Methods for Phenotyping Adult Patients in Sepsis and Septic Shock: A Scoping Review.
Despite its heterogeneous phenotypes, sepsis or life-threatening dysfunction in response to infection is often treated empirically. Identifying patient subgroups with unique pathophysiology and treatment response is critical to the advancement of sepsis care. However, phenotyping methods and results are as heterogeneous as the disease itself. This scoping review evaluates the prognostic capabilities and treatment implications of adult sepsis and septic shock phenotyping methods. Medline and Embase. We included clinical studies that described sepsis or septic shock and used any clustering method to identify sepsis phenotypes. We excluded conference abstracts, literature reviews, comments, letters to the editor, and in vitro studies. We assessed study quality using a validated risk of bias tool for observational cohort and cross-sectional studies. We extracted population, methodology, validation, and phenotyping characteristics from 17 studies. Sepsis phenotyping methods most frequently grouped patients based on the degree of inflammatory response and coagulopathy using clinical, nongenomic variables. Five articles clustered patients based on genomic or transcriptomic data. Seven articles generated patient subgroups with differential response to sepsis treatments. Cluster clinical characteristics and their associations with mortality and treatment response were heterogeneous across studies, and validity was evaluated in nine of 17 articles, hindering pooled analysis of results and derivation of universal truths regarding sepsis phenotypes, their prognostic capabilities, and their associations with treatment response. Sepsis phenotyping methods can identify high-risk patients and those with high probability of responding well to targeted treatments. Research quality was fair, but achieving generalizability and clinical impact of sepsis phenotyping will require external validation and direct comparison with alternative approaches.


Dominant lethal study of ribavirin in male rats.
Ribavirin, a new synthetic antiviral agent, was studied for dominant lethal effects in male CD rats. The drug was administered intraperitoneally at doses of 50, 100 and 200 mg/kg/day for 5 days. Males were mated weekly with 8 consecutive batches of female rats. Marginal increase in early foetal death detected in Assessment Weeks 3 and 8 in females mated with the low-dose and high-dose males were not dose-related and were most probably chance events caused by the particularly low vehicle control frequencies for these 2 weeks. Also, the slightly reduced pregnancy proportion among females mated with the high-dose treated males was to a substantial extent the effect of a single male rate which failed to fertilize any females. Ribavirin was, therefore, regarded as being devoid of any mutagenic potential demonstrable by a rat dominant lethal assay.


The influence of social structure on the propagation of social information in artificial primate groups: a graph-based simulation approach.
Observations of primate groups have shown that social learning can lead to the development of temporal stable traditions or even proto-culture. The social structure of primate groups is highly diverse and it has been proposed that differences in the group structure shall influence the patterns of social information transmission. While empirical studies have mainly focused on the psychological mechanisms of social learning in individuals, the phenomenon of information propagation within the group has received relatively little attention. This might be due to the fact that formal theories that allow actual testing have not been formulated, or were kept too simple, ignoring the social dynamics of multi-agent societies. We want to propose a network approach to social information transmission that (1) preserves the complexity of the social structure of primate groups and (2) allows direct application to empirical data. Results from simulation experiments with artificial group structures confirm that association patterns of group-members influence the expected speed of information transmission during the propagation process. Introducing a forgetting rate shows that under certain conditions the proportion of informed individuals will reach a stable rate in some systems while it will drop to zero in others. This suggests that the likelihood to observe temporal stable traditions shall differ between social systems with different structure.


Suppressed pro-inflammatory response of microglia in CX3CR1 knockout mice.
Neuronal fractalkine acts via its receptor, CX3CR1, on microglia to regulate neuroinflammation. Conflicting results have been reported in studies employing CX3CR1 deficient (Cx3cr1(-/-)) mice. Here, compared to wild-type, endotoxin-treated neuron-glial Cx3cr1(-/-)cultures produced less TNF-α, nitric oxide and superoxide; however, fractalkine treatment inhibited the release of pro-inflammatory factors in wild-type and BV-2 cell cultures. Furthermore, endotoxin-treated BV-2 cells expressing siRNA against CX3CR1 increased nitric oxide and TNF-α production. We hypothesize that CX3CL1-CX3CR1 signaling is neuroprotective and propose that the reduced production of pro-inflammatory signals in Cx3cr1(-/-)microglia may result from compensatory mechanisms and not be the direct result of CX3CR1 deficiency.


The mean kurtosis (MK) is more sensitive diagnostic biomarker than fractional anisotropy (FA) for Parkinson's disease: A diagnostic performance study and meta-analysis.
The mean kurtosis (MK) and fractional anisotropy (FA) in patients of Parkinson's disease (PD) are usually measured by diffusion kurtosis imaging (DKI) and diffusion tensor imaging (DTI), separately. In this study we perform a meta-analysis to discuss which noninvasive biomarker is more advantageous for PD, MK, or FA. Databases including Medline via PubMed, the Cochrane Central Register of Controlled Trials, Embase via OVID and China National Knowledge Infrastructure. Databases are searched up to December 31st, 2019. Four brain regions are identified for analysis based on data extracted from articles. The articles contain 5 trials with 274 total PD patients and 189 healthy controls (HCs). The results show not only significantly higher MK values of putamen, caudate, globus pallidus in PD compared to that of HCs (weighted mean difference [WMD] = 0.06, 95% CI = 0.02-0.09, P = .002, WMD = 0.03, 95% CI = 0.01-0.067, P = .01, WMD = 0.18, 95% CI = 0.11-0.24, P < .00001), but also a significantly higher FA in caudate of PD compared to HCs (WMD = 0.02, 95% CI = 0.00-0.03, P = .006). This indicates that the sharp difference detected between PD patients and HCs can be detected by DKI and DTI. By further discussing results, we found that MK could be more sensitive diagnostic biomarker than FA toward PD diagnosis.


Multiple simultaneous and sequential estrogen receptor values in patients with breast cancer.
Fifty-nine women had multiple estrogen receptor assays done, either simultaneously or sequentially. Eighty-six percent of the patients who had multiple synchronous estrogen receptor assays from various metastatic sites showed no significant discrepancy in estrogen receptor values. When estrogen receptor assays were done sequentially without intervening therapy, 83.5 percent of the patients maintained their initial positivity or negativity. However, when the second estrogen receptor determination was preceded by either chemotherapy or hormonal therapy, 33 percent of the patients had a significant discrepancy in estrogen receptor values. The most common discrepancy was estrogen receptor-positive tumors becoming estrogen receptor-negative, although a small number of patients were found whose receptor values became more positive after hormonal ablation.


Secondary rhinoplasty.
Revision rhinoplasty is a complex aesthetic and reconstructive procedure in which both functional and cosmetic principles must be considered in the planning of an appropriate operation. Different techniques must be modified according to the specific defects. The modifications may vary from simple integration of a previous poorly performed surgery to complex grafting of homologous or heterologous material. The authors report their experience with 311 cases of revision rhinoplasty.


microRNA Regulation in Estrogen Receptor-Positive Breast Cancer and Endocrine Therapy.
As de novo and acquired resistance to standard first line endocrine therapies is a growing clinical challenge for estrogen receptor-positive (ER+) breast cancer patients, understanding the mechanisms of resistance is critical to develop novel therapeutic strategies to prevent therapeutic resistance and improve patient outcomes. The widespread post-transcriptional regulatory role that microRNAs (miRNAs) can have on various oncogenic pathways has been well-documented. In particular, several miRNAs are reported to suppress ERα expression via direct binding with the 3' UTR of ESR1 mRNA, which can confer resistance to estrogen/ERα-targeted therapies. In turn, estrogen/ERα activation can modulate miRNA expression, which may contribute to ER+ breast carcinogenesis. Given the reported oncogenic and tumor suppressor functions of miRNAs in ER+ breast cancer, the targeted regulation of specific miRNAs is emerging as a promising strategy to treat ER+ breast cancer and significantly improve patient responsiveness to endocrine therapies. In this review, we highlight the major miRNA-ER regulatory mechanisms in context with ER+ breast carcinogenesis, as well as the critical miRNAs that contribute to endocrine therapy resistance or sensitivity. Collectively, this comprehensive review of the current literature sheds light on the clinical applications and challenges associated with miRNA regulatory mechanisms and novel miRNA targets that may have translational value as potential therapeutics for the treatment of ER+ breast cancer.


Correlating local chemical and structural order using Geographic Information Systems-based spatial statistics.
Analysis of nanoscale short-range chemical and/or structural order via (scanning) transmission electron microscopy (S/TEM) imaging is fundamentally limited by projection of the three dimensional sample, which averages informational along the beam direction. Extracting statistically significant spatial correlations between the structure and chemistry determined from these two-dimensional datasets thus remains challenging. Here, we apply methods commonly used in Geographic Information Systems (GIS) to determine the spatial correlation between measures of local chemistry and structure from atomic-resolution STEM imaging of a compositionally complex relaxor, Pb(Mg1/3Nb2/3)O3 (PMN). The approach is used to determine the type of ordering present and to quantify the spatial variation of chemical order, oxygen octahedral distortions, and oxygen octahedral tilts. The extent of autocorrelation and inter-feature correlation among these short-range ordered regions are then evaluated through a spatial covariance analysis, showing correlation as a function of distance. The results demonstrate that integrating GIS tools for analyzing microscopy datasets can serve to unravel subtle relationships among chemical and structural features in complex materials that can be hidden when ignoring their spatial distributions.


Composition and production rate of pharmaceutical and chemical waste from Xanthi General Hospital in Greece.
The objective of this work was to determine the composition and production rates of pharmaceutical and chemical waste produced by Xanthi General Hospital in Greece (XGH). This information is important to design and cost management systems for pharmaceutical and chemical waste, for safety and health considerations and for assessing environmental impact. A total of 233 kg pharmaceutical and 110 kg chemical waste was collected, manually separated and weighed over a period of five working weeks. The total production of pharmaceutical waste comprised 3.9% w/w of the total hazardous medical waste produced by the hospital. Total pharmaceutical waste was classified in three categories, vial waste comprising 51.1%, syringe waste with 11.4% and intravenous therapy (IV) waste with 37.5% w/w of the total. Vial pharmaceutical waste only was further classified in six major categories: antibiotics, digestive system drugs, analgesics, hormones, circulatory system drugs and "other". Production data below are presented as average (standard deviation in parenthesis). The unit production rates for total pharmaceutical waste for the hospital were 12.4 (3.90) g/patient/d and 24.6 (7.48) g/bed/d. The respective unit production rates were: (1) for vial waste 6.4 (1.6) g/patient/d and 13 (2.6) g/bed/d, (2) for syringe waste 1.4 (0.4) g/patient/d and 2.8 (0.8) g/bed/d and (3) for IV waste 4.6 (3.0) g/patient/d and 9.2 (5.9) g/bed/d. Total chemical waste was classified in four categories, chemical reagents comprising 18.2%, solvents with 52.3%, dyes and tracers with 18.2% and solid waste with 11.4% w/w of the total. The total production of chemical waste comprised 1.8% w/w of the total hazardous medical waste produced by the hospital. Thus, the sum of pharmaceutical and chemical waste was 5.7% w/w of the total hazardous medical waste produced by the hospital. The unit production rates for total chemical waste for the hospital were 5.8 (2.2) g/patient/d and 1.1 (0.4) g/exam/d. The respective unit production rates were: (1) for reagents 1.7 (2.4) g/patient/d and 0.3 (0.4) g/examination/d, (2) for solvents 248 (127) g/patient/d and 192 (101) g/examination/d, (3) for dyes and tracers 4.7 (1.4) g/patient/d and 2.5 (0.9) g/examination/d and (4) for solid waste 54 (28) g/patient/d and 42 (22) g/examination/d.


