Anti-acetylcholine receptor antibodies induced in mice by syngeneic receptor without adjuvants.
Acetylcholine receptor (AChR)-bearing membranes from the BC3H-1 cell lines were injected, without adjuvant, either intrathymically (i.t.) followed by intraperitoneal (i.p.) booster doses, or i.p. alone, into (C57BL X BALB/c)F1 mice. Over 75% of the animals developed serum anti-AChRs which reacted with the cell-line AChR and with normal mouse endplate AChR. The titres were within the lower range of those of myasthenia gravis patients, and some mice showed reduced miniature endplate potential (m.e.p.p) amplitudes. these results indicate that loss of tolerance to acetylcholine receptors can result from immunization against syngeneic AChR without adjuvant. This approach may provide a useful model for studying mechanisms of autoimmunity against acetylcholine receptor.


NUDT21 relieves sevoflurane-induced neurological damage in rats by down-regulating LIMK2.
Postoperative cognitive dysfunction (POCD) is a common complication of cognitive decline after surgery and anesthesia. Sevoflurane, as a commonly used anesthetic, was found to cause POCD. Nudix Hydrolase 21 (NUDT21), a conserved splicing factor, has been reported to exert important functions in multiple diseases' progression. In this study, the effect of NUDT21 on sevoflurane-induced POCD was elucidated. Results showed that NUDT21 was down-regulated in the hippocampal tissue of sevoflurane-induced rats. Morris water maze test results revealed that overexpression of NUDT21 improved sevoflurane-induced cognitive impairment. In addition, TUNEL assay results indicated that enhanced NUDT21 alleviated sevoflurane-induced apoptosis of hippocampal neurons. Furthermore, overexpression of NUDT21 suppressed the sevoflurane-induced LIMK2 expression. Taken together, NUDT21 alleviates sevoflurane-induced neurological damage in rats by down-regulating LIMK2, providing a novel target for the prevention of sevoflurane-induced POCD.


[The usefulness of prokinetics in the treatment of acid-related disease].
The main drugs for the acid-related disease are acid suppression agents, however, such treatment sometimes fail to obtain a satisfactory relief of symptoms. In primary care settings, it is usually difficult to discern the underlying pathophysiology of the putative acid-related symptoms whether excessive acid secretion or impaired gastrointestinal motility is involved. Prokinetic agents have the usefull effects such as the reduction in the gastroesophageal reflux episodes by increasing lower esophageal sphincter pressure, the improvement of esophageal clearance by strengthening esophageal peristalsis, the prevention of rise in intragastric pressure by ameliorating delayed gastric emptying and impaired accommodation, and the attenuation of visceral hypersensitivity by heightening the threshold to gastric distension, therefore, it is conceivable that prokinetic agents relief the acid-related symptoms via a different mechanism other than acid suppression agents. Prokinetic agents seem potent as an alternative or an additional drug in the treatment of acid-related symptoms when the acid suppression agents are ineffective.


Unique proteasome subunit Xrpn10c is a specific receptor for the antiapoptotic ubiquitin-like protein Scythe.
The Rpn10 subunit of the 26S proteasome can bind to polyubiquitinoylated and/or ubiquitin-like proteins via ubiquitin-interacting motifs (UIMs). Vertebrate Rpn10 consists of five distinct spliced isoforms, but the specific functions of these variants remain largely unknown. We report here that one of the alternative products of Xenopus Rpn10, named Xrpn10c, functions as a specific receptor for Scythe/BAG-6, which has been reported to regulate Reaper-induced apoptosis. Deletional analyses revealed that Scythe has at least two distinct domains responsible for its binding to Xrpn10c. Conversely, an Xrpn10c has a UIM-independent Scythe-binding site. The forced expression of a Scythe mutant protein lacking Xrpn10c-binding domains in Xenopus embryos induces inappropriate embryonic death, whereas the wild-type Scythe did not show any abnormality. The results indicate that Xrpn10c-binding sites of Scythe act as an essential segment linking the ubiquitin/proteasome machinery to the control of proper embryonic development.


