Adenosine and cardioprotection in the diseased heart.
Biological and mechanical stressors such as ischemia, hypoxia, cellular ATP depletion, Ca2+ overload, free radicals, pressure and volume overload, catecholamines, cytokines, and renin-angiotensin may independently cause reversible and/or irreversible cardiac dysfunction. As a defense against these forms of stress, several endogenous self-protective mechanisms are exerted to avoid cellular injury. Adenosine, a degradative substance of ATP, may act as an endogenous cardioprotective substance in pathophysiological conditions of the heart, such as myocardial ischemia and chronic heart failure. For example, when brief periods of myocardial ischemia precede sustained ischemia, infarct size is markedly limited, a phenomenon known as ischemic preconditioning. We found that ischemic preconditioning activates the enzyme responsible for adenosine release, ie, ecto-5'-nucleotidase. Furthermore, the inhibitor of ecto-5'-nucleotidase reduced the infarct size-limiting effect of ischemic preconditioning, which establishes the cause-effect relationship between activation of ecto-5'-nucleotidase and the infarct size-limiting effect. We also found that protein kinase C is responsible for the activation of ecto-5'-nucleotidase. Protein kinase C phosphorylated the serine and threonine residues of ecto-5'-nucleotidase. Therefore, we suggest that adenosine produced via ecto-5'-nucleotidase gives cardioprotection against ischemia and reperfusion injury. Also, we found that plasma adenosine levels are increased in patients with chronic heart failure. Ecto-5'-nucleotidase activity increased in the blood and the myocardium in patients with chronic heart failure, which may explain the increases in adenosine levels in the plasma and the myocardium. In addition, we found that further elevation of plasma adenosine levels due to either dipyridamole or dilazep reduces the severity of chronic heart failure. Thus, we suggest that endogenous adenosine is also beneficial in chronic heart failure. We propose potential mechanisms for cardioprotection attributable to adenosine in pathophysiological states in heart diseases. The establishment of adenosine therapy may be useful for the treatment of either ischemic heart diseases or chronic heart failure.


The phylogeny of the gene, from the "lower" naked structural genes to "higher" non transcriptional genes.
Within the nuclear eukaryotic genome there are two different information areas. One of these zones corresponds to coding DNA in which "structural genes" or "lower genes" can be found. On the other hand, disperse in the genome, there is the non-coding DNA, where redundant DNA can be found. In the latter area there are non-transcriptional genes or "higher genes" which arose with eukaryotic organisms as a result of coevolution. Viruses could have had an important role as natural vectors in the genomic evolution.


Online information-seeking behavior of Iranian web users on Google about Henoch-Schönlein purpura (HSP): an infodemiology study.
Previous studies have indicated that users' health information-seeking behavior can serve as a reflection of current health issues within a community. This study aimed to investigate the online information-seeking behavior of Iranian web users on Google about Henoch-Schönlein purpura (HSP). Google Trends (GTr) was utilized to collect big data from the internet searches conducted by Iranian web users. A focus group discussion was employed to identify users' selected keywords when searching for HSP. Additionally, keywords related to the disease's symptoms were selected based on recent clinical studies. All keywords were queried in GTr from January 1, 2012 to October 30, 2022. The outputs were saved in an Excel format and analyzed using SPSS. The highest and lowest search rates of HSP were recorded in winter and summer, respectively. There was a significant positive correlation between HSP search rates and the terms "joint pain" (P = 0.007), "vomiting" (P = 0.032), "hands and feet swelling" (P = 0.041) and "seizure" (P < 0.001). The findings were in accordance with clinical facts about HSP, such as its seasonal pattern and accompanying symptoms. It appears that the information-seeking behavior of Iranian users regarding HSP can provide valuable insights into the outbreak of this disease in Iran.


Primary clear cell carcinoma of nasal cavity: report of six cases and review of literature.
This study is to retrospectively analyze the clinical and pathological data of six cases of primary nasal clear cell carcinoma in our hospital since 1992 and to review literatures on the clinical manifestations, pathological features, immunohistochemistry, diagnosis and treatment of the disease. The pathological archives that were diagnosed as salivary gland nasal tumors in Shandong Cancer Hospital during 1992-2013 were reviewed. Careful review of sections was performed by two experienced pathologists. The samples were labeled using EnVision method. Immunostaining was performed using 3, 3'-diaminobenzidine reagent followed by counterstaining with hematoxylin. The immunohistochemical results were classified according to positive cells: no positive staining cells (-); positive cells <30% (+); positive cells between 30% and 50% (++); and positive cells >50% (+++). Among the 6 cases of primary nasal clear cell carcinoma in our hospital since 1992, 4 cases were diagnosed as clear cell carcinoma of nasal cavity after exclusion of other nasal cavity tumors with clear cells, and 2 cases were directly diagnosed as clear cell carcinoma of nasal cavity. Hyalinizing clear cell carcinoma of salivary gland (HCCC) tissues were mainly composed of polygonal epithelioid tumor cells arranged into the shapes of beehives, and separated by fibrous tissues containing rich thin-wall capillaries. The cytoplasm of HCCC cells was rich and translucent with some cells having multiple vacuoles. Reticular fiber staining showed that the tumor cells were arranged in shapes of beehives and separated by rich reticular fibers. HCCC tumor reacted differently on S-100 protein, glial fibrillary acidic protein, actin and vimentin. The ultrastructure of HCCC cells showed characteristics of ducts but no myoepithelial differentiation. This study demonstrates that correct diagnosis, timely surgical resection and postoperative radiotherapy are effective in treating nasal clear cell carcinoma.


Delineation of canine parvovirus T cell epitopes with peripheral blood mononuclear cells and T cell clones from immunized dogs.
Three synthetic peptides derived from the amino acid sequence of VP2 of canine parvovirus (CPV) which were recently shown to represent three distinct T cell epitopes for BALB/c mice could prime BALB/c mice for a CPV-specific proliferative T cell response upon immunization. Proliferative responses of peripheral blood mononuclear cells (PBMC) from CPV-immunized dogs upon stimulation with these and other peptides, covering the major part of the sequence of VP2', identified the presence of T cell epitopes for this species. Most of these epitopes were recognized by PBMC from only a minority of the dogs tested. With three newly generated canine Thyl+ T cell clones, which recognized CPV antigen in association with major histocompatibility complex class II molecules, two distinct T cell epitopes were identified within the unique sequence of VP1.


Somitogenesis in amphibian embryos. III. Effects of ambient temperature and of developmental stage upon pattern abnormalities that follow short temperature shocks.
Temperature shocks of a few minutes duration at 37 degrees C to tail-bud embryos of Rana induce zones of abnormal segmentation along the somite files subsequently produced. The immediate result of a temperature shock is a temporary arrest of development as a whole, following which the schedule of somite determination and formation is resumed at the normal rate. It is during the period immediately following this that the zone of abnormal somite pattern is determined. Thus the length of the abnormal zone reflects the total time taken by the morphogenetic system to recover from the disturbance, and might depend upon variables affecting both the duration of the initial arrest and the duration of the recovery period itself. Observations are presented demonstrating how the length of abnormal zones, caused by a temperature shock of any particular severity, are affected by three variables; (1) the ambient temperature to which the embryos were adapted before shock, (2) the ambient temperature of post-shock development, (3) the stage in somitogenesis, i.e. the number of somites already formed at the time of shock. The data (in this and previous papers of the series) support models postulating that the spatial periodicity in cell behaviour, that is somite morphogenesis, reflects a normal interaction between two hidden aspects of development, one a wavefront of cellular activation passing down the body axis, and the other having the character of a temporal periodicity throughout the tissue. Temperature shock, as well as halting the wavefront (i.e. stopping development) temporarily, leads to a subsequent period during which there is only gradual recovery of normal co-ordination between the periodicity within cells of the tissue and the wavefront progress. It is the relative rate of this recovery, alone, that is responsible for variation in the length of the abnormal zone.


IL6 gene-wide haplotype is associated with susceptibility to acute lung injury.
Experimental and clinical studies support the key role of interleukin 6 (IL-6), a potent proinflammatory cytokine, in the development of acute lung injury (ALI). Plasma IL-6 levels are influenced mainly by genetic determinants, and a -174G/C polymorphism of the gene has been recently associated with susceptibility to ALI. Here we aimed to validate the association of the IL6 gene with ALI in a case-control sample from Spain. DNA was isolated from 67 consecutive patients who fulfilled international criteria for severe sepsis and for ALI and 96 population-based controls drawn from the general population. Genotypes of the -174G/C polymorphism along with other 14 tagging variants of the IL6 gene were evaluated. Twenty polymorphisms unlinked to IL6 gene were additionally compared between cases and controls to rule out population stratification. None of the individual single-nucleotide polymorphisms was significantly associated with susceptibility to ALI. However, we found that a common haplotype from -1363 to +4835 from the transcription start site, and spanning the gene, conferred risk for susceptibility to ALI (odds ratio, 2.73; 95% confidence interval, 1.39-5.37; P = 0.003). Adjustment for relevant covariates did not modify this result. These data support the association of the IL6 gene with ALI susceptibility and illustrate the value of haplotype analysis as a robust approach for evaluating IL6 gene effects in association studies.


Bortezomib treatment produces nocifensive behavior and changes in the expression of TRPV1, CGRP, and substance P in the rat DRG, spinal cord, and sciatic nerve.
To investigate neurochemical changes associated with bortezomib-induced painful peripheral neuropathy (PN), we examined the effects of a single-dose intravenous administration of bortezomib and a well-established "chronic" schedule in a rat model of bortezomib-induced PN. The TRPV1 channel and sensory neuropeptides CGRP and substance P (SP) were studied in L4-L5 dorsal root ganglia (DRGs), spinal cord, and sciatic nerve. Behavioral measures, performed at the end of the chronic bortezomib treatment, confirmed a reduction of mechanical nociceptive threshold, whereas no difference occurred in thermal withdrawal latency. Western blot analysis showed a relative increase of TRPV1 in DRG and spinal cord after both acute and chronic bortezomib administration. Reverse transcriptase-polymerase chain reaction revealed a decrease of TRPV1 and CGRP mRNA relative levels after chronic treatment. Immunohistochemistry showed that in the DRGs, TRPV1-, CGRP-, and SP-immunoreactive neurons were mostly small- and medium-sized and the proportion of TRPV1- and CGRP-labeled neurons increased after treatment. A bortezomib-induced increase in density of TRPV1- and CGRP-immunoreactive innervation in the dorsal horn was also observed. Our findings show that bortezomib-treatment selectively affects subsets of DRG neurons likely involved in the processing of nociceptive stimuli and that neurochemical changes may contribute to development and persistence of pain in bortezomib-induced PN.


