Association between spinal morning stiffness and lumbar disc degeneration: the Rotterdam Study.
To explore the associations between spinal morning stiffness and lumbar disc degeneration (LDD). Data from a cross-sectional general population-based study (Rotterdam Study-I) were used. Intervertebral disc spaces and osteophytes of people aged ≥55 years were scored on lumbar lateral radiographs (L1-2 through L5-S1 was scored). Logistic regression analysis was used to explore associations between spinal morning stiffness and two definitions of LDD (i.e., 'narrowing' and 'osteophytes'). Spinal morning stiffness combined with low back pain and its association with LDD was also analyzed. Similar analyses were performed for knee and hip pain, morning stiffness in the legs, and radiographic knee and hip osteoarthritis (OA) in order to compare these associations with those of LDD. All analyses were adjusted for age, gender, and body mass index (BMI). Lumbar lateral radiographs were scored for 2,819 participants. Both definitions of LDD were associated with spinal morning stiffness: adjusted odds ratio (aOR) 1.3; 95% confidence interval (CI): 1.1-1.6 for 'osteophytes' and aOR 1.8; 95% CI: 1.4-2.2 for 'narrowing'. Both the odds ratios increased when spinal morning stiffness was combined with low back pain: aOR 1.5; 95% CI: 1.1-2.0 for 'osteophytes' and aOR 2.5; 95% CI: 1.9-3.4 for 'narrowing'. When morning stiffness in the legs was combined with knee or hip pain, the associations with radiographic knee or hip OA were: aOR 3.0; 95% CI: 2.1-4.1 for knee OA and aOR 3.1; 95% CI: 1.9-5.0 for hip OA. Reported spinal morning stiffness is associated with LDD. The associations increased when we combined spinal morning stiffness with low back pain. The magnitude of the association for the definition 'narrowing' is similar to the association between morning stiffness in the legs and knee or hip OA.


Isoproterenol-induced redistribution of endosomes in cardiac myocytes.
During myocardial infarction, it is well known that the cytoplasm of cardiac myocytes becomes more acidic due to lactate accumulation. The resulting necrosis is believed to result, at least in part, from the leakage of lysosomal enzymes into the cytoplasm. In addition, it has previously been shown that cytoplasm acidification in tissue culture cells can cause the redistribution of late endosomes and tubular lysosomes. In the present study, we have investigated whether lysosomal/endosomal structures were affected during isoproterenol-induced infarct-like myocardial necrosis in rat heart in vivo. In parallel, we treated rat primary myocyte cultures with a high dose of isoproterenol or low pH. We followed the fate of lysosomal enzymes, a lysosomal membrane glycoprotein and the cation-independent mannose 6-phosphate receptor. Lysosomes were intact until irreversible injury became evident suggesting that the lysosomal enzyme release concomitant with the leakage of cytoplasmic enzymes is merely a consequence of cell death. During the early phase of injury, when the myocyte cytoplasm was mildly acidified, late endosomes showed fragmentation and microtubule-dependent movement towards the periphery, while the subcellular distribution of lysosomes was unchanged. Both processes were also observed after mild artificial acidification of the cytoplasm. Our data show that late endosomes and lysosomal trafficking are affected early during isoproterenol-induced myocardial injury causing a pH-dependent redistribution of late endosomes.


Efficacy of high-dose atorvastatin or rosuvastatin loading in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a meta-analysis of randomized controlled trials with GRADE qualification of available evidence.
We aimed to summarize current evidence regarding the impact of a high-dose statin loading before percutaneous coronary intervention (PCI) on short-term outcomes in patients presenting with the acute coronary syndrome (ACS). This meta-analysis was based on a search of the MEDLINE, Cochrane Central Register of Controlled Trials, Ovid Journals, and SCOPUS for randomized controlled trials that compared high-dose atorvastatin or rosuvastatin with no or low-dose statin administered before planned PCI in statin-naive patients with ACS. The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE), myocardial infarction (MI), and all-cause mortality at 30 days. Prespecified subanalyses were performed with respect to statin and ACS type. A total of eleven trials enrolling 6291 patients were included, of which 75.4% received PCI. High-dose statin loading was associated with an overall 43% relative risk (RR) reduction in MACCE at 30 days (RR 0.57, 95% CI 0.41-0.77) in whole ACS population. This effect was primarily driven by the 39% reduction in the occurrence of MI (RR 0.61, 95% CI 0.46-0.80). No significant effect on all-cause mortality reduction was observed (RR 0.92, 95% CI 0.67-1.26). In the setting of ST-elevation myocardial infarction (STEMI), atorvastatin loading was associated with a 33% reduction in MACCE (RR 0.67, 95% CI 0.48-0.94), while in non-ST-elevation myocardial infarction ACS (NSTE-ACS), rosuvastatin loading was associated with 52% reduction in MACCE at 30 days (RR 0.48, 95% CI 0.34-0.66). The level of evidence as qualified with GRADE was low to high, depending on the outcome. A high-dose loading of statins before PCI in patients with ACS reduces MACCE and reduces the risk of MI with no impact on mortality at 30 days. Atorvastatin reduces MACCE in STEMI while rosuvastatin reduces MACCE in NSTE-ACS at 30 days.


Peroxisome biogenesis disorders.
The peroxisome biogenesis disorders (PBDs) comprise 12 autosomal recessive complementation groups (CGs). The multisystem clinical phenotype varies widely in severity and results from disturbances in both development and metabolic homeostasis. Progress over the last several years has lead to identification of the genes responsible for all of these disorders and to a much improved understanding of the biogenesis and function of the peroxisome. Increasing availability of mouse models for these disorders offers hope for a better understanding of their pathophysiology and for development of therapies that might especially benefit patients at the milder end of the clinical phenotype.


Two-time-scale analysis of a ring of coupled vibratory gyroscopes.
A coupling inertial navigation sensor (INS) system may proven to be beneficial for performance improvement, especially when the manufacturing yield is very low for meeting the specification requirement of various applications. For instance, navigation grade sensors using the current fabrication process would yield one in every few hundreds which would meet the specification requirement after careful selection process and testing. We propose to couple these sensors by putting together the "low grade" sensors in a small array of particular coupling topology to explore their stability properties of known parameter variations produced during the fabrication process. By coupling them in a particular way one may improve the system stability to effect the performance of the INS. Thus in this work we present a coupled inertial navigation sensor (CINS) system consisting of a ring of vibratory gyroscopes coupled through the driving axis of each individual gyroscope. Numerical simulations show that under certain conditions, which depend mainly on the coupling strength, the dynamics of the individual gyroscopes will synchronize with one another. The same simulations also show an optimal network size at which the effects of noise can be minimized, thus yielding a reduction in the phase drift. We quantify the reduction in the phase drift and perform an asymptotic analysis of the motion equations to determine the conditions for the existence of the synchronized state. The analysis yields an analytical expression for a critical coupling strength at which different nonzero mean oscillations merge in a pitchfork bifurcation; passed this critical coupling the synchronized state becomes locally asymptotically stable. The Liapunov-Schmidt (LS) reduction is then applied to determine the stability properties of the synchronized solution and to further show that the pitchfork bifurcation can be subcritical or supercritical, depending on the coefficient of the nonlinear terms in the equations of motion.


Are adults with intellectual disabilities socially excluded? An exploratory study in Taiwan.
The aim of this exploratory study is to examine to what extent adults with intellectual disabilities (ID) in Taiwan are socially excluded and to identify the factors that are potentially associated with such social exclusion. The research method of this study is secondary data analysis, using descriptive and χ2 statistical analysis. Two data sets, from the 2003 and 2006 surveys entitled 'Survey of Living Situation for People with Disabilities in Taiwan', were used (n = 572; n = 618). In addition, 'independent living/living within the community' (as opposed to residing in an institution), 'employment' and 'household economic situation/residing in a low-income household' were social exclusion indicators in this study. The results revealed that in the 2003 (2006) survey, 81.9% (79.6%) of the subjects fell into at least one category of social exclusion, 11.3% (12.3%) fell into two or more categories and 0.2% (1.1%) fell into all three categories. Moreover, older women with ID, with no spouse or partner, lower educational levels and greater severity of the disability had a significantly greater likelihood of being subjected to more categories of social exclusion. The finding that the proportion of adults with ID and no social exclusion has risen from 18.1% in 2003 to 20.4% in 2006 represents an encouraging trend. However, there has been a marked increase in the proportion of the subjects with more categories of social exclusion, particularly with regard to those who have to endure all three categories, from 0.2% in 2003, to 1.1% in 2006. This implies that, at the time of the last survey, there was still considerable room for improvement in the social inclusion of adults with ID in Taiwan.


Characterization of tachykinin-related peptides from different insect species on Drosophila tachykinin receptor-expressing cell line.
Drosophila tachykinin receptor, a neurokinin receptor cloned from the fruit fly Drosophila melanogaster, is a G-protein-coupled receptor, which upon activation by a peptide agonist induces a transient increase in the concentration of intracellular calcium. The functional assay based on aequorin-derived luminescence triggered by receptor-mediated changes in Ca(2+) levels was used to examine and compare the effect of tachykinin-related peptides from different species. Among the endogenous Drosophila peptides, Drm-TK I induced the strongest calcium response. The most potent tachykinin-related peptides from Leucophaea maderae, Locusta migratoria, and Calliphora vomitoria, were partial agonists at the Drosophila tachykinin receptor.


Amorphous-Amorphous Coupling Enhancing the Oxygen Evolution Reaction Activity and Stability of the NiFe-Based Catalyst.
Efficient and stable electrocatalytic water splitting plays a critical role in energy storage and conversion but is strongly restricted by the low activity and stability of catalysts associated with the complicated oxygen evolution reaction (OER). This work provides a strategy to fabricate an advanced NiFe-based catalyst to steadily speed up the OER based on a strong amorphous-amorphous coupling effect generated through amorphous CuS that induces the formation of amorphous NiFe layered double hydroxide (LDH) nanosheets (A-NiFe NS/CuS). The presence of the strong coupling effect not only modifies the electronic structure of catalytic sites to accelerate the reaction kinetics but also enhances the binding between the catalyst and substrate to strengthen the durability. In comparison to well-grown core-shell crystalline NiFe LDH on CuO, the as-synthesized amorphous A-NiFe NS/CuS gives a low overpotential of 240 mV to achieve 100 mA cm-2 and shows robust stability under 100 h of operation at the same current density. Therefore, amorphous-amorphous coupling between catalyst-substrate by elaborate and rational engineering yields an opportunity to design efficient and robust NiFe-based OER catalysts.


