Change in chromatin organization related to in vivo transcriptional activity and histone synthesis independent of DNA replication during differentiation (germination) of Physarum spherules.
During the germination of Physarum spherules, increases have been observed, at the same moment, in the level of in vivo transcriptional activity as measured by [3H] uridine incorporation, and the accessibility of DNA for ethidium bromide staining as shown by flow cytometric measurements. We suppose that the changes observed in these two processes are due to a difference in chromatin organization between the first and the second period of the premitotic germination stage. In the second period, the four nucleosome core histories are synthesized in the absence of DNA replication and may correspond to a replacement of spherulation histone variants by plasmodial histone types in nucleosomes. The synthesis of historic H4 clearly distinguishes the second period of the premitotic germination stage from a growing plasmodium G2 phase, though nuclei exhibit a G2 phase DNA content. The same pattern of histone synthesis has been found during the cell cycle following the first mitosis after germination and the growing plasmodium cell cycle, with a synthesis of two histories H2B and H2A and the high mobility group (HMG)-like protein AS3 during the G2 phase, i.e. in the absence of DNA synthesis.


The neuropsychiatric aspects of boxing.
To review the neuropsychiatry of boxing. This update considers the clinical, neuropsychological, diagnostic, neurobiological, and management aspects of boxing-related brain injury. Professional boxers with multiple bouts and repeated head blows are prone to chronic traumatic encephalopathy (CTE). Repeated head blows produce rotational acceleration of the brain, diffuse axonal injury, and other neuropathological features. CTE includes motor changes such as tremor, dysarthria, and parkinsonism; cognitive changes such as mental slowing and memory deficits; and psychiatric changes such as explosive behavior, morbid jealousy, pathological intoxication, and paranoia. Screening with neuropsychological tests and neuroimaging may help predict those boxers at risk for CTE. Boxing results in a spectrum of CTE ranging from mild, nonprogressive motor changes to dementia pugilistica. Recent emphasis on safety in the ring, rehabilitation techniques, and other interventions do not eliminate the risk for CTE. For this reason, there is an active movement to ban boxing.


The ABCs of CENPs.
Equal distribution of DNA in mitosis requires the assembly of a large proteinaceous ensemble onto the centromeric DNA, called the kinetochore. With few exceptions, kinetochore specification is independent of the DNA sequence and is determined epigenetically by deposition at the centromeric chromatin of special nucleosomes containing an H3-related histone, CENP-A. Onto centromeric CENP-A chromatin is assembled the so-called constitutive centromere-associated network (CCAN) of 16 proteins distributed in several functional groups as follows: CENP-C, CENP-H/CENP-I/CENP-K/, CENP-L/CENP-M/CENP-N, CENP-O/CENP-P/CENP-Q/CENP-R/CENP-U(50), CENP-T/CENP-W, and CENP-S/CENP-X. One role of the CCAN is to recruit outer kinetochore components further, such as KNL1, the Mis12 complex, and the Ndc80 complex (KMN network) to which attach the spindle microtubules with their structural and regulatory proteins. Among the CENPs in CCAN, CENP-C and CENP-T are required in parallel for operational kinetochore specification and spindle attachment. This review presents discussion of the latest structural and functional data on CENP-A and CENPs from the CCAN as well as their interaction with the KMN network.


Food grade titanium dioxide accumulation leads to cellular alterations in colon cells after removal of a 24-hour exposure.
Titanium dioxide food grade (E171) is one of the most used food additives containing nanoparticles. Recently, the European Food Safety Authority indicated that E171 could no longer be considered safe as a food additive due to the possibility of it being genotoxic and there is evidence that E171 administration exacerbates colon tumor formation in murine models. However, less is known about the effects of E171 accumulation once the exposure stopped, then we hypothesized that toxic effects could be detected even after E171 removal. Therefore, we investigated the effects of E171 exposure after being removed from colon cell cultures. Human colon cancer cell line (HCT116) was exposed to 0, 1, 10 and 50 μg/cm2 of E171. Our results showed that in the absence of cytotoxicity, E171 was accumulated in the cells after 24 of exposure, increasing granularity and reactive oxygen species, inducing alterations in the molecular pattern of nucleic acids and lipids, and causing nuclei enlargement, DNA damage and tubulin depolymerization. After the removal of E171, colon cells were cultured for 48 h more hours to analyze the ability to restore the previously detected alterations. As we hypothesized, the removal of E171 was unable to revert the alterations found after 24 h of exposure in colon cells. In conclusion, exposure to E171 causes alterations that cannot be reverted after 48 h if E171 is removed from colon cells.


Similarity Detection Between Virtual Patients and Medical Curriculum Using R.
This paper presents the domain of information sciences, applied informatics and biomedical engineering, proposing to develop methods for an automated detection of similarities between two particular virtual learning environments - virtual patients at Akutne.cz and the OPTIMED curriculum management system - in order to provide support to clinically oriented stages of medical and healthcare studies. For this purpose, the authors used large amounts of text-based data collected by the system for mapping medical curricula and through the system for virtual patient authoring and delivery. The proposed text-mining algorithm for an automated detection of links between content entities of these systems has been successfully implemented by the means of a web-based toolbox.


Role of adenosine kinase in the control of Streptomyces differentiations: Loss of adenosine kinase suppresses sporulation and actinorhodin biosynthesis while inducing hyperproduction of undecylprodigiosin in Streptomyces lividans.
Adenosine kinase (ADK) catalyses phosphorylation of adenosine (Ado) and generates adenosine monophosphate (AMP). ADK gene (adk(Sli), an ortholog of SCO2158) was disrupted in Streptomyces lividans by single crossover-mediated vector integration. The adk(Sli) disruption mutant (Deltaadk(Sli)) was devoid of sporulation and a plasmid copy of adk(Sli) restored sporulation ability in Deltaadk(Sli), thus indicating that loss of adk(Sli) abolishes sporulation in S. lividans. Ado supplementation strongly suppressed sporulation ability in S. lividans wild-type (wt), supporting that disruption of adk(Sli) resulted in Ado accumulation, which in turn suppressed sporulation. Cell-free experiments demonstrated that Deltaadk(Sli) lacked ADK activity and in vitro characterization confirms that adk(Sli) encodes ADK. The intracellular level of Ado was highly elevated while the AMP level was significantly reduced after loss of adk(Sli) while Deltaadk(Sli) displayed no significant derivation from wt in the levels of S-adenosylhomocysteine (SAH) and S-adenosylmethionine (SAM). Notably, Ado supplementation to wt lowered AMP content, albeit not to the level of Deltaadk(Sli), implying that the reduction of AMP level is partially forced by Ado accumulation in Deltaadk(Sli). In Deltaadk(Sli), actinorhodin (ACT) production was suppressed and undecylprodigiosin (RED) production was dramatically enhanced; however, Ado supplementation failed to exert this differential control. A promoter-probe assay verified repression of actII-orf4 and induction of redD in Deltaadk(Sli), substantiating that unknown metabolic shift(s) of ADK-deficiency evokes differential genetic control on secondary metabolism in S. lividans. The present study is the first report revealing the suppressive role of Ado in Streptomyces development and the differential regulatory function of ADK activity in Streptomyces secondary metabolism, although the underlying mechanism has yet to be elucidated.


[Phage-typing modifications induced by in vitro transfer of R plasmids. II. -- Phage-typing of Shigella sonnei (author's transl)].
Forty-two antibiotic resistance plasmids and twelve metabolic plasmids have been transferred to a strain of Shigella sonnei. The phage-typing modifications have been investigated after transfer of the different above described plasmids. Eleven of the R plasmids and five of the metabolic plasmids affect phage sensitivity. These modifications are not specific for any compatibility group.


Roadmap to strengthen global mental health systems to tackle the impact of the COVID-19 pandemic.
The COVID pandemic has been devastating for not only its direct impact on lives, physical health, socio-economic status of individuals, but also for its impact on mental health. Some individuals are affected psychologically more severely and will need additional care. However, the current health system is so fragmented and focused on caring for those infected that management of mental illness has been neglected. An integrated approach is needed to strengthen the health system, service providers and research to not only manage the current mental health problems related to COVID but develop robust strategies to overcome more long-term impact of the pandemic. A series of recommendations are outlined in this paper to help policy makers, service providers and other stakeholders, and research and research funders to strengthen existing mental health systems, develop new ones, and at the same time advance research to mitigate the mental health impact of COVID19. The recommendations refer to low, middle and high resource settings as capabilities vary greatly between countries and within countries. The recommendations for policy makers are focused on strengthening leadership and governance, finance mechanisms, and developing programme and policies that especially include the most vulnerable populations. Service provision should focus on accessible and equitable evidence-based community care models commensurate with the existing mental health capacity to deliver care, train existing primary care staff to cater to increased mental health needs, implement prevention and promotion programmes tailored to local needs, and support civil societies and employers to address the increased burden of mental illness. Researchers and research funders should focus on research to develop robust information systems that can be enhanced further by linking with other data sources to run predictive models using artificial intelligence, understand neurobiological mechanisms and community-based interventions to address the pandemic driven mental health problems in an integrated manner and use innovative digital solutions. Urgent action is needed to strengthen mental health system in all settings. The recommendations outlined can be used as a guide to develop these further or identify new ones in relation to local needs.


Mesoporous silica@chitosan@gold nanoparticles as "on/off" optical biosensor and pH-sensitive theranostic platform against cancer.
A cancer nanotheranostic system was fabricated based on mesoporous silica@chitosan@gold (MCM@CS@Au) nanosystem targeted by aptamer toward the MUC-1 positive tumor cells. Subsequently, curcumin as an efficient herbal anticancer drug was first encapsulated into chitosan-triphosphate nanoparticles and then the resulted nanoparticle was loaded into the nanosystem (MCM@CS@Au-Apt). The nanosystem successful fabrication was approved at each synthesis step through FTIR, XRD, BET, DLS, FE-SEM, HRTEM, and fluorescence spectroscopy. Besides, the interaction between aptamer and curcumin was evaluated using full atomistic molecular dynamics simulations. The mechanism of curcumin release was likewise investigated through different kinetic models. Afterwards, the potential of the designed nanosystem in targeted imaging, and drug delivery was evaluated using fluorescence microscopy and flow cytometry. It was found that the energy transfer between the base pairs in the hairpin of double strands of DNA aptamer acts as a quencher for MCM@CS@Au fluorescence culminating in an "on/off" optical biosensor. On the other hand, the presence of pH-sensitive chitosan nanoparticles creates smart nanosystem to deliver more curcumin into the desired cells. Indeed, when the aptamer specifically binds to the MUC-1 receptor, its double strands separate under the low pH condition, leading to the drug release and the recovery of the fluorescence ("On" state). Based on the toxicity results, this nanosystem had more toxicity toward the MUC-1-positive tumor cells than MUC-1-negative cells, representing its selective targeting. Therefore, this nanosystem could be introduced as a smart anticancer nanotheranostic system for tracing particular biomarkers (MUC-1), non-invasive fluorescence imaging, and targeted curcumin delivery.


