Stabilization of chitosan-based polyelectrolyte nanoparticle cargo delivery biomaterials by a multiple ionic cross-linking strategy.
PolyElectrolyte Nanoparticles (PENs) obtained by layer-by-layer self-assembly of polycations/polyanions suffer from a lack of colloidal stability in physiological conditions. We report a simple innovative approach for increasing their stability by multiple ionic cross-linkers. Herein, a chitosan-based core was stabilized by polyanions such as tripolyphosphate and dextran sulfate at pHs of 3 (aPENs) and 8 (bPENs) to improve the quality of electrostatic interactions in the core and manage self-assembly of polyethyleneimine shell onto the core. The physicochemical properties of the particles were characterized by DLS, SEM, TEM, FT-IR, and TGA. TEM micrographs showed visible core/shell structures of bPENs. From particle size and polydispersity indices, the bPENs stability was salt concentration-dependent. The release profiles of PENs using nicotinic acid demonstrated sustained release in a pH-independent manner with a good fit of Korsmeyer-Peppas model. These results suggest that multiple ionic cross-linkers can be an efficient approach to increase the colloidal stability of PENs.


Combined microvascular breast and lymphatic reconstruction with deep inferior epigastric perforator flap and gastroepiploic vascularized lymph node transfer for postmastectomy lymphedema patients.
The combination of microvascular breast reconstruction (MBR) and vascularized lymph node transfer (VLNT) in a single-stage procedure is a surgical option for women who desire breast reconstruction and postmastectomy lymphedema surgery. In this study, we present a series of patients who underwent simultaneous lymphatic and MBR with the gastroepiploic VLNT (GE-VLNT) and the deep inferior epigastric perforator (DIEP) flap respectively. Between 2018 and 2019, all consecutive patients diagnosed with lymphedema stage IIb-III International Society of Lymphology who opted to pursue simultaneous MBR with DIEP flap and GE-VLNT were included in this study. Patient demographics, comorbidities, prior radiation therapy, operative characteristics, surgical outcomes and complications were collected and analyzed. Six patients underwent simultaneous unilateral MBR with DIEP flap and GE-VLNT. The mean age was 48±10.5 years and mean body mass index was 28.2±4.5 kg/m2. The flap survival rate was 100%. One patient required re-exploration due to venous congestion of the lymph node flap but was successfully salvaged. There was no donor site morbidity at the donor or recipient site for the DIEP flap were seen. The mean circumference reduction rate was 30.0%±5.1% (P<0.001). One patient stage III underwent additional liposuction at 12 months postoperative to improve final results. The combined use of DIEP flap and GE-VLNT flaps in a single-stage procedure is a safe and reliable surgical option for patients with postmastectomy lymphedema who desire and are suitable for autologous microvascular breast and lymphatic reconstruction.


Cross-Sectional Examination of Patient and Therapist Factors Affecting Participation in Physical Therapy in Acute Care Hospital Settings.
Research has demonstrated benefits of early and continued physical therapy for patients in acute care hospitals. Despite known benefits, scheduled sessions do not always result in treatment. Reported percentages for nontreatment are 15% to 25%. Understanding when and why nontreatment occurs is fundamental to future interventions to reduce it and provide patients with needed services. The study objective was to describe nontreatment and the extent to which attributes of the patient, physical therapist, and environment affect its occurrence at a suburban community hospital. This was a cross-sectional study. Medical records for 1,252 patients who were scheduled for 6,246 physical therapy sessions were reviewed. Therapist demographics were collected via a questionnaire. Therapist sexes were equally represented, and most therapists were nonwhite and worked full time at the hospital. The nontreatment percentage for individual therapists ranged from 5.4% to 23.2%. This percentage was 1.3% for the first scheduled session but nearly 20% for the remaining sessions. In more than 30% of nontreatment events, the specific therapist attempting treatment was not identified. Patients were much less likely to experience nontreatment if they were scheduled for therapy on a Tuesday or if they were in the hospital for a musculoskeletal condition. Sunday had a particularly high percentage of nontreatment. The participants were recruited from a single hospital. The specific therapist associated with nontreatment events was not always known. Hospital and rehabilitation department policies and culture for weekend therapy staffing should be evaluated in light of the high percentage of nontreatment on Sunday. The impact of patient diagnosis on nontreatment must be evaluated further and may reflect hospital culture. Future research efforts should be designed to obtain data on the assigned therapist for all instances of nontreatment.


ROMPI-CDSA: ring-opening metathesis polymerization-induced crystallization-driven self-assembly of metallo-block copolymers.
Polymerization-induced self-assembly (PISA) and crystallization-driven self-assembly (CDSA) are among the most prevailing methods for block copolymer self-assembly. Taking the merits of scalability of PISA and dimension control of CDSA, we report one-pot synchronous PISA and CDSA via ring-opening metathesis polymerization (ROMP) to prepare nano-objects based on a crystalline poly(ruthenocene) motif. We denote this self-assembly methodology as ROMPI-CDSA to enable a simple, yet robust approach for the preparation of functional nanomaterials.


Lifestyle factors and primary glioma and meningioma tumours in the Million Women Study cohort.
Previous studies have reported inconsistent results on the effect of anthropometric and lifestyle factors on the risk of developing glioma or meningioma tumours. A prospective cohort of 1.3 million middle-aged women was used to examine these relationships. During 7.7 million women-years of follow-up, a total of 1563 women were diagnosed with a primary incident central nervous system tumour: 646 tumours were classified as glioma and 390 as meningioma. Our results show that height is related to the incidence of all central nervous system tumours with a risk of about 20% per 10 cm increase in height (relative risk=1.19, 95% CI=1.10-1.30 per 10 cm increase in height, P<0.001): the risks did not differ significantly between specified glioma and meningioma. Body mass index (BMI) was also related to central nervous system tumour incidence, with a risk of about 20% per 10 kg m(-2) increase in BMI (relative risk=1.17, 95% CI=1.03-1.34 per 10 kg m(-2) increase in BMI, P=0.02). Smoking status, alcohol intake, socioeconomic level, parity, age at first birth, and oral contraceptive use were not associated with the risk of glioma or meningioma tumours. In conclusion, for women in the United Kingdom, the incidence of glioma or meningioma tumours increases with increasing height and increasing BMI.


Degradation of bisphenol-A using ultrasonic irradiation assisted by low-concentration hydrogen peroxide.
This study investigated the degradation of bisphenol-A (BPA) by ultrasonic irradiation in the presence of different additives (H2O2, air bubbles and humic acid) under various operating conditions, i.e., ultrasonic frequency, power intensity and power density. The results demonstrated that the BPA degradation followed pseudo first-order kinetics under different experimental conditions. The optimum power intensities were 0.9, 1.8, and 3.0 W/cm2 at the frequencies of 400, 670, and 800 kHz, respectively. At the fixed frequency (800 kHz), the degradation rate of BPA was shown proportional to the increase of power density applied. With this manner, the BPA sonolysis could be facilitated at H2O2 dosage being lower than 0.1 mmol/L; while BPA degradation was hindered at H2O2 concentration in excess of 1 mmol/L. Additionally, BPA removal was shown to be inhibited by the presence of aeration and humic acid during ultrasonic irradiation. The present study suggested that the degradation rate of BPA assisted by ultrasonic irradiation was influenced by a variety of factors, and high BPA removal rate could be achieved under appropriate conditions.


Reflections on mirror therapy: a systematic review of the effect of mirror visual feedback on the brain.
Mirror visual feedback (MVF), a phenomenon where movement of one limb is perceived as movement of the other limb, has the capacity to alleviate phantom limb pain or promote motor recovery of the upper limbs after stroke. The tool has received great interest from health professionals; however, a clear understanding of the mechanisms underlying the neural recovery owing to MVF is lacking. We performed a systematic review to assess the effect of MVF on brain activation during a motor task. We searched PubMed, CINAHL, and EMBASE databases for neuroimaging studies investigating the effect of MVF on the brain. Key details for each study regarding participants, imaging methods, and results were extracted. The database search yielded 347 article, of which we identified 33 suitable for inclusion. Compared with a control condition, MVF increases neural activity in areas involved with allocation of attention and cognitive control (dorsolateral prefrontal cortex, posterior cingulate cortex, S1 and S2, precuneus). Apart from activation in the superior temporal gyrus and premotor cortex, there is little evidence that MVF activates the mirror neuron system. MVF increases the excitability of the ipsilateral primary motor cortex (M1) that projects to the "untrained" hand/arm. There is also evidence for ipsilateral projections from the contralateral M1 to the untrained/affected hand as a consequence of training with MVF. MVF can exert a strong influence on the motor network, mainly through increased cognitive penetration in action control, though the variance in methodology and the lack of studies that shed light on the functional connectivity between areas still limit insight into the actual underlying mechanisms.


Identification of polar transformation products and high molecular weight polycyclic aromatic hydrocarbons (PAHs) in contaminated soil following bioremediation.
Bioremediation is a technique commonly used to reduce the toxicity associated with polycyclic aromatic hydrocarbons (PAHs) in contaminated soils. However, the efficacy of bioremedial applications is evaluated based on the removal of a subset of parent (or unsubstituted) PAHs and does not incorporate toxic polar transformation products or the more mutagenic high molecular weight PAHs (MW≥302amu or MW302-PAHs). Previously, an effects-directed analysis approach was used to assess the effect of bioremediation on the toxicity of a coal tar-contaminated soil. Increased genotoxicity and developmental toxicity was measured postbioremedation in the more polar soil extract fractions, as compared to the less polar fractions where the targeted PAHs eluted, and could not be attributed to the 88 target PAHs analyzed for (including selected oxygen-containing PAHs). In this study, comprehensive two-dimensional gas chromatography time-of-flight and liquid chromatography quadrupole time-of-flight mass spectrometry were used to characterize transformation products in the soil extract fractions identified as toxic, previously. Additionally, the degradation of 12MW302-PAHs, picene (MW=278) and coronene (MW=300) were evaluated following bioremediation. Non-targeted analysis resulted in the tentative identification of 10 peaks with increased intensity postbioremediation (based on mass spectral library matching and fragmentation patterns from >5000 candidate peaks in the soil extracts). Several of these compounds contained oxygen, suggesting they would be relatively polar. MW302-PAHs were not significantly degraded during bioremediation, suggesting that the carcinogenic potential associated with these PAHs might remain unchanged. The results of this study suggest that polar transformation products, and MW302-PAHs, should be considered for realistic risk assessment of bioremediated soils.