FER regulates endosomal recycling and is a predictor for adjuvant taxane benefit in breast cancer.
Elevated expression of non-receptor tyrosine kinase FER is an independent prognosticator that correlates with poor survival of high-grade and basal/triple-negative breast cancer (TNBC) patients. Here, we show that high FER levels are also associated with improved outcomes after adjuvant taxane-based combination chemotherapy in high-risk, HER2-negative patients. In TNBC cells, we observe a causal relation between high FER levels and sensitivity to taxanes. Proteomics and mechanistic studies demonstrate that FER regulates endosomal recycling, a microtubule-dependent process that underpins breast cancer cell invasion. Using chemical genetics, we identify DCTN2 as a FER substrate. Our work indicates that the DCTN2 tyrosine 6 is essential for the development of tubular recycling domains in early endosomes and subsequent propagation of TNBC cell invasion in 3D. In conclusion, we show that high FER expression promotes endosomal recycling and represents a candidate predictive marker for the benefit of adjuvant taxane-containing chemotherapy in high-risk patients, including TNBC patients.


Contagion of suicidal symptoms as a function of assortative relating and shared relationship stress in college roommates.
Vulnerable people may become socially contiguous via assortative relating, and thus simultaneously susceptible to the effects of shared life stress. To test this possibility, 138 undergraduates and their roommates completed questionnaires on suicidality and stress. Consistent with an assortative relating process, roommates who chose to room together were more similar on a suicide index than were roommates who were assigned to room together. Stress in the roommate relationship amplified similarity in roommates' suicide levels. Results were consistent with the view that shared stress simultaneously affects the suicidality of people whose contiguity was pre-arranged by an assortative relating process.


The Association of CYP1A1 Gene With Cervical Cancer and Additional SNP-SNP Interaction in Chinese Women.
The aim of this study was to investigate the association between CYP1A1 gene polymorphism and cervical cancer risk, and the impact of SNP-SNP interaction on cervical cancer risk in Chinese women. A total of 728 females with a mean age of 60.1 ± 14.5 years old were selected, including 360 cervical cancer patients and 368 normal controls. Logistic regression was performed to investigate association between single-nucleotide polymorphisms (SNP) and cervical cancer risk. Generalized multifactor dimensionality reduction (GMDR) was used to analyze the SNP-SNP interaction. Logistic analysis showed a significant association between rs4646903 and increased cervical cancer risk. The carriers of homozygous mutant of rs4646903 polymorphism revealed increased cervical cancer risk than those with wild-type homozygotes, OR (95%CI) were 1.45 (1.20-1.95). There was a significant two-locus model (P = 0.0107) involving rs4646903 and rs1048943, indicating a potential SNP-SNP interaction between rs4646903 and rs1048943. Overall, the two-locus models had a cross-validation consistency of 10 of 10, and had the testing accuracy of 60.72%. Subjects with TC or CC of rs4646903 and AG or GG of rs1048943 genotype have the highest cervical cancer risk, compared to subjects with TT of rs4646903 and AA of rs1048943 genotype, OR (95%CI) was 2.03 (1.42-2.89). rs4646903 minor alleles and interaction between rs4646903 and rs1048943 were associated with increased cervical cancer risk.


Insights From a Large-Scale Whole-Genome Sequencing Study of Systolic Blood Pressure, Diastolic Blood Pressure, and Hypertension.
The availability of whole-genome sequencing data in large studies has enabled the assessment of coding and noncoding variants across the allele frequency spectrum for their associations with blood pressure. We conducted a multiancestry whole-genome sequencing analysis of blood pressure among 51 456 Trans-Omics for Precision Medicine and Centers for Common Disease Genomics program participants (stage-1). Stage-2 analyses leveraged array data from UK Biobank (N=383 145), Million Veteran Program (N=318 891), and Reasons for Geographic and Racial Differences in Stroke (N=10 643) participants, along with whole-exome sequencing data from UK Biobank (N=199 631) participants. Two blood pressure signals achieved genome-wide significance in meta-analyses of stage-1 and stage-2 single variant findings (P<5×10-8). Among them, a rare intergenic variant at novel locus, LOC100506274, was associated with lower systolic blood pressure in stage-1 (beta [SE]=-32.6 [6.0]; P=4.99×10-8) but not stage-2 analysis (P=0.11). Furthermore, a novel common variant at the known INSR locus was suggestively associated with diastolic blood pressure in stage-1 (beta [SE]=-0.36 [0.07]; P=4.18×10-7) and attained genome-wide significance in stage-2 (beta [SE]=-0.29 [0.03]; P=7.28×10-23). Nineteen additional signals suggestively associated with blood pressure in meta-analysis of single and aggregate rare variant findings (P<1×10-6 and P<1×10-4, respectively). We report one promising but unconfirmed rare variant for blood pressure and, more importantly, contribute insights for future blood pressure sequencing studies. Our findings suggest promise of aggregate analyses to complement single variant analysis strategies and the need for larger, diverse samples, and family studies to enable robust rare variant identification.


Orthograde transport of Nuclear yellow: a problem and its solution.
Nuclear yellow injections into the striatum of rats led to staining of both neuronal and glial nuclei even after less than 24 h 'transport time'. The distribution of some of the glial nuclei suggested that the dye was being transported along the striato-nigral pathway. Staining in these areas was greatly reduced if kainic acid was co-injected with the Nuclear yellow.


[Hypoplasia of the nails and end phalanges as a sequela of prenatal barbiturate exposure].
We describe a case of a Turkish boy with features of hydantoin-barbiturate-embryopathy. Main symptoms are hypoplasia, partly aplasia, of the finger- and toenails as well as the distal phalanges. His epileptic mother was treated with phenobarbiturates during the first three months of pregnancy.


Simulation of nuclear quadrupole resonance for sensor probe optimization.
A simulation method to estimate the detection efficiency of nuclear quadrupole resonance (NQR) was proposed for optimizing a sensing probe operating at radio frequencies (RFs). It first calculates the transmitted magnetic field from the probe coil to the target sample. The nuclei make quadrupole resonance by it. We considered this nonlinear reaction to estimate NQR emission by the nuclei. Then the received NQR signal intensity from the sample at the probe coil. We calculated the efficiency by testing two different probe types (solenoid and gradiometer) and by changing the relative positions of the probe and sample. The simulation results were in good agreement with the experimental results.


Essential role of obscurin in cardiac myofibrillogenesis and hypertrophic response: evidence from small interfering RNA-mediated gene silencing.
Obscurin is a recently identified giant multidomain muscle protein (approximately 800 kDa) whose structural and regulatory functions remain to be defined. The goal of this study was to examine the effect of obscurin gene silencing induced by RNA interference on the dynamics of myofibrillogenesis and hypertrophic response to phenylephrine in cultured rat cardiomyocytes. We found that that the adenoviral transfection of short interfering RNA (siRNA) constructs targeting the first coding exon of obscurin sequence resulted in progressive depletion of cellular obscurin. Confocal microscopy demonstrated that downregulation of obscurin expression led to the impaired assembly of new myofibrillar clusters and considerable aberrations of the normal structure of the contractile apparatus. While the establishment of the initial periodic pattern of alpha-actinin localization remained mainly unaffected in siRNA-transfected cells, obscurin depletion did cause the defective lateral alignment of myofibrillar bundles, leading to their abnormal bifurcation, dispersal and multiple branching. Bending of immature myofibrils, apparently associated with the loss of their rigidity, a modified titin pattern, the absence of well-formed A-bands in newly formed contractile structures as documented by a diffuse localization of sarcomeric myosin labeling, and an occasional irregular periodicity of sarcomere spacing were typical of obscurin siRNA-treated cells. These results suggest that obscurin is indispensable for spatial positioning of contractile proteins and for the structural integration and stabilization of myofibrils, especially at the stage of myosin filament incorporation and A-band assembly. This demonstrates a vital role for obscurin in myofibrillogenesis and hypertrophic growth.


Kinetic studies on Korean serum cis-AB enzymes reveal diminished A and B transferase activities.
cis-AB enzymes are rare glycosyltransferases that synthesize both blood group A and B antigens. We have identified a large cohort of Korean cis-AB blood donors and studied the N-acetylgalactosaminyltransferase (glycosyltransferase A, GTA) and galactosyltransferase (glycosyltransferase B, GTB) activity of their cis-AB serum enzymes. The cis-AB01 allele was identified by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) in 60 donors collected at the Gwangju-Chonnam Red Cross Blood Center. Enzyme assays of this cis-AB enzyme were performed on available serum samples from 16 donors with the cis-AB01/O genotype and three with the cis-AB01/A genotype. In cis-AB donors with an O allele, both the GTA and GTB activity of the cis-AB enzyme were markedly reduced compared to normal A and B controls (29% and 27%, respectively). This is consistent with the behaviour predicted from kinetic studies of a recombinant model of the corresponding AAAB enzyme. Although variable, cis-AB enzymes feature reduced GTA and GTB activities. Cis-AB enzymes feature variable but reduced GTA and GTB activities with relatively weaker GTB activity, consistent with the weak agglutination present on forward typing with anti-B.