Fabricating surfaces with tunable wettability and adhesion by ionic liquids in a wide range.
A series of surfaces that can either be fully wetted or non-wetted by three kinds of ionic liquids (ILs) are successfully designed by rationally controlling surface chemistries and structures. Meanwhile, the adhesion forces between these surfaces and the ILs can also be effectively modulated in a wide range. This fundamental research will greatly promote the development of IL-based materials in practical applications.


[Research progress on metabolism and pharmacological activities of several iridoid glycosides].
As a large category of natural products widely present in traditional Chinese medicine, iridoid glycosides have multiple pharmacological activities. Recent researches suggest that iridoid glycosides mainly exist in vivo in the forms of original form, aglycone and a series of their Ⅰ and Ⅱ metabolites under the biotransformation effect, and their metabolites have been proved to have multiple pharmacological activities. The research progress on in vivo metabolism and metabolite activities of several iridoid glycosides would be reviewed in this article, to provide a theoretical basis for the further development and utilization of iridoid compounds and their metabolites.


Semiclassical vibrational spectroscopy with Hessian databases.
We report on a new approach to ease the computational overhead of ab initio "on-the-fly" semiclassical dynamics simulations for vibrational spectroscopy. The well known bottleneck of such computations lies in the necessity to estimate the Hessian matrix for propagating the semiclassical pre-exponential factor at each step along the dynamics. The procedure proposed here is based on the creation of a dynamical database of Hessians and associated molecular geometries able to speed up calculations while preserving the accuracy of results at a satisfactory level. This new approach can be interfaced to both analytical potential energy surfaces and on-the-fly dynamics, allowing one to study even large systems previously not achievable. We present results obtained for semiclassical vibrational power spectra of methane, glycine, and N-acetyl-L-phenylalaninyl-L-methionine-amide, a molecule of biological interest made of 46 atoms.


Unpacking the "backpack of shame": Exploring intersections of stigma among Latinx people living with HIV in San Francisco, CA.
Ending the HIV epidemic requires addressing structural determinants of health, including stigma. In this qualitative study, we applied an intersectional framework to study various forms of stigma among Latinx people living with HIV (PLWH). We conducted focus groups and individual interviews with Spanish- and English-speaking Latinx PLWH (N = 19) at an HIV safety-net clinic in San Francisco, California. Using thematic analysis, we identified co-occurring forms of stigma impacting the participants' lives. Participants described the weight of co-occuring stigma related to their multiple identities, including homophobia and HIV-related stigma, both of which participants experienced in the U.S. and in their Latin American home countries. Importantly, many participants faced anti-immigrant stigma in their day-to-day interactions, which manifested as structural inequities such as difficulty finding stable housing and employment. Our findings illustrate experiences of intersectional stigma and systems of oppression. They can be used to inform policies that address social exclusion, discrimination, and stigma among Latinx PLWH. (PsycInfo Database Record (c) 2021 APA, all rights reserved).


Effects of ospemifene on drug metabolism mediated by cytochrome P450 enzymes in humans in vitro and in vivo.
The objective of these investigations was to determine the possible effects of the novel selective estrogen receptor modulator, ospemifene, on cytochrome P450 (CYP)-mediated drug metabolism. Ospemifene underwent testing for possible effects on CYP enzyme activity in human liver microsomes and in isolated human hepatocytes. Based on the results obtained in vitro, three Phase 1 crossover pharmacokinetic studies were conducted in healthy postmenopausal women to assess the in vivo effects of ospemifene on CYP-mediated drug metabolism. Ospemifene and its main metabolites 4-hydroxyospemifene and 4'-hydroxyospemifene weakly inhibited a number of CYPs (CYP2B6, CYP2C9, CYP2C19, CYP2C8, and CYP2D6) in vitro. However, only CYP2C9 activity was inhibited by 4-hydroxyospemifene at clinically relevant concentrations. Induction of CYPs by ospemifene in cultured human hepatocytes was 2.4-fold or less. The in vivo studies showed that ospemifene did not have significant effects on the areas under the plasma concentration-time curves of the tested CYP substrates warfarin (CYP2C9), bupropion (CYP2B6) and omeprazole (CYP2C19), demonstrating that pretreatment with ospemifene did not alter their metabolism. Therefore, the risk that ospemifene will affect the pharmacokinetics of drugs that are substrates for CYP enzymes is low.


Investigation of platelet adhesiveness in patients with coronary artery disease and acute myocardial infarction using the platelet adhesion assay (PADA).
Increased platelet reactivity may contribute to the development of coronary artery disease and myocardial infarction. The aim of the present study was to assess platelet adhesiveness in different stages of coronary artery disease using the platelet adhesion assay (PADA). In addition, the acute effect of coronary angiography and stent implantation on platelet adhesiveness was examined. 85 patients with stable coronary artery disease (SAP - stable angina pectoris) and 19 patients with acute myocardial infarction (AMI) were enrolled in the study. 35 volunteers served as controls. Blood sampling in SAP and AMI patients was done before coronary angiography to measure the adhesion index (AI) using the PADA. In 33 patients additional blood was drawn at the end of coronary angiography. In 6 patients blood samples were drawn also after stent implantation. In blood samples from patients with an AMI the AI was significantly higher than in blood samples from the SAP group (p < 0.01) and the control group (p < 0.01). Coronary angiography and stent implantation did not result in significant acute changes in mean AI however results show an interindividual variability in initial values as well as in AI changes during procedures. This is the first study to show that PADA, a quick and simple laboratory method for the quantitative determination of platelet adhesiveness, is able to detect platelet hyper-adhesiveness in patients with AMI.


Thelaziasis as an uncommon cause of giant papillary conjunctivitis.
We report a local human case of Thelazia callipaeda eye infection in a 49-year-old lady with history of fly contact in Hong Kong. A 49-year-old lady presented with right eye foreign body sensation for one month. She recalled a fly being stuck onto her right upper eyelashes with mascara when she went hiking in a forest trail in Hong Kong. On assessment there were a lot of giant papillae on palpebral conjunctiva. Three living worms crawling on conjunctiva were discovered and removed in total. The worms were identified as Thelazia callipaeda by morphology and molecular sequencing. After removal, her symptoms resolved completely. Human thelaziasis is probably under-reported in many countries. The presence of giant papillary conjunctivitis in non-contact lens wearers should alert clinicians to the possibility of thelaziasis in patients with compatible exposure history in endemic regions. Ophthalmologists should increase their awareness towards this uncommon disease and should not wrongly attributed the symptoms to allergic conjunctivitis.


Cellular systems for epithelial invagination.
Epithelial invagination is a fundamental module of morphogenesis that iteratively occurs to generate the architecture of many parts of a developing organism. By changing the physical properties such as the shape and/or position of a population of cells, invagination drives processes ranging from reconfiguring the entire body axis during gastrulation, to forming the primordia of the eyes, ears and multiple ducts and glands, during organogenesis. The epithelial bending required for invagination is achieved through a variety of mechanisms involving systems of cells. Here we provide an overview of the different mechanisms, some of which can work in combination, and outline the circumstances in which they apply.This article is part of the themed issue 'Systems morphodynamics: understanding the development of tissue hardware'.


Determining the geometries of transition States by use of antihydrophobic additives in water.
The quantitative effect of cosolvents on the water solubility of hydrophobic substrates can be correlated with the effect on reaction rates to determine the geometries of transition states for Diels-Alder reactions, the benzoin condensation, and alkylations of phenoxide ions and aniline. Some of these reactions have transition states with packing of hydrophobic surfaces and some do not. Methods were devised to sort out the effect of the cosolvents on solvation of hydrophobic surfaces and the effect on solvation of polar groups. The result is a set of geometries for these reactions that is consistent with theory.


Comparison of Postoperative Occupational Therapy and Narcotic Use in Two Carpometacarpal Arthroplasty Approaches.
The authors sought to determine whether differences exist in (1) the number of postoperative occupational therapy visits and (2) narcotic use in two carpometacarpal arthroplasty groups. A retrospective study comparing patients undergoing abductor pollicis longus (APL) suspensionplasty (154 patients) or flexor carpi radialis ligament reconstruction and tendon interposition (FCR LRTI) techniques (40 patients) between January 1, 2012, and August 1, 2018, was performed. Data included demographics, procedure performed, complications, number of postoperative occupational therapy visits, and postoperative morphine equivalent dosage used. Statistical testing used the chi-square test for proportions and the Wilcoxon-Mann-Whitney test for nonnormal data. The significance level was 0.05. The APL suspensionplasty and FCR LRTI groups had similar ages (58.1 ± 7.8 years versus 58.1 ± 7.7 years), sex ratios (73 percent female versus 75 percent female), and preoperative narcotic user proportions (1 percent versus 3 percent). Complication rates following the procedures were similar (21 percent and 18 percent, respectively). The number of postoperative occupational therapy visits following APL suspensionplasty (median, 0; interquartile range, 0 to 4) and FCR LRTI (median, 0; interquartile range, 0 to 4) were not significantly different (p = 0.961). There was less use of narcotics following APL suspensionplasty (median, 375 morphine equivalent dosage; interquartile range, 241.9 to 525 morphine equivalent dosage) compared with FCR LRTI (median, 462.5 morphine equivalent dosage; interquartile range, 375 to 768.8 morphine equivalent dosage), and this difference was significant (p = 0.0007). The APL suspensionplasty technique had less narcotic use and similar complication rates and occupational therapy visits compared to FCR LRTI. Prospective studies comparing postoperative pain control and function with these two carpometacarpal arthroplasty techniques may be beneficial. Therapeutic, III.


[Antineoplastic chemotherapy of head and neck tumors (author's transl)].
The antineoplastic chemotherapy as a treatment of advanced squamous head and neck tumors should be considered as a third fundamental therapy in addition to classical surgery and x-ray techniques. In comparison to other sequences the most favorable results are to be expected when chemotherapy is the first step followed by surgery and radiotherapy. The extend of remission and the median survival time by systemic combined chemotherapy of Methothrexate (MTX), Vincristine and Bleomycin on squamous cell carcinoma of the oral cavity and of the oropharynx seems to be the most acceptable treatment, while i.a. chemotherapy with MTX obviously has a most sufficient effect on hypopharynx carcinoma. A combined cis-platinum therapy or i.a. chemotherapy of MTX and Bleomycin or the combination of Vincristine, Bleomycin and low dose MTX underline good single results but the small collectives and short-term follow up do not allow any statement up to now.