Hepatitis B Reactivation Following Eradication of HCV with Direct-Acting Antiviral Drugs (DAAs) in a Cohort of Patients from Different Institutions in Egypt.
Concerns about HBV reactivation (HBVr) have been raised with the introduction of DAA for HCV treatment. The aim of the study was to assess the risk of HBVr in chronic HCV patients during or after DAA. A cohort of 166 chronic HCV patients who were treated with SOF-based DAA regimens and initially positive for HBcAb total were evaluated; 10 HBsAg-positive, 156 had past HBV exposure (HBsAg-negative/HBcAb-positive). Laboratory investigations, including liver functions tests, HBV-DNA, LSM by Transient elastography, and ARFI together with serum markers of fibrosis; APRI and FIB-4 were done at baseline and after 12 weeks of DAAs therapy. HBV-DNA levels and liver functions were monitored for assessment of HBVr. Virological HBVr was diagnosed by ≥ 1 log10 IU/ml HBV-DNA levels in 2/166 patients (1.2%) among the whole HCV cohort, who were initially positive for HBsAg; 20%. Clinical HBVr (>3 folds liver enzyme elevation) was detected in one patient with virological HBVr. Conversely, none of past HBV-infected patients experienced HBVr. All patients achieved SVR12 and had a significant decline in serum transaminases, bilirubin, APRI, and LSM measurements after HCV eradication. HBVr might be considered after successful eradication of HCV following DAAs therapy, especially among patients who are positive for HBsAg, while past HBV infection does not seem to be a predisposing condition to HBVr.


Chemical potential measurements of deoxyhemoglobin S polymerization. Determination of the phase diagram of an assembling protein.
We have used the "osmotic stress" method to determine the phase diagram of deoxyhemoglobin S polymerization. This method involves equilibration, through a semipermeable membrane, of the protein with solutions of inert polymers of known osmotic pressure. With deoxyhemoglobin A and S solutions, in which we have demonstrated achievement of equilibrium, plots of osmotic pressure versus concentration initially agree closely with the results of other methods of measurement of colligative properties. However, once the known solubility value is exceeded for the deoxyhemoglobin S solutions at various temperatures, there is a rapid rise in hemoglobin concentration over a narrow osmotic pressure range and then a more gradual increase in concentration. We believe that these two regions correspond, respectively, to the onset of the polymerization process, and of subsequent continuing growth and compression or alignment of polymer. We derive the thermodynamic values for these processes and show that the behavior of the deoxyhemoglobin S system is analogous to the phase transition for a simple chemical system. These results are relevant to understanding the intracellular polymerization of deoxyhemoglobin S in sickle cell disease, and these concepts are applicable to other protein assembly systems.


Outlook for survivors of childhood in sub-Saharan Africa: adult mortality in Tanzania. Adult Morbidity and Mortality Project.
To measure age and sex specific mortality in adults (15-59 years) in one urban and two rural areas of Tanzania. Reporting of all deaths occurring between 1 June 1992 and 31 May 1995. Eight branches in Dar es Salaam (Tanzania's largest city), 59 villages in Morogoro rural district (a poor rural area), and 47 villages in Hai district (a more prosperous rural area). 40,304 adults in Dar es Salaam, 69,964 in Hai, 50,465 in Morogoro rural. Mortality and probability of death between 15 and 59 years of age (45Q15). During the three year observation period a total of 4929 deaths were recorded in adults aged 15-59 years in all areas. Crude mortalities ranged from 6.1/1000/year for women in Hai to 15.9/1000/year for men in Morogoro rural. Age specific mortalities were up to 43 times higher than rates in England and Wales. Rates were higher in men at all ages in the two rural areas except in the age group 25 to 29 years in Hai and 20 to 34 years in Morogoro rural. In Dar es Salaam rates in men were higher only in the 40 to 59 year age group. The probability of death before age 60 of a 15 year old man (45Q15) was 47% in Dar es Salaam, 37% in Hai, and 58% in Morogoro; for women these figures were 45%, 26%, and 48%, respectively. (The average 45Q15s for men and women in established market economies are 15% and 7%, respectively.) Survivors of childhood in Tanzania continue to show high rates of mortality throughout adult life. As the health of adults is essential for the wellbeing of young and old there is an urgent need to develop policies that deal with the causes of adult mortality.


Future practice plans of orthodontic residents in the United States.
The purpose of this study was to investigate the future clinical practice plans of orthodontic residents in the United States. All program chairs and directors of the 65 US orthodontic residency programs were contacted by e-mail and telephone and asked for permission to e-mail their residents and invite them to take part in an anonymous 57-item questionnaire online. A total of 335 e-mails from 37 programs were obtained, and the survey was sent in May 2007. Basic statistics including chi-square comparative analyses were performed by sex, age, and year of program. A total of 63.04% of orthodontic residents plan to use self-ligating brackets; 84.06% plan to use Invisalign (Align Technology, Santa Clara, Calif); 92.03% plan to use temporary anchorage devices, and 72.26% plan on placing them themselves; 28.26% plan to use cone-beam computerized tomography; 92.75% plan to use a digital imaging program; 45.65% plan to use indirect bonding; and 10.87% plan to use lingual orthodontics. A total of 70.07% plan to use 2-phase treatment, and 61.59% said they will use functional appliances. A total of 81.16% plan to become certified by the American Board of Orthodontics, but only 18.12% thought certification should be mandatory for licensure; 36.50% indicated that a master of science degree should be required in their program, and 77.94% believe that a 24- to 30-month program adequately prepares them for future orthodontic practice. Newer orthodontic technologies such as self-ligating brackets, temporary anchorage devices, and Invisalign as well as functional appliances are expected to grow in popularity in the United States because of projected future use by orthodontic residents. Two-phase orthodontic treatment with functional appliance mechanics will continue to be used. Most orthodontic residents will become certified by the American Board of Orthodontics but do not believe it should be necessary for licensure. Orthodontic residents in the United States believe that a 2-year program adequately prepares them for private practice.


Cell interactions and cell signaling during hematopoietic development.
Hematopoiesis is a key process that leads to the formation of all blood cell lineages from a specialized, multipotent cell, named the hematopoietic stem cell(HSC). During development, the embryo produces several waves of hematopoiesis that produce specialized subsets of hemato- poietic cells. Tissue interactions and cell signaling play an essential role in developmental hematopoiesis by allowing the formation of hematopoietic and endothelial cells(ECs) from the mesoderm particularly in the yolksac and by instructing the different generations of hemato- poietic cells (HCs). The embryonic aortais another site where intissue interaction is essential for the production of the first HSCs that is achieved from a specialized subset of hemogenic endothelial cells. This production is tightly time-and space-controlled with the transcription factor Runx1 and the Notch signaling path way playing a key role in this process and the surrounding tissues controlling the aortics hape and fate. Here we shall briefly review how hemogenic EC differentiates from the mesoderm, how the different aortic components as semble coordinately to establish the dorso-ventral polarity resulting in the initiation of Runx1 expression in hemogenic EC and the initiation of the hematopoietic program through modulation of the Notch–Runx1 axis. These data should help elucidate the first steps in HSC commitment and bring further insights into the manipulation of adult HSCs.


Development and evaluation of diffusive gradients in thin films based on nano-sized zinc oxide particles for the in situ sampling of tetracyclines in pig breeding wastewater.
The pollution of antibiotics, including tetracyclines (TCs), in aquatic environments has become an issue of concern in recent years. Herein, an in situ sampling of TCs in pig breeding wastewater that utilizes the technique of diffusive gradients in thin films (DGT), based on commercial nanosized ZnO (nanoZnO) particles as the potential effective binding agent and a polyethersulfone (PES) membrane as the diffusion layer, was developed. The diffusion coefficients of tetracycline (TC), oxytetracycline (OTC) and chlortetracycline (CTC) in a PES membrane at 25 °C were (1.37 ± 0.06) × 10-6 cm2 s-1, (1.29 ± 0.05) × 10-6 cm2 s-1 and (1.94 ± 0.07) × 10-6 cm2 s-1, respectively. The results showed that the adsorption capacities of a gel disc containing 2.5 g L-1 of nanoZnO particles were as high as 3.93 ± 0.20 mg disc-1 for TC, 3.21 ± 0.20 mg disc-1 for OTC and 4.62 ± 0.22 mg disc-1 for CTC. Both a solution pH in the range of 5-9 and an ionic strength (as pNaCl) in the range of 1-3 had an insignificant influence on the TCs uptake by nanoZnO-DGT samplers. There was no significant influence of fulvic acid or tannic acid on the TC uptake by nanoZnO-DGT samplers at the tested mass ratios. For all spiked freshwater samples, there was no notable interference of matrices on the performance of the nanoZnO-DGT samplers, suggesting that the nanoZnO-DGT samplers yielded satisfactory results for the uptake of TCs at concentrations existing in the spiked freshwater samples. Field deployment of the nanoZnO-DGT samplers in pig breeding wastewater also exhibited excellent precision and accuracy, indicating that the nanoZnO-DGT samplers could be used as a promising method for the in situ sampling of TC antibiotics in aquatic environments.


Alkylation of protein by methyl methanesulfonate and 1-methyl-1-nitrosourea in vitro.
Methylation of horse heart cytochrome c has been examined in vitro with [methyl-14C]methanesulfonate (MMS) and [1-methyl-14C]-1-nitrosourea (MNU) as alkylating agents. Analysis of protein hydrolyzates by an automatic amino acid analyzer indicates that, at pH 9.0 with MMS, epsilon-N-monomethyl-lysine is found to be the only major methylated basic amino acid. On the other hand, the identity of the predominant basic amino acid residue which is [methyl-14C]-labeled by MNU cannot be determined at present. Peptide mapping of chymotryptic digests of cytochrome c after reaction with MMS reveals a lack of specificity in methylation of a specific lysine residue in this hemoprotein.