Comparison of bone loss induced in female rats by hindlimb unloading, ovariectomy, or both.
Clinical and experimental evidence supports a link between the effects of mechanical loading and those of estrogens on bone. The objective of this study was to compare bone loss induced in female rats by hindlimb unloading, ovariectomy, or both. Thirty-six female Wistar rats aged 12 weeks were randomized to bilateral surgical ovariectomy without tail suspension (OV) or with tail suspension for 30 days (OV-TS) or to sham surgery without tail suspension (control group, C) or with tail suspension for 30 days (TS). Bone mineral density (BMD) of the distal femoral metaphysis was measured in g/cm2 by dual X-ray absorptiometry in all 12 animals on days 0, 7, 14, and 30. On D14 and D30, BMD (mean+/-S.D.) was significantly lower in the OV, TS, and OV-TS groups than in the control group (D14: 0.239+/-0.014, 0.243+/-0.016, and 0.227+/-0.018, respectively, vs. 0.258+/-0.005 in the controls; P<0.05; and D30: 0.241+/-0.011, 0.227+/-0.015, and 0.200+/-0.018, respectively, vs. 0.279+/-0.009 in the controls; P<0.001). On D30, the percentage BMD change versus baseline (mean+/-S.D.) differed significantly between the combination (OV-TS) group (-14.26+/-8.14) and the single-intervention groups (OV: +0.99+/-6.44, P<0.001; and TS: -6.36+/-4.56, P<0.05). As early as D7, bone loss was significantly greater in the combination (OV + TS) group than in the OV group (-1.79%+/-7.17 vs. +4.29%+/-9.55; P<0.05). In female rats, the rate and severity of bone loss were greater when estrogen deprivation was combined with mechanical unloading than when either intervention was used alone. Mechanical unloading induced a greater degree of bone loss than did estrogen deprivation. In this model of high-rate bone loss, mechanical unloading may predominate over estrogen deprivation in the genesis of bone loss.


Structural and physicochemical characterization of the inclusion complexes of cyclomaltooligosaccharides (cyclodextrins) with melatonin.
The stoichiometry, geometry, stability, and solubility of the inclusion complexes of melatonin (MLT) with native cyclomaltooligosaccharides (alpha-, beta- or gamma-cyclodextrins, CDs) are determined experimentally by high-resolution NMR spectroscopy, calorimetric and solubility measurements, and mass spectrometry. The observed differences are discussed in terms of molecular recognition expression of the host-guest (h-g) interactions within the hydrophobic CDs cavities of different size. The 1:1 h-g stoichiometry in water solution prevails at low CD concentrations; the trend to form higher order associations is observed at increasing CD concentrations. The stability order beta-CD>gamma-CD>alpha-CD for the complexes in water solution and beta-CD>alpha-CD>gamma-CD for the protonated or alkali-cationated complexes in the gas phase are rationalized on the grounds of the structural data from NMR spectroscopy and of the thermodynamic parameters from calorimetric measurements.


Ontogeny of the neutral amino acid transporter SNAT1 in the developing rat.
System A is a highly regulated, Na+-dependent transporter that accepts neutral amino acids containing short, polar side chains. System A plays an important role during rat development as decreased pup weights are observed in dams infused during gestation with a non-metabolizable System A substrate. Given the potential importance of SNAT1 during development in the rat brain, we examined whether SNAT1 would be present at an earlier gestation during organogenesis in multiple organs by immunohistochemistry and immunoblotting. SNAT1 protein was observed in the developing lungs, intestines, kidneys, heart, pancreas, and skeletal muscle of rats at prenatal days 14, 17, 19, 21, and postnatal day 2 rats. SNAT1 protein expression decreased in the liver and intestine shortly after birth and as the rat matured. SNAT1 expression was constant throughout development in the lungs and kidney and increased in the heart from prenatal day 19 to postnatal day 2. Highest levels of expression in older animals were seen in organs undergoing rapid cell division.


Assessment of cross-resistance potential to serial antibiotic treatments in antibiotic-resistant Salmonella Typhimurium.
This study was designed to evaluate the cross-resistance of Salmonella Typhimurium ATCC 19585 (STWT), ciprofloxacin-resistant S. Typhimurium (STCIP), and clinically isolated S. Typhimurium CCARM 8009 (STCLI) serially exposed to a half MIC of ceftriaxone (CEF), ciprofloxacin (CIP), polymyxin B (POL), or tetracycline (TET), followed by 1 MIC of CEF, CIP, POL, and TET. The viability changes of STWT, STCIP, and STCLI exposed to different classes of antibiotics were measured to evaluate the development of cross-resistance. The relative fitness was also estimated to evaluate the reproductive success of STWT, STCIP, and STCLI consecutively exposed to a half and 1 MIC of CEF, CIP, POL, or TET. The expression levels of efflux pump-related genes (acrA, acrB, mdsA, mdsB, mdtB, and tolC) were evaluated by using a quantitative RT-PCR assay. The MIC of CIP against STCIP was increased by 128-fold compared to STWT. STCLI was highly resistant to POL (MIC = 8 μg/ml) and TET (MIC = 256 μg/ml). STWT exposed to CIP [1/2] was susceptible to POL [1] than CEF [1], CIP [1], and TET [1], STCIP exposed to CIP [1/2] was susceptible to CEF [1] and POL [1], and STCLI exposed to CIP [1/2] was susceptible to POL [1]. STCIP was cross-resistant to CEF [1/2]-CIP [1], CIP [1/2]-CIP [1], POL [1/2]-CIP [1], and TET [1/2]-CIP (Ochoa et al., 2020) [1]. The efflux pump-related genes (acrA, acrB, mdsA, mdsB, mdtB, and tolC) were overexpressed in STWT, STCIP, and STCLI exposed to serial antibiotic treatments, which was related to the development of cross-resistance. The antibiotic susceptibility profiles of STWT, STCIP, and STCLI exposed to serial antibiotic treatments are worth understanding the evolution of antibiotic resistance and developing effective therapeutic regimens against antibiotic-resistant bacteria.


Is cathelicidin a novel marker of diabetic microangiopathy in patients with type 1 diabetes?
The aim was to evaluate the relationship between higher serum cathelicidin levels with the occurrence of chronic microangiopathic complications in patients with diabetes mellitus type 1 (DM1). The study group consisted of 62 patients with DM1 (35 men), aged 30 (24-38) years and with duration of DM1 12 (9-17) years. Patients were divided into two groups depending on the level of cathelicidin, with cut-off point 24.5ng/ml (median value for the whole group) and according to the presence or absence of any microangiopathy. The group with higher serum level of cathelicidin (n=31) in comparison with patients with lower levels (n=31) had higher serum level of total cholesterol [5.0(4.5-5.6) vs 4.5(3.9-5.0) mmol/l; p=0.04], HDL cholesterol [1.9(1.5-2.1) vs 1.4(1.3-1.8) mmol/l; p=0.009], LDL cholesterol [2.6(2.2-3.1) vs 2.3(1.9-2.8) mmol/l; p=0.03] and higher TSH value [1.8(1.5-2.6) vs 1.4(0.9-2.1) mIU/L; p=0.01]. Moreover, higher serum levels of cathelicidin were in women than men (58% vs 29%, p=0.02) and in patients with vs without microangiopathy (45% vs 19%, p=0.03). In the multiple regression model higher serum level of cathelicidin was related to the presence of microangiopathy, independently from sex, waist to hip ratio, serum total cholesterol level and TSH. Patients with type 1 diabetes and presence of microangiopathy characterize higher level of serum cathelicidin. This observation may have important clinical implication and needs further investigations.


Physical Activity in Cardiac Rehabilitation: Towards Citizen-Centered Digital Evidence-Based Interventions.
Physical activity is a vital part of cardiac rehabilitation (CR). However, heart-healthy physical activity levels in people with cardiovascular disease drop significantly after CR. This exploratory study employs qualitative and survey methods within a co-creation approach. The aim is to understand the mechanisms of healthy behavior and habit formation in order to create a novel evidence-based (post-)rehabilitation approach that employs digital means to sustain long-term physical activity levels in people with cardiovascular disease.


Ki-67: More Hidden behind a 'Classic Proliferation Marker'.
Nuclear antigen Ki-67 is widely accepted as a cell proliferation marker in both research and cancer diagnostic settings. Despite its extensive use and clinical value, very little is still known about the biological function of Ki-67. A recent work published in Cell Reports has revealed important novel aspects of Ki-67 regulation that could provide new and extended prognostic and therapeutic value.


A Case of Tracheitis Sicca with Obstructive Tracheal Crusting In A 7 Year Old Boy.
Tracheitis sicca is a rare condition where there is drying and crusting of tracheal mucosa which may lead to tracheal obstruction and respiratory distress. Reported here is a case of young boy, who presented with cough, cold and respiratory distress worsening over a period of 5 days. On admission the patient was administered with dexamethasone and was intubated. However, saturation was not maintained despite assisted ventilation, and multiple episodes of self extubation always presented with stridor. Hence, otorhinolaryngology reference was taken and decision was taken to perform laryngotracheobronchoscopy. Endoscopy done showed extensive crusting in the trachea causing complete obstruction of airway above the level of carina. The crusting was meticulously removed, sent for culture, and the obstruction was relieved. The patient maintained saturation after the procedure, and was ultimately extubated and discharged.


[Non-compromised grafting policy in off-pump coronary artery bypass].
The off-pump coronary artery bypass (OPCAB) has been prevalent around the world. However the most optimal selection of graft conduits has still been controversial. Between January 2002 and April 2003, 126 consecutive isolated coronary artery bypass procedures were attempted to performed without cardiopulmonary bypass. A mean age of the patients was 69.3 (47-90). Fifteen patients were operated on emergently and 16 were urgently, including 15 patients requiring preoperative intra-aortic balloon pumping (IABP). Five patients underwent reoperative coronary bypass. All procedures were completed without cardiopulmonary bypass. The mean number of grafts per patient was 3.23 (range, 1 to 6). The skeletonized arterial conduits were aggressively used [117 left internal mammary artery (LIMA) to 155 sites, 70 right internal mammary artery (RIMA) to 79 sites, 57 right gastro-epiploic artery (RGEA) to 82 sites and 49 saphenous vein (SV) to 91 sites]. Cardiac-related hospital mortality was none. Angiographic assessment of grafts demonstrated that patency of LIMA, RIMA, RGEA and SV were 98.6%, 100%, 100%, and 97.6% respectively. OPCAB with skeletonized in situ arterial conduits is secure and feasible.


Single-cell characterization of tumor evolution from precursor diseases.
Elucidating the characteristics of precursor diseases is important to the understanding of malignant transformation during tumor progression. In a recent study, Dang et al. characterized the cellular and molecular evolution from precursor conditions to multiple myeloma (MM) by integrating single-cell RNA sequencing (scRNA-seq) and B cell-receptor sequencing (scBCR-seq).


Shifts in benthic bacterial communities associated with farming stages and a microbiological proxy for assessing sulfidic sediment conditions at fish farms.
To assess the aquaculture-induced sediment conditions associated with sulfur cycles, shifts in bacterial communities across farming stages were investigated. The sulfate reduction rate (SRR), and concentrations of acid volatile sulfide (AVS) and H2S were significantly higher at the mid- and post-farming stages than at the early stage, indicating that the aquaculture effects persist even after harvest. Incomplete organic carbon-oxidizing sulfate-reducing bacteria (IO-SRB) affiliated with Desulfobulbaceae, and gammaproteobacterial sulfur oxidizing bacteria (SOB) (Thiohalobacter, Thioprofundum, and Thiohalomonas) were dominant during the early stage, whereas fermenting bacteria (Bacteroidetes and Firmicutes) and complete oxidizing SRB (CO-SRB) belonging to Desulfobacteraceae, and epsilonproteobacterial SOB (Sulfurovum) dominated during the mid- and post-stages. The shift in SRB and SOB communities well reflected the anoxic and sulfidic conditions of farm sediment. Especially, the Sulfurovum-like SOB correlated highly and positively with H2S, AVS, and SRR, suggesting that they could be relevant microbiological proxies to assess sulfidic conditions in farm sediment.


