Response to Lindström (2020) on "The trouble with trust: Time-series analysis of social capital, income inequality, and COVID-19 deaths in 84 countries".
There is substantial cross-national variation in the damage caused by COVID-19 and scant evidence on social and cultural factors that contribute to this variation. Our ecologic study of country differences in COVID-19 mortality found that deaths have increased faster in societies that had less confidence in state institutions and less civic engagement, more social trust and group affiliations, and higher income inequality (Elgar et al., 2020). Here, we respond to three criticisms of the study raised by Lindström (2020) regarding (1) socioeconomic patterns in influenza pandemics and the current COVID-19 pandemic, (2) data gaps in cross-national studies of wealth inequality and (3) the robustness of our findings across previous survey cycles of the World Values Survey. We stand by our results and encourage further investigation using larger samples, longer time periods and different approaches and measures. It is vital for social science to contribute to policy decisions that can mitigate the enormous human toll of the pandemic.


Galactomannan and computed tomography-based preemptive antifungal therapy in neutropenic patients at high risk for invasive fungal infection: a prospective feasibility study.
Empirical antifungal therapy is the standard treatment for persistent or relapsing antibiotic-resistant neutropenic fever. However, overtreatment resulting in increased toxicity and treatment-related cost is a major shortcoming of such therapy. We assessed the feasibility of a "preemptive" approach based on the incorporation of sensitive, noninvasive diagnostic tests for consecutive high-risk neutropenic patients who had received fluconazole prophylaxis while avoiding empirical therapy. A total of 136 treatment episodes for persons who were at risk of acquiring invasive fungal infection (IFI) were screened for the presence of galactomannan with an enzyme immunoassay. A diagnostic evaluation, which included thoracic computed tomography scanning (HRCT) and bronchoscopy with lavage, was performed on the basis of well-defined clinical, radiological, and microbiological criteria. Only seropositive patients and patients with a positive microbiological test result plus supportive radiological findings received liposomal amphotericin B. Neutropenic fever developed in 117 episodes, of which at least 41 episodes (35%) satisfied existing criteria for empirical antifungal therapy. However, our protocol-driven preemptive approach reduced the rate of antifungal use for these episodes from 35% to 7.7% (a 78% reduction) and led to the early initiation of antifungal therapy in 10 episodes (7.3%) that were clinically not suspected of being IFI. No undetected cases of invasive aspergillosis were identified; 1 case of zygomycosis was missed. Breakthrough candidemia was diagnosed by conventional culture techniques and was treated successfully. With use of a preemptive approach, the 12-week survival rate for patients with IFI was 63.6% (it was 63.1% for those with invasive aspergillosis). Preemptive therapy based on enzyme immunoassay and HRCT reduced the exposure to expensive and potentially toxic drugs and offered effective antifungal control, but it failed to detect non-Aspergillus IFI.


Adaptation to oak and other fibrous, phenolic-rich foliage by a small mammal, Neotoma fuscipes.
Neotoma fuscipes, a small mammalian herbivore with apparently generalized food habits, was laboratory tested to determine its degree of dietary specialization. Woodrats from both oak woodland and coastal sage communities preferred Quercus agrifolia leaves (containing 40% phenolics and about 16% condensed tannin) over foliage from other dominant species. Approximately one-third of the oak phenolics and less than 10% of the oak condensed tannin remained in the feces. Their performance on pure oak leaves was comparable to that on a mixed diet of Quercus, Salvia, Eriogonum, and Rhus, with respect to weight maintenance, digestive efficiency and total amount ingested. Digestive efficiency was low on the oak diet (55%) relative to Salvia (77%), and to achieve similar weight levels, approximately twice as much oak as Salvia was ingested. Woodrats retained more nitrogen as oak consumption increased. Intake of oak and other foods increased with each experimental day. A sympatric species, N. lepida, was unable to maintain weight on oak leaves, although its digestive and polyphenolic-degrading capabilities, and nitrogen retention efficiency were equivalent to those of N. fuscipes. On a weight-adjusted basis, N. lepida ate about half as much oak per day as N. fuscipes. Oak intake may have been reduced by an inability to rapidly degrade fiber, which constitutes about 30% of the oak diet. In natural populations, N. fuscipes selectively feeds on evergreen sclerophyll vegetation high in fiber, tannins and related polyphenolics. Individuals ingest 2-3 plant types at a time, with a single species (oak when available) constituting most of the material consumed. Neotoma lepida diets are also dominated by a single species. The diversity of plant types eaten by different populations of N. lepida suggests that local dietary specializations may be developmentally acquired.


The geography of the US's mishandling of COVID-19: A commentary on the politics of science in democracies.
During the pandemic, many prominent global leaders and scholars have called for placing science above politics. This commentary argues that such rhetoric dangerously oversimplifies science and politics as insular from democracy and geographical context. The theory of co-construction from science and technology studies reveals the pandemic's geographic intersection with other threats to democracy, such as rising inequality and authoritarianism. Since COVID-19 figures to be central to the politics of the future, the field of geography helps to contextualise the importance of problematic trends that hinder the capacity for democracies to respond to present and future crises.


Ethnic Disparities in Blood Pressure: A Population-based Study.
Taiwan's indigenous population exhibits a higher mortality of cardiovascular disease, but current research has not reported any associations among ethnicities on the blood pressure (BP). We randomly selected representative samples in this population-based study. We measured height, weight, hip and waist circumferences, and blood pressure in a screening survey. Systolic BP and diastolic BP were significantly higher in the indigenous population. Among women, prevalence rates of DBP > 90 mmHg among indigenes (32.9 %) were significantly high than those in Han Chinese (17.4 %). Based on multivariate analysis adjusted for covariates, the results showed gender and ethnicity to be significantly correlated with systolic and diastolic BP. Gender was a modifier between ethnicity and BP. Furthermore, we found an additive effect between ethnicity and age on systolic and diastolic BP by gender. Our study showed independent additive effects on systolic BP and diastolic BP between ethnicity and age by gender.


Missed diagnosis or misdiagnosis: how often do hospitalised patients with a diagnosis of chronic obstructive pulmonary disease have spirometry that supports the diagnosis?
Chronic obstructive pulmonary disease (COPD) is one of the most common clinical diagnoses among hospital inpatients. Diagnosis requires the demonstration of post-bronchodilator airflow obstruction. However, it is uncertain how often spirometry results are available at the time a diagnostic label of COPD is applied. To identify how frequently spirometry results were available following an inpatient admission with a clinical diagnosis of COPD, and to determine how often the available spirometry results supported a clinical diagnosis of COPD. Inhaler prescription, at discharge, was also evaluated to determine one of the potential implications of diagnostic inaccuracy. A single-centre retrospective observational study was undertaken at a 400-bed metropolitan health service between October 2016 and March 2018. A total of 2239 inpatient separations occurred in 1469 individuals who had a clinical diagnosis of COPD during the study. Spirometry results were not available in 43.6% (n = 641) of those with a diagnosis of COPD. A further 19.7% (n = 289) had spirometry results available at the time of admission that did not demonstrate fixed airflow obstruction. The available prescribing data (n = 443) demonstrated that inhaled medications were prescribed in a similar pattern, regardless of the availability of spirometry or whether the results supported a clinical diagnosis of COPD. Inpatients with a clinical diagnosis of COPD frequently did not have supportive spirometry results that confirmed the diagnosis or had results inconsistent with COPD. Misdiagnosis and inappropriate prescribing require further attention to improve the quality of care in this setting.


Strategies for Managing Intraoperative Discovery of Limited Colorectal Peritoneal Metastases.
Management of limited synchronous colorectal peritoneal metastases (CRPM) is critical to outcome. Resection of the primary tumor and CRPM can be performed concurrently, followed by hyperthermic intraperitoneal chemotherapy (HIPEC) either immediately, during the same procedure (one-stage), or during a systematic second-stage procedure (two-stage). The aim of this study was to compare these two strategies for morbidity, mortality, and survival. All patients presenting with limited (initial Peritoneal Cancer Index [PCI] ≤ 10) synchronous CRPM who had undergone complete cytoreductive surgery plus HIPEC between 2000 and 2016 were selected from a prospectively maintained institutional database. Overall, 74 patients were included-31 in the one-stage group and 43 in the two-stage group. During second-stage surgery, a peritoneal recurrence was diagnosed in 37 (86%) patients, 12 of whom had a PCI > 10 (28%) and 2 of whom had unresectable disease (5%). Among the one-stage group, peritoneal recurrence occurred in 29% of patients after a median delay of 23 months. Overall survival at 1, 3, and 5 years was similar between the two groups, i.e. 96%, 59%, and 51% for the one-stage group, and 98%, 77%, and 61% for the two-stage group. A PCI > 10 at the time of HIPEC, as well as liver metastases, were independent negative prognostic factors. For incidental limited CRPM diagnosed during primary tumor resection, one-stage curative treatment is preferable, avoiding a supplementary surgical procedure. Given the critical issues associated with completeness of resection, patients should be referred to centers specialized in peritoneal surgery.


Wheat straw hemicelluloses added with cellulose nanocrystals and citric acid. Effect on film physical properties.
Wheat straw has been used as a source of hemicelluloses (WSH) and cellulose nanocrystals (CNC) for the elaboration of biodegradable films. Different films have been formed by using WSH as a matrix and different contents of CNC and citric acid. The predominant hemicelluloses were arabinoxylans. CNC reinforced the films, improving tensile strength and modulus, water resistance and water vapor barrier. Citric acid, on the other hand, presented concomitant plasticizing and crosslinking effects (the latter also evidenced by FTIR), probably due to a crosslinking extension by glycerol. The use of 5.9wt% CNC and 30wt% citric acid was defined as optimal conditions, resulting in minimum water sensitivity and permeability, while maintaining a good combination of tensile properties. Under those conditions, the films presented enhanced modulus, elongation, water resistance, and barrier to water vapor when compared to the control WSH film, and might be used for wrapping or coating a variety of foods.


Endogenous neurogenic cell response in the mature mammalian brain following traumatic injury.
In the mature mammalian brain, new neurons are generated throughout life in the neurogenic regions of the subventricular zone (SVZ) and the dentate gyrus (DG) of the hippocampus. Over the past two decades, extensive studies have examined the extent of adult neurogenesis in the SVZ and DG, the role of the adult generated new neurons in normal brain function and the underlying mechanisms regulating the process of adult neurogenesis. The extent and the function of adult neurogenesis under neuropathological conditions have also been explored in varying types of disease models in animals. Increasing evidence has indicated that these endogenous neural stem/progenitor cells may play regenerative and reparative roles in response to CNS injuries or diseases. This review will discuss the potential functions of adult neurogenesis in the injured brain and will describe the recent development of strategies aimed at harnessing this neurogenic capacity in order to repopulate and repair the injured brain following trauma.


