Building a synthesis of economic costs of biological invasions in New Zealand.
Biological invasions are a major component of anthropogenic environmental change, incurring substantial economic costs across all sectors of society and ecosystems. There have been recent syntheses of costs for a number of countries using the newly compiled InvaCost database, but New Zealand-a country renowned for its approach to invasive species management-has so far not been examined. Here we analyse reported economic damage and management costs incurred by biological invasions in New Zealand from 1968 to 2020. In total, US$69 billion (NZ$97 billion) is currently reported over this ∼50-year period, with approximately US$9 billion of this considered highly reliable, observed (c.f. projected) costs. Most (82%) of these observed economic costs are associated with damage, with comparatively little invested in management (18%). Reported costs are increasing over time, with damage averaging US$120 million per year and exceeding management expenditure in all decades. Where specified, most reported costs are from terrestrial plants and animals, with damages principally borne by primary industries such as agriculture and forestry. Management costs are more often associated with interventions by authorities and stakeholders. Relative to other countries present in the InvaCost database, New Zealand was found to spend considerably more than expected from its Gross Domestic Product on pre- and post-invasion management costs. However, some known ecologically (c.f. economically) impactful invasive species are notably absent from estimated damage costs, and management costs are not reported for a number of game animals and agricultural pathogens. Given these gaps for known and potentially damaging invaders, we urge improved cost reporting at the national scale, including improving public accessibility through increased access and digitisation of records, particularly in overlooked socioeconomic sectors and habitats. This also further highlights the importance of investment in management to curtail future damages across all sectors.


Spatial filtering of MEG signals for user-specified spherical regions.
We introduce a spatial filtering method in the spherical harmonics domain for constraining magnetoencephalographic (MEG) multichannel measurements to any user-specified spherical region of interest (ROI) inside the head. The method relies on a linear transformation of the signal space separation inner coefficients that represent the MEG signal generated by sources located inside the head. The spatial filtering is achieved effectively by constructing a spherical harmonics basis vector that is dependent on the center of the targeted ROI and it does not require any discrete division of the headspace into grids like the traditional MEG spatial filtering approaches. The validation and the performance of the method are demonstrated through both simulated and actual bilateral auditory-evoked data experiments.


Neurotrophic Properties of Silexan, an Essential Oil from the Flowers of Lavender-Preclinical Evidence for Antidepressant-Like Properties.
Silexan, a special essential oil from flowering tops of lavandula angustifolia, is used to treat subsyndromal anxiety disorders. In a recent clinical trial, Silexan also showed antidepressant effects in patients suffering from mixed anxiety-depression (ICD-10 F41.2). Since preclinical data explaining antidepressant properties of Silexan are missing, we decided to investigate if Silexan also shows antidepressant-like effects in vitro as well as in vivo models. We used the forced swimming test (FST) in rats as a simple behavioral test indicative of antidepressant activity in vivo. As environmental events and other risk factors contribute to depression through converging molecular and cellular mechanisms that disrupt neuronal function and morphology-resulting in dysfunction of the circuitry that is essential for mood regulation and cognitive function-we investigated the neurotrophic properties of Silexan in neuronal cell lines and primary hippocampal neurons. The antidepressant activity of Silexan (30 mg/kg BW) in the FST was comparable to the tricyclic antidepressant imipramine (20 mg/kg BW) after 9-day treatment. Silexan triggered neurite outgrowth and synaptogenesis in 2 different neuronal cell models and led to a significant increase in synaptogenesis in primary hippocampal neurons. Silexan led to a significant phosphorylation of protein kinase A and subsequent CREB phosphorylation. Taken together, Silexan demonstrates antidepressant-like effects in cellular as well as animal models for antidepressant activity. Therefore, our data provides preclinical evidence for the clinical antidepressant effects of Silexan in patients with mixed depression and anxiety.


The miR-1906 mimic attenuates bone loss in osteoporosis by down-regulating the TLR4/MyD88/NF-κB pathway.
In this study, the ability of microRNA-1906 (miR-1906) to attenuate bone loss in osteoporosis was evaluated by measuring the effects of a miR-1906 mimic and inhibitor on the cellular toxicity and cell viability of MC3T3-E1 cells. Bone marrow-derived macrophage (BMM) cells were isolated from female mice, and tartrate-resistant acid phosphatase signalling was performed in miR-1906 mimic-treated, receptor-activated nuclear factor kappa-B (NF-κB) ligand (RANKL)-induced osteoclasts. In-vivo, osteoporosis was induced by ovariectomy (OVX). Rats were treated with 500 nmol/kg of the miR-1906 mimic via intrathecal administration for 10 consecutive days following surgery. The effect of the miR-1906 mimic on bone mineral density (BMD) in OVX rats was observed in the whole body, lumbar vertebrae and femur. Levels of biochemical parameters and cytokines in the serum of miR-1906 mimic-treated OVX rats were analysed. The mRNA expression of toll-like receptor 4 (TLR4), myeloid differentiation primary response 88 (MyD88), p-38 and NF-κB in tibias of osteoporotic rats (induced by ovariectomy) was observed using quantitative reverse-transcription polymerase chain reaction. Treatment with the miR-1906 mimic reduced cellular toxicity and enhanced the cell viability of MC3T3-E1 cells. Furthermore, osteoclastogenesis in miR-1906 mimic-treated, RANKL-induced osteoclast cells was reduced, whereas the BMD in the miR-1906 mimic-treated group was higher than in the OVX group of rats. Treatment with the miR-1906 mimic also increased levels of biochemical parameters and cytokines in the serum of ovariectomised rats. Finally, mRNA expression levels of TLR4, MyD88, p-38 and NF-κB were lower in the tibias of miR-1906 mimic-treated rats than in those of OVX rats. In conclusion, the miR-1906 mimic reduces bone loss in rats with ovariectomy-induced osteoporosis by regulating the TLR4/MyD88/NF-κB pathway.


Screening mammography referral rates for women ages 50 to 69 years by recently-licensed family physicians: physician and practice environment correlates.
Physician mammography referral remains below optimal levels despite a long-standing recommendation that all women ages 50 to 69 years receive screening mammography every 1 to 2 years. The purpose of this study was to determine physician and practice environment predictors of family physicians' screening mammography referral rates to women ages 50-69 years. A cohort of 498 recently-licensed family physicians was followed for 18-months of incipient medical practice. The referral rate was the percentage of new clinically eligible women patients seen in a primary care context who had a screening mammogram ordered by the study physician. Mammograms and independent variables were identified from physician claims to a Canadian universal health insurance agency. The effects of factors in a conceptual framework were assessed using multivariable linear regression. Correlates of higher mammography referral rates were female gender, better general prevention knowledge, the combination of comprehensive inquiry and continuity care, lower patient volume, and lower shared primary care (multivariable model R(2) = 0.47). Factors belonging to practice environment explained more of the observed variance than did physician characteristics. Mammography referral varies enormously and almost half of the variance is explained by physician characteristics and practice preferences. Higher mammography referral is observed in practices with more comprehensive and continuity care.


Rapid mobilization of a virtual pediatric chronic pain clinic in Canada during the COVID-19 pandemic.
Studies have been conducted describing the potential for using virtual care software during disasters and public health emergencies. However, limited data exist on ways in which the Canadian health care system utilizes virtual care during disasters or public health emergencies. Due to the need for social distancing and reduction of nonessential ambulatory services during the COVID-19 pandemic, the SickKids Chronic Pain Clinic sought to transition care delivery from in person to virtual. The virtual clinic aimed to reduce risks associated with physical contact and environmental exposure without reducing access to care itself. Harnessing of various digital tools including Ontario Telemedicine Network Guestlink, Zoom, and Microsoft Teams. The Chronic Pain Clinic Team worked together to communicate with patients and families, schedule virtual visits, establish remote access to clinical data collection tools, digitize the after-visit summary, and add resources on pain self-management to the clinic's website. The Chronic Pain Clinic successfully transitioned all clinic appointments (multidisciplinary and individual; 77 appointments) over a 2-week period to virtual care. Virtual clinics did not surpass the usual time taken pre-COVID-19, suggesting that the clinic workflow was readily adaptable to virtual care. Access to quality virtual care is essential to prevent chronic pain from taking a toll on the lives of patients and families. Rapid establishment of a virtual clinic without gaps in service delivery to patients is possible given institutional support and a team culture centered around collaboration and flexibility.


[The role of vasoactive peptid in lower limbs chronic arterial insufficiency treatment].
Atherosclerosis has lead to lower limbs chronic occlusive arterial disease in 80-90 % of cases. The progress of atherosclerosis is vascular wall self-regulation process violation, and its correction can be made by completion of missing endogenous peptides. assessment of the possibility to use the vasoactive peptid of Vezugen as monotherapy in patients underwent surgery for chronic lower limbs ischemia. The results of surgical treatment of lower limbs chronic arterial insufficiency in 41 patients were studied. A comparative analysis of clinical and ultrasonic parameters of blood flow in the lower limbs before and after monotherapy was undertaken. Blood flow in the lower limbs after treatment by Vezugen monotherapy significantly improves both on clinical and on the ultrasonic parameters.


Rate of forcing and the forecastability of critical transitions.
Critical transitions are qualitative changes of state that occur when a stochastic dynamical system is forced through a critical point. Many critical transitions are preceded by characteristic fluctuations that may serve as model-independent early warning signals, implying that these events may be predictable in applications ranging from physics to biology. In nonbiological systems, the strength of such early warning signals has been shown partly to be determined by the speed at which the transition occurs. It is currently unknown whether biological systems, which are inherently high dimensional and typically display low signal-to-noise ratios, also exhibit this property, which would have important implications for how ecosystems are managed, particularly where the forces exerted on a system are anthropogenic. We examine whether the rate of forcing can alter the strength of early warning signals in (1) a model exhibiting a fold bifurcation where a state shift is driven by the harvesting of individuals, and (2) a model exhibiting a transcritical bifurcation where a state shift is driven by increased grazing pressure. These models predict that the rate of forcing can alter the detectability of early warning signals regardless of the underlying bifurcation the system exhibits, but that this result may be more pronounced in fold bifurcations. These findings have important implications for the management of biological populations, particularly harvested systems such as fisheries, and suggest that knowing the class of bifurcations a system will manifest may help discriminate between true-positive and false-positive signals.