System Transformation in Patient-Centered Medical Home (PCMH): Variable Impact on Chronically Ill Patients' Utilization.
Research connecting patient-centered medical homes (PCMHs) with improved quality and reduced utilization is inconsistent, possibly because individual domains of change, and the stage of change, are not incorporated in the research design. The objective of this study was to examine the association between stage and domain of change and patterns of health care utilization. This was a cross-sectional observational study that including 87 Minnesota clinics certified as medical homes. Patients included those receiving management for diabetes or cardiovascular disease with insurance coverage by payers participating in the study. PCMH transformation stage was defined by practice systems in place, with measurements summarized in 5 domains. Health care utilization was measured by total utilization, frequency of outpatient visits and prescriptions, and occurrence of inpatient and emergency department visits. PCMH transformation was associated with few changes in utilization, but there were important differences by the underlying domains of change. We demonstrate meaningful differences in the impact of PCMH transformation by diagnosis cohort and comorbidity status of the patient. Because the association of health care utilization with PCMH transformation varied by transformation domain and patient diagnosis, practice leaders need to be supported by research incorporating detailed measures of PCMH transformation.


Quantitative genetic analysis of skin reflectance: a multivariate approach.
Skin color is a polygenically determined quantitative trait. Although it has been used extensively in studies of between-population variation, there have been relatively few studies of the inheritance of skin color. In this article we use measurements on 359 members of the Jirel population of eastern Nepal to assess the heritabilities and additive genetic correlations of three skin reflectance measures. Skin color was measured at the upper inner arm site at three wavelengths. A maximum likelihood approach was used to estimate sex and age effects on skin reflectance, heritabilities, and phenotypic variances at each wavelength and both additive genetic and environmental correlations between wavelengths. This technique incorporated information from 36 pedigrees with 2-25 members and 173 independent individuals. Likelihood ratio tests were used to assess the significance of specific variance/covariance components. The results indicate that skin reflectances are moderately heritable at all three wavelengths. The pairwise phenotypic correlations ranged from 0.76 to 0.88. The observed additive genetic correlations were not significantly different from 1.00, suggesting that the same loci influence variation at each wavelength. This evidence for relatively complete pleiotropy implies that measurements at multiple wavelengths yield little additional genetic information, although they may be useful for reducing measurement error. Based on estimates of the genetic and phenotypic covariance matrices, we determined that skin reflectance measurements are expected to provide only as much information for assessing local between-population genetic variation as a single two-allele polymorphic marker. Therefore microevolutionary studies based on skin color variation should be viewed with caution.


SRSF3, a Splicer of the PKM Gene, Regulates Cell Growth and Maintenance of Cancer-Specific Energy Metabolism in Colon Cancer Cells.
Serine and arginine rich splicing factor 3 (SRSF3), an SR-rich family protein, has an oncogenic function in various kinds of cancer. However, the detailed mechanism of the function had not been previously clarified. Here, we showed that the SRSF3 splicer regulated the expression profile of the pyruvate kinase, which is one of the rate-limiting enzymes in glycolysis. Most cancer cells express pyruvate kinase muscle 2 (PKM2) dominantly to maintain a glycolysis-dominant energy metabolism. Overexpression of SRSF3, as well as that of another splicer, polypyrimidine tract binding protein 1 (PTBP1) and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1), in clinical cancer samples supported the notion that these proteins decreased the Pyruvate kinase muscle 1 (PKM1)/PKM2 ratio, which positively contributed to a glycolysis-dominant metabolism. The silencing of SRSF3 in human colon cancer cells induced a marked growth inhibition in both in vitro and in vivo experiments and caused an increase in the PKM1/PKM2 ratio, thus resulting in a metabolic shift from glycolysis to oxidative phosphorylation. At the same time, the silenced cells were induced to undergo autophagy. SRSF3 contributed to PKM mRNA splicing by co-operating with PTBP1 and hnRNPA1, which was validated by the results of RNP immunoprecipitation (RIP) and immunoprecipitation (IP) experiments. These findings altogether indicated that SRSF3 as a PKM splicer played a positive role in cancer-specific energy metabolism.


BMI and Cause-Specific Hospital Admissions and Costs: The UK Biobank Cohort Study.
To estimate the effect of BMI on cause-specific hospital admissions and costs in men and women is not well understood, and this study's aim is to address this. For 451,320 men and women aged 40 years or older recruited into the UK Biobank, followed up for 6 years on average, this study estimated annual rates and costs (at 2016 UK prices) of hospital admissions, overall and by diagnostic category (using International Classification of Diseases, Tenth Revision chapters), in relation to BMI. Among those who were never smokers, a 2-kg/m2 higher BMI (above 20 kg/m2 ) was associated with a 6.2% (99% CI: 5.3% to 7.2%) higher admission rate and an 8.6% (99% CI: 7.3% to 10.0%) higher annual cost in men and with a 5.7% (99% CI: 4.9% to 6.6%) higher admission rate and an 8.4% (99% CI: 7.5% to 9.3%) higher annual cost in women. Higher BMI was associated with higher admission rates and costs for many types of health conditions, particularly for endocrine, skin, and musculoskeletal disorders in both men and women and for circulatory diseases in men. BMI beyond healthy weight is strongly associated with higher annual rates of hospital admission and higher costs in both men and women across a wide range of health conditions.


Acute coronary syndrome (unstable angina and non-ST elevation MI).
In people with acute coronary syndrome (ACS) the incidence of serious adverse outcomes (such as death, acute myocardial infarction [MI], or refractory angina requiring emergency revascularisation) is 5-10% within the first 7 days and about 15% at 30 days. Between 5-14% of people with acute coronary syndrome die in the year after diagnosis, with about half of these deaths occurring within 4 weeks of diagnosis. We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of: antiplatelet; antithrombin; anti-ischaemic; lipid-lowering; and invasive treatments? We searched: Medline, Embase, The Cochrane Library, and other important databases up to May 2007 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). We found 32 systematic reviews, RCTs, or observational studies that met our inclusion criteria. In this systematic review we present information relating to the effectiveness and safety of the following interventions: aspirin, beta-blockers, calcium channel blockers, clopidogrel, direct thrombin inhibitors, glycoprotein IIb/IIIa inhibitors (oral or intravenous), heparin (low molecular weight, unfractionated), nitrates, routine early cardiac catheterisation and revascularisation, statins, and warfarin.


Lapses in perceptual decisions reflect exploration.
Perceptual decision-makers often display a constant rate of errors independent of evidence strength. These 'lapses' are treated as a nuisance arising from noise tangential to the decision, e.g. inattention or motor errors. Here, we use a multisensory decision task in rats to demonstrate that these explanations cannot account for lapses' stimulus dependence. We propose a novel explanation: lapses reflect a strategic trade-off between exploiting known rewarding actions and exploring uncertain ones. We tested this model's predictions by selectively manipulating one action's reward magnitude or probability. As uniquely predicted by this model, changes were restricted to lapses associated with that action. Finally, we show that lapses are a powerful tool for assigning decision-related computations to neural structures based on disruption experiments (here, posterior striatum and secondary motor cortex). These results suggest that lapses reflect an integral component of decision-making and are informative about action values in normal and disrupted brain states.


Differential regulation of macrophage inflammatory activation by fibrin and fibrinogen.
Fibrin is a major component of the provisional extracellular matrix formed during tissue repair following injury, and enables cell infiltration and anchoring at the wound site. Macrophages are dynamic regulators of this process, advancing and resolving inflammation in response to cues in their microenvironment. Although much is known about how soluble factors such as cytokines and chemokines regulate macrophage polarization, less is understood about how insoluble and adhesive cues, specifically the blood coagulation matrix fibrin, influence macrophage behavior. In this study, we observed that fibrin and its precursor fibrinogen elicit distinct macrophage functions. Culturing macrophages on fibrin gels fabricated by combining fibrinogen with thrombin stimulated secretion of the anti-inflammatory cytokine, interleukin-10 (IL-10). In contrast, exposure of macrophages to soluble fibrinogen stimulated high levels of inflammatory cytokine tumor necrosis factor alpha (TNF-α). Macrophages maintained their anti-inflammatory behavior when cultured on fibrin gels in the presence of soluble fibrinogen. In addition, adhesion to fibrin matrices inhibited TNF-α production in response to stimulation with LPS and IFN-γ, cytokines known to promote inflammatory macrophage polarization. Our data demonstrate that fibrin exerts a protective effect on macrophages, preventing inflammatory activation by stimuli including fibrinogen, LPS, and IFN-γ. Together, our study suggests that the presentation of fibrin(ogen) may be a key switch in regulating macrophage phenotype behavior, and this feature may provide a valuable immunomodulatory strategy for tissue healing and regeneration. Fibrin is a fibrous protein resulting from blood clotting and provides a provisional matrix into which cells migrate and to which they adhere during wound healing. Macrophages play an important role in this process, and are needed for both advancing and resolving inflammation. We demonstrate that culture of macrophages on fibrin matrices exerts an anti-inflammatory effect, whereas the soluble precursor fibrinogen stimulates inflammatory activation. Moreover, culture on fibrin completely abrogates inflammatory signaling caused by fibrinogen or known inflammatory stimuli including LPS and IFN-γ. Together, these studies show that the presentation of fibrin(ogen) is important for regulating a switch between macrophage pro- and anti-inflammatory behavior.


Molecular characterisation of varicella zoster virus genotypes in Sri Lanka.
Genotyping of wild type of varicella zoster virus (VZV) in Sri Lanka would help to distinguish the VZV wild type infection from varicella vaccine associated infections. PCR-RFLP analysis of VZV ORF 38, 54 and 62 was used for genotyping in VZV from blood or vesicular fluid from 31 patients with chickenpox or herpes zoster. The PstI restriction site of ORF 38, BglI restriction site of ORF 54 and SmaI restriction site of ORF 62 were analyzed using RFLP to determine the genotype. Except for one strain, all other VZV isolates had the genotype characteristic of the wild type VZV strain PstI+BglI+ SmaI-, which was characteristic of the Asian strain. None of the isolates had the American or the European VZV profile (PstI+BglI-) but were similar to isolates from Africa and Asia (PstI+BglI+). Interestingly, one of the VZV strains isolated from a patient with chickenpox had the characteristic genotype of the vaccine strain PstI- BglI+ SmaI+. The genotype of the VZV in Sri Lanka is similar to the Asian VZV genotype and can be easily distinguished from the VZV vaccine strain by using the polymorphisms in ORF 38, ORF 54 and ORF 62.