Escherichia coli sequence type 73 bloodstream infections in a centralized Canadian region and their association with companion animals: an ecological study.
Extraintestinal pathogenic E. coli (ExPEC) are important pathogens causing community-acquired infections in humans, including bloodstream infections (BSIs), and may also colonize and infect animals. Our aim was to investigate associations between incidence rates (IRs) of BSIs caused by ExPEC and number of dogs and cats in communities in Calgary. We used a well-characterized collection of blood isolates (n = 685) from Calgary, Alberta, Canada (2016). We used a combination of a seven-single-nucleotide-polymorphism quantitative PCR to type ExPEC into sequence types (STs). Calgary census data were used to estimate IRs per city community, as well as to investigate associations between number of companion animals per community, as obtained from licensing data, and IR of BSIs caused by each dominant ST. From the 685 isolates available, ExPEC ST131 was most prevalent (21.3% of included isolates), followed by ST73 (13.7%), ST69 (8.2%), ST95 (6.7%), and ST1193 (5.3%), respectively. Incidence of BSIs caused by ExPECs among Calgary residents was 48.8 cases per 100,000 resident-years, whereas communities had on average of 1.7 companion animals per 10 residents. No association between the number of dogs and IR of BSIs caused by ExPECs was detected for any ST. Conversely, the incidence rate of BSIs caused by ST73 was 3.6 times higher (95%CI 1.3-9.99) for every increase of 1 cat per 10 habitants in communities. Number of cats per habitant was positively associated with the incidence of BSIs caused by ExPEC ST73.


Usability of quality measures for online health information: Can commonly used technical quality criteria be reliably assessed?
Many criteria have been developed to rate the quality of online health information. To effectively evaluate quality, consumers must use quality criteria that can be reliably assessed. However, few instruments have been validated for inter-rater agreement. Therefore, we assessed the degree to which two raters could reliably assess 22 popularly cited quality criteria on a sample of 42 complementary and alternative medicine Web sites. We determined the degree of inter-rater agreement by calculating the percentage agreement, Cohen's kappa, and prevalence- and bias-adjusted kappa (PABAK). Our un-calibrated analysis showed poor inter-rater agreement on eight of the 22 quality criteria. Therefore, we created operational definitions for each of the criteria, decreased the number of assessment choices and defined where to look for the information. As a result 18 of the 22 quality criteria were reliably assessed (inter-rater agreement > or = 0.6). We conclude that even with precise definitions, some commonly used quality criteria cannot be reliably assessed. However, inter-rater agreement can be improved with precise operational definitions.


Therapeutic applications of nanobiotechnology.
Nanobiotechnology, as a novel and more specialized branch of science, has provided a number of nanostructures such as nanoparticles, by utilizing the methods, techniques, and protocols of other branches of science. Due to the unique features and physiobiological characteristics, these nanostructures or nanocarriers have provided vast methods and therapeutic techniques, against microbial infections and cancers and for tissue regeneration, tissue engineering, and immunotherapies, and for gene therapies, through drug delivery systems. However, reduced carrying capacity, abrupt and non-targeted delivery, and solubility of therapeutic agents, can affect the therapeutic applications of these biotechnological products. In this article, we explored and discussed the prominent nanobiotechnological methods and products such as nanocarriers, highlighted the features and challenges associated with these products, and attempted to conclude if available nanostructures offer any scope of improvement or enhancement. We aimed to identify and emphasize the nanobiotechnological methods and products, with greater prospect and capacity for therapeutic improvements and enhancements. We found that novel nanocarriers and nanostructures, such as nanocomposites, micelles, hydrogels, microneedles, and artificial cells, can address the associated challenges and inherited drawbacks, with help of conjugations, sustained and stimuli-responsive release, ligand binding, and targeted delivery. We recommend that nanobiotechnology, despite having few challenges and drawbacks, offers immense opportunities that can be harnessed in delivering quality therapeutics with precision and prediction. We also recommend that, by exploring the branched domains more rigorously, bottlenecks and obstacles can also be addressed and resolved in return.


Phase I/II trial of capecitabine and oxaliplatin in combination with bevacizumab and imatinib in patients with metastatic colorectal cancer: AIO KRK 0205.
Combined inhibition of platelet-derived growth factor receptor beta signalling and vascular endothelial growth factor promotes vascular normalisation in preclinical models and may lead to increased delivery of chemotherapy to tumour tissue. This phase I/II trial assessed the safety and efficacy of capecitabine plus oxaliplatin (XELOX) plus bevacizumab and imatinib in the first-line treatment of patients with metastatic colorectal cancer. Two dose levels (I/II) were defined: capecitabine 850/1000 mg m(-2) twice daily on days 1-14; oxaliplatin 100/130 mg m(-2) on day 1; bevacizumab 7.5 mg kg(-1) on day 1; imatinib 300 mg day(-1) on days 1-21 every 21 days. The primary study endpoint was safety. The phase II secondary endpoint was 6-month progression-free survival (PFS). Dose level I was chosen for phase II testing because, even though further dose escalation was permitted by the protocol, gastrointestinal toxicities were considered to be clinically significant. A total of 49 patients were evaluated. The 6-month PFS rate was 76%, median PFS was 10.6 months and median overall survival was 23.2 months. Haematological toxicities were generally mild. Sensory neuropathy and diarrhoea were the most common grade 3 toxicities. The combination of XELOX with bevacizumab and imatinib is tolerable and has promising efficacy.


Bio-inspired colorimetric film based on hygroscopic coloration of longhorn beetles (Tmesisternus isabellae).
Structure-dependent colour is caused by the interaction of light with photonic crystal structures rather than pigments. The elytra of longhorn beetles Tmesisternus isabellae appear to be iridescent green in a dry state and turn to red when exposed to humidity. Based on the hygroscopic colouration of the longhorn beetle, we have developed centimeter-scale colorimetric opal films using a novel self-assembly method. The micro-channel assisted assembly technique adopts both natural evaporation and rotational forced drying, enhancing the surface binding of silica particles and the packing density by reducing the lattice constant and structural defects. The fabricated large-scale photonic film changes its structural colour from green to red when exposed to water vapour, similarly to the colorimetric feature of the longhorn beetle. The humidity-dependent colour change of the opal film is shown to be reversible and durable over five-hundred cycles of wetting and drying.


Selective pancreatic vein catheterization for hormone assay in endocrine tumors of the pancreas.
To evaluate its potential as an alternative to angiography in the diagnosis of pancreatic tumors, we performed selective vein catheterization for hormone assay on 11 patients with islet cell tumors and islet cell hyperplasias. In all patients, the abnormal pancreatic tissue was correctly localized preoperatively by this method.


Toward an assessment of escape/avoidance coping in depression.
Models of animal behavior suggest that anxiety and major depressive disorder (MDD) may be characterized by different profiles of escape and avoidance behavior. However, the literature on coping strategies fails to distinguish between avoidance and escape coping patterns, instead grouping escape behaviors into the larger category of avoidant coping. We argue that investigating both escape and avoidance coping behavior in those with anxiety and depression may reveal distinct behavioral profiles, whereas the current conceptual framework has failed to find significant differences coping style.


Osteoclasts and hematopoiesis.
The skeletal tissue is closely associated with the hematopoietic tissue lodged in its inner cavities. Besides the well-known role of the endosteal osteoblasts in the maintenance of the hematopoietic stem cell (HSC) niche, it is an emerging concept that osteoclasts are involved in the regulation of hematopoiesis as well, although published data are still incomplete and somehow controversial. We reviewed the literature, and report here our perspective on the close relationship between bone resorption and HSC permanence in bone or egress to the circulation. We discussed the pressure that bone diseases exert on the development of hematological alterations, as well as the role of calcium and osteoclast enzymes in the regulation of HSC homeostasis. Genetic studies and preclinical experiments are described, which unveiled how bone disorders and treatments aimed at restoring the bone mass affect hematopoiesis, with consequent clinical implications. We conclude that this new field of investigation must be extended to unequivocally establish the role of osteoclasts in myelopoiesis and lymphopoiesis, and to envision treatments that can help hematological failures to be cured along with the associated bone alterations.


Intractable Nausea Due to the Area Postrema Syndrome of Neuromyelitis Optica: An Uncommon Cause of a Common Symptom.
Nausea and vomiting are common emergency department (ED) complaints. Neuromyelitis optica, a demyelinating disorder, has a predilection for the area postrema, the central nausea and vomiting center. Demyelinating lesions in this region cause intractable nausea and vomiting. We present a case of area postrema syndrome due to neuromyelitis optica in a 34-year-old woman who was seen in several EDs before the appropriate diagnosis was made. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Nausea and vomiting are complaints that commonly bring people to the ED, thus, emergency physicians are likely to be the first to encounter and diagnose the area postrema syndrome.


Cascade summing corrections for HPGe spectrometers by the Monte Carlo method.
Cascade summing corrections for application in HPGe gamma ray spectrometry have been calculated numerically by the Monte Carlo method. An algorithm has been developed which follows the path in the decay scheme from the starting state at the precursor radionuclide decay level, down to the ground state of the daughter radionuclide. With this procedure, it was possible to calculate the cascade summing correction for all gamma ray transitions present in the decay scheme. Since the cascade correction requires the values of peak and total detection efficiencies, another code has been developed in order to estimate these parameters for point and cylindrical sources. The radionuclides 60Co, 133Ba and 131I were used for testing the procedure. The results were in good agreement with values in the literature.


Structure and specific detection of staphylococcal cassette chromosome mec type VII.
Staphylococcal cassette chromosome mec (SCCmec) type VII, found in community-acquired methicillin-resistant Staphylococcus aureus belonging to multilocus sequence type (ST) 59 from Taiwan, was 41,347bp in size and flanked by 19-bp attL and attR sequences. It was inserted into the att site at the 3'-end of orfX in the orfX-orfY (putative tRNA dihydrouridine synthase) region in ST59 S. aureus. The 5'-end side 9911-bp core region of SCCmecVII, which contained attL and the cassette chromosome recombinase gene (ccrC8), was shared by other SCC structures, SCCmercury and mosaic SCCmec from Switzerland, indicating its important role in SCC evolution. The central 21,245-bp core region contained mec complex (C2b) and another ccrC gene (ccrC2), and was highly homologous to SCCmecV, but with substitutions, insertion and replacement. The 3'-end side 10,191-bp sequence was unique. Therefore, SCCmecVII has emerged through recombination and insertion events. Multiplex and real-time PCR assays were developed for specific detection of SCCmecVII.