Induction of catalase, alpha, and microsomal glutathione S-transferase in CYP2E1 overexpressing HepG2 cells and protection against short-term oxidative stress.
Induction of cytochrome P450 2E1 (CYP2E1) and the formation of reactive oxygen species (ROS) appear to be one of the mechanisms by which ethanol is hepatotoxic. Glutathione peroxidase and catalase detoxify H(2)O(2). Glutathione S-transferases (GST) provide protection from membrane lipid peroxidation, have GSH peroxidase activity, and reduce lipid hydroperoxides. Previous studies showed an up-regulation of GSH synthesis in CYP2E1 expressing HepG2 cells; this finding prompted an evaluation of the levels of other antioxidant exzymes. In CYP2E1 expressing cells, the alpha and microsomal GST messenger RNA (mRNA) are increased by 4- and 2-fold, respectively, and catalase protein and mRNA is increased by 2-fold. The increase in alpha and microsomal GST mRNA correlates with increased total enzymatic activity and is caused by increased transcription as evidenced by run-on transcription assays. In HepG2 cells transfected to express a different cytochrome P450, CYP3A4, there was an increase in alpha GST. However, in contrast to the CYP2E1 expressing cells, neither microsomal GST nor catalase were induced, suggesting some specificity for CYP2E1. In agreement with an increased antioxidant defense system, the sensitivity to added prooxidants such as menadione, antimycin A, H(2)O(2), and 4-hydroxynonenal was lower in the CYP2E1 expressing cells as compared with control cells. In conclusion, overexpression of CYP2E1 in HepG2 cells, besides elevating total GSH levels, also induces expression of catalase and alpha and microsomal GST. This induction confers resistance to the cells against several prooxidants and is suggested to reflect an adaptive response by the cells against CYP2E1-mediated oxidative stress.


[Determination of peroxidase positive cells in semen: is it a secure parameter for the diagnosis of silent genital infections?].
The presence of leukocytes, detected by peroxidase test in semen, can be a good indicator of infections in the male genital tract. Peroxidase positive cells have been positively correlated with elevated values of elastase, one of the major proteases liberated by granulocytes at the inflammation place. However, seminal granulocytes may not be adequately detected by the peroxidase test in comparison with immunological methods. To correlate the determination of peroxidase positive cells with the elastase level in the seminal plasma. Seminal plasma from 64 patients with a high number of round cells (> 106/ml) in semen, was studied. Correlation analysis was done using the Pearson correlation coefficient. No correlation between the level of granulocyte elastase and the number of peroxidase positive cells (r = 0.2237, p > 0.05), or even the number of round cells (r = 0.03934, p > 0.05) was observed. Our results suggest that the determination of peroxidase positive cells is not a reliable indicator of leukocytes in the seminal plasma and their absence do not discard a silent genital tract infection.


Basophil production.
Factors influencing basophil production from the bone marrow of ovalbumin (OA)-sensitized guinea pigs have been examined in vitro. Autologous co-cultures of marrow and spleen cells from OA-immune animals contained significantly higher numbers of basophils after 7 d of liquid culture in the presence of OA, compared with control co-cultures or with marrow cultures alone (P < 0.005). Basophils increased in co-culture as the number of spleen cells added to a fixed number of marrow cells was increased from 0.10 to 2.5 x 10(6)/ml; at each spleen cell concentration, the presence of OA significantly enhanced basophil production in vitro when compared with unstimulated co-cultures. There was no basophil production from spleen cell suspensions cultured in the absence of autologous marrow cells. Conditioned media (CM) prepared from OA-stimulated spleen cells of OA-treated animals (CM-OA) caused a specific stimulation of basophil production from normal guinea pig bone marrow cells in liquid cultures (P < 0.01). Phytohemagglutinin (PHA)- and pokeweed mitogen-stimulated CM (CM-PHA, CM-pokeweed mitogen) nonspecifically enhanced normal basophilopoiesis, causing dose-dependent increases in basophils and histamine in vitro. CM-OA and CM-PHA also preferentially stimulated formation of neutrophil-macrophage colony-forming units in semisolid methylcellulose cultures.CM-PHA prepared from T cell-enriched splenic cell suspensions contained basophil-stimulating activity, whereas T cell-depleted CM-PHA activity did not exceed control values (P < 0.01). Preliminary characterization of CM-PHA revealed that basophil-stimulating activity was predominantly heat stable and nondialyzable. These results demonstrate OA-specific, as well as mitogen-dependent T-cell regulation of guinea pig basophilopoiesis in vitro. The data are compatible with the existence of a specific "basophilopoietin" in CM derived from guinea pig splenic T cells.


Reconstituted human upper airway epithelium as 3-d in vitro model for nasal polyposis.
Primary human airway epithelial cells cultured in an air-liquid interface (ALI) develop a well-differentiated epithelium. However, neither characterization of mucociliar differentiation overtime nor the inflammatory function of reconstituted nasal polyp (NP) epithelia have been described. 1st) To develop and characterize the mucociliar differentiation overtime of human epithelial cells of chronic rhinosinusitis with nasal polyps (CRSwNP) in ALI culture system; 2nd) To corroborate that 3D in vitro model of NP reconstituted epithelium maintains, compared to control nasal mucosa (NM), an inflammatory function. Epithelial cells were obtained from 9 NP and 7 control NM, and differentiated in ALI culture for 28 days. Mucociliary differentiation was characterized at different times (0, 7, 14, 21, and 28 days) using ultrastructure analysis by electron microscopy; ΔNp63 (basal stem/progenitor cell), β-tubulin IV (cilia), and MUC5AC (goblet cell) expression by immunocytochemistry; and mucous (MUC5AC, MUC5B) and serous (Lactoferrin) secretion by ELISA. Inflammatory function of ALI cultures (at days 0, 14, and 28) through cytokine (IL-8, IL-1β, IL-6, IL-10, TNF-α, and IL-12p70) and chemokine (RANTES, MIG, MCP-1, IP-10, eotaxin-1, and GM-CSF) production was analysed by CBA (Cytometric Bead Array). In both NP and control NM ALI cultures, pseudostratified epithelium with ciliated, mucus-secreting, and basal cells were observed by electron microscopy at days 14 and 28. Displaying epithelial cell re-differentation, β-tubulin IV and MUC5AC positive cells increased, while ΔNp63 positive cells decreased overtime. No significant differences were found overtime in MUC5AC, MUC5B, and lactoferrin secretions between both ALI cultures. IL-8 and GM-CSF were significantly increased in NP compared to control NM regenerated epithelia. Reconstituted epithelia from human NP epithelial cells cultured in ALI system provides a 3D in vitro model that could be useful both for studying the role of epithelium in CRSwNP while developing new therapeutic strategies, including cell therapy, for CRSwNP.


[Development and morphofunctional characterization of the osteoblastic phenotype in cell culture in vitro].
The objective of this research was to study osteogenic properties of cultured rabbit bone marrow stromal cells, newborn rat cranium bone cells and rat osteocarcoma ROS 17-2/8 cells. For this purpose cytochemical reaction for alkaline phosphatase was performed by the Lowry method, mineral deposition was assessed by staining of the cultures after von Kossa. Cranium bone cells were shown to synthesize alkaline phosphatase (34 +/- 7 nmol/min/10(6) cells), the matrix mineralization being found. Bone marrow stromal cells displayed a lower activity alkaline phosphatase level than did cranium bone cells (4 +/- 0.6 nmol/min/10(6) cells). However, cell cultivation in the presence of dexamethasone in the medium (10(-8) M) induced a higher activity of alkaline phosphatase (9 +/- 1 nmol/min/10(6) cells), mineralization of the extracellular matrix being the case. The highest level of alkaline phosphatase activity was found for ROS 17-2/8 cells (60 +/- 12 nmol/min/10(6) cells) but no matrix mineralization was determined. According to these data, matrix calcification and formation of bone-like nodules are the most important properties of osteoblastic differentiation in vitro.


Chlorogenic acid: A potent molecule that protects cardiomyocytes from TNF-α-induced injury via inhibiting NF-κB and JNK signals.
The traditional Chinese herb Lonicerae Japonicae Flos has shown significant clinical benefits in the treatment of heart failure, but the mechanism remains unclear. As the main active ingredient found in the plasma after oral administration of Lonicerae Japonicae Flos, chlorogenic acid (CGA) has been reported to possess anti-inflammatory, anti-oxidant and anti-apoptosis function. We firstly confirmed the cardioprotective effects of CGA in transverse aortic constriction (TAC)-induced heart failure mouse model, through mitigating the TNF-α-induced toxicity. We further used TNF-α-induced cardiac injury in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) to elucidate the underlying mechanisms. CGA pre-treatment could reverse TNF-α-induced cellular injuries, including improved cell viability, increased mitochondrial membrane potential and inhibited cardiomyocytes apoptosis. We then examined the NF-κB/p65 and major mitogen-activated protein kinases (MAPKs) signalling pathways involved in TNF-α-induced apoptosis of hiPSC-CMs. Importantly, CGA can directly inhibit NF-κB signal by suppressing the phosphorylation of NF-κB/p65. As for the MAPKs, CGA suppressed the activity of only c-Jun N-terminal kinase (JNK), but enhanced extracellular signal-regulated kinase1/2 (ERK1/2) and had no effect on p38. In summary, our study revealed that CGA has profound cardioprotective effects through inhibiting the activation of NF-κB and JNK pathway, providing a novel therapeutic alternative for prevention and treatment of heart failure.


Coronary artery dynamics in vivo.
There is considerable evidence that the localization and evolution of vascular disease are mediated, at least in part, by mechanical factors. The mechanical environment of the coronary arteries, which are tethered to the beating heart, is influenced by cardiac motion; the motion of the vessels must be described quantitatively to characterize fully the mechanical forces acting on and in the vessel wall. Several techniques that have been used to characterize coronary artery dynamics from biplane cineangiograms are described and illustrated. There is considerable variability in dynamic geometric parameters from site to site along a vessel, between the right and left anterior descending arteries, and among individuals, consistent with the hypotheses that variations in stresses mediated by geometry and dynamics affect the localization of atherosclerosis and individual risk of coronary heart disease. The few frankly atherosclerotic vessels that have been examined exhibit high torsions in the neighborhood of lesions, an observation which may have etiologic or diagnostic implications.


Mycoplasma pulmonis infection with regard to embryo freezing and hysterectomy derivation.
Eggs taken from the oviducts of mice, inoculated 3 weeks previously with Mycoplasma pulmonis in the peritoneal cavity, were shown to be contaminated, and mycoplasmas were not eradicated by washing the eggs three times. Zona-free eggs were also infected. Embryos cultured for 24 hours in medium M16 were clear of infection. Sperm from infected males was not significantly worse in the fertilization of uninfected eggs.


