The thumb domain of the P51-subunit is essential for activation of HIV reverse transcriptase.
The biologically relevant and active form of human immunodeficiency virus reverse transcriptase is a heterodimer produced in a two-step dimerization process. Dimerization involves first the rapid association of the two subunits, followed by a slow conformational change yielding a fully active form. In the present study, we demonstrate that the interaction between the thumb domain of p51 and the RNase-H domain of p66 plays a major role in an essential conformational change required for proper folding of the primer/template and the tRNA-binding site, for maturation and for activation of heterodimeric reverse transcriptase. A synthetic peptide derived from the sequence within the thumb domain of p51, which forms the interface with the RNase-H domains of p66, binds heterodimeric reverse transcriptase with an apparent dissociation constant in the nanomolar range and selectively inhibits activation of heterodimeric reverse transcriptase with an inhibition constant of 1.2 microM. A detailed study of the mechanism of inhibition reveals that this peptide does not require dissociation of heterodimeric RT for efficient inhibition and does not affect subunit association, but interferes with the conformational change required for activation of heterodimeric reverse transcriptase, resulting in a decrease in the affinity of reverse transcriptase for the tRNA and an increase in the stability of the primer/template/reverse transcriptase complex. We have previously proposed that the dimeric nature of reverse transcriptase represents an interesting target for the design of antiviral agents. On the basis of this work, we propose that the conformational changes involved in the activation of reverse transcriptase similarly represent an important target for the design of novel antiviral compounds.


Association Between the Visceral Adiposity Index and Homeostatic Model Assessment of Insulin Resistance in Participants With Normal Waist Circumference.
We assessed the correlation between the visceral adiposity index (VAI; a useful indicator of adipose distribution and function) and homeostatic model assessment of insulin resistance (HOMA-IR) in participants with normal waist circumference. A cross-sectional study was conducted, which included 1834 Chinese adults. The blood pressure, anthropometric measurements, fasting and postprandial blood glucose, fasting insulin, and lipid profiles were measured. The VAI and HOMA-IR were calculated. Participants were divided into 4 groups according to the HOMA-IR level, and the correlation between the VAI and HOMA-IR was analyzed. The VAI gradually increased across the HOMA-IR quartiles ( P < .05), and a Pearson correlation analysis showed that VAI was positively related to the HOMA-IR ( P < .001) in males and females. After adjusting for the other covariates, VAI was independently correlated with the HOMA-IR. A logistic regression analysis indicated that VAI elevation was the main risk factor for the increased HOMA-IR in both genders. Overall, the VAI was closely correlated with the HOMA-IR in a population without central obesity.


Linking ontological resources using aggregatable substance identifiers to organize extracted relations.
Systems that extract biological regulatory pathway relations from free-text sources are intended to help researchers leverage vast and growing collections of research literature. Several systems to extract such relations have been developed but little work has focused on how those relations can be usefully organized (aggregated) to support visualization systems or analysis algorithms. Ontological resources that enumerate name strings for different types of biomedical objects should play a key role in the organization process. In this paper we delineate five potentially useful levels of relational granularity and propose the use of aggregatable substance identifiers to help reduce lexical ambiguity. An aggregatable substance identifier applies to a gene and its products. We merged 4 extensive lexicons and compared the extracted strings to the text of five million MEDLINE abstracts. We report on the ambiguity within and between name strings and common English words. Our results show an 89% reduction in ambiguity for the extracted human substance name strings when using an aggregatable substance approach.


Receiving quality antenatal care service increases the chance of maternal use of skilled birth attendants in Ethiopia: Using a longitudinal panel survey.
Evidence has suggested that maternal use of skilled birth attendant is the most important factor to reduce maternal mortality because of more than three-fourths of maternal deaths occur during child delivery or within 24 hours after delivery due to hemorrhage, hypertension, ruptured uterus and sepsis. In Ethiopia, more than 42% of pregnant women with 4+ antenatal care (ANC) visit did not deliver by skilled birth attendant. The factors for women not using skilled birth attendant after any ANC visit is not well-studied yet. Therefore, the aim of this study was to assess effect of quality antenatal care service on maternal use of skilled birth attendant after any antenatal care visit. This study was initiated using performance monitoring for action Ethiopia longitudinal panel survey datasets. A total of 1,511 postnatal women were included in the analysis. Generalized estimating equation Poisson regression model was used to assess the effect of quality ANC service on maternal use of skilled birth attendant by accounting the clustering nature of the data using Stata vers.16 software. This study showed that about 54% of women used skilled birth attendant during the current baby delivery (rate = 53.6%, 95% UI = 51-56%). Nearly, 39% of the women received quality (more than 75th percentile) ANC service (rate = 39.05%, 95% UI = 36-42%). The highest and the lowest antenatal care service the women received, respectively, were blood pressure measure (91.9%) and syphilis test (12.4%). Women who received better quality ANC service were 20% higher more likely to use skilled birth attendant compared to women who received low quality ANC service (adjusted IRR = 1.20, 95% UI = 1.11, 1.31). Maternal use of skilled birth attendant can be improved by providing quality ANC service during subsequent ANC visits. Improving ANC service delivery may encourage or positively reinforce women's and partner's decision to use skilled birth attendant.


Diffusion tensor MR imaging in cervical spine trauma.
Our aim was to investigate the extent and severity of changes in spinal cord diffusion tensor imaging (DTI) parameters in patients with cervical cord injury. DTI was performed in 20 symptomatic patients (mean, 45.7 +/- 17.7 years of age; 2 women, 18 men) with cervical spine trauma and 8 volunteers (mean, 34.2 +/- 10.7 years of age; 6 men, 2 women). The whole cord and regional apparent diffusion coefficient (ADC), fractional anisotropy (FA), relative anisotropy (RA), and volume ratio (VR) of patients and volunteers were compared. DTI parameters were calculated in 16 patients. MR imaging demonstrated hemorrhagic cord contusions (n = 6), nonhemorrhagic cord contusions (n = 4), and soft-tissue injury (n = 6). Medical records were reviewed for extent of neurologic deficit. Regional ADC values differed significantly between upper and mid and upper and lower (both, P < .004) cervical cord sections. FA was significantly different between upper and lower sections (P < .03). Whole cord ADC values were significantly lower in patients than in volunteers (P < .0001). Whole spine FA was not significantly decreased in patients (P < .06). ADC and FA values were significantly decreased at injury sites when compared with volunteers (P < .031 and .0001, respectively). The greatest differences in whole cord ADC, FA, RA, and VR were in patients with hemorrhagic cord contusions compared with healthy volunteers (P < .0001, .003, .0005, and .008, respectively). DTI parameters are sensitive markers of cervical cord injury, with ADC showing the greatest sensitivity. Changes in DTI parameters are most marked at injury sites and reflect the severity of cord injury.


Feasibility of Pediatric Low-Dose Facial CT Reconstructed with Filtered Back Projection Using Adequate Kernels.
To evaluate the feasibility of pediatric low-dose facial CT reconstructed with filtered back projection (FBP) using adequate kernels. We retrospectively reviewed the clinical and imaging data of children aged < 10 years who underwent facial CT at our emergency department. The patients were divided into two groups: low-dose CT (LDCT; Group A, n = 73) with a fixed 80-kVp tube potential and automatic tube current modulation (ATCM) and standard-dose CT (SDCT; Group B, n = 40) with a fixed 120-kVp tube potential and ATCM. All images were reconstructed with FBP using bone and soft tissue kernels in Group A and only bone kernel in Group B. The groups were compared in terms of image noise, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR). Two radiologists subjectively scored the overall image quality of bony and soft tissue structures. The CT dose index volume and dose-length product were recorded. Image noise was higher in Group A than in Group B in bone kernel images (p < 0.001). Group A using a soft tissue kernel showed the highest SNR and CNR for all soft tissue structures (all p < 0.001). In the qualitative analysis of bony structures, Group A scores were found to be similar to or higher than Group B scores on comparing bone kernel images. In the qualitative analysis of soft tissue structures, there was no significant difference between Group A using a soft tissue kernel and Group B using a bone kernel with a soft tissue window setting (p > 0.05). Group A showed a 76.9% reduction in radiation dose compared to Group B (3.2 ± 0.2 mGy vs. 13.9 ± 1.5 mGy; p < 0.001). The addition of a soft tissue kernel image to conventional CT reconstructed with FBP enables the use of pediatric low-dose facial CT protocol while maintaining image quality.


Evidence-based versus experience-based decision making in clinical dentistry.
Evidence-based dentistry has become a frequent topic of conversation because good practice must be based on good evidence. This article explores some of the characteristics of "best" evidence. It is concluded that a blending of sound science and practice experience is needed and it is proposed that such evidence can be generated in clinical study groups and the recently funded Centers of Discovery.


Eps15R and clathrin regulate EphB2-mediated cell repulsion.
Expression of Eph receptors and their ligands, the ephrins, have important functions in boundary formation and morphogenesis in both adult and embryonic tissue. The EphB receptors and ephrinB ligands are transmembrane proteins that are expressed in different cells and their interaction drives cell repulsion. For cell repulsion to occur, trans-endocytosis of the inter-cellular receptor-ligand EphB-ephrinB complex is required. The molecular mechanism underlying trans-endocytosis is poorly defined. Here we show that the process is clathrin- and Eps15R-mediated using Co115 colorectal cell lines stably expressing EphB2 and ephrinB1. Cell repulsion in co-cultures of EphB2- and ephrinB1-expressing cells is significantly reduced by knockdown of Eps15R but not Eps15. A novel interaction motif in Eps15R, DPFxxLDPF, is shown to bind directly to the clathrin terminal domain in vitro. Moreover, the interaction between Eps15R and clathrin is required for EphB2-mediated cell repulsion as shown in a rescue experiment in the EphB2 co-culture assay where wild type Eps15R but not the clathrin-binding mutant rescues cell repulsion. These results provide the first evidence that Eps15R together with clathrin control EphB/ephrinB trans-endocytosis and thereby cell repulsion.


