stable phenotypic low-level resistance to isoniazid, has a mutation of C (-15) --> T in the inhA promoter region, and gave consistent susceptibility test results in 141 laboratories.


The formation of prostaglandins in the postmortem cerebral cortex of Alzheimer-type dementia patients.
The formation of arachidonic acid metabolites [prostaglandin (PG)D2, PGE2, PGF2 alpha, 6oxo-PGF1 alpha and thromboxane (TX)B2] has been examined in the frontal, temporal, and parieto-occipital regions of the cortex in the postmortem brains from five patients with a pathologically verified Alzheimer-type dementia (ATD) and in eight, age-matched controls. The study disclosed that the amount of PGD2 and TXB2 found in the ATD brains was greater than in controls, and that the formation of PGD2 was significantly increased in the frontal cortex of the ATD brains. Other PG metabolites, however, showed no significant changes in the ATD group. Since it is known that PGD2 is synthesized mainly in neurons, our results seem to suggest that the preserved cortical neurons in the ATD brain have an accelerated PGD2 production.


Photofermentation of crude glycerol from biodiesel using Rhodopseudomonas palustris: comparison with organic acids and the identification of inhibitory compounds.
The growth of the biodiesel industry, and its concurrent production of glycerol, has lowered the price of glycerol 20-fold. While many options for using this glycerol have been proposed, the size of the waste stream means that generation of fuels is likely to be the only viable route. One such fuel is hydrogen, production of which can be achieved biologically. The photofermentation of glycerol to hydrogen using Rhodopseudomonas palustris was investigated by exploring the growth rate, hydrogen production rate and hydrogen yield. R. palustris grows on glycerol at a rate of 0.074h(-1), and photoferments glycerol into 97mol% hydrogen at a conversion efficiency nearing 90% of the 7mol H(2) theoretical maximum at a rate of 34mlH(2)/g(dw)/h. Some inhibition of growth by crude glycerol was seen. This was determined to be caused by saponified fatty acids, removal of which yielded a treated crude glycerol which showed no inhibition.


A novel approach to treatment in childhood acute myeloblastic leukemia and myelodysplastic syndrome with high-dose methylprednisolone as a differentiation- and apoptosis-inducing agent of myeloid leukemic cells.
Differentiation-inducing therapy with all-trans retinoic acid significantly improved the outcome in children with acute promyelocytic leukemia (APL). Therefore, use of agents that induce differentiation of leukemic cells in non-APL children appears to be a highly promising therapeutic approach. Based on the experimental studies in mice, we have shown that short-course high-dose methylprednisolone (HDMP) treatment can induce terminal differentiation of leukemic cells in children with various subtypes of acute myeloblastic leukemia (AML-M1,-M2,-M3,-M4,-M7). It has also been shown to induce apoptosis of myeloid leukemic cells with or without differentiation. Administration of HDMP as a single agent resulted in a rapid clinical improvement, a marked decrease in blast cells in both peripheral blood and bone marrow and dramatic decreases in the size of extramedullary leukemic mass in children with AML and myelodysplastic syndrome (MDS). Addition of HDMP to cytotoxic chemotherapy regimens increased the remission rate and improved the outcome in these children. Future clinical trials with HDMP would contribute to further improvements in the treatment results in these children.


A new approach for immobilization of oligonucleotides onto piezoelectric quartz crystal for preparation of a nucleic acid sensor for following hybridization.
The aim of this study is to develop a nucleic acid sensor based on piezoelectric crystal microbalance system (QCM) for following hybridization. Piezoelectric quartz crystal surfaces were first treated in a glow-discharge apparatus with ethylene diamine (EDA) plasma at 15 W (discharge power), 2.5 min (incubation time) and 35 ml/min (monomer flow rate) to create amino groups on the crystal surfaces. The thickness of the EDA-plasma film formed was about 43+/-24 A. Then, the amino groups on the crystal surfaces were converted to aldehyde groups by reacting the amino groups with glutaraldehyde (GA) at different conditions. A GA concentration of 2.5% and an incubation time of 2 h were selected as optimal values at this step, corresponding to a GA surface concentration of about 270 ng/cm2. A double strand Oligonucleotides, having one extra base on 5'-end of one of the complementary strands, were immobilized through the amino groups of this base onto the GA-modified crystals. Optimal immobilization conditions were as follows: oligonucleotide concentration: 1 microg/ml; time: 3 h; pH: 9.2 carbonate buffer; ionic strength: 0.1; and temperature: 20 degrees C. The QCM sensor carrying the covalently bound strand was used in the hybridization experiments, which showed that equilibrium is achieved in about 5 min, and the frequency shift measured is related to the concentration of the target strand to be measured within the medium.