Interplay of Endosomal pH and Ligand Occupancy in Integrin α5β1 Ubiquitination, Endocytic Sorting, and Cell Migration.
Membrane trafficking of integrins plays a pivotal role in cell proliferation and migration. How endocytosed integrins are targeted either for recycling or lysosomal delivery is not fully understood. Here, we show that fibronectin (FN) binding to α5β1 integrin triggers ubiquitination and internalization of the receptor complex. Acidification facilitates FN dissociation from integrin α5β1 in vitro and in early endosomes, promoting receptor complex deubiquitination by the USP9x and recycling to the cell surface. Depending on residual ligand occupancy of receptors, some α5β1 integrins remain ubiquitinated and are captured by ESCRT-0/I, containing histidine domain-containing protein tyrosine phosphatase (HD-PTP) and ubiquitin-associated protein 1 (UBAP1), and are directed for lysosomal proteolysis, limiting receptor downstream signaling and cell migration. Thus, HD-PTP or UBAP1 depletion confers a pro-invasive phenotype. Thus, pH-dependent FN-integrin dissociation and deubiquitination of the activated integrin α5β1 are required for receptor resensitization and cell migration, representing potential targets to modulate tumor invasiveness.


Elevated levels of TNF in the joints of adjuvant arthritic rats.
The primary purpose of this study was to determine whether local levels of tumor necrosis factor (TNF) were elevated in chronically inflamed joints in rats with adjuvant-induced arthritis (AA). We also wished to develop methodology for the quantitative measurement of joint TNF, and to examine the effects of known anti-inflammatory agents on joint TNF levels. TNF levels were measured in joints from AA rats taken during the systemic phase (day 20) of arthritic disease. Using the L929 bioassay, joint extracts from AA rats had significantly greater TNF levels (1054 +/- 147 pg/g tissue) than joint extracts from normal rats (110 +/- 42 pg/g tissue). Administration of ibuprofen failed to significantly inhibit TNF levels in the joint at a time point when paw swelling was significantly reduced. The immunomodulating agents, methotrexate, cyclosporin A (CSA) and HWA486 profoundly inhibited both joint TNF levels and paw swelling. The specificity of this assay for TNF was supported by studies with a polyclonal rabbit anti-mouse TNF antibody which neutralized 78-87% of the TNF activity in the joint extracts. Our studies demonstrate a quantitative increase in local TNF expression in adjuvant arthritis and support a role for TNF in chronic inflammation.


Effect of intra-partum Oxytocin on neonatal encephalopathy: a systematic review and meta-analysis.
Oxytocin is widely used for induction and augmentation of labour, particularly in low- and middle-income countries (LMICs). In this systematic review and meta-analysis, we examined the effect of intra-partum Oxytocin use on neonatal encephalopathy. The protocol for this study was registered with PROSPERO (ID: CRD42020165049). We searched Medline, Embase and Web of Science Core Collection databases for papers published between January 1970 and May 2021. We considered all studies involving term and near-term (≥36 weeks' gestation) primigravidae and multiparous women. We included all randomised, quasi-randomised clinical trials, retrospective studies and non-randomised prospective studies reporting intra-partum Oxytocin administration for induction and/or augmentation of labour. Our primary outcome was neonatal encephalopathy. Risk of bias was assessed in non-randomised studies using the Risk Of Bias In Non-randomised Studies of Interventions (ROBINS-I) tool. The RoB 2.0 tool was used for randomised studies. A Mantel-Haenszel statistical method and random effects analysis model were used for meta-analysis. Odds ratios were used to determine effect measure and reported with 95% confidence intervals. We included data from seven studies (6 Case-control studies, 1 cluster-randomised trial) of which 3 took place in high-income countries (HICs) and 4 in LMICs. The pooled data included a total of 24,208 women giving birth at or after 36 weeks; 7642 had intra-partum Oxytocin for induction and/or augmentation of labour, and 16,566 did not receive intra-partum Oxytocin. Oxytocin use was associated with an increased prevalence of neonatal encephalopathy (Odds Ratio 2.19, 95% CI 1.58 to 3.04; p < 0.00001). Intra-partum Oxytocin may increase the risk of neonatal encephalopathy. Future clinical trials of uterotonics should include neonatal encephalopathy as a key outcome.


Mathematical knowledge hidden in diagram of Nine-mansions based on Nine-mansions and Eight-winds discourse.
To introduce diagram of Nine-mansions in which another diagram named Xian-Tu is nested together with the mathematical knowledge hidden in them. Exploring with algebraic method the diagram of Nine-mansions and diagram of Xian-Tu nested in it and comparing the diagrams with the eight-pointed-star veins. It widely exists in the Neolithic Age's antiques found in China. The golden rectangle and golden spiral were found hidden in the diagrams and they show close relationship with eight-pointed-star veins. The mathematical knowledge does exists in the diagram of Nine-mansions and Xian-Tu, which may mean something for Traditional Chinese Medicine (TCM) for its discourse on Nine-mansions and Eight-winds obviously employed the diagram of Nine-mansions for its medical purpose.


The effect of formalin-killing of Pasteurella multocida on the antigenicity and extractability of its lipopolysaccharide.
The extraction of lipopolysaccharides (LPS) from formalin-killed (FK) Pasteurella multocida strain X-73 and from cells not exposed to formalin (NF) were compared by the Westphal and phenol-chloroform-petroleum ether (PCP) extraction procedures. The LPS was determined by: (1) serologic analyses with antiserum specific for LPS; (2) analyses for toxicity; and (3) chemical analyses for components expected to be in LPS (such as hexoses, heptoses, amino sugars, 3-deoxyoctulosonic acid, and fatty acids). Strain X-73, the strain most virulent for chickens, was markedly affected by formalin killing. Unlike many strains, which readily yield LPS into the aqueous phase when extracted with phenol at 68 degrees by the Westphal procedure, strain X-73 did so only with FK and not with NF cells. With the NF cells, LPS was extracted by EDTA from the precipitate obtained during the Westphal procedure. With the PCP procedure, LPS was extracted readily from NF cells, but not from FK cells. The change in extractability of LPS as a result of formalin-killing was the same for both the encapsulated form of X-73 and a nonencapsulated variant derived from it. Although formalin-killing affected the extractability of LPS, no antigenic differences could be detected by immunodiffusion. However, the chick-embryo toxicity of LPS extracted from NF cells was greater than that of LPS from FK cells.


In vitro attrition wear resistance of four types of paste-like bulk-fill composite resins.
Recently, the application of bulk-fill composite resins has increased significantly. Attrition wear and the consequently increased surface roughness of composite resins are among the causes of restoration failure in the posterior teeth. This study aimed to compare the attrition wear and surface roughness of four types of bulk-fill composite resins compared to a conventional composite resin. EverX-Posterior, X-tra fil, SonicFill 2, and Filtek Bulk-Fill composites (bulk-fill) and Z250 composite (conventional resin composite) were evaluated. Thirty cylindrical specimens (n = 6) were weighed and monitored for 24 h until their weight was stabilized. The primary surface roughness of the specimens was measured by a profilometer. The specimens were then subjected to attrition wear in a chewing simulator. Next, the specimens were weighed, and the surface roughness was measured again. Data were analyzed by one-way ANOVA and Tukey's post-hoc test at P < 0.05 significance level. According to one-way ANOVA, the difference in weight loss was significant among the groups (P = 0.004) but the difference in surface roughness of the groups was not significant after the attrition wear (P > 0.05). Tukey's post-hoc test showed that the weight loss of bulk-fill composites was not significantly different from that of Z250 conventional composite after the attrition wear (P > 0.05). Within the limitations of this study, it appears that the tested bulk-fill composite resins are comparable to the conventional composite regarding their attrition wear, increased surface roughness, and weight loss.


High-Throughput Tag-Sequencing Analysis of Early Events Induced by Ochratoxin A in HepG-2 Cells.
Ochratoxin A (OTA) is produced by fungi of the species Aspergillus and Penicillium. OTA has displayed hepatotoxicity in mammals. Although recent studies have indicated that OTA influences liver function, little is known regarding its impact on differential early liver toxicity. In this study, we report high-throughput tag-sequencing (Tag-seq) analysis of the transcriptome using Solexa Analyzer platform after 4 h of OTA treatment on HepG-2 cells. The analyses of differentially expressed genes revealed the substantial changes. A total of 21,449 genes were identified and quantified, with 2726 displaying significantly altered expression levels. Expression level data were then integrated with a network of gene-gene interactions, and biological pathways to obtain a systems-level view of changes in the transcriptome that occur with OTA resistance. Our data suggest that OTA exposure leads to an imbalance in zinc finger expression and shed light on splicing factor and mitochondrial-based mechanisms.


A Saccharomyces paradox: chromosomes from different species are incompatible because of anti-recombination, not because of differences in number or arrangement.
Many species are able to hybridize, but the sterility of these hybrids effectively prevents gene flow between the species, reproductively isolating them and allowing them to evolve independently. Yeast hybrids formed by Saccharomyces cerevisiae and Saccharomyces paradoxus parents are viable and able to grow by mitosis, but they are sexually sterile because most of the gametes they make by meiosis are inviable. The genomes of these two species are so diverged that they cannot recombine properly during meiosis, so they fail to segregate efficiently. Thus most hybrid gametes are inviable because they lack essential chromosomes. Recent work shows that chromosome mis-segregation explains nearly all observed hybrid sterility-genetic incompatibilities have only a small sterilising effect, and there are no significant sterilising incompatibilities in chromosome arrangement or number between the species. It is interesting that chromosomes from these species have diverged so much in sequence without changing in configuration, even though large chromosomal changes occur quite frequently, and sometimes beneficially, in evolving yeast populations.


Serum total and high molecular weight adiponectin levels are correlated with the severity of diabetic retinopathy and nephropathy.
Adiponectin is secreted specifically from adipocytes, and improves insulin sensitivity. Of its isoforms, the high molecular weight (HMW) complex is thought to be the most active. The aim of this study was to determine the relationship between serum total or HMW adiponectin and diabetic microangiopathy. We analysed 198 Japanese patients with type 2 diabetes mellitus (T2DM) whose fasting serum samples were available. Serum total adiponectin and HMW adiponectin were measured using an enzyme-linked immunosorbent assay (ELISA). Serum total adiponectin was found to have increased in the advanced stages of diabetic retinopathy (mean +/- SE, none, 6.9 +/- 0.3; simple, 8.3 +/- 1.0; preproliferative, 8.4 +/- 0.8; proliferative, 12 +/- 1.1 mg/l; anovaP = 0.0004) and nephropathy (stage I, 7.0 +/- 0.3; II, 7.7 +/- 0.5; III, 9.5 +/- 0.9; IV, 16 +/- 4.5 mg/l, P < 0.0001). Similarly, serum HMW adiponectin had increased in the advanced stages of retinopathy (3.7 +/- 0.2, 4.6 +/- 0.5, 4.6 +/- 0.6 and 6.9 +/- 0.8 mg/l, respectively, P = 0.0005) and nephropathy (3.7 +/- 0.2, 4.3 +/- 0.4, 5.3 +/- 0.7 and 7.9 +/- 2.2 mg/l, respectively, P = 0.0007). Neither serum total nor HMW adiponectin was correlated with neuropathy. The HMW/total adiponectin ratio was not correlated with microangiopathy. Multiple regression analysis revealed that serum total and HMW adiponectin were independent factors for retinopathy stage (P = 0.0055 and P = 0.0027, respectively) and nephropathy stage (P = 0.0003 and P = 0.0018, respectively), when adjusted for age, gender, body mass index (BMI) and the duration of T2DM. This correlation remained significant when serum creatinine (or estimated glomerular filtration rate) and hypertension were added as independent variables. Treatment with thiazolidinediones (TZDs) did not affect these findings. Serum total adiponectin and HMW adiponectin were found to be positively correlated with the severity of retinopathy and nephropathy but not with neuropathy in T2DM.


