[Strategy for Chronic Coronary Syndrome - PCI or optimal medical therapy].
Strategy for Chronic Coronary Syndrome - PCI or optimal medical therapy Abstract. In the new guidelines of the European Society of Cardiology (ESC), the previous term "stable coronary artery disease (CAD)" was replaced by a new term "chronic coronary syndrome (CCS)" in order to highlight the chronic but also progressive pathological character of CAD. Both optimal medical therapy and myocardial revascularization play a central role in the treatment of patients with CCS. However, due to the heterogeneity of CCS, it is a challenge to determine in clinical practice which patients may benefit from percutaneous coronary intervention (PCI). In addition, the importance of PCI is still controversial, especially in patients with CCS. Hence, this review discusses diagnostic and therapeutic approaches in patients with CCS considering the current ESC-guidelines and the ISCHEMIA Trial (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) in order to outline the optimal strategy for improving symptoms and prognosis.


Complex genetic architecture of cardiac disease in a wild type inbred strain of Drosophila melanogaster.
Natural populations of the fruit fly, Drosophila melanogaster, segregate genetic variation that leads to cardiac disease phenotypes. One nearly isogenic line from a North Carolina peach orchard, WE70, is shown to harbor two genetically distinct heart phenotypes: elevated incidence of arrhythmias, and a dramatically constricted heart diameter in both diastole and systole, with resemblance to restrictive cardiomyopathy in humans. Assuming the source to be rare variants of large effect, we performed Bulked Segregant Analysis using genomic DNA hybridization to Affymetrix chips to detect single feature polymorphisms, but found that the mutant phenotypes are more likely to have a polygenic basis. Further mapping efforts revealed a complex architecture wherein the constricted cardiomyopathy phenotype was observed in individual whole chromosome substitution lines, implying that variants on both major autosomes are sufficient to produce the phenotype. A panel of 170 Recombinant Inbred Lines (RIL) was generated, and a small subset of mutant lines selected, but these each complemented both whole chromosome substitutions, implying a non-additive (epistatic) contribution to the "disease" phenotype. Low coverage whole genome sequencing was also used to attempt to map chromosomal regions contributing to both the cardiomyopathy and arrhythmia, but a polygenic architecture had to be again inferred to be most likely. These results show that an apparently simple rare phenotype can have a complex genetic basis that would be refractory to mapping by deep sequencing in pedigrees. We present this as a cautionary tale regarding assumptions related to attempts to map new disease mutations on the assumption that probands carry a single causal mutation.


ATP-Dependent Proteolytic Activity from Spinach Leaves.
Spinach (Spinacia oleracea CV Bloomsdale Long Standing) leaf cytoplasmic starch phosphorylase and rabbit muscle phosphorylase a were inactivated by incubation with partially purified leaf extract in the presence of ATP and Mg(2+). The inactivating factor(s) were heat stable and susceptible to protease attack. Phosphorylase inactivation was prevented by incubation in the presence of p-aminobenzamidine and phenylboronic acid, or prolonged treatment with phenylmethylsulfonyl fluoride or leupeptin for the ATP-stimulated inhibitory activity. Mg(2+) -dependent inactivation was prevented by incubation with leupeptin, phenylmethylsulfonyl fluoride, p-aminobenzamidine, or 5'-adenylate. ATP-mediated inactivation of phosphorylase was stimulated by Mg(2+) with a reduction in the apparent K(m) for ATP. Casein-degrading activities with the same properties of ATP and/or Mg(2+) stimulation, heat stability, and susceptibility to proteinase inhibitors were detected suggesting that phorphorylase inactivation was due to proteolysis. The activity was greatest at about the time of flowering and also appeared to depend on the light regime.


Medial antebrachial cutaneous nerve conduction in true neurogenic thoracic outlet syndrome.
Thoracic outlet syndrome (TOS) and its diagnosis have been topics of controversy, fueled in part by the lack of an objective test for early diagnosis. True neurogenic TOS results in diagnostic EMG findings only in its later stages. We describe a series of patients in whom the diagnosis is supported by changes in the medial antebrachial cutaneous (MAC) nerve at or before the development of these typical EMG findings in median and ulnar nerves.


Polymorphisms in PTEN in breast cancer families.
Germline mutations in PTEN are the underlying genetic defect in Cowden disease, which is associated with a lifetime risk of 25-50% of developing breast cancer. To investigate the role of PTEN in inherited breast cancer in the absence of manifestations of Cowden disease, we screened 177 unrelated subjects with breast cancer who also had a family history of breast cancer in at least one relative. We found no disease associated PTEN mutations in this cohort, supporting previous studies suggesting that PTEN mutations do not contribute to inherited susceptibility to breast cancer without associated manifestations of Cowden disease. We did identify an association between a common polymorphism in intron 4 and lower mean age of diagnosis of breast cancer. While preliminary, these findings suggest that further study is warranted to determine whether this allelic variant of PTEN could function as a low penetrance breast cancer susceptibility allele.


Effect of Visual Search Training on Saccades in Age-related Macular Degeneration Subjects.
To compare the impact of unilateral versus bilateral Age-related Macular Degeneration (AMD) on saccadic movements, and to show the effect of visual search training on these eye movement performances in AMD subjects. We hypothesized that unilateral and bilateral AMD subjects had abnormal saccadic performances, and that visual search training could improve their performances. Three groups participated in visual search training: 13 elderly unilateral AMD subjects (mean age: 74.6 ± 1.6 years), 15 elderly bilateral AMD subjects (mean age: 74.2 ± 1.2 years), and 15 healthy age-matched control subjects (mean age: 70.9 ± 1.3 years). Horizontal saccadic performances were recorded before and after visual search training (Metrisquare®) with the Mobile Eye Tracker (Mobile EBT®). We analyzed the saccadic movement performances: latency, mean velocity and gain. We measured the training performances for each exercise: the time, the number of omissions and the number of errors. We analyzed the performances with Kruskal-Wallis and posthoc tests. The latency of saccades in AMD subjects is significantly longer compared to healthy elderly for 15° (p<0.03), 10° (p<0.003) and 5° (p<10-3). Unilateral and bilateral AMD subjects normalized their latency of saccades after training for small saccades (respectively p=0.30 and p=0.23 for 10°, and p=0.09 and p=0.52 for 5°). In elderly, performances depend on the saccade's amplitude. AMD subjects' saccadic movements are disrupted: the execution needs more time but is efficient. The visual search training improved the saccadic performances in AMD subjects. Further studies will aim to improve knowledge on such issues and to explore the benefit of training over time in unilateral AMD subjects.


ErbB2 overexpression on occult metastatic cells in bone marrow predicts poor clinical outcome of stage I-III breast cancer patients.
Occult hematogenous micrometastases are the major cause for metastatic relapse and cancer-related death in patients with operable primary breast cancer. Although sensitive immunocytochemical and molecular methods allow detection of individual breast cancer cells in bone marrow (BM), a major site of metastatic relapse, current detection techniques cannot discriminate between nonviable shed tumor cells and seminal metastatic cells. To address this problem, we analyzed the relevance of erbB2 overexpression on disseminated cytokeratin-18-positive breast cancer cells in the BM of 52 patients with locoregionally restricted primary breast cancer using immunocytochemical double labeling with monoclonal antibody 9G6 to the p185erbB2 oncoprotein. Expression of p185erbB2 on BM micrometastases was detected in 31 of 52 (60%) patients independent of established risk factors such as lymph node involvement, primary tumor size, differentiation grade, or expression of p185erbB2 on primary tumor cells. After a median follow-up of 64 months, patients with p185erbB2-positive BM micrometastases had developed fatal metastatic relapses more frequently than patients with p185erbB2-negative micrometastases (21 versus 7 events; P = 0.032). In multivariate analysis, the presence of p185erbB2-positive micrometastases was an independent prognostic factor with a hazard ratio of 2.78 (95% confidence interval, 1.11-6.96) for overall survival (P = 0.029). We therefore conclude that erbB2 overexpression characterizes a clinically relevant subset of breast cancer micrometastases.


Urokinase receptor antagonists inhibit angiogenesis and primary tumor growth in syngeneic mice.
Urokinase plasminogen activator (uPA) and its receptor are key components of a cell surface proteolytic cascade used by tumor cells and capillary endothelial cells for basement membrane invasion, a process required for metastasis and angiogenesis. We have cloned, expressed, and purified the epidermal growth factor-like domain of murine uPA alone and fused it to the Fc portion of human IgG as high-affinity murine urokinase receptor antagonists. These molecules are potent inhibitors of murine urokinase binding to its receptor and inhibit angiogenesis in an in vitro model of capillary tube formation in fibrin gels. In vivo, basic fibroblast growth factor-induced neovascularization and B16 melanoma growth in syngeneic mice are also substantially suppressed by these molecules. Coupled with previous studies showing inhibition of metastasis, these findings suggest that urokinase receptor antagonists may be useful therapeutically as inhibitors of tumor progression.


Anchoring quartet-based phylogenetic distances and applications to species tree reconstruction.
Inferring species trees from gene trees using the coalescent-based summary methods has been the subject of much attention, yet new scalable and accurate methods are needed. We introduce DISTIQUE, a new statistically consistent summary method for inferring species trees from gene trees under the coalescent model. We generalize our results to arbitrary phylogenetic inference problems; we show that two arbitrarily chosen leaves, called anchors, can be used to estimate relative distances between all other pairs of leaves by inferring relevant quartet trees. This results in a family of distance-based tree inference methods, with running times ranging between quadratic to quartic in the number of leaves. We show in simulated studies that DISTIQUE has comparable accuracy to leading coalescent-based summary methods and reduced running times.


PrPC displays an essential protective role from oxidative stress in an astrocyte cell line derived from PrPC knockout mice.
The PrP(C) protein, which is especially present in the cellular membrane of nervous system cells, has been extensively studied for its controversial antioxidant activity. In this study, we elucidated the free radical scavenger activity of purified murine PrP(C) in solution and its participation as a cell protector in astrocytes that were subjected to treatment with an oxidant. In vitro and using an EPR spin-trapping technique, we observed that PrP(C) decreased the oxidation of the DMPO trap in a Fenton reaction system (Cu(2+)/ascorbate/H(2)O(2)), which was demonstrated by approximately 70% less DMPO/OH(). In cultured PrP(C)-knockout astrocytes from mice, the absence of PrP(C) caused an increase in intracellular ROS (reactive oxygen species) generation during the first 3h of H(2)O(2) treatment. This rapid increase in ROS disrupted the cell cycle in the PrP(C)-knockout astrocytes, which increased the population of cells in the sub-G1 phase when compared with cultured wild-type astrocytes. We conclude that PrP(C) in solution acts as a radical scavenger, and in astrocytes, it is essential for protection from oxidative stress caused by an external chemical agent, which is a likely condition in human neurodegenerative CNS disorders and pathological conditions such as ischemia.