Multicenter validation of a simplified score to predict massive transfusion in trauma.
Several studies have described predictive models to identify trauma patients who require massive transfusion (MT). Early identification of lethal exsanguination may improve survival in this patient population. The purpose of the current study was to validate a simplified score to predict MT at multiple Level I trauma centers. All adult trauma patients treated at three Level I trauma centers from July 2006 to June 2007 who (1) were transported directly from the scene, (2) were trauma activations, and (3) received any blood transfusions during admission were included. Assessment of Blood Consumption (ABC) score developed using the same inclusion criteria for patients admitted to a single trauma center (Vanderbilt University Medical Center [VUMC]-1) between July 2005 and June 2006. ABC score calculated by assigning a value (0 or 1) to each of the four parameters: penetrating mechanism, positive focused assessment with sonography for trauma for fluid, arrival blood pressure <90 mm Hg, and arrival pulse >120 bpm. A score of 2 was used as "positive" to predict MT. Area under receiver-operating characteristic curve was calculated to compare the predictive ability of the score at each institution. There were 586 patients in the developmental (VUMC-1), 513 patients at trauma center 1 (VUMC-2), 372 at trauma center 2 (PMH), and 133 at trauma center 3 (Johns Hopkins Hospital). MT rate was similar between centers: 14% to 15%. Sensitivity and specificity for the ABC score predicting MT ranged from 75% to 90% and 67% to 88%, respectively. Correctly classified patients and area under receiver-operating characteristic curve, however, were 84% to 87% and 0.83 to 0.90, respectively. The ABC score is a valid instrument to predict MT early in the patient's care and across various demographically diverse trauma centers. Future research should focus on this score's ability to prospectively identify patients who will receive MT.


Cancer epidemiology update, following the 2011 IARC evaluation of radiofrequency electromagnetic fields (Monograph 102).
Epidemiology studies (case-control, cohort, time trend and case studies) published since the International Agency for Research on Cancer (IARC) 2011 categorization of radiofrequency radiation (RFR) from mobile phones and other wireless devices as a possible human carcinogen (Group 2B) are reviewed and summarized. Glioma is an important human cancer found to be associated with RFR in 9 case-control studies conducted in Sweden and France, as well as in some other countries. Increasing glioma incidence trends have been reported in the UK and other countries. Non-malignant endpoints linked include acoustic neuroma (vestibular Schwannoma) and meningioma. Because they allow more detailed consideration of exposure, case-control studies can be superior to cohort studies or other methods in evaluating potential risks for brain cancer. When considered with recent animal experimental evidence, the recent epidemiological studies strengthen and support the conclusion that RFR should be categorized as carcinogenic to humans (IARC Group 1). Opportunistic epidemiological studies are proposed that can be carried out through cross-sectional analyses of high, medium, and low mobile phone users with respect to hearing, vision, memory, reaction time, and other indicators that can easily be assessed through standardized computer-based tests. As exposure data are not uniformly available, billing records should be used whenever available to corroborate reported exposures.


Suppression subtractive hybridization identifies bacterial genomic regions that are possibly involved in hBD-2 regulation by enterocytes.
Human β-defensin 2 (hBD-2) is an inducible antimicrobial peptide synthesized by the epithelium to counteract bacterial adherence and invasion. It has been suggested that probiotic bacteria sustain gut barrier function via induction of defensins. The goals of this study were (i) to evaluate the potential immunomodulatory effects of 11 different Lactobacillus fermentum strains isolated from Kimere, an African fermented pearl millet (Pennisetum glaucum) dough, on the hBD-2 secretion by human intestinal CaCo-2 cell line and (ii) to examine genetic differences between two strains of L. fermentum (K2-Lb4 and K11-Lb3) which differed in their effect on the production of hBD-2 in this study. Totally, 46 strains of L. fermentum from Kimere were isolated and characterized using molecular biology methods including pulsed-field gel electrophoresis patterns. After performing time- and dose-experiments, CaCo-2 cells were incubated with or without bacteria for 12 h. L. fermentum PZ1162 was included as the positive control. Cell-free supernatants were analyzed for hBD-2 protein by enzyme-linked immunosorbent assay (ELISA). To identify potential bacterial genes associated with hBD-2 regulation, suppression subtractive hybridization (SSH) was used. Among the 11 strains tested, only two strains of bacteria, K11-Lb3 and K2-Lb6, significantly induced the production of hBD-2 by CaCo-2 cells. This effect was strain-specific, dose-dependent and particularly seems to be bacterial genomic-dependent as manifested by SSH. L. fermentum strains with and without hBD-2 inducing effect differed in genes encoding proteins involved in glycosylation of cell-wall proteins e.g. glycosyltransferase, UDP-N-acetylglucosamine 2-epimerase, rod shape-determining protein MreC, lipoprotein precursors, sugar ABC transporters, and glutamine ABC transporter ATP-binding protein. This study implies that certain strains of L. fermentum isolated from Kimere may stimulate the intestinal innate defense through the induction of hBD-2. The molecular basis of hBD-2 induction by L. fermentum strain K11-Lb3 may be based on glycosylated cell-surface structures synthesized with the aid of glycosyltransferase, UDP-N-acetylglucosamine 2-epimerase, and rod shape-determining protein MreC.


CTRL+INSERT: retrotransposons and their contribution to regulation and innovation of the transcriptome.
The human genome contains millions of fragments from retrotransposons-highly repetitive DNA sequences that were once able to "copy and paste" themselves to other regions in the genome. However, the majority of retrotransposons have lost this capacity through acquisition of mutations or through endogenous silencing mechanisms. Without this imminent threat of transposition, retrotransposons have the potential to act as a major source of genomic innovation. Indeed, large numbers of retrotransposons have been found to be active in specific contexts: as gene regulatory elements and promoters for protein-coding genes or long noncoding RNAs, among others. In this review, we summarise recent findings about retrotransposons, with implications in gene expression regulation, the expansion of gene isoform diversity and the generation of long noncoding RNAs. We highlight key examples that demonstrate their role in cellular identity and their versatility as markers of cell states, and we discuss how their dysregulation may contribute to the formation of and possibly therapeutic response in human cancers.


Association of TRAF1, TRAF2, and TRAF3 with an Epstein-Barr virus LMP1 domain important for B-lymphocyte transformation: role in NF-kappaB activation.
The Epstein-Barr virus (EBV) transforming protein LMP1 appears to be a constitutively activated tumor necrosis factor receptor (TNFR) on the basis of an intrinsic ability to aggregate in the plasma membrane and an association of its cytoplasmic carboxyl terminus (CT) with TNFR-associated factors (TRAFs). We now show that in EBV-transformed B lymphocytes most of TRAF1 or TRAF3 and 5% of TRAF2 are associated with LMP1 and that most of LMP1 is associated with TRAF1 or TRAF3. TRAF1, TRAF2, and TRAF3 bind to a single site in the LMP1 CT corresponding to amino acids (aa) 199 to 214, within a domain which is important for B-lymphocyte growth transformation (aa 187 to 231). Further deletional and alanine mutagenesis analyses and comparison with TRAF binding sequences in CD40, in CD30, and in the LMP1 of other lymphycryptoviruses provide the first evidence that PXQXT/S is a core TRAF binding motif. The negative effects of point mutations in the LMP1(1-231) core TRAF binding motif on TRAF binding and NF-kappaB activation genetically link the TRAFs to LMP1(1-231)-mediated NF-kappaB activation. NF-kappaB activation by LMP1(1-231) is likely to be mediated by TRAF1/TRAF2 heteroaggregates since TRAF1 is unique among the TRAFs in coactivating NF-kappaB with LMP1(1-231), a TRAF2 dominant-negative mutant can block LMP1(1-231)-mediated NF-kappaB activation as well as TRAF1 coactivation, and 30% of TRAF2 is associated with TRAF1 in EBV-transformed B cells. TRAF3 is a negative modulator of LMP1(1-231)-mediated NF-kappaB activation. Surprisingly, TRAF1, -2, or -3 does not interact with the terminal LMP1 CT aa 333 to 386 which can independently mediate NF-kappaB activation. The constitutive association of TRAFs with LMP1 through the aa 187 to 231 domain which is important in NF-kappaB activation and primary B-lymphocyte growth transformation implicates TRAF aggregation in LMP1 signaling.


Pediatric and Adolescent Forearm Fractures: Current Controversies and Treatment Recommendations.
Pediatric and adolescent forearm fractures continue to present treatment challenges. Despite high-level evidence to the contrary, traditional guidelines for nonsurgical treatment have been challenged in favor of surgical intervention, but it is unclear if this results in improved outcomes. Recent evidence suggests that certain open fractures in children may be successfully treated nonsurgically. Good results have been achieved with closed reduction and appropriate casting and clinical follow-up. Further research investigating functional outcomes into adulthood is needed.


Tweaking Electrical and Dielectric Properties of Nickel Oxide Nanocrystals by Varying the Surfactant.
The influence of cationic cetyltrimethylammonium bromide (CTAB) and neutral polymeric polyvinylpyrrolidone (PVP) surfactants on electrical and dielectric properties of NiO nanocrystals is investigated. It is demonstrated that, compressive strain of nanocrystals is higher with PVP than that of CTAB. Consequently surfactant type has significant influence on intrinsic defects of nanocrystals. This is attributed to the difference in stabilization of metallic ions against agglomeration that leads to variation in rate of hydrolysis. Particularly, in the case of PVP assisted synthesis, higher stabilization leads to slow nucleation rate with lower defect density. As a result the hopping time of charge carriers decreases which in turn enhances the conductivity of nanocrystals as evidenced from the shifting of dielectric loss peak to higher frequency.


Magnetocardiography study on ventricular depolarization-current pattern in patients with brugada syndrome and complete right-bundle branch blocks.
The objective of this study is to use magnetocardiography to determine the existence of a small abnormal current during ventricular depolarization in patients with Brugada syndrome. To understand this small difference in abnormal current during ventricular depolarization, we compared abnormal currents of patients with cases of complete right-bundle-branch block (CRBBB). We developed a whole-heart electrical bull's eye map (WHEBEM) that uses magnetocardiograms (MCGs) to visualize the current distribution in a circular map. MCGs of Brugada syndrome patients (n = 16), CRBBB patients (n = 10), and controls (n = 12) at rest were recorded. In the WHEBEMs of Brugada syndrome patients, the magnitude of the S-wave current in the upper-right direction of the anterior side is larger than that of the controls. In addition, the R-wave current direction is similar to that of the controls, and the R-wave vector is distributed over a larger area than that of the controls. On the other hand, the CRBBB patients have a distribution of R-wave currents over a larger area in the left anteromedian region and the left posteromedian region. Moreover, in all CRBBB patients, S-wave currents with a large magnitude have the same direction distributed over a small area. The WHEBEM findings suggest that there is an abnormal current in the direction to the upper right (in the S-wave) in the anterosuperior region of Brugada syndrome patients. We thus conclude that a WHEBEM has the potential to detect characteristics of heart disease.