Self-management and adherence to recommended follow-up after gynaecological cancer: results from the international InCHARGE study.
To assess the relationship between self-management skills and adherence to follow-up guidelines among gynecological cancer survivors in the Netherlands, Norway, and Denmark, and to assess the relationship between adherence to follow-up programs and use of additional healthcare services. For this international, multicenter, cross-sectional study, we recruited gynecological cancer survivors 1-5 years after completion of treatment. Information on follow-up visits, use of healthcare resources, self-management (measured by the Health Education Impact Questionnaire), clinical characteristics, and demographics were obtained by validated questionnaires. Participants were categorized as adherent if they attended the number of follow-up visits recommended by national guidelines, non-adherent if they had fewer visits than recommended, or over-users if they had more visits than recommended. Of 4455 invited survivors, 2428 (55%) returned the questionnaires, and 911 survivors were included in the analyses. Survivors with high self-management most frequently adhered to recommended follow-up. Non-adherent survivors showed lower self-management in the health-directed activity domain (OR 1.54, 95% CI 1.03 to 2.32) than adherent survivors. No other associations between self-management and follow-up adherence were revealed. Non-adherent survivors tended to have endometrial cancer, surgical treatment only, be older, and be Danish residents. Over-users reported more follow-up visits and also used additional healthcare services more frequently than adherent survivors. Low self-management appears to reduce the likelihood of adherence to national guidelines for gynecological cancer follow-up. Focusing on patient education for survivors at risk of low self-management to ensure adherence to recommended follow-up may improve personalization of follow-up.


Examining of Heavy Metal Concentrations in Hookah Smokers.
Hookah smoking has been spreading around the world, especially among young adults. The current study aimed to investigate the concentration of heavy metals and elements and clinical symptoms in hookah users in comparison with non-users. To the best of our knowledge, the present study represents the first scientific contribution indicating levels of several heavy metals and elements in urine and blood in hookah users and non-users as well as evaluating clinical symptoms. This research was implemented in Iran among 100 males divided into two groups (50/group): control and hookah users. Heavy metal contamination (lead, cadmium, arsenic, thallium, zinc, and copper) in blood and urine samples was assayed by graphite furnace atomic absorption spectrometry (GFAAS). Duration of hookah use was 7.06 ± 4.57 years. The mean ± SD of lead, arsenic, and thallium concentrations was 3.77 ± 2.22, 8.50 ± 4.34, and 4.22 ± 2.69 μg/L. The mean levels of blood for lead, arsenic, and urinary thallium in hookah users are significantly higher than the control group (p < 0.05). The most frequent clinical symptoms in hookah smokers were constipation and fatigue. Findings from this study might guide the development of policies to regulate hookah smoking and prevent adverse health effects associated with hookah smoking.


[Supplementary intravenous alimentation in the premature infant weighing less than 1,500 grams].
The effects of a 10% glucose solution and of a fructose plus 1.4% casein hydrolysate solution have been comparatively evaluated in infants with birth weights under 1 500 g. Children fed with glucose solution only are used as matched controls. Children fed with protein hydrolysate associated with fructose have a weight loss lower than those of the control-group. However, the time necessary to regain the birth weight is similar in both groups. The biologic data which were studied (glucosemia, calcemia, acid-base balance, clotting factors) are statistically identical in both groups. Neither of the groups showed hyperglucosemia. The survival rate is similar in both groups; caloric and proteic supplementation does not change the death rate.


Arm exercise-thallium imaging testing for the detection of coronary artery disease.
Patients with lower limb impairment are often unable to undergo a standard bicycle or treadmill test for the evaluation of coronary artery disease. To establish an alternative method of testing, 50 subjects (aged 56 +/- 10 years) performed arm ergometry testing in conjunction with myocardial thallium scintigraphy. All underwent coronary angiography; significant coronary artery disease (greater than or equal to 70% stenosis) in at least one vessel was present in 41 (82%) of the 50 patients. Thallium scintigraphy was found to have an 83% sensitivity and 78% specificity for detecting coronary disease, compared with a sensitivity and specificity of 54% (p less than 0.01) and 67% (p = NS), respectively, for exercise electrocardiography. In the subgroup of 23 patients who had no prior myocardial infarction or left bundle branch block and were not taking digitalis, thallium scintigraphy had a sensitivity of 80% versus 50% for exercise electrocardiography. Scintigraphy yielded a sensitivity of 84, 74 and 90% for one, two and three vessel disease, respectively. Noninvasive arm ergometry exercise-thallium imaging testing appears to be reliable and useful and should be considered in the evaluation of coronary artery disease in patients with lower limb impairment.


Indocyanine Green Fluorescence Angiography after Full-thickness Bowel Resection for Rectosigmoid Endometriosis-A Feasibility Study.
To evaluate feasibility of near-infrared (NIR)-indocyanine green (ICG) imaging for bowel vascularization assessment after full-thickness bowel resection for rectosigmoid endometriosis (RSE). This is a prospective, single-center, preliminary study on consecutive patients who were symptomatic submitted to discoid or segmental resection for RSE and NIR-ICG evaluation for vascular assessment of the anastomotic line from May 2018 to January 2020. Tertiary university hospital. Thirty-two women with RSE meeting eligibility criteria were included for study analysis. NIR-ICG evaluation of anastomotic line vascularization after RSE removal. Fluorescence degree of the anastomotic line was assessed with a 0 to 2 Likert scale, as follows: 0 or "absent" (no fluorescence observed), 1 or "irregular" (not uniform distribution or weak fluorescence), and 2 or "regular" (uniform distribution of fluorescence and similar to the proximal colon). In all the patients included in the study (100%), NIR-ICG imaging allowed the evaluation of fluorescence degree of the anastomotic line. No adverse reaction related to ICG use was recorded. The protocol did not greatly lengthen operating time (median, 4 [range, 3-5] minutes). Excellent interoperator agreement was observed. Most of the patients (31 of 32, 96.9%) showed regular fluorescence on the anastomotic line; in 1 patient with irregular fluorescence at NIR-ICG after discoid excision, the anastomotic suture was reinforced through interrupted stitches. We had 1 case of anastomotic leakage after segmental resection with intraoperative good fluorescence at NIR-ICG evaluation. NIR-ICG imaging for anastomotic perfusion assessment after discoid or segmental resection for RSE seems to be a feasible, safe, and reproducible method.


[The potential of instant messaging for social relations of persons 65].
Current data from Switzerland show that an increasing number of older adults (65+ years) use instant messaging services. We examined whether and how the use of WhatsApp affects different forms of older people's social capital and whether the socioemotional selectivity theory can be applied in digital environments. A qualitative study was conducted with 30 WhatsApp users in the age group 65+. The survey was based on data from ego-centered network maps and interviews using a semistructured interview guide. WhatsApp is mainly used for communication with close persons. The use of WhatsApp simplifies relationship management, increases the frequency of contact and can thus lead to intensified relationships. The use of WhatsApp can strengthen the sense of group belonging. The media is described as very low-threshold and enables spontaneity. The socioemotional selectivity theory can also be applied in digital environments. Via WhatsApp, positive contents are shared with emotionally significant people in the social network. The use of WhatsApp increases both bonding social capital as relationships are deepened and strengthened and maintaining social capital as geographical distances can be bridged.


The effect of lung stretch during sleep on airway mechanics in overweight and obese asthma.
Both obesity and sleep reduce lung volume and limit deep breaths, possibly contributing to asthma. We hypothesize that increasing lung volume dynamically during sleep would reduce airway resistance in asthma. Asthma (n=10) and control (n=10) subjects were studied during sleep at baseline and with increased lung volume via bi-level positive airway pressure (BPAP). Using forced oscillations, respiratory system resistance (R(rs)) and reactance (X(rs)) were measured during sleep and R(rs) was partitioned to upper and lower airway resistance (R(up), R(low)) using an epiglottic pressure catheter. R(rs) and R(up) increased with sleep (p<0.01) and X(rs) was decreased in REM (p=0.02) as compared to wake. R(rs), R(up), and R(low), were larger (p<0.01) and X(rs) was decreased (p<0.02) in asthma. On BPAP, R(rs) and R(up) were decreased (p<0.001) and X(rs) increased (p<0.01), but R(low) was unchanged. High R(up) was observed in asthma, which reduced with BPAP. We conclude that the upper airway is a major component of R(rs) and larger lung volume changes may be required to alter R(low).


The kinesin light chain-2, a target of mRNA stabilizing protein HuR, inhibits p53 protein phosphorylation to promote radioresistance in NSCLC.
Radioresistance hinders radiotherapy for the treatment of lung cancer. Kinesin light chain-2 (KLC2) has been found to be upregulated in lung cancer and also to be associated with poor prognosis. This study aimed to investigate the effect of KLC2 on radiosensitivity in lung cancer. The radioresistant role of KLC2 was determined by colony formation, neutral comet assay, and γH2AX immunofluorescent staining assay. We further verified the function of KLC2 in a xenograft tumor model. The downstream of KLC2 was identified through gene set enrichment analysis and validated by western blot. Finally, we analyzed clinical data from the TCGA database to reveal the upstream transcription factor of KLC2, which was validated by RNA binding protein immunoprecipitation assay. Here, we found that downregulation of KLC2 could significantly reduce colony formation, increase γH2AX level, and double-stranded DNA breaks in vitro. Meanwhile, overexpressed KLC2 significantly increased the proportion of the S phase in lung cancer cells. KLC2 knockdown could activate P53 pathway, and ultimately promoting radiosensitivity. The mRNA of KLC2 was observed to bind with Hu-antigen R (HuR). The mRNA and protein expression of KLC2 in lung cancer cells was significantly reduced when combined with siRNA-HuR. Interestingly, KLC2 overexpression significantly increased the expression of HuR in lung cancer cells. Taken together, these results indicated that HuR-KLC2 forms a positive feedback loop, which decreases the phosphorylation of p53 and thereby weaken the radiosensitivity of lung cancer cells. Our findings highlight the potential prognosis and therapeutic target value of KLC2 in lung cancer patients treated with radiotherapy.


Establishment of ornithine transcarbamylase deficiency-derived primary human hepatocyte with hepatic functions.
A long-term hepatocyte culture maintaining liver-specific functions is very essential for both basic research and the development of bioartificial liver devices in clinical application. However, primary hepatocytes rapidly lose their proliferation and hepatic functions over a few days in culture. This work is to establish an ornithine transcarbamylase deficiency (OTCD) patient-derived primary human hepatocyte (OTCD-PHH) culture with hepatic functions for providing an in vitro cell model. Liver tissue from an infant with OTCD was dispersed into single cells. The cells were cultured using conditional reprogramming. To characterize the cells, we assessed activities and mRNA expression of CYP3A4, 1A1, 2C9, as well as albumin and urea secretion. We found that the OTCD-PHH can be subpassaged for more than 15 passages. The cells do not express mRNA of fibroblast-specific maker, whereas they highly express markers of epithelial cells and hepatocytes. In addition, the OTCD-PHH retain native CYP3A4, 1A1, 2C9 activities and albumin secretion function at early passages. The OTCD-PHH at passages 2, 6, 9 and 13 have identical DNA fingerprint as the original tissue. Furthermore, under 3D culture environment, low urea production and hepatocyte marker staining of the OTCD-PHH were detected. The established OTCD-PHH maintain liver-specific functions at early passages and can be long-term cultured in vitro. We believe the established long-term OTCD-PHH culture is highly relevant to study liver diseases, particularly in infants with OTCD.