Ca++ inhibition of isoproterenol responses in mammalian skeletal muscle.
In noncontracting mouse hemidiaphragms incubated in modified Krebs-Ringer--bicarbonate buffer with 10 mM Ca++, isoproterenol-stimulated phosphorylase a formation, conversion of phosphorylase kinase to the activated form, elevation of cyclic AMP-dependent protein kinase activity ratios and increase in cyclic AMP concentrations were reduced 35 to 50% over the responses in buffer with 2.5 mM Ca++. In buffer with 10 mM Ca++, the initial rate of isoproterenol-stimulated cyclic AMP accumulation was 59% of that in buffer with 2.5 mM Ca++. The inhibitory action of Ca++ on cyclic AMP accumulation was antagonized by verapamil, but not by inhibitors of cyclic nucleotide phosphodiesterase activity. In buffer with 2.5 mM Ca++, isoproterenol-stimulated cyclic AMP accumulation was inhibited by A23187 and caffeine, agents that can increase intracellular Ca++ concentrations. In addition to Ca++, high concentrations of Co++, Ni++, Mn++ and, to a lesser extent, Sr++ inhibited the isoproterenol response. The results of these studies indicate that high buffer Ca++ concentrations inhibit the response of the glycogenolytic pathway to isoproterenol by an action on cyclic AMP formation. We propose that the site of the inhibitory action of Ca++ is the divalent metal activator site associated with hormone-stimulated adenylate cyclase activity.


[From the history of the 19th century pathology. Pathological anatomy and pathology in the first half of the 19th century].
The paper analyzes the first half of the 19th century collective notions on disease as the event that is alien to the human body (which is embodied as a living being), which occurs and develops in accordance with its own laws differing from the laws of human vital functions; on the causes and essence of diseases and the methods of their study. It also shows a place of human pathology in the structure of medical knowledge of that time and its role in the investigation of diseases.


IFN-mediated induction of MHC antigen expression on human keratinocytes and its influence on in vitro alloimmune responses.
The MHC Ag expression on the surface of keratinocytes is altered after treatment with IFN. IFN-gamma induces, as expected, a strong increase in class I MHC Ag expression as well as de novo expression of class II MHC Ag, whereas IFN-alpha 2 only slightly increases class I MHC Ag and does not induce keratinocytes to express class II MHC Ag. We used untreated and IFN-pretreated keratinocytes as stimulators and also as targets to study whether IFN-induced MHC Ag changes would alter the immunogenicity of keratinocytes in alloimmune responses. It was found that class II MHC Ag-carrying keratinocytes were unable to induce the proliferation of resting lymphocytes, but did stimulate T blasts. Untreated keratinocytes were virtually resistant to the lysis by classical CTL but became susceptible after exposure to IFN-gamma, but not IFN-alpha 2 at physiologic doses. These data demonstrate mechanisms by which the release of IFN-gamma might contribute to the development of disease such as the graft vs host disease.


Surprises From Genetic Analyses of Lipid Risk Factors for Atherosclerosis.
Observational epidemiological studies have associated plasma lipid concentrations with risk for coronary heart disease (CHD), but these studies cannot distinguish cause from mere correlation. Human genetic studies, when considered with the results of randomized controlled trials of medications, can potentially shed light on whether lipid biomarkers are causal for diseases. Genetic analyses and randomized trials suggest that low-density lipoprotein is causal for CHD, whereas high-density lipoprotein is not. Surprisingly, human genetic evidence suggests that lipoprotein(a) and triglyceride-rich lipoproteins causally contribute to CHD. Gene variants leading to higher levels of plasma apolipoprotein B-containing lipoproteins [low-density lipoprotein, triglyceride-rich lipoproteins, or lipoprotein(a)] consistently increase risk for CHD. For triglyceride-rich lipoproteins, the most compelling evidence revolves around lipoprotein lipase and its endogenous facilitator (APOA5 [apolipoprotein A-V]) and inhibitory proteins (APOC3 [apolipoprotein C-III], ANGPTL4 [angiopoietin like 4]). Combined, these genetic results anticipate that, beyond low-density lipoprotein, pharmacological lowering of triglyceride-rich lipoproteins or lipoprotein(a) will reduce risk for CHD, but this remains to be proven through randomized controlled trials.


Multi-channel electromyography-based mapping of spontaneous smiles.
Human facial muscle activation underlies highly sophisticated signaling mechanisms that are critically important for healthy physiological function. Accordingly, the necessity to analyze facial muscle activation at high-resolution and in a non-invasive manner is important for the diagnosis and treatment of many medical conditions. However, current clinical examination methods are neither precise nor quantitative. Wearable, multi-channel surface electromyography can provide a solution to this yet unmet challenge. Here, we present the design and testing of a customized surface electromyography electrode array for facial muscle mapping. Muscle activation maps were derived from repeated voluntary facial muscle activations. A customized independent component analysis algorithm and a clustering algorithm were developed to identify consistent building block activation patterns within and between participants. Finally, focusing on spontaneous smile analysis and relying on the building block mapping, we classified muscle activation sources, revealing a consistent intra-subject activation and an inter-subject variability. The herein described approach can be readily used for automated and objective mapping of facial expressions in general and in the assessment of normal and abnormal smiling in particular.


Designing climate-smart conservation: guidance and case studies.
To be successful, conservation practitioners and resource managers must fully integrate the effects of climate change into all planning projects. Some conservation practitioners are beginning to develop, test, and implement new approaches that are designed to deal with climate change. We devised four basic tenets that are essential in climate-change adaptation for conservation: protect adequate and appropriate space, reduce nonclimate stresses, use adaptive management to implement and test climate-change adaptation strategies, and work to reduce the rate and extent of climate change to reduce overall risk. To illustrate how this approach applies in the real world, we explored case studies of coral reefs in the Florida Keys; mangrove forests in Fiji, Tanzania, and Cameroon; sea-level rise and sea turtles in the Caribbean; tigers in the Sundarbans of India; and national planning in Madagascar. Through implementation of these tenets conservation efforts in each of these regions can be made more robust in the face of climate change. Although these approaches require reconsidering some traditional approaches to conservation, this new paradigm is technologically, economically, and intellectually feasible.


Rare Genetic Blood Disease Modeling in Zebrafish.
Hematopoiesis results in the correct formation of all the different blood cell types. In mammals, it starts from specific hematopoietic stem and precursor cells residing in the bone marrow. Mature blood cells are responsible for supplying oxygen to every cell of the organism and for the protection against pathogens. Therefore, inherited or de novo genetic mutations affecting blood cell formation or the regulation of their activity are responsible for numerous diseases including anemia, immunodeficiency, autoimmunity, hyper- or hypo-inflammation, and cancer. By definition, an animal disease model is an analogous version of a specific clinical condition developed by researchers to gain information about its pathophysiology. Among all the model species used in comparative medicine, mice continue to be the most common and accepted model for biomedical research. However, because of the complexity of human diseases and the intrinsic differences between humans and other species, the use of several models (possibly in distinct species) can often be more helpful and informative than the use of a single model. In recent decades, the zebrafish (Danio rerio) has become increasingly popular among researchers, because it represents an inexpensive alternative compared to mammalian models, such as mice. Numerous advantages make it an excellent animal model to be used in genetic studies and in particular in modeling human blood diseases. Comparing zebrafish hematopoiesis to mammals, it is highly conserved with few, significant differences. In addition, the zebrafish model has a high-quality, complete genomic sequence available that shows a high level of evolutionary conservation with the human genome, empowering genetic and genomic approaches. Moreover, the external fertilization, the high fecundity and the transparency of their embryos facilitate rapid, in vivo analysis of phenotypes. In addition, the ability to manipulate its genome using the last genome editing technologies, provides powerful tools for developing new disease models and understanding the pathophysiology of human disorders. This review provides an overview of the different approaches and techniques that can be used to model genetic diseases in zebrafish, discussing how this animal model has contributed to the understanding of genetic diseases, with a specific focus on the blood disorders.


Effects of the gout-causing Q141K polymorphism and a CFTR ΔF508 mimicking mutation on the processing and stability of the ABCG2 protein.
ABCG2 is an important multidrug transporter involved also in urate transport, thus its mutations can lead to the development of gout and may also alter general drug absorption, distribution and excretion. The frequent ABCG2 polymorphism, Q141K, is associated with an elevated risk of gout and has been controversially reported to reduce the plasma membrane expression and/or the transport function of the protein. In the present work we examined the stability and cellular processing of the Q141K ABCG2 variant, as well as that of the ΔF142 ABCG2, corresponding to the ΔF508 mutation in the CFTR (ABCC7) protein, causing cystic fibrosis. The processing and localization of full length ABCG2 variants were investigated in mammalian cells, followed by Western blotting and confocal microscopy, respectively. Folding and stability were examined by limited proteolysis of Sf9 insect cell membranes expressing these ABCG2 constructs. Stability of isolated nucleotide binding domains, expressed in and purified from bacteria, was studied by CD spectroscopy. We find that the Q141K variant has a mild processing defect which can be rescued by low temperature, a slightly reduced activity, and a mild folding defect, especially affecting the NBD. In contrast, the ΔF142 mutant has major processing and folding defects, and no ATPase function. We suggest that although these mutations are both localized within the NBD, based on molecular modeling their contribution to the ABCG2 structure and function is different, thus rescue strategies may be devised accordingly.