Effects of increased white blood cell count on retinal perfusion during hyperoxia-induced vasoconstriction.
Several studies have shown that administration of granulocyte-colony stimulating factor (G-CSF) is followed by an increase of white blood cell (WBC) count. There is evidence from other vascular beds that an increase in WBC count impairs blood flow regulation especially in the microcirculation. Whether this also holds true for the ocular circulation is yet unknown. In the following trial we investigated whether an increase in WBC count alters the oxygen induced vasoconstriction of retinal vessels. The study design was randomized, double-masked, placebo-controlled with two parallel groups. 24 healthy, male subjects were included. Measurements of retinal white blood cell flux with the blue-field entoptic technique, red blood cell velocity using the laser Doppler velocimeter and retinal vessel diameter using a Retinal Vessel Analyzer, were assessed at baseline and after breathing of 100% oxygen over 20 min. Thereafter 300 μg of G-CSF or placebo was administered. Measurements were repeated after another inhalation of 100% oxygen 8h later. G-CSF did not show any influence on systemic hemodynamics. WBC count increased significantly from 5.7 ± 1.6 × 10(9)/L at baseline up to 19.5 ± 4.8 × 10(9)/L 8h after G-CSF administration. As expected, oxygen breathing induced a pronounced vasoconstriction and a decrease red and white cell flux in both, the placebo and the G-CSF group (p<0.01 for both groups). Administration of G-CSF increased WBC flux, but did not affect red blood cell flux. The response of red blood cell flux and retinal vessel diameters to hyperoxia was not altered by G-CSF administration. However, leukocytosis leads to a more pronounced oxygen induced reduction in red blood cell velocity compared to the placebo group (p=0.024). Our data indicate that increased WBC count as induced with G-CSF, leads to a more pronounced reduction in retinal red blood cell flux during states of vasoconstriction. This indicates that, as in other vascular beds, an increase in WBC leads to an altered blood flow regulation.


Tobacco use by college students: a comparison of daily and nondaily smokers.
To explore demographics, contextual factors, and health risk behaviors associated with nondaily smoking by college students. In fall 2005, a random sample of 4100 students completed an online survey. Of those surveyed, 29% reported current smoking; of that 29%, 70% were nondaily smokers. Compared to daily smokers, nondaily smokers were younger, African American (compared to white), had mothers with higher education, belonged to Greek organizations, and attended private (vs public) schools. Nondaily smokers were less likely to have used illicit drugs. Nondaily and daily smokers differed on several demographic and contextual factors, but reported mostly similar health risk behaviors.


A comparison of chronic pain behavior following local application of tumor necrosis factor alpha to the normal and mechanically compressed lumbar ganglia in the rat.
To study the role of inflammatory cytokines in the initiation and persistence of radiculopathy as seen in humans, tumor necrosis factor alpha (TNF-alpha) was administered either to normal, uninjured L5 dorsal root ganglia (DRG) of rats via a hole drilled through the transverse process, or to chronically compressed L5 DRG via a hollow stainless steel rod inserted into the intervertebral foramen. In other experiments, a mixture of soluble TNF receptors (sTNF-Rs: sTNF-RIplus minussTNF-RII) was locally delivered to the chronically or acutely compressed DRG to neutralize the activity of endogenous TNF-alpha. Behavioral tests of mechanical allodynia were performed before and after TNF-alpha administration. Infusion of the normal DRG with TNF-alpha at a rate of 1 microl/h for 7 days induced ipsilateral mechanical allodynia (i.e. decreased mechanical withdrawal threshold) that lasted about 2 weeks. Infusion of the compressed DRG did not alter compression-induced allodynia within the first operative week but substantially enhanced the ipsilateral allodynia after the first postoperative week. Neutralizing the activity of endogenous TNF-alpha of the compressed DRG with sTNF-Rs reduced allodynia for 3 days, but was subsequently without effect. Similar results were obtained when sTNF-Rs were chronically administrated at the acutely compressed ganglion. Results demonstrated that exogenous TNF-alpha causes pain and mechanical allodynia when deposited at the normal DRG, and further enhances the ongoing allodynia when administrated at the compressed DRG. Results also suggest that endogenous TNF-alpha contributes to the early development of mechanical allodynia in rats with chronic DRG compression.


Characteristics of the granulocyte chemiluminescence reaction following an interaction between human neutrophils and Salmonella typhimurium bacteria.
The production of reactive oxygen metabolites by neutrophils is thought to play a key role in the host defence against invading microorganisms. The production of these oxidative metabolites can be measured as chemiluminescence. In this study, two strains of Salmonella typhimurium were used as stimuli, and the opsonin-independent CL response from neutrophils challenged with these bacteria was investigated. The strains used, S. typhimurium 395 MS and a rough (Rd Epi-2) mutant 395 MR10, differ with respect to physicochemical surface characteristics. When neutrophils were exposed to the phagocytic prey, only the MR10 bacteria induced a CL response. The response induced by the MS bacteria was less than 2% of that induced by MR10. In order to study the relation between intra and extracellularly generated CL, systems were used which selectively inhibit the intra and extracellular CL, respectively. Using these systems it was found that a predominant part of the response was of intracellular origin. When the neutrophils were treated with cytochalasin B (5 micrograms) before the addition of the bacteria, the CL response was reduced to around 37% of the value obtained from untreated cells, and the relation between the extra and the intracellular parts of the response was changed. The mechanism(s) and biological consequences of the extracellular and intracellular generation of oxygen metabolites, respectively, are discussed.


Chlorhexidine bathing to prevent healthcare-associated vancomycin-resistant Enterococcus infections: A cluster quasi-experimental controlled study at intensive care units.
Vancomycin-resistant Enterococcus (VRE), a multidrug-resistant, difficult-to-treat pathogen of healthcare-associated infections (HAIs), is now endemic at many intensive care units (ICUs). Chlorhexidine (CHG) bathing is a simple and highly effective intervention to decrease VRE acquisition, but its effect on VRE-HAIs has not been assessed in prospective studies at ICUs. This is a cluster quasi-experimental controlled study. Under active VRE surveillance and contact isolation of all identified VRE carriers, four ICUs were assigned to provide 2% CHG bathing for all patients on a daily basis (CHG group) during the intervention period, while another four ICUs were assigned to provide standard care without CHG bathing for all patients (standard care group) during the same period. The CHG group (n = 1501) had a 62% lower crude incidence of VRE-HAIs during the intervention period, compared with the baseline period (1.0 vs. 2.6 per thousand patient-days, P = 0.009), while VRE-HAIs incidence did not change in standard care group (n = 3299) (1.1 vs. 0.5 per thousand patient-days, P = 0.139). In multivariable analyses, CHG bathing was independently associated with a 70% lower risk of VRE-HAIs (adjusted odds ratio [OR] 0.3, 95% confidence interval [CI], 0.2 to 0.7, P = 0.006). In contrast, standard care during the same period had no effect on the risk of VRE-HAIs (adjusted OR 1.8, 95% CI: 0.7 to 4.7, P = 0.259). CHG bathing is a highly effective approach to prevent VRE-HAIs at ICUs, in the context of active VRE surveillance with contact isolation.


SARS-CoV-2 surveillance in Italy through phylogenomic inferences based on Hamming distances derived from pan-SNPs, -MNPs and -InDels.
Faced with the ongoing global pandemic of coronavirus disease, the 'National Reference Centre for Whole Genome Sequencing of microbial pathogens: database and bioinformatic analysis' (GENPAT) formally established at the 'Istituto Zooprofilattico Sperimentale dell'Abruzzo e del Molise' (IZSAM) in Teramo (Italy) is in charge of the SARS-CoV-2 surveillance at the genomic scale. In a context of SARS-CoV-2 surveillance requiring correct and fast assessment of epidemiological clusters from substantial amount of samples, the present study proposes an analytical workflow for identifying accurately the PANGO lineages of SARS-CoV-2 samples and building of discriminant minimum spanning trees (MST) bypassing the usual time consuming phylogenomic inferences based on multiple sequence alignment (MSA) and substitution model. GENPAT constituted two collections of SARS-CoV-2 samples. The first collection consisted of SARS-CoV-2 positive swabs collected by IZSAM from the Abruzzo region (Italy), then sequenced by next generation sequencing (NGS) and analyzed in GENPAT (n = 1592), while the second collection included samples from several Italian provinces and retrieved from the reference Global Initiative on Sharing All Influenza Data (GISAID) (n = 17,201). The main results of the present work showed that (i) GENPAT and GISAID detected the same PANGO lineages, (ii) the PANGO lineages B.1.177 (i.e. historical in Italy) and B.1.1.7 (i.e. 'UK variant') are major concerns today in several Italian provinces, and the new MST-based method (iii) clusters most of the PANGO lineages together, (iv) with a higher dicriminatory power than PANGO lineages, (v) and faster that the usual phylogenomic methods based on MSA and substitution model. The genome sequencing efforts of Italian provinces, combined with a structured national system of NGS data management, provided support for surveillance SARS-CoV-2 in Italy. We propose to build phylogenomic trees of SARS-CoV-2 variants through an accurate, discriminant and fast MST-based method avoiding the typical time consuming steps related to MSA and substitution model-based phylogenomic inference.


The role of cell population kinetics in the efficacy of penicillin--an experimental analysis and stochastic modeling of the tumour tetanus and wound tetanus of the mouse.
When investigating tetanus lethality summation curves of mice under comparable quantitative conditions following a temporarily limited administration of penicillin, the curves obtained can be calculated by the kinetics of tumour cells or wound fibroblasts. In particular, it has been shown that the optimal efficacy of penicillin, after short-time usage as compared with a long-time administration schedule, is determined by the generation time of the tetanus rods as a function of the mitotic cycle of the "pace-making" tumour cells or wound fibroblasts. Further variables of the mathematical model imply the pharmacokinetics of penicillin and the recovery process of the "hit" tetanus rods. From these results some basic experimental and clinical tetanus issues can be elucidated; thus, the mitosis theory of tetanus is being verified for the stage of incubation and of clinical manifestation, while the classical necrosis theory of the pathogenesis of tetanus infection should be valid only for the final stage.