Structure-first identification of RNA elements that regulate dengue virus genome architecture and replication.
The genomes of RNA viruses encode the information required for replication in host cells both in their linear sequence and in complex higher-order structures. A subset of these RNA genome structures show clear sequence conservation, and have been extensively described for well-characterized viruses. However, the extent to which viral RNA genomes contain functional structural elements-unable to be detected by sequence alone-that nonetheless are critical to viral fitness is largely unknown. Here, we devise a structure-first experimental strategy and use it to identify 22 structure-similar motifs across the coding sequences of the RNA genomes for the four dengue virus serotypes. At least 10 of these motifs modulate viral fitness, revealing a significant unnoticed extent of RNA structure-mediated regulation within viral coding sequences. These viral RNA structures promote a compact global genome architecture, interact with proteins, and regulate the viral replication cycle. These motifs are also thus constrained at the levels of both RNA structure and protein sequence and are potential resistance-refractory targets for antivirals and live-attenuated vaccines. Structure-first identification of conserved RNA structure enables efficient discovery of pervasive RNA-mediated regulation in viral genomes and, likely, other cellular RNAs.


The pontocerebellar system in the rat: an HRP study. I. Posterior vermis.
This study was undertaken to determine the origin of projections from the basilar pontine nuclei (BPN) and nucleus reticularis tegmentis pontis (NRTP) to the posterior vermal lobules VI-IX of the rat cerebellum. We describe the topographical organization of this component of the pontocerebellar projection, and the congruence of the cells of origin in the basilar pons with some of the major pontine afferent systems including the corticopontine and tectopontine projections. Horseradish peroxidase (HRP) was injected into the midline cerebellar vermal zones of Long-Evans hooded rats. The more sensitive chromogens, tetramethyl benzidine and benzidine dihydrochloride, were used to reveal the location of labeled neurons. With injections located near the midline, groups of labeled cells were observed bilaterally within the BPN. The basic trend of the projections noted was: lobule VIa receives a nonfocal projection from nearly all subdivisions of the BPN throughout its rostrocaudal extent, as well as a substantial input from NRTP. Lobules VIb-c receive input from NRTP, the rostral pons, and from the ventral, lateral, and medial groups of cells in the middle BPN project to lobule VII, in addition to projections from limited groups of cells in the rostral BPN. Lobule VIII receives afferents from the caudal aspect of the pontine gray. Lobules IXa-receive afferents from the medial and peduncular groups in the midline BPN, whereas lobule IXc receives inputs from a medial group and a small lateral cluster of cells in the caudal aspect of the BPN. Pontine neurons projecting to the posterior vermis originate from areas which appear to receive descending inputs from visual, auditory, and somatosensory regions of the cerebral cortex. However, a large number of pontine and NRTP neurons projecting to lobules VI and VII are located within the terminal fields of tectal neurons, perhaps indicating a stronger input from the tectum rather than visual and auditory cerebral cortical regions.


Hybrid predictor for ground-motion intensity with machine learning and conventional ground motion prediction equation.
The use of strongly biased data generally leads to large distortions in a trained machine learning model. We face this problem when constructing a predictor for earthquake-generated ground-motion intensity with machine learning. The machine learning predictor constructed in this study has an underestimation problem for strong motions, although the data fit on relatively weak ground motions is good. This underestimation problem is caused by the strong bias in available ground-motion records; there are few records of strong motions in the dataset. Therefore, we propose a hybrid approach of machine learning and conventional ground-motion prediction equation. This study demonstrates that this hybrid approach machine learning technology and physical model reduces the underestimation of strong motions and leads to better prediction than either of the individual approaches applied alone.


Streptomyces: Derived Active Extract Inhibits Candida albicans Biofilm Formation.
Candida albicans is an opportunistic pathogen that causes biofilm-associated infections. C. albicans biofilms are known to display reduced susceptibility to antimicrobials and high rates of acquired antibiotic resistance, and biofilm forming in C. albicans further hampers treatment options and highlights the need for new antibiofilm strategies. Identifying active components from desert actinomycetes strains to inhibit the formation of C. albicans biofilms represents an effective treatment strategy. In this study, actinomycetes that can inhibit C. albicans biofilm formation were isolated from the Taklimakan Desert, and the underlying mechanisms were explored. After screening the anti-C.albicans biofilm activities of culture supernatants from 170 Actinomycete strains, six strains showed significant inhibition of C. albicans biofilm formation. Microscopic examination showed a reduction in biofilm formation of C. albicans treated with supernatants from actinomycetes. Scanning electron microscopy showed that the morphological changes in biofilm cells were caused by cell membrane rupture and cell material leakage. Then, C.albicans biofilms were destroyed by changing the content of extracellular polysaccharides or degrading extracellular DNA. Finally, a preliminary study on active substances extracted from a new species (TRM43335) showed that the substances that inhibited the formation of biofilms might be peptides. This study provides preliminary evidence that desert actinomyces strains have inhibitory effects on the biofilm development of C. albicans.


Short-term effects of the activator in skeletal class II division 1 patients with different vertical skeletal pattern. A retrospective study.
The aim of this retrospective study was to analyse the effectiveness of Andresen appliance in inducing an increased mandibular dimension and, above all, to test the "null" hypotesis that the patients' vertical skelettofacial morfology could influence this increase using the Ricketts' method of VERT. Cephalometric records of 42 skeletal class II patients treated at the Orthodontic Department of Catania University were randomly selected. The sample was divided for vertical facial patterns, according to the facial classification method of Ricketts (VERT), into three groups: brachyfacial, mesiofacial and dolicofacial. Ten landmarks were located on the lateral cephalometric radiographs; growth in the horizontal-sagittal direction and in the vertical direction was evaluated using the measurements of total mandibular length (Co-Gn, Co-Pg, Ar-Pg, Ar-Gn), mandibular sagittal position (SNB, ANB) and mandibular ramus height (S-Go, Ar-Go, Co-Go). The intragroup comparisons were made using two tailed t-tests, while the intergroup comparisons were analyzed statistically using the Kruskal-Wallis test. The cephalometric values before (T0) and after (T1) treatment showed significant changes for the majority of the cephalometric variables in each group. Our findings demonstrated a statistically significant greater increase of mandibular dimension in the brachyfacial group, while similar results were found for mesiofacial and dolichofacial groups. The "null" hypothesis, that the skeletal pattern of subjects could influence the increase of mandibular dimension after Andresen treatment, had to be accepted: the brachyfacial patients showed a greater anterior mandibular displacement when compared to mesiofacial or dolichofacial group.


Immune-related adverse events with immune checkpoint inhibitors affecting the skeleton: a seminal case series.
The use of immune checkpoint inhibitors is increasing in cancer therapy today. It is critical that treatment teams become familiar with the organ systems potentially impacted by immune-related adverse events associated with these drugs. Here, we report adverse skeletal effects of immunotherapy, a phenomenon not previously described. In this retrospective case series, clinical, laboratory and imaging data were obtained in patients referred to endocrinology or rheumatology with new fractures (n = 3) or resorptive bone lesions (n = 3) that developed while on agents targeting PD-1, CTLA-4 or both. The average age of patients was 59.3 (SD 8.6), and five were male. Cancer types included melanoma, renal cell carcinoma and non-small cell lung cancer. All fracture patients had vertebral compression, and two of the three had multiple fracture sites involved. Sites of resorptive lesions included the shoulder, hand and clavicle. Biochemically, elevated or high-normal markers of bone resorption were seen in five of the six patients. Erythrocyte sedimentation rate was elevated in three of the four patients where checked. This case series represents the first description of potential skeletal adverse effects related to immune checkpoint inhibitors. These findings are important for providers caring for patients who experience musculoskeletal symptoms and may merit additional evaluation.


Safety and Efficacy of Ribociclib in Combination with Letrozole in Patients with HR+, HER2- Advanced Breast Cancer: Results from the Italian Subpopulation of Phase 3b CompLEEment-1 Study.
Ribociclib plus letrozole demonstrated manageable safety and efficacy profiles in hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) advanced breast cancer (ABC) in the Phase 3b CompLEEment-1 trial. To evaluate the safety and efficacy of ribociclib plus letrozole in the Italian subpopulation with HR+, HER2- ABC from the CompLEEment-1 trial. Patients with HR+, HER2- ABC received ribociclib (600 mg/day, 3 weeks on/1 week off) plus letrozole (2.5 mg/day) while men and premenopausal women additionally received goserelin. Patients were allowed with ≤ 1 line of prior chemotherapy and an Eastern Cooperative Oncology Group performance status of ≤ 2. The primary outcome included safety and tolerability. Of the 554 Italian patients, 246 (44.4 %) patients completed treatment. The reasons for treatment discontinuation included progressive disease (PD; 36.6 %), adverse events (AEs; 11.9 %), and death (1.6 %). All-grade AEs and grade ≥ 3 AEs occurred in 98.9 % and 77.8 % patients, respectively. The most common treatment-related AEs were neutropenia (73.6 %), followed by leukopenia (32.1 %), and nausea (25.3 %). The overall response rate was 28.2 % (95 % confidence interval [CI], 24.4-32.1); clinical benefit rate was 71.7 % (95 % CI, 67.7-75.4); and median time to progression was 26.7 months (95 % CI, 24.8-non-estimable). Health-related quality of life scores were maintained during treatment. The safety and efficacy profiles of ribociclib plus letrozole in the Italian subpopulation was found to be consistent with the CompLEEment-1 global population result, MONALEESA-2, and MONALEESA-7 outcomes, which reaffirm ribociclib plus letrozole as the frontline treatment option in patients with HR+, HER2- ABC. NCT02941926 (30 November 2016).