Robust color histogram descriptors for video segment retrieval and identification.
Effective and efficient representation of color features of multiple video frames or pictures is an important yet challenging task for visual information management systems. Key frame-based methods to represent the color features of a group of frames (GoF) are highly dependent on the selection criterion of the representative frame(s), and may lead to unreliable results. We present various histogram-based color descriptors to reliably capture and represent the color properties of multiple images or a GoF. One family of such descriptors, called alpha-trimmed average histograms, combine individual frame or image histograms using a specific filtering operation to generate robust color histograms that can eliminate the adverse effects of brightness/color variations, occlusion, and edit effects on the color representation. We show the efficacy of the alpha-trimmed average histograms for video segment retrieval applications, and illustrate how they consistently outperform key frame-based methods. Another color histogram descriptor that we introduce, called the intersection histogram, reflects the number of pixels of a given color that is common to all the frames in the GoF. We employ the intersection histogram to develop a fast and efficient algorithm for identification of the video segment to which a query frame belongs. The proposed color histogram descriptors have been included in the ISO standard MPEG-7 after extensive evaluation experiments.


The transcriptional regulator CCCTC-binding factor limits oxidative stress in endothelial cells.
The CCCTC-binding factor (CTCF) is a versatile transcriptional regulator required for embryogenesis, but its function in vascular development or in diseases with a vascular component is poorly understood. Here, we found that endothelial Ctcf is essential for mouse vascular development and limits accumulation of reactive oxygen species (ROS). Conditional knockout of Ctcf in endothelial progenitors and their descendants affected embryonic growth, and caused lethality at embryonic day 10.5 because of defective yolk sac and placental vascular development. Analysis of global gene expression revealed Frataxin (Fxn), the gene mutated in Friedreich's ataxia (FRDA), as the most strongly down-regulated gene in Ctcf-deficient placental endothelial cells. Moreover, in vitro reporter assays showed that Ctcf activates the Fxn promoter in endothelial cells. ROS are known to accumulate in the endothelium of FRDA patients. Importantly, Ctcf deficiency induced ROS-mediated DNA damage in endothelial cells in vitro, and in placental endothelium in vivo Taken together, our findings indicate that Ctcf promotes vascular development and limits oxidative stress in endothelial cells. These results reveal a function for Ctcf in vascular development, and suggest a potential mechanism for endothelial dysfunction in FRDA.


[Computerized analysis of esophageal manometry].
Computerized analysis of esophageal manometry should consider the following objectives: a) objectivation of data acquisition; b) precision in calculating the various parameters; c) speed of analysis; d) an easy-to-read and promptly understandable graphic display of the manometric data; e) computation of new parameters capable of defining normal and pathologic function. It is with these objectives in mind that we launched our research project. Five normal subjects and 10 patients, of whom 5 presented esophageal achalasia and 5 gastroesophageal reflux disease, underwent computerized esophageal manometry and were evaluated on the basis of both traditional and innovative parameters, of our own inception. Among the various indexes tested, the "Esophageal transport" parameter, calculated as the ratio of momentum (dp*dT) over speed of propagation of the esophageal contractions, gave rise to particular interest. In our opinion, this parameter can be used as an index of the dynamic function of the organ.


Pompe disease in infants: improving the prognosis by newborn screening and early treatment.
Pompe disease causes progressive, debilitating, and often life-threatening musculoskeletal, respiratory, and cardiac symptoms. Favorable outcomes with early intravenous enzyme-replacement therapy and alglucosidase alfa have been reported, but early clinical diagnosis before the development of severe symptoms has rarely been possible in infants. We recently conducted a newborn screening pilot program in Taiwan to improve the early detection of Pompe disease. Six of 206088 newborns screened tested positive and were treated for Pompe disease. Five had the rapidly progressive form of Pompe disease, characterized by cardiac and motor involvement, and were treated soon after diagnosis. The sixth patient was started on treatment at 14 months of age because of progressive muscle weakness. Outcomes were compared with treated patients whose disease was diagnosed clinically and with untreated historical control subjects. At the time of this report, patients had been treated for 14 to 32 months. The 5 infants who had early cardiac involvement demonstrated normalization of cardiac size and muscle pathology with normal physical growth and age-appropriate gains in motor development. The infant without cardiac involvement also achieved normal motor development with treatment. Survival in patients who had newborn screening was significantly improved compared with those in the untreated reference cohort (P = .001). Survival in the treated clinical comparators was reduced but not statistically different from that in the newborn screening group (P = .48). Results from this study indicate that early treatment can benefit infants with Pompe disease and highlight the advantages of early diagnosis, which can be achieved by newborn screening.


Pregnancy Research on Osteopathic Manipulation Optimizing Treatment Effects: the PROMOTE study.
The purpose of this study was to evaluate the efficacy of osteopathic manipulative treatment (OMT) to reduce low back pain and improve functioning during the third trimester in pregnancy and to improve selected outcomes of labor and delivery. Pregnancy research on osteopathic manipulation optimizing treatment effects was a randomized, placebo-controlled trial of 400 women in their third trimester. Women were assigned randomly to usual care only (UCO), usual care plus OMT (OMT), or usual care plus placebo ultrasound treatment (PUT). The study included 7 treatments over 9 weeks. The OMT protocol included specific techniques that were administered by board-certified OMT specialists. Outcomes were assessed with the use of self-report measures for pain and back-related functioning and medical records for delivery outcomes. There were 136 women in the OMT group: 131 women in the PUT group and 133 women in the UCO group. Characteristics at baseline were similar across groups. Findings indicate significant treatment effects for pain and back-related functioning (P < .001 for both groups), with outcomes for the OMT group similar to that of the PUT group; however, both groups were significantly improved compared with the UCO group. For secondary outcome of meconium-stained amniotic fluid, there were no differences among the groups. OMT was effective for mitigating pain and functional deterioration compared with UCO; however, OMT did not differ significantly from PUT. This may be attributed to PUT being a more active treatment than intended. There was no higher likelihood of conversion to high-risk status based on treatment group. Therefore, OMT is a safe, effective adjunctive modality to improve pain and functioning during the third trimester.


Succimer, an oral lead chelator.
The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of succimer when used for the treatment of lead poisoning are reviewed. Succimer is an orally active, heavy-metal chelating agent that forms stable, water-soluble complexes with lead; it also chelates other toxic heavy metals, such as arsenic and mercury. It is a designated orphan drug that is indicated for the treatment of lead poisoning, specifically in children with blood lead concentrations higher than 45 micrograms/dL. Succimer reverses the adverse metabolic effects of lead on heme synthesis while increasing urinary lead output without adversely affecting essential mineral excretion at the recommended dosage regimen. The rebound in lead concentrations that can occur after short courses of chelating therapies (caused by redistribution of lead from bone stores) may require frequent and multiple courses of chelation therapy. The most common adverse effects reported in clinical trials of succimer in children and adults were nausea, vomiting, diarrhea, appetite loss, and loose stools; these effects may be related to the drug's unpleasant mercaptan odor. There are no known drug interactions between succimer and other drugs, including iron supplements, although data are limited. The recommended initial dosage in children is 10 mg/kg or 350 mg/sq m every eight hours for five days. The dosage is then reduced to 10 mg/kg or 350 mg/sq m every 12 hours for an additional two weeks. Clinical studies indicate that succimer is relatively selective for lead and effectively lowers blood lead concentrations. Although clinical experience is limited, an oral lead chelator may offer advantages over currently available agents.


Distribution and fine structure of macrophages in the human ovary during the menstrual cycle, pregnancy and menopause.
We evaluated the distribution and ultrastructural characteristics of macrophages in the ovaries of women of reproductive ages, during pregnancy, and after menopause, by immunohistochemistry and transmission electron microscopy. Macrophages appeared around the ovarian follicle with its development. Their organelles were poorly developed, and no vacuoles or granules were observed in the cytoplasm. Macrophages were also present in the cavity of the atretic follicle, being larger in size than those in the developing follicle and characterized by cytoplasmic vacuoles and granules of a lysosomal nature. With the luteinization of the follicle, macrophages were seen to be distributed inside and outside the corpus luteum, but constituted only a minor population as compared with other kinds of leukocytes. The intracellular organelles were well-developed, including the lysosomal granules. In early pregnancy, the number of macrophages was noticeably increased in the corpus luteum. They were observed mainly outside the corpus luteum, and stained strongly with hCG immunohistochemically. Macrophages were present in the regressing corpus luteum and in the corpus albicans. Numerous lipid droplets and elongated cholesterol crystals were seen in the cytoplasm. Macrophages therefore appeared to be present throughout the ovarian cycle and may be involved in the development and atresia of the follicles and the progression and the regression of luteal tissues.


Global Prevalence of Hypertension in Children: A Systematic Review and Meta-analysis.
Reliable estimates of the prevalence of childhood hypertension serve as the basis for adequate prevention and treatment. However, the prevalence of childhood hypertension has rarely been synthesized at the global level. To conduct a systematic review and meta-analysis to assess the prevalence of hypertension in the general pediatric population. PubMed, MEDLINE, Embase, Global Health, and Global Health Library were searched from inception until June 2018, using search terms related to hypertension (hypertension OR high blood pressure OR elevated blood pressure), children (children OR adolescents), and prevalence (prevalence OR epidemiology). Studies that were conducted in the general pediatric population and quantified the prevalence of childhood hypertension were eligible. Included studies had blood pressure measurements from at least 3 separate occasions. Two authors independently extracted data. Random-effects meta-analysis was used to derive the pooled prevalence. Variations in the prevalence estimates in different subgroups, including age group, sex, setting, device, investigation period, BMI group, World Health Organization region and World Bank region, were examined by subgroup meta-analysis. Meta-regression was used to establish the age-specific prevalence of childhood hypertension and to assess its secular trend. Prevalence of childhood hypertension overall and by subgroup. A total of 47 articles were included in the meta-analysis. The pooled prevalence was 4.00% (95% CI, 3.29%-4.78%) for hypertension, 9.67% (95% CI, 7.26%-12.38%) for prehypertension, 4.00% (95% CI, 2.10%-6.48%) for stage 1 hypertension, and 0.95% (95% CI, 0.48%-1.57%) for stage 2 hypertension in children 19 years and younger. In subgroup meta-analyses, the prevalence of childhood hypertension was higher when measured by aneroid sphygmomanometer (7.23% vs 4.59% by mercury sphygmomanometer vs 2.94% by oscillometric sphygmomanometer) and among overweight and obese children (15.27% and 4.99% vs 1.90% among normal-weight children). A trend of increasing prevalence of childhood hypertension was observed during the past 2 decades, with a relative increasing rate of 75% to 79% from 2000 to 2015. In 2015, the prevalence of hypertension ranged from 4.32% (95% CI, 2.79%-6.63%) among children aged 6 years to 3.28% (95% CI, 2.25%-4.77%) among those aged 19 years and peaked at 7.89% (95% CI, 5.75%-10.75%) among those aged 14 years. This study provides a global estimation of childhood hypertension prevalence based on blood pressure measurements in at least 3 separate visits. More high-quality epidemiologic investigations on childhood hypertension are still needed.