Laparoscopic distal pancreatectomy with regional lymphadenectomy through retroperitoneal-first laparoscopic approach (Retlap) for locally advanced pancreatic body cancer.
Laparoscopic distal pancreatectomy (LDP) is widely performed [1,2]. However, LDP with regional lymphadenectomy for locally advanced pancreatic cancer (LAPC) is technically demanding [3]. We previously reported a new strategy named "retroperitoneal-first laparoscopic approach (Retlap)" for distal pancreatectomy with en bloc celiac axis resection [4]. In this study, Retlap is applied during LDP with regional lymphadenectomy (see Fig. 1). This video demonstrates the case of a 70-year-old woman with a 100 × 40-mm LAPC. Preoperative computed tomography revealed a large tumor near the root of the celiac axis and acute pancreatitis in the pancreatic head. An ample dorsal margin should be secured and regional lymphadenectomy performed because of the large tumor. In Retlap, the celiac axis was exposed using the retroperitoneal approach from the dorsal side of the pancreatic body, and then the left adrenal grand and left celiac ganglion were removed. Without interfering with the tumor, the root of the splenic artery was identified, facilitating easy performance of lymphadenectomy around the celiac axis and superior mesenteric artery in Retlap. After dividing the splenic artery, the procedure was converted to laparoscopic approach and resection was completed. The operative time and estimated blood loss were 487 min and 45 mL, respectively. Pathological examination confirmed a negative surgical margin, and R0 resection was achieved with uneventful postoperative course. Retlap was technically feasible and useful for achieving adequate and secure surgical margin and regional lymphadenectomy. Retlap can help secure the operative field of view in difficult cases of LAPC.


The characterization and differentiation of higher plants by fourier transform infrared spectroscopy.
Several techniques have been used to identify and classify plants. We proposed Fourier transform infrared (FT-IR) spectroscopy, together with hierarchical cluster analysis, as a rapid and noninvasive technique to differentiate plants based on their leaf fragments. We applied this technique to three different genera, namely, Ranunculus (Ranunculaceae), Acantholimon (Plumbaginaceae), and Astragalus (Leguminoseae). All of these genera are angiosperms and include a large number of species in Turkey. Ranunculus and Acantholimon have ornamental importance, while Astragalus is an important pharmaceutical genus. The FT-IR spectra revealed dramatic differences, which indicated the variations in lipid metabolism, carbohydrate composition, and protein conformation of the genera. Moreover, cell wall polysaccharides including diverse groups could be identified for each genus. Acantholimon was found to have the highest hydrogen capacity in its polysaccharide and proteins. A higher lignin content and a lower occurrence of decarboxylation and pectin esterification reactions were appointed for Ranunculus and Astragalus compared to Acantholimon. All these results suggested that FT-IR spectroscopy can be successfully applied to differentiate genera, as demonstrated here with Ranunculus, Astragalus, and Acantholimon. In addition, we used this technique to identify the same species from different geographical regions. In conclusion, the current FT-IR study presents a novel method for rapid and accurate molecular characterization and identification of plants based on the compositional and structural differences in their macromolecules.


Differential gene expression and aging.
It has been established that an intricate program of gene expression controls progression through the different stages in development. The equally complex biological phenomenon known as aging is genetically determined and environmentally modulated. This review focuses on the genetic component of aging, with a special emphasis on differential gene expression. At least two genetic pathways regulating organism longevity act by modifying gene expression. Many genes are also subjected to age-dependent transcriptional regulation. Some age-related gene expression changes are prevented by caloric restriction, the most robust intervention that slows down the aging process. Manipulating the expression of some age-regulated genes can extend an organism's life span. Remarkably, the activity of many transcription regulatory elements is linked to physiological age as opposed to chronological age, indicating that orderly and tightly controlled regulatory pathways are active during aging.


Recommendations on COVID-19 triage: international comparison and ethical analysis.
On March 11, 2020 the World Health Organization classified COVID-19, caused by Sars-CoV-2, as a pandemic. Although not much was known about the new virus, the first outbreaks in China and Italy showed that potentially a large number of people worldwide could fall critically ill in a short period of time. A shortage of ventilators and intensive care resources was expected in many countries, leading to concerns about restrictions of medical care and preventable deaths. In order to be prepared for this challenging situation, national triage guidance has been developed or adapted from former influenza pandemic guidelines in an increasing number of countries over the past few months. In this article, we provide a comparative analysis of triage recommendations from selected national and international professional societies, including Australia/New Zealand, Belgium, Canada, Germany, Great Britain, Italy, Pakistan, South Africa, Switzerland, the United States, and the International Society of Critical Care Medicine. We describe areas of consensus, including the importance of prognosis, patient will, transparency of the decision-making process, and psychosocial support for staff, as well as the role of justice and benefit maximization as core principles. We then probe areas of disagreement, such as the role of survival versus outcome, long-term versus short-term prognosis, the use of age and comorbidities as triage criteria, priority groups and potential tiebreakers such as 'lottery' or 'first come, first served'. Having explored a number of tensions in current guidance, we conclude with a suggestion for framework conditions that are clear, consistent and implementable. This analysis is intended to advance the ongoing debate regarding the fair allocation of limited resources and may be relevant for future policy-making.


Variation in MHC expression between undifferentiated mouse ES cells and ES cell-derived insulin-producing cell clusters.
The progeny of embryonic stem (ES) cells may eventually be used to replace damaged tissues in transplantation, yet their immunogenicity remains ill-defined. The major histocompatibility complex (MHC) is a determinant of immunogenicity in transplantation. Herein, we show differences in MHC expression between mouse ES cells and ES cell derived insulin producing cell clusters (IPCCs), including a relatively higher expression of MHC Class I in IPCCs and a faster, more dramatic induction of MHC Class I in IPCCs following challenge with interferon-gamma (IFN-gamma). MHC Class II was induced on IPCCs, but not ES cells, after exposure to IFN-gamma. Transplantation of syngeneic or allogeneic IPCCs was insufficient to trigger up-regulation of MHC class I within three days after transplantation. These data highlight differences in MHC expression between ES cells and a fully differentiated ES cell derived tissue and suggest how the progeny of ES cells may be susceptible to rejection after transplantation.


Bispecific antibodies for cancer therapy: the light at the end of the tunnel?
With 23 approvals in the US and other countries and four approvals outside US, antibodies are now widely recognized as therapeutic molecules. The therapeutic and commercial successes met by rituximab, trastuzumab, cetuximab and other mAbs have inspired antibody engineers to improve the efficacy of these molecules. Consequently, a new wave of antibodies with engineered Fc leading to much higher effector functions such as antibody-dependent cell-mediated cytotoxicity or complement-dependent cytotoxicity is being evaluated in the clinic, and several approvals are expected soon. In addition, research on a different class of antibody therapeutics, bispecific antibodies, has recently led to outstanding clinical results, and the first approval of the bispecific antibody catumaxomab, a T cell retargeting agent that was approved in the European Union in April 2009. This review describes the most recent advances and clinical study results in the field of bispecific antibodies, a new class of molecules that might outshine conventional mAbs as cancer immunotherapeutics in a near future.


Biochemical analyses reveal amino acid residues critical for cell cycle-dependent phosphorylation of human Cdc14A phosphatase by cyclin-dependent kinase 1.
Cdc14 enzymes compose a family of highly conserved phosphatases that are present in a wide range of organisms, including yeast and humans, and that preferentially reverse the phosphorylation of Cyclin-Dependent Kinase (Cdk) substrates. The budding yeast Cdc14 orthologue has essential functions in the control of late mitosis and cytokinesis. In mammals, however, the two Cdc14 homologues, Cdc14A and Cdc14B, do not play a prominent role in controlling late mitotic events, suggesting that some Cdc14 functions are not conserved across species. Moreover, in yeast, Cdc14 is regulated by changes in its subcellular location and by phosphorylation events. In contrast, little is known about the regulation of human Cdc14 phosphatases. Here, we have studied how the human Cdc14A orthologue is regulated during the cell cycle. We found that Cdc14A is phosphorylated on Ser411, Ser453 and Ser549 by Cdk1 early in mitosis and becomes dephosphorylated during late mitotic stages. Interestingly, in vivo and in vitro experiments revealed that, unlike in yeast, Cdk1-mediated phosphorylation of human Cdc14A did not control its catalytic activity but likely modulated its interaction with other proteins in early mitosis. These findings point to differences in Cdk1-mediated mechanisms of regulation between human and yeast Cdc14 orthologues.


Boswellia serrata acts on cerebral edema in patients irradiated for brain tumors: a prospective, randomized, placebo-controlled, double-blind pilot trial.
Patients irradiated for brain tumors often suffer from cerebral edema and are usually treated with dexamethasone, which has various side effects. To investigate the activity of Boswellia serrata (BS) in radiotherapy-related edema, we conducted a prospective, randomized, placebo-controlled, double-blind, pilot trial. Forty-four patients with primary or secondary malignant cerebral tumors were randomly assigned to radiotherapy plus either BS 4200 mg/day or placebo. The volume of cerebral edema in the T2-weighted magnetic resonance imaging (MRI) sequence was analyzed as a primary endpoint. Secondary endpoints were toxicity, cognitive function, quality of life, and the need for antiedematous (dexamethasone) medication. Blood samples were taken to analyze the serum concentration of boswellic acids (AKBA and KBA). Compared with baseline and if measured immediately after the end of radiotherapy and BS/placebo treatment, a reduction of cerebral edema of >75% was found in 60% of patients receiving BS and in 26% of patients receiving placebo (P = .023). These findings may be based on an additional antitumor effect. There were no severe adverse events in either group. In the BS group, 6 patients reported minor gastrointestinal discomfort. BS did not have a significant impact on quality of life or cognitive function. The dexamethasone dose during radiotherapy in both groups was not statistically different. Boswellic acids could be detected in patients' serum. BS significantly reduced cerebral edema measured by MRI in the study population. BS could potentially be steroid-sparing for patients receiving brain irradiation. Our findings will need to be further validated in larger studies.