Peripheral nerve injury induces cannabinoid receptor 2 protein expression in rat sensory neurons.
We have localized cannabinoid receptor 2 protein in rat and mouse somatic sensory nervous system, using an antibody that recognizes mouse cannabinoid receptor 2. Little or no cannabinoid receptor 2 immunoreactivity was found in sections of naive rat or mouse dorsal root ganglia or spinal cord. This was in accord with the lack of detectable cannabinoid receptor 2 mRNA in (dorsal root ganglion) neurons by in situ hybridization experiments described in the literature. However, we could detect cannabinoid receptor 2 immunoreactivity following unilateral nerve damage-either by sciatic nerve section, or by spinal nerve ligation. It was localized to the superficial laminae of the dorsal horn of the spinal cord, ipsilateral to the nerve damage, coincident with the area of termination of damaged afferents which was marked by loss of isolectin B4 binding. This upregulation was not seen in cannabinoid receptor 2 null mice. The cannabinoid receptor 2 protein in spinal cord appeared to be expressed on sensory neuron afferent terminals as it colocalized with two markers of damaged afferents, namely growth associated protein-43 and the neuropeptide galanin. Moreover, it did not colocalize with markers of activated microglial cells (OX-42) or astroglial cells (glial fibrillary acidic protein) in rat spinal cord. In the peripheral nerve, accumulation of cannabinoid receptor 2 immunoreactivity was seen in nerve sections proximal, but not distal, to the ligation site, suggesting transport down the nerve from the cell bodies. Although convincing cannabinoid receptor 2 immunoreactivity was seen in neither uninjured nor injured dorsal root ganglion neuron cell bodies in tissue sections, expression was detectable in isolated, cultured neurons that had received a prior axotomy in vivo. This clear demonstration of CB(2) receptors on sensory neurons suggests an additional cellular target for CB(2) agonist induced analgesia, at least in neuropathic models.


Understanding sexual relationships between tourists and locals in Cuzco/Peru.
Casual sexual encounters between tourists and locals have been increasingly discussed. The city of Cuzco/Peru is well known for an increased availability of such sexual opportunities. The objective of this study was to explore tourists' and locals' knowledge, attitudes, and reasoning for engaging in casual sexual relationships. In this qualitative study, 10 locals and 13 tourists were in-depth interviewed (15 women, 8 men, aged 19-50+). Participant and non-participant observations, and informal discussions provided supporting evidence. For tourists, the relationships with locals ranged from one-night-stands as part of the travel experience and having fun, to commitment for the term of a longer stay, to marriage. From the locals' point of view, these encounters ranged from sexual adventures to increase self-esteem and high standing in their circle of friends, to serious long-term commitments. In both cases, the difference in the physical appearance played a main part in the perceived attraction that had triggered the encounter. Lack of consistent condom use remains a concern along with the locals' profound lack of knowledge of STIs. Travel health advisors should place more emphasis on sexual health in pre-travel consultations. The use of condoms cannot be stressed enough. Local health professionals should aggressively increase safe sex health promotion, specifically targeting people related to the tourism industry.


Towards development of plasmacytoma cells-based expression systems utilizing alphavirus vectors: An NS0-VEE model.
Plasmacytoma (myeloma) cells have a large protein expression capacity, although their industrial use is confined to stable expression systems. Vectors derived from genomes of viruses from the genus Alphavirus allow obtaining of high yields of target proteins but their use is limited to transient expression. Little information has been published to date on attempts to combine the myeloma cells as hosts with alphaviruses as expression vectors. A plasmid construct which allows rescue of a model alphavirus Venezuelan equine encephalitis virus (VEE) upon transfection of a cell culture was created. Mutations in the capsid and nsP2 genes allow for less cytopathogenic propagation of the virus. A cDNA-copy of the genome was placed in a plasmid under the control of the CMV promoter for virus rescue following DNA transfection. Parameters for the virus rescue by electroporating of the infectious clone in murine myeloma cells (NS0) were optimized. The highest FFU counts (1.2 × 105 FFU per 10 ug DNA) were produced with 2 pulses (voltage 250 V, capacitance 960 u F) and the best electroporation buffer was selected from eight buffers. Self-sustained VEE infection was established in NS0 cultures with high titers (8 × 108 FFU/ml) of the virus, despite a fraction of infected cells dying during 5-days observation. Further development of the NS0-VEE expression system may require addressing of apoptosis induced by VEE.


Increased risk of multiple pregnancy complications following large-scale power outages during Hurricane Sandy in New York State.
Large-scale power outages (PO) are increasing in the context of climate change. Although some research has been conducted into the adverse health impacts of POs, significant gaps remain regarding whether POs would affect the health of pregnant women. We investigated the association between ED visits due to pregnancy complications and the occurence, intensity, and duration of large-scale POs in eight Sandy-affected counties in New York State (NYS). In this cross-sectional study, daily ED visits for pregnancy complications and large-scale PO data in eight counties in NYS from October to December in 2005-2014 were collected. Using time-series analysis, we estimated the relative increase in ED visits for pregnancy complications during POs compared with non-PO periods at lag 0-7 days. Short-term health impacts of PO intensity and PO duration were investigated. Estimations were also stratified by sociodemographic characteristics and disease subtypes including threatened or spontaneous abortion, threatened or early labor, hypertension complications, infections of genitourinary tract, renal diseases, gestational diabetes mellitus, mental illnesses, and cardiovascular diseases during pregnancy. From October to December in 2005-2014, there were 307,739 ED visits for pregnancy complications in the eight counties. We found significant increases in ED visits for overall pregnancy complications (16.6%, 95% confidence interval [CI]: 10.3%, 23.2%) during the Hurricane-PO period at lag 0-7 days. The ED visits increased by 8.8% per level increase in PO intensity and 1.4% per day increase in PO duration. Specifically, threatened/early delivery and gestational diabetes mellitus during the PO period increased by 26.7% (95% CI: 8.2%, 48.4%) and 111.8% (95% CI: 16.7%, 284.4%), respectively. Young adult, Black, Hispanic, and uninsured individuals were at higher risk of complications. POs may adversely impact pregnancy, especially for certain pregnancy complications and among low sociodemographic women.


Endoscopic management of acute respiratory failure related to tracheobronchial malignancies.
Endobronchial treatment has an expanding role in the treatment of tracheobronchial tumors. Most patients are treated in this way for the palliation of dyspnea caused by a tumor located in a major airway. In cases where immediate relief is required, prompt control is better achieved by the neodymium-YAG laser or by stents. These two modalities and their indications and limitations in the endoscopic management of acute respiratory failure related to tracheobronchial malignancies are discussed.


Dataset: A proxy for historical CO2 emissions related to centralised electricity generation in Europe.
This paper presents data for the estimation of carbon dioxide (CO2) emissions resulting from public generation of electricity in the period from 1990 to 2018 in European countries. The base data used in the calculation of the proxy are the national emissions reported to the United Nations Framework Convention on Climate Change (UNFCCC) and the European Union (EU) Greenhouse Gas Monitoring Mechanism. Subsequently, this data is compiled and held by the European Environment Agency (EEA) from where it is accessed. The emission data is reported aggregated from thermal power stations, district heating plants, and cogeneration in combined heat and power (CHP) plants. We calculate a proxy for emissions by electricity generation alone by combining the emissions from thermal power stations and the share of CPH emissions belonging to electricity generation. The computed data was validated on the period from 2000 to 2015 by comparing it to a secondary dataset. The found emission values of the year 1990 are of particular importance as this is a commonly used emission reference year. The provided dataset, charts and figures can be reused for both analysing past emission evolutions and building models about future electricity generation emissions in Europe. The dataset is freely available in [1]. A subset of the dataset has been applied in "CO2 quota attribution effects on the European electricity system comprised of self-centred actors" [2] to assess the effects of potential total and national CO2 quota attributions in the European electricity system of the near future.


The Normal Epithelium of Crypts Accruing Below Nonpolypoid Adenomas Thrives With Relocated Proliferating Cell-domains and p53-Up-regulated Cells.
Colonic crypts with normal epithelium albeit with corrupted shapes (CCS) were previously found beneath nonpolypoid adenomas (NPA). This study aimed to analyze the distribution of proliferating cells (PC) and p53-up-regulated cells in CCS. Sections from 48 NPA were immunostained with the proliferating-marker Ki67 and against the tumor-suppressor protein p53. Asymmetric-haphazardly distributed PC were found in 87.5% of the NPA, continuous PC-domains in 8.3%, asymmetric-haphazardly distributed single PC in 4.2% and p53-up-regulated cells in 29.2%. In 12 controls, the normal-shaped crypts revealed symmetrically-distributed PC-domains in their lower thirds, and no p53-up-regulated cells. The normal epithelium that lines the CCS below NPA, thrives with relocated PC-domains, and with occasional p53-up-regulated cells. These findings strongly suggest that the normal epithelium of CCS beneath NPA might harbor somatic mutations. The accretion of putative mutated CCS might play an important role in the evolution of nonpolypoid adenomas in the human colon.


The development of an industrial-scale fed-batch fermentation simulation.
This paper describes a simulation of an industrial-scale fed-batch fermentation that can be used as a benchmark in process systems analysis and control studies. The simulation was developed using a mechanistic model and validated using historical data collected from an industrial-scale penicillin fermentation process. Each batch was carried out in a 100,000 L bioreactor that used an industrial strain of Penicillium chrysogenum. The manipulated variables recorded during each batch were used as inputs to the simulator and the predicted outputs were then compared with the on-line and off-line measurements recorded in the real process. The simulator adapted a previously published structured model to describe the penicillin fermentation and extended it to include the main environmental effects of dissolved oxygen, viscosity, temperature, pH and dissolved carbon dioxide. In addition the effects of nitrogen and phenylacetic acid concentrations on the biomass and penicillin production rates were also included. The simulated model predictions of all the on-line and off-line process measurements, including the off-gas analysis, were in good agreement with the batch records. The simulator and industrial process data are available to download at www.industrialpenicillinsimulation.com and can be used to evaluate, study and improve on the current control strategy implemented on this facility.


Effect of Gu Tong Xian capsule on expression level of type I, II collagen and BMP-2 mRNA in rabbits with fracture during long-distance running.
The study aims to analyze and investigate the effects of Gu Tong Xian Capsule on the expression level of type I, II collagen and BMP-2 mRNA in rabbits with fracture during long-distance running. 60 adult healthy rabbits were selected as research objects, and then randomly divided into three groups including model group, positive control group and treatment group, each containing 20 rabbits. The three groups were treated with saline gastric lavage, powder for fracture and trauma, and Gu Tong Xian capsule, respectively. The rabbits of the three groups were respectively sacrificed at 1st week, 2nd weeks and 4th week after operation for sample collection. After that, the expression levels of bone collagen type I, II and BMP-2 of three groups were measured and compared with each other. At all stages, the transcriptional level of type I collagen mRNA in the treatment group were significantly higher than that in the positive control group and model group (p < 0.05); Transcriptional level of type II collagen mRNA in the treatment group increased significantly in the first week, then gradually declined in the 2nd and 4th week, with significantly difference to the model group and the positive control group (p < 0.05). In addition, the transcriptional level of bone morphogenetic protein BMP-2 mRNA at fracture site of the treatment group was higher than that of model group and positive control group (p < 0.05). Gu Tong Xian Capsule can significantly promote fracture healing of experiment rabbits and reduce fracture healing time. Moreover, it can well regulate the expression levels of type I, II collagen and transcriptional level ofBMP-2 mRNA in experiment rabbits with fracture.