Risk of cancer after assisted reproduction: a review of the available evidences and guidance to fertility counselors.
Infertile women requiring ovarian stimulation and assisted reproduction techniques (ART) are faced with difficult issues. The fear that using hormones could increase their risk of cancer is the most significant. One of the main challenges for assessing cancer risk after ART is the difficulty to separate it from the underlying condition of infertility per se. The delay or the inability to achieve a pregnancy is an important risk factor for breast, endometrial and ovarian cancer. We analyzed the current literature on the topic. The published literature in Medline and Cochrane was screened using the following keywords: ovulation induction, reproductive techniques, clomiphene, in vitro fertilization, fertility agents, female/adverse effects, female/toxicity gonadotropins/ adverse effects or gonadotropins/toxicity and "neoplasms or cancer". A total of 95 articles were evaluated. Limited evidence suggests that high doses or many cycles of clomiphene citrate could increase the risk of endometrial cancer, although the confounding factors of polycystic ovarian disease and overweight are not always considered. In some studies, ART modestly increased the risk of borderline ovarian cancer. Fertility treatments do not increase the risk of breast, cervical, endometrial and ovarian cancers, thyroid, melanoma and colon cancer. Women can be reassured that fertility drugs do not appear to significantly increase the risk of invasive ovarian, endometrial, breast or other cancers, while achieving a pregnancy at an earlier age is a significant protective factor.


The effect of intralysosomal sucrose storage on the turnover of hamster fibroblast lysosomal and Golgi-apparatus enzymes.
1. The effect of overloading of hamster fibroblast lysosomes with sucrose on the turnover of lysosomal and Golgi-apparatus enzymes was studied. Arylsulphatase B and UDP-galactose-N-acetylglucosamine galactosyltransferase were chosen as appropriate marker enzymes. The relative contributions of changes in the rates of synthesis and degradation to the increased activities of these enzymes after uptake of sucrose were examined by isotopic-labelling experiments. The effects of sucrose uptake on the degradation of total cellular protein and of the cytoplasmic enzyme, alkaline ribonuclease, were determined for comparative purposes. 2. The rates of enzyme synthesis in the presence and absence of sucrose were compared by pulse-labelling the cells with 14C-labelled amino acids, followed by isolation of purified enzymes and determination of their radioactivity. Sucrose uptake produced increases of 270% and 90% respectively in the rates of synthesis of arylsulphatase B and galactosyltransferase, whereas the rate of synthesis of alkaline ribonuclease was not affected. 3. The rates of degration of the enzymes were estimated by measuring the decay with time of the radioactivity of purified enzymes from prelabelled cells. In the absence of sucrose, the apparent half-lives of arylsulphatase B and galactosyltransferase were about 30 days and 40h respectively. After uptake of sucrose, the half-life of arylsulphatase B decreased to about 10 days and that of galactosyltransferase to 10h. Neither the half-life of alkaline ribonuclease (4 days) nor the rate of degradation of total cellular protein was affected by the uptake of sucrose. 4. These results indicate that the hyperactivity of lysosmal and Golgi-apparatus enzymes after the uptake of sucrose is accompanied by increases in the rates of both synthesis and degradation, and that the increased rates of degradation are insufficient to prevent accumulation of the excess of enzymes synthesized; also that the effects of sucrose uptake are restricted to the vacuolar apparatus.


Measurement of skin surface dose distributions in radiation therapy using poly(vinyl alcohol) cryogel dosimeters.
In external beam radiation therapy (EBRT), skin dose measurement is important to evaluate dose coverage of superficial target volumes. Treatment planning systems (TPSs) are often inaccurate in this region of the patient, so in vivo measurements are necessary for skin surface dose estimation. In this work, superficial dose distributions were measured using radiochromic translucent poly(vinyl alcohol) cryogels. The cryogels simultaneously served as bolus material, providing the necessary buildup to achieve the desired superficial dose. The relationship between dose to the skin surface and dose measured with the bolus was established using a series of oblique irradiations with gantry angles ranging from 0° to 90°. EBT-2 Gafchromic film was placed under the bolus, and the ratio of bolus-film dose was determined ranging from 0.749 ± 0.005 to 0.930 ± 0.002 for 0° and 90° gantry angles, respectively. The average ratio over 0-67.5° (0.800 ± 0.064) was used as the single correction factor to convert dose in bolus to dose to the skin surface. The correction factor was applied to bolus measurements of skin dose from head and neck intensity-modulated radiation therapy (IMRT) treatments delivered to a RANDO phantom. The resulting dose distributions were compared to film measurements using gamma analysis with a 3%/3 mm tolerance and a 10% threshold. The minimum gamma pass rate was 95.2% suggesting that the radiochromic bolus may provide an accurate estimation of skin surface dose using a simple correction factor. This study demonstrates the suitability of radiochromic cryogels for superficial dose measurements in megavoltage photon beams.


Active Plasmonics: Principles, Structures, and Applications.
Active plasmonics is a burgeoning and challenging subfield of plasmonics. It exploits the active control of surface plasmon resonance. In this review, a first-ever in-depth description of the theoretical relationship between surface plasmon resonance and its affecting factors, which forms the basis for active plasmon control, will be presented. Three categories of active plasmonic structures, consisting of plasmonic structures in tunable dielectric surroundings, plasmonic structures with tunable gap distances, and self-tunable plasmonic structures, will be proposed in terms of the modulation mechanism. The recent advances and current challenges for these three categories of active plasmonic structures will be discussed in detail. The flourishing development of active plasmonic structures opens access to new application fields. A significant part of this review will be devoted to the applications of active plasmonic structures in plasmonic sensing, tunable surface-enhanced Raman scattering, active plasmonic components, and electrochromic smart windows. This review will be concluded with a section on the future challenges and prospects for active plasmonics.


Routes to obesity: phenotypes, food choices and activity.
Gain in body weight over a number of years could be achieved through cumulative positive energy balances. These positive balances could come about through adjustments in the various components of energy expenditure or fuel utilization, together with shifts in food selection or eating patterns leading to adjustments in macronutrient intake. This means that many combinations of intake and expenditure could lead to a positive energy balance; these combinations can be called routes to body weight gain. However, these routes are difficult to trace by studying random samples of individuals. Previous investigations have found a clear association between high fat consumption and the occurrence of obesity, and although a high fat intake is a strong behavioural risk factor for weight gain, the relationship does not constitute a biological inevitability. Some normal-weight and lean individuals appear to eat a high-fat diet. To investigate reasons for this we have studied individuals initially defined by particular clusters of dietary characteristics related to fat and carbohydrate consumption. Habitual high-fat (HF) and low-fat (LF) consumers have been termed phenotypes. Various aspects of energy expenditure (physiological and behavioural) and energy intake were measured in these individuals with contrasting profiles. HF phenotypes had high intakes of fatty foods and an overall higher energy intake than LF. However, these groups of young adult males had similar BMIs and percentage body fat. The HF had a significantly higher resting metabolic rate (RMR) and a lower RQ, together with high plasma fasting leptin levels, and a higher sleeping heart rate. In HF individuals the physical activity level was somewhat lower and they had significantly more periods of sedentary behaviour than LF subjects. Although HF individuals appear to be more vulnerable to developing obesity, both phenotypes carry particular risk factors and protective factors for weight gain. The use of phenotypes has allowed the identification of different potential routes to weight gain. Different strategies are required to prevent age-related increase in body weight in these quite different individuals.


[Molecular biology of hearing].
The inner ear is our most sensitive sensory organ and can be subdivided into 3 functional units: organ of Corti, stria vascularis and spiral ganglion. The appropriate stimulus for the organ of hearing is sound which travels through the external auditory canal to the middle ear where it is transmitted to the inner ear. The inner ear habors the hair cells, the sensory cells of hearing. The inner hair cells are capable of mechanotransduction, the transformation of mechanical force into an electrical signal, which is the basic principle of hearing. The stria vascularis generates the endocochlear potential and maintains the ionic homeostasis of the endolymph. The dendrites of the spiral ganglion form synaptic contacts with the hair cells. The spiral ganglion is composed of neurons that transmit the electrical signals from the cochlea to the central nervous system. In the past years there was significant progress in research on the molecular basis of hearing. More and more genes and proteins which are related to hearing can be identified and characterized. The increasing knowledge on these genes contributes not only to a better understanding of the mechanism of hearing but also to a deeper understanding of the molecular basis of hereditary hearing loss. This basic research is a prerequisite for the development of molecular diagnostics and novel therapies for hearing loss.


The impact of neighborhood social and built environment factors across the cancer continuum: Current research, methodological considerations, and future directions.
Neighborhood social and built environments have been recognized as important contexts in which health is shaped. The authors reviewed the extent to which these neighborhood factors have been addressed in population-level cancer research by scanning the literature for research focused on specific social and/or built environment characteristics and their association with outcomes across the cancer continuum, including incidence, diagnosis, treatment, survivorship, and survival. The commonalities and differences in methodologies across studies, the current challenges in research methodology, and future directions in this research also were addressed. The assessment of social and built environment factors in relation to cancer is a relatively new field, with 82% of the 34 reviewed articles published since 2010. Across the wide range of social and built environment exposures and cancer outcomes considered by the studies, numerous associations were reported. However, the directions and magnitudes of associations varied, in large part because of the variation in cancer sites and outcomes studied, but also likely because of differences in study populations, geographic regions, and, importantly, choice of neighborhood measures and geographic scales. The authors recommend that future studies consider the life-course implications of cancer incidence and survival, integrate secondary and self-report data, consider work neighborhood environments, and further develop analytical and statistical approaches appropriate to the geospatial and multilevel nature of the data. Incorporating social and built environment factors into research on cancer etiology and outcomes can provide insights into disease processes, identify vulnerable populations, and generate results with translational impact of relevance for interventionists and policy makers.