Factors associated with bleeding events from enoxaparin used for patients with acute coronary syndrome.
Low molecular weight heparins (LMWHs) are the mainstay of treatment for acute coronary syndrome (ACS). However, bleeding, the main side effect, is associated with prolonged hospitalization and mortality. Therefore, assessment of the incidence of bleeding and associated risk factors is crucial in developing an appropriate treatment plan to prevent bleeding. A retrospective cohort study was conducted in patients with ACS admitted to a university hospital in Bangkok, Thailand between 2011 and 2015 and received enoxaparin. To estimate the incidence of bleeding events, patients were followed up for 30 days from the first enoxaparin dose. Multiple logistic regression was used to determine factors associated with bleeding events. From a total of 602 patients, the incidence of bleeding was 15.8%, of which 5.7% involved major bleeding. The risk factors for any form of bleeding were aged at least 65 years (odds ratio [OR], 1.99; 95% confidence interval [CI], 1.18 to 3.36), history of bleeding (OR, 3.79; 95% CI, 1.24 to 11.55), and history of oral anticoagulant exposure (OR, 4.73; 95% CI, 1.74 to 12.86). ACS patients treated with enoxaparin had an increased risk of bleeding if they were aged 65 years or older, had a history of bleeding events, and had a history of taking oral anticoagulants.


Magnetic resonance-guided histopathology for improved accuracy of tumor response evaluation of neoadjuvant treatment in organ-infiltrating rectal cancer.
The novel procedure of magnetic resonance-(MR) guided histopathology was applied to determine the false-negative rate of conventional histopathologic tumor response evaluation of neoadjuvant radiation/chemoradiation therapy (RT/CRT) in organ-infiltrating rectal cancer. Ninety-two consecutive patients that had received RT/CRT and proceeded to extended total mesorectal excision for organ-infiltrating rectal cancer were identified from the institutional database. For each patient, the study radiologist and pathologist separately interpreted preoperative MR images and histologic preparations from the surgical specimen, to determine whether tumor down-staging had resulted. In cases of discrepancy (52 patients), histologic sections were jointly reassessed for residual tumor in areas outside the mesorectal fascial compartment, using MR images as guidance for where to inspect. Following RT/CRT, 67.5% of cases were found to remain ypT4, even though half of the study population had complete (ypT0; 7.6%) or near-complete (sparsely remaining tumor; 43.5%) histomorphologic tumor regression. After MR-guided histologic reassessment of surgical specimens, the false-negative rate of conventional histopathology for detection of ypT4 was determined to be 41.1%. Five-year estimate for locally recurrent disease was 12.7%. This response data to neoadjuvant RT/CRT in organ-infiltrating rectal cancer indicate that tumor down-staging is over-estimated by conventional evaluation.


Intraoperative Heparin Use during Upper Extremity Arteriovenous Access Creation Does Not Affect Outcomes.
There are conflicting data about the effect of heparin use on perioperative outcomes during upper extremity arteriovenous (AV) access creation. Our goal was to assess the effect of the use and degree of intraoperative heparin on perioperative outcomes after AV access creation. All upper extremity AV access cases performed at a tertiary academic medical center between 2014 and 2017 were reviewed. Patient and procedural details including intraoperative heparin use and dosing as well as protamine use were analyzed. Full heparin dose was defined as 80-100 U/kg and partial heparin dose as less than 80 U/kg. Perioperative arterial thrombosis or distal embolism, hematoma, and early loss of primary patency within 30 days were evaluated. Multivariate analysis was performed to assess the effect of heparin use. There were 550 AV access cases identified: brachiocephalic (37.5%), brachiobasilic (29.3%), and radiocephalic fistulas (12.9%), and AV grafts (16.9%). Average patient age was 62.6 years and 58.9% were male. Full heparinization was used in 21.3%, partial heparinization in 58.7%, and no heparin was used in 20% of cases. Protamine was used in 94.9% of full heparin cases and 51.4% of partial heparin cases. No perioperative arterial thrombosis or distal embolism was observed. Perioperative wound hematoma rate was 3.4%, 3.1%, and 0.9% in full heparin, partial heparin, and no heparin cohorts, respectively (P = 0.42). Early loss of primary patency was 11.1%, 7.7%, and 6.4% for full heparin, partial heparin, and no heparin cases, respectively (P = 0.39). There were no differences in return to the operating room or perioperative survival. On multivariable analysis, full heparin use (odds ratio [OR] 3.82, 95% confidence interval [CI] 0.41-35.9, P = 0.24) and partial heparin (OR 4.03, 95% CI 0.5-32.6, P = 0.19) use were not significantly different from no heparin cases with respect to 30-day perioperative hematoma rate. Full heparin (OR 1.76, 95% CI 0.65-4.78, P = 0.26) and partial heparin (OR 1.13, 95% CI 0.46-2.75, P = 0.79) were not significantly different from no heparin cases with respect to early loss of primary patency. Intraoperative heparin use, at full or partial doses, did not affect perioperative outcomes after AV access creation. Overall complication event rate was low for all groups. AV access can be safely performed without intraoperative heparin use.


Lovastatin enhances Abeta production and senile plaque deposition in female Tg2576 mice.
A recent clinical study showed that statins, which are inhibitors of cholesterol biosynthesis pathway, reduced the prevalence of Alzheimer's disease (AD). Animal studies that have employed high cholesterol diet indicate significant relationship between cholesterol level and senile plaque deposition. Here, we investigated the effects of lovastatin on beta-amyloid production and senile plaque deposition in an animal model of AD (Tg2576 mice). As expected, lovastatin treatment reduced plasma cholesterol level in both male and female mice. However, lovastatin enhanced the amounts of beta-amyloid and other beta-secretase derived peptides in females, but not in males. Likewise, lovastatin increased the number of plaques in the hippocampus and cortex of females, but not in males. Lovastatin did not change the amounts of full-length or alpha-secretase processed amyloid precursor protein (APP), or presenilin 1 (PS1) in either sex. Thus, lovastatin lowers cholesterol level in both genders, but enhances beta-amyloid production and senile plaque deposition only in brains of female Tg2576 mice. Our results suggest that low plasma cholesterol levels might be a risk factor for AD in females.


Inverted Internal Limiting Membrane Flap Technique versus Internal Limiting Membrane Peeling for Vitrectomy in Highly Myopic Eyes with Macular Hole-Induced Retinal Detachment: An Updated Meta-Analysis.
The aim of this meta-analysis was to compare morphological and functional outcomes between vitrectomy with the inverted internal limiting membrane (ILM) flap technique and vitrectomy with internal limiting membrane peeling in highly myopic eyes with macular hole- (MH-) induced retinal detachment (MHRD). The PubMed, Web of Science, Embase, and Cochrane Library databases were comprehensively searched from inception to November 10, 2019, for published studies comparing the two techniques for the treatment of MHRD. The outcomes in the collected articles included the postoperative MH closure rate, retinal reattachment rate, and best-corrected visual acuity (BCVA). Review Manager (version 5.3) was used for analyses. In total, seven retrospective studies comparing the inverted ILM flap technique with ILM peeling for the treatment of MHRD were included. The MH closure rate was significantly higher in the inverted ILM flap group than in the ILM peeling group at 6 and 12 months after initial surgery (OR = 15.39; 95% CI: 6.68 to 35.43;P < 0.00001 and OR = 12.58, 95% CI: 3.51 to 45.08; P=0.0001), while the retinal reattachment rate was similar in both groups at 6 months after initial surgery (OR = 2.40; 95% CI: 0.89 to 6.50; P=0.08). Besides, the postoperative BCVA was significantly better in the inverted ILM flap group than in the ILM peeling group at 12 months after initial surgery (MD = -0.35; 95% CI: -0.52 to -0.18; P < 0.0001). Thus, the MH closure rate and postoperative BCVA may be better with the inverted ILM flap technique than with ILM peeling for myopic MHRD, while the postoperative retinal reattachment rate appears to be similar with both techniques. Therefore, in the future, vitrectomy with the inverted ILM flap technique should be preferred over standard ILM peeling technique for the treatment of MHRD in highly myopic eyes.


Prognostic role of cytovillin expression in patients with osteosarcoma: a meta-analysis.
Cytovillin plays structural and regulatory roles in the assembly and stabilization of specialized plasma membrane domains and in the tumor angiogenesis. Cytovillin expression has been proposed to be an effective biomarker of prognosis in patients with osteosarcoma, and many studies have been performed to assess the prognostic role of cytovillin expression in patients with osteosarcoma. We performed this meta-analysis to provide a comprehensive evaluation of the role of cytovillin expression on the overall survival rate by calculating the pooled risk ratio (RR) with corresponding 95% confidence interval (95% CI). Finally, eight studies with a total of 415 patients with osteosarcoma were included into the meta-analysis. Meta-analysis of total eight studies showed that cytovillin expression was obviously associated with lower overall survival rate in patients with osteosarcoma (RR = 0.41, 95% CI 0.28–0.58, P < 0.001). Meta-analysis of five studies with large sample still showed that cytovillin expression was obviously associated with lower overall survival rate (RR = 0.48, 95% CI 0.38–0.60, P < 0.001). In conclusion, the meta-analysis shows that cytovillin expression is obviously associated with lower overall survival rate in patients with osteosarcoma, and it is an effective biomarker of prognosis.


The transcriptional terminator XRN2 and the RNA-binding protein Sam68 link alternative polyadenylation to cell cycle progression in prostate cancer.
Alternative polyadenylation (APA) yields transcripts differing in their 3'-end, and its regulation is altered in cancer, including prostate cancer. Here we have uncovered a mechanism of APA regulation impinging on the interaction between the exonuclease XRN2 and the RNA-binding protein Sam68, whose increased expression in prostate cancer is promoted by the transcription factor MYC. Genome-wide transcriptome profiling revealed a widespread impact of the Sam68/XRN2 complex on APA. XRN2 promotes recruitment of Sam68 to its target transcripts, where it competes with the cleavage and polyadenylation specificity factor for binding to strong polyadenylation signals at distal ends of genes, thus promoting usage of suboptimal proximal polyadenylation signals. This mechanism leads to 3' untranslated region shortening and translation of transcripts encoding proteins involved in G1/S progression and proliferation. Thus, our findings indicate that the APA program driven by Sam68/XRN2 promotes cell cycle progression and may represent an actionable target for therapeutic intervention.