Efficacy and Safety of FOLFIRI Regimen in Elderly Versus Nonelderly Patients with Metastatic Colorectal or Gastric Cancer.
Irinotecan-based chemotherapy is a standard backbone of therapy in patients with metastatic colorectal cancer (CRC) or gastric cancer (GC). However, there is still a paucity of information concerning the efficacy and safety of irinotecan-based regimens in elderly patients. Using the patient cohort (n = 1,545) from the UGT1A1 genotype study, we compared the efficacy and safety between elderly and nonelderly patients with metastatic CRC (n = 934) or GC (n = 611) who received first- or second-line FOLFIRI (irinotecan, leucovorin, and 5-fluorouracil) chemotherapy. Despite lower relative dose intensity in elderly patients, progression-free survival and overall survival were similar between elderly (age ≥70 years) and nonelderly (<70 years) patients in the CRC cohort (hazard ratio [HR], 1.117; 95% confidence interval [CI], 0.927-1.345; p = .244, and HR, 0.989; 95% CI, 0.774-1.264; p = .931, respectively) and the GC cohort (HR, 1.093; 95% CI, 0.854-1.400; p = .479, and HR, 1.188; 95% CI, 0.891-1.585; p = .241, respectively). In both cohorts, febrile neutropenia (22.1% vs. 14.6% in CRC cohort and 35.2% vs. 22.5% in GC cohort) and asthenia (grade 3: 8.4% vs. 1.7% in CRC cohort and 5.5% vs. 2.9% in GC cohort) were more frequent in elderly patients. In the CRC cohort, mucositis and anorexia were more frequent in elderly patients. In the GC cohort, nausea and vomiting were less frequent in elderly patients. The efficacy of the FOLFIRI regimen was similar between elderly and nonelderly patients in both the CRC and the GC cohorts. However, special attention should be paid to elderly patients because of increased risk for febrile neutropenia and asthenia. The Oncologist 2017;22:293-303 IMPLICATIONS FOR PRACTICE: The efficacy of FOLFIRI (irinotecan, leucovorin, and 5-fluorouracil) chemotherapy in elderly patients with metastatic colorectal cancer or gastric cancer was similar to that in nonelderly patients. However, special attention should be paid to elderly patients because of the increased risk for febrile neutropenia and asthenia. These data suggest that the FOLFIRI regimen could be considered as a standard backbone of therapy in elderly patients with metastatic colorectal cancer or gastric cancer and that the clinical decision between doublet and singlet chemotherapy may not be based solely on age. However, the data require further assessment of frailty and performance status.


Stimulation of phospholipase C by the cloned mu, delta and kappa opioid receptors via chimeric G alpha(q) mutants.
Opioid receptors (mu, delta and kappa) are known to regulate diverse physiological functions and yet, at the molecular level, they are coupled to a seemingly identical set of G proteins. A recent study has discerned subtle differences between the opioid receptors in their ability to activate the pertussis toxin-insensitive G16. Differences in microarchitecture might be magnified when these receptors are provided with 'non-native' partners. Here, we examined whether the opioid receptors can interact productively with a set of chimeric Galphaq subunits which are known to link many Gi-coupled receptors to phosphoinositide-specific phospholipase C (PI-PLC). The qi5, qo5 and qz5 chimeras have the last five residues of Galphaq replaced by those of Galphai, Galphao and Galphaz, respectively. Except for mu-receptor and qo5, each pair of opioid receptor and Galphaq chimera allowed opioid agonists to stimulate PI-PLC in transfected COS-7 cells. The Galphaq chimera-mediated responses were ligand selective, agonist dose dependent and saturable. The most robust responses were obtained with kappa-receptor and qi5 or qz5, whereas the coupling of delta- and mu-receptors to Galphaq chimeras produced much weaker responses. Among the Galphaq chimeras, qo5 was less efficiently coupled to the opioid receptors. As revealed by radioligand binding assays and immunoblot analysis, differences in the efficiency of coupling were not due to variations in the expression of receptors and Galphaq chimeras. Differences in the magnitude of PI-PLC responses are thus likely to represent structural incompatibility between opioid receptors and Galphaq chimeras, suggesting that each opioid receptor possesses unique structural surfaces for the binding of G proteins.