Development of a human iPSC-derived placental barrier-on-chip model.
Although recently developed placenta-on-chip systems opened promising perspectives for placental barrier modeling, they still lack physiologically relevant trophoblasts and are poorly amenable to high-throughput studies. We aimed to implement human-induced pluripotent stem cells (hiPSC)-derived trophoblasts into a multi-well microfluidic device to develop a physiologically relevant and scalable placental barrier model. When cultured in a perfused micro-channel against a collagen-based matrix, hiPSC-derived trophoblasts self-arranged into a 3D structure showing invasive behavior, fusogenic and endocrine activities, structural integrity, and expressing placental transporters. RNA-seq analysis revealed that the microfluidic 3D environment boosted expression of genes related to early placental structural development, mainly involved in mechanosensing and cell surface receptor signaling. These results demonstrated the feasibility of generating a differentiated primitive syncytium from hiPSC in a microfluidic platform. Besides expanding hiPSC-derived trophoblast scope of applications, this study constitutes an important resource to improve placental barrier models and boost research and therapeutics evaluation in pregnancy.


Korundamine A, a novel HIV-inhibitory and antimalarial "hybrid" naphthylisoquinoline alkaloid heterodimer from Ancistrocladus korupensis.
A unique heterodimeric naphthylisoquinoline alkaloid, korundamine A (2), comprised of two different monomeric biaryl halves, has been isolated from the Cameroonian tropical liana Ancistrocladus korupensis. Korundamine A is the first "hybrid" dimer found in the Ancistrocladaceae; in vitro, it demonstrated anticytopathic activity against HIV-1 and antimalarial activity against Plasmodium falciparum.


Network computer-assisted transfusion-management system for accurate blood component-recipient identification at the bedside.
ABO-mismatched transfusions caused by human error are among the most serious problems in transfusion therapy. The major cause is misidentification of a recipient or a blood component at the bedside. A network computer-assisted transfusion-management system has been developed with bar coding as a fail-safe/fool-proof system for accurate component-recipient identification at the bedside, which allows us to monitor the usage of blood components in real time. The efficacy of this system was evaluated to prevent human errors by monitoring the transfusion process via the network and analyzing voluntary and mandatory reports with regard to transfusion errors over a 3-year period. The crossmatch-to-transfusion ratio for operations and outdate rate of RBCs were calculated to assess economic benefit. More than 60,000 blood components have been transfused perfectly to the intended recipients via the network, and one human error was prevented by the system. After establishment of the network system, the crossmatch-to-transfusion ratio for operations and outdate rate of RBCs have been gradually reduced from around 2.5 to 1.8 and from 3.9 to 0.32 percent, respectively. The network computer-assisted management system greatly contributes to safe and efficient transfusion therapy.


Protein function annotation based on heterogeneous biological networks.
Accurate annotation of protein function is the key to understanding life at the molecular level and has great implications for biomedicine and pharmaceuticals. The rapid developments of high-throughput technologies have generated huge amounts of protein-protein interaction (PPI) data, which prompts the emergence of computational methods to determine protein function. Plagued by errors and noises hidden in PPI data, these computational methods have undertaken to focus on the prediction of functions by integrating the topology of protein interaction networks and multi-source biological data. Despite effective improvement of these computational methods, it is still challenging to build a suitable network model for integrating multiplex biological data. In this paper, we constructed a heterogeneous biological network by initially integrating original protein interaction networks, protein-domain association data and protein complexes. To prove the effectiveness of the heterogeneous biological network, we applied the propagation algorithm on this network, and proposed a novel iterative model, named Propagate on Heterogeneous Biological Networks (PHN) to score and rank functions in descending order from all functional partners, Finally, we picked out top L of these predicted functions as candidates to annotate the target protein. Our comprehensive experimental results demonstrated that PHN outperformed seven other competing approaches using cross-validation. Experimental results indicated that PHN performs significantly better than competing methods and improves the Area Under the Receiver-Operating Curve (AUROC) in Biological Process (BP), Molecular Function (MF) and Cellular Components (CC) by no less than 33%, 15% and 28%, respectively. We demonstrated that integrating multi-source data into a heterogeneous biological network can preserve the complex relationship among multiplex biological data and improve the prediction accuracy of protein function by getting rid of the constraints of errors in PPI networks effectively. PHN, our proposed method, is effective for protein function prediction.