Enterotoxigenic Escherichia coli: Orchestrated host engagement.
The enterotoxigenic Escherichia coli are a pervasive cause of serious diarrheal illness in developing countries. Presently, there is no vaccine to prevent these infections, and many features of the basic pathogenesis of these organisms remain poorly understood. Until very recently most pathogenesis studies had focused almost exclusively on a small subset of known "classical" virulence genes, namely fimbrial colonization factors and the heat-labile (LT) and heat stable (ST) enterotoxins. However, recent investigations of pathogen-host interactions reveal a surprisingly complex and intricately orchestrated engagement involving the interplay of classical and "novel" virulence genes, as well as participation of genes highly conserved in the E. coli species. These studies may inform further rational approaches to vaccine development for these important pathogens.


Perceptual and arterial occlusion responses to very low load blood flow restricted exercise performed to volitional failure.
Studies examining perceptual and arterial occlusion responses between blood flow restricted exercise and high load exercise often prescribe an arbitrary number of repetitions, making it difficult for direct comparisons. Therefore, the purpose of this study was to compare these protocols when performed to volitional failure. Individuals completed four exercise conditions varying in load and pressure: (i) 15% 1RM; no restrictive pressure, (ii) 15% 1RM; 40% arterial occlusion pressure, (iii) 15% 1RM; 80% arterial occlusion pressure, and (iv) 70% 1RM; no pressure. Four sets of knee extension exercises were performed until volitional failure (or until 90 repetitions per set) was completed. A total of 23 individuals completed the study. While all conditions increased arterial occlusion pressure, the greatest increases (~30%) were observed in the blood flow restriction conditions. All lower load conditions resulted in greater RPE and discomfort than that of the high load condition, but only discomfort was increased further when adding blood flow restriction. High load exercise will likely be perceived more favourably than lower load exercise to volitional failure; however, those who are incapable or unwilling to lift heavier loads may use blood flow restriction to help reduce the volume needed to reach volitional failure, although this will likely increase discomfort.


Temporal regulation of axonal repulsion by alternative splicing of a conserved microexon in mammalian Robo1 and Robo2.
Proper connectivity of the nervous system requires temporal and spatial control of axon guidance signaling. As commissural axons navigate across the CNS midline, ROBO-mediated repulsion has traditionally been thought to be repressed before crossing, and then to become upregulated after crossing. The regulation of the ROBO receptors involves multiple mechanisms that control protein expression, trafficking, and activity. Here, we report that mammalian ROBO1 and ROBO2 are not uniformly inhibited precrossing and are instead subject to additional temporal control via alternative splicing at a conserved microexon. The NOVA splicing factors regulate the developmental expression of ROBO1 and ROBO2 variants with small sequence differences and distinct guidance activities. As a result, ROBO-mediated axonal repulsion is activated early in development to prevent premature crossing and becomes inhibited later to allow crossing. Postcrossing, the ROBO1 and ROBO2 isoforms are disinhibited to prevent midline reentry and to guide postcrossing commissural axons to distinct mediolateral positions.


Drug repositioning for gynecologic tumors: a new therapeutic strategy for cancer.
The goals of drug repositioning are to find a new pharmacological effect of a drug for which human safety and pharmacokinetics are established and to expand the therapeutic range of the drug to another disease. Such drug discovery can be performed at low cost and in the short term based on the results of previous clinical trials. New drugs for gynecologic tumors may be found by drug repositioning. For example, PPAR ligands may be effective against ovarian cancer, since PPAR activation eliminates COX-2 expression, arrests the cell cycle, and induces apoptosis. Metformin, an antidiabetic drug, is effective for endometrial cancer through inhibition of the PI3K-Akt-mTOR pathway by activating LKB1-AMPK and reduction of insulin and insulin-like growth factor-1 due to AMPK activation. COX-2 inhibitors for cervical cancer may also be examples of drug repositioning. PGE2 is induced in the arachidonate cascade by COX-2. PGE2 maintains high expression of COX-2 and induces angiogenic factors including VEGF and bFGF, causing carcinogenesis. COX-2 inhibitors suppress these actions and inhibit carcinogenesis. Combination therapy using drugs found by drug repositioning and current anticancer drugs may increase efficacy and reduce adverse drug reactions. Thus, drug repositioning may become a key approach for gynecologic cancer in drug discovery.


Sliding malar bone augmentation technique with a high le fort I surgically assisted rapid maxillary expansion.
The purpose of this report is to evaluate the effectiveness of a high Le Fort I osteotomy design, including the malar bones, which allows segment sliding over the zygoma and forces the osteotomized segment to move forward with distraction. Two patients (male, 23-and 30-year-old) with malar deficiency underwent high Le Fort I osteotomy and surgically assisted rapid maxillary expansion procedure was followed. Records were taken before and 6 months after surgery for comparison, including intra and extra oral photographs and three-dimensional cone-beam computed tomography (CBCT) images. The bone malar width and bone malar depth changings in malar region were evaluated. Preoperative and postoperative CBCT images and clinical views of the patients showed forward movement of the malar region.


Metabolic changes in Asian Muslim pregnant mothers observing the Ramadan fast in Britain.
1. Metabolic changes associated with Ramadan fasting were studied in eleven Asian pregnant mothers. This was compared with a group of control mothers undergoing a normal physiological fast. 2. At the end of the Ramadan fast day there was a significant fall in glucose, insulin, lactate and carnitine, and a rise in triglyceride, non-esterified fatty acid and 3-hydroxybutyrate. When compared with the control group, none of the Ramadan mothers had a completely normal set of biochemical values at the end of the fast day. 3. Pregnancy outcome in the two groups was comparable. 4. We are wary of the metabolic departures from normal observed in the Ramadan fasting mothers. If asked we advise mothers to take up the dispensation from fasting during pregnancy which is allowed.


Conventional Wisdom versus Actual Outcomes: Challenges in the Conduct of an Ebola Vaccine Trial in Liberia during the International Public Health Emergency.
Clinical trials are challenging endeavors. Planning and implementing an investigational vaccine trial in Liberia, in the midst of an Ebola virus disease (EVD) epidemic that World Health Organization classified a public health emergency of international concern, presented extraordinary challenges. Normally, years of preparation and a litany of tasks lay the groundwork for a successful, randomized, blinded, placebo-controlled trial focused on safety and efficacy. Difficult research settings, unpredictable events, and other unique circumstances can add complexity. The setting in Liberia was especially problematic due to an infrastructure still badly damaged following a lengthy civil war and a very fragile health-care system that was further devastated by the EVD outbreak. The Partnership for Research on Vaccines in Liberia I EVD vaccine trial was planned and implemented in less than 3 months by a Liberian and U.S. research partnership, and its Phase II substudy was fully enrolled 3 months later. Contrasting conventional wisdom with trial outcomes offers an opportunity to compare early assumptions, barriers encountered, and adaptive strategies used, with end results. Understanding what was learned can inform future trial responses when disease outbreaks, especially in resource-poor locations with minimal infrastructure, pose a significant threat to public health.


Light focusing at metallic annular slit structure coated with dielectric layers.
We report the focusing of a normally incident plane wave of 405 nm through a Ag/dielectric annular ring structure, using finite-difference time domain analysis. We first study the dependency of the focusing efficiency on slit width when the incident wave is transmitted through a single ring whose slit is filled with a dielectric. Then, light focusing by the multiple-ring structure is investigated as a function of the dielectric thickness. It is observed that the focusing is tunable between near-field and quasi-far-field regimes in the Ag/dielectric layered annular ring structure. Also, the focal intensities are remarkably enhanced by the addition of the dielectric layer, showing a Fabry-Perot-like resonance with respect to the thickness of the dielectric layer. The controllable near-field and far-field focusing offers more flexibility for applications of future nano-optic devices.


Wellbeing measures for workers: a systematic review and methodological quality appraisal.
Increasing attention on workplace wellbeing and growth in workplace wellbeing interventions has highlighted the need to measure workers' wellbeing. This systematic review sought to identify the most valid and reliable published measure/s of wellbeing for workers developed between 2010 to 2020. Electronic databases Health and Psychosocial Instruments, APA PsycInfo, and Scopus were searched. Key search terms included variations of [wellbeing OR "well-being"] AND [employee* OR worker* OR staff OR personnel]. Studies and properties of wellbeing measures were then appraised using Consensus-based Standards for the selection of health Measurement Instruments. Eighteen articles reported development of new wellbeing instruments and eleven undertook a psychometric validation of an existing wellbeing instrument in a specific country, language, or context. Generation and pilot testing of items for the 18 newly developed instruments were largely rated 'Inadequate'; only two were rated as 'Very Good'. None of the studies reported measurement properties of responsiveness, criterion validity, or content validity. The three instruments with the greatest number of positively rated measurement properties were the Personal Growth and Development Scale, The University of Tokyo Occupational Mental Health well-being 24 scale, and the Employee Well-being scale. However, none of these newly developed worker wellbeing instruments met the criteria for adequate instrument design. This review provides researchers and clinicians a synthesis of information to help inform appropriate instrument selection in measurement of workers' wellbeing. https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=79044, identifier: PROSPERO, CRD42018079044.


Standards for device implantation and follow-up: personnel, equipment, and facilities: results of the European Heart Rhythm Association Survey.
Cardiac device implantation is the most common of all invasive cardiac electrophysiological procedures. Over 250 000 devices are implanted each year in Europe. The purpose of this European Heart Rhythm Association (EHRA) survey was to assess the facilities, personnel, and protocols of members of the EHRA electrophysiology (EP) research network involved in device implantation. There were 68 responses to the questionnaire. The survey responses were mainly (84%) from medium- to high-volume device implanting centres, performing >200 implants per year, with over 50% performing >400 implants per year. Most consultants are male (85%), half of all centres had no female consultants, and only one in six had more than one female consultant. There is trend towards specialization in device implantation. The combination of device implantation and EP is still common (76% of all centres) but only 34% of centres have consultants performing device implantation and coronary intervention. Moreover, 23% of centres have all device implantation performed by consultants who do not perform any other types of procedure. Cardiac device implantation as a day case is the planned admission for routine elective device implantation in 30% of hospitals, 47% of hospitals have a single night stay, and 23% of hospitals have admission durations of two or more nights. Device implantation is available as a 24 h service, 365 days a year in 38% of hospitals. The commonest other model was as a daytime service on weekdays in 45% of hospitals.


Benzene solubility in ionic liquids: working toward an understanding of liquid clathrate formation.
The solubility of benzene in 15 imidazolium, pyrrolidinium, pyridinium, and piperidinium ionic liquids has been determined; the resulting, benzene-saturated ionic liquid solutions, also known as liquid clathrates, were examined with (1) H and (19) F nuclear magnetic resonance spectroscopy to try and understand the molecular interactions that control liquid clathrate formation. The results suggest that benzene interacts primarily with the cation of the ionic liquid, and that liquid clathrate formation (and benzene solubility) is controlled by the strength of the cation-anion interactions, that is, the stronger the cation-anion interaction, the lower the benzene solubility. Other factors that were determined to be important in the final amount of benzene in any given liquid clathrate phase included attractive interactions between the anion and benzene (when significant), and larger steric or free volume demands of the ions, both of which lead to greater benzene solubility.