Nanofiber fabric based ion-gradient-enhanced moist-electric generator with a sustained voltage output of 1.1 volts.
Moisture-enabled electricity generation as an emerging new energy-harvesting technology is one of the most fascinating and promising candidates for supplying renewable and clean power. However, existing moist-electric generators (MEGs) can only produce intermittent, brief bursts of power with voltage output less than 1 V, severely restricting their practical applications. Therefore, there is an urgent requirement for next-generation MEG devices with high efficiency and continuous energy harvesting properties. In this work, an ion-gradient-enhanced MEG consisting of electrospun nanofiber fabric and porous active electrode was demonstrated to provide a perfect solution for solving instantaneous and low electric output at the same time. The assembled MEG can produce a sustained voltage output of 1.1 V for 40 000 s without any weak signs, reaching the highest level among all reported MEGs. This remarkable performance mainly arises from the higher concentration difference induced by the introduced active electrode which enhances ion diffusion through the porous nanofiber fabric. In addition, the co-existing streaming potential also contributes to the excellent performance. Beyond power generation, the electrospun nanofiber based MEGs also demonstrate successful applications in self-powered sensors, including ammonia leak monitoring and moisture-temperature sensor for forest-fire detection. This study provides insights for the designing of innovative MEGs and opens a pioneering avenue for future energy conversion.


The Association Between Infant Feeding Methods and Female Sexual Dysfunctions.
Background: Although postpartum sexual problems are common, the impact of the infant feeding method on sexual life is still unclear. The aim of this study was to investigate the effects of different infant feeding methods and other influencing factors on female sexual life 3 months postpartum. Materials and Methods: Three hundred women from three obstetrical institutes were enrolled in this cross-sectional study. An online questionnaire was administered 3 months postpartum. Women were categorized into three groups: exclusive breastfeeding (n = 180), mixed feeding (n = 75), and formula-feeding (n = 45) groups. The infant feeding method was assessed by self-constructed questions. Sexual dysfunctions were evaluated by the Hungarian version of the Female Sexual Function Index (FSFI). Results: Of the women, 50.55% reported sexual dysfunction in the exclusive breastfeeding group, 42.66% in the mixed feeding group, and 31.11% in the formula-feeding group. Lack of sexual desire was the most prevalent dysfunction regardless of the infant feeding method. Significantly lower median scores were found in the exclusive breastfeeding group compared with the formula-feeding group for the total FSFI score (p = 0.002), arousal (p = 0.034), lubrication (p = 0.020), orgasm (p = 0.015), and pain (p = 0.021) subgroups. Breastfeeding (p = 0.032) and the quality of prepregnancy sexual life (p < 0.001) were significant factors, whereas prepregnancy dyspareunia, parity, age, income, and educational level did not predict women's postpartum sexual function. Conclusions: Our findings indicate that exclusive breastfeeding women have an increased likelihood of sexual problems 3 months postpartum. Extensive and professional counseling is needed for couples about postpartum sexuality and influencing factors such as breastfeeding to maintain sexual health and promote long-term breastfeeding.


Prospective research with vulnerable children and the risky art of preventive intervention.
The Vermont Vulnerable Child Development Project is presented as an example of community based preventive intervention research employing multiple control groups and prospective epidemiology. Discussion emphasizes both methodological issues and the pragmatics involved in choosing to use community institutions in order to study preventive interventions for very young multi-risk children living with their mentally disturbed parents. Further, a rationale is provided for anticipating and coping with the political, sociological and personality conflicts which are probably inescapable in this type of mental health research.


Exposure to uncertainty mediates the effects of traumatic brain injury on probabilistic decision-making in rats.
Primary Objective: Traumatic brain injury (TBI) is associated with numerous psychiatric comorbidities, and subclinical psychiatric symptoms. While many symptoms have been replicated in animal models of brain injury, a vast majority of studies utilize naïve rats as subjects, which fail to mimic the complex learning history of human patients.Methods and Procedures: In the current study, we evaluated the effects of a brain injury in animals with early exposure to uncertainty on post-injury decision-making in a probabilistic task, the rodent gambling task (RGT).Main Outcomes and Results: Exposure to uncertainty resulted in a heterogeneous sample relative to prior publications, and brain-injured rats showed no deficits in choice behavior compared to shams which contrasts with large, pervasive deficits in previously published work. However, TBI increased impulsivity and caused transient changes in behavioral variables indicative of initial motivational deficits (pellets earned, omitted responses). Notably, effects of amphetamine were similar on this heterogeneous sample of rats relative to a number of other published reports, suggesting consistent effects of gross monoaminergic manipulations on choice behavior, independent of experience.Conclusions: Going forward, translational studies need to consider the heterogeneity that exists at the clinical level and account for these problems when modeling diseases in animals.


Cholesterol and bile acids regulate xenosensor signaling in drug-mediated induction of cytochromes P450.
Cytochromes P450 (CYP) constitute the major enzymatic system for metabolism of xenobiotics. Here we demonstrate that transcriptional activation of CYPs by the drug-sensing nuclear receptors pregnane X receptor, constitutive androstane receptor, and the chicken xenobiotic receptor (CXR) can be modulated by endogenous cholesterol and bile acids. Bile acids induce the chicken drug-activated CYP2H1 via CXR, whereas the hydroxylated metabolites of bile acids and oxysterols inhibit drug induction. The cholesterol-sensing liver X receptor competes with CXR, pregnane X receptor, or constitutive androstane receptor for regulation of drug-responsive enhancers from chicken CYP2H1, human CYP3A4, or human CYP2B6, respectively. Thus, not only cholesterol 7 alpha-hydroxylase (CYP7A1), but also drug-inducible CYPs, are diametrically affected by these receptors. Our findings reveal new insights into the increasingly complex network of nuclear receptors regulating lipid homeostasis and drug metabolism.


Neuropsychological evaluation in primary care.
Referring a patient to a neuropsychologist for evaluation provides a level of rigorous assessment of brain function that often cannot be obtained in other ways. The neuropsychologist integrates information from the patient's medical history, laboratory tests, and imaging studies; an in-depth interview; collateral information from the family and other sources; and standardized assessment instruments to draw conclusions about diagnosis, prognosis, and response to therapy. Family physicians can use this information in the diagnosis and treatment of patients with depression, dementia, concussion, and similar conditions, as well as to address concerns about decision-making capacity. Certain assessment instruments, such as the Mini-Mental State Examination and Patient Health Questionnaire-9, are readily available and easily performed in a primary care office. Distinguishing among depression, dementia, and other conditions can be challenging, and consultation with a neuropsychologist at this level can be diagnostic and therapeutic. The neuropsychologist typically helps the patient, family, and primary care team by establishing decision-making capacity; determining driving safety; identifying traumatic brain injury deficits; distinguishing dementia from depression and other conditions; and detecting malingering. Neuropsychologists use a structured set of therapeutic activities to improve a patient's ability to think, use judgment, and make decisions (cognitive rehabilitation). Repeat neuropsychological evaluation can be invaluable in monitoring progression and treatment effects.


Effects of hyperhomocysteinaemia and metabolic syndrome on reproduction in women with polycystic ovary syndrome: a secondary analysis.
What is the association between hyperhomocysteinaemia (HHCY), metabolic syndrome, and reproductive outcomes among women with polycystic ovary syndrome (PCOS). A secondary analysis of PCOSAct with 21 sites in China. A total of 1000 women with PCOS were enrolled; 936 women with baseline homocysteine (HCY) were analysed. Higher HCY was associated with higher body mass index, free testosterone and lower FSH, fasting glucose (P < 0.001; P < 0.001; P = 0.005; P < 0.001) and ovulation rate among all participants (OR 0.59, 95% CI 0.41 to 0.86; OR 0.57, 95% CI 0.39 to 0.83 tertiles 2 and 3 versus tertile 1, respectively). The HHCY group had lower oestradiol and higher free testosterone (P = 0.04; P < 0.001) than the controls. In the metabolic syndrome group, LH, LH-FSH ratio and sex hormone-binding globulin were lowest in the metabolic syndrome group (all P < 0.001). In the HHCY group, ovulation rate decreased and the second or third trimester pregnancy loss rate increased compared with controls (OR 1.678, 95% CI 1.04 to 2.70; OR 0.03, 95% CI 0.00 to 0.42) with treatment adjustment. Compared with the controls, ovulation, conception, pregnancy, second or third trimester pregnancy loss and live birth rates were statistically lower in the metabolic syndrome group after adjusting treatment (OR 1.76, 95% CI 1.15 to 2.70; OR 1.75, 95% CI 1.15 to 2.65; OR 2.09, 95% CI 1.27 to 3.44; OR 0.02, 95% CI 0.00 to 0.33; OR 2.42 95% CI 1.42 to 4.10), and pregnancy, pregnancy loss and live birth rates remained significantly different after adjusting for treatment and sex-hormone factors (OR 1.77, 95% CI 1.05 to 2.99; OR 0.14, 95% CI 0.02 to 0.82; OR 2.02, 95% CI 1.16 to 3.50). In women with PCOS, HHCY contributes to increased pregnancy loss and reduced ovulation, and metabolic syndrome was related to defects in ovulation, conception, pregnancy, pregnancy loss and live birth, indicating that the two conditions lead to defects at various reproductive stages.


Lacrimal gland removal impairs sexual behavior in mice.
Exocrine gland-secreting peptides (ESPs) are a protein family involved in the pheromonal communication of rodents. ESP1 is a lacrimal peptide synthesized by the extraorbital glands of males of specific mouse strains that modulates the sexual behavior in females. Reportedly, BALB/c males, that produce high level of ESP1 in the tear fluid, were shown to enhance the lordosis behavior in C57BL/6 females during mating. In contrast, C57BL/6 and ICR males, both unable to express ESP1, failed to modulate this sexual behavior. Nonetheless, ICR males did become competent to enhance lordosis behavior in C57BL/6 females providing these were pre-exposed to ESP1. To exclude any strain differences, here, we investigated the pheromonal role of the extraorbital glands and indirectly of ESP1 in animals of the same strain. This was performed by applying the lordosis experimental paradigm in BALB/c mice before and after the surgical removal of these glands in males. The excision of the extraorbital glands reduced but did not abolish the production of ESP1 in the lacrimal fluid of BALB/c mice. An immunological analysis on soluble extracts of the glands that drain into the conjunctival sac revealed that the intraorbital glands (ILGs) are also responsible for the production of ESP1. The removal of both the extra and ILGs completely eliminated the tear secretion of ESP1. Extraorbital gland-deficient BALB/c mice were still able to induce lordosis behavior in sexually receptive females. In contrast, males with the removal of both the extra and ILGs failed to enhance lordosis behavior in females. Unexpectedly, C57BL/6 males did improve this sexual performance in BALB/c females. However, an analysis of the tear fluid of C57BL/6 males revealed low but detectable levels of ESP1. Overall, our study highlights the relevance of the orbital glands in modulating reproductive behavior and the sensitivity of the vomeronasal system to detect trace amount of ESP1.