BCL-6 is phosphorylated at multiple sites in its serine- and proline-clustered region by mitogen-activated protein kinase (MAPK) in vivo.
BCL-6 gene alterations have been observed in 27-45% of diffuse large B-cell lymphomas (DLBs) with chromosomal translocations at 3q27. The deregulated expression of normal BCL-6 protein caused by this chromosomal translocation is believed to be responsible for lymphomagenesis. Recently, we demonstrated that BCL-6 is expressed at high levels in germinal center B-cells as a 92-98 kDa nuclear protein in a constitutively phosphorylated form. In this study, we show that BCL-6 is phosphorylated by mitogen-activated protein kinase (MAPK) in vitro at the sites phosphorylated in vivo. These numerous phosphorylation sites were found to be located in its serine- and proline-clustered (SPC) region (amino acids-250-483). BCL-6 phosphorylation significantly increased in Ramos cells following stimulation with 12-o-tetradecanoylphorbol-13-acetate (TPA) or BCL-6- and erk1-transfected COS-7 cells stimulated with epidermal growth factor (EGF), and the increase of phosphorylation was inhibited by MEK1 inhibitor, PD98059. Furthermore, we observed that BCL-6 was associated with MAPK in vivo and its SPC region was important for this association. These results suggest that the functions of BCL-6 are regulated by phosphorylation mediated by the MAPK signaling pathway.


Selection of chemical markers for the quality control of medicinal plants of the genus Cecropia.
Several Cecropia (Cecropiaceae) species are traditionally used in Latin America for the treatment of a variety of diseases including diabetes, arterial hypertension, asthma, bronchitis, anxiety, and inflammation. At present, a number of commercial products based on these plants have been introduced into the market with very little information on methods for guaranteeing their quality and safety. This work proposes potential chemical markers for the quality control of the raw materials of Cecropia obtusifolia Bertol., Cecropia peltata L., Cecropia glaziovii Snethl., Cecropia pachystachya Trécul, and Cecropia hololeuca Miq. The Herbal Chemical Marker Ranking System (Herb MaRS) developed by the National Institute of Complementary Medicine (NICM) at the University of Western Sydney was used for selecting chemical markers for the quality control of selected medicinal species of Cecropia. This review covers the period from 1982 to 2016. Chlorogenic acid, flavonoidal glycosides (orientin, isoorientin, vitexin, isovitexin, and rutin), catechin, epicatechin, procyanidins (B2, B5, and C1), steroids (β-sitosterol), and triterpenoids (α-amyrin, pomolic, tormentic and ursolic acids) were selected as chemical markers for the quality control of the leaves. It is necessary to establish comprehensive standards for guaranteeing quality, safety and efficacy of herbal drugs. The selection of adequate chemical markers for quality control purposes requires a good knowledge about the chemical composition of medicinal plants and their associated biological properties. To the best of our knowledge this review article is the first to address the identification and quantitative determination of the chemical markers for the genus Cecropia.


Targeting Glycosylated PD-1 Induces Potent Antitumor Immunity.
Immunotherapies targeting programmed cell death protein 1 (PD-1) and programmed cell death 1 ligand 1 (PD-L1) immune checkpoints represent a major breakthrough in cancer treatment. PD-1 is an inhibitory receptor expressed on the surface of activated T cells that dampens T-cell receptor (TCR)/CD28 signaling by engaging with its ligand PD-L1 expressed on cancer cells. Despite the clinical success of PD-1 blockade using mAbs, most patients do not respond to the treatment, and the underlying regulatory mechanisms of PD-1 remain incompletely defined. Here we show that PD-1 is extensively N-glycosylated in T cells and the intensities of its specific glycoforms are altered upon TCR activation. Glycosylation was critical for maintaining PD-1 protein stability and cell surface localization. Glycosylation of PD-1, especially at the N58 site, was essential for mediating its interaction with PD-L1. The mAb STM418 specifically targeted glycosylated PD-1, exhibiting higher binding affinity to PD-1 than FDA-approved PD-1 antibodies, potently inhibiting PD-L1/PD-1 binding, and enhancing antitumor immunity. Together, these findings provide novel insights into the functional significance of PD-1 glycosylation and offer a rationale for targeting glycosylated PD-1 as a potential strategy for immunotherapy. SIGNIFICANCE: These findings demonstrate that glycosylation of PD-1 is functionally significant and targeting glycosylated PD-1 may serve as a means to improve immunotherapy response.


Characterization of the 5'-flanking region of the mouse asparagine-linked glycosylation 12 homolog gene.
Recently, we characterized multiple roles of the endoplasmic reticulum stress responsive element (ERSE) in the promotion of a unique head-to-head gene pair: mammalian asparagine-linked glycosylation 12 homolog (ALG12) and cysteine-rich with EGF-like domains 2 (CRELD2). This bidirectional promoter, which consists of fewer than 400 base pairs, separates the two genes. It has been demonstrated that the ALG12 promoter shows less transcriptional activity through ERSE, but its basic regulatory mechanism has not been characterized. In this study, we focused on well-conserved binding elements for the transcription factors for ATF6, NF-Y and YY1 and the Sp1 and Ets families in the 5'-flanking region of the mouse ALG12 gene. We characterized their dominant roles in regulating ALG12 promoter activities using several deletion and mutation luciferase reporter constructs. The ALG12 gene is expressed in three distinct cell lines: Neuro2a, C6 glioma and HeLa cells. The reporter activity in each cell line decreased similarly with serial deletions of the mouse ALG12 promoter. Mutations in the ERSE and adjacent NF-Y-binding element slightly affected reporter activity. Each of the mutations in the GC-rich sequence and YY1-binding element reduced ALG12 promoter activity, and the combination of these mutations additively decreased reporter activity. Each mutation in the tandem-arranged Ets-family consensus sequences partially attenuated ALG12 promoter activity, and mutations of all three Ets-binding elements decreased promoter activity by approximately 40%. Mutation of the three conserved regulatory elements (GC-rich, YY1 and Ets) in the ALG12 promoter decreased reporter activity by more than 90%. Our results suggest that the promoter activity of the mouse ALG12 gene is regulated in a similar manner in the three cell lines tested in this study. The well-conserved consensus sequences in the promoter of this gene synergistically contribute to maintaining basal gene expression.


Q beta and Q gamma components of intramembranous charge movement in frog cut twitch fibers.
Intramembranous charge movement was measured in frog cut twitch fibers mounted in a double Vaseline-gap chamber with a TEA.Cl solution at 13-14 degrees C in the central pool. When a fiber was depolarized from a holding potential of -90 mV to a potential near -60 mV, the current from intramembranous charge movement was outward in direction and had an early, rapid component and a late, more slowly developing component, referred to as I beta and I gamma, respectively (1979. J. Physiol. [Lond.]. 289:83-97). When the pulse to -60 mV was preceded by a 100-600-ms pulse to -40 mV, early I beta and late I gamma components were also observed, but in the inward direction. The shape of the Q gamma vs. voltage curve can be estimated with this two-pulse protocol. The first pulse to voltage V allows the amounts of Q beta and Q gamma charge in the active state to change from their respective resting levels, Q beta (-90) and Q gamma (-90), to new steady levels, Q beta (V) and Q gamma (V). A second 100-120-ms pulse, usually to -60 mV, allows the amount of Q beta charge in the active state to change from Q beta (V) to Q beta (-60) but is not sufficiently long for the amount of Q gamma charge to change completely from Q gamma (V) to Q gamma (-60). The difference between the amount of Q gamma charge at the end of the second pulse and Q gamma (-60) is estimated from the OFF charge that is observed on repolarization to -90 mV. The OFF charge vs. voltage data were fitted, with gap corrections, with a Boltzmann distribution function plus a constant. The mean values of V (the potential at which, in the steady state, charge is distributed equally between the resting and active states) and k (the voltage dependence factor) were -59.2 mV (SEM, 1.1 mV) and 1.2 mV (SEM, 0.6 mV), respectively. The one-pulse charge vs. voltage data from the same fibers were fitted with a sum of two Boltzmann functions (1990. J. Gen. Physiol. 96:257-297). The mean values of V and k for the steeply voltage-dependent Boltzmann function, which is likely to be associated with the Q gamma component of charge, were -55.3 mV (SEM, 1.3 mV) and 3.3 mV (SEM, 0.6 mV), respectively, similar to the corresponding values obtained with the two-pulse protocol.(ABSTRACT TRUNCATED AT 400 WORDS)


Loop diathermy and cold-knife conization in patients with cervical intraepithelial neoplasia: a comparative study.
One hundred and sixty-eight cases of cervical conization were performed for cervical intraepithelial neoplasia (CIN) in a 32-month study. The indications for conization were unsatisfactory colposcopic finding, abnormal epithelium that extended into the endocervical canal, a microinvasive cervical cancer, and significant discrepancy among cytology, colposcopy, and/or punch biopsy histology. In the early period of the study, conization was done by the cold-knife method (N = 107), whereas loop diathermy was used in the latter part of the study (N = 61). Both groups were similar in terms of age, indications for conization, and size of cervical cone specimens. Loop diathermy conization was done in a significantly shorter time (5.7 +/- 1.8 minute vs 15.2 +/- 6.1 minute)(P < 0.05) than cold-knife conization. However, the difference in the postoperative complications between loop diathermy(3.0%) and cold-knife conization(4.7%) was not significant. The incidence rate of residual CIN III lesions in the subsequent hysterectomy specimens, found by histological documentation on these specimens was 25.0 and 26.1 percent after loop diathermy and cold-knife conization respectively. These results suggest that loop diathermy is much easier to perform and a more time-conserving treatment modality than cold-knife conization in the management of patients with cervical intraepithelial neoplasia.


Mutation of Arabidopsis BARD1 causes meristem defects by failing to confine WUSCHEL expression to the organizing center.
Stem cell fate in the Arabidopsis thaliana shoot apical meristem (SAM) is controlled by WUSCHEL (WUS) and CLAVATA. Here, we examine BARD1 (for BRCA1-associated RING domain 1), which had previously been implicated in DNA repair functions; we find that it also regulates WUS expression. We observed severe SAM defects in the knockout mutant bard1-3. WUS transcripts accumulated >238-fold in bard1-3 compared with the wild type and were located mainly in the outermost cell layers instead of the usual organizing center. A specific WUS promoter region was recognized by nuclear protein extracts obtained from wild-type plants, and this protein-DNA complex was recognized by antibodies against BARD1. The double mutant (wus-1 bard1-3) showed prematurely terminated SAM structures identical to those of wus-1, indicating that BARD1 functions through regulation of WUS. BARD1 overexpression resulted in reduced WUS transcript levels, giving a wus-1-like phenotype. Either full-length BARD1 or a clone that encoded the C-terminal domain (BARD1:C-ter;bard1-3) was sufficient to complement the bard1-3 phenotype, indicating that BARD1 functions through its C-terminal domain. Our data suggest that BARD1 regulates SAM organization and maintenance by limiting WUS expression to the organizing center.