Proliferative activity of human thyroid cells in various age groups and its correlation with the risk of thyroid cancer after radiation exposure.
The thyroid gland is vulnerable to the carcinogenic effects of ionizing radiation, and there is a well-documented inverse correlation between thyroid cancer and age at exposure, particularly for ages less than 20 yr. One of the factors responsible for this phenomenon may be more rapid cell proliferation in children. The objective of this study was to determine the proliferative rate of normal human thyroid cells in different age groups. We used immunohistochemical analysis to determine the Ki-67 proliferative index in 117 thyroid glands obtained at autopsy, including 25 fetal thyroids (11-40 wk gestation), 55 childhood thyroids (0-19 yr), and 37 adult thyroids (20-60 yr). The rate of Ki-67 labeling in the three groups was 7.4 +/- 6.10, 0.23 +/- 0.15, and 0.08 +/- 0.04% respectively, demonstrating an overall trend for diminishing proliferative activity of thyroid cells with increasing age. However, a lack of correlation was noted between the slopes of cancer risk calculated from previous studies of irradiated populations and proliferative rate in the pediatric age intervals of 0-4 and 5-9 yr, suggesting that other factors are likely to be responsible for the particularly high sensitivity to radiation-induced thyroid cancer among the youngest children. Our findings of a general decrease in proliferative activity of thyroid cells with age may explain, at least in part, the higher risks of radiation-related thyroid cancer in children compared with adults. However, the variation in the rate of cell proliferation is unlikely to be responsible entirely for this phenomenon and other factors may also be involved.


Role of calcium on interleukin-1 production by monocytes: its relevance during T cell proliferation.
T cell proliferation, in the presence of monocytes, triggered either by an anti-CD3 monoclonal antibody (mAb) or by a mitogenic pair of anti-CD2 mAbs was inhibited either by the calcium chelator EGTA or the calcium channel blocker nifedipin. Antibodies against interleukin-1 (IL-1) inhibited T cell proliferation in both mitogenic systems. However inhibition achieved by anti-IL-1 beta Ab was greater than by anti-IL-1 alpha Ab while the combination of both anti-rIL-1 alpha Ab + anti-rIL-1 beta could completely inhibit the CD3-triggered T cell proliferation. On the other hand, IL-1 production by LPS-stimulated monocytes was strongly decreased both by EGTA and nifedipin. Northern blot analysis showed that this inhibition paralleled a decrease of IL-1 alpha and beta messenger RNA (mRNA) expression only in the presence of EGTA but not in the presence of nifedipin. These results indicate that EGTA acted at the transcriptional level while nifedipin acted at a yet undefined posttranscriptional level. Thus, it is suggested that the impairment of T cell proliferation by calcium inhibitors could result not only from an effect on Ca2+ influx in T cells but also from interfering with the function of accessory cells, such as the production of IL-1.


Candida albicans Sfl1 suppresses flocculation and filamentation.
Hyphal morphogenesis in Candida albicans is regulated by multiple pathways which act by either inducing or repressing filamentation. Most notably, Tup1, Nrg1, and Rfg1 are transcriptional repressors, while Efg1, Flo8, Cph1, and Czf1 can induce filamentation. Here, we present the functional analysis of CaSFL1, which encodes the C. albicans homolog of the Saccharomyces cerevisiae SFL1 (suppressor of flocculation) gene. Deletion of CaSFL1 results in flocculation (i.e., the formation of clumps) of yeast cells, which is most pronounced in minimal medium. The flocs contained hyphae already under noninducing conditions, and filamentation could be enhanced with hypha-inducing cues at 37 degrees C. Expression of SFL1 in a heterozygous mutant under the control of the CaMET3 promoter was shown to complement these defects and allowed switching between wild-type and mutant phenotypes. Interestingly, increased expression of SFL1 using a MET3prom-SFL1 construct prior to the induction of filamentation completely blocked germ tube formation. To localize Sfl1 in vivo, we generated a SFL1-GFP fusion. Sfl1-green fluorescent protein was found in the nucleus in both yeast cells and, to a lesser extent, hyphal cells. Using reverse transcription-PCR, we find an increased expression of ALS1, ALS3, HWP1, ECE1, and also FLO8. Our results suggest that Sfl1 functions in the repression of flocculation and filamentation and thus represents a novel negative regulator of C. albicans morphogenesis.


Optimum spacing for a pair of thick circular coils of square section.
Curves are given for the magnetic field along the axis between two circular coils of square section traversed by the same current. These curves relate the field variations, the length in which the field is within a certain allowed variation, the coil thicknesses, and their separation.