Evidence-based public policy making for medicines across countries: findings and implications for the future.
Aim: Global expenditure on medicines is rising up to 6% per year driven by increasing prevalence of non-communicable diseases (NCDs) and new premium priced medicines for cancer, orphan diseases and other complex areas. This is difficult to sustain without reforms. Methods: Extensive narrative review of published papers and contextualizing the findings to provide future guidance. Results: New models are being introduced to improve the managed entry of new medicines including managed entry agreements, fair pricing approaches and monitoring prescribing against agreed guidance. Multiple measures have also successfully been introduced to improve the prescribing of established medicines. This includes encouraging greater prescribing of generics and biosimilars versus originators and patented medicines in a class to conserve resources without compromising care. In addition, reducing inappropriate antibiotic utilization. Typically, multiple measures are the most effective. Conclusion: Multiple measures will be needed to attain and retain universal healthcare.


The effects of the molecular weight of chitosan on the tissue inflammatory response.
The molecular weight of chitosan (CS) may affect its physical properties and its ability to induce an appropriate host response. The biocompatibilities of CS membranes of low (LMWCS) and high (HMWCS) molecular weight were investigated by inserting these materials into the subcutaneous tissue of rats for 1-28 days and evaluating leukocyte infiltration, granulation tissue, fibrosis, arginase-1 immunostaining, as well as nuclear factor-κB (NF-κΒ) and fibroblast growth factor (FGF)-2 expressions. Both CS membranes induced a peak of leukocyte infiltration on the first day of insertion and stimulated granulation and fibrous tissue generation when compared to control. LMWCS induced more collagen deposition a week earlier, when compared to the control and HMWCS membrane. The membranes also increased arginase-1 immunostaining, a M2 macrophage marker. M2 macrophage is recognized as anti-inflammatory and pro-regenerative. NF-κB is an essential biomarker of the inflammatory process and induces the expression of several pro-inflammatory cytokines. The LMWCS membrane reduced inflammation, as indicated by a reduced nucleus/cytoplasm NF-κB ratio in surrounding tissue from days 7 to 14 when compared to control. On the first day, the expression of FGF-2, a biomarker of inflammatory resolution, was increased in the tissue of the LWMCS group, when compared with HMWCS, which was consistent with the type I collagen deposition. Thus, LWMCS was associated with a prior reduction of the inflammatory response and improved wound healing.


Selection of Valid Reference Genes for Reverse Transcription Quantitative PCR Analysis in Heliconius numata (Lepidoptera: Nymphalidae).
Identifying the genetic basis of adaptive variation is challenging in non-model organisms and quantitative real time PCR. is a useful tool for validating predictions regarding the expression of candidate genes. However, comparing expression levels in different conditions requires rigorous experimental design and statistical analyses. Here, we focused on the neotropical passion-vine butterflies Heliconius, non-model species studied in evolutionary biology for their adaptive variation in wing color patterns involved in mimicry and in the signaling of their toxicity to predators. We aimed at selecting stable reference genes to be used for normalization of gene expression data in RT-qPCR analyses from developing wing discs according to the minimal guidelines described in Minimum Information for publication of Quantitative Real-Time PCR Experiments (MIQE). To design internal RT-qPCR controls, we studied the stability of expression of nine candidate reference genes (actin, annexin, eF1α, FK506BP, PolyABP, PolyUBQ, RpL3, RPS3A, and tubulin) at two developmental stages (prepupal and pupal) using three widely used programs (GeNorm, NormFinder and BestKeeper). Results showed that, despite differences in statistical methods, genes RpL3, eF1α, polyABP, and annexin were stably expressed in wing discs in late larval and pupal stages of Heliconius numata This combination of genes may be used as a reference for a reliable study of differential expression in wings for instance for genes involved in important phenotypic variation, such as wing color pattern variation. Through this example, we provide general useful technical recommendations as well as relevant statistical strategies for evolutionary biologists aiming to identify candidate-genes involved adaptive variation in non-model organisms.


The Positive Effect of Women's Education on Fertility in Low-Fertility China.
Despite pervasive evidence of more educated women having lower fertility, it remains unclear whether education reduces women's fertility. This study presents new evidence of the causal effect of women's education on fertility from China, where fertility has remained below the replacement level since the early 1990s. To account for endogeneity, the study exploits the timing and varying intensity of China's higher education expansion as exogenous sources of increase in women's education. Using data from China General Social Survey (2010-2012), findings show that each year of women's education induced by the higher education expansion increases the number of children ever born by 10%. According to the average marginal effects, each additional year of women's education increases the number of children ever born by 0.14, decreases the probability of having no children by 3 percentage points, and increases the probability of having two or more children by 4 percentage points. Two mechanisms drive the positive effect of education: first, education does not cause an increase in the mean age at first marriage; second, among ever-married women, education increases their demand for children. Findings from this study have important implications for China and other low-fertility developing countries.


Differential Network Analysis via Weighted Fused Conditional Gaussian Graphical Model.
The development and prognosis of complex diseases usually involves changes in regulatory relationships among biomolecules. Understanding how the regulatory relationships change with genetic alterations can help to reveal the underlying biological mechanisms for complex diseases. Although several models have been proposed to estimate the differential network between two different states, they are not suitable to deal with situations where the molecules of interest are affected by other covariates. Nor can they make use of prior information that provides insights about the structures of biomolecular networks. In this study, we introduce a novel weighted fused conditional Gaussian graphical model to jointly estimate two state-specific biomolecular regulatory networks and their difference between two different states. Unlike previous differential network estimation methods, our model can take into account the related covariates and the prior network information when inferring differential networks. The effectiveness of our proposed model is first evaluated based on simulation studies. Experiment results demonstrate that our model outperforms other state-of-the-art differential networks estimation models in all cases. We then apply our model to identify the differential gene network between two subtypes of glioblastoma based on gene expression and miRNA expression data. Our model is able to discover known mechanisms of glioblastoma and provide interesting predictions.


The Growing Importance of Chirality in 3D Chemical Space Exploration and Modern Drug Discovery Approaches for Hit-ID: Topical Innovations.
Modern-day drug discovery is now blessed with a wide range of high-throughput hit identification (hit-ID) strategies that have been successfully validated in recent years, with particular success coming from high-throughput screening, fragment-based lead discovery, and DNA-encoded library screening. As screening efficiency and throughput increases, this enables the viable exploration of increasingly complex three-dimensional (3D) chemical structure space, with a realistic chance of identifying highly specific hit ligands with increased target specificity and reduced attrition rates in preclinical and clinical development. This minireview will explore the impact of an improved design of multifunctionalized, sp3-rich, stereodefined scaffolds on the (virtual) exploration of 3D chemical space and the specific requirements for different hit-ID technologies.


Purification and characterization of a mannose/N-acetyl-D-glucosamine-specific lectin from the seeds of Platymiscium floribundum Vogel.
Platymiscium floribundum lectin (PFL), a mannose/N-acetyl-D-glucosamine-specific lectin, was isolated from P. floribundum seeds using Sepharose-mannose affinity media chromatography. PFL is a glycoprotein that is a potent agglutinin for rabbit erythrocytes. In addition, PFL is highly stable because it is able to maintain its hemagglutinating activity after exposure to temperatures of up to 60 °C for 1 h and exposure to a wide pH range. The PFL purification process was monitored using sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and the results showed that the purified lectin consists of a single band with a molecular mass of approximately 29 kDa in either the presence or the absence of a reducing agent. The analysis of purified PFL by electrospray ionization-mass spectrometry showed that most ions had a molecular weight of 27,053 ± 2 Da, and other less abundant ions had similar molecular weights. Gel filtration shows that the lectin exists as a dimer in solution with mass at approximately 65 kDa. Sixteen peptides were sequenced, and as a result, a total of 130 amino acids were identified and resulted in a coverage of approximately 65% of the PFL sequence. The partial sequence of PFL was aligned with sequences of other lectins from evolutionarily related species, and PFL showed considerable similarity to the other lectins.


Recognizing Personality Traits Using Consumer Behavior Patterns in a Virtual Retail Store.
Virtual reality (VR) is a useful tool to study consumer behavior while they are immersed in a realistic scenario. Among several other factors, personality traits have been shown to have a substantial influence on purchasing behavior. The primary objective of this study was to classify consumers based on the Big Five personality domains using their behavior while performing different tasks in a virtual shop. The personality recognition was ascertained using behavioral measures received from VR hardware, including eye-tracking, navigation, posture and interaction. Responses from 60 participants were collected while performing free and directed search tasks in a virtual hypermarket. A set of behavioral features was processed, and the personality domains were recognized using a statistical supervised machine learning classifier algorithm via a support vector machine. The results suggest that the open-mindedness personality type can be classified using eye gaze patterns, while extraversion is related to posture and interactions. However, a combination of signals must be exhibited to detect conscientiousness and negative emotionality. The combination of all measures and tasks provides better classification accuracy for all personality domains. The study indicates that a consumer's personality can be recognized using the behavioral sensors included in commercial VR devices during a purchase in a virtual retail store.


[Effect of HCV NS5A on STAT1 phosphorylation and nuclear translocation induced by IFN alpha-2b].
To study the effect of HCV NS5A on the Janus kinase (JAK)/signal transducer and activation of transcription (STAT1) phosphorylation and translocation induced by IFN alpha-2b and to understand the possible molecular mechanism of HCV interferon resistance. Hepatocellular carcinoma cell line Huh7 was transiently transfected with HCV NS5A protein expression plasmid pCNS5A and blank plasmid pRC/CMV respectively; the cells of the same cell line, without transfection, served as controls. Immunocytochemistry was used to prove the successful transfection. Immunofluorescence and Western blot were performed to observe the difference in STAT1 phosphorylation and nuclear translocation between HCV NS5A-expressed and non-HCV NS5A-expressed cells after 30 minutes of IFN alpha-2b induction. HCV NS5A protein was detected in the cytoplasm of Huh7 cells transfected with pCNS5A, indicating the successful transfection. In comparison to the blank plasmid-transfected and non-transfected group, STAT1 phosphorylation and sequential nuclear import were reduced in the presence of HCV NS5A protein. HCV NS5A can, to some extent, inhibit phosphorylation and nuclear translocation of STAT1 in IFN alpha-2b-induced JAK/STAT pathway, which may be a possible mechanism of HCV interferon resistance.