Case report of congenital tricuspid insufficiency.
This is a report of a 16 years old male with moderate mitral disease, probably rheumatic, and with severe tricuspid insufficiency which at surgery appeared to be a congenital malformation of the tricuspid valve (absence of the anterior leaflet). A tricuspid heterograft was successfully inserted. The symptoms of congenital tricuspid insufficiency are discussed and this affection is differentiated from other causes of tricuspid insufficiency.


Inhibition of Na+,K+-stimulated ATPase in the cochlea of the guinea pig. A potential cause of disturbed inner ear function in terminal renal failure.
The frequent occurrence of sensorineural hearing loss in patients with chronic renal insufficiency prompted us to study the influence of chronic renal failure upon Na+,K+-ATPase in the inner ear of guinea pigs. Na+,K+-activated ATPase was defined as the ouabain-sensitive part of total ATPase, the activity of which was obtained in the presence of sodium, potassium and magnesium. A significant reduction of Na+,K+-activated ATPase was found in the inner ear of uremic animals. Such inhibition could be demonstrated as early as 12 hours after subtotal nephrectomy. An inverse correlation was found between serum creatinine levels and Na+,K+-activated ATPase. A similar inhibition of Na+,K+-activated ATPase in uremia is also found in other tissues (erythrocytes, renal tubules, intestinal mucosal cells, sarcolemma). Na+,K+-ATPase in the cochlea plays a key role in the maintenance of cochlear cationic gradients. It is suggested that inhibition of this enzyme system may contribute to the inner ear dysfunction in uremia.


Production of a monoclonal antibody to Vibrio cholerae non-O1 heat-stable enterotoxin (ST) which is cross-reactive with Yersinia enterocolitica ST.
A monoclonal antibody (MAb) against synthetic heat-stable enterotoxin of Vibrio cholerae non-O1 (NAG-ST) was produced. The MAb, namely, 2F, belonged to the immunoglobulin G1 class. Ascitic fluid drawn from pristane-primed BALB/c mice injected with a 2F-producing clone demonstrated anti-NAG-ST activity which could be detected in enzyme-linked immunosorbent assay even at a dilution of 1:128,000. Fifty-fold-diluted ascitic fluid could completely neutralize the activity of NAG-ST (synthetic and native) and Vibrio mimicus ST (identical to NAG-ST) in suckling mice. In the same assay, 2F could also neutralize Yersinia enterocolitica ST (Y-ST) but did not neutralize Escherichia coli STh and STp. A similar pattern of reactivity occurred in a competitive enzyme-linked immunosorbent assay with homologous and heterologous toxins. Competitive inhibition curves with synthetic peptides representing NAG-ST and its shorter analogs revealed that aspartic acid located at position 2 from the N terminus of NAG-ST was the essential residue of the recognized epitope. Significantly, in Y-ST, to which 2F cross-reacted, aspartic acid is in the corresponding position as that of NAG-ST, thereby confirming our conclusions that the epitope defining this MAb is aspartic acid.


Food habits of young and middle-aged women living outside the capital cities of Australia.
Young (18-22 years) and middle-aged (45-49 years) women living in urban and rural areas of New South Wales completed a brief food frequency questionnaire as part of a wider health survey. Urban women in both age groups consumed meat less frequently than women in rural areas, and women in the less populated rural areas were more likely to eat green and yellow vegetables and least likely to eat dried beans. There were few other geographic differences in food habits. Middle-aged women consumed reduced-fat milk, fruit, vegetables, fish, biscuits and cakes significantly more frequently, and rice, pasta, full-cream milk, fried food and take-away food less frequently than younger women. Smokers in both age groups consumed fresh fruit, vegetables and breakfast cereals significantly less frequently than non-smokers, and women with low levels of habitual physical activity consumed fresh fruit and cereals less frequently than more active women. The findings suggest that strategies aimed at changing eating behaviours should be age-group-specific and targeted specifically to smokers and less active women.


Public Imaging Datasets of Gastrointestinal Endoscopy for Artificial Intelligence: a Review.
With the advances in endoscopic technologies and artificial intelligence, a large number of endoscopic imaging datasets have been made public to researchers around the world. This study aims to review and introduce these datasets. An extensive literature search was conducted to identify appropriate datasets in PubMed, and other targeted searches were conducted in GitHub, Kaggle, and Simula to identify datasets directly. We provided a brief introduction to each dataset and evaluated the characteristics of the datasets included. Moreover, two national datasets in progress were discussed. A total of 40 datasets of endoscopic images were included, of which 34 were accessible for use. Basic and detailed information on each dataset was reported. Of all the datasets, 16 focus on polyps, and 6 focus on small bowel lesions. Most datasets (n = 16) were constructed by colonoscopy only, followed by normal gastrointestinal endoscopy and capsule endoscopy (n = 9). This review may facilitate the usage of public dataset resources in endoscopic research.


Dapsone neuropathy--report of three cases and pathologic features of a motor nerve.
We report the clinical features, electrophysiologic findings, and dapsone and isoniazid excretion studies in three young people who ingested excessive amounts (2-4 times the prescribed dose) of dapsone for hypopigmented macules and who developed, subacutely, progressive motor neuropathy a few months later. Pathologic studies on a biopsied motor nerve confirmed the electrophysiologic conclusion of distal motor axonopathy. All made a rapid recovery in a few months after dapsone was stopped, although electrical abnormalities persisted. One patient was a rapid acetylator of isoniazid.


Projectile Impact Shock-Induced Deformation of One-Component Polymer Nanocomposite Thin Films.
Matrix-free assemblies of polymer-grafted nanoparticles (PGNs) enable mechanically robust materials for a variety of structural, electronic, and optical applications. Recent quasi-static mechanical studies have identified the key parameters that enhance canopy entanglement and promote plasticity of the PGNs below Tg. Here we experimentally explore the high-strain-rate shock impact behavior of polystyrene grafted NPs and compare their energy absorption capabilities to that of homopolystyrene for film thicknesses ranging from 75 to 550 nm and for impact velocities from 350 to 800 m/s. Modeling reveals that the initial shock compression results in a rapid temperature increase at the impact site. The uniformity of this heating is consistent with observations of greater kinetic energy absorption per mass (Ep*) of thinner films due to extensive visco-plastic deformation of molten film around the penetration site. Adiabatic heating is insufficient to raise the temperature at the exit surface of the thickest films resulting in increased strain localization at the impact periphery with less melt elongation. The extent and distribution of entanglements also influence Ep*. Structurally, each NP acts as a giant cross-link node, coupling surrounding nodes via the number of canopy chains per NP and the nature and number of entanglements between canopies anchored to different NPs. Load sharing via this dual network, along with geometrical factors such as film thickness, lead to extreme Ep* arising from the sequence of instantaneous adiabatic shock heating followed by visco-plastic drawing of the film by the projectile. These observations elucidate the critical factors necessary to create robust polymer-nanocomposite multifunctional films.


A single institution 18-years retrospective analysis of malignant melanoma.
Melanoma accounts for about 2% of all cancer-related mortality in western populations. Surgical excision of localized disease is curative in many patients with 80% overall 5-year survival rate. There are many indicators of prognosis of which tumor burden is predicted by primary site with nodal status being the next most important variable. Patients with advanced stage have very high risk of developing distant metastases and should receive systemic therapy. Despite treatment, majority of locally advanced patients develop metastatic disease. A retrospective analysis of cases of malignant melanoma registered over a period of eighteen years, from October 1990 to September 2007 was done. Patient profile, presentation, disease load, treatment protocols and response on or after treatment were analyzed. The median age at diagnosis in men was 48 years and 50 years in women. At presentation, more than half of studied cases (56.5%) presented with nodal metastases at diagnosis while about three fourths (74%) had distant metastases (stage IV disease). More than half (56%) of the patients had superficial spreading type. The most common presenting complaints were swelling (70% of patients), ulcer (50% of patients) or pain (50%). Primary sites included extremities, central nervous system, abdomen, trunk, and bones. Liver, brain, abdomen and lungs were common metastatic sites. Surgical excision of primary lesion was done in about half of the cases. Four patients subsequently received palliative radiotherapy and two more received adjuvant radiotherapy. Another six patients received adjuvant chemotherapy and radiotherapy. Among treated patients, 26% showed partial response and another 8% have stable disease while 65% patients progressed on or after initial treatment. Malignant melanoma carries an overall poor prognosis especially in advanced stages. Multimodality therapy with surgery, radiotherapy and chemotherapy may provide local or nodal remission but cannot improve long term survival in advanced cases.


Cancer-promoting and Inhibiting Effects of Dietary Compounds: Role of the Aryl Hydrocarbon Receptor (AhR).
Polyaromatic hydrocarbons, heterocyclic aromatic amines and dioxin-like compounds are environmental carcinogens shown to initiate cancer in a number of tissue types including prostate and breast. These environmental carcinogens elicit their effects through interacting with the aryl hydrocarbon receptor (AhR), a ligand activated transcription factor. Naturally occurring compounds found in fruits and vegetables shown to have anti-carcinogenic effects also interact with the AhR. This review explores dietary and environmental exposure to chemical carcinogens and beneficial natural compounds whose effects are elicited by the AhR.


Polyphenols and phenolic acids from strawberry and apple decrease glucose uptake and transport by human intestinal Caco-2 cells.
The effect of polyphenols, phenolic acids and tannins (PPTs) from strawberry and apple on uptake and apical to basolateral transport of glucose was investigated using Caco-2 intestinal cell monolayers. Substantial inhibition on both uptake and transport was observed by extracts from both strawberry and apple. Using sodium-containing (glucose transporters SGLT1 and GLUT2 both active) and sodium-free (only GLUT2 active) conditions, we show that the inhibition of GLUT2 was greater than that of SGLT1. The extracts were analyzed and some of the constituent PPTs were also tested. Quercetin-3-O-rhamnoside (IC₅₀ =31 μM), phloridzin (IC₅₀=146 μM), and 5-caffeoylquinic acid (IC₅₀=2570 μM) contributed 26, 52 and 12%, respectively, to the inhibitory activity of the apple extract, whereas pelargonidin-3-O-glucoside (IC₅₀=802 μM) contributed 26% to the total inhibition by the strawberry extract. For the strawberry extract, the inhibition of transport was non-competitive based on kinetic analysis, whereas the inhibition of cellular uptake was a mixed-type inhibition, with changes in both V(max) and apparent K(m) . The results in this assay show that some PPTs inhibit glucose transport from the intestinal lumen into cells and also the GLUT2-facilitated exit on the basolateral side.