Traditional and Unconventional Dried Fruit Snacks as a Source of Health-Promoting Compounds.
Dried fruits are important, healthy and popular snacks, despite the limited information on their nutritional profiles and phytochemical composition. The present work was aimed to study the chemical composition of freeze-dried fruits from four fruit species: two common commercial snacks (apple and goji) and two innovative products (kaki and kiwi). Sugar and organic acid levels, total phenolics (TPC), and main health-promoting phytochemicals were studied by HPLC fingerprinting analysis. Furthermore, in vitro antioxidant capacity (AOC) was preliminarily observed in these products. A Principal Component Analysis (PCA) was carried out as a multivariate approach as well. The TPC ranged from 210.9 mg GAE/100g DW (kiwi) to 872.6 mg GAE/100g DW (kaki), while dried fruit antioxidant capacity ranged from 23.09 mmol Fe2+/kg DW (goji) to 137.5 mmol Fe2+/kg DW (kaki). The most important phytochemical class in apple (two cultivars), kiwi, and kaki dried fruits was phenolics (from 74.6% to 93.3%), while monoterpenes were the first class in goji (67.5%). No anthocyanins have been identified in dried fruits because these compounds are most likely converted to phenolic acids during the drying process. This research intended to stimulate large-scale exploitation of commercial dried fruits as functional foods as well.


Coinfection with Clostridium piliforme and Felid herpesvirus 1 in a kitten.
A 1-month-old Domestic Shorthair kitten was submitted for autopsy, with a history of upper respiratory tract infection and diarrhea. This was the third kitten from the same litter that had died with similar clinical findings within a period of 1 month. Severe conjunctivitis, rhinitis, tracheitis, and bronchointerstitial pneumonia were present, together with lymphohistiocytic colitis. Respiratory lesions were caused by infection with Felid herpesvirus 1. Colonic lesions were associated with the presence of long filamentous bacteria, identified as Clostridium piliforme, in the cytoplasm of epithelial cells. Our report describes a case of concurrent C. piliforme infection (Tyzzer's disease) and feline rhinotracheitis in a kitten.


Exploring Communication Strategies to Encourage COVID-19 Vaccination: Motivation-Based Message Appeals, Incidental Emotions, and Risk Perception.
Motivation-based message appeals and incidental emotions have the potential to encourage COVID-19 vaccination, especially when the motivation components of the two agree. Risk perception may also interact with self vs. other-oriented message appeals. Results from a 2 (message appeal) × 4 (incidental emotion) online experiment (N = 306) indicate that when exposed to an altruistic message, those who experienced self-transcendent emotions reported higher COVID vaccination intention than those amused or not induced with emotions. This effect, however, was not identified in the egoistic message condition. Risk perception was positively associated with self-vaccination intention but did not interact with message appeals. The main effect of risk perception and interaction effects between incidental emotions and message appeals provide important implications for addressing vaccine hesitancy and increasing vaccine uptake.


High-performance liquid chromatography with post-column 2,2'-diphenyl-1-picrylhydrazyl radical scavenging assay: methodological considerations and application to complex samples.
An improved post-column 2,2'-diphenyl-1-picrylhydrazyl (DPPH*) radical scavenging assay for the screening of antioxidants in complex matrices was developed. Experimental parameters believed to be influential to DPPH* response were studied in a univariate approach. Optimum conditions were found to be: 5 x 10(-5) M DPPH* reagent prepared in a 75% methanol: 25% 40 mM citric acid-sodium citrate buffer (pH 6) solution, degassed with nitrogen; reaction coil of 2 m x 0.25 mm i.d. PEEK tubing; detection at 521 nm; analysis at room temperature. The analytical utility of this protocol was evaluated by screening for antioxidants in thyme and green tea, in comparison with two commonly employed methodologies.


Comparison of 2 modifications of the twin-block appliance in matched Class II samples.
The purpose of this study was to compare the skeletal and dental changes contributing to Class II correction with 2 modifications of the Twin-block appliance: Twin-block appliances that use a labial bow (TB1) and Twin-block appliances that incorporate high-pull headgear and torquing spurs on the maxillary central incisors (TB2). After pretreatment equivalence was established, a total of 36 consecutively treated patients with the TB1 modification were compared with 27 patients treated with the TB2 modification. Both samples were treated in the same hospital department and the same technician made all the appliances. The cephalostat, digitizing package, and statistical methods were common to both groups. The results demonstrated that the addition of headgear to the appliance resulted in effective vertical and sagittal control of the maxillary complex and thus maximized the Class II skeletal correction in the TB2 sample. Use of the torquing springs resulted in less retroclination of the maxillary incisors in the TB2 sample when compared with the TB1 sample; however, this difference did not reach the level of statistical significance.


Pattern of declining hemoglobin concentration before cancer diagnosis.
Although anemia is widely considered an early sign of malignant disease, little is known about the pattern of hemoglobin decline before diagnosis. As an approach to understanding the duration of the preclinical phase of different types of malignant diseases, we investigated prediagnostic hemoglobin concentration changes in a large cohort of blood donors. Using a nested case-control design, we analyzed a population-based cohort comprising 1.1 million Scandinavian blood donors with complete follow-up through record linkage to population and cancer registers. A total of 16,375 cancer cases were identified, for whom we selected 161,995 controls. We used conditional logistic regression to estimate the risk of cancer in relation to hemoglobin concentration during the 5 years preceding the cancer diagnosis. Hemoglobin concentration decline began already 3 years before diagnosis of stomach cancer, multiple myeloma, and lymphatic leukemia; 2 years before diagnosis of small intestinal and colon cancer as well as of Hodgkin lymphoma. A decline was evident during the last year for non-Hodgkin lymphoma and myeloid/monocytic leukemia, whereas no change was found for cancer of the esophagus, breast or prostate. In conclusion, in this study, we have demonstrated that the pattern of declining hemoglobin concentration before cancer diagnosis varies considerably between malignancies without being a suitable screening tool for any of them. For some malignancies, however, the long duration of hemoglobin decline before clinical diagnosis suggests a substantial lead-time with systemic effects, during which earlier diagnosis should be achievable by emerging diagnostic tools.


Homology-directed dna repair, mitomycin-c resistance, and chromosome stability is restored with correction of a Brca1 mutation.
Chromosomal breaks occur spontaneously as a result of normal DNA metabolism and after exposure to DNA-damaging agents. A major pathway involved in chromosomal double-strand break repair is homologous recombination. In this pathway, a DNA sequence with similarity to a damaged chromosome directs the repair of the damage. The protein products of the hereditary breast cancer susceptibility genes, BRCA1 and BRCA2, interact with the Rad51 protein, a central component of homologous repair pathways. We have recently shown that this interaction is significant by demonstrating that Brca1- and BRCA2-deficient cells are defective in homology-directed chromosomal break repair. We confirm that Brca1-deficient embryonic stem (ES) cells are defective in gene targeting and homology-directed repair of an I-Sce I-induced chromosome break. The phenotypic paradigm that defines homology-directed repair mutants is extended to these Brca1-deficient cells by the demonstration of 100-fold sensitivity to the interstrand cross-linking agent mitomycin-C and spontaneous chromosome instability. Interestingly, although chromosome aberrations were evident, aneuploidy was not observed. Repair phenotypes are partially restored by expression of a Brca1 transgene, whereas correction of one mutated Brca1 allele through gene targeting fully restores mitomycin-C resistance and chromosome stability. We conclude that the inability to properly repair strand breaks by homology-directed repair gives rise to defects in chromosome maintenance that promote genetic instability and, it is likely, tumorigenesis.


Quantitative analysis of repeat adenovirus-mediated gene transfer into injured canine femoral arteries.
We quantitatively evaluated the effectiveness of a repeat administration of a recombinant adenoviral vector expressing bacterial Escherichia coli lacZ into the same arterial site of a relatively large animal, the dog. The replication-defective adenoviral vector was introduced percutaneously into balloon-injured femoral arteries through a double-balloon catheter. After a single dose of adenoviral vector, up to 90% of surface (73 +/- 16%, n = 7) and smooth muscle cells in multiple layers of the media showed transgene expression as evaluated by 5-bromo-4-chloro-3-indoyl beta-D-galactopyranoside histostaining without extralocal expression, as assessed by polymerase chain reaction. High-level expression (measured as beta-galactosidase activity) peaked 7 days after transfer and was transient, although it was retained for a month. Second does of the same adenovirus to the same arterial site were given 1, 2, 5, or 8 weeks after the first administration. At 1 week the second dose significantly enhanced lacZ expression. At 2, 5, or 8 weeks the second dose reinduced lacZ expression at 25% to 30% of the full expression. lacZ expression was also detected in preimmuned dogs, although the expression levels correlated inversely to the titer of neutralizing antibodies in their serum. These results demonstrate that arterial gene expression can be enhanced by a second administration of the same adenovirus after a short interval and that a repeat dose after a long interval partially but significantly reinduces gene expression despite the presence of an immune response. These data may provide an additional scientific foundation for the use of adenovirus-mediated arterial gene transfer in future clinical practice.


Stem cell therapy for treatment of epilepsy.
Epilepsy as one of the most common neurological disorders affects more than 50 million people worldwide with a higher prevalence rate in low-income countries. Excessive electrical discharges in neurons following neural cell damage or loss cause recurrent seizures. One of the most common and difficult to treat types of epilepsy is temporal lobe epilepsy (TLE) which results from hippocampal sclerosis. Nowadays, similar to other diseases, epilepsy also is a candidate for treatment with different types of stem cells. Various stem cell types were used for treatment of epilepsy in basic and experimental researches. Two major roles of stem cell therapy in epilepsy are prophylaxis against chronic epilepsy and amelioration cognitive function after the occurrence of TLE. Several animal studies have supported the use of these cells for treating drug-resistant TLE. Although stem cell therapy seems like a promising approach for treatment of epilepsy in the future however, there are some serious safety and ethical concerns that are needed to be eliminated before clinical application.


Metabolic effects of combination glipizide and human proinsulin treatment in NIDDM.
The effects of 3 mo of treatment with a combination of glipizide and human proinsulin were studied in a small group of closely monitored patients. The patients had non-insulin-dependent diabetes mellitus (NIDDM) and poor glucose regulation, despite maximal sulfonylurea therapy. This was a randomized double-blind placebo-controlled trial in which there were three treatment groups who received either 20 mg glipizide given 30 min before breakfast and dinner and human proinsulin given subcutaneously at bedtime (n = 5), glipizide and human proinsulin placebo (n = 5), or glipizide placebo and human proinsulin (n = 5). Glycemic regulation was assessed by measurements of 24-h plasma glucose profiles and glycosylated hemoglobin. Our observations demonstrate that the combination of glipizide plus human proinsulin was more effective than either agent alone in controlling overall glycemia in patients with NIDDM. The data support the concept of use of an agent during the day that has its major effects postprandially and another agent at bedtime that is relatively hepatospecific.