An E2F7-dependent transcriptional program modulates DNA damage repair and genomic stability.
The cellular response to DNA damage is essential for maintaining the integrity of the genome. Recent evidence has identified E2F7 as a key player in DNA damage-dependent transcriptional regulation of cell-cycle genes. However, the contribution of E2F7 to cellular responses upon genotoxic damage is still poorly defined. Here we show that E2F7 represses the expression of genes involved in the maintenance of genomic stability, both throughout the cell cycle and upon induction of DNA lesions that interfere with replication fork progression. Knockdown of E2F7 leads to a reduction in 53BP1 and FANCD2 foci and to fewer chromosomal aberrations following treatment with agents that cause interstrand crosslink (ICL) lesions but not upon ionizing radiation. Accordingly, E2F7-depleted cells exhibit enhanced cell-cycle re-entry and clonogenic survival after exposure to ICL-inducing agents. We further report that expression and functional activity of E2F7 are p53-independent in this context. Using a cell-based assay, we show that E2F7 restricts homologous recombination through the transcriptional repression of RAD51. Finally, we present evidence that downregulation of E2F7 confers an increased resistance to chemotherapy in recombination-deficient cells. Taken together, our results reveal an E2F7-dependent transcriptional program that contributes to the regulation of DNA repair and genomic integrity.


Graphene Nanoplatelet (GNPs) Doped Carbon Nanofiber (CNF) System: Effect of GNPs on the Graphitic Structure of Creep Stress and Non-Creep Stress Stabilized Polyacrylonitrile (PAN).
Improving the graphitic structure in carbon nanofibers (CNFs) is important for exploiting their potential in mechanical, electrical and electrochemical applications. Typically, the synthesis of carbon fibers with a highly graphitized structure demands a high temperature of almost 2500 °C. Furthermore, to achieve an improved graphitic structure, the stabilization of a precursor fiber has to be assisted by the presence of tension in order to enhance the molecular orientation. Keeping this in view, herein we report on the fabrication of graphene nanoplatelets (GNPs) doped carbon nanofibers using electrospinning followed by oxidative stabilization and carbonization. The effect of doping GNPs on the graphitic structure was investigated by carbonizing them at various temperatures (1000 °C, 1200 °C, 1500 °C and 1700 °C). Additionally, a stabilization was achieved with and without constant creep stress (only shrinkage stress) for both pristine and doped precursor nanofibers, which were eventually carbonized at 1700 °C. Our findings reveal that the GNPs doping results in improving the graphitic structure of polyacrylonitrile (PAN). Further, in addition to the templating effect during the nucleation and growth of graphitic crystals, the GNPs encapsulated in the PAN nanofiber matrix act in-situ as micro clamp units performing the anchoring function by preventing the loss of molecular orientation during the stabilization stage, when no external tension is applied to nanofiber mats. The templating effect of the entire graphitization process is reflected by an increased electrical conductivity along the fibers. Simultaneously, the electrical anisotropy is reduced, i.e., the GNPs provide effective pathways with improved conductivity acting like bridges between the nanofibers resulting in an improved conductivity across the fiber direction compared to the pristine PAN system.


XRCC4 deficiency in human subjects causes a marked neurological phenotype but no overt immunodeficiency.
Nonhomologous end-joining (NHEJ) is the major DNA double-strand break (DSB) repair mechanism in human cells. The final rejoining step requires DNA ligase IV (LIG4) together with the partner proteins X-ray repair cross-complementing protein 4 (XRCC4) and XRCC4-like factor. Patients with mutations in genes encoding LIG4, XRCC4-like factor, or the other NHEJ proteins DNA-dependent protein kinase catalytic subunit and Artemis are DSB repair defective and immunodeficient because of the requirement for NHEJ during V(D)J recombination. We found a patient displaying microcephaly and progressive ataxia but a normal immune response. We sought to determine pathogenic mutations and to describe the molecular pathogenesis of the patient. We performed next-generation exome sequencing. We evaluated the DSB repair activities and V(D)J recombination capacity of the patient's cells, as well as performing a standard blood immunologic characterization. We identified causal mutations in the XRCC4 gene. The patient's cells are radiosensitive and display the most severe DSB repair defect we have encountered using patient-derived cell lines. In marked contrast, a V(D)J recombination plasmid assay revealed that the patient's cells did not display the junction abnormalities that are characteristic of other NHEJ-defective cell lines. The mutant protein can interact efficiently with LIG4 and functions normally in in vitro assays and when transiently expressed in vivo. However, the mutation makes the protein unstable, and it undergoes proteasome-mediated degradation. Our findings reveal a novel separation of impact phenotype: there is a pronounced DSB repair defect and marked clinical neurological manifestation but no clinical immunodeficiency.


Effects of healthcare reforms on coverage, access, and disparities: quasi-experimental analysis of evidence from Massachusetts.
The 2010 Patient Protection and Affordable Care Act (PPACA) has been controversial. The potential impact of national healthcare reform may be considered using a similar set of state-level reforms including exchanges and a mandate, enacted in 2006 in Massachusetts. To evaluate the effects of reforms on healthcare access, affordability, and disparities. Interrupted time series with comparison series. Longitudinal survey data from 2002 to 2009 from the Behavioral Risk Factor Surveillance System including 178,040 nonelderly adults residing in Massachusetts, Vermont, New Hampshire, Rhode Island, and Connecticut. Analysis was conducted from January to August 2010. Massachusetts 2006 healthcare reform, which included an individual health insurance mandate. Being uninsured, having no personal doctor, and forgoing care because of cost, evaluated in Massachusetts and four comparison states before (2002-2005) and after (2007-2009) the healthcare reform. Effects on disparities defined by race, education, income, and employment also were assessed. Living in Massachusetts in 2009 was associated with a 7.6 percentage point (95% CI=3.9, 11.3) higher probability of being insured; 4.8 percentage point (-0.9, 10.6) lower probability of forgoing care because of cost; and a 6.6 percentage point (1.9, 11.3) higher probability of having a personal doctor, compared to expected levels in the absence of reform, defined by trends in control states and adjusting for socioeconomic factors. The effects of the reform on insurance coverage attenuated from 2008 to 2009. In a socioeconomically disadvantaged group, the reforms had a greater effect in improving outcomes on the absolute but not relative scale. Healthcare reforms in Massachusetts, which included a health insurance mandate, were associated with significant increases in insurance coverage and access. The absolute effects of the reform were greater for disadvantaged populations. This is important evidence to consider as debate over national healthcare reform continues.


Copper(i)-mediated carboamination of vinyl azides by aryldiazonium salts: synthesis of N2-substituted 1,2,3-triazoles.
A copper(i)-mediated carboamination cascade reaction between vinyl azides and aryldiazonium salts is described. Functionally diverse N2-substituted 1,2,3-triazoles were obtained in moderate to good yields through novel difunctionalization of vinyl azides by aryldiazonium salt sources. This method has a wide scope, good functional-group tolerance and insensitivity to an ambient atmosphere.


NADPH oxidase 4 is expressed in pulmonary artery adventitia and contributes to hypertensive vascular remodeling.
Pulmonary hypertension (PH) is a progressive disease arising from remodeling and narrowing of pulmonary arteries (PAs) resulting in high pulmonary blood pressure and ultimately right ventricular failure. Elevated production of reactive oxygen species by NADPH oxidase 4 (Nox4) is associated with increased pressure in PH. However, the cellular location of Nox4 and its contribution to aberrant vascular remodeling in PH remains poorly understood. Therefore, we sought to identify the vascular cells expressing Nox4 in PAs and determine the functional relevance of Nox4 in PH. Elevated expression of Nox4 was detected in hypertensive PAs from 3 rat PH models and human PH using qualititative real-time reverse transcription polymerase chain reaction, Western blot, and immunofluorescence. In the vascular wall, Nox4 was detected in both endothelium and adventitia, and perivascular staining was prominently increased in hypertensive lung sections, colocalizing with cells expressing fibroblast and monocyte markers and matching the adventitial location of reactive oxygen species production. Small-molecule inhibitors of Nox4 reduced adventitial reactive oxygen species generation and vascular remodeling as well as ameliorating right ventricular hypertrophy and noninvasive indices of PA stiffness in monocrotaline-treated rats as determined by morphometric analysis and high-resolution digital ultrasound. Nox4 inhibitors improved PH in both prevention and reversal protocols and reduced the expression of fibroblast markers in isolated PAs. In fibroblasts, Nox4 overexpression stimulated migration and proliferation and was necessary for matrix gene expression. These findings indicate that Nox4 is prominently expressed in the adventitia and contributes to altered fibroblast behavior, hypertensive vascular remodeling, and development of PH.


15-deoxy-δ12,14-prostaglandin j2 inhibits osteolytic breast cancer bone metastasis and estrogen deficiency-induced bone loss.
Breast cancer is the major cause of cancer death in women worldwide. The most common site of metastasis is bone. Bone metastases obstruct the normal bone remodeling process and aberrantly enhance osteoclast-mediated bone resorption, which results in osteolytic lesions. 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2) is an endogenous ligand of peroxisome proliferator-activated receptor gamma (PPARγ) that has anti-inflammatory and antitumor activity at micromolar concentrations through PPARγ-dependent and/or PPARγ-independent pathways. We investigated the inhibitory activity of 15d-PGJ2 on the bone loss that is associated with breast cancer bone metastasis and estrogen deficiency caused by cancer treatment. 15d-PGJ2 dose-dependently inhibited viability, migration, invasion, and parathyroid hormone-related protein (PTHrP) production in MDA-MB-231 breast cancer cells. 15d-PGJ2 suppressed receptor activator of nuclear factor kappa-B ligand (RANKL) mRNA levels and normalized osteoprotegerin (OPG) mRNA levels in hFOB1.19 osteoblastic cells treated with culture medium from MDA-MB-231 cells or PTHrP, which decreased the RANKL/OPG ratio. 15d-PGJ2 blocked RANKL-induced osteoclastogenesis and inhibited the formation of resorption pits by decreasing the activities of cathepsin K and matrix metalloproteinases, which are secreted by mature osteoclasts. 15d-PGJ2 exerted its effects on breast cancer and bone cells via PPARγ-independent pathways. In Balb/c nu/nu mice that received an intracardiac injection of MDA-MB-231 cells, subcutaneously injected 15d-PGJ2 substantially decreased metastatic progression, cancer cell-mediated bone destruction in femora, tibiae, and mandibles, and serum PTHrP levels. 15d-PGJ2 prevented the destruction of femoral trabecular structures in estrogen-deprived ICR mice as measured by bone morphometric parameters and serum biochemical data. Therefore, 15d-PGJ2 may be beneficial for the prevention and treatment of breast cancer-associated bone diseases.