Combination chemotherapy with vincristine, epirubicin and cyclophosphamide in small cell lung carcinoma. Polish Lung Cancer Cooperative Group.
The aim of this prospective study was to assess the activity of a combination of vincristine, epirubicin and cyclosphosphamide (VEC) in previously untreated patients with limited small cell lung carcinoma (SCLC) and to delineate the feasibility of dose escalation for epirubicin in this regimen. The chemotherapy schedule included cyclophosphamide, 1000 mg/m2, vincristine, 1 mg/m2 and escalating doses of epirubicin: 50 mg/m2, 70 mg/m2 and 90 mg/m2; respectively in three consecutive groups of patients. Drug cycles were repeated every 3 weeks. 118 patients from eight institutions were enrolled in this study between February 1986 and March 1989. Objective tumour response was observed in 81 of 116 evaluable patients (70%) including 25 patients (22%) who achieved a complete remission. Responding patients received thoracic radiation after the fourth cycle of chemotherapy. The median duration of response was 30 weeks and the median duration of survival was 52 weeks. There were no significant differences in treatment results between the consecutive groups of patients. The regimen was well tolerated for all doses of epirubicin. The main toxicities included alopecia (96%), nausea and vomiting (81%) and leukopenia (44%). Grade 4 haematological toxicity was observed in 3 patients (2.6%). No significant epirubicin dose-dependent side effects, except for mucositis were observed.


[Looking for colorectal cancer in the patients iris?].
Iridology is a noninvasive method from the field of complementary medicine that is said to detect diseases by looking for abnormalities of pigmentation and structure in the iris. Colorectal cancer is an ideal opportunity for screening programs because of its long period of development. Our study investigated the applicability of iridology as an alternative screening method for colorectal cancer. Digital color slides were obtained from both eyes of 29 patients with histologically diagnosed colorectal cancer and from 29 age- and gender-matched healthy control subjects. The slides were presented in random order to acknowledged iridologists without knowledge of the number of patients in the two categories. The iridologists correctly detected 51.7% and 53.4%, respectively, of the patients' slides; therefore, the likelihood was statistically no better than chance. Sensitivity was, respectively, 58.6% and 55.2%, and specificity was 44.8% and 51.7%. Iridology had no validity as a diagnostic tool for detecting colorectal cancer in this study.


Light-speed genomics.
A pico-scale reaction system serves as the basis for a new generation of high-throughput sequencing machines that promise to bring genome-center power down to the laboratory level.


Antibody that recognizes conformations of calmodulin in the serum from patient with chronic active hepatitis.
According to the effects of Ca++ on the reactivity, anti-calmodulin antibody in the sera of patients with autoimmune chronic active hepatitis was classified into three types, which were tentatively designated as type 1, 2 and 3. Type 1 antibody reacted with calmodulin only in the presence of free Ca++. Binding of type 2 antibody to calmodulin was inhibited by the presence of free Ca++. Type 3 antibody reacted with calmodulin regardless of the presence or absence of free Ca++. Thus the sera contained the populations of the antibody which recognized the different conformations of calmodulin molecule.


The impact of temperature on the transmissibility potential and virulence of COVID-19 in Tokyo, Japan.
Assessing the impact of temperature on COVID-19 epidemiology is critical for implementing non-pharmaceutical interventions. However, few studies have accounted for the nature of contagious diseases, i.e., their dependent happenings. We aimed to quantify the impact of temperature on the transmissibility and virulence of COVID-19 in Tokyo, Japan, employing two epidemiological measurements of transmissibility and severity: the effective reproduction number ([Formula: see text]) and case fatality risk (CFR). We estimated the [Formula: see text] and time-delay adjusted CFR and to subsequently assess the nonlinear and delayed effect of temperature on [Formula: see text] and time-delay adjusted CFR. For [Formula: see text] at low temperatures, the cumulative relative risk (RR) at the first temperature percentile (3.3 °C) was 1.3 (95% confidence interval (CI): 1.1-1.7). As for the virulence to humans, moderate cold temperatures were associated with higher CFR, and CFR also increased as the temperature rose. The cumulative RR at the 10th and 99th percentiles of temperature (5.8 °C and 30.8 °C) for CFR were 3.5 (95% CI: 1.3-10.0) and 6.4 (95% CI: 4.1-10.1). Our results suggest the importance to take precautions to avoid infection in both cold and warm seasons to avoid severe cases of COVID-19. The results and our proposed approach will also help in assessing the possible seasonal course of COVID-19 in the future.


Laparoscopic pelvic floor repair using polypropylene mesh.
The purpose of this report is to present our experience in laparoscopic pelvic floor repair using polypropylene mesh for the treatment of advanced vaginal vault prolapse and enterocele. A total of 40 patients with Baden-Walker System grade 3 or 4 vaginal vault prolapse and concurrent enterocele were recruited. Twenty patients had undergone at least one previous pelvic floor reconstructive procedure and were categorized as the recurrent prolapse group. The other 20 patients were categorized as the nonrecurrent group. All patients underwent a laparoscopic pelvic floor repair using a single piece of polypropylene mesh combined with uterosacral ligament suspension. The mean age of the study group was 60.7 years. The mean follow-up period was 26.6 months. The intraoperative major complication rate was 5% (two bladder perforations). No recurrent apical prolapse, anterior vaginal wall or posterior vaginal wall prolapse was observed at postoperative follow-up. The overall mesh erosion rate was 12.5% (5 of 40 patients), with four erosions (20%) in the recurrent prolapse group and one erosion (5%) in the nonrecurrent group. Mesh-related pain syndromes and dyspareunia was reported in 21.4% of patients in the recurrent prolapse group and 6.3% of patients in the nonrecurrent group. Laparoscopic pelvic floor repair using a single piece of polypropylene mesh combined with uterosacral ligament suspension appears to be a feasible procedure for the treatment of advanced vaginal vault prolapse and enterocele. Fewer mesh erosions and postoperative pain syndromes were seen in patients who had no previous pelvic floor reconstructive surgery.


Faslodex (ICI 182, 780), a novel estrogen receptor downregulator--future possibilities in breast cancer.
Tamoxifen is an effective treatment for breast cancer; however, as well as exerting antagonistic effects on the estrogen receptor (ER), tamoxifen acts as a partial agonists in estrogen-sensitive tissues, resulting in stimulation of the endometrium and tumor growth in some patients who become resistant to treatment.ICI 182, 780 (Faslodex), a steroidal estrogen antagonist, is the first in a new class of agent-an estrogen receptor downregulator. Pre-clinical breast cancer models show that ICI 182, 780 leads to a prolonged duration of response, and that it exerts its effects via a different mode of action to tamoxifen. This was confirmed in a small clinical study involving 19 post-menopausal advanced breast cancer patients, where ICI 182, 780 was highly effective after tamoxifen failure. Definitive evidence of the differing modes of action of ICI 182, 780 and tamoxifen, were provided in a study involving post-menopausal women with primary breast cancer, where analyses of tumor samples following short-term exposure to both drugs, showed that ICI 182, 780 reduced tumor ER levels in a dose-dependent manner, and to a significantly greater extent than tamoxifen. Additionally, unlike tamoxifen, ICI 182, 780 did not promote ER-mediated progesterone receptor expression, indicating that it lacks estrogen agonist activity. Ongoing studies in post-menopausal women with advanced breast cancer are comparing ICI 182, 780 to anastrozole and tamoxifen, respectively. Future studies being considered are whether ICI 182, 780 may also be effective in breast cancer in pre-menopausal women, in early breast cancer and in ductal carcinoma in situ in the breast, in combination with other hormonals, cytotoxics and biological modifiers.


Topical negative pressure wound therapy to prevent wound complications following caesarean delivery in high-risk obstetric patients: A randomised controlled trial.
We investigated whether the use of a prophylactic negative pressure wound therapy (NPWT) system in women undergoing caesarean would decrease wound complications in a high-risk population. A randomised controlled trial was performed. Women with risk factors for wound complications undergoing caesarean delivery were randomised to a standard dressing or NPWT placed over their caesarean wound. We standardised the closure of the subcutaneous fat and skin layers, both with Vicryl. Patients were followed for wound complications for up to 6 weeks after their caesareans. The incidence of wound complications was the primary outcome. The single-use NPWT system, PICO, was provided by Smith and Nephew for use in this trial. The trial was registered on clinicaltrials.gov, # NCT03082664. We report here on 154 women randomised to either a standard dressing or to the NPWT. Wound complication rates were equivalent between groups, with 19.4 and 19.7% (P = 0.43) of women with follow-up information available experiencing wound complications. We found no difference in wound complications in women with risk factors treated with a prophylactic NPWT system or standard wound dressing at the time of caesarean birth.


Role of menopause and hormone replacement therapy in sleep-disordered breathing.
There are suggestions that the loss of female sex hormones following menopause is critical for the development or progression of sleep-disordered breathing (SDB). We conducted a review of the literature on the role of menopause and hormone replacement therapy (HRT) in SDB risk. There is an increase in SDB during the menopausal transition period, but data on an effect beyond that of increasing age and changes in body habitus are weak or absent. Early community-based, observational studies reported a protective effect by HRT on SDB prevalence, but this could possibly be explained as a healthy user effect. Interventional studies of the effect of HRT on SDB are sparse, with only a few randomized placebo-controlled studies, often performed on small samples of women without clinically significant SDB. HRT regimens have varied and all the studies are fairly old. They do not definitely assure the alleviation of SDB and HRT cannot thus be recommended as treatment for SDB. It is concluded that there is no evidence that female sex hormone changes during menopause per se are able to explain the increase in SDB in midlife women and conclusions on the effect of HRT on SDB cannot be drawn from the current literature.


Dietary restriction influence bile formation in aging rats.
Food restriction is one of the most effective interventions which increases the survival of rodents and influences a variety of physiologic and pathologic processes. Thus, we examined whether life-long caloric restriction would influence bile formation, one of the important hepatic functions. Female Sprague Dawley rats were subjected soon after weaning to a restricted diet (60% of the diet consumed by the rats fed ad libitum) and bile formation determined at 3.5, 12 and 24 months of age. Rats had their bile ducts cannulated under nembutal anesthesia and bile collected at 10 min. intervals. Bile flow rate decreased 35% between 3.5 and 24 months of age. This decrease was associated with a reduction of the bile acid dependent fraction of bile flow (BADF) up to 12 months of age, thereafter the bile acid independent fraction (BAIF) also decreased. Phospholipid and cholesterol secretion rates increased with age, but did not correlate with bile acid secretion. In rats fed the restricted diet, bile flow was about 20% higher at 3-5 months of age when compared with the ad libitum fed group. This bile flow rate remained constant until 24 months of age. The increased bile flow was attributed to higher BADF and BAIF. The phospholipid and cholesterol secretion followed that of bile acids. It thus appears that dietary restriction exerts a beneficial effect on the age related decline in bile formation.