Risk factors for herpes zoster in Korean patients with rheumatoid arthritis treated with JAK inhibitor: a nested case-control study.
To determine the risk of herpes zoster (HZ) in Korean patients with rheumatoid arthritis (RA) receiving Janus kinase inhibitors (JAKis). We performed a nested case-control study with 1:10 matching for sex and age using single-centre prospective cohorts of patients with RA receiving targeted therapy in Korea. Then we performed conditional logistic regression analyses to determine the risk associated with JAKi use compared with biologic disease-modifying antirheumatic drug (bDMARD) use, with adjusting for various factors. We also used logistic regression analysis to identify other risk factors for the development of HZ in JAKi users. From a total of 1147 patients, 61 cases and 610 matched controls were selected. In conditional logistic regression analysis, JAKi use did not increase the risk of HZ development (OR 1.35, 95% CI 0.70 to 2.61) after adjusting for other factors. Rather, duration of RA less than 10 years (OR 0.54, 95% CI 0.30 to 0.97) and having had three or more previous targeted therapies (OR 5.29, 95% CI 1.45 to 19.31) were risk factors for HZ. Among JAKi users, higher disease activity score 28-erythrocyte sedimentation rate (DAS28-ESR) (OR 1.44, 95% CI 1.06 to 1.97) was identified as a risk factor in addition to three or more previous targeted therapies (OR 10.12, 95% CI 1.92 to 53.49). The number of previous targeted therapies, but not JAKi use, was identified as a risk factor for HZ development in Korean patients with RA in a real-world setting. High disease activity was an additional risk factor for JAKi users.


Survival experience of peritoneal dialysis patients with human immunodeficiency virus: a 17-year retrospective study.
Human immunodeficiency virus (HIV)-related renal disease is the third-leading cause of end-stage renal disease (ESRD) among African Americans aged 20-64 years. The number of HIV-infected (HIV+) patients reaching ESRD will increase exponentially over the next decade. Because of significant improvements in therapy and management during the last ten years, survival of HIV+ patients has improved. The survival experience of very long-term HIV+ peritoneal dialysis (PD) patients remains to be investigated. The objective of the present study was to examine the important differences in clinical and laboratory parameters between HIV+ and HIV-negative (HIV-) PD patients. To assess the factors associated with better survival in HIV+ PD patients, we retrospectively reviewed the charts of 488 PD patients, including 53 HIV+ patients, for the period 1987 to September 2004. We collected demographic, clinical, and laboratory data, including CD4 cell counts and history of hospitalizations and peritonitis. Maximum survival of HIV+ PD patients was 12.5 years as compared with 15.87 years in HIV-patients. Not surprisingly, HIV was a strong independent predictor of mortality in PD patients [relative risk (RR) = 3.09, p < 0.0001]. In HIV+ patients, higher CD4 counts at the initiation of dialysis were strongly associated with better survival (RR = 0.10 and p < 0.0001, > or =200 cells/mm3 vs. < or =50 cells/mm3). In univariate analysis, use of highly active antiretroviral therapy (HAART) was associated with significantly improved survival in HIV+ PD patients. Patients treated with I or 2 drugs had a 4.3-times higher mortality risk than those who received HAART therapy (p = 0.012). Independent associations were seen between HIV and younger age, African American race, male sex, and lower serum albumin. The rates of hospitalization (p < 0.0001) and peritonitis (p < 0.01) were significantly higher in HIV+ patients than in HIV-patients. Very long-term survival of HIV+ patients with chronic renal failure is possible on PD therapy. Morbidity and mortality of these patients may be improved with HAART therapy, better nutrition, and treatment of peritonitis.


Diffusion-Weighted MRI as a Biomarker of Tumor Radiation Treatment Response Heterogeneity: A Comparative Study of Whole-Volume Histogram Analysis versus Voxel-Based Functional Diffusion Map Analysis.
Treatment of glioblastoma (GBM) remains challenging due in part to its histologic intratumoral heterogeneity that contributes to its overall poor treatment response. Our goal was to evaluate a voxel-based biomarker, the functional diffusion map (fDM), as an imaging biomarker to detect heterogeneity of tumor response in a radiation dose escalation protocol using a genetically engineered murine GBM model. Twenty-four genetically engineered murine GBM models [Ink4a-Arf(-/-)/Pten(loxp/loxp)/Ntv-a RCAS/PDGF(+)/Cre(+)] were randomized in four treatment groups (n = 6 per group) consisting of daily doses of 0, 1, 2, and 4 Gy delivered for 5 days. Contrast-enhanced T1-weighted and diffusion-weighted magnetic resonance imaging (MRI) scans were acquired for tumor delineation and quantification of apparent diffusion coefficient (ADC) maps, respectively. MRI experiments were performed daily for a week and every 2 days thereafter. For each animal, the area under the curve (AUC) of the percentage change of the ADC (AUCADC) and that of the increase in fDM values (AUCfDM+) were determined within the first 5 days following therapy initiation. Animal survival increased with increasing radiation dose. Treatment induced a dose-dependent increase in tumor ADC values. The strongest correlation between survival and ADC measurements was observed using the AUCfDM+ metric (R (2) = 0.88). This study showed that the efficacy of a voxel-based imaging biomarker (fDM) was able to detect spatially varying changes in tumors, which were determined to be a more sensitive predictor of overall response versus whole-volume tumor measurements (AUCADC). Finally, fDM provided for visualization of treatment-associated spatial heterogeneity within the tumor.


Estimating Bus Cross-Sectional Flow Based on Machine Learning Algorithm Combined with Wi-Fi Probe Technology.
With expansion of city scale, the issue of public transport systems will become prominent. For single-swipe buses, the traditional method of obtaining section passenger flow is to rely on surveillance video identification or manual investigation. This paper adopts a new method: collecting wireless signals from mobile terminals inside and outside the bus by installing six Wi-Fi probes in the bus, and use machine learning algorithms to estimate passenger flow of the bus. Five features of signals were selected, and then the three machine learning algorithms of Random Forest, K-Nearest Neighbor, and Support Vector Machines were used to learn the data laws of signal features. Because the signal strength was affected by the complexity of the environment, a strain function was proposed, which varied with the degree of congestion in the bus. Finally, the error between the average of estimation result and the manual survey was 0.1338. Therefore, the method proposed is suitable for the passenger flow identification of single-swiping buses in small and medium-sized cities, which improves the operational efficiency of buses and reduces the waiting pressure of passengers during the morning and evening rush hours in the future.


Impact of Coronavirus Disease (COVID-19) Pandemic on Psychological Well-Being of the Pakistani General Population.
Background and Objectives: In order to curb the spread of coronavirus disease 2019 (COVID-19), the countries took preventive measures such as lockdown and restrictions of movements. This can lead to effects on mental health of the population. We studied the impact of COVID-19 on psychological well-being and associated factors among the Pakistani general population. Methods: An online cross-sectional survey was conducted between 26th April and 15th May and included participants from all over the Pakistan. Attitudes and worriedness about COVID-19 pandemic were assessed using a structured questionnaire. A validated English and Urdu version of the World Health Organization Well-Being Index (WHO-5) was used to assess the well-being. Factor analysis was done to extract the attitude item domains. Logistic regression was used to assess the factors associated with poor well-being. Results: A total of 1,756 people participated in the survey. Almost half 50% of the participants were male, and a similar proportion was employed. About 41% of the participants were dependent on financial sources other than salary. News was considered a source of fear as 72% assumed that avoiding such news may reduce the fear. About 68% of the population was worried about contracting the disease. The most common coping strategies used during lockdown were spending quality time with family, eating healthy food, adequate sleep, and talking to friends on phone. Prevalence of poor well-being was found to be 41.2%. Female gender, being unemployed, living in Sindh and Islamabad Capital Territory (ICT), fear of COVID-19, and having chronic illness were significantly associated with poor well-being. Similarly, coping strategies during lockdown (doing exercise; spending time with family; eating healthy food; having good sleep; contributing in social welfare work and spending time on hobbies) were also significantly associated with mental well-being. Conclusion: We found a high prevalence 41.2% of poor well-being among the Pakistani general population. We also investigated risk factors of poor well-being which included female gender, unemployment, being resident of ICT and Sindh, fear, chronic illness, and absence of coping strategies. This calls for immediate action at population level in the form of targeted mass psychological support programs to improve the mental health of population during the COVID-19 crises.


Geometry, induced magnetism and modified electronic behaviors for magnetic atom adsorption on antimonene nanotubes.
Antimonene nanotubes, a class of important derivatives of the 2D counterpart (Sb monolayer), with transition metal (TM) atom adsorption were investigated systematically based on the first-principles calculations. For a stable geometry, the lengths of TM-Sb bonds on the tube surface strongly depend on their relative electronegativity. In particular, we find that the intrinsic magnetic moment magnitude of the TM atom plays a decisive role in inducing tube magnetism, and only TM atoms with a larger intrinsic magnetic moment (≥3.0 μB) can induce the magnetism for tubes. The strong interaction and coupling between the TM d-orbital and Sb p-orbital lead to variously favorable magnetic phases, such as the spin bipolar semiconductor and half-semiconductor, which is predicted to be stable beyond room temperature. In addition, the weakening or quenching of the magnetism for the adsorbed TM atom is intimately related to the expansion of the TM atom valence electron configuration and the charge transfer. Furthermore, the TM adsorption can also effectively regulate the tube carrier mobility to the difference of several orders of magnitude, and results in significant carrier polarity and spin polarity of mobility. A sensitive electric-magnetic coupling effect was also shown to cause continuous magnetic phase transition, providing more opportunity for obtaining magneto-electric materials.


Prediction of HELLP syndrome with assessment of maternal dual hepatic blood supply by using Doppler ultrasound.
Early structural and functional changes in the systemic vasculature have been proposed to play a major pathogenetic role in HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. Our objective was to assess whether the evaluation of maternal hepatic blood supply is instructive to the prediction of onset of HELLP syndrome. Prospective observation study. Fifty-eight women with severe preeclampsia and 60 healthy pregnant controls at 25-36 weeks gestation. Angle-corrected time-averaged flow velocity and the cross-sectional area of common hepatic artery and portal vein were measured by using Doppler ultrasonography in 58 women with severe preeclampsia and in 60 healthy pregnant controls at 25-36 weeks gestation. Intravascular flow volumes were calculated from the product of the time-averaged velocity and the cross-sectional area. The total liver blood flow was taken as the sum of flow volumes in the hepatic artery and portal vein. The total liver blood flow decreased significantly to about 40% of control in 9 women with severe preeclampsia who developed HELLP syndrome within 4 days after the examination, but not in 49 women with severe preeclampsia without HELLP syndrome. The results indicated that the decrease in dual hepatic blood supply preceded the onset of HELLP syndrome.