The underexplored presence of seasonal affective disorder in the southern hemisphere: A narrative review of the Australian literature.
Seasonal Affective Disorder (SAD) is well documented in the medical literature, particularly in more northern latitudes in agreement with proposed hypotheses for SAD's pathophysiology. However, in the southern latitudes SAD's presence remains underexplored. The second largest country in the southern hemisphere is Australia. Australia has wide ranging geographical and climatic differences that are expected to support SAD's presence. The aim of this study is therefore, to establish an evidence base for SAD in Australia. PubMed and Google Scholar were searched for published peer-review studies focussed on, or related to SAD, winter depression or seasonal variation in mood in Australia. There were no time-period restrictions. Thirteen studies were identified. Studies explored the presence/nature of SAD, contributing factors, autonomic activity, treatment, and the validity of the Seasonal Pattern Assessment Questionnaire in the Australian population. An association between changes in mood and behaviour and seasonal occurrence was clearly identified, with SAD's presence varying by location. The highest percentage of study participants with SAD in a single location was observed in Tasmania, Australia's most southern state. The findings and interpretations of the studies included in this review are subject to the number of locations assessed, the number of studies undertaken at each location and individual study limitations. Ascertaining information on the prevalence and correlates of SAD in the southern hemisphere, particularly in high-risk locations could contribute to clinical literacy into the syndrome, support management practices, and promote the early identification and treatment of the disorder.


Basic fibroblast growth factor production and growth factor receptors as potential targets for melanoma therapy.
A number of growth factors can stimulate the proliferation of human malignant melanoma cell lines. We investigated the effects of exogenous growth factors including basic fibroblast growth factor (bFGF), epidermal growth factor, transforming growth factor-alpha, insulin, insulin-like growth factor-I (IGF-I), acidic fibroblast growth factor, platelet-derived growth factor, transforming growth factor-beta and nerve growth factor on six human metastatic melanoma cell lines. The mitogenic activity of each growth factor was tested using the [3H]thymidine incorporation assay. There was a variable response of the different cell lines to most growth factors. All of the melanoma cell lines tested responded to IGF-I. Furthermore, the effects of growth factors were additive, a combination of bFGF and IGF-I having the greatest effect on three melanoma cell lines tested. The quantitative radioimmunoassay for bFGF and [125I]bFGF binding assay revealed that all of these melanoma cell lines produced bFGF and expressed high affinity receptors for bFGF. A 20-mer antisense oligodeoxynucleotide against the AUG initiation site of the bFGF coding region inhibited the proliferation of Mel-Tang by 40% (p less than 0.0001) and that of SK-MEL-5 by 20% (p less than 0.005), suggesting that these cell lines are at least under partial autocrine control of proliferation by bFGF. The presence of bFGF receptors on a high percentage of melanoma cell lines makes these a potential target for melanoma therapy.


New Antiandrogen Compounds Compared to Docetaxel for Metastatic Hormone Sensitive Prostate Cancer: Results from a Network Meta-Analysis.
Docetaxel represent the standard of care in patients with metastatic, hormone sensitive prostate cancer. However, androgen receptor axis targeted therapies have also been shown to be effective. We aimed to analyze findings in randomized controlled trials investigating first-line treatment for hormone sensitive prostate cancer. We systematically reviewed the literature according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) criteria and the PICO (Population, Intervention, Comparator, Outcomes) methodology. Outcomes of interest were overall and progression-free survival, and the rate of high grade adverse events. No treatment was superior to docetaxel in terms of overall survival. However, abiraterone (HR 0.89, 95% CI 0.76-1.05), enzalutamide (HR 0.90, 95% CI 0.69-1.19) and apalutamide (HR 0.90, 95% CI 0.67-1.22) showed nonstatistically significant lower overall mortality rates than docetaxel. Abiraterone (HR 0.71, 95% CI 0.59-0.86), enzalutamide (HR 0.61, 95% CI 0.49-0.75) and apalutamide (HR 0.74, 95% CI 0.57-0.95) also showed statistically significant lower disease progression rates than docetaxel. Furthermore, abiraterone (OR 0.83, 95% CI 0.56-1.21) showed no statistically significant lower rate of high grade adverse events compared to docetaxel. Finally, enzalutamide (OR 0.56, 95% CI 0.35-0.92) and apalutamide (OR 0.44, 95% CI 0.24-0.79) showed statistically significant lower rates of high grade adverse events compared to docetaxel. Treatment with androgen receptor axis targeted therapies combined with androgen deprivation therapy in patients with hormone sensitive prostate cancer did not offer a statistically significant advantage in overall survival compared to the standard, docetaxel. However, it was associated with a lower disease progression rate. Moreover, apalutamide and enzalutamide offer a better safety profile.


Alu sequences are processed 7SL RNA genes.
7SL RNA is an abundant cytoplasmic RNA which functions in protein secretion as a component of the signal recognition particle. Alu sequences are the most abundant family of human and rodent middle repetitive DNA sequences (reviewed in ref. 2). The primary structure of human 7SL RNA consists of an Alu sequence interrupted by a 155-base pair (bp) sequence that is unique to 7SL RNA. In order to obtain information about the evolution of the Alu domain of 7SL RNA, we have determined the nucleotide sequence of a cDNA copy of Xenopus laevis 7SL RNA and of the 7SL RNA gene of Drosophila melanogaster. We find that the Xenopus sequence is 87% homologous with its human counterpart and the Drosophila 7SL RNA is 64% homologous to both the human and amphibian molecules. Despite the evolutionary distance between the species, significant blocks of homology to both the Alu and 7SL-specific portions of mammalian 7SL RNA can be found in the insect sequence. These results clearly demonstrate that the Alu sequence in 7SL RNA appeared in evolution before the mammalian radiation. We suggest that mammalian Alu sequences were derived from 7SL RNA (or DNA) by a deletion of the central 7SL-specific sequence, and are therefore processed 7SL RNA genes.


Comparison and characterization of α-amylase inducers in Aspergillus nidulans based on nuclear localization of AmyR.
AmyR, a fungal transcriptional activator responsible for induction of amylolytic genes in Aspergillus nidulans, localizes to the nucleus in response to the physiological inducer isomaltose. Maltose, kojibiose, and D: -glucose were also found to trigger the nuclear localization of GFP-AmyR. Isomaltose- and kojibiose-triggered nuclear localization was not inhibited by the glucosidase inhibitor, castanospermine, while maltose-triggered localization was inhibited. Thus, maltose itself does not appear to be an direct inducer, but its degraded or transglycosylated product does. Non-metabolizable D: -glucose analogues were also able to trigger the nuclear localization, implying that these sugars, except maltose, directly function as the inducers of AmyR nuclear entry. The inducing activity of D: -glucose was 4 orders-of-magnitude weaker compared with isomaltose. Although D: -glucose has the ability to induce α-amylase production, this activity would generally be masked by CreA-dependent carbon catabolite repression. Significant induction of α-amylase by D: -glucose was observed in creA-defective A. nidulans.


Doxorubicin mediated cardiotoxicity in rats: protective role of felodipine on cardiac indices.
Anthracyclines find vital uses in the treatment of solid tumors and other kind of malignancies. A typical side effect observed with few agents of this class is dose-dependent cardiotoxicity. Doxorubicin is one such agent which backs the generation of free radicals through metabolism of its quinone structure. This effect combined with induction of apoptotic and necrotic pathways leads to the development of irreversible cardiotoxicity. Reports showing the cardioprotective effects of felodipine have been published in the past. We chose to evaluate protective effect of felodipine in acute cardiotoxicity in rats induced by single dose of doxorubicin. Felodipine was assessed against doxorubicin-induced cardiotoxicity and we found that felodipine not only improves cardiac marker enzymes (P<0.001 for LDH; P<0.01 for CK-MB) but also prevents damage to myocardial tissue (20.61% necrosed area in doxorubicin intoxication; 11.52% necrosed area in felodipine treated group). Activation of apoptotic pathways is decelerated which is indicated by a significant reduction in myocardial caspase-3 activity (P<0.05) following felodipine pretreatment. Felodipine pretreatment was able to maintain normal cardiac morphology and histoarchitecture. Gravimetric analysis revealed beneficial effects following felodipine pretreatment. Abnormalities seen in the ECG after doxorubicin treatment were normalized to a significant extent (ST interval normalization was significant at P<0.01) in felodipine treated rats. In itself, felodipine was not found to have any detrimental effects on the myocardium or hemodynamic parameters of rats. Findings of the study suggest that pretreatment with felodipine prevents doxorubicin induced cardiotoxicity.


Neurochemical correlates of conditioned circling within localized regions of the striatum.
Two experiments were conducted to determine the effects of conditioned circling on the concentrations of dopamine (DA), 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) within discrete regions of the striatum (STR). The first study assessed the inherent regional distributions of these compounds with respect to the three primary axes: anterior-posterior, dorsal-ventral and medial-lateral. Concentrations of DA, DOPAC and HVA and the ratios of each metabolite to DA were found to vary across each dimension. However, the topographical distribution of each compound was unique. The results of the first experiment confirm that the STR is not a homogeneous structure. It is possible that the regional variations in dopamine metabolism underly the diverse functions which the STR is thought to modulate. The second experiment determined whether specific regions of the STR were differentially involved in the mediation of conditioned circling. DA metabolism, as estimated by metabolite concentrations and metabolite to DA ratios, was bilaterally increased within the anterior dorsomedial and dorsolateral STR, relative to noncircling, water-deprived controls. DOPAC and the corresponding ratio were enhanced selectively within the dorsomedial region, whereas HVA and its ratio to DA were increased preferentially within the dorsolateral STR. The ratio of DOPAC to DA was also enhanced within the anterior ventromedial STR. No other significant neurochemical effects were detected. These results support the hypothesis that the dorsal STR critically subserves circling. Moreover, it is possible that the medial and lateral regions of the dorsal STR are differentially involved in circling. These results also confirm previous reports of bilateral augmentation of striatal DA metabolism in association with high rates of conditioned circling.


Identification of symbiotic nitrogen-fixing bacteria from three African leguminous trees in Gorongosa National Park.
The symbiosis between leguminous plants and symbiotic nitrogen-fixing bacteria is a key component of terrestrial ecosystems. Woody legumes are well represented in tropical African forests but despite their ecological and socio-economic importance, they have been little studied for this symbiosis. In this study, we examined the identity and diversity of symbiotic-nitrogen fixing bacteria associated with Acacia xanthophloea, Faidherbia albida and Albizia versicolor in the Gorongosa National Park (GNP) in Mozambique. To the best of our knowledge, this is the first report on the identity of symbiotic-nitrogen fixing bacteria in this region. 166 isolates were obtained and subjected to molecular identification. BOX-A1R PCR was used to discriminate different bacterial isolates and PCR-sequencing of 16S rDNA, and two housekeeping genes, glnII and recA, was used to identify the obtained bacteria. The gene nifH was also analyzed to assess the symbiotic capacity of the obtained bacteria. All isolates from F. albida and Al. versicolor belonged to the Bradyrhizobium genus whereas isolates from Ac. xanthophloea clustered with Mesorhizobium, Rhizobium or Ensifer strains. Soil chemical analysis revealed significant differences between the soils occupied by the three studied species. Thus, we found a clear delimitation in the rhizobial communities and soils associated with Ac. xanthophloea, F. albida and Al. versicolor, and higher rhizobial diversity for Ac. xanthophloea than previously reported.


