Human ESC-derived retinal epithelial cell sheets potentiate rescue of photoreceptor cell loss in rats with retinal degeneration.
Replacing defective retinal pigment epithelial (RPE) cells with those derived from human embryonic stem cells (hESCs) or human-induced pluripotent stem cells (hiPSCs) is a potential strategy for treating retinal degenerative diseases. Early clinical trials have demonstrated that hESC-derived or hiPSC-derived RPE cells can be delivered safely as a suspension to the human eye. The next step is transplantation of hESC/hiPSC-derived RPE cells as cell sheets that are more physiological. We have developed a tissue-engineered product consisting of hESC-derived RPE cells grown as sheets on human amniotic membrane as a biocompatible substrate. We established a surgical approach to engraft this tissue-engineered product into the subretinal space of the eyes of rats with photoreceptor cell loss. We show that transplantation of the hESC-RPE cell sheets grown on a human amniotic membrane scaffold resulted in rescue of photoreceptor cell death and improved visual acuity in rats with retinal degeneration compared to hESC-RPE cells injected as a cell suspension. These results suggest that tissue-engineered hESC-RPE cell sheets produced under good manufacturing practice conditions may be a useful approach for treating diseases of retinal degeneration.


Fluorescence resonance energy transfer (FRET) analysis demonstrates dimer/oligomer formation of the human breast cancer resistance protein (BCRP/ABCG2) in intact cells.
The human breast cancer resistance protein (BCRP/ABCG2) is a half ATP-binding cassette (ABC) efflux transporter that plays an important role in drug resistance and disposition. Although BCRP is believed to function as a homodimer or homooligomer, this has not been demonstrated in vivo in intact cells. Therefore, in the present study, we investigated dimer/oligmer formation of BCRP in intact cells. Wild-type BCRP and the mutant C603A were attached to cyan or yellow fluorescence protein and expressed in HEK293 cells by transient transfection. Protein levels, cell surface expression, and efflux activities of wild-type and mutant BCRP were determined by immunoblotting, 5D3 antibody binding, and flow cytometric efflux assay, respectively. Dimer/oligomer formation of BCRP in intact cells was analyzed using fluorescence resonance energy transfer (FRET) microscopy. Wild-type BCRP and C603A were expressed in HEK293 cells at comparable levels. C603A was predominantly expressed in the plasma membrane as was wild-type protein. Furthermore, C603A retained the same mitoxantrone efflux activity and the ability of dimer/oligmer formation as wild-type BCRP. Finally, cross-linking experiments yielded data consistent with the FRET analysis. In conclusion, we have, for the first time, demonstrated that BCRP can form a dimer/oligomer in vivo in intact cells using the FRET technique. We have also shown that Cys(603) alone does not seem to be essential for dimer/oligomer formation of BCRP.


[Integration of borders: health in the national development policy context].
In recent decades, Brazil's borders with other South American countries have been associated with a negative agenda. Public intervention has aimed almost exclusively at guaranteeing national security through a variety of restrictions. In the current century, with a slow but steady shift in the geopolitical paradigm, integration among South American nations has become a priority. Border regions have now become a strategic area for South American integration and appear as such on the member countries' development agendas. Within this new context, the current study aims to contribute to the connection between the regional health and development agendas, with a focus on border regions, taking a dual approach, by analyzing the development agenda vis-à-vis the field of health and providing clues on how health actions can contribute to a more general perspective of development and integration.


Electronic structure analysis of phthalocyanine complexes using magnetic circular dichroism and magnetic circularly polarized luminescence spectroscopy.
In the study of phthalocyanine complexes using magnetic circular dichroism (MCD) spectroscopy, the electronic structure of excited states is generally discussed based on the rigid-shift approximation, in which the band profiles for left-handed circularly polarized (lcp) and right-handed circularly polarized (rcp) light are assumed to be the same. This assumption may not necessarily be valid for cases where there are multiple initial states having different geometries. Magnetic circularly polarized luminescence (MCPL) from phthalocyanine complexes can be regarded as an example of such cases, since the two degenerate emission states are split in a magnetic field and can undergo a structural deformation. Here, we investigated an alternative approach, where the lcp and rcp components are independently determined. This method, which we refer to as the direct-separation approach, allows direct determination of the distribution of the two emission states as well as the orbital angular momentum L z $$ \left|{L}_z\right| $$ . Using this approach, L z $$ \left|{L}_z\right| $$ and the distribution were determined from MCD and MCPL spectra of a series of phthalocyanine complexes. Comparison of the two methods shows that the rigid-shift and the direct-separation approaches give practically equivalent results for the systems under study, but the latter is advantageous for systems where the former is not applicable.


[William Cheselden (1688-1752) and Gerard van der Gucht (1695-1776). Surgical technique, the art of printed images and controversy in the urology book of the XVIII century].
We review the printed work of the English anatomist and surgeon William Cheselden, with special attention to the chalcographic engravings which illustrated it, mainly those by Gerard van der Gucht and the miniaturist Jacob Schijnvoet, vendicating the valuable collaboration of illustrators and printers and their essential figurative contribution to explain the texts and make them easier to understand for the reader. These images were as important as the texts and contributed considerable artistic value to the work. Likewise, we present the bitter controversy caused in the English medical-surgical society of the time, most especially in the lithotomist or "urology" community, by the publication of the work entitled "The High Operation for the Stone"by W. Cheselden. The publication coincided chronologically with the second edition of "Lithotomia Douglassiana" by John Douglas, and the scathing criticism hurled against Cheselden, one of the prime examples of which was the publication of the book entitled "Lithotomus Castratus"; in the book, both works were revised meticulously by its author, collated, analysed in detail and compared against each other, publically indicating that Cheselden plagiarised Douglas.


Ichthyophonus irregularis sp. nov. from the yellowtail flounder Limanda ferruginea from the Nova Scotia shelf.
A previously described unusual form of the protistan parasite Ichthyophonus, differing in morphological and developmental features from I. hoferi sensu Plehn & Mulsow, was recovered from yellowtail flounder Limanda ferruginea Storer from the Brown's Bank area of the Nova Scotia shelf. The nuclear gene encoding the rRNA of the small ribosomal subunit was amplified from this unusual form of Ichthyophonus using the polymerase chain reaction, sequenced and aligned with other eukaryote small subunit (ssu)-rDNAs. Inferred phylogenetic trees clearly show that its ssu-rDNA is distinct from those of 2 isolates of I. hoferi sensu Plehn & Mulsow from different hosts and geographical locations (herring in the North Sea, and yellowtail flounder from the Nova Scotia shelf). We consider the unusual form to be a separate species, I. irregularis. The occurrence of a second, distinct type of Ichthyophonus within a single host species raises the possibility that ichthyophoniasis could be produced by different (although related) pathogens, and in some cases, by concurrent infections of the two.


In vitro antitumor effect of sodium butyrate and zoledronic acid combined with traditional chemotherapeutic drugs: a paradigm of synergistic molecular targeting in the treatment of Ewing sarcoma.
Histone deacetylase inhibitors and bisphosphonates have a promising future in the treatment of cancer as targeted anticancer drugs, particularly when used together or in combination with other cytotoxic agents. However, the effects of these combined treatments have not yet been systematically evaluated in Ewing sarcoma. The in vitro effects on cellular proliferation, viability and survival were investigated in two Ewing sarcoma cell lines, SK-ES-1 and RD-ES. The cell lines were treated with sodium butyrate, a histone deacetylase inhibitor and zoledronic acid, a bisphosphonate, alone, together or in combination with chemotherapeutic drugs recommended for clinical treatment of Ewing sarcoma. The data demonstrated that the combination of sodium butyrate and zoledronic acid had a synergistic cytotoxic effect at 72 h following treatment, persisting for 10-14 days post-treatment, in both cell lines tested. All combinations between sodium butyrate or zoledronic acid and the traditional antineoplastic drugs (doxorubicin, etoposide and vincristine) demonstrated a synergistic cytotoxic effect at 72 h in SK-ES-1 and RD-ES cells, except for the combinations of sodium butyrate with vincristine and of zoledronic acid with doxorubicin, which showed only an additive effect in RD-ES cell lines as compared to each agent alone. These acute effects observed in both Ewing sarcoma cell lines were confirmed by the clonogenic assay. The present data suggest that combining histone deacetylase inhibitors and bisphosphonates with traditional chemotherapeutic drugs is a promising therapeutic strategy for the treatment of Ewing sarcoma, and provides a basis for further studies in this field.


Global spatial dynamics and vaccine-induced fitness changes of Bordetella pertussis.
As with other pathogens, competitive interactions between Bordetella pertussis strains drive infection risk. Vaccines are thought to perturb strain diversity through shifts in immune pressures; however, this has rarely been measured because of inadequate data and analytical tools. We used 3344 sequences from 23 countries to show that, on average, there are 28.1 transmission chains circulating within a subnational region, with the number of chains strongly associated with host population size. It took 5 to 10 years for B. pertussis to be homogeneously distributed throughout Europe, with the same time frame required for the United States. Increased fitness of pertactin-deficient strains after implementation of acellular vaccines, but reduced fitness otherwise, can explain long-term genotype dynamics. These findings highlight the role of vaccine policy in shifting local diversity of a pathogen that is responsible for 160,000 deaths annually.


[Effects of farnesyltransferase silencing on the migration and invasion of tongue squamous cell carcinoma].
This study aimed to explore the effects of silencing farnesyltransferase (FTase) on the migration and invasion of tongue squamous cell carcinoma (TSCC) through RNA interference. TSCC cells (CAL27 and SCC-4) were cultured in vitro and then transfected with siRNA to silence FTase expression. The tested cells were categorized as follows: experimental group (three RNA interference groups), negative control group, and blank control group. mRNA expression of FTase and HRAS in each group was analyzed by quantitative real-time polymerase chain reaction. On the basis of FTase mRNA expression, the optimum interference group (highest silencing efficiency) was selected as the experimental group for further study. The protein expression of FTase, HRAS, p65, p-p65(S536), matrix metalloprotein-9 (MMP-9), hypoxia inducible factor-1α (HIF-1α), and vascular endothelial growth factor (VEGF) was analyzed by Western blot. The invasion and migration abilities of TSCC cells were determined by Transwell invasion assay and cell wound healing assay. The mRNA and protein expression of FTase in the experimental group decreased compared with that in the negative control and blank control groups (P<0.05). The mRNA and protein expression of HRAS was not significantly different among the groups (P>0.05). In the experimental group, the protein expression of p-p65(S536), MMP-9, HIF-1α, and VEGF decreased (P<0.05), whereas that of p65 had no significant change (P>0.05). The migration and invasion abilities of the experimental group were inhibited significantly (P<0.05). Silencing FTase in vitro could effectively downregulate its expression in TSCC cell lines and reduce the migration and invasion abilities to a certain extent. FTase could be a new gene therapy target of TSCC, and this research provided a new idea for the clinical treatment of TSCC.