Dubin-Johnson Syndrome as Differential Diagnosis for Neonatal Cholestasis.
Dubin-Johnson syndrome (DJS) is an autosomal recessive disorder in which multidrug-resistance-associated protein 2 (MRP2) deficiency causes an excretion disorder of conjugated bilirubin from hepatocytes into bile canaliculi. Its clinical presentation as neonatal cholestasis (NC) is rare but represents an important differential diagnosis. We aimed to define DJS-specific characteristics in NC, in particular in contrast to biliary atresia (BA) patients, and to highlight diagnostic tools that can help to avoid invasive diagnostic tests. We performed a review of case records from 2006 to 2020 and compared 4 DJS patients to 26 patients with proven BA consecutively diagnosed from 2014 to 2017. DJS was diagnosed by urine coproporphyrin analysis (UCA) and by genetic analysis (GA) for disease-associated ABCC2 variants. Four male patients with NC were diagnosed with DJS by UCA and GA. DJS patients presenting as NC showed significantly lower values for aspartate aminotransferase (AST) (P < 0.001), for alanine aminotransferase (ALT) (P = 0.002) and for gamma-glutamyl transferase (GGT) (P < 0.001) compared with BA patients. Other examinations, however, could not clearly discriminate them (e.g.: stool colour, serum bile acids, total serum bilirubin). DJS is not only a rare differential diagnosis in NC with a suspicious phenotype (almost normal AST, ALT) but also shows overlapping features with BA. It should, therefore, be considered in every infant with NC and an atypical liver enzyme pattern to protect patients from unnecessary, invasive examinations. For this, UCA is a fast and reliable diagnostic tool. Confirmation based on GA is recommended. DJS patients have a good long-term prognosis.


CMTR1-Catalyzed 2'-O-Ribose Methylation Controls Neuronal Development by Regulating Camk2α Expression Independent of RIG-I Signaling.
Eukaryotic mRNAs are 5' end capped with a 7-methylguanosine, which is important for processing and translation of mRNAs. Cap methyltransferase 1 (CMTR1) catalyzes 2'-O-ribose methylation of the first transcribed nucleotide (N1 2'-O-Me) to mask mRNAs from innate immune surveillance by retinoic-acid-inducible gene-I (RIG-I). Nevertheless, whether this modification regulates gene expression for neuronal functions remains unexplored. Here, we find that knockdown of CMTR1 impairs dendrite development independent of secretory cytokines and RIG-I signaling. Using transcriptomic analyses, we identify altered gene expression related to dendrite morphogenesis instead of RIG-I-activated interferon signaling, such as decreased calcium/calmodulin-dependent protein kinase 2α (Camk2α). In line with these molecular changes, dendritic complexity in CMTR1-insufficient neurons is rescued by ectopic expression of CaMK2α but not by inactivation of RIG-I signaling. We further generate brain-specific CMTR1-knockout mice to validate these findings in vivo. Our study reveals the indispensable role of CMTR1-catalyzed N1 2'-O-Me in gene regulation for brain development.


[Establishment of A Myelodysplastic Syndrome Transformed to Leukemia Cell Line Stably Expressing Green Fluorescent Protein].
To establish a myelodysplastic syndrome transformed to leukemia cell line stably expressing green fluorescent protein (GFP), and to evaluate its biological characteristics and applications. SKM-1 cells were transfected by lentiviral particles with vector of GFP. The GFP positive single cell clone was isolated by limiting dilution and continued being cultured. The cells were injected into mice subcutaneously and were screened in vivo. Then SKM-1/GFP cells were obtained after tumour plaque was separated and cultivated. The cell morphology was observed by fluorescence microscopy. The GFP expression was further detected by flow cytometry. The cell proliferation was analysed by CCK-8 assay. SKM-1/GFP cells were inoculated to subcutaneous tissue of the immunodeficiency mice. The growth and invasion of the tumour were observed after tumour formation. No differences in cell morphology and growth characteristics were observed between SKM-1 cells and SKM-1/GFP cells. The rate of GFP expression was 100%. No differences in cell proliferation were observed between SKM-1 cells and SKM-1/GFP cells. The tumour mass was observed after 14 days of subcutaneous vaccination in NOD/SCID mice. Spontaneous fluorescence from plaque was observed by living fluorescence microscopy at 30th day after vaccination. Homogenous GFP positive cells were observed by fluorescence microscopy in the frozen section of tumour mass. The invasion of SKM-1/GFP cells was also detected in heart, liver, stomach and kidney of mice. A myelody-splastic syndrome transformed to leukemia cell line stably expressing green fluorescent protein has been established successfully, which can track tumor cell sensitively and can be applied to the research of minimal residual leukemia. The establishment of SKM-1/GFP cells may serve as a powerful means for studing myelodysplastic syndrome transformation.


[Pulmonary malignant lymphoma associated with bilateral diffuse linear, reticular, and consolidated shadows].
A 72-year-old asymptomatic man was admitted to our hospital with abnormal chest radiographic findings: bilateral diffuse linear, reticular, and consolidated shadows. Malignant lymphoma (diffuse small-cell B-cell lymphoma) was diagnosed histologically after an open lung biopsy and was confirmed by a genetic examination. The lymphoma cells had infiltrated widely in various regions of the lung, including the alveolar spaces and walls, the bronchial and vascular spaces, and the pleura. This diffusion of the lymphoma cells might have accounted for the chest X-ray findings. Malignant pulmonary lymphoma should be included in the differential diagnosis patients with diffuse linear, reticular, and consolidated shadows on chest X-ray films.


Phytoplankton community structure and environmental parameters in aquaculture areas of Daya Bay, South China Sea.
Environmental characteristics and phytoplankton community structure were investigated in two aquaculture areas in Dapeng Cove of Daya Bay, South China Sea, between April 2005 and June 2006. Phytoplankton abundance ranged between 5.0 and 8877.5 cells/mL, with an average of 751.8 cells/mL. The seasonal cycle of phytoplankton were demonstrated by frequent oscillations, with recurrent high abundances from late spring to autumn and a peak stage in late winter. Diatoms were the predominant phytoplankton group, accounting for 93.21% of the total abundance. The next most abundant group was the dinoflagellates, which made up only 1.24% of total abundance. High concentrations of Alexandrium tamarense (Lebour) Balech with a maximum of 603.0 cells/mL were firstly recorded in this area known for high rates of paralytic shellfish poisoning (PSP) contamination. Temperatures and salinities were within the suitable values for the growth of phytoplankton, and were important in phytoplankton seasonal fluctuations. The operation of the Daya Bay Nuclear Power Station (DNPS) exerts influences on the phytoplankton community and resulted in the high abundances of toxic dinoflagellate species during the winter months. Dissolved inorganic nitrogen (DIN) and dissolved silicate (DSi) were sufficient, and rarely limited for the growth of phytoplankton. Dissolved inorganic phosphorus (DIP) was the most necessary element for phytoplankton growth. The enriched environments accelerated the growth of small diatoms, and made for the shift in predominant species from large diatom Rhizosolenia spp. to chain-forming diatoms such as Skeletonema costatum, Pseudo-nitzschia spp. and Thalassiosira subtilis.


Genotypic interaction and gender specificity of common genetic variants in the p53/mdm2 network in Crohn's disease.
Defective p53-mediated apoptosis and cell cycle control have been implicated in the immunopathogenesis of Crohn's disease (CD). Since common functional variants of p53 (SNP72 G/C) and its key negative regulator mdm2 (SNP309 T/G) have been reported to affect cellular apoptotic and cell cycle arrest capacities, we assessed the effects of these variants on CD susceptibility and their relationship to NOD2/CARD15 as a well-established genetic CD risk factor. The variants SNP72 G/C and SNP309 T/G were genotyped in 149 European CD patients and 478 healthy controls. Subgroup analysis was performed in relation to NOD2/CARD15 status and to demographic/clinical characteristics. The p53 SNP72 CC genotype tended to be less frequent in CD. This reached statistical significance only in the male cohort (0 vs. 7.3%; p = 0.037). Genotype and allele frequencies of both single-nucleotide polymorphisms (SNPs) were otherwise not significantly different. In the combined genotypic analysis, the genotype p53 SNP72 CC was significantly underrepresented in mdm2 SNP309 TT homozygotes (0 vs. 9.7%; p = 0.034). No association was observed between NOD2/CARD15 and the respective SNPs. We report on a gender-specific protective effect of the low-apoptotic SNP72 CC genotype, and a gender-unrestricted genotypic interaction between SNP309 TT and SNP72 CC, which, for the first time, links sequence variation of the p53/mdm2 network to CD, independent of NOD2/CARD15.


Behavior modification following a diagnosis of hepatitis C infection.
To determine the extent of postdiagnosis counseling and to characterize behavior before and after diagnosis of hepatitis C infection. We interviewed 133 persons diagnosed with hepatitis C in Wyoming from 1999 to 2001. Approximately two thirds of cases received counseling at the time of diagnosis. Older and symptomatic patients were more likely to receive counseling. Counseling was significantly associated with increases in condom use, wound covering, and hepatitis A and hepatitis B vaccination, but not with changes in addictive behaviors. Counseling was an effective strategy for promoting several desirable behavior changes among persons with hepatitis C infection.


Clinical significance of dynamic measurements of seric TNF-α, HMGBl, and NSE levels and aEEG monitoring in neonatal asphyxia.
This study investigates the clinical value of monitoring blood levels of tumor necrosis factor-α (TNF-α), high mobility group protein Bl (HMGBl), and neuron-specific enolase (NSE), and examining an amplitude-integrated electroencephalogram (aEEG) for the diagnosis and short-term prognosis of brain damage caused by neonatal asphyxia. Sixty full-term neonates born in Yidu Central Hospital from January to December 2015 were enrolled in the study. The neonates were classified into one of 3 groups: 23 neonates in the mild asphyxia group, 7 in a severe asphyxia group and 30 in a control group admitted to the NICU but without asphyxia. The neonates presenting asphyxia received standard neonatal resuscitation before they were transferred to the NICU. The dynamic changes of the umbilical artery/peripheral blood TNF-α, HMGBl, and NSE levels and aEEG results were monitored and compared among the groups. The umbilical artery and serum TNF-α, HMGBl, and NSE levels at day 1 were significantly higher in the two asphyxia groups than in the control group; and the values were higher in the severe asphyxia group (p <0.05). Furthermore, the correlation coefficients between TNF-α and HMGB1, TNF-α and NSE, and HMGB1 and NSE at all the monitoring time points were positive: 0.5516, 26.943 and 15.87, respectively (p <0.001). Additionally, the neonates with abnormal aEEG results at 6 hours postpartum had higher serum TNF-α, HMGBl and NSE levels than those with normal aEEG results (p <0.05). The patients with persistently abnormal or progressively deteriorating aEEG results usually had a poor evolution. The dynamic monitoring of TNF-α, HMGBl, and NSE levels combined with aEEG can provide useful evidence for the early diagnosis, the determination of severity and the short-term prognosis of brain damage caused by neonatal asphyxia.


