Use of Irradiated Homologous Costal Cartilage in Rhinoplasty: Complications in Relation to Graft Location.
Nasal septal cartilage and conchal cartilages are preferred sources of grafts in augmentation rhinoplasty. Rib cartilage can also be used, but it may evoke a patient's concerns about a scar and an extensive surgery. In such cases, irradiated homologous costal cartilage (IHCC) can be a useful alternative. However, controversy still exists in many literatures regarding complications with use of IHCC. Therefore, the authors reviewed our experiences with IHCC in rhinoplasty and analyzed the complications in relation to graft location. A retrospective chart review was made of all patients who underwent rhinoplasty with IHCC between 2007 and 2015. A total of 323 patients were included. The authors considered the cases that required revision surgery for external aesthetic changes as complications. The authors defined major complications, including resorption, infection, fracture, or warping. The total complication rate was 8%. Two fractures (0.6%), 4 fragmentation (1.2%), 4 resorptions (1.2%), 4 infections (1.2%), and 2 warpings (0.6%) were noted. Most of these complications occurred for the septal extension graft. Other complications, including 1 nasal obstruction, 2 visible contours, 3 caudal septal deviations, and 4 cases of unfavorable results (patient unsatisfactions), were noted. Based on the outcomes of this study, the authors concluded that IHCC is a useful and reliable source of cartilage graft and can serve as an alternative graft material for rhinoplasty. However, care must be taken in use of IHCC graft in areas under tension such as septal extension graft, though its complication rate is low.


Zernike representation of corneal topography height data after nonmechanical penetrating keratoplasty.
To demonstrate a mathematical method for decomposition of discrete corneal topography height data into a set of Zernike polynomials and to demonstrate the clinical applicability of these computations in the postkeratoplasty cornea. Fifty consecutive patients with either Fuchs' dystrophy (n = 20) or keratoconus (n = 30) were seen at 3 months, 6 months, and 1 year (before suture removal) and again after suture removal following nonmechanical trephination with the excimer laser. Patients were assessed using regular keratometry, corneal topography (TMS-1, simulated keratometry [SimK]), subjective refraction, and best-corrected visual acuity (VA) at each interval. A set of Zernike coefficients with radial degree 8 was calculated to fit two model surfaces: a complete representation (TOTAL) and a representation with parabolic terms only to define an approximate spherocylindrical surface (PARABOLIC). The root mean square error (RMS) was calculated comparing the corneal raw height data with TOTAL (TOTALRMS) and PARABOLIC (PARABOLICRMS). The cylinder of subjective refraction was correlated with the keratometric readings, the SimK, and the respective Zernike parameter. Visual acuity was correlated with the tilt components of the Zernike expansion. The measured corneal surface could be approximated by the composed surface 1 with TOTALRMS < or = 1.93 microm and by surface 2 with PARABOLICRMS < or = 3.66 microm. Mean keratometric reading after suture removal was 2.8+/-0.6 D. At all follow-up examinations, the SimK yielded higher values, whereas the keratometric reading and the refractive cylinder yielded lower values than the respective Zernike parameter. The correlation of the Zernike representation and the refractive cylinder (P = 0.02 at 3 months, P = 0.05 at 6 months and at 1 year, and P = 0.01 after suture removal) was much better than the correlation of the SimK and refractive cylinder (P = 0.3 at 3 months, P = 0.4 at 6 months, P = 0.2 at 1 year, and P = 0.1 after suture removal). Visual acuity increased from 0.23+/-0.10 at the 3-month evaluation to 0.54+/-0.19 after suture removal. After suture removal, there was a statistically significant inverse correlation between VA and tilt (P = 0.02 in patients with keratoconus and P = 0.05 in those with Fuchs' dystrophy). Zernike representation of corneal topography height data renders a reconstruction of clinically relevant corneal topography parameters with a marked reduction of redundance and a small error. Correlation of amount/axis of refractive cylinder with respective Zernike parameters is more accurate than with keratometry or respective SimK values of corneal topography analysis.


Homogeneous catalysis of valeronitrile hydrolysis under supercritical conditions.
Supercritical nitrile hydrolysis can be used for both, amide and acid production as well as waste water treatment, as the hydrolysis products show good biodegradability. The conventional process at ambient conditions requires large amounts of mineral acid or base. Approaches that use supercritical water as a green solvent without a catalyst have been investigated over recent years. Findings for valeronitrile hydrolysis presented recently showed promising reaction rates and valeric acid yields. In an attempt to further maximize product yield and to better understand the impact of the pH, reactions in dilute sulfuric acid (0.01 mol L(-1)) were performed in a continuous high-pressure laboratory-scale apparatus at 400-500 °C, 30 MPa, and a maximum residence time of 100 s. Results from both reaction media were compared with regard to productivity and sustainability.


Translation of HIV/AIDS knowledge into behavior change among secondary school adolescents in Uganda: A review.
The human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) pandemic is primarily affecting young people worldwide, with those between the ages of 15 and 24 accounting for nearly half of all new infections. This paper was written to effectively translate HIV/AIDS knowledge into actionable behavioral changes among secondary school students in Uganda by empowering them with comprehensive information, fostering a deeper understanding of preventive measures, and facilitating the development of responsible and informed decision-making skills, thereby reducing the incidence of HIV/AIDS transmission within this demographic. There is a relationship between risk perception and behavior change in HIV/AIDS prevention among high school students. This can be explained by the high proportion of secondary school students who think they are at risk of HIV infection; this perception may be related to having had early sex, being sexually active, and knowing someone has died of HIV. High school students regularly engage in risky sexual behaviors, such as not using condoms and having multiple lifelong partners. Student behavior is significantly influenced by HIV and AIDS prevention initiatives such as youth-friendly services, peer education, and condom use.


Inter- and intrarater reliability of Hurley staging for hidradenitis suppurativa.
Hidradenitis suppurativa (HS) is a chronic, inflammatory and recurrent skin disease. Different staging instruments have been suggested, but none has achieved universal acceptance. Despite the fact that Hurley staging is one of the most widely applied HS disease severity staging instruments, it has not been validated. To determine the inter- and intrarater reliability of the Hurley staging system. Fifteen raters (five plastic surgeons, five general surgeons and five dermatologists) independently staged 30 photos of patients with HS according to Hurley staging at two time points. Reliability was assessed using kappa (&kgr;) statistics, and multivariable logistic regressions were used to determine independent risk factors for photos with discordant staging. Inter-rater reliability was moderate for the three stages of HS [κ = 0·59, 95% confidence interval (CI) 0·48-0·70]. It was moderate for Hurley stage I (κ = 0·45, 95% CI 0·32-0·55) and stage II (κ = 0·51, 95% CI 0·31-0·71) and it was almost perfect for stage III (κ = 0·81, 95% CI 0·62-1·00). The intrarater reliability was substantial for all stages and all raters (κ = 0·65, 95% CI 0·58-0·72). For stage I it was moderate (κ = 0·50, 95% CI 0·38-0·62), for stage II it was substantial (κ = 0·62, 95% CI 0·51-0·73) and for stage III it was almost perfect (κ = 0·82, 95% CI 0·77-0·87). Hurley stages II and III were less likely to result in discordant staging than Hurley stage I (odds ratios 0·47, 95% CI 0·29-0·77 and 0·21, 95% CI 0·12-0·38, respectively). The mean time spent on staging a photo was 14 s. Hurley staging is reliable for rapid severity assessment of HS, with moderate inter-rater and substantial intrarater reliability for all stages. It is best for assessing Hurley stage III HS, which is an indication for surgery.


Long-Term Potassium Monitoring and Dynamics in Heart Failure and Risk of Mortality.
The prognostic value of long-term potassium monitoring and dynamics in heart failure has not been characterized completely. We sought to determine the association between serum potassium values collected at follow-up with all-cause mortality in a prospective and consecutive cohort of patients discharged from a previous acute heart failure admission. Serum potassium was measured at every physician-patient encounter, including hospital admissions and ambulatory settings. The multivariable-adjusted association of serum potassium with mortality was assessed by using comprehensive state-of-the-art regression methods that can accommodate time-dependent exposure modeling. The study sample included 2164 patients with a total of 16 116 potassium observations. Mean potassium at discharge was 4.3±0.48 mEq/L. Hypokalemia (<3.5 mEq/L), normokalemia (3.5-5.0 mEq/L), and hyperkalemia (>5 mEq/L) were observed at the index admission in 77 (3.6%), 1965 (90.8%), and 122 (5.6%) patients, respectively. At a median follow-up of 2.8 years (range, 0.03-12.8 years), 1090 patients died (50.4%). On a continuous scale, the multivariable-adjusted association of potassium values and mortality revealed a nonlinear association (U-shaped) with higher risk at both ends of its distribution (omnibus P=0.001). Likewise, the adjusted hazard ratios for hypokalemia and hyperkalemia, normokalemia as reference, were 2.35 (95% confidence interval, 1.40-3.93; P=0.001) and 1.55 (95% confidence interval, 1.11-2.16; P=0.011), respectively (omnibus P=0.0003). Furthermore, dynamic changes in potassium were independently associated with substantial differences in mortality risk. Potassium normalization was independently associated with lower mortality risk (P=0.001). Either modeled continuously or categorically, serum potassium levels during long-term monitoring were independently associated with mortality in patients with heart failure. Likewise, persistence of abnormal potassium levels was linked to a higher risk of death in comparison with patients who maintained or returned to normal values.


Ribbon Synapses and Visual Processing in the Retina.
The first synapses transmitting visual information contain an unusual organelle, the ribbon, which is involved in the transport and priming of vesicles to be released at the active zone. The ribbon is one of many design features that allow efficient refilling of the active zone, which in turn enables graded changes in membrane potential to be transmitted using a continuous mode of neurotransmitter release. The ribbon also plays a key role in supplying vesicles for rapid and transient bursts of release that signal fast changes, such as the onset of light. We increasingly understand how the physiological properties of ribbon synapses determine basic transformations of the visual signal and, in particular, how the process of refilling the active zone regulates the gain and adaptive properties of the retinal circuit. The molecular basis of ribbon function is, however, far from clear.