Measurement and analysis of water ecological carrying capacity in the Yangtze River Economic Belt, China.
Water ecological carrying capacity (WECC) is a crucial index for measuring regional sustainable development. To investigate the evolution of WECC in the Yangtze River Economic Belt (YREB), this study constructed a comprehensive index system consisting of 23 indicators from six interconnected dimensions of water systems. The back propagation neural network (BPNN) model was used to quantify WECC in YREB from 2010 to 2021, and ArcGIS was utilized to visualize the distribution of WECC. To identify sensitive indicators under subsystems, sensitivity analysis was conducted based on the one-at-a-time (OAT) method. Additionally, time-series prediction of WECC was performed using the exponential smoothing (ES) method. Finally, the coupling coordinated degree (CCD) of subsystems in each province from 2010 to 2021 was calculated. The results indicated that the average WECC in YREB gradually increased from 2010 to 2021, with significant provincial differences. Sensitivity analysis revealed that R1, U2, Q4, S2, M3 and B1 had the most substantial impacts on the WECC of subsystems (Sub-CC). The fitting curve between the CCD and WECC showed that as CCD increased, the growth rate of WECC gradually slowed down. Based on these findings, relevant suggestions were proposed to improve WECC and promote the regional sustainable development in YREB.


Vitellogenin, steroid plasma levels and spawning performance of cultured female Senegalese sole (Solea senegalensis).
The Senegalese sole (Solea senegalensis) is a high value market flatfish, which aquaculture is compromised by severe reproductive problems; these are mostly found in soles hatched and raised in captivity (F1 generation). To gain knowledge on the reproductive dysfunctions observed in cultured (F1) Senegalese sole, this work aimed at developing a specific vitellogenin (VTG) ELISA, for the measurement of plasma VTG levels in this species. Profiles of VTG were correlated with those of sexual steroids and spawning performance of an F1 broodstock, during three consecutive years. The Senegalese sole VTG (ssVTG) was purified by precipitation with MgCl(2)-EDTA and anion-exchange chromatography and showed a molecular mass of 172 kDa, by SDS-PAGE. Specific antibodies were obtained and used to develop a competitive ELISA, which had a sensitivity of 3.6 ng ml(-1), and inter- and intra-assay coefficients of variation of 9.5% (n=29) and 6.7% (n=12), respectively. Annual profiles of plasma VTG showed a major peak at pre-spawning, and a second minor rise around autumn, which mirrored plasma profiles of both estradiol (E(2)) and testosterone (T) levels. Spontaneous spawning occurred every year in the spring season, but no fertilized eggs were obtained. In conclusion, this study described, for the first time, the purification and development of a sensitive and specific ELISA for Senegalese sole VTG. The endocrine and spawning data suggested that F1 female broodstock showed normal VTG and steroid releasing profiles in captivity with occurrence of spontaneous spawning, but no fertilization of the eggs was recorded.


AdipoR2 recruits protein interactors to promote fatty acid elongation and membrane fluidity.
The human AdipoR2 and its Caenorhabditis elegans homolog PAQR-2 are multipass plasma membrane proteins that protect cells against membrane rigidification. However, how AdipoR2 promotes membrane fluidity mechanistically is not clear. Using 13C-labeled fatty acids, we show that AdipoR2 can promote the elongation and incorporation of membrane-fluidizing polyunsaturated fatty acids into phospholipids. To elucidate the molecular basis of these activities, we performed immunoprecipitations of tagged AdipoR2 and PAQR-2 expressed in HEK293 cells or whole C. elegans, respectively, and identified coimmunoprecipitated proteins using mass spectrometry. We found that several of the evolutionarily conserved AdipoR2/PAQR-2 interactors are important for fatty acid elongation and incorporation into phospholipids. We experimentally verified some of these interactions, namely, with the dehydratase HACD3 that is essential for the third of four steps in long-chain fatty acid elongation and ACSL4 that is important for activation of unsaturated fatty acids and their channeling into phospholipids. We conclude that AdipoR2 and PAQR-2 can recruit protein interactors to promote the production and incorporation of unsaturated fatty acids into phospholipids.


Cr(VI) retention and transport through Fe(III)-coated natural zeolite.
Cr(VI) is a group A chemical based on the weight of evidence of carcinogenicity. Its transport and retention in soils and groundwater have been studied extensively. Zeolite is a major component in deposits originated from volcanic ash and tuff after alteration. In this study, zeolite aggregates with the particle size of 1.4-2.4mm were preloaded with Fe(III). The influence of present Fe(III) on Cr(VI) retention by and transport through zeolite was studied under batch and column experiments. The added Fe(III) resulted in an enhanced Cr(VI) retention by the zeolite with a capacity of 82mg/kg. The Cr(VI) adsorption on Fe(III)-zeolite followed a pseudo-second order kinetically and the Freundlich adsorption isotherm thermodynamically. Fitting the column experimental data to HYDRUS-1D resulted in a retardation factor of 3 in comparison to 5 calculated from batch tests at an initial Cr(VI) concentration of 3mg/L. The results from this study showed that enhanced adsorption and retention of Cr(VI) may happen in soils derived from volcanic ash and tuff that contains significant amounts of zeolite with extensive Fe(III) coating.


Parosteal Lipoma of the Proximal Phalanx of Hand.
Parosteal lipomas are rare benign tumors accounting for less than 0.1% of all primary bone tumors. Only 3 cases of parosteal lipoma have been previously described affecting the distal and middle phalanges. We describe a case of parosteal lipoma in a 45-year-old man involving the proximal phalanx of the right middle finger. The tumor was marginally excised with the osseous attachment. There was no clinical or radiological recurrence at a follow-up of 2 years, with full range of movement at the proximal interphalangeal joint.


Phosphodiesterase III inhibitor attenuates rat sinusoidal obstruction syndrome through inhibition of platelet aggregation in Disse's space.
Sinusoidal obstruction syndrome (SOS) is a serious drug-induced liver injury. However, the pathophysiology of the disease remains unclear. This study investigated the effects of cilostazol (CZ), a phosphodiesterase III inhibitor, in a monocrotaline (MCT)-induced rat model of SOS. Male Wistar rats were administrated MCT to induce SOS. Rats were divided into control, MCT, and MCT + CZ groups. In the MCT + CZ group, CZ was administered at 48 h, 24 h, and 30 min prior to and 8 h and 24 h after MCT administration. The MCT group was treated with water instead of CZ. At 48 h after MCT administration, blood and liver samples were collected to assess biochemistry and liver histology. Expression of rat endothelial cell antigen, CD34, CD41, P-selectin, and caspase-3 in the liver were analyzed. Plasminogen activator inhibitor-1 (PAI-1) in hepatocytes was analyzed using western blotting and polymerase chain reaction. In the MCT group, macroscopic findings showed a dark-red liver surface. Histological findings showed sinusoidal dilatation, coagulative necrosis of hepatocytes, and endothelial damage of the central vein. These changes were attenuated in the MCT + CZ group. Elevated serum transaminase and decreased platelet counts were observed in the MCT + CZ group compared with those in the MCT group. Treatment with CZ reduced MCT-induced damage to the liver sinusoidal endothelial cells, inhibited extravasated platelet aggregation, and suppressed hepatocyte apoptosis around the central vein. CZ attenuated hepatic PAI-1 protein and mRNA levels. Cilostazol attenuated MCT-induced SOS by preventing damage to liver sinusoidal endothelial cells and extravasated platelet aggregation. Hepatic PAI-1 levels were suppressed with CZ treatment.


The species-specific ratios of 2,3-butanediol and acetoin isomers as a tool to evaluate wine yeast performance.
The isomers of 2,3-butanediol [R,R; S,S; R,S (meso-form)] and of acetoin (R,S) were determined in laboratory wine fermentations carried out by 50 yeast strains, 10 for each of the following species, Saccharomyces cerevisiae, Kloeckera apiculata, Candida stellata, Metschnikowia pulcherrima and Brettanomyces bruxellensis, in order to evaluate if such parameters might be used to differentiate wines obtained with different yeast species. According to analysis of variance (ANOVA), the strains of the same species behaved similarly, whereas the five yeast species behaved differently so that species-specific profiles were recognized. Moreover, the discriminant analysis grouped the wines into five groups, each including the 10 wines obtained by the 10 yeast strains of the same species. Trials were also included where musts partially fermented by non-Saccharomyces species were inoculated with a selected strain of S. cerevisiae to complete fermentation, and the content in 2,3-butanediol and acetoin isomers was again determined and statistical analysis was performed. Although the final values of these parameters resembled those obtained in pure fermentation with S. cerevisiae, statistical analysis discriminated wines according to the yeast species performing the first fermentation phase.


CDK4/6 inhibitors, PI3K/mTOR inhibitors, and HDAC inhibitors as second-line treatments for hormone receptor-positive, HER2-negative advanced breast cancer: a network meta-analysis.
This study sought to compare the benefits and safety of agents including Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors, and histone deacetylase (HDAC) inhibitors as second-line treatments for these patients by conducting a comprehensive systematic review and network meta-analysis. The Medline, Embase and Cochrane Library databases were searched for randomized trials comparing CDK4/6 inhibitors, PI3K/mTOR inhibitors, or HDAC inhibitors vs. placebo with the addition of exemestane or fulvestrant as second-line treatments in patients with HR + advanced breast cancer up to December 16, 2021. Outcomes of interest were progression-free survival (PFS), overall response rate (ORR), overall survival (OS), clinical benefit rate (CBR), and grade 3-4 adverse drug events (ADEs). The present study was conducted according to the Cochrane Collaboration and PRISMA statements. The overall effect was pooled using the random effects model. Seventeen studies with a total of 9,100 participants were included in the current study. Compared with placebo plus fulvestrant, PFS was significantly improved by CDK4/6 inhibitor plus fulvestrant, mTOR inhibitor plus fulvestrant, mTOR inhibitor plus exemestane, and PI3K inhibitor plus fulvestrant, but not HDAC inhibitor plus exemestane. While mTOR inhibitor plus exemestane was the best regimen (SUCRA value 89.5%), the mTOR inhibitor plus exemestane regimen induced more severe adverse events (SAEs) than the HDAC inhibitor plus exemestane regimen [OR, 95% CI: 2.40 (1.40-4.10)]. mTOR inhibitor and CDK4/6 inhibitor-based regimens demonstrated superior clinical efficacy and comparable safety profiles as second-line treatment in patients with HR-positive, HER2-negative advanced breast cancer.