Binding multidentate ligands to Ni2+: kinetic identification of preferential binding sites.
The kinetics of the reactions between [Ni(MeOH)6](2+) (hereafter Ni(2+)) and a variety of neutral Schiff base multidentate ligands have been measured in methanol at 25.0 °C using stopped-flow spectrophotometry. The ligands contain a variety of different potential donor sites (phenolic OH, imine N, pyridyl N and NH groups), different structural components and substituents. The kinetic studies explore how systematic changes to the composition of the ligands affect the rates of binding. The results are consistent with the Eigen-Wilkins mechanism in which the ligand initially forms an outer-sphere association with Ni(2+) prior to dissociation of a coordinated solvent molecule and binding to the metal ion. The general features that emerge from these studies are as follows. (i) For ligands with the same donor set, the rates of binding are all similar irrespective of changes to the ligand framework (bridge and substituents). (ii) Comparison of structurally analogous ligands shows that the presence of pyridyl or NH groups in the multidentate results in significantly faster reactions. (iii) With ligands containing multiple NH groups, the rate of ligand binding increases as the number of NH groups increases. The extent to which these kinetic features can be attributed to preferential binding of particular donor groups is discussed.


Effects of interval training on quality of life and cardiometabolic risk markers in older adults: a randomized controlled trial.
To explore the effects of 10 weeks of progressive vigorous interval training as a single intervention on health-related quality of life (HRQoL) and cardiometabolic risk markers in centrally obese 70-year-old individuals. A randomized controlled trial (ClinicalTrials.gov registration no. NCT03450655) including seventy-seven community-dwelling 70-year-old men and women with central obesity defined as > 1 kg visceral adipose tissue for women and > 2 kg for men. Participants randomized to the intervention group were offered a 10-week progressive vigorous interval training program performed three times per week. Control subjects were asked to maintain their daily living and routines throughout the trial. All participants in both groups had received tailored lifestyle recommendations focused on diet and physical activity at one occasion within 12 months prior to trial initiation. Prespecified outcome measures included: changes in HRQoL using the Short Form Health Survey Questionnaire (SF-36), blood pressure; resting heart rate (HR) and blood lipids. All analyses were conducted on an intention-to-treat basis. The intervention resulted in significant effects on the SF-36 mental component summary (MCS) score and the mental health (MH) subscale (P< 0.05 for both), when compared to the control group. Specifically, the intervention group increased their MCS score by 6.3 points (95% confidence interval [CI] = 0.3-12.3) and their MH score by 6.0 points (95% CI = 1.7-10.4) compared to the control group. Moreover, significant effects were seen on resting HR, total cholesterol and LDL-cholesterol (P<0.05 for all). It was shown that 10 weeks of vigorous interval training as a single intervention was sufficient to improve mental aspects of HRQoL in older individuals with central obesity, which is a critical aspect of healthy ageing. Positive effects were seen also on cardiometabolic risk markers.


Myocardial contractile efficiency increases in proportion to a fetal enzyme shift in chronically infarcted rat hearts.
Changes in creatine kinase (CK) and lactate dehydrogenase (LDH) isoform expression occur in residual tissue after myocardial infarction. It is unknown how these changes correlate with cardiac remodeling, contractile performance and efficiency. Rats were subjected to left coronary artery ligation (MI) or sham operation (sham). Left ventricular end-diastolic pressure (EDP) was measured in vivo 8 weeks later. Hearts were isolated, buffer-perfused (Langendorff) at constant pressure and isovolumetric left ventricular (LV) pressure-volume (PV) curves were recorded. LV PV areas (PVA) were calculated and related to oxygen consumption. Biopsies of intact left ventricular tissue were taken for biochemical measurements. Correlations between in vivo EDP and biochemical parameters were found: Total CK activity (r = -.47, p = .022), CK isoenzyme percentage for BB (r = +.57, p = .004), MB (r = +.54, p = .006) and CK-mito (r = -.51, p = .012), total creatine content (r = -.61, p = .002) and the ratio of LDH5/LDH1 (r = .49, p = .016). Correlations were also detected for left ventricular volume and PVAs at in vivo EDP demonstrating that the extent of CK and LDH system alterations correlate with the extent of LV dilatation and mechanical energy requirements. The slope of the MVO(2)-PVA relation decreased significantly with increasing values of in vivo EDP (r = -.68, p = 0.0003) indicating increased contractile ef.ciency. Improved efficiency correlated with the increase in fetal CK isoenzyme expression. Thus, contractile efficiency increases parallel to the extent of left ventricular dilatation and dysfunction. CK and LDH system changes in residual intact myocardium also occur proportional to LV dysfunction.


Genetic Factors and Genotype-Environment Interactions Contribute to Variation in Melanin Production in the Fungal Pathogen Cryptococcus neoformans.
Cryptococcosis is a common opportunistic fungal infection that often disseminates into the central nervous system, leading to meningitis. Production of melanin pigments during infections is one of the most important virulence factors of its causal agent, the human pathogenic yeast Cryptococcus neoformans species complex. However, almost nothing is known about the patterns of variation in melanin production among clinical and environmental strains and the potential effects of such variations on virulence. In this study, we assembled a global collection of C. neoformans var. neoformans strains and investigated their patterns of melanin variation and potential contributors to such variations. Our analyses revealed that genetic differences and genotype-environment interactions explained up to 59% and 43% of the population's melanin variance respectively, depending on the tested environments. In comparison, environmental factors alone contributed relatively little to melanin variance. We also identified specific changes within the LAC1 gene, whose protein product catalyzes melanin synthesis, to be associated with variable melanin levels. This study provides fresh insights into the origin and evolution of virulence traits in fungal pathogens while highlighting the complex interplay between genetic and environmental factors that lead to phenotypic variance.


Recurrent Aphthous Stomatitis as a Result of Zinc Deficiency.
The purpose of this study is to evaluate the results of patients, with a chief complaint of recurrent aphthous stomatitis (RAS), who were found to have zinc deficiency as the predisposing factor and received appropriate replacement therapy. A retrospective study was conducted using data from the medical records of patients with a chief complaint of RAS. Patients with potential ulcer-causing conditions were excluded. All patients were intraorally examined to rule out trauma-associated aetiologies. Blood tests were ordered to measure total blood count, serum transferrin, ferritin, zinc, folic acid and vitamin B12 levels. A total of 48 patients, 34 with zinc deficiency and 14 with both zinc and iron deficiencies, were included in this study. Patients received an initial three-monthly replacement treatment and blood tests for the certain deficiencies were repeated at the end of this time interval. Two patients with zinc deficiency reported no relief due to incorrect intake of tablets with milk. Following correct instructions, all patients reached normal serum mineral levels and reported no recurrences. All patients remained asymptomatic and their mineral levels were monitored in every 3 months to detect any abnormalities. Overall mean follow-up for this study was 12.06 months (range: 8-28 months, SD: ± 5.7). Zinc deficiency should be considered and investigated as part of the diagnostic process of RAS. A simple blood test may aid in correct diagnosis and complete resolution of this recurring condition rather than constant prescription of certain medicines to suppress the symptoms.


Targeting shear gradient activated von Willebrand factor by the novel single-chain antibody A1 reduces occlusive thrombus formation in vitro.
Intraluminal thrombus formation precipitates conditions such as acute myocardial infarction and disturbs local blood flow resulting in areas of rapidly changing blood flow velocities and steep gradients of blood shear rate. Shear rate gradients are known to be pro-thrombotic with an important role for the shear-sensitive plasma protein von Willebrand factor (VWF). Here, we developed a single-chain antibody (scFv) that targets a shear gradient specific conformation of VWF to specifically inhibit platelet adhesion at sites of SRGs but not in areas of constant shear. Microfluidic flow channels with stenotic segments were used to create shear rate gradients during blood perfusion. VWF-GPIbα interactions were increased at sites of shear rate gradients compared to constant shear rate of matched magnitude. The scFv-A1 specifically reduced VWF-GPIbα binding and thrombus formation at sites of SRGs but did not block platelet deposition and aggregation under constant shear rate in upstream sections of the channels. Significantly, the scFv A1 attenuated platelet aggregation only in the later stages of thrombus formation. In the absence of shear, direct binding of scFv-A1 to VWF could not be detected and scFV-A1 did not inhibit ristocetin induced platelet agglutination. We have exploited the pro-aggregatory effects of SRGs on VWF dependent platelet aggregation and developed the shear-gradient sensitive scFv-A1 antibody that inhibits platelet aggregation exclusively at sites of shear rate gradients. The lack of VWF inhibition in non-stenosed vessel segments places scFV-A1 in an entirely new class of anti-platelet therapy for selective blockade of pathological thrombus formation while maintaining normal haemostasis.


Unclaimed prescriptions after automated prescription transmittals to pharmacies.
To assess the extent of and the reasons for unclaimed prescriptions, primary non-compliance, after automated transmittals to pharmacies. Cross-sectional study in 3 health care districts (population 240,000) in the southernmost of Sweden on unclaimed electronic prescriptions (e-prescriptions), transmitted to 21 pharmacies during the period of 3 months (2000) and semi-structured interview study with patients not claiming their e-prescriptions transmitted to 4 pharmacies during a period of 3 weeks (2001). Proportion of unclaimed e-prescriptions of total number of (dispensed and unclaimed) e-prescriptions and reasons for primary non-compliance. In total, 2171 (2.4%) e-prescriptions remained unclaimed at the pharmacies. The peak non-redemption rate was observed for those 15-24 years old (5.5%). The lowest rate was observed for those 65-74 years old. Men had a higher non-redemption rate than women. The highest rate for men was observed 25-34 years old (6.6%). Drugs for the musculoskeletal system (ATC group M) had higher non-redemption rates than expected (3.9%), and antibiotics (ATC-group J) lower (1.7%). Adolescents and young adults, 15-24 years old, had high non-compliance rates for drugs for the musculoskeletal system (14%) and anti-asthmatic drugs (11%). Of 78 interviewed patients, not claiming their e-prescriptions, 61% reported no need to have the prescription dispensed. However, unintentional non-compliance was reported by 28%, most of them were not aware that a prescription had been transmitted to the pharmacy. Thirteen percent reported that non-redemption had given further medical problems or made obtaining a new prescription necessary. Primary non-compliance was generally low, but there were differences related to age, gender and type of drugs. The most common reason reported for non-redemption was that the prescription was not needed, but some patients were unaware that prescriptions were issued and transmitted to the pharmacy.