The effect of segmental bronchoprovocation with allergen on airway lymphocyte function.
We hypothesized that allergen-induced airway eosinophilia is linked to activation or recruitment of T cells in the airway and generation of interleukin-5 (IL-5). To evaluate this hypothesis, we performed bronchoscopy with segmental antigen bronchoprovocation in 12 atopic subjects. Bronchoalveolar lavage (BAL) was done 5 min and 48 h after challenge with saline or antigen. Airway cells were isolated and then stimulated ex vivo with a T-cell mitogen, phytohemagglutinin (PHA), and cytokine release was determined. Cells retrieved from the saline-challenged segment secreted principally interferon-gamma (IFN-gamma) and IL-2. In contrast, cells obtained 48 h after allergen challenge secreted high levels of IL-5 and small but increased amounts of IL-4, IL-10, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Although CD4+ T cells were a major source of IL-5, there were no significant changes in the relative proportion of CD4+ cells in response to bronchoprovocation. Additionally, ex vivo secretion of IL-5 by airway cells correlated closely with amounts of IL-5 and eosinophils present in the bronchoalveolar lavage fluid (BALF). These observations suggest that following exposure to allergen, airway T cells are functionally but not phenotypically different from resident airway T cells, and that T cells within the airway contribute to eosinophilic airway inflammation through the secretion of IL-5.


[A case of aortic dissection after the termination of cardiopulmonary bypass].
We report, a case of aortic dissection after the termination of cardiopulmonary bypass (CPB), which was diagnosed by transesophageal echocardiography (TEE). A 70-year old male with aortic regurgitation received aortic valve replacement. After the termination of CPB, the aortic dissection was diagnosed by TEE. Furthermore wall motion abnormality was found by TEE, and aorto-coronary bypass was performed after observation by TEE. This case report suggests that TEE is useful not only for diagnosis but also for therapeutic orientation of aortic dissection.


Matters of life and death: the hospital of San Pedro in Puebla, 1790-1802.
The last decade of the eighteenth century may be described as a "golden age" in the history of the Hospital of San Pedro of Puebla. Under the stewardship of its director, Father Ignacio Domenech, San Pedro underwent an extensive renovation of its physical plant and a thorough administrative reorganization that turned it into one of the best medical care and research institutions in New Spain. The article draws a profile of the patients who filled the hospital's wards and adds a human dimension to the many names and ailments listed in the registries. It also describes the valiant efforts of the medical staff who daily shared the patients' struggle against illness. Fighting immense odds, the practitioners sought to provide good-quality care and to further their limited understanding of disease. A detailed analysis of San Pedro's everyday life reveals a portrait of human suffering, professional dedication, and humanity's pursuit of knowledge.


[Endovascular aortic balloon catheter occlusion for severe renal trauma].
Control of the renal vascular pedicle in a context of severe renal trauma in a haemodynamically unstable patient is difficult due to the large retroperitoneal haematoma. Laparotomy in these exsanguinated patients is associated with a risk of cardiac arrest due to hypovolaemia. The authors describe an endovascular aortic balloon catheter occlusion technique prior to laparotomy for haemostasis nephrectomy in a haemodynamically unstable patient presenting an abdominal compartment syndrome. In the light of this case, the authors discuss vascular control in the context of surgical management of severe renal trauma.


PKG-I inhibition attenuates vascular endothelial growth factor-stimulated angiogenesis.
Vascular endothelial growth factor (VEGF) stimulates nitric oxide (NO) production, which mediates many of its angiogenic actions. However, the angiogenic pathways that operate downstream of NO following VEGF treatment are not well characterized. Herein, we used DT-2 and DT-3, two highly selective cGMP-dependent protein kinase I peptide inhibitors to determine the contribution of PKG-I in VEGF-stimulated angiogenesis. Incubation of chicken chorioallantoic membranes (CAM) with PKG-I peptide inhibitors decreased vascular length in a dose-dependent manner, with DT-3 being more effective than DT-2. Moreover, inhibition of PKG-I with DT-3 abolished the angiogenic response elicited by VEGF in the rabbit eye cornea. PKG-I inhibition also blocked VEGF-stimulated vascular leakage. In vitro, treatment of cells with VEGF stimulated phosphorylation of the PKG substrate VASP through VEGFR2 activation; the VEGF-stimulated VASP phosphorylation was reduced by DT-2. Pre-treatment of cells with DT-2 or DT-3 inhibited VEGF-stimulated mitogen-activated protein kinase cascades (ERK1/2 and p38), growth, migration and sprouting of endothelial cells. The above observations taken together identify PKG-I as a downstream effector of VEGFR2 in EC and provide a rational basis for the use of PKG-I inhibitors in disease states characterized by excessive neovascularization.


RIP-Cre revisited, evidence for impairments of pancreatic beta-cell function.
The Cre/loxP recombinase system for performing conditional gene targeting experiments has been very useful in exploring genetic pathways that control both the development and function of pancreatic beta-cells. One particular line of transgenic mice (B6.Cg-Tg(Ins2-cre)25Mgn/J), commonly called RIP-Cre, in which expression of Cre recombinase is controlled by a short fragment of the rat insulin II gene promoter has been used in at least 21 studies on at least 17 genes. In most of these studies inactivation of the gene of interest was associated with either glucose intolerance or frank diabetes. Experimental evidence has been gradually emerging to suggest that RIP-Cre mice alone display glucose intolerance. In this study experiments from three laboratories demonstrate that RIP-Cre mice, in the absence of genes targeted by loxP sites, are glucose intolerant, possibly due to impaired insulin secretion. In addition, we review the use of RIP-Cre mice and discuss possible molecular underpinnings and ramifications of our findings.


Four-Dimensional Untargeted Profiling of N-Acylethanolamine Lipids in the Mouse Brain Using Ion Mobility-Mass Spectrometry.
N-Acylethanolamines (NAE) are a class of essential signaling lipids that are involved in a variety of physiological processes, such as energy homeostasis, anti-inflammatory responses, and neurological functions. NAE lipids are functionally different yet structurally similar and often have low concentrations in biological systems. Therefore, the comprehensive analysis of NAE lipids in complex biological matrices is very challenging. In this work, we developed an ion mobility-mass spectrometry (IM-MS) based four-dimensional (4D) untargeted technology for comprehensive analysis of NAE lipids. First, we employed the picolinyl derivatization to significantly improve ionization sensitivity of NAE lipids by 2-9-fold. Next, we developed a two-step quantitative structure-retention relationship (QSRR) strategy and used the AllCCS software to curate a 4D library for 170 NAE lipids with information on m/z, retention time, collision cross-section, and MS/MS spectra. Then, we developed a 4D untargeted technology empowered by the 4D library to support unambiguous identifications of NAE lipids. Using this technology, we readily identified a total of 68 NAE lipids across different biological samples. Finally, we used the 4D untargeted technology to comprehensively quantify 47 NAE lipids in 10 functional regions in the mouse brain and revealed a broad spectrum of the age-associated changes in NAE lipids across brain regions. We envision that the comprehensive analysis of NAE lipids will strengthen our understanding of their functions in regulating distinct physiological activities.


Sequential Ensemble-Decision Aliquot Ranking Isolation and Fluorescence In Situ Hybridization Identification of Rare Cells from Blood by Using Concentrated Peripheral Blood Mononuclear Cells.
Isolation and analysis of circulating rare cells is a promising approach for early detection of cancer and other diseases and for prenatal diagnosis. Isolation of rare cells is usually difficult due to their heterogeneity as well as their low abundance in peripheral blood. We previously reported a two-stage ensemble-decision aliquot ranking platform (S-eDAR) for isolating circulating tumor cells from whole blood with high throughput, high recovery rate (>90%), and good purity (>70%), allowing detection of low surface antigen-expressing cancer cells linked to metastasis. However, due to the scarcity of these cells, large sample volumes and large quantities of antibodies were required to isolate sufficient cells for downstream analysis. Here, we drastically increased the number of nucleated cells analyzed by first concentrating peripheral blood mononuclear cells (PBMCs) from whole blood by density gradient centrifugation. The S-eDAR platform was capable of isolating rare cells from concentrated PBMCs (108/mL, equivalent to processing ∼20 mL of whole blood in the 1 mL sample volume used by our instrument) at a high recovery rate (>85%). We then applied the S-eDAR platform for isolating rare fetal nucleated red blood cells (fNRBCs) from concentrated PBMCs spiked with umbilical cord blood cells and confirmed fNRBC recovery by immunostaining and fluorescence in situ hybridization, demonstrating the potential of the S-eDAR system for isolating rare fetal cells from maternal PBMCs to improve noninvasive prenatal diagnosis.


Knowledge, attitude and practice of people with HIV regarding a healthy lifestyle: clinical trial.
To evaluate the effectiveness of an educational booklet on the knowledge, attitude and practice of a healthy lifestyle in people with HIV. Randomized clinical trial with 75 intervention group patients using the booklet, and 75 control group patients undergoing usual service care. Data collection occurred in four moments, with a Survey pertaining Knowledge, Attitude and Practice. Nonparametric analysis of variance of repeated measures was used. 70 participants in the intervention group and 74 in the control group completed the study. In terms of knowledge, there was no difference between groups, the booklet impact came late, increasing after reassessments. In attitudes, there was a difference between groups in the two- and four-month reassessments compared to the baseline. In practices, there was a difference in the intervention group compared to the control group at two, four, and six months compared to baseline. The booklet was effective in improving healthy lifestyle knowledge, attitudes, and practices in people with HIV.


Integration of facial and newly learned visual cues in speech perception.
We are developing technology to translate acoustic characteristics of speech into visual cues that can be used to supplement speechreading when hearing is limited. Research and theory have established that perceivers are influenced by multiple sources of sensory and contextual information in spoken language processing. Previous research has also shown that additional sources of information can be learned and used to supplement those that are normally available but have been degraded by sensory impairment or difficult environments. We tested whether people can combine or integrate information from the face and information from newly learned cues in an optimal manner. Subjects first learned the visual cues and then were tested under three conditions.Words were presented with just the face, just the visual cues, or both together. Performance was much better with both cues than with either one alone. Similar to the description of previous results with audible and visible speech, the present results were well described by the Fuzzy Logical Model of Perception (Massaro, 1998), which predicts optimal or maximally efficient integration.