Role of the sodium ion in acute renal failure.
Acute renal failure (ARF), an abrupt decline in renal function in its simplest terms, continues to elude precise pathophysiologic definition in human as well as experimental models. In the setting of ischemic or toxic renal injury, the role of sodium chloride as the major constituent of extracellular fluid volume (ECFV) is critically important in the maintenance of renal blood flow. Renal perfusion can be severely curtailed in states of ECFV depletion by activation of the renin-angiotensin axis leading to profound intrarenal hemodynamic alterations. This review will discuss evidence for the role of sodium chloride in the pathogenesis and modification of ischemic and toxic ARF. Much of the data arises from studies in experimental animal models of human disease. The results of clinical studies will be emphasized when available.


Pleckstrin homology-like domain, family A, member 1 (PHLDA1) and cancer.
Pleckstrin homology-like domain, family A, member 1 (PHLDA1) encodes a member of an evolutionarily conserved pleckstrin homology-related domain protein family. It was first identified as a potential transcription factor required for Fas expression and activation-induced apoptosis in mouse T cell hybridomas. The exact molecular and biological functions of PHLDA1 remain to be elucidated. However, its expression is induced by a variety of external stimuli and there is evidence that it may function as a transcriptional activator that acts as a mediator of apoptosis, proliferation, differentiation and cell migration dependent on the cellular type and context. Recently, PHLDA1 has received attention due to its association with cancer. In the present review, the current knowledge of PHLDA1 protein structure, expression regulation and function is summarized. In addition, the current data in the literature is reviewed with regards to the role of PHLDA1 in cancer pathogenesis.


Geographic variance in the frequency of the t(14;18) translocation in follicular lymphoma: an Israeli series compared to the world.
It has been suggested that differences in the frequency of the t(14;18) translocation in follicular lymphoma might explain ethno-geographic variation in the incidence of these tumors. We tested Israeli follicular lymphoma patients for the frequency of the t(14;18) translocation, and reviewed the published literature, comparing the frequency in our series with data from different parts of the world. Tissue specimens from 36 Israeli follicular lymphoma patients were tested for presence of the translocation by PCR amplification of the MBR breakpoint. Twenty-two of the 36 patients (61%) tested positive. A systematic search of the literature yielded 35 papers reporting the frequency of the t(14;18) translocation in follicular lymphoma. We analyzed cytogenetic data and molecular data separately. For each method, data were pooled from all studies within each of three geographical regions - USA, East Asia and Europe. Pooled data from cytogenetic studies show a low frequency of the translocation in the Far East (38%) compared to the USA (71%), with an intermediate frequency found in Europe (61%). Molecular studies show a similar frequency of the translocation in the Far East and Europe, significantly lower than the frequency in pooled data from American studies. The frequency in our Israeli series is relatively high, comparable to that detected in the USA. We suggest that the apparent geographical differences we describe are unlikely to be caused by a difference in the biology of the tumor, and are more likely due to technical and methodological factors. We conclude that it is unlikely that differences in the frequency of the t(14;18) translocation explain the difference in the epidemiology of lymphoma between East and West.


Comparative evaluation of clinical performance of ceramic and resin inlays, onlays, and overlays: A systematic review and meta analysis.
Advances in adhesive technologies and escalation in esthetic demands have increased indications for tooth-colored, partial coverage restorations. Recently, material knowledge has evolved, new materials have been developed, and no systematic review has answered the question posed by practitioners: Is the clinical efficacy of resin or ceramic better, for inlay, onlay, and overlay in the long run? The aim of this systematic review and meta-analysis was to evaluate the clinical performance of ceramic and resin inlays, onlays, and overlays and to identify the complication types associated with the main clinical outcomes. Two reviewers (VN and AJ) searched PubMed, Embase, and Cochrane Central registry of controlled trials for published articles between 1983 and 2020 conforming to Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines for systematic reviews. Only clinical studies which met the following criteria were included (1) studies regarding ceramic and resin inlays, onlays, and overlays were included; (2) randomized controlled trials, retrospective or prospective studies conducted in humans; (3) studies with a dropout rate <50% 4) studies with a follow-up higher than 5 years. Of 1718 articles, 21 articles were selected. At 5 years, the estimated survival rates for resin (n = 129) was 86%, feldspathic porcelain (n = 1048) was 90%, and glass ceramic (n = 2218) was 92%; at 10 years, the survival of resin was 75% (n = 115), feldspathic porcelain was 91% (n = 1829), and glass ceramic was 89% (n = 1075). The meta-regression indicated that ceramic partial coverage restorations (feldspathic porcelain and glass-ceramic) outperformed resin partial coverage restorations both at 5-year and 10-year follow-up. When compared between ceramic types, glass ceramics outperformed feldspathic porcelain at 5 years' follow-up and feldspathic porcelain outperformed glass ceramics at 10 years' follow-up. The failures were mostly due to fractures (6.2%), endodontic problems (3%), secondary caries (1.7%), and debonding which was 0.9%.


Processing of bulk metallic glass.
Bulk metallic glass (BMG) formers are multicomponent alloys that vitrify with remarkable ease during solidification. Technological interest in these materials has been generated by their unique properties, which often surpass those of conventional structural materials. The metastable nature of BMGs, however, has imposed a barrier to broad commercial adoption, particularly where the processing requirements of these alloys conflict with conventional metal processing methods. Research on the crystallization of BMG formers has uncovered novel thermoplastic forming (TPF)-based processing opportunities. Unique among metal processing methods, TPF utilizes the dramatic softening exhibited by a BMG as it approaches its glass-transition temperature and decouples the rapid cooling required to form a glass from the forming step. This article reviews crystallization processes in BMG former and summarizes and compares TPF-based processing methods. Finally, an assessment of scientific and technological advancements required for broader commercial utilization of BMGs will be made.


The regulatory network of cell-cycle progression is fundamentally different in plants versus yeast or metazoans.
Plant growth and proliferation control is coming into a global focus due to recent ecological and economical developments. Plants represent not only the largest food supply for mankind but also may serve as a global source of renewable energies. However, plant breeding has to accomplish a tremendous boost in yield to match the growing demand of a still rapidly increasing human population. Moreover, breeding has to adjust to changing environmental conditions, in particular increased drought. Regulation of cell-cycle control is a major determinant of plant growth and therefore an obvious target for plant breeding. Furthermore, cell-cycle control is also crucial for the DNA damage response, for instance upon irradiation. Thus, an in-depth understanding of plant cell-cycle regulation is of importance beyond a scientific point of view. The mere presence of many conserved core cell-cycle regulators, e.g. CDKs, cyclins, or CDK inhibitors, has formed the idea that the cell cycle in plants is exactly or at least very similarly controlled as in yeast or human cells. Here together with a recent publication we demonstrate that this dogma is not true and show that the control of entry into mitosis is fundamentally different in plants versus yeast or metazoans. Our findings build an important base for the understanding and ultimate modulation of plant growth not only during unperturbed but also under harsh environmental conditions.


Atypical manifestations of herpes simplex encephalitis.
The diagnosis of herpes simplex encephalitis is readily considered in patients with focal findings on neurologic and radiologic examinations. In the two patients we have described, the diagnosis was delayed because clinical findings were attributed to other medical conditions, and radiologic studies were nondiagnostic. A high index of suspicion and repeated neuroradiologic tests are recommended in patients with unexplained encephalitis.


Sequence of the alpha subunit of photoreceptor G protein: homologies between transducin, ras, and elongation factors.
A bovine retinal complementary DNA clone encoding the alpha subunit of transducin (T alpha) was isolated with the use of synthetic oligodeoxynucleotides as probes, and the complete nucleotide sequence of the insert was determined. THe predicted protein sequence of 354 amino acids includes the known sequences of four tryptic peptides and sequences adjacent to the residues that undergo adenosine diphosphate ribosylation by cholera toxin and pertussis toxin. On the basis of homologies to other proteins, such as the elongation factors of protein synthesis and the ras oncogene proteins, regions are identified that are predicted to be acylated and involved in guanine nucleotide binding and hydrolysis. Amino acid sequence similarity between T alpha and ras is confined to these regions of the molecules.


Epidemiology of autoimmune and inflammatory diseases in a French nationwide HIV cohort.
HIV infection and inflammatory and autoimmune diseases (IADs) are both related to immune dysfunction. Epidemiological data on IAD in patients living with HIV (PLHIV) are scarce. The aim of this study was thus to estimate the prevalence of 26 IAD among PLHIV followed in a large French multicenter cohort in the combination antiretroviral therapy (cART) era (from January 2000 to July 2013), and to describe their occurrence according to cART onset, the immuno-virological status of patients and hepatitis C virus (HCV) and/or hepatitis B virus coinfection. During the study period, 33 403 PLHIV were included in the Dat'AIDS cohort; 1381 patients with an IAD were identified. The most prevalent IADs were psoriasis, sarcoidosis, rheumatoid arthritis, ankylosing spondyloarthritis, Grave's disease, autoimmune hemolytic anemia, immune thrombocytopenia and chronic inflammatory bowel disease. In contrast, the prevalence of systemic lupus erythematosus and multiple sclerosis were low. Most patients (59%) developed IAD after HIV infection with a mean delay of 10.6 ± 6.4 years. Compared with the entire cohort, HCV coinfection was significantly more frequent in patients with psoriasis, Grave's disease and immune thrombocytopenia, and chronic hepatitis B in patients was more frequent in those with immune thrombocytopenia and autoimmune hemolytic anemia. Among patients developing IAD after the diagnosis of HIV infection, 572 (70%) were on antiretroviral therapy and 419 of them (73%) had undetectable HIV viral load. Our study showed that some IAD are not rare among PLHIV and occur mostly in patients with immuno-virological control under cART. The higher frequency of HCV or hepatitis B virus coinfection for some IAD is also confirmed.


Middle cerebral artery blood flow velocity during a 4 km cycling time trial.
This study sought to describe middle cerebral artery blood flow velocity (MCAv) during a 4 km cycling time trial, and relate it to different pacing strategies adopted by participants. After familiarisation and a standardised exercise protocol, 15 male trained cyclists rode a 4 km time trial on a cycling ergometer. MCAv was assessed via transcranial Doppler ultrasound in the right hemisphere at resting baseline, and throughout the time trial. Mean arterial pressure, end-tidal partial pressure of carbon dioxide (PetCO2) and heart rate were assessed alongside MCAv. Plasma lactate was assessed post time trial. Data were compared depending upon whether participants completed the time trial with a positive (first half faster than the last) or negative pacing profile although there was no difference in the time to completion with either pacing strategy (positive 344 ± 23 s, negative 334 ± 14 s; p = 0.394). Lower mean MCAv (positive pacing -7.6 ± 14.2%, negative pacing +21.2 ± 15.0% compared to resting baseline measures; p = 0.004) and lower PetCO2 (significant interaction p < 0.001) towards the end of the time trial were observed with positive compared to negative pacing. Heart rate and lactate did not differ between pacing strategies. Changes in MCAv appear to depend on the pacing strategy adopted, with a positive pacing strategy likely to contribute to a hyperventilatory drop in PetCO2 and subsequent reduction in MCAv. Although lower cerebral blood flow cannot be directly linked to an inability to raise or maintain power output during the closing stages of the time trial, this potential contributor to fatigue is worth further investigation.