Leptin therapy alters appetite and neural responses to food stimuli in brain areas of leptin-sensitive subjects without altering brain structure.
Leptin is a key regulator of energy intake and expenditure. Individuals with congenital leptin deficiency demonstrate structural and functional brain changes when given leptin. However, whether acquired leptin deficiency may operate similarly is unclear. We set out to determine whether the brains of individuals with acquired leptin deficiency may react to leptin in a similar manner. We used functional magnetic resonance imaging before and after short- and long-term metreleptin treatment in three leptin-sensitive patients with acquired hypoleptinemia. Nine healthy women were scanned as normoleptinemic controls. The setting was an academic medical center. The participants were 3 hypoleptinemic women and nine normoleptinemic, matched women. We used metreleptin, recombinant leptin, therapy for 24 weeks in hypoleptinemic women only. We measured neural changes in response to viewing food as compared to nonfood images. We hypothesized that metreleptin treatment would increase brain activity in areas related to cognitive control and inhibition and would decrease brain activity in areas related to reward processing, as compared to the normoleptinemic counterparts. Unlike patients with congenital leptin deficiency, hypoleptinemic patients demonstrated no structural brain differences from healthy controls and/or structural changes in response to treatment. Short-term metreleptin treatment in leptin-sensitive hypoleptinemic subjects enhances areas involved in detecting the salience and rewarding value of food during fasting, whereas long-term treatment decreases attention to food and the rewarding value of food after feeding. Furthermore, hypothalamic activity is modulated by metreleptin treatment, and leptin decreases functional connectivity of the hypothalamus to key feeding-related areas in these hypoleptinemic subjects. Leptin replacement in acutely hypoleptinemic women did not alter brain structure but did alter functional cortical activity to food cues in key feeding and reward-related areas.


Similarities between Salmonella Enteritidis isolated from humans and captive wild animals in South Africa.
Salmonella is well recognized as an aetiological agent of gastrointestinal and diarrhoeal disease. Salmonella enterica serotype Enteritidis (Salmonella Enteritidis) is one of the commonest serotypes associated with foodborne illness. In South Africa, we compared Salmonella Enteritidis strains isolated from humans with gastroenteritis and strains isolated from captive wild animals, between June 2011 and July 2012. Bacteria were phenotypically characterized using standard microbiological techniques. Genotypic relatedness of isolates was investigated by pulsed-field gel electrophoresis (PFGE) analysis. a diversity of 27 PFGE patterns amongst 196 human non-invasive isolates was shown; two PFGE patterns predominated and accounted for 74% of all human isolates. Human isolates showed a 12% prevalence rate for nalidixic acid resistance. Animal isolates from 5 different sources were investigated. With the exception of an isolate from a ground hornbill, all animal isolates (jaguar, crocodile, lion and poultry) showed PFGE pattern matches to a human isolate. Animal isolates showed susceptibility to all antimicrobial agents tested, with the exception of nalidixic acid resistance in isolates from the lion and poultry source. Our data showed similarities between Salmonella Enteritidis strains isolated from humans and captive wild animals, suggesting a probable common source for strains from humans and animals.


The Use of Scaffolds in Cartilage Regeneration.
Scaffolds are important tools in tissue engineering and play a unique role in tissue regeneration and repair of damaged tissues. A variety of natural, synthetic, and composite scaffold types can be used in cartilage tissue engineering. The limited capability of cartilage to repair itself has always been a problem during recovery from damage. The success of cartilage regeneration is dependent on a couple of factors, but the basic properties of scaffolds are biocompatibility, degradability under physiological conditions, and structural support for cell attachment. In this review, we summarize the use of different scaffold types in cartilage regeneration.


Understanding feasibility and acceptability of implementation of linking delivery of family planning and infant vaccination care in rural Maharashtra, India: a qualitative study.
Linking family planning with infant vaccination care has the potential to increase contraceptive use among postpartum women in rural settings. We explored the multilevel factors that can facilitate or impede uptake of contraception at the time of infant vaccination among postpartum women and couples in rural Maharashtra, India. We conducted 60 semi-structured interviews with key stakeholders including: postpartum married women (n = 20), husbands (n = 10), and mothers-in-law (n = 10) of postpartum women, frontline healthcare workers (auxiliary nurse midwives (ANMs) and Accredited Social Health Activists (ASHAs), (n = 10), and community leaders (physician medical officers and village panchayat leaders) (n = 10). We sought to assess the feasibility and acceptability of delivering community-based postpartum family planning care in rural India at the time of infant vaccination. The Consolidated Framework for Implementation Research (CFIR) was used to design a structured interview guide and codebook. Data were analyzed via directed content analysis. Three major themes emerged: (1) Social fertility and gender norms including son preference and male control over contraceptive decision-making influence postpartum contraceptive access and choice. (2) Linking contraceptive care and infant vaccination is perceived as potentially feasible and acceptable to implement by families, health workers, and community leaders. The intervention provides care to women and families in a convenient way where they are in their community. (3) Barriers and facilitators to linked infant postpartum contraception and infant vaccination were identified across the five CFIR domains. Key barriers included limited staff and space (inner setting), and contraceptive method targets for clinics and financial incentives for clinicians who provide specific methods (outer setting). Key facilitators included convenience of timing and location for families (intervention characteristics), the opportunity to engage husbands in decision-making when they attend infant vaccination visits (participant characteristics), and programmatic support from governmental and community leaders (process of implementation). Linked provision of family planning and infant vaccination care may be feasible and accessible in rural India utilizing strategies identified to reduce barriers and facilitate provision of care. A gender-transformative intervention that addresses gender and social norms has greater potential to impact reproductive autonomy and couples' contraceptive decision-making.


The expression pattern and cellular localisation of Myosin VI during the Drosophila melanogaster life cycle.
Myosin VI is a motor protein which is necessary for the morphogenesis of epithelial tissues during Drosophila development. The spatial and temporal expression of Myosin VI was examined by expressing a GFP (Green Fluorescent Protein) tagged Myosin VI molecule (PGM), under the control of a Myosin VI-Gal4 line. PGM was present in tissues that were shown previously to express Myosin VI, such as the ovarian follicle epithelium, and the individualization complex; and in other tissues, including the trachea, the midgut, the salivary glands and the imaginal discs. The GFP-tagged Myosin V1 rescued the male sterile phenotype of Jaguar showing it is functional in vivo. Within individual cells, the role of the head and neck domain and the tail domain in targeting of the Myosin V1 molecule was examined by investigating the localisation of the separate domains tagged to GFP. In salivary glands and follicle cells the head and neck domains were concentrated in the cell nucleus, where the minus end of each actin filament is located. We found that the tail domain anchors the whole molecule outside of the nucleus. Similarly, in the individualization complex in the testes, the tail anchors the whole molecule to the base of the complex while the separated head with neck domain becomes scattered along the entire actin molecule suggesting the cellular location may be determined by cargo proteins that bind to the tail domain rather than by the movement of Myosin VI along the actin filaments.


Midface distraction following Le Fort III and monobloc osteotomies: problems and solutions.
Distraction osteogenesis has been used increasingly for midfacial advancement in patients with syndromic craniosynostosis and in severe developmental hypoplasia of the midface. In these patients, the degree of advancement required is often so great that restriction of the adjacent soft tissues may preclude stable advancement in one stage. Whereas distraction is an ideal solution by which to gradually lengthen both the bones and the soft tissues, potential problems remain in translating the distraction forces to the midface. In these patients, severe developmental hypoplasia may be associated with weak union between the zygoma and the maxilla, increasing the chance of zygomaticomaxillary dysjunction when using internal devices that translate distraction force to the maxilla through the zygoma. Eight cases are reported in which either internal or external distraction systems were used for midface advancement following Le Fort III (n = 7) or monobloc (n = 1) osteotomies. Cases of patients in whom hypoplasia at the zygomaticomaxillary junction altered or impaired plans for midface distraction were reported from three host institutions. Seven patients had midface hypoplasia associated with syndromic craniosynostosis, and one patient had severe developmental midface hypoplasia. The distraction protocol was modified to successfully complete midface advancement in light of weakness at the zygomaticomaxillary junction in seven patients. Modifications included change from an internal to an external distraction system in two patients, rigid fixation and bone graft stabilization of the midface in one patient, and plate stabilization of a fractured or unstable zygomaticomaxillary junction followed by resumption of internal distraction in four patients. Previous infection and bone loss involving both malar complexes precluded one patient from being a candidate for an internal distraction system. Using a problem-based approach, successful advancement of the midface ranging from 9 to 26 mm at the occlusal level as measured by preoperative and postoperative cephalograms was undergone by all patients. Advantages and disadvantages of the respective distraction systems are reviewed to better understand unique patient characteristics leading to the successful use of these devices for correction of severe midface hypoplasia.