Radioembolization with yttrium-90 microspheres for pancreatic cancer liver metastases: results from a pilot study.
Patients with liver metastases from pancreatic adenocarcinomas have a dismal prognosis. Surgical resection remains the only curative option but is appropriate for only a minority of patients as a treatment option. This is the first study to examine the safety and efficacy of radioembolization with yttirum-90 microspheres for these patients. All patients with histologically proven pancreatic carcinoma liver metastases referred to a single institution from 2006-2009 were included in the study. After radioembolization, follow-up abdominal computed tomography scans were performed to assess response according to the Response Criteria in Solid Tumors guidelines. Seven patients were identified from our prospectively collected data base. Of the five patients with available computed tomography follow-up, 2 patients achieved a partial response and 1 patient had stable disease. One patient with partial response survived for nearly 15 months after radioembolization therapy. No patient experienced major post-radioembolization complications. Radioembolization with yttrium-90 microspheres may have a useful role in treating patients with pancreatic carcinoma liver metastases in a multimodality setting. Results of the current study warrant further investigation of this novel treatment.


Treatment of early-stage nonbulky Hodgkin lymphoma.
Excellent results have been achieved in the treatment of early-stage Hodgkin lymphoma for more than 30 years with radiation therapy alone or the combined modalities of radiotherapy and chemotherapy. A major concern has been the long-term toxicity of treatment, most of which is attributable to radiotherapy. Recent trials that attempt to decrease acute and long-term toxicity are reviewed. To address the problem of late treatment morbidity, randomized trials of combined-modality therapy have been conducted demonstrating that the number of chemotherapy cycles and the extent and doses of radiotherapy can be reduced. Several studies, including three randomized trials of chemotherapy alone vs. combined-modality therapy, suggest that chemotherapy alone is a reasonable option for the treatment of nonbulky early-stage Hodgkin lymphoma. Positron emission tomography after one or two cycles of chemotherapy has been found to be highly predictive of treatment outcome for Hodgkin lymphoma. Combination chemotherapy alone including gemcitabine, a highly active drug with a favorable toxicity profile, with positron emission tomography early during treatment is under evaluation. Less toxic regimens with the aid of positron emission tomography may reduce the short-term and long-term toxicities of treatment of early-stage nonbulky Hodgkin lymphoma.


Desloratadine for allergic rhinitis.
Seasonal allergic rhinitis (SAR) and perennial allergic rhinitis (PAR) affect up to 40% of the population (depending on geographical area), and are associated with significant morbidity, socioeconomic costs and reductions in quality of life. Antihistamines are a first-line therapy, with newer nonsedating agents having superseded sedating first-generation drugs. Desloratadine is a nonsedating, nonimpairing antihistamine that is effective in relieving nasal and non-nasal symptoms of SAR and PAR, including nasal congestion. Desloratadine has a 24-h duration of action, enabling once-daily dosing and providing relief of morning symptoms. Clinical trials have demonstrated that it has no performance impairment, cardiovascular effects or clinically relevant interactions with other tested medications. This article reviews the use of desloratadine in the treatment of SAR and PAR.


Overexpression of cyclin D1 messenger RNA predicts for poor prognosis in estrogen receptor-positive breast cancer.
Cyclin D1 is a key cell cycle regulatory protein with demonstrated oncogenic activity in a variety of malignancies. Cyclin D1 mRNA and protein are overexpressed in approximately 50% of primary breast carcinomas; however, the pathophysiological consequences of increased expression remain unclear. To investigate the functional sequelae of cyclin D1 mRNA overexpression, we analyzed clinical outcome in relation to the cyclin D1 mRNA level in 253 primary breast cancer patients (median follow-up, 75 months) with particular reference to estrogen receptor (ER) status and endocrine response. Overall, with the exception of the relationship between cyclin D1 mRNA expression and the ER, cyclin D1 mRNA was not associated with other clinicopathological features such as age, menopausal status, axillary lymph node status, vascular invasion, tumor size, type, and grade. However, in patients with ER-positive tumors (n = 182), high levels of cyclin D1 mRNA were associated with increased risk of relapse (P = 0.0016), local recurrence (P = 0.025), metastasis (P = 0.019), and death (P = 0.025). In contrast, there were no clinical correlations with cyclin D1 expression in ER-negative disease (n = 71). In 33 patients who received endocrine therapy for their primary or recurrent breast cancers, there was an apparent association between a high cyclin D1 mRNA level and a shorter response duration within the ER-positive subgroup (P = 0.04). Our findings indicate that overexpression of cyclin D1 mRNA correlates with a worse prognosis within the ER-positive breast cancer phenotype and may be a contributing factor to the development of endocrine resistance in ER-positive disease.


[Effect of osmolar concentration of culture media on exocytosis in isolated presynaptic nerve endings of rat brain ].
The effect of hypotonic and hypertonic shock on exocytosis in rat brain synaptosomes was studied using the fluorescent dye acridine orange. It was shown that an increase in medium osmolarity leads to calcium-independent exocytosis. The response of the probe was directly proportional to the amount of osmolithes added. A decrease in medium osmolarity to 230 mOsm led to an increase of acridine orange fluorescence, which is comparable with exocytosis occurring by the action of 15 mM KCl. This effect was independent of calcium concentration. It is assumed that, under hypotonic shock, part of neurotransmitters are released from the vesicular pool.


Regularities in species' niches reveal the world's climate regions.
Climate regions form the basis of many ecological, evolutionary, and conservation studies. However, our understanding of climate regions is limited to how they shape vegetation: they do not account for the distribution of animals. Here, we develop a network-based framework to identify important climates worldwide based on regularities in realized niches of about 26,000 tetrapods. We show that high-energy climates, including deserts, tropical savannas, and steppes, are consistent across animal- and plant-derived classifications, indicating similar underlying climatic determinants. Conversely, temperate climates differ across all groups, suggesting that these climates allow for idiosyncratic adaptations. Finally, we show how the integration of niche classifications with geographical information enables the detection of climatic transition zones and the signal of geographic and historical processes. Our results identify the climates shaping the distribution of tetrapods and call for caution when using general climate classifications to study the ecology, evolution, or conservation of specific taxa.


Expression and localization of sterile alpha motif domain containing 5 is associated with cell type and malignancy of biliary tree.
Cholangiocarcinoma (CC) is a type of relatively rare neoplasm in adenocarcinoma. The characteristics of CCs as well as biliary epithelial cells are heterogeneous at the different portion of the biliary tree. There are two candidate stem/progenitor cells of the biliary tree, i.e., biliary tree stem/progenitor cell (BTSC) at the peribiliary gland (PBG) of large bile ducts and liver stem/progenitor cell (LPC) at the canals of Hering of peripheral small bile duct. Although previous reports suggest that intrahepatic CC (ICC) can arise from such stem/progenitor cells, the characteristic difference between BTSC and LPC in pathological process needs further investigation, and the etiology of CC remains poorly understood. Here we show that Sterile alpha motif domain containing 5 (SAMD5) is exclusively expressed in PBGs of large bile ducts in normal mice. Using a mouse model of cholestatic liver disease, we demonstrated that SAMD5 expression was upregulated in the large bile duct at the hepatic hilum, the extrahepatic bile duct and PBGs, but not in proliferating intrahepatic ductules, suggesting that SAMD5 is expressed in BTSC but not LPC. Intriguingly, human ICCs and extrahepatic CCs exhibited striking nuclear localization of SAMD5 while the normal hilar large bile duct displayed slight-to-moderate expression in cytoplasm. In vitro experiments using siRNA for SAMD5 revealed that SAMD5 expression was associated with the cell cycle regulation of CC cell lines. SAMD5 is a novel marker for PBG but not LPC in mice. In humans, the expression and location of SAMD5 could become a promising diagnostic marker for the cell type as well as malignancy of bile ducts and CCs.


Measuring moral distress in pharmacy and clinical practice.
This article presents the development, validation and application of an instrument to measure everyday moral distress in different health care settings. The concept of moral distress has been discussed and developed over 20 years. A few instruments have been developed to measure it, predominantly in nursing. The instrument presented here consists of two factors: level of moral distress, and tolerance/openness towards moral dilemmas. It was tested in four medical departments and three pharmacies, where 259 staff members completed a questionnaire. The two factors were found to be reliable. Differences in levels of moral distress were found between pharmacies and clinical departments, and between the youngest and oldest age groups; departmental staff and the youngest group experienced higher levels of moral distress. Departments reported less tolerance/openness towards moral dilemmas than pharmacies. The instrument needs to be tested further, but its strengths are the focus on everyday ethical dilemmas and its usefulness in different health care settings.


Characterization of opioid-sensitive neurons in the anteroventral third ventricle region of polydipsic inbred mice in vitro.
In previous studies we found that in the extremely polydipsic special strain of mice, STR/N, spontaneous drinking was greatly attenuated by injection of the opioid antagonists given intracerebroventricularly as well as subcutaneously. Therefore, we investigated, using hypothalamic slice preparations, responses of neurons in the anteroventral third ventricle region (AV3V) of the STR/N and its control, Swiss/Webster (S/W) mice to morphine and opiate peptides. An application of morphine at 10(-6) M to the circulating medium inhibited activities of 44% of AV3V neurons (45 of 102) in the STR/N, and 59% (76/129) in the S/W, demonstrating that morphine affected a smaller proportion of neurons of the polydipsic mice than that of controls. Opioid agonists for 3 receptor types, mu, delta and kappa, at 10(-6) to 10(-5) M inhibited AV3V neurons in both the STR/N and S/W mice, but to a different degree. No cell of either strain was excited by morphine or any of the opioids. The mu-receptor agonist, [D-Ala2,N-Me-Phe4,Gly5-ol]-enkephalin (DAGO), was the most potent inhibitor of AV3V neurons; in the STR/N 53% (25/47), and in the S/W 77% (34/44) were inhibited. The kappa-agonist, dynorphin A-(1-13) (DYN), inhibited fewer cells in the STR/N (9%, 4/47), compared with the S/W (36%, 16/44). Only a few cells responded to the delta-agonist, [D-Pen2,5]enkephalin (DPDPE), in both strains. The inhibitory actions of the opiates were reversibly blocked by naloxone, and persisted under synaptic blockade. The threshold concentration of morphine or DAGO for inhibition of AV3V neurons was higher in the STR/N (approximately 10(-8) M for both morphine and DAGO) than in S/W mice (approximately 10(-9) M for morphine and less than 10(-9) M for DAGO). Although the AV3V also contains angiotensin II-sensitive neurons, they were not affected by morphine (10(-6) M). Similarly neurons inhibited by morphine were not excited by angiotensin II (10(-7) M); some neurons were unresponsive to both chemicals. We conclude that morphine and opiate peptides directly inhibit the AV3V neurons of both the STR/N and S/W strains of mice and the sensitivity of these neurons to the opiates is lower in the polydipsic inbred mice compared to their controls. The results, together with our behavioral studies, suggest involvement of the central opioid system in the polydipsia of the STR/N mice.