Early life PCB138 exposure induces kidney injury secondary to hyperuricemia in male mice.
Polychlorinated biphenyls (PCBs) are a class of persistent organic pollutants (POPs) that have adverse effects on human health. However, the long-term health effects and potential mechanism of neonatal exposure to PCBs are still unclear. In this study, nursing male mice exposed to PCB138 at 0.5, 5, and 50 μg/kg body weight (bw) from postnatal day (PND) 3 to PND 21 exhibited increased serum uric acid levels and liver uric acid synthase activity at 210 days of age. We also found an increased kidney somatic index in the 50 μg/kg group and kidney fibrosis in the 5 and 50 μg/kg groups. Mechanistically, PCB138 induced mitochondrial dysfunction and endoplasmic reticulum (ER) stress, which might have led to inflammatory responses, such as activation of the NF-κB (nuclear factor kappa-B) and NLRP3 (NOD-like receptor protein 3) pathways. The inflammatory response might regulate renal fibrosis and hypertrophy. In summary, this study reports a long-term effect of neonatal PCB exposure on uric acid metabolism and secondary nephrotoxicity and clarifies the underlying mechanism. Our work also indicates that early life pollutant exposure may be an important cause of diseases later in life.


Tat-CIAPIN1 inhibits hippocampal neuronal cell damage through the MAPK and apoptotic signaling pathways.
Cytokine-induced apoptosis inhibitor 1 (CIAPIN1) protein is widely expressed in the brain and it is known that this protein is involved in cell survival including dopaminergic neuronal cells. Oxidative stress is known as one of the major causes of degenerative diseases including ischemia. In this study, we investigated the effect of CIAPIN1 protein on hippocampal neuronal (HT-22) cell damage induced by hydrogen peroxide (H2O2) and in an animal model of ischemia using Tat-CIAPIN1 fusion protein which can transduce into cells. Tat-CIAPIN1 protein transduced into HT-22 cells and significantly inhibited cell death, DNA fragmentation, and reactive oxygen species (ROS) generation. Also, Tat-CIAPIN1 protein enhances cell survival via the regulation of Akt, MAPK, NF-κB and apoptotic signaling pathways in the H2O2 treated cells. In an ischemic animal model, Tat-CIAPIN1 protein transduced into the brain and protected neuronal cell death of hippocampal CA1 region induced by ischemic insult. In conclusion, we demonstrated that Tat-CIAPIN1 protein has protective effects against hippocampal neuronal cell damage induced by ischemic injury, suggesting that Tat-CIAPIN1 protein may provide a potential therapeutic agent for ischemia.


Transgenic systems in drug discovery: from target identification to humanized mice.
Pharmaceutical companies are faced with the challenge that only approximately 10% of compounds tested in costly clinical trials eventually become a new drug. Investment in early discovery research can decrease this attrition in late-stage R&D and focus resources on the best targets. Transgenic technology influences decision-making in target identification, target validation, and can also provide better models for human diseases, as well as models designed to alert researchers early about potential issues with drug metabolism and toxicity. Here we review how transgenic technology can reduce the late-stage attrition by increasing the quality of both the target and the compound.


Global analysis of iron metabolism-related genes identifies potential mechanisms of gliomagenesis and reveals novel targets.
This study aimed to investigate key regulators of aberrant iron metabolism in gliomas, and evaluate their effect on biological functions and clinical translational relevance. We used transcriptomic data from multiple cross-platform glioma cohorts to identify key iron metabolism-related genes (IMRGs) based on a series of bioinformatic and machine learning methods. The associations between IMRGs and prognosis, mesenchymal phenotype, and genomic alterations were analyzed in silico. The performance of the IMRGs-based signature in predicting temozolomide (TMZ) treatment sensitivity was evaluated. In vitro and in vivo experiments were used to explore the biological functions of these key IMRGs. HMOX1, LTF, and STEAP3 were identified as the most essential IMRGs in gliomas. The expression levels of these genes were strongly related to clinicopathological and molecular features. The robust IMRG-based gene signature could be used for prognosis prediction. These genes facilitate mesenchymal transformation, driver gene mutations, and oncogenic alterations in gliomas. The gene signature was also associated with TMZ resistance. HMOX1, LTF, and STEAP3 knockdown in glioma cells significantly reduced cell proliferation, colony formation, migration, and malignant invasion. The study presented a comprehensive view of key regulators underpinning iron metabolism in gliomas and provided new insights into novel therapeutic approaches.


Care of the Neonatal Intensive Care Unit Graduate after Discharge.
Premature and critically ill term infants are often discharged from the neonatal intensive care unit (NICU) with ongoing medical problems, including respiratory problems; growth, nutrition and feeding problems; and neurologic injury. At discharge, they may also be dependent on technology such as supplemental oxygen, tracheostomy, mechanical ventilation, feeding tube, and monitors. Primary care physicians must have special knowledge and understanding of the medical complications of NICU graduates to coordinate post-discharge care. We examine the most common post-discharge medical problems in premature and critically ill term infants and inform the primary care provider about expected outcomes and possible new problems.


In Silico, In Vitro, and In Vivo Investigations on Adapalene as Repurposed Third Generation Retinoid against Multiple Myeloma and Leukemia.
The majority of hematopoietic cancers in adults are incurable and exhibit unpredictable remitting-relapsing patterns in response to various therapies. The proto-oncogene c-MYC has been associated with tumorigenesis, especially in hematological neoplasms. Therefore, targeting c-MYC is crucial to find effective, novel treatments for blood malignancies. To date, there are no clinically approved c-MYC inhibitors. In this study, we virtually screened 1578 Food and Drug Administration (FDA)-approved drugs from the ZINC15 database against c-MYC. The top 117 compounds from PyRx-based screening with the best binding affinities to c-MYC were subjected to molecular docking studies with AutoDock 4.2.6. Retinoids consist of synthetic and natural vitamin A derivatives. All-trans-retinoic acid (ATRA) were highly effective in hematological malignancies. In this study, adapalene, a third-generation retinoid usually used to treat acne vulgaris, was selected as a potent c-MYC inhibitor as it robustly bound to c-MYC with a lowest binding energy (LBE) of -7.27 kcal/mol, a predicted inhibition constant (pKi) of 4.69 µM, and a dissociation constant (Kd value) of 3.05 µM. Thus, we examined its impact on multiple myeloma (MM) cells in vitro and evaluated its efficiency in vivo using a xenograft tumor zebrafish model. We demonstrated that adapalene exerted substantial cytotoxicity against a panel of nine MM and two leukemic cell lines, with AMO1 cells being the most susceptible one (IC50 = 1.76 ± 0.39 µM) and, hence, the focus of this work. Adapalene (0.5 × IC50, 1 × IC50, 2 × IC50) decreased c-MYC expression and transcriptional activity in AMO1 cells in a dose-dependent manner. An examination of the cell cycle revealed that adapalene halted the cells in the G2/M phase and increased the portion of cells in the sub-G0/G1 phase after 48 and 72 h, indicating that cells failed to initiate mitosis, and consequently, cell death was triggered. Adapalene also increased the number of p-H3(Ser10) positive AMO1 cells, which is a further proof of its ability to prevent mitotic exit. Confocal imaging demonstrated that adapalene destroyed the tubulin network of U2OS cells stably transfected with a cDNA coding for α-tubulin-GFP, refraining the migration of malignant cells. Furthermore, adapalene induced DNA damage in AMO1 cells. It also induced apoptosis and autophagy, as demonstrated by flow cytometry and western blotting. Finally, adapalene impeded tumor growth in a xenograft tumor zebrafish model. In summary, the discovery of the vitamin A derivative adapalene as a c-MYC inhibitor reveals its potential as an avant-garde treatment for MM.


Prevalence of human papillomavirus cervical infection in an Italian asymptomatic population.
In the last decade many studies have definitely shown that human papillomaviruses (HPVs) are the major cause of cervical carcinogenesis and, in the last few years, HPV testing has been proposed as a new and more powerful tool for cervical cancer screening. This issue is now receiving considerable attention in scientific and non scientific press and HPV testing could be considered the most important change in this field since the introduction of cervical cytology. This paper reports our prevalence data of HPV infection collected in the '90s, while a follow up of these patients is ongoing. For this study we used polymerase chain reaction (PCR) to search HPV DNA sequences in cervical cell scrapings obtained from 503 asymptomatic women attending regular cervical cancer screening program in the city of Genova, Italy. All patients were also submitted to a self-administered, standardized, questionnaire regarding their life style and sexual activity. On the basis of the presence of HPV DNA sequences women were separated into two groups: "infected" and "non infected" and a statistical analysis of the factors potentially associated with the infection group membership was carried out. The infection rate was 15.9% and the most frequent viral type was HPV 16. Our HPV positivity rate (15.9%) was consistent to that reported by other studies on European populations.


Exosomal mir-625-3p derived from hypoxic lung cancer cells facilitates metastasis by targeting SCAI.
Tumor hypoxia is a feature of tumor micro-environment (TME), which provides a suitable environment for tumor cells migration and invasion. However, up to now, the function of exosomes derived from hypoxic tumor cells is still not fully understood. The present study is aimed to explore the underlying mechanisms of lung cancer-secreted exosomes-mediated tumor metastasis under hypoxia. Exosomes were isolated from normoxic or hypoxic NCI-H446 cells. Some characteristic proteins were detected by western blots. Levels of CD63, CD 9 and CD 81 proteins were up-regulated on the membrane of exosomes secreted by hypoxic NCI-H446 cells. Basing on the results from miRNA sequencing, qRT-PCR and wound healing assay, hsa-miR-625-3p was discovered to be accumulated inside hypoxic exosomes and responsible for the metastasis of lung cancer cell. Further experiments from luciferase reporter gene assay demonstrated hsa-miR-625-3p could directly inhibit SCAI expression through binding with its 3'UTR, which suggested the mechanisms by which exosomal hsa-miR-625-3p suppressed tumor cells migration. Exosomal miR-625-3p derived from hypoxic small lung cancer cells accelerated tumor cells migration through inhibiting SCAI directly.