Targeted manipulation of the sortilin-progranulin axis rescues progranulin haploinsufficiency.
Progranulin (GRN) mutations causing haploinsufficiency are a major cause of frontotemporal lobar degeneration (FTLD-TDP). Recent discoveries demonstrating sortilin (SORT1) is a neuronal receptor for PGRN endocytosis and a determinant of plasma PGRN levels portend the development of enhancers targeting the SORT1-PGRN axis. We demonstrate the preclinical efficacy of several approaches through which impairing PGRN's interaction with SORT1 restores extracellular PGRN levels. Our report is the first to demonstrate the efficacy of enhancing PGRN levels in iPSC neurons derived from frontotemporal dementia (FTD) patients with PGRN deficiency. We validate a small molecule preferentially increases extracellular PGRN by reducing SORT1 levels in various mammalian cell lines and patient-derived iPSC neurons and lymphocytes. We further demonstrate that SORT1 antagonists and a small-molecule binder of PGRN₅₈₈₋₅₉₃, residues critical for PGRN-SORT1 binding, inhibit SORT1-mediated PGRN endocytosis. Collectively, our data demonstrate that the SORT1-PGRN axis is a viable target for PGRN-based therapy, particularly in FTD-GRN patients.


A combined culture-based methodology for surveillance of hospital-acquired infections and timely remedial action in a tertiary care hospital in Delhi, India.
The mortality, morbidity and economic loss accompanying hospital acquired infection (HAI) needs constant surveillance. The usefulness of an integrated culture-based watch on the incidence of HAI was established at a tertiary care, multidisciplinary hospital in Delhi. Isolates from all culture-positive hospitalized cases including antibiotic susceptibility profiles were shared instantly with clinicians and nursing personnel. HAI categorization was based on the interval between hospital admission and isolation of a pathogen. The monthly incidence of HAI was calculated as episodes per 100 admissions, while the nature of HAI isolates including infection sites were computed annually. During 2008 to 2010, the monthly HAI rates ranged from 0 to 0.9 per 100 admissions, with no significant difference in annual incidence (P = 0.45, Kruskal Wallis). There was a subtle but insignificant change in HAI localization in urine, blood, pulmonary tissues or surgical sites of the patients (P = 0.104). While 197 of the 229 isolates were Gram-negative, Klebsiella species, E Coli, Pseudomonas aeroginosa, there were 32 methicillin-sensitive Staphylococcus aureus (P < 0.0001). The combined strategy of constant surveillance of all culture-positive hospitalized cases and dialogues with clinicians, and nursing personnel enabled a monitoring of HAI incidence and ensured freedom from any spikes of HAI episodes or their cross infection, it was possible to monitor the incidence of HAI and to ensure there were no episodes on any spikes or a cross-infection. An identical nonstop approach should result in an earlier detection and management of HAI.


Increased Succinate Accumulation Induces ROS Generation in In Vivo Ischemia/Reperfusion-Affected Rat Kidney Mitochondria.
Mitochondria are recognized as main reactive oxygen species (ROS) producers, involving ROS generation by mitochondrial complexes I and III. Lately, the focus has been shifting to the ROS generation by complex II. Contribution of complex II (SDH) to ROS generation still remains debatable, especially in in vivo settings. Moreover, it is not completely defined at what time of ischemia the first alterations in mitochondria and the cell begin, which is especially important with renal arterial clamping in vivo during kidney surgery, as it predicts the postischemic kidney function. The aim of this study on an in vivo rat kidney ischemia/reperfusion model was to determine if there is a connection among (a) duration of kidney ischemia and mitochondrial dysfunction and (b) succinate dehydrogenase activity, succinate accumulation, and ROS generation in mitochondria at low and saturating succinate concentrations. Our results point out that (1) mitochondrial disturbances can occur even after 30 min of kidney ischemia/reperfusion in vivo and increase progressively with the prolonged time of ischemia; (2) accumulation of succinate in cytosol after ischemia/reperfusion correlated with increased H2O2 generation mediated by complex II, which was most noticeable with physiological succinate concentrations; and (3) ischemia/reperfusion induced cell necrosis, indicated by the changes in LDH activity. In conclusion, our new findings on the accumulation of succinate in cytosol and changes in SDH activity during kidney ischemia/reperfusion may be important for energy production after reperfusion, when complex I activity is suppressed. On the other hand, an increased activity of succinate dehydrogenase is associated with the increased ROS generation, especially with physiological succinate concentrations. All these observations play an important role in understanding the mechanisms which occur in the early phase of ischemia/reperfusion injury in vivo and may provide new ideas for novel therapeutic approaches or injury prevention; therefore, more detailed studies are necessary in the future.