Cortical responses of infants with and without a genetic risk for dyslexia: I. Age effects.
We studied auditory event-related potentials (ERP) in newborns and 6-month-old infants, about half of whom had a familial risk for dyslexia. Syllables varying in vowel duration were presented in an oddball paradigm, in which ERPs to deviating stimuli are assumed to reflect automatic change detection in the brain. The ERPs of newborns had slow positive deflections typical of their age, but significant stimulus and group effects were found only by the age of 6 months. In both groups, the responses to the deviant /ka/ were more positive than those to the standard /kaa/ stimuli, contrary to the findings of adult ERPs to duration changes. The results also suggested differences in brain activation pattern between the groups.


Adverse events in the hospitalized elderly.
This descriptive study examined the incidence, onset, and correlates of adverse events (acute confusion, adverse drug reactions, nutritional problems, pressure ulcers, falls, and transient urinary incontinence) experienced by elderly persons hospitalized for acute illness. The researchers studied 64 patients (mean age 74.4 years) for the duration of their hospitalization. Over half (54%) experienced some degree of acute confusion during their hospitalization. There was a 24% incidence of pressure ulcers and a 2% incidence of adverse reactions to medications. No instances of falls or transient urinary incontinence were observed or documented in this sample. Nutritional problems were identified in one third of the sample. Predictive profiles of patients at risk for adverse events associated with hospitalization were developed and provide directions for patient care and further research.


A longitudinal study of family size expectations among young blacks and whites.
This study is concerned with the stability of family size expectations and the direction of change in such expectations among young people in the United States. "In the...study, 437 low-income respondents, both black and white, male and female, answered a question on expected family size both at high school age and four years later. Respondents varied in their consistency with 78% of those first naming one or two children, but only 9% of those expecting no children, naming the same number at the second interview. Consistency was also found to vary by sex and race. Support was found for the hypothesis that change in expectations is related to the proximity of parenthood decision."


Seroprevalence of Enzootic Teschen Disease in the Wild Boar Population in Ukraine.
Teschen disease is an acute fatal enterovirus encephalomyelitis of pigs, characterized by a range of central nervous system disorders. The cause of porcine enterovirus encephalomyelitis is the picornavirus porcine teschovirus-1 (PTV-1). There are at least 12 disctinct serotypes of PTVs, where PTV-2 to PTV-12 serogroups are associated with other forms of disease (Talfan disease or poliomyelitis suum) or benign enzootic paresis. Combined, PTVs have been found to have a high seroprevalence, up to 65%, in healthy pig populations in Europe. PTVs have also been detected in wild boar, including the divergent PTV-13 serogroup; wild suids may represent a sylvatic reservoir capable of carrying the virus long distances. In Ukraine, Teschen disease is widespread and causes lethal disease in domestic pigs. To understand temporal and geographical distribution of Teschen disease virus (PTV-1) in wild boar in Ukraine (2001-2013), we analyzed seroprevalence of 6840 blood serum samples from hunted suids using a virus microneutralization assay. A total of 1364 samples (19.9%) were seropositive, with average antibody titer ratios 5.89 ± 0.03 log2 (range 5-12 log2). Teschen seroprevalence was temporally and geographically concentrated in the northern and western regions of Ukraine, corresponding to forested regions (polissya) and overlapping with wild boar populations and habitats, suggesting endemicity in wild boar. The virus sporadically emerged in central, southern, and eastern forested regions, suggesting long-distance movement of infected wild suids. Thus, wild boar should be monitored for potential transboundary spread in forested and mountain regions and spillover of PTVs to domestic swine populations.


DSM-flux: A new technology for reliable Combined Sewer Overflow discharge monitoring with low uncertainties.
In the past ten years, governments from the European Union have been encouraged to collect volume and quality data for all the effluent overflows from separated stormwater and combined sewer systems that result in a significant environmental impact on receiving water bodies. Methods to monitor and control these flows require improvements, particularly for complex Combined Sewer Overflow (CSO) structures. The DSM-flux (Device for Stormwater and combined sewer flows Monitoring and the control of pollutant fluxes) is a new pre-designed and pre-calibrated channel that provides appropriate hydraulic conditions suitable for measurement of overflow rates and volumes by means of one water level gauge. In this paper, a stage-discharge relation for the DSM-flux is obtained experimentally and validated for multiple inflow hydraulic configurations. Uncertainties in CSO discharges and volumes are estimated within the Guide to the expression of Uncertainty in Measurement (GUM) framework. Whatever the upstream hydraulic conditions are, relative uncertainties are lower than 15% and 2% for the investigated discharges and volumes, respectively.


A benchmark theoretical study of the electronic ground state and of the singlet-triplet split of benzene and linear acenes.
A benchmark theoretical study of the electronic ground state and of the vertical and adiabatic singlet-triplet (ST) excitation energies of benzene (n=1) and n-acenes (C(4n+2)H(2n+4)) ranging from naphthalene (n=2) to heptacene (n=7) is presented, on the ground of single- and multireference calculations based on restricted or unrestricted zero-order wave functions. High-level and large scale treatments of electronic correlation in the ground state are found to be necessary for compensating giant but unphysical symmetry-breaking effects in unrestricted single-reference treatments. The composition of multiconfigurational wave functions, the topologies of natural orbitals in symmetry-unrestricted CASSCF calculations, the T1 diagnostics of coupled cluster theory, and further energy-based criteria demonstrate that all investigated systems exhibit a (1)A(g) singlet closed-shell electronic ground state. Singlet-triplet (S(0)-T(1)) energy gaps can therefore be very accurately determined by applying the principles of a focal point analysis onto the results of a series of single-point and symmetry-restricted calculations employing correlation consistent cc-pVXZ basis sets (X=D, T, Q, 5) and single-reference methods [HF, MP2, MP3, MP4SDQ, CCSD, CCSD(T)] of improving quality. According to our best estimates, which amount to a dual extrapolation of energy differences to the level of coupled cluster theory including single, double, and perturbative estimates of connected triple excitations [CCSD(T)] in the limit of an asymptotically complete basis set (cc-pVinfinityZ), the S(0)-T(1) vertical excitation energies of benzene (n=1) and n-acenes (n=2-7) amount to 100.79, 76.28, 56.97, 40.69, 31.51, 22.96, and 18.16 kcal/mol, respectively. Values of 87.02, 62.87, 46.22, 32.23, 24.19, 16.79, and 12.56 kcal/mol are correspondingly obtained at the CCSD(T)/cc-pVinfinityZ level for the S(0)-T(1) adiabatic excitation energies, upon including B3LYP/cc-PVTZ corrections for zero-point vibrational energies. In line with the absence of Peierls distortions, extrapolations of results indicate a vanishingly small S(0)-T(1) energy gap of 0 to approximately 4 kcal/mol (approximately 0.17 eV) in the limit of an infinitely large polyacene.


Mechanisms of leptin secretion from white adipocytes.
The mechanisms regulating leptin secretion were investigated in isolated rat white adipocytes. Insulin (1-100 nM) linearly stimulated leptin secretion from incubated adipocytes for at least 2 h. The adrenergic agonists norepinephrine, isoproterenol (two nonselective beta-agonists), or CL-316243 (potent beta3) all inhibited insulin (10 nM)-stimulated leptin release. The inhibitory effects of norepinephrine and isoproterenol could be reversed not only by the nonselective antagonist propranolol but also by the selective antagonists ICI-89406 (beta1) or ICI-118551 (beta2), the beta2-antagonist being less effective than the beta1. Insulin-stimulated leptin secretion could also be inhibited by a series of agents increasing intracellular cAMP levels, such as lipolytic hormones (ACTH and thyrotropin-stimulating hormone), various nonhydrolyzable cAMP analogs, pertussis toxin, forskolin, methylxanthines (caffeine, theophylline, IBMX), and specific inhibitors of phosphodiesterase III (imazodan, milrinone, and amrinone). Significantly, antilipolytic agents other than insulin (adenosine, nicotinic acid, acipimox, and orthovanadate) did not mimic the acute stimulatory effects of insulin on leptin secretion under these conditions. We conclude that norepinephrine specifically inhibits insulin-stimulated leptin secretion not only via the low-affinity beta3-adrenoceptors but also via the high-affinity beta1/beta2-adrenoceptors. Moreover, it is suggested that 1) activation of phosphodiesterase III by insulin represents an important metabolic step in stimulation of leptin secretion, and 2) lipolytic hormones competitively counterregulate the stimulatory effects of insulin by activating the adenylate cyclase system.


Blood Pressure is Associated with Rapid Kidney Function Decline in a Very Elderly Hypertensive Chinese Population.
In prior analyses, blood pressure (BP) was related to rapid kidney function decline (RKFD). However, studies of this relationship in populations of advanced age are lacking. In the present study, we therefore examined the relationship between BP and RKFD in a population of 284 hypertensive Chinese individuals over the age of 80. All study participants were diagnosed with hypertension (systolic BP [SBP] 160-200 mmHg; diastolic BP [DBP] <110 mmHg). RKFD was defined based upon a decline in estimated glomerular filtration rate (eGFR) >5mL/min per 1.73 m2 per year during follow-up. The Cox regression models (competing risk models) were used for calculating hazard ratios (HRs) to examine the relationship between SBP, DBP, pulse pressure (PP) and RKFD. Over a 3.3-year median follow-up period, 68 study participants (23.9%) were diagnosed with RKFD, while 35 (12.3%) died. After adjusting for confounding variables, we determined that each 10 mmHg rise in SBP and PP was associated with a 34% and 110% increase, respectively, in RKFD risk (adjusted HR: 1.34, 95% confidence interval [CI]: 1.05-1.71 for SBP, p=0.02; HR: 2.10, 95% CI: 0.87-5.08 for PP, p=0.10). In addition, we determined that each 10 mmHg increase in DBP was linked to a 10% reduction in RKFD risk (adjusted HR: 0.90, 95% CI: 0.70-1.14, p=0.37). Our results indicate that SBP, but not DBP or PP, is positively correlated with RKFD risk in a very elderly hypertensive Chinese population.


[Dimorphous leprosy].
In 1981 we observed two cases of leprosy in Salzburg. The two Vietnamese refugees already had advanced borderline disease. Treatment with dapsone resulted in clearing of the skin in both cases. One of the patients developed a leprosy reaction during treatment.