Impact of Different Pairings of Respondents on Scores on the Supports Intensity Scale-Adult Version (SIS-A).
This secondary analysis examined the impact of respondent-level factors on scores on the Supports Intensity Scale-Adult Version (SIS-A) to determine if there were patterns of differences in SIS-A scores based on the number of respondents and the pairings of respondents that were included in SIS-A interviews. Results indicated that having fewer respondents led to a greater variability in SIS-A scores whereas having more respondents led to higher mean, overall support need scores. When respondents included an adult with intellectual disability (ID) the mean score was significantly lower. However, there were complex influences of pairing an adult with ID with either a professional or family member on SIS-A scores. Implications for administering and using the SIS-A are discussed.


Shifting gears versus sudden stops: qualitative study of consultations about driving in patients with cognitive impairment.
General practitioners (GPs) report finding consultations on fitness to drive (FtD) in people with cognitive impairment difficult and potentially damaging to the physician-patient relationship. We aimed to explore GP and patient experiences to understand how the negative impacts associated with FtD consultations may be mitigated. Individual qualitative interviews were conducted with GPs (n=12) and patients/carers (n=6) in Ireland. We recruited a maximum variation sample of GPs using criteria of length of time qualified, practice location and practice size. Patients with cognitive impairment were recruited via driving assessment services and participating general practices. Interviews were audio-recorded, transcribed and analysed thematically by the multidisciplinary research team using an approach informed by the framework method. The issue of FtD arose in consultations in two ways: introduced by GPs to proactively prepare patients for future driving cessation or by patients who urgently needed a medical report for an expiring driving license. The former strategy, implementable by GPs who had strong relational continuity with their patients, helped prevent crisis consultations from arising. The latter scenario became acrimonious if cognition had not been openly discussed with patients previously and was now potentially impacting on their right to drive. Patients called for greater clarity and empathy for the threat of driving cessation from their GPs. GPs used their longitudinal relationship with cognitively impaired patients to reduce the potential for conflict in consultations on FtD. These efforts could be augmented by explicit discussion of cognitive impairment at an earlier stage for all affected patients. Patients would benefit from greater input into planning driving cessation and acknowledgement from their GPs of the impact this may have on their quality of life.


NK92 Expressing Anti-BCMA CAR and Secreted TRAIL for the Treatment of Multiple Myeloma: Preliminary In Vitro Assessment.
Multiple myeloma (MM) has witnessed improved patient outcomes through advancements in therapeutic approaches. Notably, allogeneic stem cell transplantation, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies have contributed to enhanced quality of life. Recently, a promising avenue has emerged with chimeric antigen receptor (CAR) T cells targeting B-cell maturation antigen (BCMA), expressed widely on MM cells. To mitigate risks associated with allogenic T cells, we investigated the potential of BCMA CAR expression in natural killer cells (NKs), known for potent cytotoxicity and minimal side effects. Using the NK-92 cell line, we co-expressed BCMA CAR and soluble tumor necrosis factor-related apoptosis-inducing ligand (sTRAIL) employing the piggyBac transposon system. Engineered NK cells (CAR-NK-92-TRAIL) demonstrated robust cytotoxicity against a panel of MM cell lines and primary patient samples, outperforming unmodified NK-92 cells with a mean difference in viability of 45.1% (±26.1%, depending on the target cell line). Combination therapy was explored with the proteasome inhibitor bortezomib (BZ) and γ-secretase inhibitors (GSIs), leading to a significant synergistic effect in combination with CAR-NK-92-TRAIL cells. This synergy was evident in cytotoxicity assays where a notable decrease in MM cell viability was observed in combinatorial therapy compared to single treatment. In summary, our study demonstrates the therapeutic potential of the CAR-NK-92-TRAIL cells for the treatment of MM. The synergistic impact of combining these engineered NK cells with BZ and GSI supports further development of allogeneic CAR-based products for effective MM therapy.


Near-field intensity pattern at the output of silica-based graded-index multimode fibers under selective excitation with a single-mode fiber.
Selective excitation of graded-index multimode fibers (GI-MMFs) with a single-mode fiber (SMF) has gained increased interest for telecommunication applications. It has been proposed as a way to enhance the transmission bandwidth of GI-MMF links and/or create parallel communication channels over the same GI-MMF. Although the effect of SMF excitation on the transmission bandwidth has been investigated, its impact on the near-field intensity pattern at the output face of the GI-MMF has not been systematically addressed. We have carried out an analysis of the near-field intensity pattern at the output face of silica-based GI-MMFs excited by a radially offset SMF. Simulation results exhibit all of the features displayed by experimental ones. It turns out that differential mode attenuation and delay, full intra-group mode mixing, and small deviations in the refractive index profile of the GI-MMF do not affect the overall shape of the near-field intensity, which is determined by the radial offset of the input SMF. This can be exploited in mode group diversity multiplexing links. The effect of defects in the refractive index profile, such as a central dip or peak, is also examined.


Albuminuria as a predictor of cardiovascular and renal outcomes in people with known atherosclerotic cardiovascular disease.
Microalbuminuria predicts elevated cardiovascular risk in those with and without diabetes. In diabetes, microalbuminuria also heralds overt diabetic nephropathy. The predictive value of albuminuria below the microalbuminuria cutoff, and the development of overt nephropathy in nondiabetics with microalbuminuria, have not been well studied. We review findings of the HOPE Study. The HOPE Study database includes data on first morning urine albumin/creatinine ratio (ACR) in 9043 participants at baseline, and in 7674 participants at baseline and at last follow-up. Inclusion criteria were known vascular disease or diabetes, plus one other cardiovascular risk factor; exclusion criteria included heart failure or known impaired left ventricular function, dipstick-positive proteinuria (> 1+), and serum-creatinine > 2.3 mg/dL (200 micromol/L). Microalbuminuria was defined as an ACR > or = 2 mg/mmol. Microalbuminuria at baseline approximately doubled the relative risk (RR) of the primary outcome (myocardial infarction, stroke, or CV death). For every 1 mg/mmol rise of ACR, even below the level of microalbuminuria, the adjusted hazard of the primary outcome increased by about 15%. Baseline microalbuminuria predicted subsequent clinical proteinuria, RR 17.5, similarly in participants without and with diabetes. New microalbuminuria developed in 1542 participants, and clinical proteinuria in 317. Albuminuria is a continuous risk factor for CV events even below the level of microalbuminuria. Microalbuminuria predicts clinical proteinuria in nondiabetics.


Breast cancer: multidisciplinary care and clinical outcomes.
A multidisciplinary approach to the management of breast cancer is the standard of care in developed health systems. We performed a systematic review to assess the extent and quality of evidence on whether multidisciplinary care (MDC), or related aspects of care contribute to clinical outcomes in breast cancer, and in particular whether these influence survival. Only two primary studies have looked at MDC and neither of these studies considered long-term outcomes. The studies of MDC (case series) provide weak evidence that MDC may alter treatment patterns. Several population-based cohort studies showed that related aspects of team work, specialist (surgeon) and hospital workload and specialisation, are associated with improved survival. This group of studies used better quality design with more clearly defined outcome measures, and most of the studies have allowed for possible confounding variables. Evidence of a survival benefit was most consistent for specialist (surgeon) effect. However, the reasons behind the improved survival reported in these studies are unclear, and it is unlikely that this is entirely attributable to treatment patterns. We conclude that although intrinsically multidisciplinary care should be associated with better survival, there remains a paucity of evidence to support this. Studies of the long-term clinical effects of MDC in breast cancer should be a priority for future evaluation.


Hepatocarcinogenesis in chronic hepatitis C patients achieving a sustained virological response to interferon: significance of lifelong periodic cancer screening for improving outcomes.
Due to advances in interferon (IFN) therapy for chronic hepatitis C, most elderly patients, and even many of those with advanced hepatic fibrosis, now achieve a sustained virological response (SVR). However, carcinogenesis remains problematic in these patients. Hence, we aimed to elucidate risk factors for hepatocarcinogenesis in SVR patients and to present an appropriate follow-up protocol for improving outcomes. We retrospectively studied 562 consecutive SVR patients for a median observation period of 4.8 years. Hepatocellular carcinoma was diagnosed in 31 patients (5.5%). Respective cumulative incidences were 3.1, 10.1, and 15.9% at 5, 10, and 15 years after completion of IFN therapy. The proportional hazards model identified moderate or advanced fibrosis stage, advanced age, habitual alcohol consumption, and alpha-fetoprotein elevation as determinants of carcinogenesis, with hazard ratios of 10.7 (p < 0.001), 4.1 (p < 0.01), 3.9 (p < 0.01), and 2.6 (p < 0.05), respectively. Carcinoma was diagnosed in 26% of patients more than 10 years after completion of IFN therapy. Unexpectedly, F2 fibrosis was detected in 42% of these patients. The 5-year survival rate was 93% in the patients who had received periodic cancer screening but only 60% in those who had not. We recommend that SVR patients be observed at 6-month intervals, at a minimum, to facilitate diagnosis at an early stage, for as long as possible after completion of therapy even if not at an advanced stage of fibrosis.


The nuclear shuttle protein of Tomato leaf curl New Delhi virus is a pathogenicity determinant.
The role of the movement protein (MP) and nuclear shuttle protein (NSP) in the pathogenicity of Tomato leaf curl New Delhi virus (ToLCNDV), a bipartite begomovirus, was studied. Both genes were expressed in Nicotiana benthamiana, Nicotiana tabacum, and Lycopersicon esculentum plants with the Potato virus X (PVX) expression vector or by stable transformation of gene constructs under the control of the 35S promoter in N. tabacum. No phenotypic changes were observed in any of the three species when the MP was expressed from the PVX vector or constitutively expressed in transgenic plants. Expression of the ToLCNDV NSP from the PVX vector in N. benthamiana resulted in leaf curling that is typical of the disease symptoms caused by ToLCNDV in this species. Expression of NSP from PVX in N. tabacum and L. esculentum resulted in a hypersensitive response (HR), demonstrating that the ToLCVDV NSP is a target of host defense responses in these hosts. The NSP, when expressed as a transgene under the control of the 35S promoter, resulted in necrotic lesions in expanded leaves that initiated from a point and then spread across the leaf. The necrotic response was systemic in all the transgenic plants. Deletion of 100 amino acids from the C terminus did not compromise the HR response, suggesting that this region has no role in HR. Deletion of 60 or 100 amino acids from the N terminus of NSP abolished the HR response, suggesting that these sequences are required for the HR response. These findings demonstrate that the ToLCNDV NSP is a pathogenicity determinant as well as a target of host defense responses.