Tight-binding calculations of the optical properties of Si nanocrystals in a SiO2 matrix.
We develop an empirical tight binding approach for the modeling of the electronic states and optical properties of Si nanocrystals embedded in a SiO2 matrix. To simulate the wide band gap SiO2 matrix we use the virtual crystal approximation. The tight-binding parameters of the material with the diamond crystal lattice are fitted to the band structure of β-cristobalite. This model of the SiO2 matrix allows us to reproduce the band structure of real Si nanocrystals embedded in a SiO2 matrix. In this model, we compute the absorption spectra of the system. The calculations are in an excellent agreement with experimental data. We find that an important part of the high-energy absorption is defined by the spatially indirect, but direct in k-space transitions between holes inside the nanocrystal and electrons in the matrix.


Assessment of Therapy-Related Myeloid Neoplasms in Patients With Neuroendocrine Tumors After Peptide Receptor Radionuclide Therapy: A Systematic Review.
Peptide receptor radionuclide therapy (PRRT) is a tumor-targeted treatment that uses radiation to induce tumor cell death in neuroendocrine tumors (NET) via β particle-emitting radionuclide linked to a somatostatin peptide analog. Therapy-related myeloid neoplasm (t-MN) has been reported as a potential long-term and frequently lethal adverse event after PRRT. However, the incidence, time of diagnosis, and nature of t-MN is unclear. Therefore, a systematic review is helpful to study the incidence and characteristics of t-MN after PRRT in patients with NET. To systematically evaluate the literature and report the incidence, time of diagnosis, and nature of t-MN after PRRT. MEDLINE, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials for articles and abstracts reporting studies of different designs studying more than 1 patient (randomized clinical trials, prospective phase I or phase II, retrospective studies, and case series) were searched from database inception through April 2019. Studies of interest included patients with NET who were treated with PRRT and reported the incidence of t-MN, if any. The primary outcome was the incidence of t-MN. Twenty-eight articles were identified comprising 7334 patients who were treated with PRRT for NET. The main reason of exclusion was not reporting the t-MN incidence. The incidence of t-MN was variable between studies with mean (SD) incidence of 2.61% (4.38%). Of all 134 cases, cytogenetic abnormalities were reported in 32 patients with the most common abnormality being complex cytogenetics, consistent with myeloid neoplasms following exposure to alkylating agents or irradiation. The risk of t-MN after PRRT is small but not insignificant given the poor prognosis after t-MN diagnosis. Close monitoring is warranted to identify such patients early in the disease course when hematologic abnormalities persist.


The interplay between voluntary food intake, dietary carbohydrate-lipid ratio and nutrient metabolism in an amphibian, (Xenopus laevis).
Digestion of food and metabolism of frogs are little studied at the moment, and such processes could be very particular in the case of amphibians, given their ectothermic and carnivorous nature which may lead them to use nutrients through specific biochemical pathways. In the present study, 24 adult Xenopus laevis (six replicates with two frogs per treatment) were randomly assigned to two diets with different carbohydrate:fat ratio (4.5:1 and 2.1:1), changing the dietary glucogenic and lipogenic proportions. Food intake (FI) per unit metabolic body weight (MBW) as well as macronutrient digestibility were calculated, and circulating blood acylcarnitines and amino acids measured, in order to evaluate the effect of the diet treatments. Results demonstrated that food intake regulated most of the changes in the parameters evaluated; significant differences were obtained in crude protein and fat digestibilities through the effect of FI/MBW (p<0.05), whereas diet treatment had a significant effect on the levels of malonyl-CoA. Food intake also significantly impacted malonyl, isovaleryl, hydroxyisovaleryl and long chain fatty acid concentrations; significant (p<0.05) interactions between those metabolites were detected owing to diet. The findings obtained suggest that food intake was the main factor controlling digestion and metabolism in X. laevis, with frogs preferring to utilise protein and fat as primary sources for energy production in the citric acid cycle, reflecting characteristics of a strict carnivore physiological model.


[Charles Phillips (1811-1870), a famous urologist, born in Liege, and yet unknown in that city].
Charles Phillips was born in Liege at the beginning of the XIXth century. In that city, he studied medicine and, later, lectured, during a few years, initially, at the School of Medicine, and, later, at the School of Veterinary Medicine. Having trained in several European centres, he settled in Paris where he soon became a well-known urologist. Remarkably intelligent and inventive, he was also a great medical artist; he produced some wonderful books and invented several devices that are still in use to-day in basic urology. Surprisingly, his name is almost unknown nowadays in his city of origin.


Absence of otoacoustic emissions in subjects with normal audiometric thresholds implies exposure to noise.
Otoacoustic emissions and contra-lateral sound activated efferent suppression of emissions were examined to determine whether they provide any early indication of auditory damage from exposure to noise. Three groups were studied: noise exposed workers (n=50, mean age 42 years), patients with Meniere's disease (n=24, mean age 48 years) and normal subjects (n=24, mean age 41 years). All subjects underwent routine pure tone audiometry, tympanometry and otoacoustic emission testing. As a number of studies have shown that with hearing threshold better than 30 dB HL, emissions are almost always present and are generally absent with hearing loss greater than 30 dB HL, subjects in this study were sub grouped into these two categories in order to examine the incidence of emissions. Absence of emissions in subjects with mean hearing thresholds better than 30 dB HL varied from 0% in normal controls, 8% in patients with Meniere's disease and a significantly high 56% in noise exposed workers despite similar mean hearing thresholds for all groups. The mean transient emission levels for the noise exposed workers was significantly lower than the controls and Meniere's groups. This study clearly indicates that in the noise-exposed group there is sub clinical and sub audiometric damage to the outer hair cells responsible for generation of otoacoustic emissions. Of those with normal otoacoustic emissions, the efferent suppression was absent in 60% of noise exposed workers but in only 3.8% of control subjects implying that the efferent control may also be affected in a significant proportion despite normal hearing thresholds and emissions.


Implementation of online video consultations in a regional health network: a management feasibility analysis from an orthopedic perspective.
Regional health care networks with interfaces between clinics, general practitioners and patients can act faster when utilizing digital measures. This manuscript describes the establishment of an online video consultation service in a clinic and its broad health care region to exemplify challenges and solutions for potential future approaches from a management perspective. The underlying pilot project was planned and implemented for follow-up monitoring and consultative presentation of orthopedic and trauma patients within the Bundeswehr Medical Service from 2018 to 2020. With predominantly positive evaluation results regarding quality and acceptance among users, this research investigated organizational and processual aspects including total quality management, strategic control and change management approaches. The affected main and subprocesses of patient treatment could be streamlined by the project, as physician recommendations and arrangements could be accelerated and patient travel could be significantly reduced. A SWOT and portfolio analysis showed a high potential for improving existing patient treatment processes for health care enterprises via the use of digital technology. The involved staff should be strategically included at an early stage and continuously involved. By means of a PDCA cycle, the processes of the given project could be exemplarily illustrated with an outlook in the future. It has proven successful to consciously use management approaches to establish telemedical integrated care structures in a health region. Recommendations for the strategic introduction of an online video consultation for regional network strengthening and care development for a patient-oriented increase in efficiency could be compiled.


Methodology of receptor research--a philosophical perspective.
Two examples taken from the philosophy of physics (measurement and experiment) show the dependence of quantitative data and of causal judgements on technical aims that are invested into both laboratory research and the concept formation of a successful science. Accordingly, methodology is defined as the theory of methods, i.e. of the rules governing actions constitutive of research and the phrasing of its results. Judgement on methods is a matter of means-and-ends rationality. The objects and relations under consideration are not natural but technical ones. With respect to analytical chemistry, a problem concerning the application of mathematics to quantitative data is described in order to argue for the irreducibility of measurement of macroscopic quantities (like volume) to the counting of numbers of micro-objects (like molecules): the basic concepts of microbiology, analytic chemistry and toxicology remain related to certain theoretical (and corresponding experimental) contexts. Starting from the perspective that receptor research is dealing with the effects of chemical substances on organisms, a few constraints on receptor research are characterised. The idealisation of causes and effects by describing them in terms of chemistry (on a molecular level) hinges on a problematic presupposition. It is objected that there is neither a way down from levels more complex to simpler ones nor a way up from simple to complex levels in so far as the criteria for medical diagnoses are not causally linked with chemical descriptions. As a result, the significance of the traditional connection between the medical treatment of persons and the manageableness of health effects by pharmaceutical means is stressed. Whether molecular models, theories and explanations are helpful for a phenomenological description has to be tested accordingly but cannot generally be presupposed.


Plasmodium falciparum gametocyte carriage is associated with subsequent Plasmodium vivax relapse after treatment.
Mixed P. falciparum/P. vivax infections are common in southeast Asia. When patients with P. falciparum malaria are treated and followed for several weeks, a significant proportion will develop P. vivax malaria. In a combined analysis of 243 patients recruited to two malaria treatment trials in western Cambodia, 20/43 (47%) of those with P. falciparum gametocytes on admission developed P. vivax malaria by Day 28 of follow-up. The presence of Pf gametocytes on an initial blood smear was associated with a 3.5-fold greater rate of vivax parasitemia post-treatment (IRR = 3.5, 95% CI 2.0-6.0, p<0.001). The increased rate of post-treatment P. vivax infection persisted when correlates of exposure and immunity such as a history of malaria, male gender, and age were controlled for (IRR = 3.0, 95% CI 1.9-4.7, p<0.001). Polymerase chain reaction (PCR) confirmed that only a low proportion of subjects (5/55 or 9.1%) who developed vivax during follow-up had detectable Pv parasites in the peripheral blood at baseline. Molecular detection of falciparum gametocytes by reverse transcriptase PCR in a subset of patients strengthened the observed association, while PCR detection of Pv parasitemia at follow-up was similar to microscopy results. These findings suggest that the majority of vivax infections arising after treatment of falciparum malaria originate from relapsing liver-stage parasites. In settings such as western Cambodia, the presence of both sexual and asexual forms of P. falciparum on blood smear at presentation with acute falciparum malaria serves as a marker for possible occult P. vivax coinfection and subsequent relapse. These patients may benefit from empiric treatment with an 8-aminoquinolone such as primaquine.