Local Inflammatory Response Can Predict Clinical Outcome in Patients with Curatively Resected Stage-IIB Colon Cancer: An Advanced Methodological Study.
Although local inflammatory response (LIR) is a reliable survival marker in colon cancers (CCs), there is no consensus on its use in daily practice. We investigated the prognostic value of LIR in a highly homogeneous population with a well-designed methodology. Eighty stage-IIB CC patients operated between 2002 and 2012 were included in the study. Standardization was investigated for extra-biopsy evaluation methods (magnification, staining, and counting). Model A was used for intra-biopsy evaluation methods (block, section, and focus). So, this study makes important contributions to the standardization of pathological evaluations. In method 1, the following analyzes showed more successful results for LIR: relationship with prognostic factors [tumour deposits (p=0.017), Crohn's-like reaction (p=0.019), advanced grade, (p=0.012), positive surgical margin (p=0.019), perineural invasion (p=0.025), mismatch repair proteins-proficiency (p=0.031)], reproducibility of the study (Kappa=0.49-0.73, Intra-class correlation=0.442-0.724), and correlation of estimates (r=0.704). The cut-off value was also quite useful (area of under ROC=0.820 [0.694-0.920]). In univariate analysis, low LIR was related to poor overall survival (OS; p<0.001) and poor relapse-free survival (RFS, p=0.001) . Multivariate analysis confirmed that low LIR is an independent poor survival marker for OS (Hazard Ratio [HR]=1.32 [1.08-1.61, p=0.005) and RFS (HR=1.50 [1.22-1.85], p<0.001). Our results showed that low LIR had an independent prognostic significance in stage -IIB CCs. We also recommend using model A and method 1 for successful results and standardization.


Probing antiphospholipid-mediated thrombosis: the interplay between anticardiolipin antibodies and endothelial cells.
The association of antiphospholipid (aPL) antibodies with thrombosis in patients with antiphospholipid syndrome (APS) is well documented in humans and in animal studies. However, the mechanisms by which aPL antibodies induce thrombosis are the subject of much current study. It has been suggested that aPL may activate endothelial cells (ECs), thus creating a hypercoagulable state that precedes and contributes to thrombosis in patients with APS. Several studies have shown that aPL upregulate ECs' adhesion molecules (CAMs): intercellular cell adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-selectin (E-sel) or induce tissue factor (TF) in monocytes in vitro. Similarly, the incubation of EC with antibodies reacting with beta2glycoprotein I (beta2GPI) has been shown to induce EC activation with concomitant upregulation of CAMs, IL-6 production and alteration of prostaglandin metabolism. Our group has shown that aPL-mediated upregulation of adhesion molecules on ECs correlates with an increased adhesion of leukocytes to endothelium in the microcirculation of mouse cremaster muscle, a n indication of EC activation in vivo, andwith enhanced thrombosis in vivo. In another series of studies, investigators have shown that upregulation of expression of adhesion molecules by some murine monoclonal anti-beta2glycoprotein I (anti-beta2GPI) antibodies correlated with fetal resorption in mice in vivo. More recently, one study showed that the anti-hypercholesterolaemic drug fluvastatin inhibited the aPL-mediated enhanced adhesion of monocytes to ECs in vitro. Data from our laboratories indicate that fluvastatin also reverses thrombus formation and activation of EC induced by aPL in an in vivo mouse model. As additional support for the hypothesis that aPL antibodies activate ECs and may create an hypercoagulable state in APS patients, two recent studies indicated that levels of soluble ICAM-1 and VCAM-1 were significantly increased in the plasma of patients with APS and recurrent thrombosis. Furthermore, studies utilizing knockout mice and specific monoclonal anti-VCAM-1 antibodies have demonstrated that expression of ICAM-1, P-selectin, E-selectin and VCAM-1 are important in in vivo aPL-mediated thrombosis and EC activation in mice. Recent data suggests that aPL antibodies also induce expression of TF not only in monocytes but in ECs. Hence, the interference of aPL with the TF mechanism may be another important mechanism by which these antibodies create a hypercoagulable state and prone patients to thrombosis. Specifically, how aPL alters EC activation state and the molecular and intracellular mechanisms involved have not yet been defined. APL may interact with specific cell surface receptors (proteins and/or lipids) induce signals that have consequences downstream, and that ultimately will result in upregulation of cell surface proteins (i.e., CAMs and TF) and subsequently induce EC activation. In that regard, our group recently showed that aPL-mediated upregulation of adhesion molecules in ECs is preceded by activation of the nuclear factor kappa B (NFkappaB). Other intracellular mechanisms triggered by aPL are not completely understood and are the subject of current investigation. In conclusion, studies suggest that activation of ECs by aPL is an important mechanism that may precede thrombus formation in patients with APS. Hence, the interplay between aPL antibodies and ECs is important inthe pathogenesis of thrombosis in APS.


Contribution of suicide and injuries to pregnancy-related mortality in low-income and middle-income countries: a systematic review and meta-analysis.
Although suicide is one of the leading causes of deaths in young women in low-income and middle-income countries, the contribution of suicide and injuries to pregnancy-related mortality remains unknown. We did a systematic review to identify studies reporting the proportion of pregnancy-related deaths attributable to suicide or injuries, or both, in low-income and middle-income countries. We used a random-effects meta-analysis to calculate the pooled prevalence of pregnancy-related deaths attributable to suicide, stratified by WHO region. To account for the possible misclassification of suicide deaths as injuries, we calculated the pooled prevalence of deaths attributable to injuries, and undertook a sensitivity analysis reclassifying the leading methods of suicides among women in low-income and middle-income countries (burns, poisoning, falling, or drowning) as suicide. We identified 36 studies from 21 countries. The pooled total prevalence across the regions was 1·00% for suicide (95% CI 0·54-1·57) and 5·06% for injuries (3·72-6·58). Reclassifying the leading suicide methods from injuries to suicide increased the pooled prevalence of pregnancy-related deaths attributed to suicide to 1·68% (1·09-2·37). Americas (3·03%, 1·20-5·49), the eastern Mediterranean region (3·55%, 0·37-9·37), and the southeast Asia region (2·19%, 1·04-3·68) had the highest prevalence for suicide, with the western Pacific (1·16%, 0·00-4·67) and Africa (0·65%, 0·45-0·88) regions having the lowest. The available data suggest a modest contribution of injuries and suicide to pregnancy-related mortality in low-income and middle-income countries with wide regional variations. However, this study might have underestimated suicide deaths because of the absence of recognition and inclusion of these causes in eligible studies. We recommend that injury-related and other co-incidental causes of death are included in the WHO definition of maternal mortality to promote measurement and effective intervention for reduction of maternal mortality in low-income and middle-income countries. National Institute of Mental Health.


Depletion of tissue angiotensin-converting enzyme differentially influences the intrarenal and urinary expression of angiotensin peptides.
The relative contribution of circulating versus tissue renin-angiotensin systems to the tissue expression of angiotensin peptides in the kidney remains unresolved. To address this issue, intrarenal and urinary levels of the peptide products of the renin-angiotensin system were assessed in a tissue angiotensin-converting enzyme knockout (tisACE-/-) mouse model. Systolic blood pressure was significantly lower (64.6+/-3.6 versus 81.4+/-4.5 mm Hg; P<0.02) and urinary volume was increased (7.25+/-0.86 versus 2.86+/-0.48 mL/d; P<0.001) in tisACE-/- mice compared with wild-type mice. Intrarenal angiotensin II was 80% lower in tisACE-/- mice compared with wild-type mice (5.17+/-0.60 versus 25.5+/-2.4 fmol/mg protein; P<0.001). Intrarenal angiotensin I levels also declined by a comparable extent (73%) in the tisACE-/- mice (P<0.01). Intrarenal angiotensin-(1-7) concentrations were similar between the strains, but the ratio of intrarenal angiotensin-(1-7) to angiotensin II and angiotensin I in tisACE-/- mice increased 470% and 355%, respectively, compared with wild-type mice. Urinary excretion of angiotensin II and angiotensin-(1-7) were not different, but the excretion of angiotensin I increased 270% in tisACE-/- mice (P<0.01). These studies suggest 2 potential mechanisms for the reduction of intrarenal angiotensin II in tisACE-/- mice: (1) an attenuated capacity to form angiotensin II by renal angiotensin-converting enzyme and (2) significant depletion of its direct precursor angiotensin I in renal tissue. Sustained intrarenal levels of angiotensin-(1-7) may contribute to chronic hypotension and polyuria in tisACE-/- mice, particularly in the context of depleted angiotensin II in the kidney.


Radiotherapy in brain-stem gliomas in children.
Twenty-one children with brain-stem glioma are discussed. Sixteen received radiotherapy and five were too sick to be irradiated. The mean survival was 3.4 weeks for the non-irradiated group and 8.7 months for the treated group, two of the latter being still alive five and ten months after diagnosis. From the literature and our cases the effect of radiotherapy in brain-stem glioma in childhood is not clear. Differences in patient-selection criteria and the mode and doses of irradiation between the reported series may account for the divergent results, but in our cases radiotherapy did not prolong survival as significantly as compared with the reported series. Elevated intracranial pressure is not rare in patients with a brain-stem glioma, as may be concluded from the present series and from the literature.


Extraocular muscle sideslip and orbital geometry in monkeys.
The belly of each extraocular muscle is elastically coupled to both the globe and orbit. The dependence of muscle planes on gaze angle must be determined experimentally. In monkeys, radio-opaque markers were implanted along the upper and lower margins of a lateral rectus. A scleral search coil was implanted in the other eye. With the eye in various gaze positions, X-ray images were made to show the LR in the lateral view. We found that as the eye rotates vertically over 50 deg (+/- 25 deg), the point of tangency of the LR with the globe slips an average of 5.1 mm vertically with respect to the globe, allowing this point--and so the muscle plane--to remain approximately fixed relative to the orbit. The results of quantitative orbital dissections are presented in support of the sideslip calculations.