Study on nonlinear constitutive model of skin under compression load over a wide range of strain rates.
In wound ballistics, skin has obvious blocking effect in the biological target penetration of projectiles. An analytical description of skin mechanical properties under compression can set the basis for the numerical simulation and the evaluation of blocking effect. In this study, an improved three-parameter solid visco-elastic model was proposed to describe the skin creep phenomenon. And then combined with Maxwell and Ogden model, a new nonlinear skin constitutive model, consisting of hyper-elastic unit, creep unit and relaxation unit in parallel, was established. Here, we examine the material properties of freshly harvested porcine skin in compression at strain rates from 0.01/s to 4000/s. The model is verified by comparison with the experimental results by our test and that in the literature at different strain rates. It shows that calculated results of the constitutive model agree well with the experiment data at extremely low to high strain rates, which is useful for the description of the heterogeneous, nonlinear viscoelastic, relaxation and creep mechanical response of skin under compression.


Comparative and cumulative quantitative risk assessments on a novel heated tobacco product versus the 3R4F reference cigarette.
Novel tobacco products that heat rather than burn tobacco (heated tobacco products or HTPs) have been shown to produce lower levels of harmful and potentially harmful constituents than conventional combusted cigarettes. The present study uses a quantitative risk assessment approach to compare non-cancer and cancer risk estimates for emissions generated by an HTP with smoke from a reference cigarette (3R4F). Fifty-four analytes were evaluated from the HTP aerosol and the 3R4F cigarette smoke. Emissions were generated using the ISO and the Health Canada Intense smoking regimes. The measured values were extrapolated to define a conservative exposure assumption for per day use and lifetime use based on an estimated maximum usage level of 400 puffs per day i.e., approximately 8 HTP tobacco capsules or 40 combustible cigarettes. Non-cancer and cancer risk estimates were calculated using these exposure assumptions for individual and per health outcome domains based on toxicological reference values derived by regulatory and/or public health agencies. The results of this assessment showed a reduction of non-cancer and cancer risk estimates by more than 90 % for the HTP versus the 3R4F cigarette, regardless of the smoking regime.


Engineered delta ribozymes can simultaneously knock down the expression of the genes encoding uracil phosphoribosyltransferase and hypoxanthine-xanthine-guanine phosphoribosyltransferase in Toxoplasma gondii.
Engineered delta ribozymes or HDV ribozymes were used as gene expression modulators in Toxoplasma gondii. The substrate recognition sequence of the trans-acting delta ribozyme, which was derived from the self-cleaving motif located on the antigenomic strand of the hepatitis delta virus genome, was modified to target T. gondii transcripts. The mRNA encoding two well-documented genes, namely uracil phosphoribosyltransferase (UPRT) and hypoxanthine-xanthine-guanine-phosphoribosyltransferase (HXGPRT) of T. gondii were chosen as the targets for the ribozymes. UPRT and HXGPRT are the operative enzymes of the pyrimidine and purine salvage pathway, respectively. The knockdown of UPRT or HXGPRT expression by the engineered ribozymes resulted in parasites with lower levels of the corresponding transcripts and diminished their abilities to assimilate radioactive pyrimidine or purine analogs. Five out of six engineered ribozymes could cleave their substrates and gave rise to the products, which were detected by primer extension assays. Upon electroporation of individual active ribozymes against the UPRT gene, the uracil incorporation was decreased. Similarly, the ribozymes against HXGPRT caused decreased incorporation of hypoxanthine. When the most active ribozyme against UPRT was used in a combination with the best HXGPRT specific ribozyme, the incorporation of both uracil and hypoxanthine were decreased. Northern blot analysis revealed that the target transcripts were lowered to an undetectable level when specific ribozymes were used, and that the transcripts of the housekeeping gene remained intact. The ribozyme system should thus prove to be effective for the study of gene expression in T. gondii.


A Robust Emphysema Severity Measure Based on Disease Subtypes.
We propose a novel single index for the quantification of emphysema severity based on an aggregation of multiple computed tomographic features evident in the lung parenchyma of smokers. Our goal was to demonstrate that this single index provides complementary information to the current standard measure of emphysema, percent emphysema (percent low attenuation areas [LAA%]), and may be superior in its association with clinically relevant outcomes. The inputs to our algorithm were objective assessments of multiple emphysema subtypes (normal tissue; panlobular; paraseptal; and mild, moderate, and severe centrilobular emphysema). We applied dimensionality reduction techniques to the emphysema quantities to find a space that maximizes the variance of these subtypes. A single emphysema severity index was then derived from a parametrization of the reduced space, and the clinical utility of the measure was explored in a large cross-sectional cohort of 8914 subjects from the COPDGene Study. There was a statistically significant association between the severity index and the LAA%. Subjects with more severe chronic obstructive pulmonary disease (higher Global initiative for Obstructive Lung Disease stage) tended to have a higher computed tomography severity index. Finally, the severity index was associated with clinical outcomes such as lung function and provided a stronger association to these measures than the LAA%. The method provides a single clinically relevant index that can assess the severity of emphysema and that provides information that is complimentary to the more commonly used LAA%.


Cystic nephroma: a case report and review of the literature.
The spectrum of cystic renal neoplasms includes both benign and malignant tumors and the order is as follows: benign multilocular cyst, multilocular cystic renal cell cancer and cystic renal cell cancer. Gross similarities among multicystic tumors of the kidney may cause conflict in the diagnosis and treatment of these lesions. We report a 53-year old male patient who presented with a mild persistent left flank pain and a painful left renal mass. After a series of examinations including abdominal ultrasound, intravenous pyelography and computed tomography, he underwent radical nephrectomy. Microscopic examination of the resected tissue showed the typical characteristics of a cystic nephroma. Immuno-histological staining of the epithelium of the tumour with CK 19 suggested an aberrant renal tubular differentiation. Cystic nephroma is a relatively rare benign lesion of the kidney. Since 1892, only 200 cases have been reported in the international literature. The non-specific clinical findings and the poor contribution of imaging examinations make the preoperative distinction from other cystic renal neoplasias difficult. Final diagnosis can be established in the histopathological examination of the completely rejected tumor in the pathology laboratory.


Modulatory role of adenosine and its receptors in epilepsy: possible therapeutic approaches.
Adenosine is considered to be the brain's endogenous anticonvulsant as many studies have showed and it is responsible for seizure arrest and postictal refractoriness. Alterations in the adenosinergic system (adenosine and its receptors) have been referred by many previous studies indicating that deficiencies or modifications in the function of this purinergic system may contribute to epileptogenesis. Due to this emerging implication of adenosine in the managing of seizures, a new field of adenosine-based therapies has been introduced including adenosine itself, adenosine receptor agonists and antagonists and adenosine kinase inhibitors. The method with the least side effects (heart rate, blood pressure, temperature or even sedation) is being quested including intracerebral implantation of adenosine releasing cells or devices.


Molecular analysis of intrafamiliar transmission of Moraxella catarrhalis.
The possible intrafamiliar transmission of Moraxella catarrhalis was evaluated in 3 pairs between children and their parents, and 8 pairs between siblings from 11 families. Of the 22 isolates, all were found producing beta-lactamase. Molecular typing by pulsed-field gel electrophoresis (PFGE) with Not I and Spe I showed that the PFGE patterns in 2 of 3 pairs between children and their parents, and 4 of 8 pairs between siblings were indistinguishable and those of the remaining pairs were different. These data indicate a possible high rate of intrafamiliar transmission of M. catarrhalis.


Stavudine, nevirapine and ritonavir in stable antiretroviral therapy-experienced children with human immunodeficiency virus infection.
The efficacy and tolerance of switching from zidovudine (ZDV) and lamivudine (3TC) in clinically stable HIV-infected children with incomplete viral suppression to stavudine (d4T), nevirapine (NVP) and ritonavir (RTV) has not been determined. Aim. To evaluate the safety, tolerance, antiviral activity and immunologic changes after the change to a three drug combination. During a clinical trial in which HIV-infected antiretroviral-experienced children were initially randomized to receive d4T/RTV, ZDV/3TC/RTV or ZDV/3TC (Step 1), 48 children who had HIV RNA > or = 10,000 copies/ml after > or = 12 weeks of ZDV/3TC therapy in Step 1 were switched to d4T/NVP/RTV in Step 2. The proportion of children receiving therapy with HIV RNA < or = 400 copies/ml at Study Weeks 24 and 48 receiving d4T/NVP/RTV in Step 2 were compared with children receiving RTV-containing regimens in Step 1. At 24 weeks of treatment with d4T/NVP/RTV in Step 2, 48% (23 of 48) of children had HIV RNA < or = 400 copies/ml compared with 34% (31 of 92) and 47% (44 of 93) receiving d4T/RTV or ZDV/3TC/RTV for 24 weeks in Step 1; at 48 weeks virologic response was 44, 27 and 42% in Step 2 d4T/NVP/RTV, Step 1 d4T/RTV and Step 1 ZDV/3TC/RTV arms, respectively. A delay of 7 to 12 months in the initiation of protease inhibitor-containing combination therapy in children receiving dual nucleoside analogue therapy did not adversely affect the RNA response during the first 48 weeks of treatment.


Importance of gender for the display of social impairment in pairbond disrupted gerbils.
Gerbils form stable male/female pairbonds. Disruption of these has been shown to have consequences for subsequent social behaviour. The response in males is typically a decrease in the initiation of social contacts, whilst females typically freeze when approached. The current studies examined the influence on these phenomena of the gender of the stimulus animal. Data revealed that a similar increase in immobile-in-contact was seen in pairbond disrupted females regardless of whether they were interacting with males or females. By contrast, reductions in social behaviour were only seen in males when interacting with other males. Social investigation was increased when interacting with females. These results are interpreted in the context of gerbil social organisation in the wild. That is, whilst females continue to represent a possibility for opportunistic mating, decreased social investigation and offense directed towards other males indicates a reduced capacity for territorial defence. Together, present findings demonstrate that there are clear sex-differences in the behavioural effects of pairbond disruption in gerbils but that it is only in males that the expression of these effects is influenced by the sex of the stimulus animal.


Semantics and the multisensory brain: how meaning modulates processes of audio-visual integration.
By using meaningful stimuli, multisensory research has recently started to investigate the impact of stimulus content on crossmodal integration. Variations in this respect have often been termed as "semantic". In this paper we will review work related to the question for which tasks the influence of semantic factors has been found and which cortical networks are most likely to mediate these effects. More specifically, the focus of this paper will be on processing of object stimuli presented in the auditory and visual sensory modalities. Furthermore, we will investigate which cortical regions are particularly responsive to experimental variations of content by comparing semantically matching ("congruent") and mismatching ("incongruent") experimental conditions. In this context, recent neuroimaging studies point toward a possible functional differentiation of temporal and frontal cortical regions, with the former being more responsive to semantically congruent and the latter to semantically incongruent audio-visual (AV) stimulation. To account for these differential effects, we will suggest in the final section of this paper a possible synthesis of these data on semantic modulation of AV integration with findings from neuroimaging studies and theoretical accounts of semantic memory.