Choline Supplementation With a Structured Lipid in Children With Cystic Fibrosis: A Randomized Placebo-Controlled Trial.
Choline depletion is seen in cystic fibrosis (CF) and pancreatic insufficiency in spite of enzyme treatment and may result in liver, fatty acid, and muscle abnormalities. This study evaluated the efficacy and safety of an easily absorbed choline-rich structured lipid (LYM-X-SORB™ [LXS]) to improve choline status. Children with CF and pancreatic insufficiency were randomized to LXS or placebo in a 12-month double blind trial. Dietary choline intake, plasma cholines, plasma and fecal phospholipids, coefficient of fat absorption, pulmonary function, growth status, body composition, and safety measures were assessed. Magnetic resonance spectroscopy for calf muscle choline and liver fat were assessed in a subgroup and compared with a healthy comparison group matched for age, sex, and body size. A total of 110 subjects were enrolled (age 10.4 ± 3.0 years). Baseline dietary choline, 88% recommended, increased 3-fold in the LXS group. Plasma choline, betaine, and dimethylglycine increased in the LXS but not placebo (P = 0.007). Plasma lysophosphatidylcholine and phosphatidylcholine increased, and fecal phosphatidylcholine/phosphatidylethanolamine ratio decreased (P ≤ 0.05) in LXS only, accompanied by a 6% coefficient of fat absorption increase (P = 0.001). Children with CF had higher liver fat than healthy children and depleted calf muscle choline at baseline. Muscle choline concentration increased in LXS and was associated with improvement in plasma choline status. No relevant changes in safety measures were evident. LXS had improved choline intake, plasma choline status, and muscle choline stores compared with placebo group. The choline-rich supplement was safe, accepted by participants, and improved choline status in children with CF.


Vive la difference!
The subfields of the primate visual cortex differ in their cytological composition, including the relative width of the layers. In this issue of Neuron, Lukaszewicz et al. report that the origin of these laminar, and thus areal, differences can be traced to the kinetics of progenitor cell divisions in the subjacent proliferative zones that generate neurons that migrate radially to the appropriate layers at each side of the cytoarchitectonic border.


Isolation of cell-free bacterial inclusion bodies.
Bacterial inclusion bodies are submicron protein clusters usually found in recombinant bacteria that have been traditionally considered as undesirable products from protein production processes. However, being fully biocompatible, they have been recently characterized as nanoparticulate inert materials useful as scaffolds for tissue engineering, with potentially wider applicability in biomedicine and material sciences. Current protocols for inclusion body isolation from Escherichia coli usually offer between 95 to 99% of protein recovery, what in practical terms, might imply extensive bacterial cell contamination, not compatible with the use of inclusion bodies in biological interfaces. Using an appropriate combination of chemical and mechanical cell disruption methods we have established a convenient procedure for the recovery of bacterial inclusion bodies with undetectable levels of viable cell contamination, below 10⁻¹ cfu/ml, keeping the particulate organization of these aggregates regarding size and protein folding features. The application of the developed protocol allows obtaining bacterial free inclusion bodies suitable for use in mammalian cell cultures and other biological interfaces.


Factors affecting residents transition from long term care facilities to the community: a scoping review.
Long-term care facilities (LTCFs) are often places where persons with complex health needs that cannot be met in a community setting, reside and are cared for until death. However, not all persons experience continuous declines in health and functioning. For some residents who experience improvement in personal abilities and increased independence, transition from the LTCF to the community may be an option. This scoping review aimed to synthetize the existing evidence regarding the transition process from discharge planning to intervention and evaluation of outcomes for residents transitioning from LTCFs to the community. This review followed a five-stage scoping review framework to describe the current knowledge base related to transition from LTCFs to community based private dwellings as the location of the discharge (example: Person's own home or shared private home with a family member, friend, or neighbour). Of the 4221 articles retrieved in the search of 6 databases, 36 articles met the criteria for inclusion in this review. The majority of studies focussed on an older adult population (aged 65 years or greater), were conducted in the USA, and were limited to small geographic regions. There was a lack of consistency in terminology used to describe both the facilities as well as the transition process. Literature consisted of a broad array of study designs; sample sizes ranged from less than 10 to more than 500,000. Persons who were younger, married, female, received intense therapy, and who expressed a desire to transition to a community setting were more likely to transition out of a LTCF while those who exhibited cognitive impairment were less likely to transition out of a LTCF to the community. Findings highlight the heterogeneity and paucity of research examining transition of persons from LTCFs to the community. Overall, it remains unclear what best practices support the discharge planning and transition process and whether or not discharge from a LTCF to the community promotes the health, wellbeing, and quality of life of the persons. More research is needed in this area before we can start to confidently answer the research questions.