A CT-based deep learning system for automatic assessment of aortic root morphology for TAVI planning.
Accurate planning of transcatheter aortic valve implantation (TAVI) is important to minimize complications, and it requires anatomic evaluation of the aortic root (AR), commonly performed through 3D computed tomography (CT) image analysis. Currently, there is no standard automated solution for this process. Two convolutional neural networks with 3D U-Net architectures (model 1 and model 2) were trained on 310 CT scans for AR analysis. Model 1 performs AR segmentation and model 2 identifies the aortic annulus and sinotubular junction (STJ) contours. After training, the two models were integrated into a fully automated pipeline for geometric analysis of the AR. Results were validated against manual measurements of 178 TAVI candidates. The trained CNNs segmented the AR, annulus, and STJ effectively, resulting in mean Dice scores of 0.93 for the AR, and mean surface distances of 0.73 mm and 0.99 mm for the annulus and STJ, respectively. Automatic measurements were in good agreement with manual annotations, yielding annulus diameters that differed by 0.52 [-2.96, 4.00] mm (bias and 95% limits of agreement for manual minus algorithm). Evaluating the area-derived diameter, bias, and limits of agreement were 0.07 [-0.25, 0.39] mm. STJ and sinuses diameters computed by the automatic method yielded differences of 0.16 [-2.03, 2.34] and 0.1 [-2.93, 3.13] mm, respectively. The proposed tool is a fully automatic solution to quantify morphological biomarkers for pre-TAVI planning. The method was validated against manual annotation from clinical experts and showed to be quick and effective in assessing AR anatomy, with potential for time and cost savings.


Inhibition of 37/67kDa Laminin-1 Receptor Restores APP Maturation and Reduces Amyloid-β in Human Skin Fibroblasts from Familial Alzheimer's Disease.
Alzheimer's disease (AD) is a fatal neurodegenerative disorder caused by protein misfolding and aggregation, affecting brain function and causing dementia. Amyloid beta (Aβ), a peptide deriving from amyloid precursor protein (APP) cleavage by-and γ-secretases, is considered a pathological hallmark of AD. Our previous study, together with several lines of evidence, identified a strict link between APP, Aβ and 37/67kDa laminin receptor (LR), finding the possibility to regulate intracellular APP localization and maturation through modulation of the receptor. Here, we report that in fibroblasts from familial AD (fAD), APP was prevalently expressed as an immature isoform and accumulated preferentially in the transferrin-positive recycling compartment rather than in the Golgi apparatus. Moreover, besides the altered mitochondrial network exhibited by fAD patient cells, the levels of pAkt and pGSK3 were reduced in respect to healthy control fibroblasts and were accompanied by an increased amount of secreted Aβ in conditioned medium from cell cultures. Interestingly, these features were reversed by inhibition of 37/67kDa LR by NSC47924 a small molecule that was able to rescue the "typical" APP localization in the Golgi apparatus, with consequences on the Aβ level and mitochondrial network. Altogether, these findings suggest that 37/67kDa LR modulation may represent a useful tool to control APP trafficking and Aβ levels with implications in Alzheimer's disease.


Validation of the Khorana Score for Prediction of Venous Thromboembolism After Robot-Assisted Radical Cystectomy.
Introduction: The Khorana score (KS) is used to predict the risk of venous thromboembolism (VTE) for cancer patients. We sought to assess the association between KS and VTE for patients who underwent robot-assisted radical cystectomy (RARC). Materials and Methods: We reviewed our prospectively maintained quality assurance RARC database between 2005 and 2020. KS was calculated for all patients (one point for each body mass index [BMI] ≥35 kg/m2, platelet count ≥350 × 109/L, leukocyte count >11 × 109/L, and hemoglobin level <10 g/dL, or use of erythropoiesis-stimulating agents). All patients received one point by default for the cancer type (bladder). Patients were divided into intermediate-risk (KS 1-2) or high-risk (KS ≥3) groups. Receiver operating characteristic curve was used to assess the ability of KS to predict VTE. Kaplan-Meier curves were stratified based on their KS risk and used to depict overall survival (OS). Multivariate analysis (MVA) was used to identify variables associated with VTE. Results: Out of 589 patients, 33 (6%) developed VTE (18 had deep vein thrombosis and 15 had pulmonary embolism). Five hundred forty-six (93%) patients had intermediate-risk KS and 30 (5%) of them developed VTE. Forty-three (7%) patients were classified as high-risk KS and 3 (7%) developed VTE. This difference was not significant (p = 0.73). The KS area under the curve for VTE prediction was 0.51. On MVA, BMI ≥35 kg/m2 (odds ratio [OR] 2.69, confidence interval [CI] 1.19-6.11, p = 0.02), longer inpatient stay (OR 1.04, CI 1.003-1.07, p = 0.03), and ≥pT3 disease (OR 2.29, CI 1.11-4.71, p = 0.03) were associated with VTE, whereas KS was not associated with VTE (p = 0.68). Five-year OS of patients with intermediate KS was 53% compared with 30% for high-risk KS (log rank p < 0.01). Conclusion: KS underestimated VTE risk after RARC and showed poor accuracy. This highlights the need to develop procedure-specific tools to estimate the risk of VTE after RARC.


Do pigeons prefer information in the absence of differential reinforcement?
Prior research has indicated that pigeons do not prefer an alternative that provides a sample (for matching to sample) over an alternative that does not provide a sample (i.e., there is no indication of which comparison stimulus is correct). However, Zentall and Stagner (Journal of Experimental Psychology. Animal Behavior Processes 36:506-509, 2010) showed that when delay of reinforcement was controlled, pigeons had a strong preference for matching over pseudomatching (i.e., there was a sample, but it did not indicate which comparison stimulus was correct). Experiment 1 of the present study replicated and extended the results of the Zentall and Stagner (Journal of Experimental Psychology. Animal Behavior Processes 36:506-509, 2010) study by including an identity relation between the sample and one of the comparison stimuli in both the matching and pseudomatching tasks. In Experiment 2, in which we asked whether the pigeons would still prefer matching if we equated the two tasks for probability of reinforcement, we found no systematic preference for matching over pseudomatching. Thus, it appears that in the absence of differential reinforcement, the information provided by a sample that signals which of the two comparison stimuli is correct is insufficient to produce a preference for that alternative.


Modulatory influence of melatonin on apical periodontitis in Wistar rats fed a high-fat diet.
This study aimed to evaluate the influence of high-fat diet (HFD) and melatonin (MEL) treatment on the progression of inflammation and alveolar bone resorption (ABR) in rats with AP. Forty male Wistar rats were divided into four groups: apical periodontitis (AP), HFDAP, APMEL and HFDAPMEL. The animals were fed an HFD or standard diet for 107 days. On the 7th day, the rats were subjected to AP, and after 70 days, the rats in the MEL groups were treated with MEL for 30 days. Post treatment, the animals were euthanized, and their jaws were retrieved for evaluation of bone resorption, intensity of the inflammatory response, and immunohistochemical analysis including tartrate-resistant acid phosphatase (TRAP) and interleukin-1β (IL-1β) levels and tumor necrosis factor (TNF)-α expression. The APMEL group showed reduction in the inflammatory infiltrate and IL-1β expression relation to HFDAP, while the TNF-α levels did not differ among the groups. The HFDAP group showed an increase in the ABR. MEL reduced the TRAP levels in the APMEL and HFDAPMEL groups. while MEL could reduce TRAP levels in the APMEL and HFDAPMEL groups, the reduction in the HFDAPMEL group was smaller than that in the APMEL group, demonstrating that the interaction between AP and HFD decreased the anti-resorptive effects of MEL.


Reduced insulin clearance in normal subjects due to extreme hyperinsulinemia.
Insulin clearance was assessed in five normal subjects infused with insulin at a rate of 10 mU.kg-1.min-1 for 12-16 hours, which produced insulin levels of 1500-2000 microU/ml (approximately 10(-8) M). This level approximates the Kd of low affinity insulin binding sites, whereas previous clearance studies had been performed at insulin concentrations of 10(-9) M or less, approximating the Kd of the high affinity insulin receptor. The metabolic clearance rate for insulin during the infusion averaged 214 +/- 29 ml.min-1.m-2, which is half of that reported previously when lower insulin levels were achieved. Upon termination of the insulin infusion, the disappearance of insulin was markedly prolonged with an average "half-life" of 62 minutes. The rapidity with which hyperinsulinemia altered clearance suggested that down-regulation of insulin receptors was probably not the explanation for the reduced clearance. To elucidate the cause for the observed decrease in insulin clearance, five additional subjects were studied. If insulin was infused for 3.0-4.5 hours, the half-life of insulin disappearance was intermediate between that for an insulin bolus dose and that for a 12-16 hour insulin infusion. Administration of an insulin bolus dose at the end of a 12-hour infusion, while the insulin concentration was still approximately 10(-8) M, or 140 min later, when the insulin concentration was 10(-9) M, was followed by rapid disappearance with half-lives of 1.5 and 6-8 minutes, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)


Uterine NK cells mediate inflammation-induced fetal demise in IL-10-null mice.
Specialized NK cells are recruited in high numbers to the mammalian embryo implantation sites, yet remain pregnancy compatible. It is not well understood whether uterine NK (uNK) cells become adversely activated and mediate fetal demise, a common complication of early pregnancy. In this study we show that mating of IL-10(-/-) mice resulted in fetal resorption or intrauterine growth restriction in response to very low doses of LPS. Pregnancy in congenic wild-type mice was normal even at 10-fold higher LPS doses. Fetal resorption in IL-10(-/-) mice was associated with a significant increase in uNK cell cytotoxic activation and invasion into the placenta. Depletion of uNK cells, TNF-alpha neutralization, or IL-10 administration rescued pregnancy in LPS-treated IL-10(-/-) animals. Our results identify an immune mechanism of fetal demise involving IL-10 deficiency, NK cells, and inflammation. These results may provide insight into adverse pregnancy outcomes in humans.


Non-Modulator Therapies: Developing a Therapy for Every Cystic Fibrosis Patient.
Cystic fibrosis transmembrane conductance regulator (CFTR) modulator therapy brings hope to most patients with cystic fibrosis (CF), but not all. For approximately 12% of CF patients with premature termination codon mutations, large deletions, insertions, and frameshifts, the CFTR modulator therapy is not effective. Many believe that genetic-based therapies such as RNA therapies, DNA therapies, and gene editing technologies will be needed to treat mutations that are not responsive to modulator therapy. Delivery of these therapeutic agents to affected cells is the major challenge that will need to be overcome if we are to harness the power of these emerging therapies for the treatment of CF.


Current trends in Antenatal Screening Services: Results from a regional survey.
To identify variations in current antenatal screening programmes across one region and compare results with a previous survey. A cross section descriptive survey. All maternity units within the region of Northern Ireland. Eleven maternity units were invited and ten agreed to participate. The number of written policies for individual screening tests; the range of screening tests offered; the frequency of training opportunities for health professionals; and the information systems in place to record data. There is variation in service provision across maternity units and, in particular, inconsistency in the offer of serum screening tests for Down syndrome. A lack of training opportunities for health professionals involved in offering screening was highlighted, and no common information system employed. While improvements have been made since 2002, variations persist. This is leading to inequalities in the provision of antenatal screening services across Northern Ireland.