Laser Treatment for Patients With Vulvodynia and Interstitial Cystitis/Bladder Pain Syndrome: A Case Series (The UNICORN-3 Study).
Introduction Interstitial cystitis/bladder pain syndrome (IC/BPS) is a chronic pain disorder characterized by urgency, frequency of urination, and pelvic pain. Women with IC/BPS often experience sexual dysfunction, vulvodynia, and vaginal health issues. Combined erbium and neodymium yttrium aluminum garnet (YAG) laser treatments targeting the vagina and vulva have shown promise in improving symptoms. Our study aims to investigate the effectiveness of these combined laser treatments in women with IC/BPS and vulvodynia. Methods Women diagnosed with vulvodynia and IC/BPS underwent combined laser treatment using vaginal erbium:YAG laser (VEL) and neodymium:YAG laser (Nd:YAG). Various parameters were evaluated, including the vulvodynia test, numeric rating scale (NRS-11) for pain, interstitial cystitis symptom index and problem index (ICSI and ICPI), pelvic pain and urgency/frequency symptom score (PUF), and mean urination volume/daily urination frequency in a three-day urination diary. Treatment was administered three times, with intervals of one month between each session, and follow-up evaluations were conducted at six and 12 months. All statistical analyses were designed and programmed by the AI chatbot GPT-4 (chatGPT-4). Results Fifteen female patients diagnosed with vulvodynia and IC/BPS were treated with three sessions of VEL + Nd:YAG. Significant improvements were observed in the vulvodynia test, NRS-11 scores, PUF, ICSI scores, ICPI scores, mean urination volume, and daily urination frequency at six and 12 months (p<0.01). Short-term improvements in IC/BPS pain scores correlated with improvements in the vulvodynia test (p=0.007), suggesting a synergistic effect. However, no significant correlations were found at 12 months. Conclusion Combined laser treatments targeting the vagina and vulva showed significant therapeutic effects in women with IC/BPS and vulvodynia. The addition of Nd:YAG to the VEL treatment enhanced outcomes. Short-term improvements in IC/BPS pain scores correlated with improvements in the vulvodynia test, indicating a synergistic effect. Long-term improvements in both vulvodynia and IC/BPS symptoms may occur independently. These findings highlight the importance of comprehensive approaches for treating coexisting vulvodynia and IC/BPS.


Baseline aortic pulse wave velocity is associated with central and peripheral pressor responses during the cold pressor test in healthy subjects.
Cold environmental temperatures increase sympathetic nerve activity and blood pressure, and increase the risk of acute cardiovascular events in aged individuals. The acute risk of cardiovascular events increases with aortic pulse wave velocity as well as elevated central and peripheral pulse pressures. The aim of this study was to examine the independent influence of aortic pulse wave velocity upon central and peripheral pressor responses to sympathetic activation via the cold pressor test (CPT). Twenty-two healthy subjects (age: 18-73 years) completed a CPT with the left hand immersed in 2-4°C water for 3 min. During the CPT, central (from: 36 ± 7 to: 51 ± 12 mmHg) and peripheral pulse pressure increased (from: 54 ± 7 to: 66 ± 11; both P < 0.05). In all subjects the increase in central pulse pressure during the CPT was independently associated with baseline aortic pulse wave velocity (r2 = 0.221, P = 0.027) but not age (P > 0.05). In a subset of subjects with higher arterial stiffness, the increase in peripheral pulse pressure during the CPT was independently associated with baseline aortic pulse wave velocity (r2 = 0.415, P = 0.032) but not age (P > 0.05). These data indicate that central and peripheral pulse pressure responses during sympathetic activation are positively and independently associated with aortic pulse wave velocity through a wide age range. Decreasing aortic pulse wave velocity in aged individuals with elevated arterial stiffness may help reduce the incidence of acute cardiovascular events upon exposure to cold environmental temperatures.


PAQR5 Expression Is Suppressed by TGFβ1 and Associated With a Poor Survival Outcome in Renal Clear Cell Carcinoma.
Renal cell carcinoma (RCC) was sex-hormone responsive, and clinical trials using progesterone significantly reduced the incidence of distal metastasis after radical nephrectomy. Recently membrane-bound progesterone receptors (mPRs) were discovered to mediate the non-genomic effect of progesterone. Aberrant expressions of these mPRs were reported in human breast, ovarian, urinary bladder, brain, uterine, and prostate cancers. However, their expression profiles in RCC are yet to be assessed. Multiple datasets from RNA sequencing (RNA-seq), cDNA microarray, and proteomic analysis were used to compare gene expression between cancerous and normal kidney tissues. Immunohistochemistry was conducted to examine protein expression in kidney tissues. Promoter methylation levels were assessed for correlation analysis with gene expression. Of the seven membrane-bound progesterone receptor genes, the progestin and adipoQ receptor-5 (PAQR5) gene is predominantly expressed in normal kidney tissue but was significantly downregulated in RCC tissues. PAQR5 downregulation correlated with tumor stage, cancer grade, lymph node invasion, and distal metastasis only in clear cell RCC (ccRCC) tissues. PAQR5 downregulation was associated with an increased promoter DNA methylation and a poor survival outcome in ccRCC patients. In addition, PAQR5 expression inversely correlated with transforming growth factor beta-1 (TGFB1) expression, and TGFβ1 treatment significantly reduced PAQR5 gene expression. PAQR5 is a novel prognostic biomarker in ccRCC and is negatively regulated by the TGFβ1 pathway.


High-Output Cardiac Failure Due to Hereditary Hemorrhagic Telangiectasia: A Case of an Extra-Cardiac Left to Right Shunt.
High-output cardiac failure is a rare complication of hereditary hemorrhagic telangiectasia and can potentially be mistaken for other entities. We present a case of high-output cardiac failure because of large hepatic arteriovenous malformations, review the literature regarding the cardiac manifestations of the disease, and discuss the possible differential diagnoses.


Digital plasmonic nanobubble detection for rapid and ultrasensitive virus diagnostics.
Rapid and sensitive diagnostics of infectious diseases is an urgent and unmet need as evidenced by the COVID-19 pandemic. Here, we report a strategy, based on DIgitAl plasMONic nanobubble Detection (DIAMOND), to address this need. Plasmonic nanobubbles are transient vapor bubbles generated by laser heating of plasmonic nanoparticles (NPs) and allow single-NP detection. Using gold NPs as labels and an optofluidic setup, we demonstrate that DIAMOND achieves compartment-free digital counting and works on homogeneous immunoassays without separation and amplification steps. DIAMOND allows specific detection of respiratory syncytial virus spiked in nasal swab samples and achieves a detection limit of ~100 PFU/mL (equivalent to 1 RNA copy/µL), which is competitive with digital isothermal amplification for virus detection. Therefore, DIAMOND has the advantages including one-step and single-NP detection, direct sensing of intact viruses at room temperature, and no complex liquid handling, and is a platform technology for rapid and ultrasensitive diagnostics.


D-dimers are degraded by human neutrophil elastase.
To see if D-dimers were degraded by human neutrophil elastase (HNE), cross-linked fibrin was obtained by adding thrombin to purified fibrinogen in the presence of calcium ions and factor XIII, and the fibrin clot subsequently degraded by plasmin. Thereafter, the supernatant containing fibrin degradation products was removed and incubated with HNE. D-dimer levels were measured by two rapid semiquantitative tests, a latex agglutination test and the Nycocard immunofiltration test, and a quantitative ELISA-method. With increasing incubation time, D-dimer levels as measured by the latex and Nycocard tests rapidly decreased and subsequently became undetectable, while the ELISA D-dimer values remained essentially unchanged. By using SDS-electrophoresis and immunoblotting, the degradation of plasmic derivatives of cross-linked fibrin by fiNE was visualised. We conclude that in a purified system, D-dimers formed during plasmin mediated lysis of cross linked fibrin are further degraded by HNE. Such HNE degradation reduces the D-dimer concentration as measured by rapid semiquantitive tests, and may be partly responsible for discrepant results when using different D-dimer assays.


Availability of essential amino acids and nitrogen in vegan diets.
Vegan children often fail to grow as well as their omnivorous cohorts despite protein intakes that exceed RDA. Explanations for inadequate growth include deficiencies of energy, calcium, zinc and vitamins B-12 and D. Due to decreased bioavailability, amino acids and nitrogen in vegan diets may be inadequate to support normal growth. Bioavailability of amino acids and nitrogen may be decreased by dietary fiber, food processing and storage, inadequate energy, and other unknown factors. Bioavailability should be considered when evaluating adequacy of intakes of protein, amino acids and nitrogen from vegan diets by infants and children.


A Three-Pulse Release Tablet for Amoxicillin: Preparation, Pharmacokinetic Study and Physiologically Based Pharmacokinetic Modeling.
Amoxicillin is a commonly used antibiotic which has a short half-life in human. The frequent administration of amoxicillin is often required to keep the plasma drug level in an effective range. The short dosing interval of amoxicillin could also cause some side effects and drug resistance, and impair its therapeutic efficacy and patients' compliance. Therefore, a three-pulse release tablet of amoxicillin is desired to generate sustained release in vivo, and thus to avoid the above mentioned disadvantages. The pulsatile release tablet consists of three pulsatile components: one immediate-release granule and two delayed release pellets, all containing amoxicillin. The preparation of a pulsatile release tablet of amoxicillin mainly includes wet granulation craft, extrusion/spheronization craft, pellet coating craft, mixing craft, tablet compression craft and film coating craft. Box-Behnken design, Scanning Electron Microscope and in vitro drug release test were used to help the optimization of formulations. A crossover pharmacokinetic study was performed to compare the pharmacokinetic profile of our in-house pulsatile tablet with that of commercial immediate release tablet. The pharmacokinetic profile of this pulse formulation was simulated by physiologically based pharmacokinetic (PBPK) model with the help of Simcyp®. Single factor experiments identify four important factors of the formulation, namely, coating weight of Eudragit L30 D-55 (X1), coating weight of AQOAT AS-HF (X2), the extrusion screen aperture (X3) and compression forces (X4). The interrelations of the four factors were uncovered by a Box-Behnken design to help to determine the optimal formulation. The immediate-release granule, two delayed release pellets, together with other excipients, namely, Avicel PH 102, colloidal silicon dioxide, polyplasdone and magnesium stearate were mixed, and compressed into tablets, which was subsequently coated with Opadry® film to produce pulsatile tablet of amoxicillin. In vitro release study firstly indicated a three-pulse release profile of the tablet. Later the pulse tablet was found to generate the sustained release of amoxicillin in beagle dogs. Furthermore, the Simcyp® software was used to simulate the in vivo concentration time curve model of the three-pulse release tablet for amoxicillin in both human and beagle dog. The prediction by PBPK model nicely fitted the observation in human and beagle dog. This study has demonstrated the interrelation of factors affecting the pulsatile formulation of amoxicillin using a Box-Behnken design. The three-pulse release tablets of amoxicillin were proven to generate pulsatile release in vitro and sustained release in vivo. This formulation was also found to extend the effective plasma concentration in human compared to the tablet of immediate release based on the simulation data by PBPK modeling. This study provides an example of using PBPK to guide the development of pulsatile dosage forms.