Cultural context shapes essentialist beliefs about religion.
The present study investigates the processes by which essentialist beliefs about religious categories develop. Children (ages 5 and 10) and adults (n = 350) from 2 religious groups (Jewish and Christian), with a range of levels of religiosity, completed switched-at-birth tasks in which they were told that a baby had been born to parents of 1 religion but raised by parents of another religion. Results indicated that younger children saw religion-based categories as possible essential kinds, regardless of the child's own religious background, but that culture-specific patterns emerged across development. This work shows that cultural context plays a powerful role in guiding the development of essentialist beliefs about religious categories. (PsycINFO Database Record


Representing suicide: Giving voice to a desire to die?
Drawing on interview and online ethnographic data from a study of suicide on the railways, this paper describes the ways in which many of the concepts, assumptions and practices of mainstream suicide prevention are challenged in the accounts of those who are planning, or have enacted, a suicide attempt. We reflect on the ethical dilemmas which can arise for researchers (and practitioners) when lived experience accounts diverge - theoretically, morally and in terms of practical implications - from present-day expert ones. In online, 'pro-choice' suicide discussions, people describe beliefs, attitudes, ways of thinking and acting which stand in contrast to existing professional and clinical descriptions of suicide and suicidal behaviour. Most obviously, there is often a rejection of 'pro-life' positions, which are framed as ideological, oppressive and naïve. For researchers engaging in online ethnography of 'pro-choice' spaces, dilemmas can arise in relation to the representation of perspectives which fundamentally challenge not only prevailing norms within suicide research and prevention practice but socio-cultural norms more widely. Similar issues can arise when considering how best to represent research participants when their accounts diverge from accepted 'expert' knowledge and beliefs. In-depth qualitative interviews with those who have thought about or attempted to take their own life indicate that existing theories and models of suicide which start from assumptions of deficit and pathology underestimate the extent to which suicide, as the end result of an often-complex series of actions, requires a person to engage in logistical processes of planning, decision-making, imagination and adaptation. The accounts described here, gathered using two different methodological approaches, highlight the ethical issues which can surface when there are competing claims to (expert) knowledge, as well as differences in beliefs, attitudes and moral stance towards life and death. We argue that researchers need to reflect on their own ethical-moral position in relation to suicide, and on the practical consequences of their privileging of some voices at the expense of other, less well represented, ones.


Characterization and mutational studies of equine infectious anemia virus dUTPase.
The macrophage tropic lentivirus, equine infectious anemia virus (EIAV), encodes a dUTPase in the pol gene that is required for efficient replication in macrophages. Two naturally occurring variants of the enzyme were expressed as recombinant proteins in Escherichia coli; metal chelate affinity chromatography was used to purify histidine-tagged recombinant enzymes to greater than 80% homogeneity in a single chromatographic step. Biochemical and enzymatic analyses of these preparations suggest that this method yields dUTPase that is suitable for detailed mutational analysis. Specific activities of preparations ranged from 4 x 10(3) to 5 x 10(4) units/mg. Recombinant EIAV dUTPase was highly specific for dUTP with a Km in the range of 3 to 8 microM. The enzyme was sensitive to inhibition by dUDP with little inhibition by other nucleotides or the reaction products, dUMP and PPi. The subunit organization of recombinant EIAV dUTPase was probed by gel filtration, glycerol gradient centrifugation, and chemical cross-linking, and is a trimer. We have begun mutational analyses by targeting a conserved domain present at the carboxyl terminus of all dUTPases that shares high homology to the phosphate binding loops (P-loops) of a number of ATP- and GTP-binding phosphatases. The P-loop-like motif of dUTPases is glycine rich but lacks the invariant lysine found in authentic P-loops. Deletion of this motif leads to loss of dUTPase activity; a series of point mutations that have been shown to inactivate authentic P-loops also abolish EIAV dUTPase activity.


Prevalence and temporal stability of selected clostridial groups in irritable bowel syndrome in relation to predominant faecal bacteria.
The differences in faecal bacterial population between irritable bowel syndrome (IBS) and control subjects have been reported in several studies. The aim of the present study was to compare the predominant and clostridial faecal microbiota of IBS subjects and healthy controls by applying denaturing gradient gel electrophoresis (DGGE) and a recently developed multiplexed and quantitative hybridization-based technique, transcript analysis with the aid of affinity capture (TRAC). According to the results, the studied clostridial groups (Clostridium histolyticum, Clostridium coccoides-Eubacterium rectale, Clostridium lituseburense and Clostridium leptum) represented the dominant faecal microbiota of most of the studied subjects, comprising altogether 29-87% of the total bacteria as determined by the hybridized 16S rRNA. The C. coccoides-E. rectale group was the dominant subgroup of clostridia, contributing a mean of 43% of the total bacteria in control subjects and 30% (constipation type) to 50% (diarrhoea type) in different IBS symptom category subjects. The proportion of the C. coccoides-E. rectale group was found to be significantly lower in the constipation-type IBS subjects than in the control subjects. DNA-based PCR-DGGE and RNA-based RT-PCR-DGGE analyses targeted to the predominant bacterial population showed considerable biodiversity as well as uniqueness of the microbiota in each subject, in both control and IBS subject groups. The RT-PCR-DGGE profiles of the IBS subjects further indicated higher instability of the bacterial population compared to the control subjects. The observations suggest that clostridial microbiota, in addition to the instability of the active predominant faecal bacterial population, may be involved in IBS.


Reliability of clinical nodal status regarding response to neoadjuvant chemoradiotherapy compared with surgery alone and prognosis in esophageal cancer patients.
Background: Clinical nodal (cN) staging is a key element in treatment decisions in patients with esophageal cancer (EC). The reliability of cN status regarding the effect on response and survival after neoadjuvant chemoradiotherapy (nCRT) with esophagectomy was evaluated in determining the up- and downstaged pathological nodal (pN) status after surgery alone. Material and methods: From a prospective database, we included all 395 EC patients who had surgery with curative intent with or without nCRT between 2000 and 2015. All patients were staged by a standard pretreatment protocol: 16-64 mdCT, 18 F-FDG-PET or 18 F-FDG-PET/CT and EUS ± FNA. After propensity score matching on baseline clinical tumor and nodal (cT/N) stage and histopathology, a surgery-alone and nCRT group (each N = 135) were formed. Clinical and pathological N stage was scored as equal (cN = pN), downstaged (cN > pN) or upstaged (cN < pN). Prognostic impact on disease free survival (DFS) was assessed with multivariable Cox regression analysis (factors with p value <.1 on univariable analysis). Results: The surgery-alone and nCRT group did not differ in cT/N status. Pathologic examination revealed equal staging (32 vs. 27%), nodal up (43 vs. 16%) and downstaging (25 vs. 56%), respectively (p < .001). Nodal up-staging was common in cT3-4a tumors and adenocarcinomas in the surgery-alone group, while nodal downstaging was found in half of cT1-2 and cT3-4 regardless of tumortype after nCRT. Prognostic factors for DFS were pN (p = .002) and lymph-angioinvasion (p = .016) in surgery-alone, and upper abdominal cN metastases (p = .012) and lymph node ratio (p = .034) in the nCRT group. Conclusions: Despite modern staging methods, correct cN staging remains difficult in EC. Nodal overstaging (cN > pN) occurred more often than understaging impeding an adequate assessment of pathologic complete response and prognosis after nCRT.


Revisiting the coordination chemistry for preparing manganese oxide nanocrystals in the presence of oleylamine and oleic acid.
By pyrolyzing manganese(II) acetate in 1-octadecene in the presence of oleylamine and oleic acid, manganese oxide nanocrystals were prepared. It was observed that both MnO and Mn3O4 nanocrystals were simultaneously formed by quickly heating the reaction mixture up to 250 °C, while a preheating procedure carried out at 100 °C led to uniform MnO nanocubes that developed into eight-arm MnO nanocrystals upon prolonged reaction. To understand the mechanisms for forming these two different kinds of manganese oxide nanocrystals, i.e., Mn3O4 and MnO, the coordination between oleic acid/oleylamine and Mn(2+) was investigated. The detailed investigations suggest that Mn(2+)-oleylamine coordination is kinetically driven and favorable for the formation of Mn3O4 nanocrystals due to the relatively low electronegativity of N from oleylamine, while Mn(2+)-oleate coordination is thermodynamically driven and can prevent the central metal ion (Mn(2+)) from being oxidized owing to the relatively high electronegativity of O from the oleate ligand. Following these new insights, by properly balancing the coordination of oleic acid and oleylamine to Mn(2+), the selective synthesis of MnO and Mn3O4 nanocrystals with uniform shapes was successfully achieved.


Practical aspects of vaccination of poultry against avian influenza virus.
Although little has changed in vaccine technology for avian influenza virus (AIV) in the past 20 years, the approach to vaccination of poultry (chickens, turkeys and ducks) for avian influenza has evolved as highly pathogenic AIV has become endemic in several regions of the world. Vaccination for low pathogenicity AIV is also becoming routine in regions where there is a high level of field challenge. In contrast, some countries will not use vaccination at all and some will only use it on an emergency basis during eradication efforts (i.e. stamping-out). There are pros and cons to each approach and, since every outbreak situation is different, no one method will work equally well in all situations. Numerous practical aspects must be considered when developing an AIV control program with vaccination as a component, such as: (1) the goals of vaccination must be defined; (2) the population to be vaccinated must be clearly identified; (3) there must be a plan to obtain and administer good quality vaccine in a timely manner and to achieve adequate coverage with the available resources; (4) risk factors for vaccine failure should be mitigated as much as possible; and, most importantly, (5) biosecurity must be maintained as much as possible, if not enhanced, during the vaccination period.