Recombinant immunoblot assay for hepatitis C virus antibody in chronic hepatitis.
Testing for hepatitis C virus by ELISA requires confirmation by recombinant immunoblot assay (RIBA). The first-generation RIBA uses the same antigen as used in the ELISA and one further antigen. A second-generation RIBA in which two further antigens are present, detects positivity that is not found by either the ELISA or the original RIBA. Consequently, although it is adequate to test ELISA positive sera with the first-generation RIBA, the second-generation assay is recommended for confirming negativity.


Selective chemical ablation of the enteric plexus in mice.
Although genetically aganglionic mice such as piebald lethal and lethal spotted mice exhibit striking similarities to the human condition of Hirschsprung's disease (HD), the aganglionic segment is very short and always located in the distal part of the rectum. Topical application of benzalkonium chloride (BAC) to the rectum of rats has been reported to result in segmental aganglionosis. To induce chemical ablation of the enteric plexus in mice to produce an aperistaltic narrow segment simulating HD, 32 mice were divided into three groups: (1) abdominal (n=12), for sigmoid colon treatment; (2) rectal (n=10), for rectum treatment; and (3) controls (n=10). For groups 1 and 2, 0.1% BAC was applied to a 1-cm serosal surface of the bowel for 15 min. In the controls, isotonic saline was applied in this fashion. A detailed histologic examination was performed using hematoxylin and eosin staining and acetylcholinesterase histochemistry. Ten animals (9 in group 1 and 1 in group 2) died 1 to 9 weeks after BAC treatment. Autopsy revealed a narrow segment of bowel at the site of BAC treatment and marked dilatation of the bowel proximal to the narrow segment. The remaining animals were killed 12 weeks after BAC treatment. Histologic examination demonstrated normal myenteric and submucous plexuses in the controls, whereas there was a total lack of innervation in the BAC-treated segments.Topical application of BAC thus successfully produced a narrow aganglionic segment of bowel in normal mice. This model provides the basis for future studies to investigate the pathophysiology of HD and megacolon and for comparison with genetically aganglionic mice.


miR-182 targets CHL1 and controls tumor growth and invasion in papillary thyroid carcinoma.
In this study, we investigated the role and underlying mechanism of action of miR-182 in papillary thyroid carcinoma (PTC). Bioinformatics analysis revealed close homolog of LI (CHL1) as a potential target of miR-182. Upregulation of miR-182 was significantly correlated with CHL1 downregulation in human PTC tissues and cell lines. miR-182 suppressed the expression of CHL1 mRNA through direct targeting of the 3'-untranslated region (3'-UTR). Downregulation of miR-182 suppressed growth and invasion of PTC cells. Silencing of CHL1 counteracted the effects of miR-182 suppression, while its overexpression mimicked these effects. Our data collectively indicate that miR-182 in PTC promotes cell proliferation and invasion through direct suppression of CHL1, supporting the potential utility of miR-182 inhibition as a novel therapeutic strategy against PTC.


Cerebrospinal fluid lactate dehydrogenase activities in patients with central nervous system metastases.
Lactate dehydrogenase activities were determined in CSF from 350 patients suffering from various neurological diseases. Reference values were established as 0-26 U/l. Slight elevations of CSF LDH activities were observed in patients with the following disorders: brain metastasis and spinal epidural metastasis from solid carcinomas, primary central nervous system tumours, cerebrovascular accident, polyneuropathy and head injury. Marked elevations were observed incidentally in patients in these groups and in a considerable number of patients with bacterial meningitis and with leptomeningeal spread from solid or haematologic malignancies. When other diagnostic information is available for the proper estimation of the pre-test likelihood of disease, CSF LDH activities exceeding 50 U/l are suggestive for meningeal carcinomatosis.


Higher cumulative dose of topical corticosteroids is associated with osteoporosis and major osteoporotic fracture: A nationwide case-control study.
Connections between long-term use of topical corticosteroids (TCSs) of varying potency and osteoporosis and major osteoporotic fracture (MOF) are unclear. Susceptibility to adverse bone effects of TCSs in different sex, age and ethnic groups is unknown too. To demonstrate the association between cumulative dose of TCSs of varying potency and osteoporosis and MOF in Taiwanese population, with stratified analysis of sex and age. We conducted a nationwide case-control study and obtained data from Taiwan National Health Insurance Research Database. Cumulative TCS doses in different exposure periods were calculated, and the potency of TCSs was converted to prednisolone equivalent. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for osteoporosis and MOF associated with TCS use. From 2017 to 2020, 129,682 osteoporosis cases and 34,999 MOF cases were selected and randomly matched with 518,728 and 139,996 controls by sex and age. We found clear dose-response relationships between long-term TCS exposure and osteoporosis and MOF. For example, compared to no TCS use, adjusted ORs of osteoporosis were 1.216 (95% CI 1.189-1.243), 1.260 (95% CI, 1.241-1.280) and 1.341 (95% CI, 1.314-1.369) for exposure to low, medium and high cumulative TCS doses, respectively, over 5 years. Adjusted ORs of MOF were 1.118 (95% CI 1.069-1.170), 1.191 (95% CI, 1.156-1.227) and 1.288 (95% CI, 1.238-1.340) for exposure to low, medium and high cumulative TCS doses, respectively, over 5 years. Stratified analysis showed women had higher ORs of osteoporosis and MOF compared to men. Younger people (<50 years) had highest OR of osteoporosis compared to other age groups. Higher cumulative TCS dose was associated with increased risk of osteoporosis and MOF. Long-term use of TCSs should be cautious, especially in susceptible populations such as women and young people.


Machine learning for detection of interictal epileptiform discharges.
The electroencephalogram (EEG) is a fundamental tool in the diagnosis and classification of epilepsy. In particular, Interictal Epileptiform Discharges (IEDs) reflect an increased likelihood of seizures and are routinely assessed by visual analysis of the EEG. Visual assessment is, however, time consuming and prone to subjectivity, leading to a high misdiagnosis rate and motivating the development of automated approaches. Research towards automating IED detection started 45 years ago. Approaches range from mimetic methods to deep learning techniques. We review different approaches to IED detection, discussing their performance and limitations. Traditional machine learning and deep learning methods have yielded the best results so far and their application in the field is still growing. Standardization of datasets and outcome measures is necessary to compare models more objectively and decide which should be implemented in a clinical setting.


Nutrient and energy content, in vitro ruminal fermentation characteristics and methanogenic potential of alpine forage plant species during early summer.
Plants growing on alpine meadows are reported to be rich in phenols. Such compounds may affect ruminal fermentation and reduce the plants' methanogenic potential, making alpine grazing advantageous in this respect. The objective of this study was to quantify nutrients and phenols in Alpine forage grasses, herbs and trees collected over 2 years and, in a 24 h in vitro incubation, their effects on ruminal fermentation parameters. The highest in vitro gas production, resulting in metabolisable energy values around 10 MJ kg⁻¹, were found with Alchemilla xanthochlora and Crepis aurea (herbaceous species) and with Sambucus nigra leaves and flowers (tree species). Related to the amount of total gas production, methane formation was highest with Nardus stricta, and lowest with S. nigra and A. xanthochlora. In addition, Castanea sativa leaves led to an exceptional low methane production, but this was accompanied by severely impaired ruminal fermentation. When the data were analysed by principal component analysis, phenol concentrations were negatively related with methane proportion in total gas. Variation in methane production potential across the investigated forages was small. The two goals of limited methane production potential and high nutritive value for ruminants were met best by A. xanthochlora and S. nigra.


Liver transplantation for patients with alcoholic liver disease: an open question.
End-stage alcoholic liver disease is a recognised indication for liver transplantation but some questions on the matter remain open. It is difficult to quantify alcohol consumption, and a single definition of post-transplant relapse is lacking. Moreover, there are no internationally accepted criteria for the selection of candidates for liver transplantation and the eligibility parameters for these patients are controversial. Additional clinical and psychological evaluations are necessary in this setting, especially to establish the risk of alcohol relapse. Nevertheless, patient and graft survival rates after liver transplantation in alcoholic liver disease are comparable to those after transplant for other aetiologies, alcohol consumption relapse being one of the most important problems in the post-transplant phase. In conclusion, alcohol-related liver disease is a good indication for liver transplantation. The main future goals are to formulate a well-defined pre-transplant approach and a single definition of alcohol relapse and to improve prevention strategies.


Teaching deception skills in a game-play context to three adolescents with autism.
Baron-Cohen (1992) found that students with autism are impaired in their ability to deceive. A multiple-baseline across-subjects design was conceptualized to test the hypothesis that such students could be taught to deceive. Two conditions were presented in baseline and treatment phases. In Condition 1, the student guessed in which hand a small object was hidden when the experimenter presented two closed fists. In Condition 2, the student hid the object and presented two closed fists to the experimenter for a guess. Reinforcement was delivered contingently upon independent guessing during Condition 1 in both baseline and treatment phases. Under Condition 2, reinforcement was delivered noncontingently during the baseline phase and contingently upon successive approximations to the target behavior of deception during the treatment phase. All students displayed the acquisition of at least three of the responses included in the deception response during the baseline phase, and two students showed an erratic acquisition of the total skill during the baseline phase. Results indicate that students with autism can learn to deceive, even without formal intensive training.


Cardiac magnetic resonance imaging in stable ischaemic heart disease.
Cardiac magnetic resonance imaging (CMR) is a new robust versatile non-invasive imaging technique that can detect global and regional myocardial dysfunction, presence of myocardial ischaemia and myocardial scar tissue in one imaging session without radiation, with superb spatial and temporal resolution, inherited three-dimensional data collection and with relatively safe contrast material. The reproducibility of CMR is high which makes it possible to use this technique for serial assessment to evaluate the effect of revascularisation therapy in patients with ischaemic heart disease.