Comparative studies of the major histocompatibility complex in French Canadian and non-French Canadian Caucasians with systemic lupus erythematosus.
To investigate and compare the predisposing role of major histocompatibility complex (MHC) genes in systemic lupus erythematosus (SLE) in French Canadian and non-French Canadian (mainly Anglo-Saxon descent) Caucasian subjects. HLA-A, B, C (serology), DR, and DQ (restriction fragment length polymorphism [RFLP] typing) were determined. RFLP defining a large C4A,21-OHA deletion (Taq I C4) and an Nco I tumor necrosis factor alpha (TNF alpha) RFLP were analyzed in 91 Caucasian Canadians and 91 ethnically matched control subjects. In the total SLE and non-French Canadian SLE populations, HLA-B8, DR3(DR17), Dw24, DQ2, and the C4A gene deletion were associated with SLE. These HLA specificities and the C4A gene deletion were not significantly increased in French Canadian SLE patients compared with ethnically matched controls. When present in French Canadians, the C4A gene deletion was less closely associated with HLA-DR3(DR17), Dw24, DQ2 than in other Caucasians. HLA-DQ6 was associated with SLE in French Canadians. No association of the 2-allele Nco I TNF alpha RFLP with SLE was found in this population, in either ethnic group. These results support the importance of ethnic background in the study of MHC genes and SLE. The extended HLA-B8,DR3,C4A null haplotype is found mainly in SLE patients of Anglo-Saxon descent, while the DQ6 specificity is associated with SLE in French Canadians. This relatively genetically homogeneous Caucasian population offers the opportunity to study non-HLA-B8,DR3-linked MHC influence in SLE.


A Year Through the COVID-19 Pandemic: Deleterious Impact of Hormonal Contraception on Psychological Distress in Women.
Women are more at risk than men of suffering from psychological distress during disease outbreaks. Interestingly, no biological factors have been studied to explain this disparity in such contexts. Sex hormone variations induced by hormonal contraceptives (HC) have been associated with mental health vulnerabilities. However, most studies have examined current effects of HC without considering whether a chronic modulation of sex hormone levels could induce long-lasting effects that persist after HC cessation. To date, the role of HC on psychological health in women during a disease outbreak is still unknown. We aimed to investigate both current and long-term effects of HC on psychological distress throughout the COVID-19 pandemic. At four time points during the COVID-19 pandemic (June 2020, September 2020, December 2020, March 2021), we collected self-reported data on psychological distress, assessing symptoms of post-traumatic stress [via the Impact of Event Scale-Revised (IES-R)], symptoms of depression, anxiety, and stress [via the Depression Anxiety Stress Scales (DASS-21)]. Linear mixed models were first used to compare men (n = 49), naturally cycling women (n = 73), and women using HC (n = 32) across time. To examine long-lasting effects of HC, exploratory analyses were restricted to women, comparing current HC users (n = 32), past users (n = 56), and never users (n = 17). The first model revealed that women taking HC reported stable post-traumatic stress symptoms across time, compared to naturally cycling women and men who showed a significant decrease from T1 to T2. HC users also reported greater DASS-21 total scores over time. Moreover, HC users reported higher stress and anxiety symptoms than men. In the second model, results showed that past HC users had similar anxiety levels as current HC users. These two groups reported significantly more anxiety symptoms than never users. HC users report increased distress during the pandemic relative to naturally cycling women and men. Our results also suggest a long-lasting effect of HC intake, highlighting the importance of considering both the current use of HC and its history. This could provide some insight into potential avenues for explaining why some women are prone to higher psychological distress than men.


Role of Computed Tomography (CT) in Localisation and Characterisation of Suprahyoid Neck Masses.
Suprahyoid neck lesions are difficult to assess only by means of clinical inspection and therefore imaging techniques are required to precisely evaluate suprahyoid neck spaces. The aim of this study was to evaluate the distinctive role of computed tomography in the assessment of anatomical source and pathological type of masses involving the suprahyoid neck spaces. Sixty patients presenting with suprahyoid neck masses underwent computed tomography of the neck. The CT findings were correlated with histopathological findings and a final diagnosis was made. Overall, male preponderance was seen except in the case of parotid space lesions where female predominance was seen. The most common aetiology was squamous cell carcinoma and the majority of cases (30%) were seen in patients aged 41-50 years. The majority of lesions were found in the pharyngeal mucosal space (n=16) with squamous cell carcinoma being the most common pathology. In the parotid space, pleomorphic adenoma and in the prestyloid parapharyngeal space, squamous cell carcinoma were the most common lesions, respectively. In the retropharyngeal space, an equal incidence of malignant and inflammatory aetiologies was seen. Abscesses were the most common lesions in the prevertebral space. The pleomorphic adenoma was the most common benign tumour and was also the second most common tumour in the suprahyoid neck spaces. CT had an excellent correlation with histopathological findings with sensitivity of 96.4%, specificity of 100%, positive predictive value of 100% and a negative predictive value of 91.67%. Computed tomography definitely has a major role to play in the evaluation of suprahyoid neck masses as it has an excellent correlation with post-operative histopathological diagnosis.


Balancing the spatial demands of the developing dentition with the mechanical demands of the catarrhine mandibular symphysis.
The superior transverse torus of the catarrhine mandible has been shown to effectively reduce bending at the symphysis during unilateral postcanine biting. While the adult superior transverse torus contains trabecular bone, the juvenile one is almost entirely filled by developing permanent incisors until their eruption. This study uses finite elements analysis (FEA) to investigate whether the presence of developing incisors in the juvenile symphysis increases strains on the superior transverse torus. Two FE models of a juvenile Macaca fascicularis mandible were created: one included all the developing teeth; the second was modified to remove the incisor tooth crypts by filling them with trabecular bone. The models were loaded identically to simulate static physiological unilateral biting on dp(4) and strain magnitudes, patterns and distributions of the two FE models were compared. The FEA results show a notable increase in strain magnitudes by up to 40% when the developing incisors are present. The results indicate that, in order to maintain the same symphyseal strain magnitudes during chewing, the presence of the incisors in the symphysis necessitates a larger superior transverse torus in the juvenile than would be required if the superior transverse torus did not house the developing incisors. These results highlight the adaptational balance of the symphyseal morphology throughout ontogeny between biomechanics and the spatial demands of the developing dentition. Based on the findings we therefore propose that the spatial requirements of the developing incisors during ontogeny can act as a constraint on the functional adaptation and subsequent adult morphology observed in the catarrhine mandibular symphysis.


Porcine bocavirus: achievements in the past five years.
Porcine bocavirus is a recently discovered virus that infects pigs and is classified within the Bocavirus genus (family Parvoviridae, subfamily Parvovirinae). The viral genome constitutes linear single-stranded DNA and has three open reading frames that encode four proteins: NS1, NP1, VP1, and VP2. There have been more than seven genotypes discovered to date. These genotypes have been classified into three groups based on VP1 sequence. Porcine bocavirus is much more prevalent in piglets that are co-infected with other pathogens than in healthy piglets. The virus can be detected using PCR, loop-mediated isothermal amplification, cell cultures, indirect immunofluorescence, and other molecular virology techniques. Porcine bocavirus has been detected in various samples, including stool, serum, lymph nodes, and tonsils. Because this virus was discovered only five years ago, there are still many unanswered questions that require further research. This review summarizes the current state of knowledge and primary research achievements regarding porcine bocavirus.


Existence of molten globule state in homocysteine-induced protein covalent modifications.
Homocysteine thiolactone is a toxic metabolite produced from homocysteine by amino-acyl t-RNA synthetase in error editing reaction. The basic cause of toxicity of homocysteine thiolactone is believed to be due to the adduct formation with lysine residues (known as protein N-homocysteinylation) leading to protein aggregation and loss of enzyme function. There was no data available until now that showed the effect of homocysteine thiolactone on the native state structural changes that led to aggregate formation. In the present study we have investigated the time dependent structural changes due to homocysteine thiolactone induced modifications on three different proteins having different physico-chemical properties (cytochrome-c, lysozyme and alpha lactalbumin). We discovered that N-homocysteinylation leads to the formation of molten globule state--an important protein folding intermediate in the protein folding pathway. We also found that the formation of the molten globule state might be responsible for the appearance of aggregate formation. The study indicates the importance of protein folding intermediate state in eliciting the homocysteine thiolactone toxicity.


Safety of prasterone in breast cancer survivors treated with aromatase inhibitors: the VIBRA pilot study.
Due to safety concerns on estrogen-based treatments for genitourinary syndrome of menopause (GSM) in breast cancer survivors (BCS), new options are appearing, such as androgen-based treatments, which according to proprieties would not be transformed systemically to estrogens in patients receiving aromatase inhibitors (AIs). The aim of this pilot study is to assess the security and efficacy of vaginal prasterone (dehydroepiandrostenedione [DHEA]) in BCS treated with AIs. This open, prospective, pilot study included 10 BCS treated with AIs. All participants complained of severe GSM. DHEA was administrated as a vaginal ovule. Participants were instructed to use one ovule every night during the first month, and one ovule every two nights for the entire five remaining months. The patients were requested to attend seriated visits after the beginning of the prasterone treatment to evaluate symptoms, physical improvement and serum estradiol. Mean serum estradiol remained low from 3.4 pg/ml to 4.3 pg/ml (p = 0.9136) after 6 months of follow-up. The visual analog scale of dyspareunia improved from 8.5 to mean values after treatment of 0.4 (p = 0.0178). The Vaginal Health Index (VHI) scale and Female Sexual Function Index improved from 9.75 to 15.8 (p = 0.0277) and from an initial score of 11.2 to 20.6 (p = 0.0277), respectively. Vaginal pH changed from basal 8.1 to final 6.5 (p = 0.0330). Symptoms and physical examination regarding sexuality and vaginal health improved significantly, while serum estradiol remained at low levels. Prasterone seems a safe and effective option to treat GSM in BCS receiving AIs.