Effects of different adjuvants in the context of intramuscular and intranasal routes on humoral and cellular immune responses induced by detergent-split A/H3N2 influenza vaccines in mice.
Influenza A/H3N2 viruses have caused the most severe epidemics since 1968 despite current immunization programs with inactivated vaccines. We undertook a side-by-side preclinical evaluation of different adjuvants (Alum, AS03, and Protollin) and routes of administration (intramuscular [i.m.] and intranasal [i.n.]) for assessing their effect on the immunogenicity and cross-reactivity of inactivated split vaccines (A/H3N2/New York/55/2004). Humoral and T cell-mediated immune responses against the homologous virus and a heterologous drifted strain (A/H3N2/Wisconsin/67/2005) were measured in BALB/c mice at 2, 6, and 19 weeks postboost. The AS03- and Alum-adjuvanted i.m. vaccines induced at least an 8-fold increase over the nonadjuvanted vaccine in functional antibody titers against both the homotypic and heterotypic strains and low IgG2a and high IgG1 levels, suggesting a mixed Th1/Th2 response with a Th2 trend. The Protollin-adjuvanted i.n. vaccine induced the lowest IgG1/IgG2a ratio, which is indicative of a mixed Th1/Th2-type profile with a Th1 trend. This adjuvanted vaccine was the only vaccine to stimulate a mucosal IgA response. Whatever the timing after the boost, both hemagglutination inhibition (HAI) and microneutralization (MN) titers were higher with the AS03-adjuvanted i.m. vaccine than with the protollin-adjuvanted i.n. vaccine. Finally, the Alum-adjuvanted i.m. vaccine and the lower-dose Protollin-adjuvanted i.n. vaccine elicited significantly higher CD4(+) Th1 and Th2 responses and more gamma interferon (IFN-γ)-producing CD8(+) T cells than the nonadjuvanted vaccine. Our data indicate that the adjuvanted vaccines tested in this study can elicit stronger, more persistent, and broader immune responses against A/H3N2 strains than nonadjuvanted inactivated influenza vaccines.


Coordination polymer hybridized Au nanocages: a nanoplatform for dual-modality imaging guided near-infrared driven photothermal therapy in vivo.
Coordination polymer hybridized Au nanocages (AuNC@CPs) were prepared via a dialysis process by combining Au nanocages with a coordination polymer, which was derived from (pq)2Ir(Hdcbpy) and Dy(OOCCH3)3. After hybridization, the localized surface plasmon resonance (LSPR) peak of the AuNC@CPs exhibited an evident red shift in comparison with that of the Au nanocages, which was due to a variation in the dielectric constant caused by the coordination polymer. Notably, inspired by their excellent photothermal, photoacoustic, and magnetic properties in solution, AuNC@CPs were used for near-infrared (NIR)-driven photothermal therapy (PTT) guided by photoacoustic (PA) and magnetic resonance (MR) imaging in vivo. Owing to their remarkable performance, the AuNC@CPs would represent promising nanoprobes for theranostics.


Microphthalmia-associated transcription factor controls the DNA damage response and a lineage-specific senescence program in melanomas.
Apoptosis and senescence are cellular failsafe programs that counteract excessive mitogenic signaling observed in cancer cells. Melanoma is known for its notorious resistance to apoptotic processes; therefore, senescence, which remains poorly understood in melanomas, can be viewed as a therapeutic alternative. Microphthalmia-associated transcription factor (MITF), in which its M transcript is specifically expressed in melanocyte cells, plays a critical role in melanoma proliferation, and its specific inhibition is associated with G(0)-G(1) growth arrest. Interestingly, decreased MITF expression has been described in senescent melanocytes, and we have observed an inhibition of MITF expression in melanoma cells exposed to chemotherapeutic drugs that induce their senescence. All these observations thereby question the role of MITF in controlling senescence in melanoma cells. Here, we report that long-term depletion of MITF in melanoma cells triggers a senescence program characterized by typical morphologic and biochemical changes associated with a sustained growth arrest. Further, we show that MITF-silenced cells engage a DNA damage response (DDR) signaling pathway, leading to p53 upregulation, which is critically required for senescence entry. This study uncovers the existence of a lineage-restricted DDR/p53 signaling pathway that is inhibited by MITF to prevent senescence and favor melanoma cell proliferation.


Fatigue in multiple sclerosis: multidimensional assessment and response to symptomatic treatment.
Sixty relapsing remitting multiple sclerosis (MS) patients were selected on the basis of their score on the Fatigue Severity Scale (FSS) and formed two groups: 40 patients (fatigued MS; MSf) scored above the 75th percentile of a previously assessed representative MS sample (100 patients), and 20 age- and sex-matched patients (nonfatigued MS patients; MSnf) scored below the 25th percentile. The patients underwent clinical evaluation (Expanded Disability Status Scale (EDSS)), further assessment of fatigue (Fatigue Impact Scale), scales evaluating depression (Hamilton Depression Rating Scale (HDRS) and Beck's Depression Inventory (BDI)) and neuropsychological tests. All patients were evaluated for muscle fatigability and central activation by means of a biomechanical test of sustained contraction; they also underwent somatosensory evoked potentials (SSEPs) and transcranial magnetic stimulation (TMS). The patients of the MSf subgroup were then randomized to one of the following two treatments: 4-aminopyridine (4-AP) 24 mg/day and fluoxetine (FLX) 20 mg/day. After a one-week titration this treatment proceeded for 8 weeks. At the end of the treatment, EDSS, fatigue and depression scores were further evaluated. At baseline, fatigue test scores consistently correlated with depression and cognitive test scores, but not with the fatigability test. Fatigue scores decreased in both treatment groups in a similar way. Due to the design of the study, this cannot be disjoined from a placebo effect. The changes of fatigue scores could not be predicted in the FLX group, whereas in the 4-AP group higher basal fatigability test scores were associated with greater reduction in fatigue scores.


Knowledge on treatment modalities and attitude of Nairobi University students towards dental care.
The objective of this study was to determine the knowledge and attitude of Nairobi University students towards dental health care in Kenya. A self administered questionnaire given to 400 students in person who responded and handed them over immediately. The students had a mean age of 22.4 years, 45.3% were males and 54.5% were females. Extractions, restorations and replacement of teeth were known to majority of the students. However, almost half of the students preferred extraction to restoration and 49.2% considered restoration of deciduous teeth unnecessary. 79% indicated that they would undergo scaling. It is therefore recommended that an effective mode of transmitting positive information about various dental treatment modalities be established.


Walking Metals for Remote Functionalization.
The distant and selective activation of unreactive C-H and C-C bonds remains one of the biggest challenges in organic chemistry. In recent years, the development of remote functionalization has received growing interest as it allows for the activation of rather challenging C-H and C-C bonds distant from the initiation point by means of a "metal-walk". A "metal-walk" or "chain-walk" is defined by an iterative series of consecutive 1,2- or 1,3-hydride shifts of a metal complex along a single hydrocarbon chain. With this approach, simple building blocks or mixtures thereof can be transformed into complex scaffolds in a convergent and unified strategy. A variety of catalytic systems have been developed and refined over the past decade ranging from late-transition-metal complexes to more sustainable iron- and cobalt-based systems. As the possibilities of this field are slowly unfolding, this area of research will contribute considerably to provide solutions to yet unmet synthetic challenges.


[Bioethical interpretation of intensive care] .
The bioethical interpretation concerns both those receiving intensive care (IC) and the nature of the treatment itself. The principle of autonomy expressed in the doctor-patient relationship is achieved through the use of informed consent and may also be used in the unique context of patients in IC. Organ-function replacement treatment raises the ethical question of the definition and management of the limit to treatment. The appropriateness of IC can be defined by clinical and ethical criteria and aims to avoid inappropriately excessive treatment. In order to improve the decision-making process involving bioethical questions, the authors outline a number of working approaches: the use of informed consent even in IC, the possible role of Advanced Directives in IC, epidemiological studies, operator training.


Inactivation of human pathogens during phase II composting of manure-based mushroom growth substrate.
Commercial production of white button mushrooms (Agaricus bisporus) requires a specialized growth substrate prepared from composted agricultural by-products. Because horse and poultry manures are widely used in substrate formulations, there is a need to determine the extent to which the composting process is capable of eliminating human pathogens. In this study, partially composted substrate was inoculated with a pathogen cocktail (log 10⁶ to 10⁸ CFU/g) containing Listeria monocytogenes, Escherichia coli O157:H7, and Salmonella. Pathogen and indicator-organism reductions were followed at temperatures that typically occurred during a standard 6-day phase II pasteurization and conditioning procedure. Controlled-temperature water bath studies at 48.8, 54.4, and 60°C demonstrated complete destruction of the three pathogens after 36.0, 8.0, and 0.5 h, respectively. Destruction of L. monocytogenes and E. coli O157:H7 at 54.4°C occurred more slowly than E. coli, total coliforms, Enterobacteriaceae, and Salmonella. Microbial reductions that occurred during a standard 6-day phase II pasteurization and conditioning treatment were studied in a small-scale mushroom production research facility. After phase II composting, E. coli, coliforms, and Enterobacteriaceae were below detectable levels, and inoculated pathogens were not detected by direct plating or by enrichment. The results of this study show that a phase II composting process can be an effective control measure for eliminating risks associated with the use of composted animal manures during mushroom production. Growers are encouraged to validate and verify their own composting processes through periodic microbial testing for pathogens and to conduct studies to assure uniform distribution of substrate temperatures during phase II.


Amorphization of Low Soluble Drug with Amino Acids to Improve Its Therapeutic Efficacy: a State-of-Art-Review.
Low aqueous solubility of drug candidates is an ongoing challenge and pharmaceutical manufacturers pay close attention to amorphization (AMORP) technology to improve the solubility of drugs that dissolve poorly. Amorphous drug typically exhibits much higher apparent solubility than their crystalline form due to high energy state that enable them to produce a supersaturated state in the gastrointestinal tract and thereby improve bioavailability. The stability and augmented solubility in co-amorphous (COA) formulations is influenced by molecular interactions. COA are excellent carriers-based drug delivery systems for biopharmaceutical classification system (BCS) class II and class IV drugs. The three important critical quality attributes, such as co-formability, physical stability, and dissolution performance, are necessary to illustrate the COA systems. New amorphous-stabilized carriers-based fabrication techniques that improve drug loading and degree of AMORP have been the focus of emerging AMORP technology. Numerous low-molecular-weight compounds, particularly amino acids such as glutamic acid, arginine, isoleucine, leucine, valine, alanine, glycine, etc., have been employed as potential co-formers. The review focus on the prevailing drug AMORP strategies used in pharmaceutical research, including in situ AMORP, COA systems, and mesoporous particle-based methods. Moreover, brief characterization techniques and the application of the different amino acids in stabilization and solubility improvements have been related.