Parenting stress and impact of illness in parents of children with coeliac disease.
Coeliac disease (CD) is a chronic disease which could stress patients and their family. Although, poor attention has been paid to the quality of life in CD children and to the functioning of families with CD children. The study aims to evaluate the parenting perception of the CD impact and the parenting distress level. A group of 74 parents of CD children compiled the Impact Childhood Illness Scale and the Parenting Stress Index which is also compiled by 74 parents of health children. The assessment does not reveal a significant impact of CD on patient's personal life although some critical areas emerged. Results evidenced an higher level of parenting stress in parents of CD children than parents of healthy children. CD, if suitably managed, has not a critical impact on parenting perception. Although, CD certainly put parents through an higher risk of a distress related to parenting role than parents with health children. A early identification of parenting distress in a pediatric chronic illness could facilitate the adjustment to pathology.


Antigen-antibody interactions in capillary electrophoresis.
Immunoreactions in combination with separations by capillary electrophoresis (CE) are increasingly being used to quantitate specific analytes in biological fluids. Both competitive and non-competitive approaches have been used for the purpose and, in selected cases, now compare favorably with conventional quantitative immunoassays with respect to concentration limits of detection. CE is also a useful method to evaluate antigen-antibody binding on-line and offers unique possibilities for binding constant estimates, also for weakly binding antibodies and antibody fragments. In this review we cover recent developments in the use of antigen-antibody interactions in conjunction with CE and conclude that continued development of miniaturization, on-line preconcentration and more sensitive detection schemes will contribute to the further dissemination of CE-based immunoassays building on already established affinity CE approaches.


Chemotherapy-Enriched THBS2-Deficient Cancer Stem Cells Drive Hepatocarcinogenesis through Matrix Softness Induced Histone H3 Modifications.
The physical microenvironment is a critical mediator of tumor behavior. However, detailed biological and mechanistic insight is lacking. The present study reveals the role of chemotherapy-enriched CD133+ liver cancer stem cells (CSCs) with THBS2 deficiency. This subpopulation of cells contributes to a more aggressive cancer and functional stemness phenotype in hepatocellular carcinoma (HCC) by remodeling the extracellular matrix (ECM) through the regulation of matrix metalloproteinase (MMP) activity, collagen degradation, and matrix stiffness. The local soft spots created by these liver CSCs can enhance stemness and drug resistance and provide a route of escape to facilitate HCC metastasis. Interestingly, a positive feed-forward loop is identified where a local soft spot microenvironment in the HCC tumor is enriched with CD133 expressing cells that secrete markedly less ECM-modifying THBS2 upon histone H3 modification at its promoter region, allowing the maintenance of a localized soft spot matrix. Clinically, THBS2 deficiency is also correlated with low HCC survival, where high levels of CSCs with low THBS2 expression in HCC are associated with decreased collagen fiber deposits and an invasive tumor front. The findings have implications for the treatment of cancer stemness and for the prevention of tumor outgrowth through disseminated tumor cells.


When global and local molecular descriptors are more than the sum of its parts: Simple, But Not Simpler?
In this report, we introduce a set of aggregation operators (AOs) to calculate global and local (group and atom type) molecular descriptors (MDs) as a generalization of the classical approach of molecular encoding using the sum of the atomic (or fragment) contributions. These AOs are implemented in a new and free software denominated MD-LOVIs ( http://tomocomd.com/md-lovis ), which allows for the calculation of MDs from atomic weights vector and LOVIs (local vertex invariants). This software was developed in Java programming language and employed the Chemical Development Kit (CDK) library for handling chemical structures and the calculation of atomic weights. An analysis of the complexities of the algorithms presented herein demonstrates that these aspects were efficiently implemented. The calculation speed experiments show that the MD-LOVIs software has satisfactory behavior when compared to software such as Padel, CDKDescriptor, DRAGON and Bluecal software. Shannon's entropy (SE)-based variability studies demonstrate that MD-LOVIs yields indices with greater information content when compared to those of popular academic and commercial software. A principal component analysis reveals that our approach captures chemical information orthogonal to that codified by the DRAGON, Padel and Mold2 software, as a result of the several generalizations in MD-LOVIs not used in other programs. Lastly, three QSARs were built using multiple linear regression with genetic algorithms, and the statistical parameters of these models demonstrate that the MD-LOVIs indices obtained with AOs yield better performance than those obtained when the summation operator is used exclusively. Moreover, it is also revealed that the MD-LOVIs indices yield models with comparable to superior performance when compared to other QSAR methodologies reported in the literature, despite their simplicity. The studies performed herein collectively demonstrated that MD-LOVIs software generates indices as simple as possible, but not simpler and that use of AOs enhances the diversity of the chemical information codified, which consequently improves the performance of traditional MDs.


Longitudinal risk of suicide outcomes in people with severe mental illness following an emergency department visit and the effects of suicide prevention treatment.
Individuals with severe mental illness (SMI), including bipolar disorder (BD) and schizophrenia-spectrum disorders (SSD), are at high risk for suicide. However, suicide research often excludes individuals with SMI. The current research examined differences in suicide outcomes (i.e., suicide attempt or death) for adults with and without BD and SSD diagnoses following an emergency department (ED) visit and investigated the efficacy of the Coping Long Term with Active Suicide Program (CLASP) intervention in reducing suicide outcomes among people with SMI. 1235 adults presenting with recent suicidality were recruited from 8 different EDs across the United States. Using a quasi-experimental, stepped wedge series design, participants were followed for 52-weeks with or without subsequent provision of CLASP. Participants in the SSD group and the BD group had significantly shorter time to and higher rate of suicide outcomes than participants with other psychiatric diagnoses in all study phases and in non-CLASP phases, respectively. Participants with BD receiving the CLASP intervention had significantly longer time to suicide outcomes than those not receiving CLASP; these differences were not observed among those with SSD. Study limitations include self-reported psychiatric diagnosis, exclusion of homeless participants, and small sample size of participants with SSD. Participants with SMI were at higher risk for suicide outcomes than participants with other psychiatric diagnoses. CLASP was efficacious among those participants with BD. Psychiatric diagnosis may be a key indicator of prospective suicide risk. More intensive and specialized follow-up mental health treatment may be necessary for those with SSD.


The Relationship Between Child Mortality Rates and Prevalence of Celiac Disease.
Some evidence suggests that prevalence of celiac disease in the general population is increasing over time. Because the prognosis of celiac disease was a dismal one before discovering the role of gluten, our aim was to investigate a possible relationship between children under-5 mortality rates and prevalence rates of celiac disease. Thanks to a literature review, we found 27 studies performed in 17 different countries describing the prevalence of celiac disease in schoolchildren; between 1995 and 2011, 4 studies were performed in Italy. A meta-analysis of prevalence rates was performed. Prevalence was compared between specific country under-5 mortality groups, publication year, and age. In the last decades, under-5 mortality rates have been decreasing all over the world. This reduction is paralleled by an increase of the prevalence of celiac disease. The Spearman correlation coefficient was -63%, 95% confidence interval -82% to -33% (P < 0.001). So, the higher the mortality rate, the lower the prevalence of CD. This finding is confirmed by the meta-analysis of the 4 studies conducted in Italy over time. The under-5 mortality rate seems to influence the prevalence of celiac disease in the general population. In the near future, the number of patients with celiac disease will increase, thanks to the better environmental conditions that nowadays allow a better survival of children with celiac disease.


A family study of trichotillomania and chronic hair pulling.
Little is known about the etiology of hair pulling (HP) and its relationship to other obsessive compulsive (OC) spectrum disorders. In a large-sample family study, we examined the familial aggregation of HP and co-transmission of obsessive compulsive disorder (OCD) and skin picking (SP). Our sample consisted of 110 proband cases with HP and 48 controls without HP, plus 128 first-degree case relatives and 50 first-degree control relatives. Case versus control relatives had higher recurrence risk estimates for both HP and OCD but not SP. The finding that HP is familial is consistent with the only existing twin study. Additional analyses suggest that there may be a familial subtype of HP with comorbid OCD. Those adult proband cases with HP + OCD had more anxiety and depression than cases without OCD. Probands with HP + OCD also had earlier onset of OCD. Identification of an HP subtype with comorbid OCD may have significant theoretical and treatment implications. The data did not provide evidence for an etiologic relationship between HP and SP. Replication of these findings in future studies with larger cohorts of case and control relatives is warranted.


Innate-like functions of natural killer T cell subsets result from highly divergent gene programs.
Natural killer T cells (NKT cells) have stimulatory or inhibitory effects on the immune response that can be attributed in part to the existence of functional subsets of NKT cells. These subsets have been characterized only on the basis of the differential expression of a few transcription factors and cell-surface molecules. Here we have analyzed purified populations of thymic NKT cell subsets at both the transcriptomic level and epigenomic level and by single-cell RNA sequencing. Our data indicated that despite their similar antigen specificity, the functional NKT cell subsets were highly divergent populations with many gene-expression and epigenetic differences. Therefore, the thymus 'imprints' distinct gene programs on subsets of innate-like NKT cells that probably impart differences in proliferative capacity, homing, and effector functions.


Observations on the synthesis of carcinoembryonic antigen by an established human colonic carcinoma cell line.
Some properties and kinetics of synthesis of the carcinoembryonic antigen (CEA-LoVo) produced by an established human colon carcinoma cell line were analyzed. CEA-LoVo was assayed by the method of Chu and Reynoso which was standardized against the activity of the First British Standard for CEA. CEA-LoVo was stable at -20 and 4 degrees C. At 37 degrees C, CEA-LoVo degraded at the rate of 1.4%/day in cell-free supernatants, and at the rate of 6.6%/day in the supernatants of monolayer cultures. CEA-LoVo was sensitive to enzymatic treatment with trypsin (approximately 55% loss)) and extraction of PCA (> 70% loss). The elution profile of CEA-LoVo in Concanavalin A-Sepharose B coincided with that of the First British Standard for CEA. No A or B blood group antigenic activity was noted. Studies employing immunofluorescent and horseradish peroxidase-labeled antibody techniques demonstrated heavy membrane and moderate intracytoplasmic localization. The greatest amount of net synthesis occurred for cells in the stationary phase while CEA-LoVo release occurred maximally in the lag phase.