Investigating the Role of Metabolism for Antibiotic Combination Therapies in Pseudomonas aeruginosa.
Antibacterial resistance poses a severe threat to public health; an anticipated 14-fold increase in multidrug-resistant (MDR) bacterial infections is expected to occur by 2050. Contrary to antibiotics, combination therapies are the standard of care for antiviral and anticancer treatments, as synergistic drug-drug interactions can decrease dosage and resistance development. In this study, we investigated combination treatments of a novel succinate dehydrogenase inhibitor (promysalin) with specific inhibitors of metabolism and efflux alongside a panel of clinically approved antibiotics in synergy studies. Through these investigations, we determined that promysalin can work synergistically with vancomycin and antagonistically with aminoglycosides and a glyoxylate shunt pathway inhibitor at subinhibitory concentrations; however, these cooperative effects do not reduce minimum inhibitory concentrations. The variability of these results underscores the complexity of targeting metabolism for combination therapies in antibiotic development.


Support vector regression correlates single-sweep evoked brain potentials to gastrointestinal symptoms in diabetes mellitus patients.
Diabetes mellitus (DM) is a multi-factorial and complex disease causing autonomic neuropathy and gastrointestinal symptoms in some patients. The neural mechanisms behind these symptoms are poorly understood, but it is believed that both peripheral and central mechanisms are involved. To gain further knowledge of the central mechanisms, the aim of this study was to identify biomarkers for the altered brain activity in type-1 DM patients compared to healthy volunteers (HV), and to correlate the obtained biomarkers to clinical patient scores. The study included 14 DM patients and 15 HV, with brain activity recorded as multi-channel electroencephalography evoked brain potentials (EPs) elicited by painful electrical stimulations in the esophagus. The single-sweep EPs were decomposed by an optimized discrete wavelet transform (DWT), and averaged for each channel. The DWT features from the DM patients were discriminated from the HV by a support vector machine (SVM) applied in regression mode. For the optimal DWT, the discriminative features were extracted and the SVM regression value representing the overall alteration of the EP was correlated to the clinical scores. A classification performance of 86.2% (P=0.01) was obtained by applying a majority voting scheme to the 5 best performing channels. The biomarker was identified as decreased theta band activity. The regression value was correlated to symptoms reported by the patients (P=0.04). The methodology is an improvement of the present approach to study central mechanisms in diabetes mellitus, and may provide a future application for a clinical tool to optimize treatment in individual patients.


SARS-CoV-2 spreads through cell-to-cell transmission.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a highly transmissible coronavirus responsible for the global COVID-19 pandemic. Herein, we provide evidence that SARS-CoV-2 spreads through cell-cell contact in cultures, mediated by the spike glycoprotein. SARS-CoV-2 spike is more efficient in facilitating cell-to-cell transmission than is SARS-CoV spike, which reflects, in part, their differential cell-cell fusion activity. Interestingly, treatment of cocultured cells with endosomal entry inhibitors impairs cell-to-cell transmission, implicating endosomal membrane fusion as an underlying mechanism. Compared with cell-free infection, cell-to-cell transmission of SARS-CoV-2 is refractory to inhibition by neutralizing antibody or convalescent sera of COVID-19 patients. While angiotensin-converting enzyme 2 enhances cell-to-cell transmission, we find that it is not absolutely required. Notably, despite differences in cell-free infectivity, the authentic variants of concern (VOCs) B.1.1.7 (alpha) and B.1.351 (beta) have similar cell-to-cell transmission capability. Moreover, B.1.351 is more resistant to neutralization by vaccinee sera in cell-free infection, whereas B.1.1.7 is more resistant to inhibition by vaccinee sera in cell-to-cell transmission. Overall, our study reveals critical features of SARS-CoV-2 spike-mediated cell-to-cell transmission, with important implications for a better understanding of SARS-CoV-2 spread and pathogenesis.


Whose genes are they? The Human Genome Diversity Project.
The Human Genome Diversity Project (HGDP) has targeted several hundred indigenous peoples worldwide as their source of genetic material. Proponents for this project claim that information derived by analyzing these materials may be used for a variety of purposes ranging from finding a cure for diabetes to resolving debates about human origins. However, the HGDP plan raises many issues for indigenous people. This paper describes the project as well as the possible ethical and policy implications for Native communities.


Specific binding, stimulation of rodent urinary bladder epithelial ornithine decarboxylase, and induction of transitional cell hyperplasia by the skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate.
The effects of intraurethral or i.p. administration of a mouse skin tumor promoter phorbol ester, 12-O-tetradecanoylphorbol-13-acetate (TPA), on rodent urinary bladder transitional epithelium were studied. TPA, when instilled into the urinary bladder of inbred rats (female Fischer, F344) or mice (C3H, ICR, C57BL X DBA/2 F1) at a dose as low as 0.16 nmol, led to a significant (about 10-fold) increase in bladder ornithine decarboxylase (EC 18.104.22.168) (ODC) activity. Peak ODC activity was observed at about 6 hr, and enzyme activity returned to base levels about 14 hr after intravesical TPA. Administration of TPA i.p. in dimethyl sulfoxide also induced vesical ODC at 4 hr after treatment. The magnitude of vesical ODC induction correlated well with the ability of a series of phorbol esters to promote mouse skin tumor formation (TPA greater than phorbol didecanoate greater than phorbol dibenzoate, and phorbol diacetate or phorbol did not induce bladder ODC activity). Mezerein, a second stage mouse skin tumor promoter, induced urinary bladder ODC as much as TPA did. Increased ODC activity by TPA was the result of an increased amount of ODC protein localized mostly (greater than 60%) in urinary bladder mucosa. Intraurethrally administered TPA induced transitional cell hyperplasia starting at Day 2, and it persisted for about 7 days. The urothelium regained normal histology 13 days after TPA treatment. TPA bound specifically and with high affinity to murine bladder mucosa and muscularis particulate preparations. Scatchard analysis of mucosal binding revealed a Kd of 0.82 nM; at saturation, 2.43 pmol were bound per mg protein. Since TPA binds specifically to urinary bladder epithelium, and the induction of ODC activity is one of the properties of tumor promoters, one may conclude that TPA may promote urinary bladder carcinogenesis. Intravesical saccharin also induced urinary bladder ODC activity, but TPA at equimolar quantity was far more potent than saccharin. Thus TPA, being a structurally well-defined molecule, may be a useful compound to study the phenomenon of the tumor promotion stage in urinary bladder carcinogenesis.


Autonomous and Assisted Control for Synthetic Microbiology.
The control of microbes and microbial consortia to achieve specific functions requires synthetic circuits that can reliably cope with internal and external perturbations. Circuits that naturally evolved to regulate biological functions are frequently robust to alterations in their parameters. As the complexity of synthetic circuits increases, synthetic biologists need to implement such robust control "by design". This is especially true for intercellular signaling circuits for synthetic consortia, where robustness is highly desirable, but its mechanisms remain unclear. Cybergenetics, the interface between synthetic biology and control theory, offers two approaches to this challenge: external (computer-aided) and internal (autonomous) control. Here, we review natural and synthetic microbial systems with robustness, and outline experimental approaches to implement such robust control in microbial consortia through population-level cybergenetics. We propose that harnessing natural intercellular circuit topologies with robust evolved functions can help to achieve similar robust control in synthetic intercellular circuits. A "hybrid biology" approach, where robust synthetic microbes interact with natural consortia and-additionally-with external computers, could become a useful tool for health and environmental applications.


Large Iodine Variability in Retail Cows' Milk in the U.S.: A Follow-Up Study among Different Retail Outlets.
In a previous study, large variability in iodine content was found among samples of store brand retail milk at a single time point in a sampling taken from 24 nationwide U.S. locations for the USDA FoodData Central database, but the sampling plan was not designed to detect differences among locations. This follow-up study was carried out to evaluate iodine levels in retail milk across the U.S. over time. Milk samples (2% fat) were collected bimonthly in fourteen locations for one year and analyzed in duplicate. Control materials were used to support accuracy of results and ensure precision across analytical batches. The overall mean and standard error (SE) for iodine concentration were 82.5 (7.0) µg/240 mL serving, which was comparable to the previous national mean [85.0 (5.5) µg/240 mL]. A similar wide range among individual samples was detected (27.9-282 µg/240 mL). For some locations, the mean iodine concentration differed significantly from others, and differed from the national average by amounts ranging from -47 µg to +37 µg per serving. The between-sample range within location was large for some (up to 229 µg/serving) and minimal for others (as little as 13.2 µg/serving). These findings suggest iodine intake from some retail milk supplies could be over- or underestimated relative to the national average, even if the national average is suitable for population-wide intake estimates.


Epidemiology of mammalian hepatitis E virus infection.
Mammalian hepatitis E virus (HEV), the etiological agent of hepatitis E in humans, is a recently discovered infectious agent. It was identified for the first time in 1983 using electron microscopy on a faecal specimen of a person infected with non-A, non-B enterically-transmitted hepatitis. Based on retrospective and prospective studies, HEV was long described as one of the leading causes of acute viral hepatitis in tropical and subtropical countries, whereas in developed countries hepatitis E was considered an imported disease from HEV hyperendemic countries. Data from studies conducted during the past decade have greatly shifted our knowledge on the epidemiology and clinical spectrum of HEV. Recently, it has been shown that contrary to previous beliefs, hepatitis E is also an endemic disease in several developed countries, particularly in Japan and in Europe, as evidenced by reports of high anti-HEV immunoglobulin G prevalence in healthy individuals and an increasing number of non-travel-related acute hepatitis E cases. Moreover, a porcine reservoir and growing evidence of zoonotic transmission have been reported in these countries. This review summarizes the current knowledge on the epidemiology and prevention of transmission of mammalian HEV.