Altered olfactory function in the MRL model of CNS lupus.
Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that damages several bodily systems, including the CNS. Brain atrophy and diverse neuropsychiatric manifestations are common and serious complications of SLE. Recently, it has been reported that many patients with CNS involvement also present with olfactory deficits of unknown etiology. Similar to CNS SLE, spontaneous development of lupus-like disease in MRL/lpr mice is accompanied by neurodegeneration in periventricular regions and a constellation of behavioral deficits dependent on olfaction. To test the possibility that olfactory dysfunction also occurs in autoimmune mice, we presently examine odor-guided behaviors using a battery of paradigms. Indeed, lupus-prone males spent less time exploring unfamiliar conspecifics and demonstrated age-dependant performance deficits when exposed to low concentrations of attractant and repellant odors. The emergence of olfactory changes was associated with a skewed distribution of DCX(+) cells in the proximal portion of the rostral migratory stream (RMS). The present results are consistent with the hypothesis that the onset of a SLE-like condition affects periventricular regions, including the RMS, as evidenced by disrupted migration of neuronal precursor cells toward the olfactory bulb. If so, ensuing hyposmia and/or olfactory memory deficit may contribute to altered performance in other behavioral tasks and reflect a prodrome of brain damage induced by chronic autoimmune disease.


[Role of calcium in the contraction of normal tonic muscle fibers and following denervation].
Studies in the frog isolated tonic muscle fibers revealed that change of the external calcium concentration normally has no effect on the magnitude of the potassium and caffeine contractures, whereas in denervated fibers a decrease of successively evoked potassium and caffeine contractures occurs in calcium-free solution. The adaptive relaxation of potassium contracture in denervated fibers accelerates with increase of potassium ions and decelerates with increase of calcium. Analysis of these phenomena suggests that: 1) the intracellular calcium alone participates in activation of contraction of these fibers, and 2) the effect of changes in external calcium concentration on the character of contraction is based on the calcium action upon the cell membrane rather than on changes of its amount.


Acquisition of the Cardinal Principle Coincides with Improvement in Approximate Number System Acuity in Preschoolers.
Human mathematical abilities comprise both learned, symbolic representations of number and unlearned, non-symbolic evolutionarily primitive cognitive systems for representing quantities. However, the mechanisms by which our symbolic (verbal) number system becomes integrated with the non-symbolic (non-verbal) representations of approximate magnitude (supported by the Approximate Number System, or ANS) are not well understood. To explore this connection, forty-six children participated in a 6-month longitudinal study assessing verbal number knowledge and non-verbal numerical acuity. Cross-sectional analyses revealed a strong relationship between verbal number knowledge and ANS acuity. Longitudinal analyses suggested that increases in ANS acuity were most strongly related to the acquisition of the cardinal principle, but not to other milestones of verbal number acquisition. These findings suggest that experience with culture and language is intimately linked to changes in the properties of a core cognitive system.


Microbial community responses to bioremediation treatments for the mitigation of low-dose anthracene in marine coastal sediments of Bizerte lagoon (Tunisia).
The main goals of this study were to investigate (1) the behavior of microbial communities in response to low-dose bioavailable anthracene addition in lightly contaminated sediment from Bizerte Lagoon and (2) the effects of bioremediation treatments on microbial biomass, activity, and community structure. Sediment microcosms amended with 1 ppm anthracene were incubated in triplicate during 30 days. Biostimulation (addition of nitrogen and phosphorus fertilizer) and bioaugmentation (inoculation of a hydrocarbonoclastic bacterium) were used as bioremediation treatments. Bacterial biomass was estimated using flow cytometry. Sediment oxygen consumption was measured with oxygen microelectrodes. Bacterial community structure was assessed by molecular fingerprints (terminal restriction fragment length polymorphism; T-RFLP) analysis. Anthracene contamination resulted in a significant reduction of bacterial abundance with an impact on cell integrity. Concomitantly, sediment oxygen consumption was strongly inhibited. Correspondence analysis on T-RFLP data indicated that bacterial community structures from anthracene-contaminated microcosms were different from that of the control. Interestingly, the changes observed in microbial biomass, structure, and activities as a result of anthracene contamination were not alleviated even with the use of biostimulation and combination of biostimulation and bioaugmentation strategy for anthracene bioremediation. Nevertheless, both treatment methods resulted in different community structures relative to the contaminated and control microcosms with the appearance of distinct populations. Anthracene spiking severely affected microbial communities, suggesting dominance of nontolerant populations in this lightly-contaminated sediment. Although biostimulation and/or bioaugmentation treatments did not alleviate the anthracene toxic effects, the changes observed in microbial population and structure suggest that the proposed treatments might be promising to promote bacterial growth. Further works are still required to propose a more efficient strategy to stimulate biodegradation that takes into account the complex interactions between species for resource access.


Predicting Colonoscopy Time: A Quality Improvement Initiative.
There is lack of consensus on the optimal time allotted for colonoscopy, which increases patient wait times. Our aim was to identify and quantify the individual pre-procedural factors that determine the total procedure time (TPT) of colonoscopy. This retrospective study involved 4,494 subjects, undergoing outpatient colonoscopy. Effects of age, sex, body mass index, abdominal surgery history, procedure indication (screening, surveillance, or diagnostic), procedure session (morning or afternoon), and endoscopist's experience (fellow or attending) on TPT were evaluated using multiple regression analysis. A p<0.05 was considered significant. A total of 1,239 subjects satisfied the inclusion/exclusion criteria. Women, older individuals, and those with a history of abdominal surgery were found to have a shorter TPT (p>0.05) as did afternoon session colonoscopies (p=0.004). Less experienced endoscopists had longer TPTs (p>0.05). Screening (p=0.01) and surveillance (p=0.008) colonoscopies had a longer TPT than diagnostic procedures. Overall, the F-value of the regression model was 0.0009. The indication for colonoscopy and the time of day have statistically significant associations with TPT. These results will help in streamlining workflow, reduce wait time, and improve patient satisfaction.


A systematic review on biological activities of prenylated flavonoids.
Prenylated flavonoids are a unique class of naturally occurring flavonoids that exist especially for the plant's self-defensive strategy. This special class of flavonoids increases the bioactivities of their backbone flavonoids with non-prenylation; therefore, prenylated flavonoids have more potential to be developed and utilized. The number, position and type of the prenyl group on the flavonoids backbone structure may have close relationships with the bioactivities of flavonoids. PubMed and WEB OF KNOWLEDGE® were used to search articles published in English between 1 January 2002 and 31 December 2012, which discuss the structure-activity relationship between prenylated flavonoids and their bioactivities. It is proposed that the prenyl-moiety makes the backbone compound more lipophilic, which leads to its high affinity with cell membranes. The prenylation brings the flavonoids with enhancement of antibacterial, anti-inflammatory, antioxidant, cytotoxicity, larvicidal as well as estrogenic activities. However, it is reported that the prenyl-moiety decreases the bioavailability and plasma absorption of prenylated flavonoids. The prenyl group affects the bioactivities of flavonoids in certain ways, while the action mechanisms and the structure-activity relationship as well as more in vivo studies even clinical validation trials need to be further investigated.


Key differences in molecular complexes of the cholecystokinin receptor with structurally related peptide agonist, partial agonist, and antagonist.
The molecular basis of docking of receptor ligands having differences in biological activity and their subsequent effects on receptor conformation represent areas of great interest. In this work, we focus on the sulfated tyrosyl residue in position 27 of cholecystokinin (CCK) and its spatial approximation with the type A CCK receptor residue Arg(197) that has been predicted from mutagenesis experiments. We have examined the requirement for sulfation of this residue in a series of structurally related peptide agonists, partial agonists, and antagonists using assays of receptor binding and biological activity. Whereas sulfation of CCK position 27 was critical for affinity and potency of a full agonist, it had progressively less effect as the biological activity of the ligand was reduced. It had an intermediate effect on the partial agonist and no effect on the antagonist. In addition, photoaffinity labeling was used to determine the spatial approximations between the receptor and residue 27 of the agonist and antagonist in this series. Direct photoaffinity labeling with a full agonist probe confirmed the spatial approximation of ligand residue 27 and receptor residue Arg(197) in the active complex. Of note, the analogous antagonist probe labeled a distinct region within the receptor amino terminus, confirming a key structural difference in active and inactive complexes.


Psychological Coping with Job Loss. Empirical Study to Contribute to the Development of Unemployed People.
Having a job is an essential part of people's development. Unemployment, on the contrary, is one of the most frustrating experiences of life with greater psychological consequences for people's lives. In this sense, psychology has contributed to an increase in knowledge about the personal and social experience of unemployment. This article discusses indicators of anxiety and depression in unemployed people, modulating socio-demographic variables, and coping strategies involved in the higher and lower levels of anxiety and depression. For this, a sample of 244 unemployed people who are users of the Career Service Centre of the Andalusian Public Employment Service of the city of Huelva is used for a descriptive and analytical cross-sectional study. The results show that only 5.7% of the participants do not have depressive symptoms. With regards to anxiety levels, 41.3% of participants have no anxiety. Unemployed people with high anxiety and depression scores have developed maladaptive coping strategies such as substance use, self-blaming, or denial. It is necessary to assess the importance of the unemployment process and the incorporation of appropriate coping strategies that facilitate new integration in the labour market, such as planification, emotional or social support and self-distraction between others.


[Transmembrane transport activity of paclitaxel regulated by fangchinoline in MDR1-mDCK II cells].
To research the regulation of transmembrane transport activity of paclitaxel influenced by fangchinoline in MDR1-MDCK II cells. Paclitaxel, one of the substrate of P-gp, was selected as the model drug. Verapamil hydrochloride was adopted as the active control to investigate the bilateral transport activity of paclitaxel regulated by fangchinoline in MDR1-MDCK II cells. RP-HPLC was applied to determine the concentration of paclitaxel in the transporting medium, which was used to calculate apparent permeability coefficient of paclitaxel across MDR1-MDCK I1 monolayer cells. The efflux rate of paclitaxel was faster than the absorption rates across the MDR1-MDCK II monolayer cells with highly expressed P-gp. The absorption rates of paclitaxel combinated with fangchinoline and verapamil hydrochloride respectively were remarkably increased and the efflux rate was decreased. The reversal effect of the fangchinoline was stronger than the verapamil hydrochloride with the same molar concention. Fangchinoline can apparently decrease the efflux of paclitaxel and inhibit the multidrug resistance of antitumor drug mediated by P-gp.