Audiovestibular phenotype associated with a COL11A1 mutation in Marshall syndrome.
Marshall syndrome is a dominant disorder characterized by craniofacial and skeletal abnormalities, sensorineural hearing loss, myopia, and cataracts, and is associated with splicing mutations in COL11A1. To determine the auditory and vestibular phenotypes associated with a COL11A1 splicing. Clinical otolaryngologic, audiologic, vestibular, and radiologic evaluations of the auditory and vestibular systems. Three affected individuals from a family cosegregating Marshall syndrome and a COL11A1 splice site mutation. The study subjects have progressive sensorineural hearing loss that is predominantly cochlear in origin and asymptomatic dysfunction of the central and peripheral vestibular systems. Computed tomography detected no malformations of temporal bone structures. The observed auditory and vestibular abnormalities are not caused by defective morphogenesis of the osseous labyrinth, but by more direct effects of the COL11A1 mutation on the membranous labyrinth and the central nervous system. The onset and degree of hearing loss associated with COL11A1 mutations are useful clinical features to differentiate Marshall syndrome from the phenotypically similar Stickler syndrome.


Analysis of the second harmonic generation signal from a liquid/air and liquid/liquid interface.
Three different liquid interfaces, water/air, thiophene/air, and water/thiophene, were probed using the second harmonic generation (SHG) technique. Thiophene and water have been chosen because the hyperpolarizability of these molecules has already been measured or calculated and the different values can be found in literature. We have studied the microscopic structure of these interfaces by comparing the components of the second order susceptibility tensor determined from the SHG polarization curve analysis with those determined via a molecular dynamics (MD) simulation of these interfaces. We have indeed computed the structure and orientation of water and thiophene molecules at the liquid/air and liquid/liquid (L/L) interfaces as a function of the distance from the interface. The integrated susceptibility values calculated by MD simulations agree well with SHG results and validate the choice of force fields that should permit to quantify more complex L/L interfaces.


Use of telehealth services among Nepali living overseas during Covid-19 pandemic: The opportunities, limitations, lessons learned and recommendations.
There are estimated over 8 million Nepali migrants spread across various countries around the globe. Though the majority of them enjoy good health in general, a large proportion of them suffer from non-communicable diseases, mental health issues and communicable diseases. Telemedicine services, which are organized by Non-Resident Nepali Association (NRNA), have been proven to be effective in addressing some of the health and medical needs of the migrant Nepali workers. The purpose of this study is to assess the use of tele-health services among Nepali migrant population and examine the limitations. During the pandemic period from March 2020 through August 2021, Nepali in different countries utilized telehealth services. Mental health issues, chronic diseases, skin diseases were the most common ailments people sought telehealth services for. Many of them sought for urgent medical consultations related to Covid-19 symptoms and ailments. Digital gap, lack of cross-border regulations and unwillingness to utilize telemedicine were the challenges the service faced in the optimal utilization of such services. Training and education, use of easy Apps and subsidies from the government would help in the long-term use and sustainability of telehealth services amongst the Nepali migrants.


Effects of ACEi and ARB on post-exercise hypotension induced by exercises conducted at different times of day in hypertensive men.
Post-exercise hypotension (PEH) is greater after evening than morning exercise, but antihypertensive drugs may affect the evening potentiation of PEH. Objective: To compare morning and evening PEH in hypertensives receiving angiotensin-converting enzyme inhibitors (ACEi) or angiotensin II receptor blockers (ARB). Hypertensive men receiving ACEi (n = 14) or ARB (n = 15) underwent, in a random order, two maximal exercise tests (cycle ergometer, 15 watts/min until exhaustion) with one conducted in the morning (7 and 9 a.m.) and the other in the evening (8 and 10 p.m.). Auscultatory blood pressure (BP) was assessed in triplicate before and 30 min after the exercises. Changes in BP (post-exercise - pre-exercise) were compared between the groups and the sessions using a two-way mixed ANOVA and considering P < .05 as significant. In the ARB group, systolic BP decrease was greater after the evening than the morning exercise, while in the ACEi group, it was not different after the exercises conducted at the different times of the day. Additionally, after the evening exercise, systolic BP decrease was lower in the ACEi than the ARB group (ARB = -11 ± 8 vs -6 ± 6 and ACEi = -6 ± 7 vs. -8 ± 5 mmHg, evening vs. morning, respectively, P for interaction = 0.014). ACEi, but not ARB use, blunts the greater PEH that occurs after exercise conducted in the evening than in the morning.


Needlestick and sharps injuries in an Indonesian tertiary teaching hospital from 2014 to 2017: a cohort study.
Needlestick and sharps injuries among healthcare workers (HCWs) pose significant occupational health problems. We aim to provide incidence and other epidemiological aspects of needlestick and sharp injuries (NSSIs) among HCWs in a tertiary teaching hospital in Indonesia, to inform the evaluation of NSSIs prevention programme. A cohort study was conducted at Cipto Mangunkusumo Hospital in Jakarta. We analysed data of the sharps injury programme at the hospital between January 2014 and December 2017. Incidence of NSSIs was calculated per 1000 person-years (1000-PY). Over the 4-year period, a total of 286 NSSIs were reported. The mean NSSIs incidence rate for 4 years was 13.3/1000-PY, peaking in 2015 (15.5/1000-PY) then decreasing afterward. Most NSSIs were experienced by nurses (42.7%), but the highest incidence was among midwives (18.9/1000-PY), followed by nurses, medical students and medical doctors (15.2/1000-PY, 12.6/1000-PY and 11.8/1000-PY, respectively). The devices causing the highest proportion of NSSIs were hollow-bore needles (66.8%), followed by suture needles (14.3%) and solid needles (10.8%). 9.4% of NSSIs were related to insulin pen injection. Of all the incidents, 31.3% occurred during surgical procedures, 25.9% during blood collections, 14.3% during administering injection of drugs and 13.3% during waste cleaning. In conclusion, this study showed varied incidences of NSSI among different occupations, with the highest among midwives and nurses. Many unsafe work practices still continue, which is of utmost concern. We suggest opportunities for prevention including training and cultivating safer workplace practices.


Characterization of the low-density-lipoprotein-receptor-independent interaction of beta-very-low-density lipoprotein with rat and human parenchymal liver cells in vitro.
beta-Migrating very-low-density lipoprotein (beta-VLDL) is a cholesteryl-ester-enriched lipoprotein which under normal conditions is rapidly cleared by parenchymal liver cells. In this study the characteristics of the interaction of beta-VLDL with rat parenchymal cells, Hep G2 cells and human parenchymal cells are evaluated. The binding of beta-VLDL to these cells follows saturation kinetics (Bmax. respectively 117, 106 and 103 ng of beta-VLDL apoliprotein/mg of cell protein), with a relatively high affinity (Kd respectively for beta-VLDL of 10.7, 5.1 and 8.4 micrograms/ml). Competition studies of unlabelled beta-VLDL, low-density lipoprotein (LDL) or acetylated LDL with the binding of radiolabelled beta-VLDL indicate that a LDL-receptor-independent, Ca(2+)-independent, specific recognition site for beta-VLDL is present on rat and human parenchymal cells, whereas with Hep G2 cells or mouse macrophages beta-VLDL recognition is performed by the LDL receptor. The binding of beta-VLDL to Hep G2 cells was down-regulated by 89% by prolonged exposure to beta-VLDL, whereas for human parenchymal and rat parenchymal cells down-regulation of 44% and 20% respectively was observed. Studies with antibodies against the LDL receptor support the presence of a LDL-receptor-independent specific beta-VLDL recognition site on rat and human parenchymal cells. It is concluded that a LDL-receptor-independent recognition site for beta-VLDL is present on rat and human parenchymal liver cells. The presence of a LDL-receptor-independent recognition site on human parenchymal cells may mediate in vivo the uptake of beta-VLDL during consumption of a cholesterol-rich diet, when LDL receptors are down-regulated, thus protecting against the extrahepatic accumulation of the atherogenic beta-VLDL constituents.


Diabetes and covid-19: more than the sum of two morbidities.
The coronavirus disease 2019 (covid-19) pandemic has caused a public health emergency worldwide. Risk, severity and mortality of the disease have been associated with non-communicable chronic diseases, such as diabetes mellitus. Accumulated evidence has caused great concern in countries with high prevalence of this morbidity, such as Brazil. This text shows the picture of diabetes in Brazil, followed by epidemiological data and explanatory hypothesis for the association between diabetes and covid-19. We emphasized how the burden of these two morbidities in a middle-income country has aggravated this pandemic scenario. The comprehension of this association and biological plausibility may help face this pandemic and future challenges.


The v-fms oncogene induces factor-independent growth and transformation of the interleukin-3-dependent myeloid cell line FDC-P1.
The normal cellular counterpart of the v-fms oncogene product is a receptor for the mononuclear phagocyte colony-stimulating factor, CSF-1. An interleukin-3 (IL-3)-dependent mouse myeloid cell line, FDC-P1, was infected with a murine retrovirus vector containing v-fms linked to a gene encoding resistance to neomycin (neo). Infected cells selected for resistance to the aminoglycoside G418 contained few proviral DNA copies per haploid genome, expressed low levels of the v-fms-coded glycoprotein, remained IL-3 dependent for growth, and were nontumorigenic in nude mice. In contrast, infected cells selected for their ability to grow in the absence of IL-3 contained an increased number of proviral insertions, expressed high levels of the v-fms-coded glycoprotein, and were tumorigenic in nude mice. The IL-3-independent cells expressed IL-3 receptors of comparable number and affinity to those detected in uninfected FDC-P1 cells and did not produce a growth factor able to support replication of the parental cells. Thus, the synthesis of high levels of the v-fms gene product in FDC-P1 cells abrogated their requirement for IL-3 and rendered the cells tumorigenic by a nonautocrine mechanism. The data suggest that v-fms encodes a promiscuous tyrosine kinase able to transform cells of the myeloid lineage that do not normally express CSF-1 receptors.