The potential and flux landscape theory of evolution.
We established the potential and flux landscape theory for evolution. We found explicitly the conventional Wright's gradient adaptive landscape based on the mean fitness is inadequate to describe the general evolutionary dynamics. We show the intrinsic potential as being Lyapunov function(monotonically decreasing in time) does exist and can define the adaptive landscape for general evolution dynamics for studying global stability. The driving force determining the dynamics can be decomposed into gradient of potential landscape and curl probability flux. Non-zero flux causes detailed balance breaking and measures how far the evolution from equilibrium state. The gradient of intrinsic potential and curl flux are perpendicular to each other in zero fluctuation limit resembling electric and magnetic forces on electrons. We quantified intrinsic energy, entropy and free energy of evolution and constructed non-equilibrium thermodynamics. The intrinsic non-equilibrium free energy is a Lyapunov function. Both intrinsic potential and free energy can be used to quantify the global stability and robustness of evolution. We investigated an example of three allele evolutionary dynamics with frequency dependent selection (detailed balance broken). We uncovered the underlying single, triple, and limit cycle attractor landscapes. We found quantitative criterions for stability through landscape topography. We also quantified evolution pathways and found paths do not follow potential gradient and are irreversible due to non-zero flux. We generalized the original Fisher's fundamental theorem to the general (i.e., frequency dependent selection) regime of evolution by linking the adaptive rate with not only genetic variance related to the potential but also the flux. We show there is an optimum potential where curl flux resulting from biotic interactions of individuals within a species or between species can sustain an endless evolution even if the physical environment is unchanged. We offer a theoretical basis for explaining the corresponding Red Queen hypothesis proposed by Van Valen. Our work provides a theoretical foundation for evolutionary dynamics.


Decreases of brain serotonin following a food restriction schedule of 4 weeks in male and female rats.
Male and female rats fed on a restricted feeding (RF) schedule of 4 weeks to produce 20-25% reduction in body weight, were killed before (starved) and after (fed) the presentation of food to compare 5-hydroxytryptamine (5-HT) metabolism in the hypothalamus with respective freely feeding (FF) controls and to monitor sex differences in RF-induced changes of 5-HT. RF decreased plasma tryptophan concentration in RF starved and RF fed females and also in RF starved males. In the hypothalamus tryptophan levels decreased in RF starved and RF fed female rats and RF fed males. 5-HT decreased in both RF starved and RF fed male and female rats and the decreases were comparable in the two sexes. 5-hydroxyindoleacetic acid (5-HIAA), a major metabolite of 5-HT was not affected. Food restriction decreased 5-HT concentration in the rest of the brain of male but not female rats. Possible implications of the findings in the pathogenesis of food restriction/starvation related disease anorexia nervosa and its greater occurrence in women than men is discussed.


Oligozoospermia: a seven-year survey of the incidence, chromosomal aberrations, treatment and pregnancy rate.
No sperm count should be regarded too low to consider extensive treatment in order to improve semen or to correct any possible abnormalities in femal partners. The infertile couple should be given devoted care and advice to improve their sexual relations and their psychological attitude towards the problem of infertility. A pregnancy rate of 51.9% where the husband's count was less than 10 million/ml, offers adequate support for this statement. In cases of mental trauma inflicted on patients by a verdict of inability to achieve parenthood--on people who have already suffered severe psychological shock and tension resulting from a period of infertility--discouragement lessens the already doubtful chances of achieving pregnancy. In no circumstance should oligozoospermic patients receive treatment for infertility unless a chromosomal analysis has been completed and found normal, since our rate of chromosomal anomalies (11.4%) in a group of oligozoospermic patients is considered to be too high.


Mindfulness meditation-related pain relief: evidence for unique brain mechanisms in the regulation of pain.
The cognitive modulation of pain is influenced by a number of factors ranging from attention, beliefs, conditioning, expectations, mood, and the regulation of emotional responses to noxious sensory events. Recently, mindfulness meditation has been found attenuate pain through some of these mechanisms including enhanced cognitive and emotional control, as well as altering the contextual evaluation of sensory events. This review discusses the brain mechanisms involved in mindfulness meditation-related pain relief across different meditative techniques, expertise and training levels, experimental procedures, and neuroimaging methodologies. Converging lines of neuroimaging evidence reveal that mindfulness meditation-related pain relief is associated with unique appraisal cognitive processes depending on expertise level and meditation tradition. Moreover, it is postulated that mindfulness meditation-related pain relief may share a common final pathway with other cognitive techniques in the modulation of pain.


Prevalence of liver injury and correlation with clinical outcomes in patients with COVID-19: systematic review with meta-analysis.
Liver involvement of SARS-CoV-2 infection has been reported in several papers, but without homogeneous findings. We aimed to systematically review the prevalence of liver involvement in patients with SARS-CoV-2 infection at their hospital admission, and its correlation with disease severity and clinical outcomes in patients with or without pre-existing chronic liver disease. We systematically searched PubMed, Embase, Web of Science, Medline, PMC, clinical trial registries, and other Coronavirus family publications for studies reporting data on SARS-CoV-2 infection or COVID-19 and liver function tests (LFTs) alterations, as well as clinical course of patients with chronic liver disease or cirrhosis. Case reports, preprints, editorials, reviews were excluded. We also revised literature to describe the background of liver involvement during SARS-CoV-2 infection. 36 studies, including 20724 patients with SARS-CoV-2 infection, were included. The pooled prevalence of LFTs abnormalities at admission was 46.9% (AST 26.5%, ALT 22.8%, GGT 22.5%, ALP 5.7%, tBIL 8.0%). ALT, AST, tBIL were independent predictors of disease severity (ALT OR 1.54, 95% CI 1.17-2.03; AST OR 3.17, 95% CI 2.10-4.77; tBIL OR 2.32, 95% CI 1.18-4.58) and in-hospital mortality (ALT OR 1.48, 95% CI 1.12-1.96; AST OR 4.39, 95% CI 2.68-7.18; tBIL OR 7.75, 95% CI 2.28-26.40). Heterogeneity among studies was high. The few available data also reported that COVID-19 was associated with increased risk of liver decompensation and mortality in patients with liver cirrhosis. LFTs alterations were reported in up to 47% of unselected patients with COVID-19 and were associated with severe disease or in-hospital mortality. In cirrhotic patients, COVID-19 was associated with high risk of liver decompensation or mortality.


HiRIEF LC-MS enables deep proteome coverage and unbiased proteogenomics.
We present a liquid chromatography-mass spectrometry (LC-MS)-based method permitting unbiased (gene prediction-independent) genome-wide discovery of protein-coding loci in higher eukaryotes. Using high-resolution isoelectric focusing (HiRIEF) at the peptide level in the 3.7-5.0 pH range and accurate peptide isoelectric point (pI) prediction, we probed the six-reading-frame translation of the human and mouse genomes and identified 98 and 52 previously undiscovered protein-coding loci, respectively. The method also enabled deep proteome coverage, identifying 13,078 human and 10,637 mouse proteins.


Dimeric peptides with three different linkers self-assemble with phospholipids to form peptide nanodiscs that stabilize membrane proteins.
Three dimers of the amphipathic α-helical peptide 18A have been synthesized with different interhelical linkers inserted between the two copies of 18A. The dimeric peptides were denoted 'beltides' where Beltide-1 refers to the 18A-dimer without a linker, Beltide-2 is the 18A-dimer with proline (Pro) as a linker and Beltide-3 is the 18A-dimer linked by two glycines (Gly-Gly). The self-assembly of the beltides with the phospholipid DMPC was studied with and without the incorporated membrane protein bacteriorhodopsin (bR) through a combination of coarse-grained MD simulations, size-exclusion chromatography (SEC), circular dichroism (CD) spectroscopy, small-angle scattering (SAS), static light scattering (SLS) and UV-Vis spectroscopy. For all three beltides, MD and combined small-angle X-ray and -neutron scattering were consistent with a disc structure composed by a phospholipid bilayer surrounded by a belt of peptides and with a total disc diameter of approximately 10 nm. CD confirmed that all three beltides were α-helical in the free form and with DMPC. However, as shown by SEC the different interhelical linkers clearly led to different properties of the beltides. Beltide-3, with the Gly-Gly linker, was very adaptable such that peptide nanodiscs could be formed for a broad range of different peptide to lipid stoichiometries and therefore also possible disc-sizes. On the other hand, both Beltide-2 with the Pro linker and Beltide-1 without a linker were less adaptable and would only form discs of certain peptide to lipid stoichiometries. SLS revealed that the structural stability of the formed peptide nanodiscs was also highly affected by the linkers and it was found that Beltide-1 gave more stable discs than the other two beltides. With respect to membrane protein stabilization, each of the three beltides in combination with DMPC stabilizes the seven-helix transmembrane protein bacteriorhodopsin significantly better than the detergent octyl glucoside, but no significant difference was observed between the three beltides. We conclude that adaptability, size, and structural stability can be tuned by changing the interhelical linker while maintaining the properties of the discs with respect to membrane protein stabilization.


Mechanisms of protein import and routing in chloroplasts.
The vast majority of the approximately 3000 different proteins required to build a fully functional chloroplast are encoded by the nuclear genome and translated on cytosolic ribosomes. As chloroplasts are each surrounded by a double-membrane system, or envelope, sophisticated mechanisms are necessary to mediate the import of these nucleus-encoded proteins into chloroplasts. Once inside the organelle, many chloroplast proteins engage one of four additional protein sorting mechanisms that direct targeting to the internal thylakoid membrane system.


Longitudinal double-spin asymmetry and cross section for inclusive jet production in polarized proton collisions at square root of s = 200 GeV.
We report a measurement of the longitudinal double-spin asymmetry A(LL) and the differential cross section for inclusive midrapidity jet production in polarized proton collisions at square root of s = 200 GeV. The cross section data cover transverse momenta 5 < pT < 50 GeV/c and agree with next-to-leading order perturbative QCD evaluations. The A(LL) data cover 5 < pT < 17 GeV/c and disfavor at 98% C.L. maximal positive gluon polarization in the polarized nucleon.