Increased expression of N-methyl-D-aspartate receptor subunit 2D in the skin of patients with fibromyalgia.
We studied the expression of N-methyl-D-aspartate receptors (NMDAR) in skin of patients with fibromyalgia (FM) to investigate their role. The presence of NMDAR subtype 2B (NR2B) and subtype 2D (NR2D) was examined in skin tissues by immunohistochemistry and immunoblot. Skin tissues from 11 female patients with FM were examined and compared to those of 8 age- and sex-matched healthy controls. NR2D expression was increased in the skin of patients with FM versus controls. There was no difference in the expression of NR2B between FM patients and controls. The increased expression of NMDAR found in FM skin could be indicative of a more generalized increase in other peripheral nerves. This suggests that NR2D-selective antagonists may have implications in the treatment of allodynia in patients with FM.


Cerebral perfusion pressure in women with preeclampsia is elevated even after treatment of elevated blood pressure.
Cerebral perfusion pressure (CPP) is elevated in preeclampsia, and may predispose to cerebrovascular complications and progression to eclampsia. We estimated zero flow pressure (ZFP) and CPP using simultaneously obtained arterial blood pressure and middle cerebral artery blood flow velocity in 10 women with preeclampsia, all treated with methyldopa with or without nifedipine, and 18 healthy pregnant controls. Mean ± SD ZFP was lower in women with preeclampsia than in controls (16.8 ± 10.9 vs. 31.7 ± 15.0 mmHg, p = 0.01) whereas CPP was considerably higher (82.3 ± 17.7 vs. 55.0 ± 11.7 mmHg, p < 0.001), as was the cerebral flow index (41.9 ± 18.0 vs. 25.6 ± 11.2, p = 0.02). There was a significant correlation between blood pressure and CPP in women with preeclampsia, but not in controls. Women with preeclampsia may have an increased cerebral perfusion due to a reduced ZFP and increased CPP despite treatment with antihypertensive medication. More rigorous antihypertensive therapy, aimed at reducing CPP, could result in a decrease in cerebral complications in women with preeclampsia.


Increasing preferred step rate during running reduces plantar pressures.
Increasing preferred step rate during running is a commonly used strategy in the management of running-related injuries. This study investigated the effect of different step rates on plantar pressures during running. Thirty-two healthy runners ran at a comfortable speed on a treadmill at five step rates (preferred, ±5%, and ±10%). For each step rate, plantar pressure data were collected using the pedar-X in-shoe system. Compared to running with a preferred step rate, a 10% increase in step rate significantly reduced peak pressure (144.5±46.5 vs 129.3±51 kPa; P=.033) and maximum force (382.3±157.6 vs 334.0±159.8 N; P=.021) at the rearfoot, and reduced maximum force (426.4±130.4 vs 400.0±116.6 N; P=.001) at the midfoot. In contrast, a 10% decrease in step rate significantly increased peak pressure (144.5±46.5 vs 161.5±49.3 kPa; P=.011) and maximum force (382.3±157.6 vs 425.4±155.3 N; P=.032) at the rearfoot. Changing step rate by 5% provided no effect on plantar pressures, and no differences in plantar pressures were observed at the medial forefoot, lateral forefoot or hallux between the step rates. This study's findings indicate that increasing preferred step rate by 10% during running will reduce plantar pressures at the rearfoot and midfoot, while decreasing step rate by 10% will increase plantar pressures at the rearfoot. However, changing preferred step rate by 5% will provide no effect on plantar pressures, and forefoot pressures are unaffected by changes in step rate.


[Bilateral persistent hyaloid artery. A case report].
A 5-year-old male presented with bilateral poor vision, esotropia and a previous diagnosis of cataract since he was 1 year old. The physical examination revealed bilateral posterior paracentric capsule opacification, vitreous cavity with a permeable pulsatile blood filled hyaloid artery in both eyes. He was kept under observation. Persistent hyaloid artery is an uncommon faulty primary vitreous regression, often unilateral (although it may be bilateral) and sporadic, associated with microphthalmos. It may be complicated with glaucoma and phthisis bulbi. Vitrectomy plus lensectomy or simple observation are the accepted treatment options.


[Principles of current classification of duodenitis].
The paper considers the principles of classification of chronic duodenitis. The current classification of chronic duodenitis may be divided into three parts: endoscopic, histological, and etiological. The characterizing terms of the endoscopic part are as follows: erythema, hemorrhages, atrophy, erosions, follicles. The endoscopic localization of duodenitis is as follows: proximal and distal portions (panduodenitis, including bulbitis in the proximal portion and postbulbitis in the distal portion, palpilitis). The nonspecific terms of the histological part are as follows: activity, inflammation, and atrophy. Its specific terms are: ventricular metaplasia, ventricular heterotopia, Helicobacter pylori, granulomas, lymphatic follicles, eosinophilic infiltration, lymphocytic infiltration. The following morphological categories of duodenitis are: nonatrophic, nodular, granulomatous, eosinophilic, and lymphocytic. The morphological localization of duodenitis is as follows: proximal and distal portions (panduodenitis, including bulbitis in the proximal portion and postbulbitis in the distal portion). The following degrees of its severity are: none changes, mild, moderate, and sever. The types (etiological factors) of duodenitis are as follows: acid-associated, drug-dependent, toxic (eliminating), and isolated nonspecific (idiopathic). Its special forms are: H. pylori-induced, granulomatous (Crohn's disease, sarcoidosis), nodal (Crohn's disease, sarcoidosis, acid-associated diseases), eosinophilic (unspecified allergens), lymphocytic (gluten-induced).


A choice procedure for drug reinforcers: cocaine and methylphenidate in the rhesus monkey.
A choice procedure was developed to compare the reinforcing efficacy of drug solutions delivered via intravenous catheters to rhesus monkeys. Choices were arranged between doses of cocaine or methylphenidate and saline, different doses of the same drug and doses of both drugs. In each session, monkeys were allowed to self-inject one solution five times in the presence of a stimulus. Thirty minutes after the fifth injection, a second solution could be self-injected five times in the presence of a different stimulus. Thirty minutes later, choice trials began in which both stimuli were present and monkeys could choose one of the two solutions. Rate of responding decreased with increases in dose for both cocaine (0.05-1.5 mg/kg) and methylphenidate (0.075-0.7 mg/kg). Response rates maintained by cocaine were 2 to 3 times higher than those maintained by methylphenidate. Drug was always chosen over saline. Higher doses of cocaine were preferred to lower doses except when both were above 0.5 mg/kg, when no preference was shown. Higher doses of methylphenidate were preferred over low doses, but compared to cocaine, a greater absolute difference between dose magnitude was required to demonstrate preference. When equal doses of cocaine and methylphenidate were compared, no preference was shown. On other comparisons between the drugs, the higher dose was generally preferred regardless of the drug. The reinforcing efficacy of drugs must be considered not only in terms of response rate maintained or reinforcement schedule but also with reference to concurrently available drugs.


Relationship between plasma plasminogen activator inhibitor-1 and hypertension in American Indians: findings from the Strong Heart Study.
Deficient plasminogen activator inhibitor-1 (PAI-1) prevented hypertension in mice. Plasma PAI-1 was associated with hypertension in cross-sectional analyses, but the prospective association of PAI-1 with incident hypertension in large epidemiological studies is scarce. Leveraging two longitudinal cohorts of American Indians in the Strong Heart Study (SHS, N = 1019) and the Strong Heart Family Study (SHFS, N = 1502), we examined the prospective association of plasma PAI-1 with incident hypertension by multivariate logistic regression, adjusting for age, sex, study site, smoking, drinking, dietary sodium, obesity, lipids, fasting glucose, kidney function, inflammation, and follow-up years. Family relatedness in the SHFS was accounted for using the GLIMMIX procedure. Plasma PAI-1 level at baseline was measured by immunoassay. All participants were free of hypertension, cardiovascular diseases, and chronic kidney disease at baseline. A total of 305 and 258 participants, respectively, from the SHS (57 ± 7 years) and the SHFS (33 ± 13 years) developed incident hypertension during follow-up. In the SHS, higher level of log-transformed PAI-1 was associated with 1.35-fold increased risk of hypertension [odds ratio (OR) (95% confidence interval): 1.35 (1.06-1.72)]. Analysis using categorical PAI-1 (in tertiles) showed that participants in the highest tertile (≥58 ng/ml) had 63% increased risk for hypertension [OR = 1.63 (1.12-2.37)] compared with those in the lowest tertile (<33 ng/ml). This association was confirmed in the SHFS with similar effect sizes [OR = 1.41 (1.11-1.81) for log-transformed PAI-1; OR = 1.64 (1.08-2.50) for categorical PAI-1: ≥58 vs. <33 ng/ml]. A higher level of plasma PAI-1 is significantly associated with hypertension in American Indians, independent of established risk factors. The potential causality warrants further investigation.


Predictors of suicide attempts in patients with borderline personality disorder over 16 years of prospective follow-up.
It is clinically important to understand the factors that increase the likelihood of the frequent and recurrent suicide attempts seen in those with borderline personality disorder (BPD). Although several studies have examined this subject in a cross-sectional manner, the aim of this study was to determine the most clinically relevant baseline and time-varying predictors of suicide attempts over 16 years of prospective follow-up among patients with BPD. Two-hundred and ninety in-patients meeting Revised Diagnostic Interview for Borderlines (DIB-R) and DSM-III-R criteria for BPD were assessed during their index admission using a series of semistructured interviews and self-report measures. These subjects were then reassessed using the same instruments every 2 years. The generalized estimating equations (GEE) approach was used to model the odds of suicide attempts in longitudinal analyses, controlling for assessment period, yielding an odds ratio (OR) and 95% confidence interval (CI) for each predictor. Nineteen variables were found to be significant bivariate predictors of suicide attempts. Eight of these, seven of which were time-varying, remained significant in multivariate analyses: diagnosis of major depressive disorder (MDD), substance use disorder (SUD), post-traumatic stress disorder (PTSD), presence of self-harm, adult sexual assault, having a caretaker who has completed suicide, affective instability, and more severe dissociation. The results of this study suggest that prediction of suicide attempts among borderline patients is complex, involving co-occurring disorders, co-occurring symptoms of BPD (self-harm, affective reactivity and dissociation), adult adversity, and a family history of completed suicide.