Testing gender invariance of the hospital anxiety and depression scale using the classical approach and Bayesian approach.
Measurement invariance is an important attribute for the Hospital Anxiety and Depression Scale (HADS). Most of the confirmatory factor analysis studies on the HADS adopt the classical maximum likelihood approach. The restrictive assumptions of exact-zero cross-loadings and residual correlations in the classical approach can lead to inadequate model fit and biased parameter estimates. The present study adopted both the classical approach and the alternative Bayesian approach to examine the measurement and structural invariance of the HADS across gender. A Chinese sample of 326 males and 427 females was used to examine the two-factor model of the HADS across gender. Configural and scalar invariance of the HADS were evaluated using the classical approach with the robust-weighted least-square estimator and the Bayesian approach with zero-mean, small-variance informative priors to cross-loadings and residual correlations. Acceptable and excellent model fits were found for the two-factor model under the classical and Bayesian approaches, respectively. The two-factor model displayed scalar invariance across gender using both approaches. In terms of structural invariance, females showed a significantly higher mean in the anxiety factor than males under both approaches. The HADS demonstrated measurement invariance across gender and appears to be a well-developed instrument for assessment of anxiety and depression. The Bayesian approach is an alternative and flexible tool that could be used in future invariance studies.


Changes in cisternal compartment based on stage of lactation and time since milk ejection in the udder of dairy cows.
Two experiments were conducted to study changes induced by stage of lactation and milk ejection in the cisternal compartment of the udder in dairy cows. In experiment 1, 18 cows grouped according to stage of lactation were used 12 h after milking for measuring alveolar and cisternal milk volumes (by cannula) and cisternal area (by ultrasonography) in the front quarters. Cisternal milk and cisternal area were correlated (r = 0.74 to 0.82) for all stages of lactation. As lactation advanced, volumes of alveolar and cisternal milk and cisternal area decreased. Proportion of cisternal milk varied between stages (early, 33.2%; mid, 23.1%; and late, 42.6%). In experiment 2, 7 cows were used to show return of milk from cisternal to alveolar compartments when milk ejection was induced without milking. Cisternal area was measured before (0 min) and after (3, 15, 30, and 60 min) an i.v. oxytocin (OT) injection administered immediately before normal a.m. and p.m. milking times. Cisternal area increased dramatically from 0 to 3 min (98%) and decreased slowly thereafter. The 0- and 3-min data provide clear evidence of milk ejection, and their difference indicated cistern elasticity. Maximum cisternal area in each cow was similar for the 8- and 16-h milking intervals, indicating that in both cases the cistern was completely full of milk. Decrease in cisternal area after 3 min was significant at 15, 30, and 60 min. Decreased cisternal area was interpreted as the reflux of cisternal milk to the alveolar compartment. We termed this 'cisternal recoil.' In conclusion, ultrasonography was a useful method to evaluate dynamic changes in cisternal milk throughout lactation and after udder stimulation in dairy cows. Evidence exists that udder cisterns decrease when lactation advances and milk returns to the alveolar compartment when cows remain unmilked after milk ejection.


Ozonolysis can produce long-lived greenhouse gases from commercial refrigerants.
Hydrofluoroolefins are being adopted as sustainable alternatives to long-lived fluorine- and chlorine-containing gases and are finding current or potential mass-market applications as refrigerants, among a myriad of other uses. Their olefinic bond affords relatively rapid reaction with hydroxyl radicals present in the atmosphere, leading to short lifetimes and proportionally small global warming potentials. However, this type of functionality also allows reaction with ozone, and whilst these reactions are slow, we show that the products of these reactions can be extremely long-lived. Our chamber measurements show that several industrially important hydrofluoroolefins produce CHF3 (fluoroform, HFC-23), a potent, long-lived greenhouse gas. When this process is accounted for in atmospheric chemical and transport modeling simulations, we find that the total radiative effect of certain compounds can be several times that of the direct radiative effect currently recommended by the World Meteorological Organization. Our supporting quantum chemical calculations indicate that a large range of exothermicity is exhibited in the initial stages of ozonolysis, which has a powerful influence on the CHF3 yield. Furthermore, we identify certain molecular configurations that preclude the formation of long-lived greenhouse gases. This demonstrates the importance of product quantification and ozonolysis kinetics in determining the overall environmental impact of hydrofluoroolefin emissions.


A preliminary analysis of the phenomenology of skin-picking in Prader-Willi syndrome.
To examine the nature and psychosocial correlates of skin-picking behavior in youth with Prader-Willi Syndrome (PWS). Parents of 67 youth (aged 5-19 years) with PWS were recruited to complete an internet-based survey that included measures of: skin-picking behaviors, the automatic and/or focused nature of skin-picking, severity of skin-picking symptoms, anxiety symptoms, developmental functioning, symptoms of inattention, impulsivity, and oppositionality, and quality of life. Results indicated that skin-picking was endorsed in 95.5% of youth. Direct associations of moderate strength were found between skin-picking severity and symptoms of anxiety, inattention, oppositionality, developmental functioning, and quality of life. Other descriptive data, such as areas picked, cutaneous factors, antecedents, and consequences related to skin-picking are reported. The prevalence and consequences associated with skin-picking in PWS indicate a greater need for clinician awareness of the behavior and interventions tailored to meet the needs of this population.


Diversity and cold adaptation of culturable endophytic fungi from bryophytes in the Fildes Region, King George Island, maritime Antarctica.
Endophytic fungi associated with three bryophyte species in the Fildes Region, King George Island, maritime Antarctica, that is, the liverwort Barbilophozia hatcheri, the mosses Chorisodontium aciphyllum and Sanionia uncinata, were studied by culture-dependent method. A total of 128 endophytic fungi were isolated from 1329 tissue segments of 14 samples. The colonization rate of endophytic fungi in three bryophytes species were 12.3%, 12.1%, and 8.7%, respectively. These isolates were identified to 21 taxa, with 15 Ascomycota, 5 Basidiomycota, and 1 unidentified fungus, based on morphological characteristics and sequence analyses of ITS region and D1/D2 domain. The dominant fungal endophyte was Hyaloscyphaceae sp. in B. hatcheri, Rhizoscyphus sp. in C. aciphyllum, and one unidentified fungus in S. uncinata; and their relative frequencies were 33.3%, 32.1%, and 80.0%, respectively. Furthermore, different Shannon-Weiner diversity indices (0.91-1.99) for endophytic fungi and low endophytic fungal composition similarities (0.19-0.40) were found in three bryophyte species. Growth temperature tests indicated that 21 taxa belong to psychrophiles (9), psychrotrophs (11), and mesophile (1). The results herein demonstrate that the Antarctic bryophytes are an interesting source of fungal endophytes and the endophytic fungal composition is different among the bryophyte species, and suggest that these fungal endophytes are adapted to cold stress in Antarctica.


Prescribing patterns among paediatric inpatients in a teaching hospital in western Nepal.
Infants and children constitute a large proportion of the population in developing countries. In Nepal, studies on drug use patterns in the paediatric age group are lacking in hospitals in the western region. The present study was carried out to obtain demographical information and information on the prescribing patterns of drugs. The antibiotic sensitivity patterns of commonly-isolated micro-organisms and the mean cost of drugs were obtained. The study was carried out over a four-month period (December 1, 2003 to March 31, 2004) at the Manipal Teaching Hospital, a tertiary care hospital in Pokhara, western Nepal. The case records of patients discharged from the paediatrics ward during the study period were analysed. Mean number of drugs prescribed was calculated. The percentage of admissions that were prescribed antibiotics was determined. 356 patients were admitted during the study period, of which 228 were male. The median duration of hospitalisation was four days. The mean number of drugs prescribed per admission was 4.5. 789 drugs (48.9 percent) were prescribed by the parenteral route. Antibiotics were prescribed in 249 admissions (69.9 percent). Staphylococcus aureus, Escherichia coli, and Acinetobacter species were the common organisms isolated, and were resistant in some cases to the commonly-used antibiotics. The mean (+/- standard deviation) cost of drugs per admission was 5.4 (+/-1.6) US dollars. Prescribing by generic name should be encouraged. Use of parenteral antibiotics was high and route conversion programmes should be instituted. Use of antibiotics for predominantly viral infections should be reduced. Treatment guidelines for common conditions should be formulated.


The reorganization of a monographic reference collection.
Reference monographs in the Health Sciences Library of the College of Medicine and Dentistry of New Jersey were reorganized recently according to form, in order to enable both librarians and patrons to utilize these materials more efficiently. This reorganization reflects the unique characteristics of reference books as differentiated from the regular monographic collection, since reference materials are frequently consulted for quick "look-ups." A reference category scheme was developed and implemented, based on observations of and comparisons with reference collections of eight medical libraries in the New York metropolitan area. The reorganization enhances the retrievability of materials from this collection.


Singular-optical coloring of regularly scattered white light.
When the surface roughness is comparable with the wavelength of the probing radiation, the scattered field contains both the regular (forward-scattered) component of coherent nature and the diffusely scattered part. Coloring of the regular component of white light scattered by a colorless dielectric slab with a rough surface is considered as a peculiar effect of singular optics with zero (infinitely extended) interference fringes. To explain the observed alternation of colors with respect to the increasing depth of the surface roughness, we apply a model of transition layers associated with the surface roughness. By applying the chromascopic technique, it is shown that the modifications of the normalized spectrum of the forward-scattered white light can be interpreted as the effect of a quarter-wavelength (anti-reflecting) layer for some spectral component of a polychromatic probing beam.


Uniform binding of aminoacylated transfer RNAs to the ribosomal A and P sites.
The association and dissociation rate constants of eight different E. coli aminoacyl-tRNAs (aa-tRNAs) for E. coli ribosomes programmed with mRNAs of defined sequences were determined. Identical association and dissociation rate constants were observed for all eight aa-tRNAs in both the ribosomal A and P sites despite substantial differences in tRNA sequence, the type of esterified amino acid, and posttranscriptional modifications. These results indicate that the overall binding of all aa-tRNAs to the ribosome is uniform. However, when either the esterified amino acid or the tRNA modifications were removed, binding was no longer uniform. These results suggest that differences in tRNA sequences and tRNA modifications have evolved to offset differential thermodynamic contributions of the esterified amino acid and the codon-anticodon interaction so that ribosomal binding of all aa-tRNAs remains uniform.


A technique for repeated sampling of pure cerebrospinal fluid from the conscious rabbit.
For the study of drug pharmacokinetics' a reliable method for repeated sampling of uncontaminated cerebrospinal fluid (CSF) from a conscious rabbit was established. The subdural space was punctured between a spinous processes of the lumbar vertebrae. A catheter was inserted through a cannula and pushed up to the region of the cisterna magna. After removing the cannula, the distal end of the catheter was sealed and placed subcutaneously until the onset of the experiments. Ten days after the insertion, samples of clear and colorless CSF up to 1 ml could be withdrawn.