Outbreaks of hand, foot, and mouth disease by enterovirus 71. High incidence of complication disorders of central nervous system.
In Japan we have had two outbreaks of hand, foot, and mouth disease associated with disorders of the central nervous system, one in 1973 and the other in 1978. The isolated virus in both outbreaks was enterovirus 71. Central nervous system disorders were present in 24% of patients in 1973 and in 8% of patients in 1978. These disorders were localised encephalitis with cerebellar signs as the main feature, aseptic meningitis, and polio-like paresis. The enterovirus 71 isolated in Japan had strong dermatotropic as well as neurotropic tendencies. However in cross-neutralisation tests, no difference in antigenicity from the prototype, BrCr strain, was recognised.


Diabetic foot biomechanics and gait dysfunction.
Diabetic foot complications represent significant morbidity and precede most of the lower extremity amputations performed. Peripheral neuropathy is a frequent complication of diabetes shown to affect gait. Glycosylation of soft tissues can also affect gait. The purpose of this review article is to highlight the changes in gait for persons with diabetes and highlight the effects of glycosylation on soft tissues at the foot-ground interface. PubMed, the Cochrane Library, and EBSCOhost on-line databases were searched for articles pertaining to diabetes and gait. Bibliographies from relevant manuscripts were also searched. Patients with diabetes frequently exhibit a conservative gait strategy where there is slower walking speed, wider base of gait, and prolonged double support time. Glycosylation affects are observed in the lower extremities. Initially, skin thickness decreases and skin hardness increases; tendons thicken; muscles atrophy and exhibit activation delays; bones become less dense; joints have limited mobility; and fat pads are less thick, demonstrate fibrotic atrophy, migrate distally, and may be stiffer. In conclusion, there do appear to be gait changes in patients with diabetes. These changes, coupled with local soft tissue changes from advanced glycosylated end products, also alter a patient's gait, putting them at risk of foot ulceration. Better elucidation of these changes throughout the entire spectrum of diabetes disease can help design better treatments and potentially reduce the unnecessarily high prevalence of foot ulcers and amputation.


The association of medications with sedative properties with oral health behaviour in community-dwelling older people.
The objective of this study was to determine whether drugs with sedative properties are related to oral health behaviour-such as frequency of toothbrushing, using toothpaste and dental visits-and oral hygiene, measured by the number of teeth with dental plaque, among community-dwelling older people. The study population consisted of 159 community-dwelling, dentate, non-smoking, older people from the Oral Health GeMS study (Geriatric Multidisciplinary Strategy for the Good Care of Older People study). The data were collected by interviews and clinical examinations during 2004-2005. Sedative properties of drugs were assessed using the sedative load (SL) model. Logistic and Poisson regression models were used to estimate odds ratios/relative risks (OR/RR) and 95% confidence intervals (CI). After adjusting for confounding factors, SL associated with infrequent toothbrushing (OR 1.72, CI: 0.61-4.89), toothpaste use less than twice a day (OR 3.34, CI: 1.39-8.12), non-regular dental visits (OR 2.28 CI: 0.91-5.30) and the number of teeth with dental plaque (RR 1.20 CI: 1.04-1.39) compared to participants without a SL. The results of this study suggest that use of drugs with sedative properties indicates poor oral health behaviour among older people.


Use of immune globulin to prevent symptomatic cytomegalovirus disease in transplant recipients--a meta-analysis.
The objective of this meta-analysis was to review the evidence for the use of immune globulin in the prevention of symptomatic cytomegalovirus (CMV) disease in transplant recipients. A computerized search of Medline from 1980 to October 1991 was conducted using the textword "cytomegalo:" and the subheading "prevention and control" for studies in all languages. Reference lists, a manual search of relevant literature and communication with internationally recognized experts were used to locate additional studies. Of the studies identified, 18 met the inclusion criteria (population: transplant recipients; intervention: immune globulin; outcome: symptomatic cytomegalovirus disease; study design: randomized controlled trial). The meta-analysis of the 18 studies showed a reduction in the incidence of symptomatic CMV disease in the group receiving immune globulin as compared to the untreated group. The common odds ratio was 0.58 (95% C.I. 0.42 to 0.77). Analyses of combining trials by subgroups of polyvalent immune globulin, hyperimmune globulin, bone marrow recipients and solid organ recipients resulted in common odds ratios comparable to the overall common odds ratio. Common odds ratios for the trials reporting cytomegalovirus interstitial pneumonia, cytomegalovirus death, overall death and graft loss ranged from 0.47 to 0.69. Common odds ratios for the effect of immune globulin prophylaxis analyzed by pre-transplant patient/donor cytomegalovirus antibody status ranged from 0.32 to 0.50. In conclusion, the use of immune globulin as passive immunization for the prevention of symptomatic cytomegalovirus disease in the transplant population is supported by this meta-analysis. The response is similar in both bone marrow and solid organ transplant recipients.(ABSTRACT TRUNCATED AT 250 WORDS)


Association of intercellular adhesion molecule 1 with the multichain high-affinity interleukin 2 receptor.
Previously, using flow cytometric resonance energy transfer and lateral diffusion measurements, we demonstrated that a 95-kDa protein identified by two monoclonal antibodies (OKT27 and OKT27b) interacts physically with the 55-kDa alpha protein of the high-affinity interleukin 2 (IL-2) receptor. In the present study, this 95-kDa protein (p95) was purified and amino acid sequence data were obtained that showed strong homology to the human intercellular adhesion molecule 1 (ICAM-1). The identity of the p95 protein with ICAM-1 was confirmed by sequential immunoprecipitations using OKT27 and an antibody, WEHI-CAM-1, that is directed toward ICAM-1. We confirmed the physical proximity of p95/ICAM-1 to the IL-2 receptor alpha subunit by demonstrating that radiolabeled IL-2 could be cross-linked to this protein expressed on activated T cells. In functional studies, the antibodies OKT27 and OKT27b inhibited T-cell proliferative responses to OKT3, to soluble antigen, and to heterologous cells (mixed lymphocyte reaction). However, these antibodies did not inhibit IL-2-induced proliferation of an IL-2-dependent T-cell line. Taken together with our previous observations, the present studies suggest that ICAM-1 is in proximity and interacts physically with the high-affinity IL-2 receptor. The association of ICAM-1 with the IL-2 receptor may facilitate the paracrine IL-2-mediated stimulation of T cells expressing IL-2 receptors by augmenting homotypic T-T-cell interaction, by receptor-directed focusing of IL-2 release by helper T cells, and by focusing IL-2 receptors of the physically linked cells to the site of lymphocyte function-associated antigen 1-ICAM-1-IL-2 receptor interaction.


Intrathecal chemotherapy: brain tissue profiles after ventriculocisternal perfusion.
Ventriculocisternal perfusions with five isotopically labeled drugs were performed in the rhesus monkey and the resultant tissue diffusion concentration profiles in caudate nucleus were analyzed. The periventricular distribution space with respect to perfusate concentration was measured and expressed as microliters per 100 mg wet weight: hydroxyurea = 56; methotrexate = 27; thiotepa = 28; 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) = 64 and cytosine arabinoside greater than 170. The apparent diffusion constants in caudate nucleus were determined for hydroxyurea and methotrexate (2.0 and 1.2 X 10(-6) cm2/sec, respectively); capillary permeability expressed as an extracellular space-transcapillary exchange half-time was estimated to be greater than 2 hours for both compounds. The extracellular fluid-transcapillary half-time was measured for thiotepa and BCNU (1.0 and 0.8 minute, respectively). Cytosine arabinoside continued to be concentrated by periventricular caudate nucleus during the course of perfusion; perfusate clearance measurements suggest a low capillary permeability. The apparent parenchymal diffusion constant and the capillary permeability of a drug in brain are discussed and are considered useful parameters for predicting drug levels after intrathecal administration.


Evaluating the impact of heat stress as measured by temperature-humidity index (THI) on test-day milk yield of small holder dairy cattle in a sub-Sahara African climate.
This study evaluates the effect of heat stress on milk production and describes the pattern of response of milk yield to increasing heat load, using temperature-humidity index (THI) on test-day milk records of small holder dairy cattle herds in the sub-Saharan African climate of Tanzania. Climate data obtained from aWhere, an agricultural weather data platform (http://www.awhere.com) was analysed with 14,367 first lactation test day milk records of 3511 dairy cows collected between 2016 and 2019. THI was calculated from daily maximal temperatures and daily minimum humidity. Three sets of analysis were performed. In the first and second analysis, two mixed effect repeatability models were fitted with THI treated as a categorical variable grouped into 5 classes (THI1= [61 - 66], THI2= [67 - 71], THI3= [72 - 78], THI4=[79 - 81], THI5=[82 - 86]), to obtain least squares estimates of THI effect on milk production, and as a continuous variable within THI classes to identify THI thresholds at which milk yield started to decline. In the third analyses, one quadratic polynomial regression (POL) and three regression spline functions namely piecewise linear spline function (PLF), natural splines function (NSF) and cubic splines function (CSF) were fitted to determine the average effect of THI on milk yield in the population and describe the pattern of response of milk yield to increasing head load. The results show that heat stress reduced milk yield by 4.16% to 14.42% across THI groups, with daily milk yield being the highest in THI1 (7.40±0.39 litres) and the lowest in THI4 (6.33±0.32). Regression coefficients within groups showed significant daily milk yield decrease in THI2 (-0.09) and THI3 (-0.06), but not for other THI classes, indicating that cows experienced heat stress between THI values of 67 and 76 and milk loss plateaued afterwards, suggesting that the animals acclimatized to heat stress conditions beyond THI value of 76. At the population level, THI and its squared term were significantly negatively and positively (-0.61, 0.004) associated with milk production, indicating a non-linear relationship between milk yield and THI. The CSF model showed better goodness of fit and predictive ability than other models for predicting future population response of milk yield to heat stress in small holder dairy farms in Tanzania. Herd management strategies and animal husbandry measures are needed in small holder dairy farms in Tanzania to minimize the impact of heat stress on milk yield and income of the farmers.


Neural correlates of sequence learning with stochastic feedback.
Although much is known about decision making under uncertainty when only a single step is required in the decision process, less is known about sequential decision making. We carried out a stochastic sequence learning task in which subjects had to use noisy feedback to learn sequences of button presses. We compared flat and hierarchical behavioral models and found that although both models predicted the choices of the group of subjects equally well, only the hierarchical model correlated significantly with learning-related changes in the magneto-encephalographic response. The significant modulations in the magneto-encephalographic signal occurred 83 msec before button press and 67 msec after button press. We also localized the sources of these effects and found that the early effect localized to the insula, whereas the late effect localized to the premotor cortex.