Effect of chromium supplementation on the glucose homeostasis and anthropometry of type 2 diabetic patients: Double blind, randomized clinical trial: Chromium, glucose homeostasis and anthropometry.
To evaluate the effect of chromium supplementation on the glucose homeostasis and anthropometry of type 2 diabetic patients. Fifty-six individuals with type 2 Diabetes were randomized on a double blind clinical trial into three groups: placebo (NC0), 50μg (NC50) and 200μg (NC200) of chromium nicotinate. Glucose homeostasis, anthropometry and physical activity intensity were evaluated at the beginning, at day 45 and at day 90. Energy intake was evaluated at the beginning, between the beginning and 45 days, and between days 45 and 90 of the study. There were no differences within or between groups for HOMA-IR, waist circumference, body fat percentage, lean body mass percentage and total energy intake during the trial. There was an increase of the HOMA-β in group NC0 (p=0.0349) and a decrease of 1.08kg in group NC50 (p=0.0048) at 90 days. The relation between body mass index, body fat percentage and insulin sensitivity did not change in the placebo and supplemented groups (p>0.05). In the effect of the intervention, for each 1cm increase in waist circumference there was an increase of 1.90±0.63 in HOMA-IR (p=0.0087) and 16.31±5.27% in HOMA-β (p=0.0073) in group NC200. No difference was seen in the intensity of physical activity within the groups and in the comparison between the supplemented groups (NC50 and NC200) and placebo (NC0) at 90 days. There was an increase in energy expenditure in physical activity at 90days (p=0.0371) of intervention in the group subjects NC50. As for total energy intake, there were no differences within or between the groups during the study. 50μg and 200μg supplementation with chromium nicotinate for 90days did not promote improvements in glucose homeostasis and anthropometry in individuals with type 2 diabetes mellitus.


Oxidation of thiosulfate to tetrathionate by an haloarchaeon isolated from hypersaline habitat.
A novel, extremely halophilic, neutrophilic archaeon was isolated from a mixed sediment sample from different hypersaline lakes in Kulunda steppe (Altai, Russia) at 4 M NaCl with acetate and thiosulfate as substrates. The enrichment culture developed in two phases. During the first phase, a rapid growth of heterotrophic, red-colored, polymorphic rods occurred with the concomitant oxidation of thiosulfate to tetrathionate. The latter was subsequently oxidized to sulfate during a second, slower phase by extremely halophilic, chemolithoautotrophic bacteria belonging to the gamma subdivision of the Proteobacteria. The archaeal strain HG 1 was isolated from the first phase of the enrichment culture using acetate as substrate. It was able to oxidize thiosulfate to tetrathionate during heterotrophic growth with acetate-a property not yet demonstrated for any of the known haloarchaea. The presence of tetrathionate synthase, the enzyme responsible for thiosulfate oxidation, was detected in strain HG 1. The activity was associated with membranes and depended specifically on Cl-, in contrast to the similar activity in extremely halophilic sulfur-oxidizing Gammaproteobacteria from the same enrichment, which was soluble and demanded both Na+ and Cl- . Strain HG 1 was identified as a member of the genus Natronorubrum.


Us'em: the user-centered design of a device for motivating stroke patients to use their impaired arm-hand in daily life activities.
Stroke leaves the majority of its survivors with an impairment of the upper extremity that affects their ability to live independently and their quality of life. Rehabilitation research shows that practice of everyday life activities in a natural context may sustain or even improve arm-hand performance, even during chronic stages after stroke. Based on this insight we designed, developed and evaluated Us'em; this consists of two watch-like accelerometry devices that provide feedback to stroke patients regarding the usage of their impaired versus their non-affected upper extremity. System usability and treatment credibility/expectancy were evaluated positively by therapists and patients.