Effects of aging on sleep in the golden hamster.
The golden hamster (Mesocricetus auratus) has been a model organism for the study of circadian rhythmicity and, in particular, the effects of age on the circadian system. Surprisingly, nothing is known about the effects of advanced age on sleep in this species. As a first step in determining the effects of aging on sleep in the golden hamster, we recorded sleep for 24 hours in 12 young (3 months) and 18 old (17-18 months) golden hamsters entrained to a 14:10 light:dark (LD) cycle. Aged hamsters exhibited small but significant increases in overall NREM sleep time, primarily due to an increase in time the old animals spent in the NREM sleep state during the dark period relative to the young hamsters. There were no significant differences in REM sleep, median sleep episode length, or the number of arousals. The most striking differences between the sleep of young and old hamsters was in NREM delta (0.5-4 Hz) power per epoch. Old hamsters showed approximately 27% less (p=0.0004) delta power per NREM epoch than young hamsters. It is possible that increased NREM sleep time in the old hamsters may be a failed attempt to maintain cumulative delta power; ie, old hamsters may have more NREM sleep in order to make up for the lower intensity of their sleep. This decline in delta power with age parallels earlier findings in cats and humans, although has it not been previously reported in rodents.


Proton transfer events in GFP.
Proton transfer is one of the most important elementary processes in biology. Green fluorescent protein (GFP) serves as an important model system to elucidate the mechanistic details of this reaction, because in GFP proton transfer can be induced by light absorption. Illumination initiates proton transfer through a 'proton-wire', formed by the chromophore (the proton donor), water molecule W22, Ser205 and Glu222 (the acceptor), on a picosecond time scale. To obtain a more refined view of this process, we have used a combined approach of time resolved mid-infrared spectroscopy and visible pump-dump-probe spectroscopy to resolve with atomic resolution how and how fast protons move through this wire. Our results indicate that absorption of light by GFP induces in 3 ps (10 ps in D(2)O) a shift of the equilibrium positions of all protons in the H-bonded network, leading to a partial protonation of Glu222 and to a so-called low barrier hydrogen bond (LBHB) for the chromophore's proton, giving rise to dual emission at 475 and 508 nm. This state is followed by a repositioning of the protons on the wire in 10 ps (80 ps in D(2)O), ultimately forming the fully deprotonated chromophore and protonated Glu222.


Large-size, high-uniformity, random silver nanowire networks as transparent electrodes for crystalline silicon wafer solar cells.
Metal nanowire networks are emerging as next generation transparent electrodes for photovoltaic devices. We demonstrate the application of random silver nanowire networks as the top electrode on crystalline silicon wafer solar cells. The dependence of transmittance and sheet resistance on the surface coverage is measured. Superior optical and electrical properties are observed due to the large-size, highly-uniform nature of these networks. When applying the nanowire networks on the solar cells with an optimized two-step annealing process, we achieved as large as 19% enhancement on the energy conversion efficiency. The detailed analysis reveals that the enhancement is mainly caused by the improved electrical properties of the solar cells due to the silver nanowire networks. Our result reveals that this technology is a promising alternative transparent electrode technology for crystalline silicon wafer solar cells.


Optimizing efficiency of psychopathology assessment through quantitative modeling: development of a brief form of the Externalizing Spectrum Inventory.
The Externalizing Spectrum Inventory (ESI; Krueger, Markon, Patrick, Benning, & Kramer, 2007) provides for integrated, hierarchical assessment of a broad range of problem behaviors and traits in the domain of deficient impulse control. The ESI assesses traits and problems in this domain through 23 lower order facet scales organized around 3 higher order dimensions, reflecting general disinhibition, callous aggression, and substance abuse. The full-form ESI contains 415 items, and a shorter form would be useful for questionnaire screening studies or multimethod research protocols. In the current work, we employed item response theory and structural modeling methods to create a 160-item brief form (ESI-BF) that provides for efficient measurement of the ESI's lower order facets and quantification of its higher order dimensions either as scale-based factors or as item-based composites. The ESI-BF is recommended for use in research on psychological or neurobiological correlates of problems such as risk-taking, delinquency, aggression, and substance abuse, and studies of general and specific mechanisms that give rise to problems of these kinds.


Long noncoding RNA modulates alternative splicing regulators in Arabidopsis.
Alternative splicing (AS) of pre-mRNA represents a major mechanism underlying increased transcriptome and proteome complexity. Here, we show that the nuclear speckle RNA-binding protein (NSR) and the AS competitor long noncoding RNA (or ASCO-lncRNA) constitute an AS regulatory module. AtNSR-GFP translational fusions are expressed in primary and lateral root (LR) meristems. Double Atnsr mutants and ASCO overexpressors exhibit an altered ability to form LRs after auxin treatment. Interestingly, auxin induces a major change in AS patterns of many genes, a response largely dependent on NSRs. RNA immunoprecipitation assays demonstrate that AtNSRs interact not only with their alternatively spliced mRNA targets but also with the ASCO-RNA in vivo. The ASCO-RNA displaces an AS target from an NSR-containing complex in vitro. Expression of ASCO-RNA in Arabidopsis affects the splicing patterns of several NSR-regulated mRNA targets. Hence, lncRNA can hijack nuclear AS regulators to modulate AS patterns during development.


Toll-like receptor signaling and SIGIRR in renal fibrosis upon unilateral ureteral obstruction.
Innate immune activation via IL-1R or Toll-like receptors (TLR) contibutes to acute kidney injury but its role in tissue remodeling during chronic kidney disease is unclear. SIGIRR is an inhibitor of TLR-induced cytokine and chemokine expression in intrarenal immune cells, therefore, we hypothesized that Sigirr-deficiency would aggravate postobstructive renal fibrosis. The expression of TLRs as well as endogenous TLR agonists increased within six days after UUO in obstructed compared to unobstructed kidneys while SIGIRR itself was downregulated by day 10. However, lack of SIGIRR did not affect the intrarenal mRNA expression of proinflammatory and profibrotic mediators as well as the numbers of intrarenal macrophages and T cells or morphometric markers of tubular atrophy and interstitial fibrosis. Because SIGIRR is known to block TLR/IL-1R signaling at the level of the intracellular adaptor molecule MyD88 UUO experiments were also performed in mice deficient for either MyD88, TLR2 or TLR9. After UUO there was no significant change of tubular interstitial damage and interstitial fibrosis in neither of these mice compared to wildtype counterparts. Additional in-vitro studies with CD90+ renal fibroblasts revealed that TLR agonists induce the expression of IL-6 and MCP-1/CCL2 but not of TGF-β, collagen-1α or smooth muscle actin. Together, postobstructive renal interstitial fibrosis and tubular atrophy develop independent of SIGIRR, TLR2, TLR9, and MyD88. These data argue against a significant role of these molecules in renal fibrosis.


A multicenter study of romiplostim for chemotherapy-induced thrombocytopenia in solid tumors and hematologic malignancies.
Chemotherapy-induced thrombocytopenia (CIT) frequently complicates cancer treatment causing chemotherapy delays, dose reductions, and discontinuation. There is no FDA-approved agent available to manage CIT. This study retrospectively evaluated patients with CIT treated on institutional romiplostim treatment pathways at 4 U.S. centers. The primary outcome was achievement of a romiplostim response [median on-romiplostim platelet count (Plt) ≥75x109/L and ≥30x109/L above baseline]. Secondary outcomes included time to Plt≥100x109/L and rates of the following: Plt<100x109/L, Plt<75x109/L, Plt<50x109/L, thrombocytosis, chemotherapy dose reduction/treatment delay, platelet transfusion, bleeding, and thromboembolism. Multivariable regression was used to identify predictors of romiplostim non-response and compare weekly dosing with intracycle/intermittent dosing. 173 patients (153 solid tumor, 20 lymphoma or myeloma) were treated, with 170 (98%) receiving a median of 4 (range, 1-36) additional chemotherapy cycles on romiplostim. Romiplostim was effective in solid tumor patients: 71% of patients achieved a romiplostim response, 79% avoided chemotherapy dose reductions/treatment delays and 89% avoided platelet transfusions. Median per-patient Plt on romiplostim was significantly higher than baseline (116x109/L vs. 60x109/L, P<0.001). Bone marrow tumor invasion, prior pelvic irradiation, and prior temozolomide predicted romiplostim non-response. Bleeding rates were lower than historical CIT cohorts and thrombosis rates were not elevated. Weekly dosing was superior to intracycle dosing with higher response rates and less chemotherapy dose reductions/treatment delays (IRR 3.00, 95% CI 1.30-6.91, P=0.010) or bleeding (IRR 4.84, 95% CI 1.18-19.89, P=0.029). Blunted response (10% response rate) was seen in non-myeloid hematologic malignancy patients with bone marrow involvement. In conclusion, romiplostim was safe and effective for CIT in most solid tumor patients.


High prevalence of hepatic steatosis and vascular thrombosis in COVID-19: A systematic review and meta-analysis of autopsy data.
Coronavirus disease 2019 (COVID-19) disease can frequently affect the liver. Data on hepatic histopathological findings in COVID-19 is scarce. To characterize hepatic pathological findings in patients with COVID-19. We conducted a systematic review with meta-analysis registered on PROSPERO (CRD42020192813), following PRISMA guidelines. Eligible trials were those including patients of any age and COVID-19 diagnosis based on a molecular test. Histopathological reports from deceased COVID-19 patients undergoing autopsy or liver biopsy were reviewed. Articles including less than ten patients were excluded. Proportions were pooled using random-effects models. Q statistic and I 2 were used to assess heterogeneity and levels of evidence, respectively. We identified 18 studies from 7 countries; all were case reports and case series from autopsies. All the patients were over 15 years old, and 67.2% were male. We performed a meta-analysis of 5 studies, including 116 patients. Pooled prevalence estimates of liver histopathological findings were hepatic steatosis 55.1% [95% confidence interval (CI): 46.2-63.8], congestion of hepatic sinuses 34.7% (95%CI: 7.9-68.4), vascular thrombosis 29.4% (95%CI: 0.4-87.2), fibrosis 20.5% (95%CI: 0.6-57.9), Kupffer cell hyperplasia 13.5% (95%CI: 0.6-54.3), portal inflammation 13.2% (95%CI: 0.1-48.8), and lobular inflammation 11.6% (95%CI: 0.3-35.7). We also identified the presence of venous outflow obstruction, phlebosclerosis of the portal vein, herniated portal vein, periportal abnormal vessels, hemophagocytosis, and necrosis. We found a high prevalence of hepatic steatosis and vascular thrombosis as major histological liver features. Other frequent findings included portal and lobular inflammation and Kupffer cell hyperplasia or proliferation. Further studies are needed to establish the mechanisms and implications of these findings.