Non-polio enteroviruses circulation in acute flaccid paralysis cases and sewage in Senegal from 2013 to 2021.
Several factors can cause acute flaccid paralysis cases including non-polio enteroviruses. In Senegal, few studies on non-polio enteroviruses (NPEV) have been performed. Our study assess the molecular epidemiology of non-polio enteroviruses in Senegal from 2013 to 2021 through the previously existing programs for surveillance of polioviruses. A total of 3815 stool samples and 281 sewage samples were collected. After virus isolation by cell culture, non-polio enteroviruses-positive isolates were confirmed by reverse transcriptase-quantitative polymerase chain reaction. Following this detection, the positive samples were subjected to molecular characterization. Our data showed that 15.22% and 52.66% were positive in cell culture for non-polio enteroviruses in acute flaccid paralysis surveillance and environmental surveillance, respectively. These non-polio enteroviruses-positive isolates were detected all year round but tend to unequal peaks of circulation, and the age group 0-5 years was more vulnerable to infection (84.4%). Genetic characterization revealed the circulation of enteroviruses species infecting humans (Enterovirus A - Enterovirus D): Enterovirus A (29.2%) and Enterovirus B (63.1%) isolates from both the acute flaccid paralysis surveillance and environmental surveillance while Enterovirus C (5.3%) and Enterovirus D (2.4%) were only isolated from the acute flaccid paralysis surveillance. However, the highly prevalent Enterovirus B species from the acute flaccid paralysis surveillance included echovirus 7 and echovirus 13, whereas coxsackievirus A6 was the predominant species from the environmental surveillance. This first 8-year period study of NPEV in Senegal showed that NPEV represent important viral etiologies associated with acute flaccid paralysis cases and circulating in environmental surveillance in Senegal and highlighted the need to promote effective long-term strategies for monitoring of non-polio enteroviruses infections.


Impaired hormonal responses to hypoglycemia in spontaneously diabetic and recurrently hypoglycemic rats. Reversibility and stimulus specificity of the deficits.
To evaluate the roles of iatrogenic hypoglycemia and diabetes per se in the pathogenesis of defective hormonal counterregulation against hypoglycemia in insulin-dependent diabetes mellitus (IDDM), nondiabetic, and spontaneously diabetic BB/Wor rats were studied using a euglycemic/hypoglycemic clamp. In nondiabetic rats, recurrent (4 wk) insulin-induced hypoglycemia (mean daily glucose, MDG, 59 mg/dl) dramatically reduced glucagon and epinephrine responses by 84 and 94%, respectively, to a standardized glucose fall from 110 to 50 mg/dl. These deficits persisted for > 4 d after restoring normoglycemia, and were specific for hypoglycemia, with normal glucagon and epinephrine responses to arginine and hypovolemia, respectively. After 4 wk of normoglycemia, hormonal counterregulation increased, with the epinephrine, but not the glucagon response reaching control values. In diabetic BB rats (MDG 245 mg/dl with intermittent hypoglycemia), glucagon and epinephrine counterregulation were reduced by 86 and 90%, respectively. Chronic iatrogenic hypoglycemia (MDG 52 mg/dl) further suppressed counterregulation. Prospective elimination of hypoglycemia (MDG 432 mg/dl) improved, but did not normalize hormonal counterregulation. In diabetic rats, the glucagon defect appeared to be specific for hypoglycemia, whereas deficient epinephrine secretion also occurred during hypovolemia. We concluded that both recurrent hypoglycemia and the diabetic state independently lead to defective hormonal counterregulation. These data suggest that in IDDM iatrogenic hypoglycemia magnifies preexisting counterregulatory defects, thereby increasing the risk of severe hypoglycemia.


Communications with Kansas physicians.
The uneven geographic distribution of population, physicians and treatment facilities in Kansas may at times create difficulties in bringing unusual patient problems and needed medical expertise together. Technology currently exists for establishing communication links ranging from live, two-way, audio-video communication connections and computers to the common telephone. This survey indicates that the medical community has great interest in developing functional and cost-effective links. The two campuses of the medical school are working to provide better and broader communications access to the physicians of the state.


A study of in vivo degradation of two vital home bleaching gels.
This study investigated hydrogen peroxide (H2O2) concentration of two home bleaching gels, in their dispensing syringes and their degradation in vivo in intraoral bleaching trays. Two bleaching gels were studied, 7.5% hydrogen peroxide (HP) and 20% carbamide peroxide (CP). The concentration of H2O2 was determined in dispensing syringes. Twenty individuals were involved in this study. The gels were placed in trays of both arches and their degradation determined at 5, 10, 15, 20, 30, 40, 60 and 75 min. The concentrations of H2O2 in syringes were (HP) 8.12% and (CP) 7.95%. For the HP gel in custom-trays the concentration of H2O2 was 73% at 5 min and 42% after 75 min. In the 20% CP gel it was 75% at 5 min and 39% after 75 min. Activity decreased linearly up to 75 min, where the mean concentration of H2O2 exceeded 35% for the CP and HP gels.


Time-lapse microscopy of Streptomyces coelicolor growth and sporulation.
Bacteria from the genus Streptomyces are among the most complex of all prokaryotes; not only do they grow as a complex mycelium, they also differentiate to form aerial hyphae before developing further to form spore chains. This developmental heterogeneity of streptomycete microcolonies makes studying the dynamic processes that contribute to growth and development a challenging procedure. As a result, in order to study the mechanisms that underpin streptomycete growth, we have developed a system for studying hyphal extension, protein trafficking, and sporulation by time-lapse microscopy. Through the use of time-lapse microscopy we have demonstrated that Streptomyces coelicolor germ tubes undergo a temporary arrest in their growth when in close proximity to sibling extension sites. Following germination, in this system, hyphae extended at a rate of approximately 20 microm h(-1), which was not significantly different from the rate at which the apical ring of the cytokinetic protein FtsZ progressed along extending hyphae through a spiraling movement. Although we were able to generate movies for streptomycete sporulation, we were unable to do so for either the erection of aerial hyphae or the early stages of sporulation. Despite this, it was possible to demonstrate an arrest of aerial hyphal development that we suggest is through the depolymerization of FtsZ-enhanced green fluorescent protein (GFP). Consequently, the imaging system reported here provides a system that allows the dynamic movement of GFP-tagged proteins involved in growth and development of S. coelicolor to be tracked and their role in cytokinesis to be characterized during the streptomycete life cycle.


Use of pH 9.5 Tris-HCl buffer containing 5% urea for antigen retrieval immunohistochemistry.
Successful antigen retrieval (AR) immunohistochemistry is dependent on the temperature, heating time, and pH value of the AR solutions. There is no single standardized AR solution, however, that is suitable for all antibodies "routinely" used in surgical pathology for immunostaining archival tissue sections. We tested a variety of AR solutions varying in pH value, chemical composition, and molarity. Based upon preliminary results, we compared three AR solutions: 0.1 M Tris-HCl buffer, pH 9.5, containing 5% urea, 0.1 M Tris-HCl buffer pH 9.5 without urea, and citrate buffer, pH 6.0. Each AR solution was tested with a panel of 34 antibodies using microwave heating for antigen retrieval. The heating conditions were standardized at 10 min and an automated stainer was used to standardize the immunostaining method. The Tris-HCl containing urea was superior to pH 6.0 citrate buffer for 22 antibodies. In 12 cases, Tris-HCl with urea was also superior to Tris-HCl alone. In 12 cases, the intensity was similar for all three retrieval solutions. The staining obtained with Tris-HCl with urea was equal to or better than with pH 6.0 citrate buffer in all cases. The Tris-HCl with urea solution is satisfactory for AR of most antibodies employed in routine surgical pathology.


Oxidative stress and cytotoxicity induced by ferric-nitrilotriacetate in HepG2 cells that express cytochrome P450 2E1.
Iron can potentiate the toxicity of ethanol. Ethanol increases the content of cytochrome P450 2E1 (CYP2E1), which generates reactive oxygen species, and transition metals such as iron are powerful catalysts of hydroxyl radical formation and lipid peroxidation. Experiments were carried out to attempt to link CYP2E1, iron, and oxidative stress as a potential mechanism by which iron increases ethanol toxicity. The addition of ferric-nitrilotriacetate (Fe-NTA) to a HepG2 cell line expressing CYP2E1 decreased cell viability, whereas little effect was observed in control cells not expressing CYP2E1. Toxicity in the CYP2E1-expressing cells was markedly enhanced after the depletion of glutathione. Lipid peroxidation was increased by Fe-NTA, especially in cell extracts and medium from the CYP2E1-expressing cells. Toxicity was completely prevented by vitamin E or by 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid, which also decreased the lipid peroxidation. Levels of ATP were lowered by Fe-NTA, and this was associated with a decreased rate of oxygen consumption by permeabilized cells with substrates donating electrons to complexes I, II, and IV of the respiratory chain. This mitochondrial damage was prevented by vitamin E. Toxicity was accompanied by DNA fragmentation, and this fragmentation was prevented by antioxidants. Overexpression of bcl-2 decreased the toxicity and DNA fragmentation produced by the combination of CYP2E1 plus Fe-NTA, as did a peptide inhibitor of caspase 3. These results suggest that elevated generation of reactive oxygen species in HepG2 cells expressing CYP2E1 leads to lipid peroxidation in the presence of iron, and the ensuing prooxidative state damages mitochondria, releasing factors that activate caspase 3, leading to a loss in cell viability and DNA fragmentation.


Are patients with erythema migrans who have leukopenia and/or thrombocytopenia coinfected with Anaplasma phagocytophilum or tick-borne encephalitis virus?
Lyme borreliosis (LB), tick-borne encephalitis (TBE) and human granulocytic anaplasmosis (HGA) are endemic in central part of Slovenia. We tested the hypothesis that patients with erythema migrans (EM) from this region, who have leukopenia and/or thrombocytopenia (typical findings in HGA and in the initial phase of TBE but not in patients with LB) are coinfected with Anaplasma phagocytophilum and/or with TBE virus, i.e. that cytopenia is a result of concomitant HGA or the initial phase of TBE. Comparison of clinical and laboratory findings for 67 patients with EM who disclosed leukopenia/thrombocytopenia with the corresponding results in sex- and age-matched patients with EM and normal blood cell counts revealed no differences. In addition, patients with typical EM and leukopenia and/or thrombocytopenia tested negative for the presence of IgM and IgG antibodies to TBE virus by ELISA as well as for the presence of specific IgG antibodies to A. phagocytophilum antigens by IFA in acute and convalescent serum samples. Thus, none of 67 patients (95% CI: 0 to 5.3%) with typical EM (the presence of this skin lesion attests for early Lyme borreliosis and is the evidence for a recent tick bite) was found to be coinfected with A. phagocytophilum or had a recent primary infection with TBE virus. The findings in the present study indicate that in Slovenia, and probably in other European countries endemic for LB, TBE and HGA, patients with early LB are rarely coinfected with the other tick-transmitted agents.