Isolation of L-forms in a clinical microbiology laboratory.
Previous studies have demonstrated that L-forms of bacteria may play a role in persistent, chronic, or recurrent urinary-tract infections. A 2-year program was initiated to determine the feasibility of culturing for L-forms on a routine basis, and to determine the effectiveness of such a program. In relation to the total number of specimens, few L-forms were actually isolated. In comparison with the amount of equipment and technician time required, the return was negligible; only 0.5% of all urine specimens were positive for L-forms. An increase to only 1.2% was noted when culturing for L-forms was limited to patients with a diagnosis of bacteriuria or pyelonephritis. It is recommended that this technique be reserved for those patients with a long history of recurrent urinary-tract infections, after other attempts to cure the patient have met with failure.


Comparative assessment of the thermal tolerance of spotted stemborer, Chilo partellus (Lepidoptera: Crambidae) and its larval parasitoid, Cotesia sesamiae (Hymenoptera: Braconidae).
Under stressful thermal environments, insects adjust their behavior and physiology to maintain key life-history activities and improve survival. For interacting species, mutual or antagonistic, thermal stress may affect the participants in differing ways, which may then affect the outcome of the ecological relationship. In agroecosystems, this may be the fate of relationships between insect pests and their antagonistic parasitoids under acute and chronic thermal variability. Against this background, we investigated the thermal tolerance of different developmental stages of Chilo partellus Swinhoe (Lepidoptera: Crambidae) and its larval parasitoid, Cotesia sesamiae Cameron (Hymenoptera: Braconidae) using both dynamic and static protocols. When exposed for 2 h to a static temperature, lower lethal temperatures ranged from -9 to 6 °C, -14 to -2 °C, and -1 to 4 °C while upper lethal temperatures ranged from 37 to 48 °C, 41 to 49 °C, and 36 to 39 °C for C. partellus eggs, larvae, and C. sesamiae adults, respectively. Faster heating rates improved critical thermal maxima (CTmax ) in C. partellus larvae and adult C. partellus and C. sesamiae. Lower cooling rates improved critical thermal minima (CTmin ) in C. partellus and C. sesamiae adults while compromising CTmin in C. partellus larvae. The mean supercooling points (SCPs) for C. partellus larvae, pupae, and adults were -11.82 ± 1.78, -10.43 ± 1.73 and -15.75 ± 2.47, respectively. Heat knock-down time (HKDT) and chill-coma recovery time (CCRT) varied significantly between C. partellus larvae and adults. Larvae had higher HKDT than adults, while the latter recovered significantly faster following chill-coma. Current results suggest developmental stage differences in C. partellus thermal tolerance (with respect to lethal temperatures and critical thermal limits) and a compromised temperature tolerance of parasitoid C. sesamiae relative to its host, suggesting potential asynchrony between host-parasitoid population phenology and consequently biocontrol efficacy under global change. These results have broad implications to biological pest management insect-natural enemy interactions under rapidly changing thermal environments.


Human polyomaviruses and other human viruses in neuroendocrine tumors.
While the association of the Merkel cell polyomavirus (MCV) with the neuroendocrine Merkel cell carcinomas (MCC) has been shown recently, it is unknown whether other human polyomaviruses (HPyV) may be associated with neuroendocrine tumours (NETs) of distinct entities. Using novel, highly sensitive polyomavirus genotyping assays, we evaluated the prevalence of eight distinct HPyVs in a selection of 51 NETs from different entities. In addition, we analyzed these NETs for the presence of DNA from 12 adeno-associated virus (AAV) genotypes, adeno virus-5, 27 mucosal human papillomavirus (HPV) genotypes, hepatitis B (HBV), 8 human herpes viruses (HHV), and xenotropic murine leukemia virus-related virus (XMRV). 43 of the 50 (86%) NETs were positive for the DNA integrity control. Of these, 2 of 3 MCCs (67%) were positive for MCV. NETs from other entities, however, were negative for all HPyVs. Only a small subset of lung and appendix NETs were positive for EBV, HHV-6, and -7. While the association of MCV with MCC was confirmed, other human viruses could not be identified as potentially causative agents of other NETs. Our findings suggest that the human viruses tested for in this study do not play a comparable role in NETs like the polyomavirus MCV in MCC.


Conventional oral systemic chemotherapy for postoperative hepatocellular carcinoma: A systematic review.
The findings of randomized clinical trials (RCTs) regarding the efficacy of adjuvant conventional oral systemic chemotherapy (COSC) for patients with hepatocellular carcinoma (HCC) following curative hepatic resection (HR) are contradictory. Therefore, a systematic review of RCTs is required to evaluate the clinical efficacy of adjuvant COSC. Sources such as Medline, Embase and the Cochrane Library were systematically searched and all the RCTs comparing curative HR alone to HR plus COSC for HCC were identified. The odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. No treatment-related mortality was reported by the included RCTs and the adverse effects of COSC were generally mild. However, adjuvant COSC did not achieve a statistically significant improvement in the 1-, 3- and 5-year overall survival (OR=1.43, 95% CI: 0.58-3.56, P=0.44; OR=1.39, 95% CI: 0.75-2.55, P=0.29; and OR=1.20, 95% CI: 0.46-3.16, P=0.71, respectively). In addition, adjuvant COSC did not achieve a statistically significant decrease in the incidence of 1-, 3- and 5-year tumor recurrence, with pooled ORs of 0.92 (95% CI: 0.26-1.35, P=0.66); 0.82 (95% CI: 0.66-1.01, P=0.06); and 0.84 (95% CI: 0.71-1.01, P=0.06), respectively. Narrative reviews offer no evidence supporting the use of COSC. Adjuvant COSC has provided marginal benefits for HCC patients following curative HR. Considering the efficacy of sorafenib for advanced HCC and the results of this systematic review, no further trials should be performed to assess the efficacy of adjuvant COSC.


Biological laser printing: a novel technique for creating heterogeneous 3-dimensional cell patterns.
We have developed a laser-based printing technique, called biological laser printing (BioLP). BioLP is a non-contact, orifice-free technique that rapidly deposits fL to nL scale volumes of biological material with spatial accuracy better than 5 microm. The printer's orifice-free nature allows for transfer of a wide range of biological material onto a variety of substrates. Control of transfer is performed via a computer-aided design/computer-aided manufacturing (CAD/CAM) system which allows for deposition rates up to 100 pixels of biological material per second using the current laser systems. In this article, we present a description of the apparatus, a model of the transfer process, and a comparison to other biological printing techniques. Further, examples of current system capabilities, such as adjacent deposition of multiple cell types, large-scale cell arrays, and preliminary experiments on creating multi-layer cell constructs are presented. These cell printing experiments not only demonstrate near 100% viability, they also are the first steps toward using BioLP to create heterogeneous 3-dimensional constructs for use in tissue engineering applications.


[Studies of physical and chemical properties of the vacuum UV-irradiated molecules of human hemoglobin and its components (heme and globin)].
The purpose of the present work is to study the vacuum ultraviolet radiation action on the optical and chromatographic characteristics of human hemoglobin molecules and their components - haem and globin. Using the methods of spectrophotometry and thin layer chromatography (TLC), we have investigated into the structural changes of molecules of human hemoglobin, haem and globin, induced by the influence of vacuum UV light (gamma = 118-134 nm, dose - 1.2 kJ/m2). It has been shown that vacuum ultraviolet radiation induces an infringement of the higher types of the spatial organization ofglobin molecules, thus leading to the changes in the structural state of the albuminous globule.


The functional role of some tomato products on lipid profile and liver function in adult rats.
This study was carried out to investigate the functional role of lycopene obtained from powder prepared from fresh tomato, tomato paste, and ketchup that contained equal amounts of lycopene based on levels of intake on body weight gain (BWG), feed intake, feed efficiency ratio (FER), lipid profiles, atherogenic index, and liver enzymes of hyperlipidemic rats. Forty-eight male albino rats were divided into two main groups: the first group (n = 6 rats) was kept on the basal diet as a normal control, while the second group (n = 42 rats) was fed a hyperlipidemic diet for 5 weeks to induce hyperlipidemia. The latter group was divided into seven subgroups: the first subgroup was the positive control group, while the others were supplemented with one of the tomato products at one of two levels (10 or 20 mg of lycopene/kg of diet). BWG, feed intake, and FER were calculated, and blood samples were collected to determine total lipids, total cholesterol, triglycerides, lipoprotein fractions, atherogenic index, and liver function in sera. Relative organ weights were also calculated. Results revealed that administration of various tomato products produced a significant reduction in feed intake except for the hyperlipidemic group that supplemented with the lower lycopene level from tomato paste. In addition, BWG and FER were not influenced by addition of tomato products at any level of intake. Hyperlipidemic rats supplemented with tomato powder, tomato paste, or ketchup showed significant improvement in almost all the parameters studied compared to the positive control group. Results showed that the higher lycopene level from tomato paste produced significant improvement in all lipid parameters, followed by 10 mg of lycopene/kg from tomato paste, which caused significant elevation in high-density lipoprotein cholesterol comparable to that of the negative control group. The lowest atherogenic index was achieved by addition of the lower lycopene level from tomato paste followed by the higher lycopene level from the same source. So, because of the positive effect of tomato products on the tested parameters an increase in consumption of tomato and its products in the diet is recommended. Nutrition education programs should be encouraged to inform the public of the importance of tomato and its products, especially tomato paste and ketchup, in decreasing the risk of hyperlipidemia.


Story and science: how providers and parents can utilize storytelling to combat anti-vaccine misinformation.
With little or no evidence-based information to back up claims of vaccine danger, anti-vaccine activists have relied on the power of storytelling to infect an entire generation of parents with fear of and doubt about vaccines. These parent accounts of perceived vaccine injury, coupled with Andrew Wakefield's fraudulent research study linking the MMR vaccine to autism, created a substantial amount of vaccine hesitancy in new parents, which manifests in both vaccine refusal and the adoption of delayed vaccine schedules. The tools used by the medical and public health communities to counteract the anti-vaccine movement include statistics, research, and other evidence-based information, often delivered verbally or in the form of the CDC's Vaccine Information Statements. This approach may not be effective enough on its own to convince vaccine-hesitant parents that vaccines are safe, effective, and crucial to their children's health. Utilizing some of the storytelling strategies used by the anti-vaccine movement, in addition to evidence-based vaccine information, could potentially offer providers, public health officials, and pro-vaccine parents an opportunity to mount a much stronger defense against anti-vaccine messaging.