Safety and efficacy of risedronate in reducing fracture risk in osteoporotic women aged 80 and older: implications for the use of antiresorptive agents in the old and oldest old.
To determine the efficacy of risedronate in reducing vertebral fracture risk in women aged 80 and older with osteoporosis. Pooled analysis of data from three randomized, double-blind, controlled, 3-year-fracture-endpoint trials conducted from November 1993 to April 1998: Hip Intervention Program (HIP), Vertebral Efficacy with Risedronate Therapy-Multinational (VERT-MN), and VERT-North America (NA). Office-based practices, research centers, and osteoporosis clinics in Europe, North America, and Australia. Osteoporotic (femoral neck bone mineral density T-score < -2.5 standard deviations or at least one prevalent vertebral fracture) women aged 80 and older. Patients received placebo (n=688) or risedronate 5 mg/d (n=704) for up to 3 years. All patients received 1,000 mg/d calcium and, if baseline levels were low, up to 500 IU/d vitamin D. Cumulative incidence of new vertebral fractures. After 1 year, the risk of new vertebral fractures in the risedronate group was 81% lower than with placebo (95% confidence interval=60-91%; P<.001). The number of women who needed to be treated to prevent one new vertebral fracture after 1 year was 12. This early onset of efficacy was consistent across the clinical programs, and antifracture efficacy was confirmed over 3 years. Risedronate was well tolerated, with a safety profile comparable with that of placebo. These findings provide the first evidence that, even in the very old, reducing bone resorption rate remains an effective treatment strategy for osteoporosis. Because each therapeutic agent used for the treatment of osteoporosis may have unique characteristics, the observations made in this study should not be assumed to apply to other bisphosphonates.


Impact of robotic surgery on obstetric-gynecologic resident training.
To compare the volume and type of surgical techniques for hysterectomies performed prior to and after the introduction of robotic surgery at our institution and to assess the potential impact on obstetric-gynecologic resident training. A retrospective study examined the number and types of hysterectomies performed at our institution during the 18 months prior to, and the 18 months after, the introduction of a robotic surgical system. Procedures performed during both time periods were compared by number and percentage using the chi2 or Fisher's exact test for counts < 5. A total of 903 hysterectomies were performed from July 1, 2005, to July 1, 2008. There were 444 hysterectomies in the prerobotic surgical system group and 459 hysterectomies in the postrobotic surgical system group. There was a statistically significant decrease in the number of laparoscopically assisted vaginal hysterectomies (94 vs. 36; p < 0.001) and total abdominal hysterectomies (249 vs. 203; p < 0.001) performed. This study demonstrated a significant impact on the volume and type of surgical techniques for hysterectomies performed prior to and after the introduction of robotic surgery at our institution. This observation may have direct consequences for obstetric-gynecologic resident surgical experience.


Prediction of HIV-1 sensitivity to broadly neutralizing antibodies shows a trend towards resistance over time.
Treatment with broadly neutralizing antibodies (bNAbs) has proven effective against HIV-1 infections in humanized mice, non-human primates, and humans. Due to the high mutation rate of HIV-1, resistance testing of the patient's viral strains to the bNAbs is still inevitable. So far, bNAb resistance can only be tested in expensive and time-consuming neutralization experiments. Here, we introduce well-performing computational models that predict the neutralization response of HIV-1 to bNAbs given only the envelope sequence of the virus. Using non-linear support vector machines based on a string kernel, the models learnt even the important binding sites of bNAbs with more complex epitopes, i.e., the CD4 binding site targeting bNAbs, proving thereby the biological relevance of the models. To increase the interpretability of the models, we additionally provide a new kind of motif logo for each query sequence, visualizing those residues of the test sequence that influenced the prediction outcome the most. Moreover, we predicted the neutralization sensitivity of around 34,000 HIV-1 samples from different time points to a broad range of bNAbs, enabling the first analysis of HIV resistance to bNAbs on a global scale. The analysis showed for many of the bNAbs a trend towards antibody resistance over time, which had previously only been discovered for a small non-representative subset of the global HIV-1 population.