Measurement invariance of neuropsychological tests in diverse older persons.
Comparability of meaning of neuropsychological test results across ethnic, linguistic, and cultural groups is important for clinicians challenged with assessing increasing numbers of older ethnic minorities. We examined the dimensional structure of a neuropsychological test battery in linguistically and demographically diverse older adults. The Spanish and English Neuropsychological Assessment Scales (SENAS), developed to provide psychometrically sound measures of cognition for multiethnic and multilingual applications, was administered to a community dwelling sample of 760 Whites, 443 African Americans, 451 English-speaking Hispanics, and 882 Spanish-speaking Hispanics. Cognitive function spanned a broad range from normal to mildly impaired to demented. Multiple group confirmatory factor analysis was used to examine equivalence of the dimensional structure for the SENAS across the groups defined by language and ethnicity. Covariance among 16 SENAS tests was best explained by five cognitive dimensions corresponding to episodic memory, semantic memory/language, spatial ability, attention/working memory, and verbal fluency. Multiple Group confirmatory factor analysis supported a common dimensional structure in the diverse groups. Measures of episodic memory showed the most compelling evidence of measurement equivalence across groups. Measurement equivalence was observed for most but not all measures of semantic memory/language and spatial ability. Measures of attention/working memory defined a common dimension in the different groups, but results suggest that scores are not strictly comparable across groups. These results support the applicability of the SENAS for use with multiethnic and bilingual older adults, and more broadly, provide evidence of similar dimensions of cognition in the groups represented in the study.


Duration between onset and time of obtaining initial treatment among people with anxiety and mood disorders: an international survey of members of mental health patient advocate groups.
Self-report data obtained from members of advocate groups for patients with anxiety or mood disorders in 11 countries were used to study time to initial professional help-seeking after incident episodes. Data were taken from 3516 self-administered questionnaires completed by members of GAMIAN, an international consortium of mental health patient advocate groups. Reports about age at onset and age at first seeking treatment were obtained retrospectively. Approximately 40% of respondents reported that they sought treatment in the same year as the first onset of their disorder. The median delay in help-seeking was 8 years for the remainder of respondents. Synthetic cohort analysis suggests that delays have decreased in recent cohorts. However, time to initial help-seeking in all cohorts and all countries was found to be inversely related to age at onset. Although caution is needed in generalizing the results beyond members of patient advocate groups, the key patterns found here were also found in previous analyses of general population surveys carried out in the US and Canada. The critical and consistent finding in all these studies is that presumably curable adolescents with early-onset disorders are, in effect, ignored by the treatment system in these countries. Aggressive outreach and intervention among early-onset cases might prove to be a cost-effective approach both to prevent the onset of secondary disorders and to improve success in treating primary disorders.


Role of protein phosphatase 2A in Alzheimer's disease.
Alzheimer disease (AD) is the most common cause of dementia in adults. Aberrant hyperphosphorylation of microtubule associated protein Tau and neurofilament-M/H is one of the pathological hallmarks of AD. Most of the therapeutic strategies for treating AD are based on the inhibition of protein kinases such as glycogen synthase kinase-3β, cyclin-dependent kinase 5, and other Tau kinases. Here, we focus on protein phosphatase 2A (PP2A) as a key player in AD. PP2A expression and activity are downregulated in AD brain, contributing to the aberrant phosphorylation of Tau and NF proteins in AD. Recent data published from our lab as well as others on PP2A deregulation in AD is reviewed. The role of peptidyl prolyl isomerase Pin1 in regulation of PP2A mediated neurodegeneration is further analyzed. Development of drugs for AD could be based on restoration of PP2A activity or targeting Pin1.


Potential benefits of nintendo wii fit among people with multiple sclerosis: a longitudinal pilot study.
We examined the potential of Nintendo Wii Fit (Nintendo Co, Ltd, Kyoto, Japan) to increase physical activity (PA) behavior and health among people with multiple sclerosis (MS). The study consisted of a repeated-measures design with a baseline control period and involved 30 people with MS who had the ability to walk 25 feet with or without a cane (26 individuals were included in the analyses). Nintendo Wii was set up in the homes of participants, who were prescribed a Wii Fit exercise program lasting 14 weeks, 3 days a week. The Physical Activity and Disability Survey, Modified Fatigue Impact Scale, and 36-item Short Form Health Status Survey were administered three times before participants gained access to Wii Fit (control period, at 2-week intervals), and three times after they received Wii Fit (posttest 1: immediately after; posttest 2: 7 weeks after; posttest 3: 14 weeks after). Mobility, balance, strength, and weight were assessed at the first pretest, immediately prior to obtaining access to Wii Fit, and 7 weeks after obtaining access to Wii Fit. Results from the questionnaires indicated that PA significantly improved at week 7, but at week 14, PA levels declined relative to week 7 and the difference was no longer significant compared with the control period. Physical assessments indicated that balance and strength significantly improved at week 7. One adverse event was reported (repetitive knee injury). Physical assessments indicated that people with MS may be able to improve their fitness levels by using Wii Fit. Future studies should incorporate behavior change strategies to promote long-term use of Wii Fit, and explore whether individuals with more severe symptoms of MS can safely use Wii Fit.


Good's buffers as a basis for developing self-buffering and biocompatible ionic liquids for biological research.
This work reports a promising approach to the development of novel self-buffering and biocompatible ionic liquids for biological research in which the anions are derived from biological buffers (Good's buffers, GB). Five Good's buffers (Tricine, TES, CHES, HEPES, and MES) were neutralized with four suitable hydroxide bases (1-ethyl-3-methylimidazolium, tetramethylammonium, tetraethylammonium, and tetrabutylammonium) producing 20 Good's buffer ionic liquids (GB-ILs). The presence of the buffering action of the synthesized GB-ILs was ascertained by measuring their pH-profiles in water. Moreover, a series of mixed GB-ILs with wide buffering ranges were formulated as universal buffers. The impact of GB-ILs on bovine serum albumin (BSA), here used as a model protein, is discussed and compared with more conventional ILs using spectroscopic techniques, such as infrared and dynamic light scattering. They appear to display, in general, a greater stabilizing effect on the protein secondary structure than conventional ILs. A molecular docking study was also carried out to investigate on the binding sites of GB-IL ions to BSA. We further used the QSAR-human serum albumin binding model, log K(HSA), to calculate the binding affinity of some conventional ILs/GB-ILs to HSA. The toxicity of the GB and GB-ILs was additionally evaluated revealing that they are non-toxic against Vitro fischeri. Finally, the GB-ILs were also shown to be able to form aqueous biphasic systems when combined with aqueous solutions of inorganic or organic salts, and we tested their extraction capability for BSA. These systems were able to extract BSA with an outstanding extraction efficiency of 100% in a single step for the GB-IL-rich phase, and, as a result, the use of GB-IL-based ABS for the separation and extraction of other added-value biomolecules is highly encouraging and worthy of further investigation.


Functional performance after tibial rotationplasty.
We measured muscle strength, joint motion, and gait parameters and determined the electromyographic activities of the ankle and knee during walking, running, and stair-climbing in two children who had had a tibial rotationplasty for osteosarcoma of the distal end of the femur. Both had marked loss of strength in the plantar flexors on the side of the prosthesis compared with the sound side, although electromyographic recordings showed that the rotated calf muscles, to a substantial degree, had assumed the function of extensors of the prosthetic knee. Despite some abnormalities in gait, both children walked at speeds that were comparable to those of normal children. They could also run, climb stairs by stepping up with both limbs, and participate in many recreational activities. The functional abilities of these children suggested that rotationplasty, in patients with a similar lesion, is a worth-while alternative to above-the-knee amputation.


Trans-Aconitic Acid in Range Grasses in Early Spring.
trans-Aconitate ion, an inhibitor of the tricarboxylic acid cycle, was identified in range grasses as trans-aconitic acid, which was isolated in crystalline form. It occurs in surprisingly high concentrations in early-season forage grasses. Dry-weight concentrations of trans-aconitate vary with season and species; concentrations of between I and 2.5 percent are common in mixed pasture grasses, but are higher in certain species such as Hordeum leporinum (3.5 percent) and Phalaris tuberosa var. stenoptera (4.2 percent). Leaves of western larkspur (Delphinium hesperium) contain 12.2 percent trans-aconitate. trans-Aconitate may be partially responsible for nutritional disorders, such as grass tetany (hypomagnesemia), that occur in grazing cattle in early spring.


Alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women.
Osteoporosis is an abnormal reduction in bone mass and bone deterioration leading to increased fracture risk. Alendronate belongs to the bisphosphonate class of drugs, which act to inhibit bone resorption by interfering with the activity of osteoclasts. To assess the efficacy of alendronate in the primary and secondary prevention of osteoporotic fractures in postmenopausal women. We searched CENTRAL, MEDLINE and EMBASE for relevant randomized controlled trials published between 1966 to 2007. Women receiving at least one year of alendronate, for postmenopausal osteoporosis, were compared to those receiving placebo and/or concurrent calcium/vitamin D. The outcome was fracture incidence. We undertook study selection and data abstraction in duplicate. We performed meta-analysis of fracture outcomes using relative risks and a > 15% relative change was considered clinically important. We assessed study quality through reporting of allocation concealment, blinding and withdrawals. Eleven trials representing 12,068 women were included in the review. Relative (RRR) and absolute (ARR) risk reductions for the 10 mg dose were as follows. For vertebral fractures, a significant 45% RRR was found (RR 0.55, 95% CI 0.45 to 0.67). This was significant for both primary prevention, with 45% RRR (RR 0.55, 95% CI 0.38 to 0.80) and 2% ARR, and secondary prevention with 45% RRR (RR 0.55, 95% CI 0.43 to 0.69) and 6% ARR. For non-vertebral fractures, a significant 16% RRR was found (RR 0.84, 95% CI 0.74 to 0.94). This was significant for secondary prevention, with 23% RRR (RR 0.77, 95% CI 0.64 to 0.92) and 2% ARR, but not for primary prevention (RR 0.89, 95% CI 0.76 to 1.04). There was a significant 40% RRR in hip fractures (RR 0.60, 95% CI 0.40 to 0.92), but only secondary prevention was significant with 53% RRR (RR 0.47, 95% CI 0.26 to 0.85) and 1% ARR. The only significance found for wrist was in secondary prevention, with a 50% RRR (RR 0.50 95% CI 0.34 to 0.73) and 2% ARR. For adverse events, we found no statistically significant differences in any included study. However, observational data raise concerns regarding potential risk for upper gastrointestinal injury and, less commonly, osteonecrosis of the jaw. At 10 mg per day, both clinically important and statistically significant reductions in vertebral, non-vertebral, hip and wrist fractures were observed for secondary prevention ('gold' level evidence, www.cochranemsk.org). We found no statistically significant results for primary prevention, with the exception of vertebral fractures, for which the reduction was clinically important ('gold' level evidence).