Cost-utility analysis of apixaban compared with usual care for primary thromboprophylaxis in ambulatory patients with cancer.
Apixaban (2.5 mg) taken twice daily has been shown to substantially reduce the risk of venous thromboembolism (VTE) compared with placebo for the primary thromboprophylaxis of ambulatory patients with cancer who are starting chemotherapy and are at intermediate-to-high risk of VTE. We aimed to compare the health system costs and health benefits associated with primary thromboprophylaxis using apixaban with those associated with the current standard of care (where no primary thromboprophylaxis is given), from the perspective of Canada's publicly funded health care system in this subpopulation of patients with cancer over a lifetime horizon. We performed a cost-utility analysis to estimate the incremental cost per quality-adjusted life-year (QALY) gained with primary thromboprophylaxis using apixaban. We obtained baseline event rates and the efficacy of apixaban from the Apixaban for the Prevention of Venous Thromboembolism in High-Risk Ambulatory Cancer Patients (AVERT) trial on apixaban prophylaxis. We estimated relative risk for bleeding, risk of complications associated with VTE treatment, mortality rates, costs and utilities from other published sources. Over a lifetime horizon, apixaban resulted in lower costs to the health system (Can$7902.98 v. Can$14 875.82) and an improvement in QALYs (9.089 v. 9.006). The key driver of cost-effectiveness results was the relative risk of VTE as a result of apixaban. Results from the probabilistic analysis showed that at a willingness to pay of Can$50 000 per QALY, the strategy with the highest probability of being most cost-effective was apixaban, with a probability of 99.87%. We found that apixaban is a cost-saving option for the primary thromboprophylaxis of ambulatory patients with cancer who are starting chemotherapy and are at intermediate-to-high risk of VTE.


CRISPR-based adaptive immune systems.
CRISPR-Cas systems are recently discovered, RNA-based immune systems that control invasions of viruses and plasmids in archaea and bacteria. Prokaryotes with CRISPR-Cas immune systems capture short invader sequences within the CRISPR loci in their genomes, and small RNAs produced from the CRISPR loci (CRISPR (cr)RNAs) guide Cas proteins to recognize and degrade (or otherwise silence) the invading nucleic acids. There are multiple variations of the pathway found among prokaryotes, each mediated by largely distinct components and mechanisms that we are only beginning to delineate. Here we will review our current understanding of the remarkable CRISPR-Cas pathways with particular attention to studies relevant to systems found in the archaea.


Acute or chronic inflammation role in gastrointestinal oncology.
The following letter to the editor highlights the review titled "Inflammatory bowel disease-related colorectal cancer: Past, present and future perspectives" in World J Gastrointest Oncol 2022 March 15; 14(3): 547-567. It is necessary to explore the role of inflammation in promoting tumorigenesis and development of gastrointestinal cancers.


The possible role of estrogen and selective estrogen receptor modulators in a rat model of Parkinson's disease.
The aim of the present study was to assess and compare the effect of 17β-estradiol and two different selective estrogen receptor modulators (SERMs), tamoxifen and raloxifene, as well as a selective estrogen receptor alpha agonist, propyl-pyrazole-triol (PPT) and a selective estrogen receptor beta agonist, diarylpropionitrile (DPN), on behavioral and biochemical alterations in 6-hydroxydopamine (6-OHDA)-induced nigral dopaminergic cell death in rats. 80 female Wister rats were used. Animals were divided into eight equal groups: Group I; Sham operated, Group II; subjected to ovariectomy (OVX), Group III; OVX rats received striatal injection of 6-OHDA, Groups IV-VIII; OVX rats received striatal injection of 6-OHDA and were injected daily with 17β-estradiol, tamoxifen, raloxifene, PPT and DPN respectively for 5days before 6-OHDA and continued for further 2weeks. Results showed that striatal injection of 6-OHDA produced significant behavioral alteration suggestive of PD, together with significant decrease in striatal dopamine, homovanillic acid (HVA) and 3,4-dihydroxyphenyl acetic acid (DOPAC) concentrations. 6-OHDA-induced nigral dopaminergic cell death was characterized by oxidative stress, evidenced by significant decrease in striatal glutathione peroxidase activity, as well as apoptosis, evidenced by significant increase in nigral caspase-3 activity. Treatment with 17β-estradiol, raloxifene, PPT, but neither tamoxifen nor DPN, resulted in significant amelioration of the behavioral and biochemical alterations induced by 6-OHDA. These findings suggest that estrogen and some SERMs having estrogenic agonist activity in the brain, like raloxifene, might exert beneficial effect in PD.


Part 2: Design, synthesis and evaluation of hydroxyproline-derived α2δ ligands.
Conformational constraint has been used to design a potent series of α(2)δ ligands derived from the readily available starting material (2S,4R)-hydroxy-l-proline. The ligands have improved physicochemistry and potency compared to their linear counterparts (described in our earlier publication) and the lead compound has been progressed to clinical development.


Vitamin D status in early pregnancy and risk of preeclampsia.
We sought to examine the association between maternal serum 25-hydroxyvitamin D (25[OH]D) concentration in early pregnancy and the subsequent diagnosis of preeclampsia (PE). This was a nested case-control study from 2 prospective Canadian cohorts conducted in Quebec City, Quebec, and Halifax, Nova Scotia, from 2002 through 2010. Participants were pregnant women (n = 169 cases with PE and 1975 controls). Maternal serum was drawn <20 weeks of gestation, and 25(OH)D measurement was performed. Cases were ascertained from medical records. Logistic regression analysis was used to estimate adjusted odds ratios with 95% confidence intervals. Women who developed PE had a significantly lower 25(OH)D concentration at a mean gestational age of 14 weeks compared with women in the control group (mean ± SD 25[OH]D 47.2 ± 17.7 vs 52.3 ± 17.2 nmol/L, P < .0001). Women with 25(OH)D <30 nmol/L compared to those with at least 50 nmol/L had a greater risk of developing PE (adjusted odds ratio, 2.23; 95% confidence interval, 1.29-3.83) after adjustment for prepregnancy body mass index, maternal age, smoking, parity, season and year of blood collection, gestational week at blood collection, and cohort site. Exploratory analysis with cubic splines demonstrated a dose-response relationship between maternal 25(OH)D and risk of PE, up to levels around 50 nmol/L, where the association appeared to plateau. Maternal vitamin D deficiency early in pregnancy defined as 25(OH)D <30 nmol/L may be an independent risk factor for PE. The relevance of vitamin D supplementation for women of childbearing age should be explored as a strategy for reducing PE and for promoting a healthier pregnancy.


[How Often is Rare Really Rare? A Survey on the Frequency of Rare Diseases at a University Hospital].
The prevalence of rare diseases in hospitals and in university hospitals is unknown. As the ICD-10 coding system does not adequately represent rare diagnoses, the prevalence of rare diseases cannot be estimated based on ICD-10 coded discharge diagnoses. The current hospital reimbursement system does not seem to be designed to capture performance-related higher expenditures in the treatment of rare diseases. The aim of this study was to help estimate the frequency of rare diseases among inpatients treated at a university hospital where documentation of rare diseases is obligatory by analyzing the case load of such diseases for a given year. Since 2017, rare diseases have been coded for all inpatients treated at the University Hospital Dresden. This coding is based on the Orpha identification number, which was implemented in the hospital information system ORBIS for this purpose. Result For illustrative purposes, cases in 2019 were evaluated. During this period, 19% of all 70 937 inpatients seen at the University Hospital Dresden were coded as having a rare disease. For the first time, a prospective and complete documentation of rare diseases was implemented at a German university hospital. The prevalence of rare diseases of 6 to 8% as defined by the European Union was exceeded several fold. Probably it underestimates the actual prevalence considerably, since the quality of the coding correlates on user compliance. Nevertheless, the results of this survey underline the special role of patients with rare diseases in the medical care at university hospitals.


Immunoglobulin M in human amniotic fluid and its possible association with neural-tube malformations.
Immunoglobulin M (IgM) was found in the amniotic fluid from two fetuses with neural tube defects but no in that from normal fetuses. The possible associations of IgM with abnormalities of the central nervous system are discussed.


Frankliniella species from China, with nomenclatural changes and illustrated key (Thysanoptera, Thripidae).
Species of the genus Frankliniella are almost all originally from the New World. Although eleven species in this genus have been listed from China before, only seven species here are recognised. The records of F. pallida and F. tritici from China are rejected as inadequately supported, F. hainanensis is a new synonym of F. schultzei, and F. zizaniophila is now considered a member of the genus Iridothrips. An identification key for the seven species is provided here, two of them are widespread across the Palearctic (F. intonsa and F. tenuicornis), one is presumably Oriental (F. lilivora), and four are introduced from the Americas (F. occidentalis, F. schultzei, F. cephalica and F. williamsi).


Synthesis of ferrocene-labeled steroids via copper-catalyzed azide-alkyne cycloaddition. Reactivity difference between 2β-, 6β- and 16β-azido-androstanes.
Copper-catalyzed cycloaddition of steroidal azides and ferrocenyl-alkynes were found to be an efficient methodology for the synthesis of ferrocene-labeled steroids. At the same time, a great difference between the reactivity of 2β- or 16β-azido-androstanes and a sterically hindered 6β-azido steroid toward both ferrocenyl-alkynes and simple alkynes, such as phenylacetylene, 1-octyne, propargyl acetate and methyl propiolate, was observed.


Pathology of Tnf-deficient mice infected with Plasmodium chabaudi adami 408XZ.
Tumor necrosis factor alpha (Tnf) plays a pleiotropic role in murine malaria. Some investigations have correlated Tnf with hypothermia, hyperlactatemia, hypoglycemia, and a suppression of the erythropoietic response, although others have not. In this study, we have evaluated parasitemia, survival rate and several pathological features in C57BL/6JTnf(-/-) and C57BL/6JTnf(+/+) mice after infection with Plasmodium chabaudi adami 408XZ. Compared to the C57BL/6JTnf(+/+) mice, C57BL/6JTnf(-/-) mice showed increased parasitemia and decreased survival rate, whereas blood glucose, blood lactate and body weight were not significantly different. However, C57BL/6JTnf(-/-) mice suffered significantly more from severe anemia and hypothermia than C57BL/6JTnf(+/+) mice. These results suggest that Tnf is an important mediator of parasite control, but not of anemia development. We hypothesize that the high mortality observed in the Tnf knock-out mice is due to increased anemia and pathology as a direct result of increased levels of parasitemia.