MLP-RL-CRD: diagnosis of cardiovascular risk in athletes using a reinforcement learning-based multilayer perceptron.
Pre-participation medical screening of athletes is necessary to pinpoint individuals susceptible to cardiovascular events. The article presents a reinforcement learning (RL)-based multilayer perceptron, termed MLP-RL-CRD, designed to detect cardiovascular risk among athletes. The model underwent training using a publicized dataset that included the anthropological measurements (such as height and weight) and biomedical metrics (covering blood pressure and pulse rate) of 26,002 athletes. To address the data imbalance, a novel RL-based technique was adopted. The problem was framed as a series of sequential decisions in which an agent classified a received instance and received a reward at each level. To resolve the insensitivity to the initialization of conventional gradient-based learning methods, a mutual learning-based artificial bee colony (ML-ABC) was proposed. The model outcomes were validated against positive (P) and negative (N) ECG findings that had been labeled by experts to signify individuals "at risk" and "not at risk," respectively. The MLP-RL-CRD approach achieves superior outcomes (F-measure 87.4\%; geometric mean 89.6\%) compared with other deep models and traditional machine learning techniques. Optimal values for crucial parameters, including the reward function, were identified for the model based on experiments on the study dataset. Ablation studies, which omitted elements of the suggested model, affirmed the autonomous, positive, stepwise influence of these components on performing the model. This study introduces a novel, effective method for early cardiovascular risk detection in athletes, merging reinforcement learning and multilayer perceptrons, advancing medical screening and predictive healthcare. The results could have far-reaching implications for athlete health management and the broader field of predictive healthcare analytics.


Effect of rhIL-6 infusion on GH-->IGF-I axis mediators in humans.
Exercise leads to simultaneous increases in mediators signaling apparently antagonistic functional responses such as growth factors and inflammatory mediators. The aim of the present study was to demonstrate the physiological effect of IL-6 on circulating components of the growth hormone (GH)-insulin-like growth factor-I (IGF-I) axis. Twelve men (ages 26 +/- 2 yr) were divided into two groups (n = 6 in each group), receiving either albumin or recombinant human (rh) IL-6 infusion. IL-6 was infused via an antecubital vein, and a contralateral antecubital vein was used for blood sampling. The IL-6 dose was chosen to reach plasma levels of IL-6 characteristic of intense exercise (5 microg/h, for 3 h, resulting in plasma levels of 100 pg/ml). Blood samples for GH, GH binding protein, IGF-I, and IGF binding protein (IGFBP)-1 and -3 were collected at baseline, 30 min, and 1, 2, 3, 4, 5, and 8 h after the beginning of the rhIL-6 infusion. IL-6 levels increased only in the rhIL-6-infused group (P < 0.0005) and returned to baseline after the infusion was stopped. IL-6 infusion led to a significant increase in GH, peaking 1 h after the beginning of infusion (P < 0.001). A decrease in total IGF-I levels was noted only in the rhIL-6-infused group (P < 0.027). An initial decrease in IGFBP-1 levels was noted in both groups during infusion (P < 0.03). Following the initial decrease, there was a significant increase in IGFBP-1 levels only in the IL-6-infused participants, peaking at 2 after the infusion cessation (P < 0.001). IL-6 infusion had no effect on GH binding protein, IGFBP-3, and acid-labile subunit levels. rhIL-6 levels similar to the levels found after strenuous exercise induced a typical exercise-associated GH-->IGF-I axis response (increase GH, decreased IGF-I, and elevated IGFBP-1). The results suggest that IL-6 plays a role in the GH-->IGF-I response to intense exercise.


A proinflammatory role for proteolytically cleaved annexin A1 in neutrophil transendothelial migration.
Neutrophil extravasation, a critical component of innate immunity must be tightly regulated to prevent inadvertent or prolonged inflammation and subsequent tissue damage. We have shown previously that endothelial ERK1/2 signaling essential for neutrophil transendothelial migration is induced by a soluble factor produced by activated neutrophils. In this study, we demonstrate that the soluble neutrophil factor is a truncated form of annexin A1 (AnxA1) that can be generated by calpain 1 cleavage of the N terminus, thus identifying a novel proinflammatory function to AnxA1. In contrast, neither the full-length protein nor the N-terminal 26 aa peptide, previously shown to be antiinflammatory, were able to activate Erk. Our data suggest that two different fragments of AnxA1 have opposing functions in inflammation. We also provide evidence that C-terminal AnxA1 functions by increasing ICAM1 clustering around adherent neutrophils to anchor them to the endothelium and promote transmigration through the transcellular route.


Plug-and-play genetic access to drosophila cell types using exchangeable exon cassettes.
Genetically encoded effectors are important tools for probing cellular function in living animals, but improved methods for directing their expression to specific cell types are required. Here, we introduce a simple, versatile method for achieving cell-type-specific expression of transgenes that leverages the untapped potential of "coding introns" (i.e., introns between coding exons). Our method couples the expression of a transgene to that of a native gene expressed in the cells of interest using intronically inserted "plug-and-play" cassettes (called "Trojan exons") that carry a splice acceptor site followed by the coding sequences of T2A peptide and an effector transgene. We demonstrate the efficacy of this approach in Drosophila using lines containing suitable MiMIC (Minos-mediated integration cassette) transposons and a palette of Trojan exons capable of expressing a range of commonly used transcription factors. We also introduce an exchangeable, MiMIC-like Trojan exon construct that can be targeted to coding introns using the Crispr/Cas system.


Targeting brain serotonin synthesis: insights into neurodevelopmental disorders with long-term outcomes related to negative emotionality, aggression and antisocial behaviour.
Aggression, which comprises multi-faceted traits ranging from negative emotionality to antisocial behaviour, is influenced by an interaction of biological, psychological and social variables. Failure in social adjustment, aggressiveness and violence represent the most detrimental long-term outcome of neurodevelopmental disorders. With the exception of brain-specific tryptophan hydroxylase-2 (Tph2), which generates serotonin (5-HT) in raphe neurons, the contribution of gene variation to aggression-related behaviour in genetically modified mouse models has been previously appraised (Lesch 2005 Novartis Found Symp. 268, 111-140; Lesch & Merschdorf 2000 Behav. Sci. Law 18, 581-604). Genetic inactivation of Tph2 function in mice led to the identification of phenotypic changes, ranging from growth retardation and late-onset obesity, to enhanced conditioned fear response, increased aggression and depression-like behaviour. This spectrum of consequences, which are amplified by stress-related epigenetic interactions, are attributable to deficient brain 5-HT synthesis during development and adulthood. Human data relating altered TPH2 function to personality traits of negative emotionality and neurodevelopmental disorders characterized by deficits in cognitive control and emotion regulation are based on genetic association and are therefore not as robust as the experimental mouse results. Mouse models in conjunction with approaches focusing on TPH2 variants in humans provide unexpected views of 5-HT's role in brain development and in disorders related to negative emotionality, aggression and antisocial behaviour.


The safety and effectiveness of a self-made negative pressure suction device in the treatment of chronic wounds.
Chronic wounds are wounds that are not healed or have no healing tendency for more than 1 month due to various factors. In clinical nursing, chronic wounds are often not properly treated, and the treatment efficiency is low. Therefore, it is very important to explore effective methods to deal with chronic wounds. To explore the effect of a self-made negative pressure suction device (NPSD) in the nursing of chronic wounds in the elderly. A total of 50 elderly patients with chronic wounds who were hospitalised in our hospital from January 2020 to December 2022 were selected as participants by convenient sampling. According to the random number table method, they were divided into a control group and an observation group, with 25 people in each group. The control group was treated with chloroplast foam dressing, debridement gel and alginate dressing. The observation group was treated with a self-made NPSD on the basis of the control group. The wound healing of the two groups was observed. After the intervention of the self-made NPSD, the granulation tissue coverage rate and wound volume reduction rate of the observation group were significantly increased (p < 0.05), and the positive rate of bacterial infection was significantly decreased (p < 0.05). After 3 months of intervention, the total effective rate of the observation group was significantly higher than that of the control group (χ2 = 3.869, p = 0.0492). The self-made NPSD can effectively promote the healing of a chronic wound.


Tales from the crypt: a parasitoid manipulates the behaviour of its parasite host.
There are many examples of apparent manipulation of host phenotype by parasites, yet few examples of hypermanipulation-where a phenotype-manipulating parasite is itself manipulated by a parasite. Moreover, few studies confirm manipulation is occurring by quantifying whether the host's changed phenotype increases parasite fitness. Here we describe a novel case of hypermanipulation, in which the crypt gall wasp Bassettia pallida (a phenotypic manipulator of its tree host) is manipulated by the parasitoid crypt-keeper wasp Euderus set, and show that the host's changed behaviour increases parasitoid fitness. Bassettia pallida parasitizes sand live oaks and induces the formation of a 'crypt' within developing stems. When parasitized by E. set, B. pallida adults excavate an emergence hole in the crypt wall, plug the hole with their head and die. We show experimentally that this phenomenon benefits E. set, as E. set that need to excavate an emergence hole themselves are about three times more likely to die trapped in the crypt. In addition, we discuss museum and field data to explore the distribution of the crypt-keeping phenomena.


Marginal adaptation of direct composite and sandwich restorations in Class II cavities with cervical margins in dentine.
The aim of this study was to evaluate the marginal adaptation of direct Class II sandwich restorations with resin-modified glass-ionomer cements and compomers in comparison to base and total bond restorations. For sandwich restorations with a triple cure resin-modified glass-ionomer cement the influence of different light curing techniques was also evaluated. Large butt-joint class II cavities with cervical margins 1 mm below the cemento-enamel junction were cut into 120 extracted human molars. The cavities (15 groups, n = 8) were filled using a sandwich, base or total bond technique with materials from five different manufacturers. A three-sited light curing technique was used in 13 groups. For the material combination Vitremer/Z100 two additional groups with a different wand positioning and a metal matrix were evaluated. After water storage for 21 days and thermocycling (2000x, 5-55 degrees C), replicas were quantitatively analysed in the SEM. Statistical analysis was performed with the Kruskal-Wallis test and the Bonferroni test at p < 0.05. The marginal adaptation of vertical enamel margins was not dependent on the restorative technique. For margins in dentine, marginal adaptation was significantly better with the sandwich technique than with a base or total bond technique for all materials. There were no significant differences between the base and total bond technique. Overall, resin-modified glass-ionomer cements showed somewhat better results than compomers in sandwich restorations, though differences were not significant for some criteria. Vitremer/Z100 sandwich restorations applied with a metal matrix showed the highest mean percentage of excellent margins of all experimental groups. Both resin-modified glass-ionomer cements and compomers can improve the marginal quality when used in a sandwich technique. Further research is necessary to determine the ideal material combination for sandwich restorations.