The environment of inpatient healthcare delivery and its influence on the outcome of care.
This paper addresses issues arising in the literature regarding the environmental design of inpatient healthcare settings and their impact on care. Environmental design in healthcare settings is an important feature of the holistic delivery of healthcare. The environmental influence of the delivery of care is manifested by such things as lighting, proximity to bedside, technology, family involvement, and space. The need to respond rapidly in places such as emergency and intensive care can override space needs for family support. In some settings with aging buildings, the available space is no longer appropriate to the needs-for example, the need for privacy in emergency departments. Many aspects of care have changed over the last three decades and the environment of care appears not to have been adapted to contemporary healthcare requirements nor involved consumers in ascertaining environmental requirements. The issues found in the literature are addressed under five themes: the design of physical space, family needs, privacy considerations, the impact of technology, and patient safety. There is a need for greater input into the design of healthcare spaces from those who use them, to incorporate dignified and expedient care delivery in the care of the person and to meet the needs of family.Preferred Citation: O'Connor, M., O'Brien, A., Bloomer, M., Morphett, J., Peters, L., Hall, H., … Munro, I. (2012). The environment of inpatient healthcare delivery and its influence on the outcome of care. Health Environments Research & Design Journal, 6(1), 105-117.


Dietary bovine lactoferrin increases intestinal cell proliferation in neonatal piglets.
Lactoferrin is a bioactive milk protein that stimulates cell proliferation in vitro; however, limited in vivo evidence exists to allow lactoferrin to be incorporated into infant formula. Herein, the effect of dietary bovine lactoferrin (bLF) on neonatal intestinal growth and maturation was investigated guided by the hypothesis that bLF would increase cellular proliferation leading to functional differences in neonatal piglets. Colostrum-deprived piglets were fed formula containing 0.4 [control (Ctrl)], 1.0 (LF1), or 3.6 (LF3) g bLF/L for the first 7 or 14 d of life. To provide passive immunity, sow serum was provided orally during the first 36 h of life. Intestinal cell proliferation, histomorphology, mucosal DNA concentration, enzyme activity, gene expression, and fecal bLF content were measured. Intestinal enzyme activity, DNA concentration, and villus length were unaffected by bLF. However, crypt proliferation was 60% greater in LF1- and LF3-fed piglets than in Ctrl piglets, and crypt depth and area were 20% greater in LF3-fed piglets than in Ctrl piglets. Crypt cells from LF3-fed piglets had 3-fold higher β-catenin mRNA expression than did crypt cells from Ctrl piglets. Last, feces of piglets fed bLF contained intact bLF, suggesting that some bLF was resistant to digestion and could potentially affect intestinal proliferation through direct interaction with intestinal epithelial cells. This study is the first to our knowledge to show that dietary bLF stimulates crypt cell proliferation in vivo. The increased β-catenin expression indicates that Wnt signaling may in part mediate the stimulatory effect of bLF on intestinal cell proliferation.


A cyclical appearance of antibody-producing cells after a single injection of serum protein antigen.
After a single intravenous injection of rabbits with aggregated HuIgG, IgM- and IgG-plaque-forming cells (PFC) in both the spleens and peripheral blood of rabbits peaked 5, 13, and 21 days after injection, while almost no PFC could be detected on days 8 and 16. The available data suggest that the secondary peaks of PFC (days 13 and 21) resulted from stimulation of memory cells by persisting antigen that was localized in the germinal centers in the spleen. No such persistence of antigen occurred in the lymph nodes, and these lymphoid tissues did not exhibit secondary peaks of PFC. The identical kinetic patterns for IgM- and IgG-PFC indicate that the major portion of IgG-PFC did not result from IgM-secreting cells switching to IgG synthesis and secretion. The present data suggest that the antibody produced and present at the site of interaction between committed cells and antigen is responsible for the regulation of antibody synthesis to persisting antigens. Possible cellular events involved in both the regulation and an apparent synchronous appearance of antibody producing cells in the spleens of rabbits were presented.


Single-cell analysis of shared signatures and transcriptional diversity during zebrafish development.
During development, animals generate distinct cell populations with specific identities, functions, and morphologies. We mapped transcriptionally distinct populations across 489,686 cells from 62 stages during wild-type zebrafish embryogenesis and early larval development (3-120 h post-fertilization). Using these data, we identified the limited catalog of gene expression programs reused across multiple tissues and their cell-type-specific adaptations. We also determined the duration each transcriptional state is present during development and identify unexpected long-term cycling populations. Focused clustering and transcriptional trajectory analyses of non-skeletal muscle and endoderm identified transcriptional profiles and candidate transcriptional regulators of understudied cell types and subpopulations, including the pneumatic duct, individual intestinal smooth muscle layers, spatially distinct pericyte subpopulations, and recently discovered best4+ cells. To enable additional discoveries, we make this comprehensive transcriptional atlas of early zebrafish development available through our website, Daniocell.


Smartphone apps for the self-management of low back pain: A systematic review.
Guidelines for low back pain (LBP) often recommend the use of self-management such as unsupervised exercise, booklets, and online education. Another potentially useful way for patients to self-manage LBP is by using smartphone applications (apps). However, to date, there has been no rigorous evaluation of LBP apps and no guidance for consumers on how to select high-quality, evidence-based apps. This chapter reviews smartphone apps for the self-management of LBP and evaluates their content quality and whether they recommend evidence-based interventions. This chapter shows that generally app developers are selecting interventions that are endorsed by guidelines, although their quality is low. There are many apps available for the self-management of LBP, but their effectiveness in improving patient outcomes has not been rigorously assessed. App developers need to work closely with healthcare professionals, researchers, and patients to ensure app content is accurate, evidence based, and engaging.


DrugLogit: logistic discrimination between drugs and nondrugs including disease-specificity by assigning probabilities based on molecular properties.
The increasing knowledge of both structure and activity of compounds provides a good basis for enhancing the pharmacological characterization of chemical libraries. In addition, pharmacology can be seen as incorporating both advances from molecular biology as well as chemical sciences, with innovative insight provided from studying target-ligand data from a ligand molecular point of view. Predictions and profiling of libraries of drug candidates have previously focused mainly on certain cases of oral bioavailability. Inclusion of other administration routes and disease-specificity would improve the precision of drug profiling. In this work, recent data are extended, and a probability-based approach is introduced for quantitative and gradual classification of compounds into categories of drugs/nondrugs, as well as for disease- or organ-specificity. Using experimental data of over 1067 compounds and multivariate logistic regressions, the classification shows good performance in training and independent test cases. The regressions have high statistical significance in terms of the robustness of coefficients and 95% confidence intervals provided by a 1000-fold bootstrapping resampling. Besides their good predictive power, the classification functions remain chemically interpretable, containing only one to five variables in total, and the physicochemical terms involved can be easily calculated. The present approach is useful for an improved description and filtering of compound libraries. It can also be applied sequentially or in combinations of filters, as well as adapted to particular use cases. The scores and equations may be able to suggest possible routes for compound or library modification. The data is made available for reuse by others, and the equations are freely accessible at http://hermes.chem.ut.ee/~alfx/druglogit.html.


Positive Outliers Among African American Women and the Factors Associated with Long-Term Physical Activity Maintenance.
Studying positive outliers, individuals who have achieved success with long-term (> 6-month) physical activity (PA) engagement, may be an important approach for understanding strategies for improving leisure-time PA maintenance among African American (AA) women. This cross-sectional, mixed-methods study (1) examined the personal characteristics, PA patterns, and behavioral practices of positive outliers among AA women and (2) compared characteristics of those who maintain PA at recommended levels (HIGH, ≥ 150 min/week > 6 months) with those who maintain low PA volumes (LOW, < 150 min/week > 6 months). A large sample of positive outliers completed this study (n = 290), and most became physically active on their own (76.2%). These AA women were committed to maintaining an active lifestyle, accumulated 249.7 ± 105.8 min of PA/week, and engaged in a variety of activities. Their behavioral practices included scheduling PA during the week (85.9%), goal-setting (82.4%), engaging in PA with others (55.9%), self-monitoring (78.3%), and having a backup plan for missed sessions (54.8%). HIGH maintainers (84.9%) made up most of the sample, and these women were characteristically similar to LOW maintainers with few differences. HIGH maintainers have been active longer, achieved higher commitment scores, and engaged in PA at a higher frequency, duration, and intensity, resulting in higher weekly PA volume compared to LOW maintainers (273.8 ± 96.1 vs. 114.4 ± 24.3 min per week, p ≤ 0.001). Our findings identify factors that may be important for successful PA maintenance among AA women and may help to inform the development of effective behavioral interventions to promote sustained, long-term PA engagement in this population.


BRONCHIOLAR EMPHYSEMA. A REPORT OF A NECROPSIED CASE OF DIFFUSE BRONCHIOLECTASIS AND REVIEW OF THE LITERATURE.
Bronchiolar emphysema is a rare, insidious, progressive, bilateral pulmonary fibrosis with diffusion defect. Death follows in five to 10 years after the onset of symptoms because of respiratory failure, cor pulmonale or pneumothorax. In the 20 cases reviewed, the lungs typically showed bosselation of their pleural surfaces, giving the appearance and consistency of a liver involved by Laennec's cirrhosis. Cross sections showed honeycombing chiefly along the lung margins. Microscopically, cystic dilatation of terminal bronchioles was present, with obliteration of the remaining peripheral lung tissue by a dense pulmonary fibrosis. Hyperplasia of smooth muscle and elastica was prominent.Bronchiolar emphysema is a clinicopathologic entity, the etiology of which is unknown and likely multiple. Bronchiolectasis and superimposed recurrent infection are essential in its pathogenesis. Thickening of alveolar walls may play a decisive role in determining the characteristic site of the bronchiolar dilatation.