Effect of interferon-alpha therapy on bone marrow fibrosis in chronic myelogenous leukemia.
The aim of this study was to investigate the influence of interferon-alpha (IFN-alpha) on bone marrow fibrosis associated with chronic myelogenous leukemia (CML). Eighty-two bone marrow biopsies from 41 patients in chronic phase CML were stained with Snook's reticulin stain for argyrophilic fibers. Grading of reticulin fibrosis (scale of 1 to 4) was according to the quantity and pattern of distribution of reticulin. The interval between biopsies was a median of 25 months (range 12 to 40 months). Patients had been treated with IFN-alpha for at least 12 months, were still on IFN-alpha therapy during the study, and had achieved at least a complete hematological response. Before the start of IFN-alpha therapy, reticulin fibrosis was grade 1-2 in 23 patients (56%) and grade 3-4 in 18 (44%). During IFN-alpha therapy, reticulin fibrosis in bone marrow did not worsen or was reduced in 33 patients (80%) and increased by one grade in eight patients (20%). Only five patients (12%) with limited fibrosis (grade 1-2) before start of IFN-alpha therapy showed an increase towards significant fibrosis (grade 3-4), while eight of the 18 patients (44%) with grade 3-4 fibrosis achieved a decrease of fiber content in bone marrow. In summary, IFN-alpha was not associated with an enhancing effect on myelofibrosis in patients with CML and may have prevented increasing fibrosis in patients who respond to therapy.


Sodium channel β1 subunits participate in regulated intramembrane proteolysis-excitation coupling.
Loss-of-function (LOF) variants in SCN1B, encoding voltage-gated sodium channel β1 subunits, are linked to human diseases with high risk of sudden death, including developmental and epileptic encephalopathy and cardiac arrhythmia. β1 Subunits modulate the cell-surface localization, gating, and kinetics of sodium channel pore-forming α subunits. They also participate in cell-cell and cell-matrix adhesion, resulting in intracellular signal transduction, promotion of cell migration, calcium handling, and regulation of cell morphology. Here, we investigated regulated intramembrane proteolysis (RIP) of β1 by BACE1 and γ-secretase and show that β1 subunits are substrates for sequential RIP by BACE1 and γ-secretase, resulting in the generation of a soluble intracellular domain (ICD) that is translocated to the nucleus. Using RNA sequencing, we identified a subset of genes that are downregulated by β1-ICD overexpression in heterologous cells but upregulated in Scn1b-null cardiac tissue, which lacks β1-ICD signaling, suggesting that the β1-ICD may normally function as a molecular brake on gene transcription in vivo. We propose that human disease variants resulting in SCN1B LOF cause transcriptional dysregulation that contributes to altered excitability. Moreover, these results provide important insights into the mechanism of SCN1B-linked channelopathies, adding RIP-excitation coupling to the multifunctionality of sodium channel β1 subunits.


Toward an Optimal Pedagogy for Teamwork.
Teamwork and collaboration are increasingly listed as core competencies for undergraduate health professions education. Despite the clear mandate for teamwork training, the optimal method for providing that training is much less certain. In this Perspective, the authors propose a three-level classification of pedagogical approaches to teamwork training based on the presence of two key learning factors: interdependent work and explicit training in teamwork. In this classification framework, level 1-minimal team learning-is where learners work in small groups but neither of the key learning factors is present. Level 2-implicit team learning-engages learners in interdependent learning activities but does not include an explicit focus on teamwork. Level 3-explicit team learning-creates environments where teams work interdependently toward common goals and are given explicit instruction and practice in teamwork. The authors provide examples that demonstrate each level. They then propose that the third level of team learning, explicit team learning, represents a best practice approach in teaching teamwork, highlighting their experience with an explicit team learning course at the University of Colorado Anschutz Medical Campus. Finally, they discuss several challenges to implementing explicit team-learning-based curricula: the lack of a common teamwork model on which to anchor such a curriculum; the question of whether the knowledge, skills, and attitudes acquired during training would be transferable to the authentic clinical environment; and effectively evaluating the impact of explicit team learning.


First application of the HETPHEN concept to new heteroleptic bis(diimine) copper(I) complexes as sensitizers in dye sensitized solar cells.
We report here the synthesis and full chemical and physical characterizations of the first stable heteroleptic copper(I)-bis(diimine) complexes designed for implementation in dye sensitized solar cells (DSC). Thanks to the HETPHEN concept, pure and stable heteroleptic copper(I) complexes were isolated. Anchorage of the sensitizers was provided by 2,2'-biquinoline-4,4'-dicarboxylic acid (dcbqH2), while sterically challenged ligands 2,9-dimesityl-1,10-phenanthroline (L0) and N-hexyl-2,9-dimesityl-1,10-phenanthroline-[a:b]imidazo-(4'-dianisylaminophenyl) (L1) were used to complete the copper(I) coordination sphere. The resulting heteroleptic complexes C1 and C2 exhibit a broad MLCT transition spreading over a wide wavelength domain, especially when adsorbed onto nanoparticulate TiO2 photoanodes, providing a rather comprehensive visible light collection. The corresponding DSC were evaluated under AM 1.5 simulated solar light and rather weak performances were obtained owing to small J(sc) and V(oc). This is due to a combination of low extinction coefficient and poor driving forces for the various interfacial processes. However, significant improvements in the performances were monitored upon ageing in the dark, likely due to beneficial reorganization of the dye monolayers. The possibility to isolate stable asymmetric systems paves the way for structurally assisted photo-induced charge injection from the chemisorbed copper(i) based sensitizers into the conduction band of TiO2, through charge vectorialization.


Complications after placement of an intracoronary stent: nursing implications.
Care of patients after stent placement has evolved with the goal of reducing thrombosis and bleeding. Initially, all patients received full antithrombotic therapy; now most receive antiplatelet therapy only. Despite this evolution, no description of the differences in complications and nursing care with these two treatments has been published. To determine the differences in complications and nursing care for patients receiving different pharmacological therapies after placement of an intracoronary stent. A nonrandomized, noncontrolled, retrospective, comparative design was used with 176 sequential patients assigned to treatment groups on the basis of the adjunctive pharmacological therapy the patient received after placement of a stent. The equivalency of baseline characteristics and risk of complications, as well as the differences in length of stay, intensity of nursing care, and frequencies of bleeding and ischemic or thrombotic events were determined for the two groups: 65 patients who received anticoagulant therapy and 111 patients who received antiplatelet therapy. The two groups were equivalent with respect to baseline characteristics of sex, concomitant illness, and cardiac condition before stent placement. The two groups differed with respect to predisposing risks for bleeding and ischemic or thrombotic events. Patients receiving antiplatelet therapy alone had significantly shorter lengths of stay, less use of intensive care, fewer requirements for nursing care, and fewer bleeding complications, with no increase in ischemic or thrombotic events. Patients receiving anticoagulant therapy had more complications and required a higher intensity of nursing care than did patients who received antiplatelet therapy alone.


Ultraviolet-B-radiation-induced changes in nicotinamide and glutathione metabolism and gene expression in plants.
Pea (Pisum sativum L. cv. Greenfeast) plants were exposed to supplementary ultraviolet-B (UV-B) radiation (biologically effective dose rates normalised to 300 nm, UV-B[BE,300]: 0.18, 0.32 or 1.4 W m[-2]). Leaf nicotinamide, trigonelline, GSHtot (total glutathione) and GSSG (oxidised glutathione) levels remained unchanged after exposure to the lowest dose rates. 1.4 W m(-2) UV-B(BE,300) gave rise to 60-fold and 4.5-fold increases in GSSG and GSHtot, respectively. 3.5-fold and 9.5-fold increases were found in nicotinamide and trigonelline, respectively. cab (Chlorophyll-a/b-binding protein) transcript levels decreased and CHS (chalcone synthase) and PAL (phenylalanine ammonia-lyase) mRNA increased after shorter UV-B exposures (hours) to the higher dose rate of UV-B, and after exposure to the intermediate dose rate. CHS and PAL mRNAs also increased after prolonged exposure to the lowest dose rate. cab transcripts completely disappeared, whereas CHS and PAL mRNA levels rose by 60-fold and 17-fold, respectively, after 12 h exposure at the highest dose rate and 12 h of development. Our results indicate that nicotinamide or trigonelline do not function as signalling compounds for CHS and PAL gene expression. Elevated nicotinamide and trigonelline levels occur in response to UV-B, but only at UV-B doses high enough to cause oxidative stress.


Altered cyclic-AMP receptor activity and morphogenesis in a chemosensory mutant of Dictyostelium discoideum.
The functional properties of the cell-surface cyclic-AMP receptor that controls chemotaxis were found to be altered in an aggregation mutant of Dictyostelium discoideum. The mutant aggregated without stream formation and had a tenfold increased cell-density requirement for the initiation of aggregation. After aggregation, mounds formed multiple tips and subsequently subdivided to give multiple fruits that were small and abnormally proportioned. Cyclic-AMP-induced light-scattering changes in cell suspensions indicated that the mutant had a diminished response to external cyclic-AMP signals. Associated with these altered functional responses was a physical change in the cyclic-AMP sensory system. Cyclic-AMP-binding studies showed that the parent had two classes of cyclic-AMP binding sites, i.e., Kd = 32 and 110 nM. In contrast, the mutant had two- to threefold or more high-affinity sites (Kd = 25 nM) and altered low-affinity sites (Kd less than 3 microM). These results indicate that both affinity classes of binding site are independently mutable. This observation suggests that the two affinity classes can be interconverted by mutation, or the mutation alters a single molecular species and its equilibrium between binding sites with different affinities for cyclic AMP, as postulated in receptor cycling models.


Risk of Lymphoma Associated with Anti-TNF Therapy in Patients with Inflammatory Bowel Disease: Implications for Therapy.
Anti-tumor necrosis factor alpha (ATA) therapy plays a significant role in the treatment of moderate to severe inflammatory bowel disease (IBD). There are concerns regarding risks associated with their use, including malignancy and, specifically, lymphoma. Many previous studies have sought to determine whether there is a true link between ATA therapy in IBD and development of lymphoma. However they have been hindered by short follow-up times, few cases, and confounding factors such as previous thiopurine exposure. This review seeks to update the literature by evaluating more recent studies assessing the link between ATA monotherapy and lymphoma development. It also summarizes findings of those studies and provides additional clinical guidance pertaining to this class of biologic therapy.