[Embryonal morphogenesis of the intraorgan circulatory bed, lymphatic outflow pathways and innervation structures].
Development of the circulation bed in human embryogenesis is brought about by a loop-like growth of vessels manifesting in proliferation, integration and morphofunctional transformation of the vascular loops. Proliferation of the loops ensures the blood inflow and reflux at all levels while their integration is followed by formation of hemocirculation system with appearance of the connective and major capillaries which serve the basis for development of true capillaries and capillary network in which precapillary arterioles and postcapillary venules can be distinguished. Hemocirculation system is completed by formation of the arteriolar and venular collaterals and arteriolo-venular anastomoses. Non-participation in the angiogenesis of the autogenic vessel endotheliocytes and their widespread necrosis give grounds to suggest that they are genetically condemned to death. Development of lymph vessels and innervation occurs simultaneously and together with blood vessels by mechanism of their centrifugal growth.


A Trunk Stabilization Exercise Warm-up May Reduce Ankle Injuries in Junior Soccer Players.
The aim of this study was to investigate the efficacy of a trunk stabilization exercise warm-up program in reducing the incidence of lower extremity injuries among male junior soccer players. Two junior soccer teams participated in this study. The intervention (INT) team performed three trunk stabilization exercises before practice sessions and games, while a control (CON) team performed their usual warm-up without trunk exercises. Both teams engaged in regular soccer training and games, and were followed for the incidence of injury. As a result, overall injury incidence rates (IRs) were 2.65 injuries/1,000 h and 4.94 injuries/1,000 h in the INT and CON teams, respectively (incidence rate ratio [IRR]=0.54, 95% confidence interval [CI]=0.32-0.89, p=0.013). The IR of acute injuries was significantly lower in the INT team (1.91 injuries/1,000 h) than in the CON team (4.06 injuries/1,000 h) (IRR=0.47, 95%CI=0.26-0.84, p=0.009). Regarding injury sites, the IRs of ankle injuries in the INT team (0.32 injuries/1,000 h) were significantly lower than that in the CON team (2.28 injuries/1,000 h) (IRR=0.14, 95%CI=0.04-0.47, p<0.001). These results suggest that a warm-up program comprising trunk stabilization exercises alone can prevent acute injuries, especially ankle injuries.


Clinical Benefit of NMDA Receptor Antagonists in a Patient With ATP1A2 Gene Mutation.
Mutations in the ATP1A2 gene cause familial hemiplegic migraine type 2, alternating hemiplegia of childhood, and cerebellar function deficits, epilepsy, and mental retardation. These symptoms are likely related to glutamatergic hyperexcitability. Our patient is a 12-year-old boy with a history of complex partial seizures, attention-deficit/hyperactivity disorder, and fine motor difficulty. During early childhood, he had episodes of a self-resolving right-sided hemiparesis and focal epilepsy. His seizures did not respond to several antiepileptic medications but stopped after he received valproate. His intermittent episodes of hemiplegia persisted. Additionally, he had pronounced bilateral fine motor impairment and significant executive deficits that gradually worsened. The whole exome sequencing revealed a de novo missense mutation in the ATP1A2 gene and a maternally inherited POLG gene mutation of unknown clinical significance. We hypothesized that glutamatergic excitotoxicity due to the ATP1A2 mutation contributed to the pathogenesis of our patient's condition. He was started on N-methyl-D-aspartate receptor antagonists (memantine and dextromethorphan), as well as coenzyme Q10 One year later, he showed significant improvement in sustained attention, learning efficiency, general cognitive efficiency, and fine motor dexterity. We postulate that N-methyl-D-aspartate receptor antagonists were effective for behavioral, cognitive, and cerebellar symptoms in our patient with ATP1A2 gene mutation.


A national audit of colonic interposition for esophageal replacement.
Esophageal replacement by colonic interposition is an uncommon procedure. This study sought to identify the frequency of this operation in England, identify techniques and associated problems, and also assess health-related quality of life (HR QOL) from the two largest centers performing this procedure. Hospital Episode Statistics were used to identify patients and centers undertaking colon interposition between March 2001 and March 2015. An online survey of UK consultants discussed methods and experience. HR QOL was assessed using the Short Form 36(SF-36v2) with additional gastrointestinal questions. Hospital Episode Statistics identified 328 interpositions (22 in pediatric hospitals). The two highest volume units did 42 and 45 operations, respectively. Thirty-four surgeons (79% response rate) replied to the survey. Fifty-two percent preferred to use the left colon with 81% preferring a substernal placement. The HR QOL survey was performed on 24 patients with a median of 3 years after surgery (ranging from 9 months to 10 years) from the two largest centers and a 56% response rate. Five patients had physical QOL scores above population average and 10 had mental scores above population average. All patients had early satiety, 20 described dysphagia, and 18 regularly took antireflux medication. There was an estimated mean loss of 13.1% body weight (10.6 kg) postoperatively and three patients still relied on a feeding tube for nutrition after an average of 3 years. Colon interposition results in an acceptable long-term QOL. Few centers regularly perform this operation, and centralizing to high-volume centers may lead to better outcomes.


In Vitro Immunological Cross-Reactivity of Thai Polyvalent and Monovalent Antivenoms with Asian Viper Venoms.
The intravenous administration of polyclonal antibodies known as antivenom is the only effective treatment for snakebite envenomed victims, but because of inter-specific variation in the toxic components of snake venoms, these therapies have variable efficacies against different snake species and/or different populations of the same species. In this study, we sought to characterize the in vitro venom binding capability and in vitro cross-neutralizing activity of antivenom, specifically the Hemato Polyvalent antivenom (HPAV; The Queen Saovabha Memorial Institute (QSMI) of the Thai Red Cross Society, Thailand) and three monovalent antivenoms (QSMI) specific to Daboia siamensis, Calloselasma rhodostoma, and Trimeresurus albolabris venoms, against a variety of South Asian and Southeast Asian viper venoms (Calloselasma rhodostoma, Daboia russelii, Hypnale hypnale, Trimeresurus albolabris, Trimeresurus purpureomaculatus, Trimeresurus hageni, and Trimeresurus fucatus). Using ELISA and immunoblotting approaches, we find that the majority of protein components in the viper venoms were recognized and bound by the HPAV polyvalent antivenom, while the monospecific antivenom made against T.albolabris extensively recognized toxins present in the venom of related species, T. purpureomaculatus, T. hageni, and T. fucatus. In vitro coagulation assays using bovine plasma revealed similar findings, with HPAV antivenom significantly inhibiting the coagulopathic activities of all tested viper venoms and T. albolabris antivenom inhibiting the venoms from Malaysian arboreal pit vipers. We also show that the monovalent C. rhodostoma antivenom exhibits highly comparable levels of immunological binding and in vitro venom neutralization to venom from both Thailand and Malaysia, despite previous reports of considerable intraspecific venom variation. Our findings suggest that Thai antivenoms from QSMI may by useful therapeutics for managing snake envenomings caused by a number of Southeast Asian viper species and populations for which no specific antivenom currently exists and thus should be explored further to assess their clinical utility in treating snakebite victims.


Sublethal Photodynamic Treatment Does Not Lead to Development of Resistance.
A promising new alternative approach for eradication of antibiotic-resistant strains is to expose microbes to photosensitizers, which upon illumination generate reactive oxygen species. Among the requirements for a potent, medically applicable photosensitizer, are high efficacy in killing microbes and low toxicity to the host. Since photodynamic treatment is based on production of reactive species which are potentially DNA damaging and mutagenic, it might be expected that under selective pressure, microbes would develop resistance. The aim of this study was to determine if antibacterial photodynamic treatment with a highly photoefficient photosensitizer, Zn(II) meso-tetrakis(N-n-hexylpyridinium-2-yl)porphyrin would lead to development of resistance. To answer that question, bacterial cultures were subjected to multiple cycles of sublethal photodynamic stress and regrowth, and to continuous growth under photodynamic exposure. Antibiotic-resistant Staphylococcus aureus and Escherichia coli clinical isolates were also tested for susceptibility to photodynamic inactivation and for development of resistance. Results demonstrated that multiple photodynamic exposures and regrowth of surviving cells or continuous growth under sublethal photodynamic conditions, did not lead to development of resistance to photosensitizers or to antibiotics. Antibiotic-resistant E. coli and S. aureus were as sensitive to photodynamic killing as were their antibiotic-sensitive counterparts and no changes in their sensitivity to antibiotics or to photodynamic inactivation after multiple cycles of photodynamic treatment and regrowth were observed. In conclusion, photosensitizers with high photodynamic antimicrobial efficiency can be used successfully for eradication of antibiotic-resistant bacterial strains without causing development of resistance.


Synthesis and optical properties of bacteriochlorophyll-a derivatives having various C3 substituents on the bacteriochlorin pi-system.
Methyl bacteriopyropheophorbide-a derivatives having a series of substituents at the C3 position were prepared and their optical properties were compared with the corresponding chlorin analogues. Two kinds of oxidation reaction (C3-vinyl --> formyl --> carboxy group) were found to be applicable with a little alteration of the free-base bacteriochlorin macrocycles. The Qx and Qy electronic absorption peak positions of synthetic bacteriochlorins in CH2Cl2 were affected by the C3 substituents and found to be more sensitive than those of the chlorins. The observed Qx/Qy peaks in their monomeric states were shifted to a longer wavelength in the order of 1-hydroxyethyl < hydroxymethyl < acetoxymethyl < vinyl < acetyl < carboxy < formyl < 2,2-dicyanoethynyl group. Zinc complex with the C3-hydroxymethyl group formed self-aggregates in a nonpolar organic solvent, which showed the largest red-shift of the Qy band (2380 cm(-1), 726 nm in THF to 878 nm in 1% THF-cyclohexane) among those of the synthetic self-aggregative (bacterio)chlorins examined.