[Role and mechanism of tranilast preventing the progression of tubulointerstilial fibrosis in diabetic kidney diseases].
To determine the role and mechanism of tranilast preventing the progression of tubulointerstilial fibrosis in diabetic kidney disease (DKD). Sprague-Dawley rats were randomly divided into a control group (n=6), DKD model group (n=8), low dose tranilast group [200 mg/(kg.d), n=8], and high dose tranilast group [400 mg/(kg.d), n=8]. Tranilast was administered daily after the model was built. Rats were sacrificed at day 56, 24 hour urine was collected to measure 24-hour urine albumin excretion, and blood was collected to determine the renal function and serum albumin. Then the kidneys were harvested and subjected to studies. The expression of C3aR, E-cadherin, α-SMA, fibronectin(FN), collagen I (Col I), stem cell factor (SCF) and c-kit were detected by immunohistochemical staining respectively. The expression of E-cadherin, α-SMA, FN, Col I, SCF and c-kit protein was analyzed by Western blot, and the expression of FN, Col I, SCF and c-kit mRNA was examined by RT-PCR. Tranilast can inhibit the infiltration of mast cells in the kidneys of DKD rats. The expression of α-SMA in the kidneys of DKD rats inereased significantly (P<0.05), while the expression of E-cadherin decreased (P<0.05). Tranilast increased the expression of E-cadherin and decreased the expression of α-SMA in the prophase of DKD dose dependently. The expressions of FN and Col I were increased in the tubulointerstitial fields in DKD model rats (P<0.05). After the tranilast treatment, these changes were relieved to a certein degree (P<0.05). The expression of SCF and c-kit in the tubular and interstitial tissue was slight. The increased expressions of SCF and c-kit protein and mRNA in DKD model rats were downregulated by tranilat (P<0.05). The expressions of SCF and c-kit were positively correlated with the infiltration degree of mast cells and the expressions of FN, Col I. Mast cells participate in and aggravate the renal tubulointerstitial fibrosis in DKD rats. Tranilast can reverse the EMT of renal tubular cells and inhibit the tubulointersitial fibrosis of DKD by blocking the infiltration of mast cells induced by SCF/c-kit pathway.


Toxic interactions of benzyl alcohol with bacterial endotoxin.
Acute toxic interactions of intravenously administered benzyl alcohol and Escherichia coli O55:B5 (Boivin preparation) endotoxin were examined in rodents. Lethality studies in male CD-1 mice demonstrated that these agents were more toxic when administered in combination than when either was administered alone. Prophylactic treatment with diazepam (5 mg/kg intraperitoneally) protected against lethality induced by either the combination or the endotoxin yet offered little, if any, protection against the lethal effects of benzyl alcohol. Similar treatments with naloxone (5 mg/kg intraperitoneally) failed to protect against either endotoxin-induced or benzyl alcohol-induced lethality, but they significantly protected against the lethal effects of the combination. Although hexobarbital-induced sleeping time was prolonged in endotoxin-treated mice (but was normal in benzyl alcohol-treated mice), a more protracted effect on sleeping time was observed in mice treated with both benzyl alcohol and endotoxin. Moreover, male Wistar rats treated with benzyl alcohol (40 mg) showed no evidence of hepatic lesions, but rats treated in combination with sublethal doses of the alcohol (40 mg) and the endotoxin (0.4 mg) developed hepatic lesions which were severe than those observed in rats treated with endotoxin (0.4 mg) alone. A correlation between altered blood chemistry values and severity of hepatic lesions was demonstrated. These data show in vivo toxic interactions between benzyl alcohol and bacterial endotoxin. In addition, our results indicate that the toxic effects induced by the benzyl alcohol-endotoxin combination are due to an enhancement of the lethal properties of bacterial endotoxin.


Overt and subclinical hypothyroidism among Bangladeshi pregnant women and its effect on fetomaternal outcome.
Thyroid disorders are among the common endocrine problems in pregnant women. It is now well established that not only overt but subclinical thyroid dysfunction also has adverse effects on maternal and fetal outcome. There are few data from Bangladesh about the prevalence of thyroid dysfunction in pregnancy. With this background, this study aims to find out thyroid dysfunction (both overt and subclinical hypothyroidism) in pregnancy and its impact on obstetrical outcome. We studied the evaluation of 50 admitted pregnancies corresponding to 29 women with subclinical hypothyroidism and rest 21 was overt hypothyroidism. Detailed history and examination were performed. Apart from routine obstetrical investigations, Thyroid Stimulating Hormone (TSH) estimation was done. Their obstetrical and perinatal outcomes were noted. Overt hypothyroidism was significantly (p < 0.05) higher in 25 to 44 years age group. However two and three abortions were significantly (p < 0.05) higher in overt hypothyroidism patients. In sub clinical hypothyroidism 86.2% conceived firstly within 2 years and 66.7% in overt hypothyroidism patients conceived firstly in between 3 to 5 years after marriage. Overt hypothyroids were prone to have pregnancy-induced hypertension 42.9%, intrauterine growth restriction (P = 0.001) and gestational diabetes (38.1%) as compared to subclinical cases. Neonatal complications were significantly more in overt hypothyroidism group. Mean TSH level was significantly (p < 0.05) higher in overt hypothyroidism patients but mean FT4 level was almost similar in both groups. Majority of the patient underwent caesarean section in both groups due to associated medical and obstetrical complications. None of the babies showed hypothyroidism by cord blood tests. In this analysis our results showed that overt hypothyroidism among Bangladeshi pregnant women are associated with more maternal complication & adverse parental outcome than subclinical hypothyroidism. The adequate treatment of hypothyroidism during gestation minimizes risks and generally, makes it possible for pregnancies to be carried to term without complications. Significant adverse effects on maternal and fetal outcome were seen emphasizing the importance of routine antenatal thyroid screening.


Transbronchial Cryobiopsy in Interstitial Lung Disease: Are We on the Right Path?
A definitive and specific diagnosis of interstitial lung disease (ILD) often requires a histologic analysis of the lung parenchyma. A transbronchial biopsy with forceps has a limited diagnostic yield for idiopathic interstitial pneumonias. The incorporation of a transbronchial lung cryobiopsy for diagnosing ILD appears to be very promising, although there are only a few published studies in this regard. Our paper shows the results of using this technique in our center. This was a prospective study including 55 patients with ILD diagnosed from January 2012 to January 2015. The methodology used, the overall diagnostic yield, and the number and the location of samples, in addition to complications, have been reported. In 38 (69%), 10 (20.8%), and 7 (12.7%) cases, we obtained a certain, highly likely, and unclassifiable diagnosis of interstitial pneumonia, respectively. With 18 cases, usual interstitial pneumonia was the most common diagnosis. The most common complication was a pneumothorax in 8 patients (14.5%). A transbronchial lung cryobiopsy using a flexible cryoprobe has a good diagnostic yield and might be an alternative to consider in cases of diffuse ILD in which a histologic sample is required for diagnosis. This technique could avoid a large number of surgical biopsies.


Induction of Neuroendocrine Differentiation in Prostate Cancer Cells by Dovitinib (TKI-258) and its Therapeutic Implications.
Prostate cancer (PCa) remains the second-leading cause of cancer-related deaths in American men with an estimated mortality of more than 26,000 in 2016 alone. Aggressive and metastatic tumors are treated with androgen deprivation therapies (ADT); however, the tumors acquire resistance and develop into lethal castration resistant prostate cancer (CRPC). With the advent of better therapeutics, the incidences of a more aggressive neuroendocrine prostate cancer (NEPC) variant continue to emerge. Although de novo occurrences of NEPC are rare, more than 25% of the therapy-resistant patients on highly potent new-generation anti-androgen therapies end up with NEPC. This, along with previous observations of an increase in the number of such NE cells in aggressive tumors, has been suggested as a mechanism of resistance development during prostate cancer progression. Dovitinib (TKI-258/CHIR-258) is a pan receptor tyrosine kinase (RTK) inhibitor that targets VEGFR, FGFR, PDGFR, and KIT. It has shown efficacy in mouse-model of PCa bone metastasis, and is presently in clinical trials for several cancers. We observed that both androgen receptor (AR) positive and AR-negative PCa cells differentiate into a NE phenotype upon treatment with Dovitinib. The NE differentiation was also observed when mice harboring PC3-xenografted tumors were systemically treated with Dovitinib. The mechanistic underpinnings of this differentiation are unclear, but seem to be supported through MAPK-, PI3K-, and Wnt-signaling pathways. Further elucidation of the differentiation process will enable the identification of alternative salvage or combination therapies to overcome the potential resistance development.


The role of an antibiotic envelope in the prevention of major cardiac implantable electronic device infections: A systematic review and meta-analysis.
Over the past decade, rates of cardiac implantable electronic device (CIED) related infections have increased and been associated with increased morbidity, mortality and financial burden on healthcare systems. To examine the effect of an antibacterial envelope in reducing major CIED related infections, we performed a systematic review and meta-analysis by searching PubMed/MEDLINE, CENTRAL, Google scholar and Clinicaltrials.gov for studies that examined the effect of an antibiotic envelope in reducing major related CIED infections, comprising of device-related endocarditis, systemic infection requiring systemic antibiotics and or device extraction, compared to control up till February 15th, 2020. A random-effects meta-analysis was conducted by calculating risk ratios (RR) and respective 95% confidence intervals (CI). We include 6 studies that comprise of 11,897 patients, of which 5844 received an antibiotic envelope and 6053 did not. Compared with control, utilization of an antibiotic envelope at the time of procedure was associated with a significant 74% relative risk reduction in major CIED related infections among patients at high risk for infection (RR: 0.26 [95% CI, 0.08-0.85]; P = .03), while no significant reduction was observed among patients enrolled from studies with any risk for infection (RR: 0.53 [95% CI, 0.06-4.52]; P = .56). Additionally, no reduction in mortality among patients that received an envelope compared to control was observed (RR: 1.15 [95% CI, 0.53-2.50]; P = .72). The utilization of an antibiotic envelope at the time of device implantation or upgrade reduces major CIED infections, especially if used in patients perceived to be at higher risk for infection.


Further investigation of the discriminative stimulus properties of MDA.
Rats trained to discriminate either (+)-amphetamine or (+/-)-MDA from saline in a two-lever drug discrimination task, were used to study the stimulus effects of MDA and its two optical isomers. Amphetamine-stimulus generalization occurred to S(+)-MDA, but not to its enantiomer R(-)-MDA. This, coupled with our earlier finding of DOM-stimulus generalization to R(-)-MDA but not to S(+)-MDA, suggests that the stimulus effects of S(+)-MDA are predominantly amphetamine-like while those of R(-)-MDA are more DOM-like. Thus, animals trained to discriminate racemic MDA from saline can apparently recognize members of both classes of agents.