Backcrosses to Brassica napus of hybrids between B. juncea and B. napus as a source of herbicide-resistant volunteer-like feral populations.
Introgression between genetically modified (GM) crops and wild relatives is considered to potentially modify the genetic background of the wild species. The emergence of volunteer-like feral populations through backcross of hybrids to the crop is also a concern. The progeny of spontaneous hybrids between mutant herbicide-resistant oilseed rape (Brassica napus) and wild B. juncea was obtained. Parents, F(2) and BC(1) to B. napus were planted together in the field so as to study their performance. The chromosome number of BC(1) followed a Normal distribution. Mendelian ratio of the herbicide-resistance gene was found. The F(2) produced less seeds than B. napus, and BC(1) had intermediate production. Herbicide-resistant BC(1) were not different of their susceptible counterparts for plant weight, seed weight and seed number, but most of them exhibited B. napus morphology and larger flowers than the susceptible BC(1). They displayed an important genetic variability allowing further adaptation and propagation of the herbicide-resistance gene. Pollen flow to susceptible plants within the mixed stand was observed. As a consequence, the resistant BC(1) produced with B. napus pollen could frequently occur and easily establish as a false feral crop population within fields and along roadsides.


Conventional MRI findings in hereditary degenerative ataxias: a pictorial review.
Cerebellar ataxias are a large and heterogeneous group of disorders. The evaluation of brain parenchyma via MRI plays a central role in the diagnostic assessment of these conditions, being mandatory to exclude the presence of other underlying causes in determining the clinical phenotype. Once these possible causes are ruled out, the diagnosis is usually researched in the wide range of hereditary or sporadic ataxias. We here propose a review of the main clinical and conventional imaging findings of the most common hereditary degenerative ataxias, to help neuroradiologists in the evaluation of these patients. Hereditary degenerative ataxias are all usually characterized from a neuroimaging standpoint by the presence, in almost all cases, of cerebellar atrophy. Nevertheless, a proper assessment of imaging data, extending beyond the mere evaluation of cerebellar atrophy, evaluating also the pattern of volume loss as well as concomitant MRI signs, is crucial to achieve a proper diagnosis. The integration of typical neuroradiological characteristics, along with patient's clinical history and laboratory data, could allow the neuroradiologist to identify some conditions and exclude others, addressing the neurologist to the more appropriate genetic testing.


Transgenome transcription and replication in the liver and extrahepatic tissues of a human hepatitis B virus transgenic mouse.
We have produced a transgenic mouse (B32-1) carrying the complete genome of the human hepatitis B virus (HBV). High titers of the viral surface (HBsAg) and the e antigen (HBeAg) were detected in the serum of the mouse. In the liver and 12 of 16 extrahepatic tissues analyzed, Northern blot hybridization indicated the presence of the 2.1-kilobase (kb) and the 3.5-kb major HBV transcripts. A liver cDNA library was constructed from which the liver RNAs from four cDNA clones with splicing were found. Sequencing analysis showed that the splicing occurred between nucleotides 2451 and 487 of the viral genome, resulting in a truncated viral polymerase gene, as in human hepatocytes. Southern blot analysis of total DNA preparations of the tissues revealed the presence of episomal HBV genome, indicating replication of the viral transgenome in these tissues. However, replication was detected only in some but not all of the tissues that transcribed the 3.5-kb RNA. Partial double-stranded as well as full-length and subgenomic-length single-stranded HBV DNA species of discrete sizes were detected which may represent replication intermediates of preferred replication termination sites of the HBV transgenome. Since many molecular characteristics of mouse B32-1 were similar to those found in HBV-infected humans, HBV transgenic mice similar to B32-1 would be useful in further elucidation of other aspects of the replication and transcription mechanisms of HBV in the liver and extrahepatic tissues.


Relaxation induced by ferritin: a better understanding for an improved MRI iron quantification.
Ferritin, the iron storing protein, is known to darken T2-weighted MRI. This darkening can be used to non-invasively measure iron content. However, ferritin's behavior is not the same in tissue as in solution, a discrepancy that remains unexplained by the recently developed theory matching the NMR properties of ferritin solutions. A better understanding of the relaxation induced by ferritin in tissue could help for the development of new MRI protocols of iron quantification. In this short review, the main relaxation properties of ferritin in solution and in tissue are presented together with a discussion of the possible reasons for the faster transverse relaxation observed in tissues.


Treatment of heart failure with fosinopril: an angiotensin converting enzyme inhibitor with a dual and compensatory route of excretion.
Congestive heart failure (CHF) is one of the most common and clinically important cardiovascular diseases. This pathologic state is characterized not only by well-defined hemodynamic alterations, but also by complex abnormalities involving the sympathetic nervous system, the renin-angiotensin system, and other hormones involved in cardiovascular homeostasis. In addition, there is an abnormality in the homeostatic cardiovascular control exerted by arterial baroreceptors and the viscoelastic properties of medium-size arteries are altered, causing a reduction in arterial compliance. All of these abnormalities can be favorably affected by angiotensin converting enzyme (ACE) inhibitors, which have been shown to improve not only the hemodynamic and neurohumoral profiles of CHF, but also patient survival. CHF is accompanied with a decline or some sort of effect on renal function. An ACE inhibitor with a dual route of excretion, such as fosinopril, may be especially useful in treating patients with CHF.


The role of interventional pulmonology for the postoperative bronchopleural fistula.
: Postoperative bronchopleural fistula (BPF) remains a serious complication due to its high morbidity and mortality. Although various endoscopic techniques have been defined for the closure of BPF previously, no standard algorithm yet exists. To study the effectiveness and safety of various endoscopic procedures in an interventional pulmonology unit. The medical data of 15 postoperative BPF patients, who were undergone endoscopic intervention were retrospectively investigated. The mean size of the fistulas determined by bronchoscopic evaluation was 7.93 ± 3.26 mm (range 3-15 mm). Applied procedures were as follows: stent implantation (n: 8, 53.3%), stent implantation and polidocanol application (n: 4, 26.7%), only Argon Plasma Coagulation (APC) application (n: 2,13.3%), polidocanol application (n: 1,6.7%). Complete fistula closure was achieved in three of the 15 patients (20%). The procedures were partly successful in five (33.3%) patients and failed to be successful in seven (46.6%) patients. Survival rates in regard to procedural success were determined and a statistically significant difference was found in five-year survival rates (P = 0.027, P < 0.05). Our results demonstrated that bronchoscopic procedures can be safely and effectively performed in patients who were not eligible for surgery for various reasons.


Effect of the microstructure on the lifetime of dental ceramics.
To evaluate the effect of the microstructure on the Weibull and slow crack growth (SCG) parameters and on the lifetime of three ceramics used as framework materials for fixed partial dentures (FPDs) (YZ - Vita In-Ceram YZ; IZ - Vita In-Ceram Zirconia; AL - Vita In-Ceram AL) and of two veneering porcelains (VM7 and VM9). Bar-shaped specimens were fabricated according to the manufacturer's instructions. Specimens were tested in three-point flexure in 37°C artificial saliva. Weibull analysis (n=30) and a constant stress-rate test (n=10) were used to determine the Weibull modulus (m) and SCG coefficient (n), respectively. Microstructural and fractographic analyzes were performed using SEM. ANOVA and Tukey's test (α=0.05) were used to statistically analyze data obtained with both microstructural and fractographic analyzes. YZ and AL presented high crystalline content and low porosity (0.1-0.2%). YZ had the highest characteristic strength (σ(0)) value (911MPa) followed by AL (488MPa) and IZ (423MPa). Lower σ(0) values were observed for the porcelains (68-75MPa). Except for IZ and VM7, m values were similar among the ceramic materials. Higher n values were found for YZ (76) and AL (72), followed by IZ (54) and the veneering materials (36-44). Lifetime predictions showed that YZ was the material with the best mechanical performance. The size of the critical flaw was similar among the framework materials (34-48μm) and among the porcelains (75-86μm). The microstructure influenced the mechanical and SCG behavior of the studied materials and, consequently, the lifetime predictions.


Correction: Virus-mimicking nanosystems: from design to biomedical applications.
Correction for 'Virus-mimicking nanosystems: from design to biomedical applications' by Hao-Yang Liu et al., Chem. Soc. Rev., 2023, 52, 8481-8499, https://doi.org/10.1039/D3CS00138E.


Stretching and imaging single DNA molecules and chromatin.
The advent of single-molecule biology has allowed unprecedented insight into the dynamic behavior of biological macromolecules and their complexes. Unexpected properties, masked by the asynchronous behavior of myriads of molecules in bulk experiments, can be revealed; equally importantly, individual members of a molecular population often exhibit distinct features in their properties. Finally, the single-molecule approaches allow us to study the behavior of biological macromolecules under applied tension or torsion: understanding the mechanical properties of these molecules helps us understand how they function in the cell. The aim of this chapter is to summarize and critically evaluate the properties of single DNA molecules and of single chromatin fibers. The use of the high-resolution imaging capabilities of the atomic force microscopy has been covered, together with manipulating techniques such as optical fibers, optical and magnetic tweezers, and flow fields. We have learned a lot about DNA and how it responds to applied forces. It is also clear that even though the study of the properties of individual chromatin fibers has just begun, the single-molecule approaches are expected to provide a wealth of information concerning the mechanical properties of chromatin and the way its structure changes during processes like transcription and replication.


Achieving high uptake of human papillomavirus vaccine in Cameroon: lessons learned in overcoming challenges.
Cameroon has the highest age-standardized incidence rate of cervical cancer (30/100,000 women) in Central Africa. In 2010-2011, the Cameroon Baptist Convention Health Services (CBCHS) received donated human papillomavirus (HPV) vaccine, Gardasil, from Merck & Co. Inc. through Axios Healthcare Development to immunize 6400 girls aged 9-13 years. The aim was to inform the Cameroon Ministry of Health (MOH) of the acceptability, feasibility, and optimal delivery strategies for HPV vaccine. Following approval by the MOH, CBCHS nurses educated girls, parents, and communities about HPV, cervical cancer, and HPV vaccine through multimedia coverage, brochures, posters, and presentations. Because educators were initially reluctant to allow immunization in schools, due to fear of adverse events, the nurses performed 40.7% of vaccinations in the clinics, 34.5% in community venues, and only 24.7% in schools. When no adverse events were reported, more schools and communities permitted HPV vaccine immunization on their premises. To recover administrative costs, CBCHS charged a fee of US$8 per 3-dose series only to those who were able to pay. Despite the fee, 84.6% of the 6,851 girls who received the first dose received all three doses. With adequate education of all stakeholders, HPV vaccination is acceptable and feasible in Cameroon. Following this demonstration project, in 2014 the Global Access to Vaccines and Immunization (GAVI) Alliance awarded the Cameroon MOH HPV vaccine at a price of US$4.50 per dose to immunize sixth grade girls and girls aged 10 years who are not in school in two districts of Cameroon.