Social media use in HPV-, cervical cancer-, and cervical screening-related research: A scoping review.
In response to the World Health Organization's global call to eliminate cervical cancer, many countries have targets to implement HPV primary screening. Social media may offer opportunities to promote uptake of HPV screening. We aimed to describe the extent of the scientific literature regarding social media research on human papillomavirus (HPV), cervical cancer and cervical screening. Seven databases were searched for peer-reviewed English-language studies related to social media research and HPV, cervical cancer and cervical screening published up to November 2023. One reviewer completed the title/abstract screening and two reviewers independently reviewed full-text articles. Data extraction was carried out by one reviewer and verified by a second reviewer. Information such as the research topic, social media platform of interest, participant characteristics, methods, analysis type, outcome measures, and key findings were collected. In the 58 articles included, researchers used social media in the following ways: evaluate content, recruit participants or disseminate a survey/questionnaire, disseminate health communication content, examine the relationship between social media use and outcomes, and to conduct experiments testing the effects of social media content on outcomes. Twitter and Facebook were the most common platforms mentioned. Four articles explicitly mentioned theory. Opportunities for research are identified such as further exploration of how newer social media platforms such as Instagram and TikTok can be used to share HPV content, examination of appropriate images for effective communication, and determining key features of social media content to promote information sharing and improve cervical screening knowledge, attitudes and behaviours.


Optimization of Ultrasonic-Microwave Synergistic Extraction of Ricinine from Castor Cake by Response Surface Methodology.
Castor cake is the residue in castor oil production in which many active components exist and the major one among them is ricinine. In this study, optimization of extraction of ricinine from castor cake using ultrasonic-microwave synergistic extraction (UMSE) was investigated to obtain high yield and purity by Box-Behnken design (BBD) response surface design. The optimal conditions of extraction were: ultrasound power 342 W, extracting time 5 min, microwave power 395 W, and non-significant factor of liquid/solid ratio 1:10. The crude extraction was recrystallized from ethanol. As a result, the maximum yield of ricinine was approximately 67.52%. The purity of ricinine was 99.39% which was determined by high performance liquid chromatography (HPLC). Additionally, the structure of purified ricinine was identified by fourier transforms infrared (FTIR) and liquid chromatography-mass spectrometry (LC-MS). Scanning electron microscope (SEM) was used to characterize the prismatic crystals morphology of ricinine. Results demonstrated that the present method combined the advantages of ultrasonic extraction and microwave extraction, which is time-saving with high extraction yield. Our results offer a suitable method for large-scale isolation of ricinine.


Maternal cardiac arrest.
The review is intended to serve as a practical clinical aid for the clinician called to maternal cardiac arrest. Anesthesia complications comprise an important cause of maternal cardiac arrest in developed countries Also predominant are hemorrhage and infections. Recent in-depth reports highlight fractionated care for pregnant women with cardiac and also probably neurological comorbidities. Pathology reports reveal a prevalence of thromboembolic phenomena that is higher than previously assumed but still rare. These are accompanied by particularly high mortality rates. The presenting rhythms of cardiac arrest which differ from most cardiac arrest populations, suggest the need for further in-depth investigation of both the causes and management of these cases. Despite these, outcomes are far better than those of most arrests. Key differences in treatment include are consideration of early airway management and possible medication complications. Pulseless electrical activity and VF should always alert to the possibility of hemorrhage. Echocardiography can diagnose thromboembolism. Also different are the need for Left uterine displacement and early delivery within after 4-5 min of initiation of resuscitation effort in cases with suspected compromise of the venous return or a poor likelihood of a good maternal outcome. Maternal cardiac arrest should be managed similarly to other adult cardiac arrests. At the same time its unique reversible causes require a different form of thought regarding diagnosis and treatment during the code.


The European Registry for Patients with Mechanical Circulatory Support (EUROMACS) of the European Association for Cardio-Thoracic Surgery (EACTS): second report.
The European Registry for Patients with Mechanical Circulatory Support (EUROMACS) was founded in Berlin, Germany. EUROMACS is supported fully by the European Association for Cardio-Thoracic Surgery (EACTS) and, since 2014, has functioned as a committee of the EACTS. The purpose of having the EUROMACS as a part of the EACTS is to accumulate clinical data related to long-term mechanical circulatory support for scientific purposes and to publish annual reports. Participating hospitals contributed surgical and cardiological pre-, peri- and long-term postoperative data of mechanical circulatory support implants to the registry. Data for all implants performed from 1 January 2011 to 31 December 2016 were analysed. Several auditing methods were used to monitor the quality of the data. Data could be provided for in-depth studies, and custom data could be provided at the request of clinicians and scientists. This report includes updates of patient characteristics, implant frequency, mortality rates and adverse events. Fifty-two hospitals participated in the registry. This report is based on 2947 registered implants in 2681 patients. Survival of adult patients (>17 years of age) with continuous-flow left ventricular assist devices with a mean follow-up of 391 days was 69% (95% confidence interval 66-71%) 1 year after implantation. On average, patients were observed for 12 months (median 7 months, range 0-70 months). When we investigated for adverse events, we found an overall event rate per 100 patient-months of 3.56 for device malfunction, 6.45 for major bleeding, 6.18 for major infection and 3.03 for neurological events within the first 3 months after implantation. Compared to the first EUROMACS report, the number of participating hospitals increased from 21 to 52 (+148%), whereas the number of registered implants more than tripled from 825 to 2947 (+257%). The increase in the number of participating hospitals led us to increase the quality control measures through data input control, on-site audits and statistical analyses.


Self-regulation of growth in three dimensions.
Multi-cell spheroids were grown in soft agar. When each spheroid was cultured in a large volume of medium, frequently renewed, all spheroids eventually reached a dormant phase at a diameter of approximately 3-4 mm and a population of approximately 10(6) cells. In the dormant spheroid, newly generated cells at the periphery balanced those lost by necrosis in the center. We propose that this dormant phase is due to a gradual reduction in the ratio of surface area to volume: a size is achieved beyond which there is insufficient surface area for the spheroid to eliminate catabolites and absorb nutrients. Thus, in the face of unlimited space and of new medium, three-dimensional cell populations become self-regulating. This phenomenon contrasts with standard tissue culture in which cell populations, living on a flat plane in two dimensions, will not stop growing in the face of unlimited space and new medium because the ratio of surface area to volume remains constant. These experiments provide a mechanism for our observations in vivo: before vascularization, solid tumors live by simple diffusion as three-dimensional spheroids or ellipsoids. They become dormant at a diameter of only a few millimeters; once vascularized, they are released from this dormant phase and begin exponential growth. Thus, tumor dormancy resulting from absence of angiogenesis in vivo, may operate by the same mechanism responsible for dormancy of spheroids in vitro.


[Effects of deformational plagiocephaly during the first 12 months on the psychomotor development of prematurely born infants].
The link between deformational plagiocephaly and psychomotor development is a recurrent question in medical publications. Main publications concentrate on term infants, but there is a lack of data on the impact of deformational plagiocephaly on the long-term neurodevelopment of premature infants. We attempted to establish a possible relation between deformational plagiocephaly during the 1st year of life and the psychomotor score at 4 years in prematurely born infants. Other risk factors potentially impacting the psychomotor score were also studied. A retrospective study of the files of the children followed by the "Naître et Devenir Région PACA Ouest Corse Sud" healthcare network and included in the database allowed us to select a cohort of 594 infants born prematurely at under 33 weeks of gestational age. These children were developmentally evaluated during the 1st year of life and at 4 years or age using the "EVAL Mater" test. The "Naître et Devenir" network is following up infants born prematurely at under 33 weeks of gestation in the West Provence Alpes Côte d'Azur and South Corsica region, from discharge to 7 years. A group of 170 specially trained pediatricians follow these infants developmentally at term, 3, 6, 9, 12, 18, and 24 months of corrected age and 3, 4 5, 6, and 7 years. Data are collected in a specially designed database. There was no significant link between deformational plagiocephaly during the 1st year of life and a pathological psychomotor score at age 4, but some risk factors were demonstrated: male gender, birth at under 28 weeks of gestational age, weight at birth under 1000g, having a Latal and Ferriero neuromotor score equal to or greater than 2 at 3 months of corrected age, and to a lesser extent having a prescription for physiotherapy during the 1st year. The research on deformational plagiocephaly in the full-term infant suggests a relation between deformational plagiocephaly and developmental delay predominantly on the motor side, with an increased rate of special needs services at school age. The question is raised of whether deformational plagiocephaly is the cause of the delay or an early sign of cerebral anomaly with an early motor delay in full-term infants. The results suggest that deformational plagiocephaly in the prematurely born infant may not be related to neurodevelopmental delay but simply to the extended time spent in the supine position because of the early birth associated with physiological hypotonia and axial extension. Other risk factors such as male gender, birth before 28 weeks of gestation, weight less than 1000g, a Latal and Ferriero neuromotor score greater than 2 at 3 months of corrected age, and having a prescription for physiotherapy during the 1st year of life are strongly related to delayed psychomotor development at age 4.


Antimicrobial management measures to limit resistance: A process-based conceptual framework.
To curb the trend toward increasingly resistant microorganisms, we must at least ensure that antibiotics are used in accordance with the best available scientific evidence. Here we review the control and streamlining measures aimed at optimizing the use of antibiotics, placing an emphasis on their demonstrated effectiveness in the intensive care unit environment. Because of their wide variety, the measures have been organized along the process of choosing, dosing, delivering, and then adjusting the initial antibiotics according to the culture results. By clarifying the range of options available, this process-based conceptual framework assists in best adapting a creative mixture of control measures to a particular healthcare system. The framework also facilitates the overview of a proposed multidisciplinary antibiotic management program, thereby helping to secure the administrative and local provider support necessary for its implementation and continued improvement.


Changes in mRNA/protein expression and signaling pathways in in vivo passaged mouse ovarian cancer cells.
The cure rate for late stage epithelial ovarian cancer (EOC) has not significantly improved over several decades. New and more effective targets and treatment modalities are urgently needed. RNA-seq analyses of a syngeneic EOC cell pair, representing more and less aggressive tumor cells in vivo were conducted. Bioinformatics analyses of the RNA-seq data and biological signaling and function studies have identified new targets, such as ZIP4 in EOC. Many up-regulated tumor promoting signaling pathways have been identified which are mainly grouped into three cellular activities: 1) cell proliferation and apoptosis resistance; 2) cell skeleton and adhesion changes; and 3) carbohydrate metabolic reprograming. Unexpectedly, lipid metabolism has been the major down-regulated signaling pathway in the more aggressive EOC cells. In addition, we found that hypoxic responsive genes were at the center stage of regulation and detected functional changes were related to cancer stem cell-like activities. Moreover, our genetic, cellular, biochemical, and lipidomic analyses indicated that cells grown in 2D vs. 3D, or attached vs. suspended had dramatic changes. The important clinical implications of peritoneal cavity floating tumor cells are supported by the data proved in this work. Overall, the RNA-seq data provide a landscape of gene expression alterations during tumor progression.