Keratin subtypes in carcinomas of the uterine cervix: implications for histogenesis and differential diagnosis.
Normal epithelia and carcinomas of the human uterine cervix were studied by monoclonal antibodies chain specific for cytokeratins 4, 8, 10, 13, 14, 18, and 19. Most cells in 13 examined squamous carcinomas revealed a cytokeratin phenotype detected in ectocervical basal cells and endocervical subcolumnar reserve cells: 8+, 14+, 18+, 19+, 4-, 10-, 13-. We propose that these two cell types are closely related or identical and that squamous carcinoma of the cervix originates in this cell type. In more differentiated tumor cells cytokeratins 4, 10, and 13, which are present in suprabasal layers of the normal ectocervical epithelium, were coexpressed with basal cell cytokeratins. Thus, contrary to previous beliefs, all cytokeratins detected in carcinomas were also present in normal epithelium of uterine cervix. The cytokeratin profile of cervical adenocarcinomas corresponded to that of columnar endocervical cells (8+, 18+, 19+), although two of the three adenocarcinomas also expressed cytokeratin 4, which in the normal endocervix was detected in scattered single columnar cells only. The new monoclonal antibody DE-K14, specific for cytokeratin 14, proved a specific marker of subcolumnar reserve cells in the endocervix. It was also the only one that reacted with all cervical squamous carcinomas but with none of the cervical adenocarcinomas and, as such, has a potential value for pathological differential diagnosis of cervical tumors.


Detecting fast, online reasoning processes in clinical decision making.
In an experiment that used the inconsistency paradigm, experienced clinical psychologists and psychology students performed a reading task using clinical reports and a diagnostic judgment task. The clinical reports provided information about the symptoms of hypothetical clients who had been previously diagnosed with a specific mental disorder. Reading times of inconsistent target sentences were slower than those of control sentences, demonstrating an inconsistency effect. The results also showed that experienced clinicians gave different weights to different symptoms according to their relevance when fluently reading the clinical reports provided, despite the fact that all the symptoms were of equal diagnostic value according to the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; American Psychiatric Association, 2000). The diagnostic judgment task yielded a similar pattern of results. In contrast to previous findings, the results of the reading task may be taken as direct evidence of the intervention of reasoning processes that occur very early, rapidly, and online. We suggest that these processes are based on the representation of mental disorders and that these representations are particularly suited to fast retrieval from memory and to making inferences. They may also be related to the clinicians' causal reasoning. The implications of these results for clinician training are also discussed.


[Colonic perforation in percutaneous surgery of the kidney. Report of two cases].
We show our experience about iatrogenic damage of colon secondarily to percutaneous surgery of the kidney. One of them treated by means of open surgery, the other by conservative procedures. Making discussion on risk factors, as well as the diagnostic therapeutical aspects.


Deinococcus koreensis sp. nov., a gamma radiation-resistant bacterium isolated from river water.
A gamma radiation-resistant, Gram-stain-negative, rod-shaped bacterial strain, designated SJW1-2T, was isolated from freshwater samples collected from the Seomjin River, Republic of Korea. The 16S rRNA gene sequence analyses showed that strain SJW1-2T was most closely related to Deinococcus metalli 1PNM-19T (94.3 % sequence similarity) and formed a robust phylogenetic clade with other species of the genus Deinococcus. The optimum growth pH and temperature for the isolate were pH 7.0-7.5 and 25 °C, respectively. Strain SJW1-2T exhibited high resistance to gamma radiation. The predominant respiratory quinone was MK-8. The polar lipid profile consisted of different unidentified glycolipids, two unidentified lipids, two unidentified phospholipids and an unidentified phosphoglycolipid. The major peptidoglycan amino acids were alanine, d-glutamic acid, glycine and l-ornithine. The predominant fatty acids (>10 %) were summed feature 3 (C16 : 1ω7c and/or C16 : 1ω6c) (25.2 %) and C16 : 0 (21.2 %), and the DNA G+C content was 69.5 mol%. On the basis of phenotypic, genotypic and phylogenetic analyses, strain SJW1-2T (=KACC 19332T=NBRC 112908T) represents a novel species of the genus Deinococcus, for which the name Deinococcus koreensis sp. nov. is proposed.


The regulation of troponins I, C and ANP by GATA4 and Nkx2-5 in heart of hibernating thirteen-lined ground squirrels, Ictidomys tridecemlineatus.
Hibernation is an adaptive strategy used by various mammals to survive the winter under situations of low ambient temperatures and limited or no food availability. The heart of hibernating thirteen-lined ground squirrels (Ictidomys tridecemlineatus) has the remarkable ability to descend to low, near 0°C temperatures without falling into cardiac arrest. We hypothesized that the transcription factors GATA4 and Nkx2-5 may play a role in cardioprotection by facilitating the expression of key downstream targets such as troponin I, troponin C, and ANP (atrial natriuretic peptide). This study measured relative changes in transcript levels, protein levels, protein post-translational modifications, and transcription factor binding over six stages: euthermic control (EC), entrance into torpor (EN), early torpor (ET), late torpor (LT), early arousal (EA), and interbout arousal (IA). We found differential regulation of GATA4 whereby transcript/protein expression, post-translational modification (phosphorylation of serine 261), and DNA binding were enhanced during the transitory phases (entrance and arousal) of hibernation. Activation of GATA4 was paired with increases in cardiac troponin I, troponin C and ANP protein levels during entrance, while increases in p-GATA4 DNA binding during early arousal was paired with decreases in troponin I and no changes in troponin C and ANP protein levels. Unlike its binding partner, the relative mRNA/protein expression and DNA binding of Nkx2-5 did not change during hibernation. This suggests that either Nkx2-5 does not play a substantial role or other regulatory mechanisms not presently studied (e.g. posttranslational modifications) are important during hibernation. The data suggest a significant role for GATA4-mediated gene transcription in the differential regulation of genes which aid cardiac-specific challenges associated with torpor-arousal.


Interplay between whole-genome doubling and the accumulation of deleterious alterations in cancer evolution.
Whole-genome doubling (WGD) is a prevalent event in cancer, involving a doubling of the entire chromosome complement. However, despite its prevalence and prognostic relevance, the evolutionary selection pressures for WGD in cancer have not been investigated. Here, we combine evolutionary simulations with an analysis of cancer sequencing data to explore WGD during cancer evolution. Simulations suggest that WGD can be selected to mitigate the irreversible, ratchet-like, accumulation of deleterious somatic alterations, provided that they occur at a sufficiently high rate. Consistent with this, we observe an enrichment for WGD in tumor types with extensive loss of heterozygosity, including lung squamous cell carcinoma and triple-negative breast cancers, and we find evidence for negative selection against homozygous loss of essential genes before, but not after, WGD. Finally, we demonstrate that loss of heterozygosity and temporal dissection of mutations can be exploited to identify novel tumor suppressor genes and to obtain a deeper characterization of known cancer genes.


Development of sensitive immunoassays to detect amylin and amylin-like peptides in unextracted plasma.
Amylin is a 37-amino-acid polypeptide synthesized in and secreted from pancreatic beta cells along with insulin. Its biological actions include the slowing and reduction of postmeal increases in plasma glucose concentrations. Studies of the basic amylin biology in humans have been hampered by the lack of a rapid, sensitive assay capable of measuring physiological concentrations of amylin in small volumes of plasma. We report here two sandwich-type immunoassays that use pairs of monoclonal antibodies, the fluorescent substrate 4-methylumbelliferyl phosphate, and the enzyme alkaline phosphatase. The minimum detectable concentration of amylin in 50 microL of plasma was 0.5 to 2 pmol/L, and the dynamic range was 2 to 100 pmol/L. The assays had average intraassay CVs of <10%, average interassay CVs of <15%, and good linearity on dilution and recovery of added amylin. The two assays use the same detection antibody, which binds to the carboxyl terminus of the molecule, but different capture antibodies. One of the assays measures only human amylin; the other also detects amylin-like peptides. Examples of measurements in human plasma are provided in subjects with impaired glucose tolerance and in nondiabetic controls.


Ticks as potential vectors of Mycobacterium leprae: Use of tick cell lines to culture the bacilli and generate transgenic strains.
Leprosy is an infectious disease caused by Mycobacterium leprae and frequently resulting in irreversible deformities and disabilities. Ticks play an important role in infectious disease transmission due to their low host specificity, worldwide distribution, and the biological ability to support transovarial transmission of a wide spectrum of pathogens, including viruses, bacteria and protozoa. To investigate a possible role for ticks as vectors of leprosy, we assessed transovarial transmission of M. leprae in artificially-fed adult female Amblyomma sculptum ticks, and infection and growth of M. leprae in tick cell lines. Our results revealed M. leprae RNA and antigens persisting in the midgut and present in the ovaries of adult female A. sculptum at least 2 days after oral infection, and present in their progeny (eggs and larvae), which demonstrates the occurrence of transovarial transmission of this pathogen. Infected tick larvae were able to inoculate viable bacilli during blood-feeding on a rabbit. Moreover, following inoculation with M. leprae, the Ixodes scapularis embryo-derived tick cell line IDE8 supported a detectable increase in the number of bacilli for at least 20 days, presenting a doubling time of approximately 12 days. As far as we know, this is the first in vitro cellular system able to promote growth of M. leprae. Finally, we successfully transformed a clinical M. leprae isolate by inserting the reporter plasmid pCHERRY3; transformed bacteria infected and grew in IDE8 cells over a 2-month period. Taken together, our data not only support the hypothesis that ticks may have the potential to act as a reservoir and/or vector of leprosy, but also suggest the feasibility of technological development of tick cell lines as a tool for large-scale production of M. leprae bacteria, as well as describing for the first time a method for their transformation.


Venom variability and envenoming severity outcomes of the Crotalus scutulatus scutulatus (Mojave rattlesnake) from Southern Arizona.
Twenty-one Mojave rattlesnakes, Crotalus scutulatus scutulatus (C. s. scutulatus), were collected from Arizona and New Mexico U.S.A. Venom proteome of each specimen was analyzed using reverse-phase HPLC and SDS-PAGE. The toxicity of venoms was analyzed using lethal dose 50 (LD(50)). Health severity outcomes between two Arizona counties U.S.A., Pima and Cochise, were determined by retrospective chart review of the Arizona Poison and Drug Information Center (APDIC) database between the years of 2002 and 2009. Six phenotypes (A-F) were identified based on three venom protein families; Mojave toxin, snake venom metalloproteinases PI and PIII (SVMP), and myotoxin-A. Venom changed geographically from SVMP-rich to Mojave toxin-rich phenotypes as you move from south central to southeastern Arizona. Phenotypes containing myotoxin-A were only found in the transitional zone between the SVMP and Mojave toxin phenotypes. Venom samples containing the largest amounts of SVMP or Mojave toxin had the highest and lowest LD(50s), respectively. There was a significant difference when comparing the presence of neurotoxic effects between Pima and Cochise counties (p=0.001). No significant difference was found when comparing severity (p=0.32), number of antivenom vials administered (p=0.17), days spent in a health care facility (p=0.23) or envenomation per 100,000 population (p=0.06). Although not part of the original data to be collected, death and intubations, were also noted. There is a 10× increased risk of death and a 50× increased risk of intubations if envenomated in Cochise County.