Effort, exaggeration and malingering after concussion.
Although most individuals who suffer a mild traumatic brain injury have complete recovery, a number experience persistent symptoms that appear inconsistent with the severity of the injury. Symptoms may be ascribed to malingering, exaggeration or poor effort on cognitive testing. The purpose of this paper is to propose that previously unconsidered factors, informed by social psychology and behavioural economics, can appear as 'symptom magnification' or 'poor effort', which are incorrectly interpreted as the result of a conscious process. These are complex and multi-determined behaviours with a unique differential diagnosis which have important implications for research, evaluation and treatment.


Handle Region Peptide Ameliorating Insulin Resistance but Not β Cell Functions in Male Rats Neonatally Treated with Sodium L-Glutamate.
Handle region peptide (HRP), which was recognized as a blocker of (pro)renin receptor ((P)RR), may block the function of (P)RR. The aim of this study was to investigate the effect of HRP with a large dose of 1 mg/kg/d on glucose status in the rats treated neonatally with monosodium L-glutamate (MSG). At the age of 8 weeks, the MSG rats were randomly divided into MSG control group, HRP treated group with minipump (MSG-HRP group), losartan treated group (MSG-L group), and HRP and losartan cotreated group (MSG-HRP-L group) and fed with high-fat diet for 4 weeks. Losartan but not HRP increased the levels of insulin releasing and ameliorate glucose status although both losartan and HRP improved insulin sensitivity. On the one hand, both losartan and HRP decreased levels of pancreatic local Ang-II and NADPH oxidase activity as well as its subunits P(22phox). On the other hand, losartan but not HRP decreased α -cell mass and number of PCNA-positive cells located periphery of the islets and decreased picrosirius red stained area in islets. HRP ameliorating insulin resistance but not β -cell functions leads to hyperglycemia in the end in male MSG rats, and the dual characters of HRP may partly account for the phenomenon.


Evaluation of magnetic fluid hyperthermia in a standard rat model of prostate cancer.
To examine the feasibility and potential of magnetic fluid hyperthermia (MFH) as a minimally invasive method for hyperthermia treatment of prostate cancer. Orthotopic Dunning R3327 prostate tumors were induced in 20 male Copenhagen rats. The animals either received MFH treatment following intratumoral administration of magnetic fluids or were used as either tumor growth controls for determination of iron distribution in selected organs or as histologic controls without MFH treatment. The MFH treatments were carried out at 45 degrees C or 50 degrees C using an AC magnetic field applicator system designed for small animals. Sequential treatments with MFH were possible following a single intratumoral injection of magnetic fluid. Intratumoral temperatures of 50 degrees C and more were obtained and were monitored online using fluoro-optic thermometry. Four days after MFH treatments, 79% of the injected dose of ferrites was still present in the prostate. The successful intraprostatic nanoparticle infiltration and stable steady-state intratumoral treatment temperatures demonstrate the feasibility of MFH in a prostate cancer model. Efficacy and survival benefit must be confirmed in further experiments.


Medical groups' adoption of electronic health records and information systems.
We surveyed a nationally representative sample of medical group practices to assess their current use of information technology (IT). Our results suggest that adoption of electronic health records (EHRs) is progressing slowly, at least in smaller practices, although a number of group practices plan to implement an EHR within the next two years. Moreover, the process of choosing and implementing an EHR appears to be more complex and varied than we expected. This suggests a need for greater support for practices, particularly smaller ones, in this quest if the benefits expected from EHRs are to be realized.


Symptomatic hepatic metastasis of insulinoma 15 years after pancreatic resection.
Malignant insulinomas are infrequent endocrine tumors with miscellaneous clinical courses. In this report, we present a rare case of insulinoma that recurred with solitary hepatic metastasis 15 years after the initial resection of the primary tumor from the pancreas. A 20-year-old woman first presented with the symptoms of hypoglycemia in 1996. The diagnosis of pancreatic insulinoma was confirmed by laboratory findings, and the initial surgery had been performed involving complete enucleation of the pancreatic mass. Histopathologically, the tumor was diagnosed as a benign adenoma. After 15 years, the patient experienced symptoms of hypoglycemia again, and laboratory findings and abdominal computed tomography identified a lesion in the liver. Intraoperative ultrasound did not show any lesion in the pancreas, and wedge resection was performed for the hepatic lesion. Postoperative blood glucose levels returned to normal. Histopathologic examination confirmed the diagnosis of liver metastasis of a neuroendocrine tumor. This is the longest interval between primary tumor and the metastasis reported in the literature, for insulinoma. Thus, it should be remembered that long-term follow-up is mandatory for the patients with insulinoma even after resection of the primary tumor. Resection is recommended when a metastatic lesion is observed.


Mild depressive symptoms are associated with amplified and prolonged inflammatory responses after influenza virus vaccination in older adults.
Depression is associated with enhanced production of proinflammatory cytokines that influence a spectrum of conditions associated with aging, including cardiovascular disease, osteoporosis, arthritis, type 2 diabetes mellitus, certain cancers, periodontal disease, frailty, and functional decline. In this prospective community study, we assessed the relationship between depressive symptoms and changes in inflammatory response after an influenza virus vaccination. To study the dynamics of interleukin (IL) 6 levels in plasma in response to an immunological challenge, we obtained blood samples in 119 older adults (mean age, 71.21 +/- 8.68 years [SD]) immediately before an annual influenza vaccination and again 2 weeks later. The short form of the Beck Depression Inventory, completed at these same times, provided information on depressive symptoms. The number of depressive symptoms in this sample was low on average before vaccination (mean +/- SD number of symptoms, 3.07 +/- 3.09) and did not change significantly after vaccination. Participants with more depressive symptoms had higher levels of IL-6 before and after vaccination than did those who reported fewer symptoms; moreover, individuals reporting more depressive symptoms also showed an increase in plasma IL-6 levels 2 weeks later, while there was little change in IL-6 levels among those reporting few or no symptoms. Even a modest number of depressive symptoms may sensitize the inflammatory response system in older adults and produce amplified and prolonged inflammatory responses after infection and other immunological challenges. Sustained and/or amplified inflammatory responses could accelerate a range of age-related diseases.


Factors influencing patient education in shared medical appointments: Integrative literature review.
This integrative literature review investigates the factors influencing patient education in Shared Medical Appointments. Following template analysis method, we used key concepts of the Social Cognitive Theory (SCT) and Social Constructivism as a priori themes. After detailed analysis of the included studies, we deduced subthemes, forming a final template. Based on this final template, we analysed our data again as a final check. We included 22 studies. We found that the factors feeling of bonding, humour, feeling of safety, access to information, time, relationship participants-staff, modelling and self-regulation influence the education of SMA participants. Furthermore, we found that health care providers function both as leaders and peers. We found eight factors that influence the education of SMA participants. Health care providers exert influence on these factors, but in turn, they are also influenced by them in their transfer of knowledge. In order to create a climate of learning and to promote transfer of knowledge, these eight factors should be considered. Health care providers should be aware of their roles and they might need some extra skills for their leadership roles. This can also lead to practical implications for the curriculum in medical schools.


Proximate factors affecting the larval life history of Acanthocephalus lucii (Acanthocephala).
The growth and eventual size of larval helminths in their intermediate hosts presumably has a variety of fitness consequences. Therefore, elucidating the proximate factors affecting parasite development within intermediate hosts should provide insight into the evolution of parasite life histories. An experimental infection that resulted in heavy intensities of an acanthocephalan (Acanthocephalus lucii) in its isopod intermediate host (Asellus aquaticus) permitted the examination of parasite developmental responses to variable levels of resource availability and intraspecific competition. Isopods were infected by exposure to egg-containing fish feces, and larval infrapopulations were monitored throughout the course of A. lucii development. The relative rate of parasite growth slowed over time, and indications of resource constraints on developing parasites, e.g., crowding effects, were only observed in late infections. Consequently, the factors likely representative of resource availability to larval parasites (host size and molting rate) primarily affected parasite size in late infections. Moreover, at this stage of infection, competitive interactions, gauged by variation in worm size, seemed to be alleviated by greater resources, i.e., larger hosts that molted more frequently. The relatively rapid, unconstrained growth of young parasites may be worse for host viability than the slower, resource-limited growth of larger parasites.


[A case of the management of inappropriate fixtures position with implant-retained overdenture].
A 71-year-old woman came to our clinic complaining of discomfort and esthetic problem of upper and lower anterior region caused by implants inserted in inappropriate positions. For this case implant-retained removable dentures with telescope crowns and magnet attachments were applied. The patient was followed for >5 years without any problems. Telescope crown may cause excessive stress for implants; however, in this case adequate maintenance including adjustments of occlusion and the fitness of denture base may have contributed to the longtime success. Problems caused by implants inserted in inappropriate positions were overcome using implant-retained removable dentures with both telescope crowns and magnet attachments.


[Fluorouracil and doxorubicin - cardiotoxic cytostatics in the workplace].
The aim of the study is to analyze the potential occupational hazards of fluorouracil (FU) and doxorubicin (DOX). The literature review was based on factual and bibliographic scientific databases of the available peer-reviewed journals and the so-called gray literature. In Poland, the process of determining the acceptable levels of occupational exposure for selected anticancer drugs has been underway since 2014, and the basis for determining the maximum allowable concentration values is usually the concentration equivalent to 0.1% of the lowest therapeutic dose found in the literature. In addition, uncertainty coefficients are used, which take into account the mechanism of action of the cytostatics, the dynamics of metabolism, the assessment of classification and labeling for carcinogenic, mutagenic, genotoxic, reproductive toxicity, organ toxicity, the ability to accumulate cytostatics, the assessment of cumulative effects with other cytostatics, the physicochemical form and data completeness. Where possible, the risk of additional cancer is estimated. Directive 2004/37/EC on the protection of workers from the risks related to exposure to carcinogens at work (the carcinogens and mutagens directive ‒ CMD) is a key legal solution in the field of public health in the European Union, focused on the issue of occupational cancer. These cytostatics, FU and DOX, are genotoxic and are classified as hazardous. Life-threatening heart damage is a serious side effect of both FU and DOX. The analysis has shown that the inclusion of dangerous drugs in the list of substances subject to the requirements of the CMD is completely justified. The cytostatics classification and labeling procedure should be harmonized throughout the European Union, which will ensure a reliable and credible risk management in this area. Med Pr. 2020;71(3):363-73.