Late pliocene faunal turnover in the turkana basin, kenya and ethiopia
Analysis of a large sample of well-dated fossil mammals from localities in the Turkana Basin of Kenya and Ethiopia revealed sampling biases that affect patterns of faunal turnover during the late Pliocene. When these biases were accounted for, results indicated that 58 to 77 percent of the mammal species were replaced between 3.0 and 1.8 million years ago (Ma). Overall diversity increased from 3.0 to 2.0 Ma but then declined. No distinct turnover pulse is seen between 2.8 and 2.5 Ma; instead, the most significant period of faunal change began after 2.5 Ma and continued through 1.8 Ma.


Cost-effectiveness of continuous positive airway pressure therapy for moderate to severe obstructive sleep apnea/hypopnea.
Obstructive sleep apnea/hypopnea (OSAH) is a common disorder characterized by recurrent collapse of the upper airway during sleep, and is associated with an increased risk of motor vehicle crashes (MVCs). Common first-line therapy for OSAH is continuous positive airway pressure (CPAP). We assessed the cost-effectiveness of CPAP therapy vs none for the treatment of OSAH. We used a 5-year Markov model that considers the costs and quality-of-life improvements of CPAP therapy, accounting for the gains from reduced MVC rates. Utility values were obtained from published studies. The MVC rates under the CPAP and no-CPAP scenarios were calculated from National Highway Traffic Safety Administration data and a systematic review of published studies. Costs of MVCs, equipment, and physicians were obtained from US Medicare and the National Highway Traffic Safety Administration. The target population included male and female patients aged 25 to 54 years and newly diagnosed as having moderate to severe OSAH. We examined the findings from the perspectives of a third-party payer and society. From a third-party payer or a societal perspective, CPAP therapy was more effective but more costly than no CPAP, with incremental cost-effectiveness ratios of $3354 or $314 per quality-adjusted life-year gained, respectively. The incremental cost-effectiveness ratio estimate was most dependent on viewpoint (varying more than 10-fold between societal and third-party payer perspectives) and choice of utility measurement method (varying more than 5-fold between the use of standard gamble and EuroQol 5D utility assessment values). When quality of life, costs of therapy, and MVC outcomes are considered, CPAP therapy for patients with OSAH is economically attractive.


Usefulness of a selective neutrophil elastase inhibitor (sivelestat) in septic ARDS patients after gastrointestinal surgery.
The usefulness of a neutrophil elastase inhibitor (sivelestat) was evaluated for treating septic acute respiratory distress syndrome (ARDS) after gastrointestinal surgery. The subjects were 36 patients with septic ARDS after gastrointestinal surgery. ARDS was defined as acute lung injury associated with systemic inflammatory response syndrome. Sivelestat was intravenously administered at a dose of 0.2 mg/kg/hr continuously for 3 days or more. The effectiveness of sivelestat was evaluated based on the lung injury score, P/F ratio, and ventilator free days (VFD). Marked responses were observed in 12 patients (33.3%), responses in 17 (47.2%), and no response in 7 (19.4%). In the patients with marked responses or responses (responders), the P/F ratio was significantly improved on day 3 of drug administration and at the end of administration compared with the pre-administration ratio. Comparison between the responders and non-responders showed significant differences on day 3 and at the end of drug administration. VFD significantly differed between the responders (18.8 days) and the non-responders (11.0 days). In conclusion, sivelestat may be effective against septic ARDS. The effectiveness of the drug could be determined based on improvement in oxygenation ability on day 3 of drug administration.


Ovarian function after hysterectomy in an Irish hospital population.
A group of 52 women following hysterectomy with conservation of one or both ovaries was compared with an age-matched control group attending with menstrual irregularity/menorrhagia, in terms of proportions of women with postmenopausal endocrine profiles, and climacteric symptoms. The mean age for the groups was 42 years, and the mean interval between hysterectomy and the time of the study was 3.5 years. Endocrine levels were postmenopausal in six study and two control patients, and this difference was not significant. Vasomotor symptoms were a complaint of 28 (54%) of the study group and 18 (35%) of the control group, while 30 (58%) and 18 (35%) respectively had at least two other non-specific symptoms. In the absence of prospective studies elucidating the effect of hysterectomy on ovarian function, endocrine profiles should be performed in hysterectomised women complaining of symptoms.


Antidepressants in chronic idiopathic urticaria.
Chronic idiopathic urticaria (CIU) is a common disease estimated to affect 0.1% of the population and can be very difficult to treat. Many psychotropic medications have been reported to be successful in treating refractory CIU. The purpose of this article was to discuss the pathophysiology of chronic urticaria and provide practicing allergists and dermatologists alternative treatment options in the management of refractory CIU, especially in those who have concurrent psychiatric comorbidity. A review was performed of pertinent literature pertaining to the pathophysiology of CIU and the many psychotropic medications reportedly successful in disease management. Although more research is needed, this article serves to broaden the mind of the physician treating CIU.


APRI and FIB-4 performance to assess liver fibrosis against predefined Fibroscan values in chronic hepatitis C virus infection.
Chronic hepatitis C (CHC) infection can leads to chronic liver disease, fibrosis, then cirrhosis, and, finally, hepatocellular carcinoma (HCC); moreover, it is the most common indication for liver transplantation. Liver biopsy is still the gold standard method for the staging of liver fibrosis as it is an invasive procedure with complications. There are some noninvasive methods such as fibroscan that are now the investigation of choice; FIB-4 and aminotransferase to platelet ratio index (APRI) are other noninvasive tools to assess liver fibrosis by using aspartate aminotransferase (AST), alanine aminotransferase (ALT), platelet count, and age. This study aims to evaluate the efficacy and performance of FIB-4 and APRI against fibroscan in patients infected with the hepatitis C virus. It is a cross-sectional study that was conducted in a tertiary health care center in Uttar Pradesh, India, from January 2017 to January 2020. Fibroscan was done for all patients. A blood sample was used to determine AST, ALT, and platelet count. FIB-4 and APRI were calculated from laboratory data. 187 of the 487 patients in the study have F0-F1 fibrosis, 69 have F2, 53 have F3 fibrosis, and 178 have cirrhosis. Based on receiver operating characteristic (ROC) analysis, single optimum cut-offs for diagnosing significant fibrosis and cirrhosis were 1.2 for APRI and 2.25 for FIB-4. Compared with Fibroscan, APRI and FIB-4 showed good performance in detecting the patients without liver fibrosis as well as satisfactory performance in detecting significant fibrosis. These scores should be used in combination with other noninvasive scores for an accurate assessment of liver fibrosis.


Diagnosis of adrenal failure in critically ill patients.
In the last two decades there was important evolution on the knowledge of the function of the hypothalamic-pituitary-adrenal axis. In the last decade, the expression "relative adrenal insufficiency" (RAI) was created, and more recently "critical illness-related corticosteroid insufficiency" (CIRCI) was used to designate those patients in which cortisol production was not sufficiently increased in stress situations. Patients with CIRCI have elevated hospital morbidity and mortality. Currently, there is a wide discussion about diagnostic criteria for this dysfunction. Besides basal cortisol, some publications now study the role of other tests, such as cortrosyn test - either in low (1 μg) or high doses (250 μg); free cortisol, salivary cortisol, metyrapone test and others. With this review, we aimed at summarizing the results of the most influent papers that intended to define diagnostic criteria for CIRCI. We also suggest an approach for CIRCI diagnosis and make it clear that the decision about steroid therapy in septic shock patients is matter apart from RAI.


Vanishing bile duct and Stevens-Johnson syndrome associated with ciprofloxacin treated with tacrolimus.
Stevens-Johnson syndrome (SJS) is a serious and potentially life-threatening disease. Vanishing bile duct syndrome (VBDS) is a rare cause of progressive cholestasis. Both syndromes are mostly related with drugs. We report a case of a patient with ciprofloxacin-induced SJS and acute onset of VBDS, and reviewed the related literature. It is the first case of ciprofloxacin-induced VBDS successfully treated with tacrolimus. This case reminds physicians of the importance of drug reactions, their severity, techniques for diagnosis and methods of management.


Neuroprotection by PlGF gene-modified human mesenchymal stem cells after cerebral ischaemia.
Intravenous delivery of mesenchymal stem cells (MSCs) prepared from adult bone marrow reduces infarction size and ameliorates functional deficits in rat cerebral ischaemia models. Placental growth factor (PlGF) is angiogenic to impaired non-neural tissue. To test the hypothesis that PlGF contributes to the therapeutic benefits of MSC delivery in cerebral ischaemia, we compared the efficacy of systemic delivery of human MSCs (hMSCs) and hMSCs transfected with a fibre-mutant F/RGD adenovirus vector with a PlGF gene (PlGF-hMSCs). A permanent middle cerebral artery occlusion (MCAO) was induced by intraluminal vascular occlusion with a microfilament. hMSCs and PlGF-hMSCs were intravenously injected into the rats 3 h after MCAO. Lesion size was assessed at 3 and 6 h, and 1, 3, 4 and 7 days using MR imaging and histology. Functional outcome was assessed using the limb placement test and the treadmill stress test. Both hMSCs and PlGF-hMSCs reduced lesion volume, induced angiogenesis and elicited functional improvement compared with the control sham group, but the effect was greater in the PlGF-hMSC group. Enzyme-linked immunosorbent assay of the infarcted hemisphere revealed an increase in PlGF in both hMSC groups, but a greater increase in the PlGF-hMSC group. These data support the hypothesis that PlGF contributes to neuroprotection and angiogenesis in cerebral ischaemia, and cellular delivery of PlGF to the brain can be achieved by intravenous delivery of hMSCs.


Clinical Significance of Circulating Cell-Free DNA Detection in Multiple Myeloma: A Meta-Analysis.
Circulating cell-free DNA (cfDNA) detection, a non-invasive method, appears promising for genetic analyses as well as quantitative assessment of tumor burden in patients with cancer. Although the analysis of cfDNA for clinical prognosis and monitoring disease burden in multiple myeloma (MM) has been recently studied, the results are unclear. In this meta-analysis, we explored the clinical significance of circulating cfDNA detection in patients with MM. We searched PubMed, Embase, and the Cochrane Library for eligible studies published up until July 25, 2021. Diagnostic accuracy variables were calculated and analyzed using Meta-Disc, and prognostic data were analyzed using Review Manager. Overall, seven studies comprising 235 myeloma patients met our inclusion criteria. The overall sensitivity and specificity of cfDNA to detect minimal residual disease (MRD) were 0.58 and 0.91, respectively. Moreover, higher levels of cfDNA were associated with worse progression-free survival as well as with poor overall survival. Our meta-analysis revealed that ctDNA detection has an obvious advantage in terms of MRD detection specificity, but it showed no superiority over bone marrow assessment in terms of MRD detection sensitivity, and higher levels of cfDNA were indicative of worse prognosis in patients with MM. cfDNA detection is a non-invasive method and thus shows promise as a good alternative to BM biopsies for monitoring clonal evolution and tumor burden so as to guide the treatment of patients with MM.