[Antinuclear, anticentromere and anti-ScL-70 antibodies in rheumatic diseases].
Methods are described that are used for the titration of antinuclear, anticentromere, and anti-Scl-70 antibodies in systemic scleroderma, systemic lupus erythematosus, and rheumatoid arthritis: indirect immunofluorescence with various antigenic substrates (sections of fresh-frozen rat liver and Hep-2 cell culture), counter-current immunoelectrophoresis, isolation of Scl-70 antigen. Use of Hep-2 cells as a substrate for indirect immunofluorescence was found clinically and diagnostically more effective since it permitted the detection of anticentromere antibodies and anti-Scl-70. Nucleolar, mottled, homogeneous, marginal immunofluorescence types were observed when rat liver sections and Hep-2 cells were used for substrates. Anticentromere antibodies and anti-Scl-70 were isolated significantly more frequently in systemic lupus erythematosus or rheumatoid arthritis.


Specificity of humoral and cellular immune response against recombinant particles of nucleocapsid protein of human hepatitis B virus in rabbits.
Nucleocapsid (core) protein of hepatitis B virus (HBcAg) induces potent cellular and humoral responses that have a clear protective potential. Rabbits were immunized by particles formed by recombinant molecules of HBcAg carrying N-terminally inserted heterologous sequences. Specificity of humoral and cellular immune response against HBcAg and selection of HBcAg epitopes was surveyed. Immunological properties of the recombinant particles were similar to those of the original HBcAg. Recombinant particles were not toxic to the peripheral blood mononuclear cells (PBMC) of non-immune or HBcAg-immunized animals ex vivo. Proliferative response of PBMC (T-lymphocytes) to HBcAg in immunized animals increased in a concentration-dependent manner in the broad interval of HBcAg concentrations (10-104 ng/ml). On the contrary, a narrow bell-shaped HBcAg dose-dependence curve was earlier observed for T-lymphocytes of donors immune to HBV after natural infection that was probably due to the cytotoxic effect of HBcAg on the expressing cells. Specificity of humoral and cellular immune response against HBcAg particles in the immunized animals and in natural infection with hepatitis B virus (HBV) was compared. Immunization with recombinant HBcAg particles induced potent anti-HBcAg antibody responses: high (up to 2.107) titers of anti-HBcAg antibodies were reached. Appearance of anti-HBcAg antibodies was in every case preceded by an increasing T-cell response to the whole protein and HBcAg-derived peptides, thus mimicking immune responses during acute HBV infection in humans. A predominant universal (haplotype-independent) T-helper cell epitope (amino acid residues (aa) 61-85 of HBcAg (p61-85)) was recognized by T-cells of all animals. Transient antibody response against p61-85 was recorded during the early stages of immunization in spite of the fact that a major B-cell epitope localized in this region is supposed to be purely conformational. A sequence representing another cluster of immunodominant T-cell epitopes of mice and HBV infected humans, aa 121-140 (p121-140), was not immunogenic on the T-cell level. However, it appeared to be a potent B-cell immunogen, despite a common assumption that HBcAg and p121-140 are not cross-reactive at the B-cell level. A possibility that anti-p121-140 antibodies were induced by an exposed region of the native particulate HBcAg and not by the denatured protein molecules, was confirmed by recognition of the particulate HBcAg by antibodies specific to synthetic peptides representing aa 120-140 of HBcAg. The data point to the exposition of aa 121-140 on the surface of the particles.


Aging-regulated TUG1 is dispensable for endothelial cell function.
The evolutionary conserved Taurine Upregulated Gene 1 (TUG1) is a ubiquitously expressed gene that is one of the highest expressed genes in human and rodent endothelial cells (ECs). We here show that TUG1 expression decreases significantly in aging mouse carotid artery ECs and human ECs in vitro, indicating a potential role in the aging endothelial vasculature system. We therefore investigated if, and how, TUG1 might function in aging ECs, but despite extensive phenotyping found no alterations in basal EC proliferation, apoptosis, barrier function, migration, mitochondrial function, or monocyte adhesion upon TUG1 silencing in vitro. TUG1 knockdown did slightly and significantly decrease cumulative sprout length upon vascular endothelial growth factor A stimulation in human umbilical vein endothelial cells (HUVECs), though TUG1-silenced HUVECs displayed no transcriptome-wide mRNA expression changes explaining this effect. Further, ectopic expression of the highly conserved and recently discovered 153 amino acid protein translated from certain TUG1 transcript isoforms did not alter angiogenic sprouting in vitro. Our data show that, despite a high expression and strong evolutionary conservation of both the TUG1 locus and the protein sequence it encodes, TUG1 does not seem to play a major role in basic endothelial cell function.


Heterogeneity of Second-Line Treatment for Patients With Multiple Myeloma in the Connect MM Registry (2010-2016).
The treatment landscape for multiple myeloma (MM) has undergone recent changes with the regulatory approval of several new therapies indicated for second- and later-line disease. Using data from Connect MM, the largest multisite, primarily community-based, prospective, observational registry of MM patients in the United States, selection of second-line treatments was evaluated during a 5-year period from 2010 to 2016. Eligible patients were aged ≥ 18 years, had newly diagnosed MM ≤ 2 months before study entry, and were followed for up to 8 years. Patients who received ≥ 2 lines of therapy were analyzed. "Tepee" plots of stacked area graphs differentiated treatments by color to allow visualization of second-line treatment trends in MM patients. As of February 2017, 855 of 2897 treated patients had progressed to second-line treatment. Treatment selection was heterogeneous; shifting patterns of treatment choices coincided with the approval status of newer agents. The most common treatment regimens in the early part of the decade were lenalidomide and/or bortezomib, with or without dexamethasone, with increasing use of newer agents (carfilzomib, pomalidomide, daratumumab, and elotuzumab) and triplet combinations over time. The influence of the baseline patient characteristics of age, history of diabetes, peripheral neuropathy, and renal function on treatment choice was also examined. These findings indicate that community physicians are current in their MM management practices, with uptake of new drugs and acquaintance with results of randomized clinical trials using combinations almost concurrent with their regulatory approval and publication.


UBE3A Suppresses Overnutrition-Induced Expression of the Steatosis Target Genes of MLL4 by Degrading MLL4.
Regulation of the protein stability of epigenetic regulators remains ill-defined despite its potential applicability in epigenetic therapies. The histone H3-lysine 4-methyltransferase MLL4 is an epigenetic transcriptional coactivator that directs overnutrition-induced obesity and fatty liver formation, and Mll4+/- mice are resistant to both. Here we show that the E3 ubiquitin ligase UBE3A targets MLL4 for degradation, thereby suppressing high-fat diet (HFD)-induced expression of the hepatic steatosis target genes of MLL4. In contrast to Mll4+/- mice, Ube3a+/- mice are hypersensitive to HFD-induced obesity and fatty liver development. Ube3a+/-;Mll4+/- mice lose this hypersensitivity, supporting roles of increased MLL4 levels in both phenotypes of Ube3a+/- mice. Correspondingly, our comparative studies with wild-type, Ube3a+/- and Ube3a-/- and UBE3A-overexpressing transgenic mouse livers demonstrate an inverse correlation of UBE3A protein levels with MLL4 protein levels, expression of the steatosis target genes of MLL4, and their decoration by H3-lysine 4-monomethylation, a surrogate marker for the epigenetic action of MLL4. Conclusion: UBE3A indirectly exerts an epigenetic regulation of obesity and steatosis by degrading MLL4. This UBE3A-MLL4 regulatory axis provides a potential therapeutic venue for treating various MLL4-directed pathogeneses, including obesity and hepatic steatosis.


Catheter-related thrombosis in patients with refractory lymphoma undergoing autologous stem cell transplantation.
Long-term indwelling central venous catheters have eased the administration of drugs, blood products, and hyperalimentation to patients with cancer. However, their use is associated with thrombotic complications. We report here on the thrombotic complications prospectively observed in 46 patients with refractory lymphoma (22 Hodgkin's disease, 24 non-Hodgkin's lymphoma) who had placement of one or more catheters in preparation for autologous stem cell transplantation (ASCT). Thrombosis of 26 catheters in 19 patients was observed. Specific abnormalities of hemostasis were equally common in patients who developed thrombosis and in those who did not. Thrombotic complications were more common in patients with Hodgkin's disease (13/22) than in patients with non-Hodgkin's lymphoma (6/24, p = 0.04). Although more patients with Hodgkin's disease had received prior splenectomy and/or irradiation to the area involved by thrombosis than patients with non-Hodgkin's lymphoma, the incidence of splenectomy and irradiation was similar for patients with Hodgkin's disease who developed thrombosis and those who did not. Therefore, although the etiology remains unexplained, patients with Hodgkin's disease undergoing intensive chemotherapy and ASCT appear to have a higher incidence of catheter-related thrombosis than patients with non-Hodgkin's lymphoma undergoing similar therapy.


County council politicians' attitudes toward suicide and suicide prevention: a qualitative cross-cultural study.
The purpose of the present study was to compare county council politicians' attitudes toward suicide and suicide prevention in five European countries. A questionnaire was distributed and here the responses to the open-ended questions are analyzed qualitatively. Considerable differences were found in what the politicians in the five countries believed to be the most important causes of suicide and how suicide can be prevented. There were also differences in to what degree the politicians revealed a judgmental attitude toward suicide, which seemed to be related to the magnitude of the problem in the respective countries. A certain implicit inconsistency in the logic directing the politicians' responses was found when their views on causes to suicide and suicide prevention strategies were compared. The responses indicate a need for increased consciousness and knowledge about suicide and suicide prevention among politicians in all the five countries. This is important since they are responsible for initiating and funding suicide preventive efforts.