Effect of low-dose clorgyline on 24-hour urinary monoamine excretion in patients with rapidly cycling bipolar affective disorder.
Effects of clorgyline on urinary excretion of norepinephrine, dopamine, tyramine, and their major metabolites, 5-hydroxyindoleacetic acid and phenylethylamine, were studied in four women who suffered from primary, bipolar affective disorder. All patients had rapid mood cycles and were nonresponsive to lithium carbonate. During placebo administration, a strong correlation was found between the excretion rates of norepinephrine and dopamine and their respective metabolites. Clorgyline, 5 to 10 mg every or every other day, reduced overall-body norepinephrine turnover by 55% and increased tyramine but did not alter 5-hydroxyindoleacetic acid, phenylethylamine, or p-hydroxyphenylacetic acid excretion. These findings demonstrate the clinical actions of low-dose clorgyline and clorgyline's specificity as a monoamine oxidase A (MAO-A) inhibitor in vivo in humans, as well as the effects of specific MAO-A inhibition on monoamine metabolism.


The preparation and function of the hypertensin-converting enzyme.
It has been shown by use of isolated, perfused rat kidneys that hypertensin II is a potent vasoconstrictor substance while hypertensin I is not. Hence it would appear that in intact animals the pressor activity of hypertensin I results from its rapid conversion to hypertensin II. An enzyme which effects this conversion has been procured from horse plasma in a semipurified form by means of ammonium sulfate fractionation and isoelectric precipitation. A method is described for estimating the activity of the enzyme. An example of the use of the preparation in converting purified hypertensin I to hypertensin II has been described.


Two Novel Mosquitocidal Peptides Isolated from the Venom of the Bahia Scarlet Tarantula (Lasiodora klugi).
Effective control of diseases transmitted by Aedes aegypti is primarily achieved through vector control by chemical insecticides. However, the emergence of insecticide resistance in A. aegypti undermines current control efforts. Arachnid venoms are rich in toxins with activity against dipteran insects and we therefore employed a panel of 41 spider and 9 scorpion venoms to screen for mosquitocidal toxins. Using an assay-guided fractionation approach, we isolated two peptides from the venom of the tarantula Lasiodora klugi with activity against adult A. aegypti. The isolated peptides were named U-TRTX-Lk1a and U-TRTX-Lk2a and comprised 41 and 49 residues with monoisotopic masses of 4687.02 Da and 5718.88 Da, respectively. U-TRTX-Lk1a exhibited an LD50 of 38.3 pmol/g when injected into A. aegypti and its modeled structure conformed to the inhibitor cystine knot motif. U-TRTX-Lk2a has an LD50 of 45.4 pmol/g against adult A. aegypti and its predicted structure conforms to the disulfide-directed β-hairpin motif. These spider-venom peptides represent potential leads for the development of novel control agents for A. aegypti.


Biomarkers Associated with Bleeding Risk in the Setting of Atrial Fibrillation.
Prevention of thromboembolic disease, mainly stroke, with oral anticoagulants remains a major therapeutic goal in patients with atrial fibrillation. Unfortunately, despite the high efficacy, anticoagulant therapy is associated with a significant risk of, frequently catastrophic, and hemorrhagic complications. Among different clinical and laboratory parameters related to an increased risk of bleeding, several biological markers have been recognized and various risk scores for bleeding have been developed. The aim of the present study is to review current evidence regarding the different biomarkers associated with raised bleeding risk in atrial fibrillation. Data originating from large cohorts or the recent large-scale trials of atrial fibrillation have linked numerous individual biomarkers to an increased bleeding risk. Such a relation was revealed for markers of cardiac physiology, such as troponin, BNP and NT-proBNP, markers of renal function, such as GFR and Cystatin or hepatic function, markers involving the system of coagulation, such as D-dimer and Von Willebrand factor, hematologic markers, such as low haemoglobin or low platelets, inflammatory markers, such as interleukin-6, other factors such as GDF-15 and vitamin-E and finally genetic polymorphisms. Many such biomarkers are incorporated in the bleeding risk schemata developed for the prediction of the hemorrhagic risk. Biomarkers were introduced in clinical practice in order to better estimate the potential risk of haemorrhage in these patients and increase the prognostic impact of clinical risk scores. In the last years this concept is gaining significant importance.


Monte-Carlo prediction of changes in areas of west Cumbria requiring restrictions on sheep following the Chernobyl accident.
Following the 1986 Chernobyl accident radiocaesium levels in sheep meat in some upland areas of the United Kingdom were above the national intervention limit. West Cumbria was one of these areas and restrictions are currently still in place. In addition to deposition from the Chernobyl accident, Cumbria has been subject to radiocaesium deposition from atmospheric nuclear weapons tests, the 1957 Windscale accident and routine releases from the Sellafield nuclear reprocessing plant. A Monte-Carlo approach has been used to try to predict areas in west Cumbria where radiocaesium activity concentrations in lamb meat would require the imposition of restrictions at different times after the Chernobyl accident. The approach models the transfer of radiocaesium from soil to vegetation, based upon soil organic matter, and from vegetation to lamb meat. Spatial inputs are soil organic matter and total post-Chernobyl (137)Cs and (134)Cs deposition; a ratio of Chernobyl (137)Cs to (134)Cs deposition has been used to differentiate Chernobyl and pre-Chernobyl (137)Cs deposition. Comparisons of predicted radiocaesium transfer from soil-vegetation and the spatial variation in lamb (137)Cs activity concentrations are good and predicted restricted areas with time after Chernobyl compare well to the restricted areas set by UK government. We predict that restrictions may be required until 2024 and that in some areas the contribution of pre-Chernobyl (137)Cs to predicted lamb radiocaesium activity concentrations is significant, such that restrictions may only have been required until 1994 as a consequence of Chernobyl radiocaesium deposition alone. This work represents a novel implementation of a spatial radioecological model using a Monte-Carlo approach.


Ecology of E. coli O157:H7 and Salmonella enterica in the primary vegetable production chain.
There is an increased concern that plants might be more important as a carrier for human enteric pathogens like E. coli O157:H7 and Salmonella enterica serovars than previously thought. This review summarizes the knowledge available on the ecology of E. coli O157:H7 and Salmonella enterica in the primary production chain of leafy green vegetables (in particular lettuce), including manure, manure-amended soil, and crop. Based on the available literature, suggestions are made for the control of these pathogens. The suggested approach of oligotrophication of agro-ecosystems fits in the wider approach to lower environmental emissions of nutrients from manure application and to enhance the suppression against plant pathogens.


Prospect of Combination and Sequential Therapies for Postmenopausal Osteoporosis.
Osteoporosis is a systemic bone disease, which is associated with the osteoporotic fracture. Along with prolonged life expectancy, the fracture risk increases dramatically with age. So far, it is usually the first choice to using antiresorptive agents. However, current clinical therapeutic treatments are not enough to inhibit the long-term bone loss and the rising risk of bone fractures. Recently, combination and sequential therapies with anti-osteoporosis drugs have become an inevitable trend. The purpose of this review is to summarize the present knowledge related to the combination and sequential therapies with anti-osteoporosis drugs. All articles published in PubMed until 2016 on the combination and sequential therapies with antiosteoporosis drugs were reviewed and the relevant literature was described in this review. As the first-line therapy for osteoporosis, the long-term safety and efficacy on bisphosphonate, teriparatide, and new anti-osteoporosis drugs are ongoing concerns. Combination or sequential therapies of boneforming agents and anti-resorptive agents, or two kinds of anti-resorptive agents, or strontium ranelate and other anti-osteoporosis agents have the advantages on BMD compared with monotherapy. So far, it is still an important public health strategy to therapy on the osteoporosis and related fracture. Alternatively, the combination and sequential therapies with anti-osteoporosis drugs are promising approaches for prevention and treatment of osteoporosis and have far-reaching significance.


Acuariidae (Nematoda) in Procellariiformes (Aves) on the southern coast of Rio Grande do Sul, Brazil.
Acuariidae nematodes are normally found in the digestive tract of aquatic birds, including Procellariiformes. Were examined Calonectris borealis (n = 4), Diomedea exulans (n = 1), Macronectes giganteus (n = 8), Thalassarche chlororhynchos (n = 5), Thalassarche melanophrys (n = 15), Procellaria aequinoctialis (n = 4), Puffinus gravis (n = 2) and Puffinus puffinus (n = 6), collected on the southern coast of RS, Brazil. A total of 16 birds (35.5%) were parasitized by two species of Acuariidae. Stegophorus diomedeae and Seuratia shipleyi were identified, with prevalences of 26.1% and 21.7%, respectively. Few studies on nematodes in Procellariiformes have been conducted. Here, the acuariids Seuratia shipleyi in Calonectris borealis and Procellaria aequinoctialis and Stegophorus diomedeae in Diomedea exulans, Procellaria aequinoctialis and Thalassarche chlororhynchos were reported for the first time.


The effect of raising the bite without mandibular protrusion on obstructive sleep apnoea.
It has recently been suggested that wearing a maxillary occlusal splint (i.e. a hard acrylic resin dental appliance that covers the occlusal surfaces of the maxillary dentition and that is being indicated for the treatment of, e.g. temporomandibular pain) may be associated with a risk of aggravating obstructive sleep apnoea (OSA). The present study tested the hypothesis that raising the bite without mandibular protrusion in OSA patients is associated with an increase in the apnoea-hypopnoea index (AHI). Eighteen OSA patients (13 men; 49·5 ± 8·1 years old) received a mandibular advancement device in 0% protrusion of the mandible (0%MAD). The MAD caused a bite rise of 6 mm as measured interincisally. Polysomnographic recordings were obtained at baseline and with the 0%MAD in situ. No statistically significant difference in AHI was noted between the baseline night and the 0%MAD night. However, nine patients had an aggravation in AHI during the night they used the 0%MAD. Taking into account the previously established smallest detectable difference of 12·8 in AHI, the AHI increased in only two of the patients. The outcomes of this study suggest that an increased jaw gape without mandibular protrusion might be associated with a risk of aggravation of OSA for some, but not for all OSA patients. Dental practitioners should be aware of this possible association when treating patients with oral devices that raise the bite.