The shorter the better: reducing fixed primer regions of oligonucleotide libraries for aptamer selection.
Oligonucleotide aptamers are highly structured DNA or RNA molecules, or modified versions thereof, that can bind to targets with specific affinities comparable to antibodies. They are identified through an in vitro selection process termed SELEX (Systematic Evolution of Ligands by EXponential enrichment) to recognize a wide variety of targets, from small molecules to proteins, and from cultured cells to whole organisms. Aptamers possess a number of desirable properties, such as ease of synthesis, stability, robustness, and lack of immunogenicity. Standard SELEX libraries require two primers, one on each side of a central random domain, to amplify the target-bound sequences via PCR or RT-PCR. However, these primer sequences cause non-specific binding by their nature, and have been reported to lead to large numbers of false-positive binding sequences, or to interfere with binding of sequences within the random regions. This review is focused on methods which have been developed to eliminate fixed primer interference during the SELEX process.


Associations of big endothelin-1 and C-reactive protein in atrial fibrillation.
Atrial fibrillation (AF) is associated with inflammation and endothelial dysfunction. However, the association between inflammation (as indexed by high-sensitivity C-reactive protein, hs-CRP) and endothelial function [as indexed by big endothelin-1 (ET-1)] in AF patients remains unclear. We enrolled 128 patients with lone AF, among which 83 had paroxysmal AF, and 45 had persistent AF. Eighty-two age- and gender-matched controls of paroxysmal supraventricular tachycardia without AF history were evaluated. Plasma hs-CRP, big ET-1 levels and other clinical characteristics were compared among the groups. Patients with persistent AF had higher hs-CRP concentrations than those with paroxysmal AF (P < 0.05), both groups had higher hs-CRP level than controls (P < 0.05). Patients with persistent AF had higher big ET-1 level than those with paroxysmal AF, although the difference did not reach the statistical significance (P > 0.05), and both groups had higher big ET-1 levels than controls (P < 0.05). Multiple regression analyses revealed hs-CRP as an independent determinant of AF (P < 0.001). Further adjusted for big ET-1, both big ET-1 and hs-CRP were independent predictors for AF (P < 0.001), but the odds ratio for hs-CRP in predicting AF attenuated from 8.043 to 3.241. There was a positive relation between hs-CRP level and big ET-1 level in paroxysmal AF patients (r = 0.563, P < 0.05), however, the relationship in persistent AF patients was poor (r = 0.094, P < 0.05). Both plasma hs-CRP and big ET-1 levels are elevated in lone AF patients, and are associated with AF. In paroxysmal lone AF patients, there were significant positive correlations between plasma hs-CRP level and big ET-1 level.


Spatial analysis of canine leishmaniasis in an area of transmission of the semi-arid region of the State of Paraíba, Brazil.
Visceral leishmaniasis is a widely distributed zoonosis and canine infection is an important indicator of risk for the occurrence of the disease in humans. The goal of this analysis was to study the spatial clustering of canine leishmaniasis (CL) in the municipality of Santa Luzia, state of Paraíba. For this, 749 samples of canine plasma were tested using three serological tests. The dog was considered positive if it reacted in two serological tests. The location of the residences was performed with a Global Positioning System receiver (GPS Garmin® eTrex 30), and used to perform georeferencing and spatial analysis. The prevalence of CL was 15.49% and it was observed that most cases of the urban area were concentrated in the Frei Damião neighborhood, on the outskirts of the city, where a high-risk cluster for the occurrence of the disease was formed (p = 0.02; RR = 2.48). No statistically significant cluster was observed in rural areas. CL is widely distributed in the municipality of Santa Luzia in a heterogeneous manner and with a tendency to urbanization. The areas identified with high prevalence and highest risk should be prioritized to maximize the efficiency of the Visceral Leishmaniasis Surveillance and Control Program and minimize the chance of new canine and human cases.


Variational Dynamic for Self-Supervised Exploration in Deep Reinforcement Learning.
Efficient exploration remains a challenging problem in reinforcement learning, especially for tasks where extrinsic rewards from environments are sparse or even totally disregarded. Significant advances based on intrinsic motivation show promising results in simple environments but often get stuck in environments with multimodal and stochastic dynamics. In this work, we propose a variational dynamic model based on the conditional variational inference to model the multimodality and stochasticity. We consider the environmental state-action transition as a conditional generative process by generating the next-state prediction under the condition of the current state, action, and latent variable, which provides a better understanding of the dynamics and leads to a better performance in exploration. We derive an upper bound of the negative log likelihood of the environmental transition and use such an upper bound as the intrinsic reward for exploration, which allows the agent to learn skills by self-supervised exploration without observing extrinsic rewards. We evaluate the proposed method on several image-based simulation tasks and a real robotic manipulating task. Our method outperforms several state-of-the-art environment model-based exploration approaches.