The Apolipoprotein C1 is involved in breast cancer progression via EMT and MAPK/JNK pathway.
Apolipoprotein C1 (APOC1) is a member of the apolipoprotein family. In recent years, more and more studies have shown that APOC1 participates in the occurrence and development of cancer. However, there is no systematic study about the specific functions and underlying mechanisms of APOC1 in breast carcinogenesis. The APOC1 was found significantly over-expressed in breast cancer tissues. The correlation of APOC1 expression with the prognosis and the clinicopathological characteristics were subsequently analyzed. APOC1 overexpression was correlated with higher TNM stage and positive lymph node metastasis. APOC1 enhanced the proliferation, invasion, and migration ability of breast cancer cell lines (MDA-MB-231 and MCF-7) in vitro. APOC1 inhibited E-cadherin expression and promoted Vimentin's expression, which suggested that APOC1 played a crucial role in the epithelial-mesenchymal transition (EMT) process of the breast cancer cell. Moreover, APOC1 participated in the progression of breast cancer by regulating the JNK/MAPK pathway. Thus, our results demonstrated that APOC1 might be used as a novel biomarker for prognosis and diagnostic in breast cancer patients.


Estimation of FMO3 Ontogeny by Mechanistic Population Pharmacokinetic Modelling of Risdiplam and Its Impact on Drug-Drug Interactions in Children.
Spinal muscular atrophy (SMA) is a progressive neuromuscular disease caused by insufficient levels of survival motor neuron (SMN) protein. Risdiplam (EvrysdiTM) increases SMN protein and is approved for the treatment of SMA. Risdiplam has high oral bioavailability and is primarily eliminated through hepatic metabolism by flavin-containing monooxygenase3 (FMO3) and cytochrome P450 (CYP) 3A, by 75% and 20%, respectively. While the FMO3 ontogeny is critical input data for the prediction of risdiplam pharmacokinetics (PK) in children, it was mostly studied in vitro, and robust in vivo FMO3 ontogeny is currently lacking. We derived in vivo FMO3 ontogeny by mechanistic population PK modelling of risdiplam and investigated its impact on drug-drug interactions in children. Population and physiologically based PK (PPK and PBPK) modelling conducted during the development of risdiplam were integrated into a mechanistic PPK (Mech-PPK) model to estimate in vivo FMO3 ontogeny. A total of 10,205 risdiplam plasma concentration-time data from 525 subjects aged 2 months-61 years were included. Six different structural models were examined to describe the in vivo FMO3 ontogeny. Impact of the newly estimated FMO3 ontogeny on predictions of drug-drug interaction (DDI) in children was investigated by simulations for dual CYP3A-FMO3 substrates including risdiplam and theoretical substrates covering a range of metabolic fractions (fm) of CYP3A and FMO3 (fmCYP3A:fmFMO3 = 10%:90%, 50%:50%, 90%:10%). All six models consistently predicted higher FMO3 expression/activity in children, reaching a maximum at the age of 2 years with an approximately threefold difference compared with adults. Different trajectories of FMO3 ontogeny in infants < 4 months of age were predicted by the six models, likely due to limited observations for this age range. Use of this in vivo FMO3 ontogeny function improved prediction of risdiplam PK in children compared to in vitro FMO3 ontogeny functions. The simulations of theoretical dual CYP3A-FMO3 substrates predicted comparable or decreased CYP3A-victim DDI propensity in children compared to adults across the range of fm values. Refinement of FMO3 ontogeny in the risdiplam model had no impact on the previously predicted low CYP3A-victim or -perpetrator DDI risk of risdiplam in children. Mech-PPK modelling successfully estimated in vivo FMO3 ontogeny from risdiplam data collected from 525 subjects aged 2 months-61 years. To our knowledge, this is the first investigation of in vivo FMO3 ontogeny by population approach using comprehensive data covering a wide age range. Derivation of a robust in vivo FMO3 ontogeny function has significant implications on the prospective prediction of PK and DDI in children for other FMO3 substrates in the future, as illustrated in the current study for FMO3 and/or dual CYP3A-FMO3 substrates. NCT02633709, NCT03032172, NCT02908685, NCT02913482, NCT03988907.


Automatic generation of minimum dataset and quality indicators from data collected routinely by the clinical information system in an intensive care unit.
Quality indicators (QIs) are being increasingly used in medicine to compare and improve the quality of care delivered. The feasibility of data collection is an important prerequisite for QIs. Information technology can improve efforts to measure processes and outcomes. In intensive care units (ICU), QIs can be automatically measured by exploiting data from clinical information systems (CIS). To describe the development and application of a tool to automatically generate a minimum dataset (MDS) and a set of ICU quality metrics from CIS data. We used the definitions for MDS and QIs proposed by the Spanish Society of Critical Care Medicine and Coronary Units. Our tool uses an extraction, transform, and load process implemented with Python to extract data stored in various tables in the CIS database and create a new associative database. This new database is uploaded to Qlik Sense, which constructs the MDS and calculates the QIs by applying the required metrics. The tool was tested using data from patients attended in a 30-bed polyvalent ICU during a six-year period. We describe the definitions and metrics, and we report the MDS and QI measurements obtained through the analysis of 4546 admissions. The results show that our ICU's performance on the QIs analyzed meets the standards proposed by our national scientific society. This is the first step toward using a tool to automatically obtain a set of actionable QIs to monitor and improve the quality of care in ICUs, eliminating the need for professionals to enter data manually, thus saving time and ensuring data quality.


Relationships among body mass index, parental perceptions, birthweight and parental weight after referral to a weight clinic.
We sought to determine whether, in a specialty referral clinic, parental perceptions of their child's obesity were commensurate with the child's body mass index z score. Secondarily, we examined the impact of birth weight and parental body mass index on their child's body mass index z score and review results of an intake questionnaire. Cross-sectional study University of Michigan from March 21, 2003 through June 30, 2004 Eighty-two children ages 1-20.2 years of age Body mass index z score for all participants was calculated. An intake questionnaire was completed by caregivers in which they were asked to describe their child as little overweight, overweight, very overweight or obese. Mean body mass index z score was compared to each parental descriptor. Regression analysis related body mass index z score to birthweight and parental body mass index. Body mass index z score was not related to parental descriptors. Maternal body mass index and child birthweight were predictors of the child's body mass index z score (r2=0.15, p<0.05; and r2=0.11, p<0.05, respectively). Both together produced a better model than either alone (r2=0.23, p<0.05). There was no relationship between paternal and child body mass index z score (p>0.05). There is a divergence between the parental perception of childhood obesity and the clinical definition that persists even in the context of an explicit referral. Given the significant impact of maternal weight on childhood overweight, education for prevention of overweight youth should encompass prenatal, early childhood and adolescent health maintenance.


[Neurofunctional MRI at high magnetic fields].
Functional magnetic resonance imaging (fMRI) examinations are limited in their sensitivity due to the low activation-induced signal change. Within short tolerable scan times the spatial resolution is thus limited. fMRI is a reliable tool in neuroscience as well as for clinical applications such as presurgical mapping of brain function. The fMRI sensitivity improves greatly (more than linearly) with increasing magnetic field strengths. For many years this was the main driving force in the push towards higher field strengths, such as 7 T. The sensitivity gain is greatest for high spatial resolution and fMRI with very high sub-millimeter resolution becomes feasible. Current results demonstrate that the localization of the blood oxygenation level dependent (BOLD) signal is better than previously assumed. High-field fMRI not only allows quantitative improvements but also opens the way to new information content, such as columnar and layer-dependent functional structures of the cortex. This may pave the way for further information, e.g. the directionality of cortico-cortical connections; however, these possibilities also pose new challenges. New methods for processing such high resolution data are required which do not require spatial smoothing and preserve the high information content. Common spatial resolutions of 2-3 mm are still very well suited for examinations at 3 T where they benefit from the low signal void, lower geometrical distortion and reduced acoustic noise. To achieve higher resolution at 7 T parallel imaging and geometric distortion correction are essential and permit the best congruence with structural data. The echo time at 7 T should be adjusted to about 20-25 ms. Data processing for single subjects or patients should be performed with little or no smoothing to retain resolution. Group studies could achieve good correlation with local normalization. New methods for information extraction, such as multivariate pattern analysis may allow combination of group data without the need for voxel-based congruence.


Material and functional properties of articular cartilage and patellofemoral contact mechanics in an experimental model of osteoarthritis.
The purposes of this study were to determine the in situ functional and material properties of articular cartilage in an experimental model of joint injury, and to quantify the corresponding in situ joint contact mechanics. Experiments were performed in the anterior cruciate ligament (ACL) transected knee of the cat and the corresponding, intact contralateral knee, 16 weeks following intervention. Cartilage thickness, stiffness, effective Young's modulus, and permeability were measured and derived from six locations of the knee. The total contact area and peak pressures in the patellofemoral joint were obtained in situ using Fuji Pressensor film, and comparisons between experimental and contralateral joint were made for corresponding loading conditions. Total joint contact area and peak pressure were increased and decreased significantly (alpha=0.01), respectively, in the experimental compared to the contralateral joint. Articular cartilage thickness and stiffness were increased and decreased significantly (alpha=0.01), respectively, in the experimental compared to the contralateral joint in the four femoral and patellar test locations. Articular cartilage material properties (effective Young's modulus and permeability) were the same in the ACL-transected and intact joints. These results demonstrate for the first time the effect of changes in articular cartilage properties on the load transmission across a joint. They further demonstrate a substantial change in the joint contact mechanics within 16 weeks of ACL transection. The results were corroborated by theoretical analysis of the contact mechanics in the intact and ACL-transected knee using biphasic contact analysis and direct input of cartilage properties and joint surface geometry from the experimental animals. We conclude that the joint contact mechanics in the ACL-transected cat change within 16 weeks of experimental intervention.


In vitro characterization of a chitosan skin regenerating template as a scaffold for cells cultivation.
Chitosan is a marine-derived product that has been widely used in clinical applications, especially in skin reconstruction. The mammalian scaffolds derived from bovine and porcine material have many limitations, for example, prion transmission and religious concerns. Therefore, we created a chitosan skin regenerating template (SRT) and investigated the behavior of fibroblast cell-scaffold constructs. Primary human dermal fibroblasts (HDF) were isolated and then characterized using vimentin and versican. HDF were seeded into chitosan SRT at a density of 3×10(6) cells/cm(2) for fourteen days. Histological analysis and live cells imaging revealed that the cell-chitosan constructs within interconnected porous chitosan showed significant interaction between the cells as well as between the cells and the chitosan. Scanning electron microscopy (SEM) analysis revealed cells spreading and covering the pores. As the pore sizes of the chitosan SRT range between 40-140 μm, an average porosity is about 93 ± 12.57% and water uptake ratio of chitosan SRT is 536.02 ± 14.29%, it is a supportive template for fibroblast attachment and has potential in applications as a dermal substitute.