A dual-axis tilt acquisition geometry for digital musculoskeletal tomosynthesis.
Digital tomosynthesis (DT) is a limited angle tomographic x-ray technique. It is an attractive low-dose alternative to computed tomography (CT) in many imaging applications. However, the DT dataset is incomplete, which leads to out-of-focus artifacts and limited axial resolution. In this paper, a novel dual-axis tilt acquisition geometry is proposed and evaluated. This geometry solves some issues in tomosynthesis with the traditional scanning geometry by scanning the object with a set of perpendicular arcs. In this geometry the acquisition in the additional perpendicular direction is done using a tiltable object supporting platform. The proposed geometry allows for capturing more singularities of the Radon transform, filling the Fourier space with more data and better approximating the Tuy-Smith conditions. In order to evaluate the proposed system, several studies have been carried out. To validate the simulation setup the performance of the traditional scanning geometry has been simulated and compared to known results from the literature. It has also been shown that the possible improvement of the image quality in the traditional geometry is limited. These limitations can be partially overcome by using the proposed dual-axis tilt geometry. The novel geometry is superior and with the same number of projections better reconstructed images can be obtained. All studies have been made using a software tomosynthesis simulator. A micro-CT reconstruction of a bone has been used as a software phantom. Simultaneous algebraic reconstruction has been used to reconstruct simulated projections. As a conclusion, acquiring data outside the standard arc allows for improving performance of musculoskeletal tomosynthesis. With the proposed dual-axis acquisition geometry a performance gain is achieved without an increase in dose and major modifications to the instrumentation of existing tomosynthesis devices.


[Postileal nutrient digestibility in cattle].
Four heifers of an average live weight of 301 kg supplied with ileocaecal re-entrant cannulae received rations consisting of 4 kg hay (variants A und B), 1 kg coarse wheat meal, 0.4 kg molasses, 100 g urea and 30 g mixed minerals per animal and day. After a 14-day preliminary feeding period the ileum digesta was quantitatively collected at the re-entrant cannula over 24 h. 10% of the digesta were used for analysis, the remainder was heated to 37 degrees C and returned. Under consideration of the digesta passage through the colon the 24-hour collection of faeces was started after a 6-hour delay after the first replacement of digesta. Losses of nutrients were calculated from the values analysed from digesta and faeces. No differences could be ascertained between the two hay variants. On an average of the two rations the nutrient losses of the scaffold substances-equivalent to the digestibility in the colon-showed the following values: crude fibre = 10.6%, NDF = 10.4%, ADF = 11.9% and hemicellulose = 7.4%. The losses of the other nutrients, corresponding to their apparent digestibility, had the following values: crude protein = 12.1%, crude fat = 10.7%, N-free extracts = 18.9%, ash = 31.2%, dry matter = 17.5%. The water balance showed that 8.2 l water of the 23.4 l supplied with the ileum digesta were excreted in faeces.


Anthriscus sylvestris Deoxypodophyllotoxin Synthase Involved in Podophyllotoxin Biosynthesis.
Tetrahydrofuran ring formation from dibenzylbutyrolactone lignans is a key step in the biosynthesis of aryltetralin lignans including deoxypodophyllotoxin and podophyllotoxin. Previously, Fe (II)- and 2-oxoglutarate-dependent dioxygenase (2-ODD) from Podophyllum hexandrum (Himalayan mayapple, Berberidaceae) was found to catalyze cyclization of a dibenzylbutyrolactone lignan, yatein, to give deoxypodophyllotoxin and designated as deoxypodophyllotoxin synthase (DPS). Recently, we reported that the biosynthesis of deoxypodophyllotoxin and podophyllotoxin evolved in a lineage-specific manner in phylogenetically unrelated plant species such as P. hexandrum and Anthriscus sylvestris (cow parsley, Apiaceae). Therefore, a comprehensive understanding of the characteristics of DPSs that catalyze the cyclization of yatein to deoxypodophyllotoxin in various plant species is important. However, for other plant species than P. hexandrum, the isolation of the DPS enzyme gene and the type of the enzyme, e.g., whether it is 2-ODD or another type of enzyme such as cytochrome P-450 has not been reported. Here, we report the identification and characterization of A. sylvestris DPS (AsDPS). Phylogenetic analysis showed that AsDPS belonged to the 2-ODD superfamily and shared moderate amino acid sequence identity (40.8%) with PhDPS. Recombinant protein assay indicated that AsDPS and PhDPS differ in terms of the selectivity of substrate enantiomers. Protein modeling using Alpha-Fold2 and site-directed mutagenesis indicated that the Tyr305 residue of AsDPS probably contributes to substrate recognition. This study advances our understanding of the podophyllotoxin biosynthetic pathway in A. sylvestris and provides new insight into 2-ODD involved in plant secondary (specialized) metabolism.


[Exploring the dark continent: medical image and brain].
Until the late 19th century, direct observation of the central nervous system was practically impossible. The discovery of X-rays in 1895 and their subsequent application in the field of medicine brought about a shift of paradigm that completely revolutionised the way in which neurology was practised. The possibility of viewing the inside of the brain had a pronounced impact on clinical practice, and enriched the diagnosis and treatment of brain pathologies in a manner that was unimaginable up until then. The aim of this study is to describe the birth and development of medical imaging of the brain, from the discovery of X-rays and the early days of radiography to the appearance of computerised tomography and magnetic resonance in the 60s, both of which are techniques that were to change the world of diagnostic imaging forever. This brief overview of the history of radiology also includes the origins of angiography and other techniques that are no longer in use, but which were ground-breaking innovations in their time, such as ventriculography or pneumoencephalography. The procedures and techniques described in this article made it possible to view the inside of the brain, thereby facilitating the diagnosis and treatment of a number of neurological processes.


Contrast sensitivity of thyroid associated ophthalmopathy patients without obvious optic neuropathy.
To compare the contrast sensitivity levels of thyroid associated ophthalmopathy (TAO) patients without obvious optic neuropathy with those of healthy people. Forty eyes of 20 TAO patients without dysthyroid optic neuropathy and 40 eyes of 20 healthy subjects were evaluated in this prospective case-controlled study. The contrast sensitivity functions (CSFs) of all subjects were measured by the functional acuity contrast test (FACT) in five frequencies which were 1,5 cpd (A), 3 cpd (B), 6 cpd (C), 12 cpd (D), and 18 cpd (E). Results were compared for both groups, and a correlation of CSF with Hertel and clinical activity scores was assessed. There was no statistically significant difference between TAO patients and control groups for age and sex. TAO patients had lower levels than the control group in all the frequencies of CSFs (P < 0.05) and the difference in contrast sensitivity functions between the groups seems to be more significant in higher frequencies (B, C, D, and E) (P < 0.001). TAO patients without DON can have contrast sensitivity loss and this would probably imply subtle optic nerve dysfunction in early disease phase.


[The effects and mechanisms of interleukin-22 and interferon-γ on epithelial-mesenchymal transition of pleural mesothelial cells].
To investigate the effects of interleukin (IL)-22 and interferon (IFN)-γ on epithelial-mesenchymal transition (EMT) of pleural mesothelial cells, and to explore the relevant signal transduction pathways, in tuberculous pleural effusion. Twenty-two patients (12 males and 10 females, age range 22-64 years, mean 38.4 years) with tuberculous pleurisy hospitalized in department of respiratory medicine of the First People's Hospital of Foshan were recruited from July 2013 to June 2014. Diagnosis was confirmed by pathology. Freshly isolated pleural mesothelial cells (PMCs) from tuberculous pleural effusion were cultured either in medium alone as control, or stimulated with IL-22 and/or IFN-γ, and the phosphorylated signal transducers and activators of transcription (STAT) signalings in PMCs were determined by flowcytometry. In some experiments, STAT inhibitors were added into coculture with IL-22 and/or IFN-γ, and then morphological changes of PMCs were observed, and the expressions of epithelial markers such as cytokeratin-8 and E-cadherin as well as mesenchymal markers such as vimentin and α-Smooth muscle actin (SMA) were also determined by flow cytometry. As compared with the control group, IFN-γ induced epithelial-mesenchymal transition of PMCs via a STAT1 pathway as evidenced by down-regulation of cytokeratin-8 [(43.8 ± 2.8)% vs (14.3 ± 1.5)%,t=8.1, P<0.05] and E-cadherin [(43.8 ± 1.9)% vs (13.4 ± 1.2)%, t=9.7, P<0.05], and by up-regulation of vimentin [(41.2 ± 2.4)% vs (70.6 ± 3.6)%,t=8.5, P<0.05] and α-SMA [(55.8 ± 2.0)% vs (80.6 ± 2.9)%,t=7.2, P<0.05]. IL-22 not only maintained the epithelial property of PMCs, but also reverted IFN-γ-induced EMT [cytokeratin-8 (62.4 ± 3.1)%, E-cadherin (46.5 ± 3.6)%, vimentin (36.7 ± 2.8)%, and α-SMA (35.2 ± 2.5)% in 'IFN-γ + IL-22' group, all P<0.05 as compared with those of IFN-γ group]. Whereas addition of STAT3 inhibitor significantly abrogated such anti-EMT effect of IL-22 on PMCs [cytokeratin-8 (16.7 ± 0.7)%, E-cadherin (14.4 ± 0.9)%, vimentin (67.9 ± 2.5)%, and α-SMA (79.2 ± 5.7)% in 'IFN-γ + IL-22 + STAT3 inhibitor' group, all P<0.05 as compared with those of 'IFN-γ + IL-22' group]. The IL-22-STAT3 signal pathway could revert IFN-γ-induced EMT of PMCs, and might play a protective role in anti-pleural fibrosis in tuberculous pleurisy.