Acute hypoxia activates neuroendocrine, but not presympathetic, neurons in the paraventricular nucleus of the hypothalamus: differential role of nitric oxide.
Hypoxia results in decreased arterial Po2, arterial chemoreflex activation, and compensatory increases in breathing, sympathetic outflow, and neuroendocrine secretions, including increased secretion of AVP, corticotropin-releasing hormone (CRH), adrenocorticotropin hormone (ACTH), and corticosterone. In addition to a brain stem pathway, including the nucleus tractus solitarius (nTS) and the rostral ventrolateral medulla (RVLM), medullary pathways to the paraventricular nucleus of the hypothalamus (PVN) contribute to chemoreflex responses. Experiments evaluated activation of specific cell phenotypes within the PVN following an acute hypoxic stimulus (AH; 2 h, 10% O2) in conscious rats. Retrograde tracers (from spinal cord and RVLM) labeled presympathetic (PreS) neurons, and immunohistochemistry identified AVP- and CRH-immunoreactive (IR) cells. c-Fos-IR was an index of neuronal activation. Hypoxia activated AVP-IR (~6%) and CRH-IR (~15%) cells, but not PreS cells in the PVN, suggesting that sympathoexcitation during moderate AH is mediated mainly by a pathway that does not include PreS neurons in the PVN. Approximately 14 to 17% of all PVN cell phenotypes examined expressed neuronal nitric oxide synthase (nNOS-IR). AH activated only nNOS-negative AVP-IR neurons. In contrast ~23% of activated CRH-IR neurons in the PVN contained nNOS. In the median eminence, CRH-IR terminals were closely opposed to tanycyte processes and end-feet (vimentin-IR) in the external zone, where vascular NO participates in tanycyte retraction to facilitate neuropeptide secretion into the pituitary portal circulation. Results are consistent with an inhibitory role of NO on AVP and PreS neurons in the PVN and an excitatory role of NO on CRH secretion in the PVN and median eminence.


Early auxin-regulated polyadenylylated mRNA sequences in pea stem tissue.
Polyadenylylated mRNA from etiolated pea stem segments treated with or without 20 muM indoleacetic acid (IAA) for various periods of time was assayed by translating it in a wheat germ extract containing [(35)S]methionine and separating the translation products by two-dimensional gel electrophoresis. Within 2 hr IAA causes at least five mRNA sequences to increase in translational activity, relative to initial levels and to simultaneous controls; three of these rise significantly within 20 min after exposure of tissue to IAA but are apparently not elevated at 10 min, whereas the others begin to increase at successive times later than 30 min, and still others begin to change only later than 2 hr. These observations indicate an early, highly selective IAA regulation of mRNA amounts or activities, becoming progressively more extensive with time. The earliest detected enhancement seems close to the primary action of IAA but appears not to be rapid enough to be responsible for auxin induction of cell enlargement.


Inhaled Corticosteroid Treatment Regimens and Health Outcomes in a UK COPD Population Study.
Inhaled corticosteroids (ICS) are a prevailing treatment option for COPD patients but recent guidelines have relegated their use predominantly to patients with frequent exacerbations. Yet large numbers of patients worldwide are currently treated with ICS-containing regimens. We wished to determine in routine clinical practice how common ICS withdrawal is and the differences in health outcomes between patients managed on ICS-containing and non-ICS containing regimens. COPD patients were identified from the UK primary care electronic healthcare records, between 2014 and 2018. Patients were grouped into three treatment regimens: long-acting beta-agonist (LABA) and inhaled corticosteroids (ICS), LABA and long-acting muscarinic antagonist (LAMA), and triple therapy (LABA, LAMA and ICS). Annual incidence of ICS withdrawal was measured. Multivariable logistic regression was used to identify patient factors associated with withdrawal. Multivariable Poisson regression was used to assess the association of exacerbations and hospitalised pneumonia between the ICS-containing regimens (LABA-ICS and triple therapy) and patients prescribed LABA-LAMA. Of 117,046 patients, around three-quarters were prescribed ICS-containing inhalers but ICS withdrawal occurred annually in only approximately 2-3% of patients. Exacerbations in the past year, but not a past history of pneumonia, were associated with ICS withdrawal. A total of 31,034 patients using three treatment regimens (LABA-ICS, LABA-LAMA or triple therapy) were assessed for their relative risk of exacerbations and pneumonia; the exacerbation risk was slightly lower in LABA-ICS users but the same in triple therapy users, as compared to LABA-LAMA users (LABA-ICS adjusted IRR=0.82 (95% CI 0.73-0.93), triple adjusted IRR=0.99 (95% CI 0.88-1.11)). There was no difference in the pneumonia risk (LABA-ICS adjusted IRR=0.96 (95% CI 0.71-1.31), triple adjusted IRR=1.16 (95% CI 0.87-1.57)). Use of ICS-containing inhaled medication is prevalent across the UK while ICS withdrawal from established treatment was relatively uncommon. Exacerbations and pneumonia risk was similar between the ICS-containing and non-ICS containing treatment regimens.


Structural alterations at the neuromuscular junctions of matrix metalloproteinase 3 null mutant mice.
Matrix metalloproteinases are important regulators of extracellular matrix molecules and cell-cell signaling. Antibodies to matrix metalloproteinase 3 (MMP3) recognize molecules at the frog neuromuscular junction, and MMP3 can remove agrin from synaptic basal lamina (VanSaun & Werle, 2000). To gain insight into the possible roles of MMP3 at the neuromuscular junction, detailed observations were made on the structure and function of the neuromuscular junctions in MMP3 null mutant mice. Striking differences were found in the appearance of the postsynaptic apparatus of MMP3 null mutant mice. Endplates had an increased volume of AChR stained regions within the endplate structure, leaving only small regions devoid of AChRs. Individual postsynaptic gutters were wider, containing prominent lines that represent the AChRs concentrated at the tops of the junctional folds. Electron microscopy revealed a dramatic increase in the number and size of the junctional folds, in addition to ectopically located junctional folds. Electrophysiological recordings revealed no change in quantal content or MEPP frequency, but there was an increase in MEPP rise time in a subset of endplates. No differences were observed in the rate or extent of developmental synapse elimination. In vitro cleavage experiments revealed that MMP3 directly cleaves agrin. Increased agrin immunofluorescence was observed at the neuromuscular junctions of MMP3 null mutant mice. These results provide strong evidence that MMP3 is involved in the control of synaptic structure at the neuromuscular junction and they support the hypothesis that MMP3 is involved in the regulation of agrin at the neuromuscular junction.


Influence of birthplace on breast cancer diagnosis and treatment for Hispanic women.
Research has shown that Hispanic women in the United States are diagnosed with breast cancer at more advanced stages and initiate treatment later than non-Hispanic white women. We investigated whether stage at breast cancer diagnosis and receipt of primary therapy differ by ethnicity and birthplace among US-born Hispanic, foreign-born Hispanic, and white women. We studied 31,012 Hispanic women and 372,313 white women with a first diagnosis of invasive breast cancer during 1988 and 2005 living in a SEER area. We used multinomial logistic regression to assess the association of ethnicity and birthplace with stage at diagnosis and, among women with stage I or II cancers, primary therapy [mastectomy, breast-conserving surgery (BCS) with radiation, BCS without radiation], adjusting for other patient and tumor characteristics. Rates of stage at diagnosis differed significantly by race/ethnicity and birthplace (P < 0.001). Foreign-born Hispanics had lower adjusted rates of stage I breast cancer at diagnosis (35.4%) than US-born Hispanics (40.6%), birthplace-unknown Hispanics (42.3%), and whites (47.4%). Receipt of primary therapy also differed significantly by race/ethnicity and birthplace (P < 0.001). Foreign-born Hispanics and birthplace-unknown Hispanics had lower rates of BCS with radiation (34.9%, 30.7%) than US-born Hispanics (41.5%) and whites (38.8%). Foreign-born Hispanic women in the United States have a lower probability of being diagnosed at earlier stages of breast cancer and, for women with early-stage disease, of receiving radiation following BCS compared to US-born Hispanics and whites. Identifying factors mediating these disparities may help in developing culturally and linguistically appropriate interventions and improving outcomes.


Home telemonitoring (forced expiratory volume in 1 s) in children with severe asthma does not reduce exacerbations.
Some children with severe asthma develop frequent exacerbations despite intensive treatment. We sought to assess the outcome (severe exacerbations and healthcare use, lung function, quality of life and maintenance treatment) of a strategy based on daily home spirometry with teletransmission to an expert medical centre and whether it differs from that of a conventional strategy. 50 children with severe uncontrolled asthma were enrolled in a 12-month prospective study and were randomised into two groups: 1) treatment managed with daily home spirometry and medical feedback (HM) and 2) conventional treatment (CT). The children's mean age was 10.9 yrs (95% confidence interval 10.2-11.6). 44 children completed the study (21 in the HM group and 23 in the CT group). The median number of severe exacerbations per patient was 2.0 (interquartile range 1.0-4.0) in the HM group and 3.0 (1.0-4.0) in the CT group (p=0.38 with adjustment for age). There were no significant differences between the two groups for unscheduled visits (HM 5.0 (3.0-7.0), CT 3.0 (2.0-7.0); p=0.30), lung function (pre-β(2)-agonist forced expiratory volume in 1 s (FEV(1)) p=0.13), Paediatric Asthma Quality of Life Questionnaire scores (p=0.61) and median daily dose of inhaled corticosteroids (p=0.86). A treatment strategy based on daily FEV(1) monitoring with medical feedback did not reduce severe asthma exacerbations.


[Wasting syndrome in cancer patients: pathophysiology, clinical manifestations and drug therapy].
Wasting is a syndrome related to patient functional impairment that characterizes many conditions, including cancer. The development of wasting includes changes in the metabolism, as well as in hormones and other cell mediators, which trigger a syndrome that cannot be solved by forced nutrient ingestion. The goal of this study is to review the pathophysiological components of wasting, as well as its clinical manifestations and the available specific drug therapy options for the treatment of this condition. To this end, a review of papers published during the last four years has been carried out. The treatment of wasting with drugs includes a number of combination therapies for the underlying condition, nutritional support administration, and specific drug therapy for the wasting clinical picture. Currently, the clinical efficacy of cyproheptadine, hydrazine and pentoxyfilline in the treatment of anorexia is uncertain. Only progestagen derivatives have shown to increase appetite and food intake, and to improve nutritional status, in these patients. Corticoids also appear to increase appetite, but their effects are short-lasting.