The Korea Nurses' Health Study: A Prospective Cohort Study.
The Korea Nurses' Health Study (KNHS) is a prospective cohort study of female nurses, focusing on the effects of occupational, environmental, and lifestyle risk factors on the health of Korean women. Female registered nurses aged 20-45 years and living in the Republic of Korea were invited to join the study, which began in July 2013. They were asked to complete a web-based baseline survey. The study protocols and questionnaires related to the KNHS are based on the Nurses' Health Study 3 (NHS3) in the United States, although they were modified to reflect the Korean lifestyle. Participants were asked about demographic, lifestyle factors, disease history, occupational exposure, reproductive factors, and dietary habits during their adolescence: Follow-up questionnaires were/will be completed at 6-8 month intervals after the baseline survey. If a participant became pregnant, she answered additional questionnaires containing pregnancy-related information. Among 157,569 eligible female nurses, 20,613 (13.1%) completed the web-based baseline questionnaire. The mean age of the participants was 29.4 ± 5.9 years, and more than half of them were in their 20s. Eighty-eight percent of the participants had worked night shifts as a nurse (mean, 5.3 ± 4.3 nights per month). Approximately 80% of the participants had a body mass index below 23 kg/m2. Gastrointestinal diseases were the most prevalent health issues (25.9%). The findings from this prospective cohort study will help to identify the effects of lifestyle-related and occupational factors on reproductive health and development of chronic diseases in Korean women.


Patients with SATB2-associated syndrome exhibiting multiple odontomas.
Special AT-rich sequence-binding protein 2 (SATB2)-associated syndrome (SAS) is characterized by alterations of SATB2. Its clinical features include intellectual disability and craniofacial abnormalities, such as cleft palate, dysmorphic features, and dental abnormalities. Here, we describe three previously undiagnosed, unrelated patients with SAS who exhibited dental abnormalities, including multiple odontomas. Although isolated odontomas are common, multiple odontomas are rare. Individuals in families 1 and 3 underwent whole-exome sequencing. Patient 2 and parents underwent targeted amplicon sequencing. On the basis of the hg19/GRCh37 reference and the RefSeq mRNA NM_001172517, respective heterozygous mutations were found and validated in Patients 1, 2, and 3: a splice-site mutation (chr2:g.200137396C > T, c.1741-1G > A), a nonsense mutation (chr2:g.200213750G > A, c.847C > T, p.R283*), and a frame-shift mutations (chr2:g.200188589_200188590del, c.1478_1479del, p.Q493Rfs*19). All mutations occurred de novo. The mutations in Patients 1 and 3 were novel; the mutation in Patient 2 has been described previously. Tooth mesenchymal cells derived from Patient 2 showed diminished SATB2 expression. Multiple odontomas were evident in the patients in this report; however, this has not been recognized previously as a SAS-associated phenotype. We propose that multiple odontomas be considered as an occasional manifestation of SAS.


New Antimicrobial Phenyl Alkenoic Acids Isolated from an Oil Palm Rhizosphere-Associated Actinomycete, Streptomyces palmae CMU-AB204T.
Basal stem rot (BSR), or Ganoderma rot disease, is the most serious disease associated with the oil palm plant of Southeast Asian countries. A basidiomycetous fungus, Ganoderma boninense, is the causative microbe of this disease. To control BSR in oil palm plantations, biological control agents are gaining attention as a major alternative to chemical fungicides. In the course of searching for effective actinomycetes as potential biological control agents for BSR, Streptomyces palmae CMU-AB204T was isolated from oil palm rhizosphere soil collected on the campus of Chiang Mai University. The culture broth of this strain showed significant antimicrobial activities against several bacteria and phytopathogenic fungi including G. boninense. Antifungal and antibacterial compounds were isolated by antimicrobial activity-guided purification using chromatographic methods. Their structures were elucidated by spectroscopic techniques, including Nuclear Magnetic Resonance (NMR), Mass Spectrometry (MS), Ultraviolet (UV), and Infrared (IR) analyses. The current study isolated new phenyl alkenoic acids 1-6 and three known compounds, anguinomycin A (7), leptomycin A (8), and actinopyrone A (9) as antimicrobial agents. Compounds 1 and 2 displayed broad antifungal activity, though they did not show antibacterial activity. Compounds 3 and 4 revealed a strong antibacterial activity against both Gram-positive and Gram-negative bacteria including the phytopathogenic strain Xanthomonas campestris pv. oryzae. Compounds 7-9 displayed antifungal activity against Ganoderma. Thus, the antifungal compounds obtained in this study may play a role in protecting oil palm plants from Ganoderma infection with the strain S. palmae CMU-AB204T.


Prognostic Analysis of KCNQ2 Patients via Combining EEG Deep Features and Machine Learning Classifiers.
Pathogenic variants of the KCNQ2 gene often induces neonatal epilepsy in clinical. For better treatment, infants with confirmed KCNQ2 pathogenic variant and epilepsy symptoms need to adjust their treatment plans according to the outcome after taking antiseizure medicines (ASMs). This process is often time-consuming and requires long-term follow-up, which undoubtedly causes unnecessary psychological and economic burdens. In this study, we investigate the feasibility to predict the outcome of KCNQ2 patients via Electroencephalogram (EEG). By using the combination of deep networks and classical classifiers, the abnormal brain pathological activities recorded in EEGs can be encoded into deep features and decoded into specific KCNQ2 outcomes, thus taking the advantage of both powerful feature extraction capability from deep networks and stronger classification ability from classical classifiers. Specifically, we acquire 10-channel EEG signals from 33 infants with KCNQ2 pathogenic variants after taking ASMs. Two well-trained models (Resnet-50 and Resnet-18) are employed to extract deep features from the EEG spectrums. We achieve an accuracy of 78.7% to predict the KCNQ2 outcome of each infant. To our best knowledge, this is the first study to employ potential EEG pathological differences to predict the outcomes of KCNQ2 patients. The investigation of automatic KCNQ2 outcome prediction may contribute to a more convenient diagnosis mechanism for KCNQ2 patients.


Lack of effect of thymus and spleen on the incubation period of Creutzfeldt-Jakob disease in mice.
Genetically athymic and asplenic (Lasat), athymic (Nude), asplenic (Dh) or normal littermate (Hetero) mice with a BALB/c genetic background were injected either intracerebrally or intraperitoneally with a 1% or 10% homogenate of mouse brains infected with the Fukuoka 1 strain of the Creutzfeldt-Jakob disease (CJD) agent. As there were no significant differences in incubation periods among the five groups (Lasat, Nude, Dh, Hetero and BALB/c) inoculated with the same dilution, via the same route, it was concluded that cell-mediated immunity dependent on the thymus plays no significant role in host defence against the CJD agent, and the spleen, a critical site of agent replication, is apparently not an obligatory source from which infection spreads to the central nervous system.


Skeletal functions of vitamin K-dependent proteins: not just for clotting anymore.
Osteocalcin and matrix Gla protein (MGP) are two vitamin K-dependent proteins present in bone and cartilage. Transgenic mice models were recently developed to isolate the function of each of these proteins. While osteocalcin-deficient mice have increased bone formation, MGP-deficient mice have abnormal calcification leading to osteopenia, fractures, and premature death owing to arterial calcification.


Thoracoscopic wedge resection in single-lung patients.
The thoracoscopic approach has become a standard procedure in the field of lung resections. However, its advantage in single-lung patients has not yet been well studied. We describe a series of successful thoracoscopic wedge resections in patients presenting with lung cancer after contralateral pneumonectomy. Eight patients, with a previous pneumonectomy (5 right and 3 left) for lung cancer, underwent resection for a suspicious neoplasm on the remaining lung. All lesions were detected in the asymptomatic phase during regular follow-up after pneumonectomy based on repeated computer tomography (CT). Only single peripheral lesions less than 2 cm were eligible for wedge resection were eligible for surgery. Video-assisted thoracoscopic, margin-free tumor wedge resections, were performed during apnea windows with the lung in a deflated position. All patients were treated by a wedge resections smaller than a single segment. Only one patient needed a mini-thoracotomy conversion to accomplish a safe margin-free resection. Median total surgical operative time was 37 minutes. There were no postoperative deaths, while morbidity was 12.5%. Thoracoscopic surgery represents a feasible surgical option in selected patients after contralateral pneumonectomy, with careful preoperative assessment and using short apnea windows in good collaboration with anesthesiologists. Histological definition, made possible by the surgical-procedure, gives patients the possibility to eventually undergo further targeted therapies. Randomized prospective trials are necessary to assess the best management of peripheral small lung nodules in single-lung patients, in particular to define which patients can benefit from a surgical approach.


Immunohistochemical expression of IDH1 in gliomas: a tissue microarray-based approach.
Mutations in the gene encoding isocitrate dehydrogenase (IDH1) have been reported in gliomas. This study analyses a series of 184 glioma cases in a tissue microarray (TMA)-based approach to assess the frequency of R132H point mutations in formalin-fixed, paraffin-embedded tissue samples. A total of 195 gliomas (30 pilocytic astrocytoma (PA), 45 diffuse astrocytoma [DA], 75 glioblastoma multiforme [GBM], 25 oligodendroglioma [OLIG] and 20 ependymoma [EPEN]). A TMA of core size 1.0 mm was constructed using a semi-automatic tissue arrayer. Immunohistochemical staining for IDH1, p53 and EGFR proteins was performed by the labeled sterptavidin avidin biotin LSAB method. The frequency of mutant IDH1 detection by immunohistochemistry on formalin-fixed, paraffin-embedded tissue was 15.8% in 29/184 tumors found suitable for evaluation. DA, OLIG and GBM showed IDH1 expression in 17/40 (42.5%), 5/22 (22.7%) and 7/72 (9.7%) cases, respectively. Of all the GBMs, prim-GBM showed immunoexpression in 1/7 (1.5%) while sec-GBM showed IDH1 expression in 6/7 (85.7%). PA and EPEN did not react with anti-IDH1 antibody. DA and GBM showed positive correlation with p53, but IDH1 and EGFR coexpression was rare. Monoclonal antibody to IDH1 (R132) is a useful and less-labor-intensive method to detect mutations in gliomas. IDH1 is a useful immunohistochemical marker to differentiate reactive gliosis from low-grade astrocytoma, has potential as an independent prognostic marker and also helps in distinguishing primary from secondary GBM. Its sensitivity and specificity need to be assessed by simultaneous sequencing and its validation on clinically annotated samples.