Retinoic acid receptor gamma: specific immunodetection and phosphorylation.
Synthetic peptides corresponding to cDNA-deduced amino acid sequences unique to the human and mouse retinoic acid receptor gamma 1 (hRAR-gamma 1 and mRAR-gamma 1, respectively) were used to generate anti-RAR-gamma 1 antibodies. Four mAbs were selected, which were directed against peptides found in region A1 (Ab1 gamma (A1)), region F (Ab2 gamma (mF) and Ab4 gamma (hF)) and region D2 (Ab5 gamma (D2)). These antibodies specifically immunoprecipitated and recognized by Western blotting RAR-gamma 1 proteins in COS-1 cells transfected with expression vectors containing the RAR-gamma 1 cDNAs. They all reacted with both human and mouse RAR-gamma 1 proteins, except Ab4 gamma (hF) that was specific for hRAR-gamma 1. Rabbit polyclonal antibodies, directed against a peptide from the mRAR-gamma 1 F region were also obtained (RP gamma (mF)) and found to be specific for mouse RAR-gamma 1 protein. Furthermore, in gel retardation/shift assays the antibodies specifically retarded the migration of complexes obtained with a RA response element (RARE). Antibodies raised against regions D2 and F also recognized the RAR-gamma 2 isoform which differs from RAR-gamma 1 only in the A region. On the other hand, antibodies directed against the A1 region of RAR-gamma 1 (Ab1 gamma (A1)) only reacted with the RAR-gamma 1 protein. The antibodies characterized here allowed us to detect the presence of mRAR-gamma 1 and gamma 2 isoforms in mouse embryos and F9 embryonal carcinoma cells nuclear extracts. They were also used to demonstrate that the mRAR-gamma 1 protein can be phosphorylated and that the phosphorylation occurs mainly in the NH2-terminal A/B region.


Mobilities of the inner three core residues and the Man(alpha 1--6) branch of the glycan at Asn78 of the alpha-subunit of human chorionic gonadotropin are restricted by the protein.
Human chorionic gonadotropin (hCG) is a heterodimeric glycoprotein hormone involved in the maintenance of the corpus luteum in early pregnancy. The free alpha-subunit of hCG has a biological activity of its own, namely, stimulation of prolactin secretion from term pregnancy decidual cells [Blithe, D. L., et al. (1991) Endocrinology 129, 2257-2259]. Glycosylation at Asn78 of the alpha-subunit is required for the stability of the protein, but the exact nature of the stabilizing effect is not known. In our previous study, it was indicated that GlcNAc-1 at Asn78 has a reduced mobility, whereas the glycan at Asn52 is highly mobile [De Beer, T., et al. (1996) Eur. J. Biochem. 241, 229-242]. In the present investigation, it is shown that the PNGase F susceptibility of the Asn52-linked glycan in the free alpha-subunit is absent in the heterodimer. Thus, the high mobility of the glycan at Asn52 may be characteristic for the free alpha-subunit. For accurate modeling of alpha hCG, knowledge of the behavior of each of the glycans is essential. In this context, the mobility of the glycans and their interactions with the protein are explored by NMR spectroscopy using desialylated, partially deglycosylated free alpha-subunit (as-pd alpha) carrying glycans at Asn78 only. NOEs between GlcNAc-2 and several amino acid residues indicate that GlcNAc-2 is involved in stabilizing alpha hCG. From the values of 13C relaxation parameters T2 and T1 rho of the constituting monosaccharide residues, it was concluded that the inner three residues have a severely restricted mobility. The Man-4 and Man-4' residues of the diantennary oligosaccharide exhibit a similar relaxation behavior, suggesting that the Man-4' branch occurs in a single conformation of the C5-C6 linkage of Man-3 instead of in rapidly interconverting conformations that are known to exist for this linkage for the free oligosaccharide.


Stability of twenty-five analytes in human serum at 22 degrees C, 4 degrees C, and -20 degrees C.
The stability of 25 analytes from serum of healthy donors was determined at room temperature, 4 degrees C, and -20 degrees C over 48 h, 14 days, and 4 months, respectively. Glucose, blood urea nitrogen, sodium, potassium, chloride, creatinine, calcium, phosphorus, uric acid, total protein, albumin, triglycerides, lipase, total creatine kinase, gamma-glutamyltransferase, iron, magnesium, and cholesterol were stable at all three temperatures for the specified times. Carbon dioxide, aspartate and alanine aminotransferases, lactate dehydrogenase, amylase, alkaline phosphatase, and high-density lipoprotein cholesterol demonstrated some loss over time. Proper storage temperatures and times must be considered for these analytes if measurement is not to take place immediately after specimen collection.


Molecular diversity sculpted by fungal PKS-NRPS hybrids.
Fungal polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) hybrids manufacture a wide range of structurally diverse secondary metabolites that play an eminent role in the environment, as molecular tools and leads for therapeutic development. To date, a dozen PKS-NRPS megasynthetases can be linked to the corresponding secondary metabolites, which stand out because of their structural complexity. The diversity of their structures, biological activities, and biosynthetic routes are particularly intriguing considering the iterative use of the catalytic domains of the biosynthetic enzymes-implying an enigmatic biosynthetic code. This review provides an overview of the characterized fungal PKS-NRPS hybrids, their manifold functionalities, and the diversity of the resulting secondary metabolites, as well as molecular engineering attempts that highly improved the understanding of their cryptic programming.


Cognitive activity and cutaneous blood flow.
Serial subtraction and multiplication problems were performed orally by 21 healthy human subjects during two three-minute periods separated by a 22-minute rest interval. During the period of mental activity, cutaneous blood flow in the finger fell to 59%, digital cutaneous pulse pressure fell to 62%, and heart rate increased by 24% of the subjects' initial baseline values. Cutaneous blood flow in the malar region did not change. Because vasomotor control of the finger skin is principally vasoconstrictor and that of the malar area vasodilator, these results suggest that mental activity unrelated to obvious stress may provoke changes in cutaneous blood flow in areas controlled by sympathetic vasoconstrictor fibers. Simultaneous changes in digital cutaneous blood flow, digital cutaneous pulse pressure, and heart rate indicate an autonomic-mediated effect.


Attachment of Moraxella catarrhalis to pharyngeal epithelial cells is mediated by a glycosphingolipid receptor.
Moraxella catarrhalis is one of the major pathogens of respiratory infections and has the ability to attach to the pharyngeal cells iva fimbriae. We characterized the epithelial cell receptor to which fimbriate M. catarrhalis binds. Neuraminidase pretreatment of pharyngeal epithelial cells resulted in a significant decrease of M. catarrhalis attachment, suggesting interaction with the sialic acid component. The attachment was not decreased in M. catarrhalis pretreated with 2 and 1 mg/ml of fucose, N-acetyl-neuraminic acid, N-acetyl-glucosamine, N-acetyl-galactosamine, acetyl-salicylic acid and colominic acid. However, M. catarrhalis treated with gangliosides M1, M2, D1a, D1b and T1a at a concentration of 2.5 micrograms/ml had significantly decreased the attachment compared to the control. In contrast treatment with gangliosides M3 and asialoganglioside M1 did not decrease the attachment of M. catarrhalis and thereby provided evidence for specificity of the inhibition. Concentration dependent effects of ganglioside M2 on the attachment were also observed. Other fimbriate isolates of M. catarrhalis showed decrease in attachment after treatment with ganglioside M2. However there was no effect on attachment when a nonfimbriate isolate was treated with ganglioside M2. This study indicates that the receptor of fimbriate M. catarrhalis on pharyngeal epithelial cells resides in the sequences of ganglioside M2.


Lymphogranuloma venereum and HIV infection: misdiagnosed as Crohn's disease.
The report describes a young Caucasian homosexual man who presented with a 4-month history of bloody diarrhoea and weight loss. Over the next 4 months he was investigated for inflammatory bowel disease and subsequently started on mesalazine and prednisolone as an outpatient. Within a month of starting treatment his symptoms worsened, leading to his self-referral to the genitourinary medicine clinic. The patient was subsequently diagnosed with advanced HIV infection and lymphogranuloma venereum infection. The patient was treated with doxycycline for 3 weeks and started on antiretrovirals. One month later the patient is symptom free with a recovering immune system.


Effect of vestibular stimulation on spatial and verbal memory in college students.
Excessive stress may have an adverse effect on learning and memory of students. It was reported that stimulation of the vestibular system enhances memory through its connections with the hippocampus, limbic system and neo cortex. This study aims to assess the effectiveness of vestibular stimulation in the modulation of memory in healthy human subjects. For this longitudinal follow-up study, we assessed spatial and verbal memory of participants followed by vestibular stimulation. A total of 240 healthy college students of 18-24 years, of either sex were selected after obtaining written consent from them. Participants were randomly assigned into four groups-control male and female group and vestibular male and female groups. Vestibular stimulation was administered by making the participants swing on a swing, according to their comfort (back to front direction) as standardized by previous methods. Spatial and verbal memory tests were used to assess memory. Data were analysed using two-way ANOVA followed by the Bonferroni post-hoc tests to compare differences between groups. Baseline values of spatial and verbal memory scores were not significantly different between the control and intervention groups. Significant enhancement was observed in spatial memory following vestibular stimulation in males but not female subjects. Contrary to this, significant decrease in spatial memory was observed in both males and females due to pre-examination stress who did not receive any vestibular stimulation. Significant enhancement was observed in verbal memory scores in both males and females who received vestibular stimulation, whereas verbal memory was significantly decreased in males and females in the control groups during the pre-examination period. Our study provides evidence to support vestibular stimulation as an efficient method to enhance memory and to prevent pre-examination associated stress-induced changes on memory. We recommend vestibular stimulation as a simple approach to improve verbal memory among students to cope with their pre-examination stress.


Functionalized aliphatic polyketones with germicide activity.
The COVID-19 pandemic has further confirmed to the community that direct contact with contaminated surfaces and objects represents an important source of pathogen spreading among humans. Therefore, it is of paramount importance to design effective germicidal paints to ensure a rapid and potent disinfectant action of surfaces. In this work, we design novel germicide polymeric coatings by inserting quaternary ammonium and sugar groups on the macromolecular backbone, thus respectively endowing the polymer with germicide features and hydrophilicity to interact with the surfaces. An aliphatic polyketone was selected as a starting polymer matrix that was functionalized with primary amine derivatives via the Paal-Knorr reaction. The resulting polymers were deposited on cellulose filter papers and checkboard charts with excellent coating yield and substrate coverage as determined by scanning electron microscopy for cellulose. Remarkably, the substrates coated by the functional polymers bearing quaternary ammonium compounds showed excellent bactericide properties with antibacterial rate of 99% and logarithmic reduction of >3. Notably, the polymers with higher hydrophobicity showed better retention on the substrate after being treated with water at neutral pH.