Apolipoprotein B mRNA editing in 12 different mammalian species: hepatic expression is reflected in low concentrations of apoB-containing plasma lipoproteins.
Two different isoproteins are encoded by the apolipoprotein (apo) B gene, apoB-48 and apoB-100. ApoB-48, core component of intestinally derived chylomicrons, has an accelerated plasma turnover as compared with the full-length protein apoB-100. A posttranscriptional modification of the apoB mRNA by conversion of cytidine into uridine at nucleotide position 6666 changes the genomically encoded glutamine codon CAA at amino acid residue 2153 into a translational stop codon UAA. This mRNA editing explains the formation of the truncated isoform apoB-48. In the present investigation editing of apoB mRNA in liver and intestine from 12 different mammalian species was measured by a quantitative primer extension analysis of reverse-transcribed and polymerase chain reaction- (PCR) amplified apoB mRNA in order to determine whether i) editing of apoB mRNA is generally restricted to the intestine or may also be found in the liver of other species than rodents, and ii) hepatic expression of apoB mRNA editing influences lipoprotein concentrations in plasma. Intestinal apoB mRNA was edited at high levels in all species, 40% in sheep, 73% in horse, 82% in pig, 84% in dog, 84% in cat, 87% in guinea pig, 88% in rat, 89% in mouse, and > 90% in human, monkey, cow, and rabbit. In liver apoB mRNA was edited to 18% in dog, to 43% in horse, to 62% in rat, and to 70% in mouse. Low levels of editing below 1% were detected in liver of rabbit and guinea pig. In contrast, hepatic apoB mRNA from human, monkey, pig, cow, sheep, and cat liver was not edited. The results of the primer extension analysis were confirmed by cloning and sequencing of the PCR products from dog, horse, cat, guinea pig, sheep, and cow for all of which the apoB cDNA sequence had not been established by previous investigations. Primer extension analysis of apoB mRNA from dog intestine and dog liver indicated C/U editing at C6655 in addition to C6666. Cloning and sequencing of apoB cDNA from dog liver and intestine confirmed additional C/U editing at C6655 which changes ACA for threonine at amino acid residue 2149 into AUA for isoleucine. Synthesis and secretion of apoB-48-containing lipoproteins from liver was demonstrated by pulse labeling of freshly isolated horse hepatocytes and immunoprecipitation with apoB-specific antibodies or density gradient ultracentrifugation. The concentrations of VLDL, LDL, and HDL in all species were determined after fractionation by density gradient ultracentrifugation.(ABSTRACT TRUNCATED AT 400 WORDS)


Immigration status and end-stage kidney disease: Role of policy and access to care.
Immigration status is an important mitigating factor in determining the provision of dialysis and kidney-related care. Immigrants make up the largest uninsured group in the country. For immigrants with end-stage kidney disease (ESKD), dialysis access varies by insurance type and by state, leading to great variability in the availability of kidney care. In some states, undocumented immigrants may only qualify for hemodialysis when critically ill (emergency hemodialysis), which is associated with higher mortality, hospital length of stay, and cost, in addition to an emotional burden on patients, their caregivers, and healthcare professionals. Barriers to effective care for immigrants with ESKD include immigration status, insurance access, and availability of pre-end stage kidney disease care, vascular access, and transplant. Effective strategies for improving dialysis care for immigrants include advocacy at the state and federal level, broadening definitions under Emergency Medicaid, and improving benefits for home therapies and transplantation options.


Extrapontine myelinolysis in a nine-year-old child.
Extrapontine myelinolysis in the pediatric age group is very rare. We report a nine-year-old girl with the classical clinical syndrome of pontine and extrapontine myelinolysis following liver trauma due to a traffic accident. She was referred to our hospital for further investigation of convulsions due to severe postoperative hyponatremia. She had no hypoxic event or other identifiable cause for the neurological symptoms. Neurological deterioration began about two days after correction of hyponatremia and followed a period of temporary improvement in hyponatremic encephalopathy. Diagnosis of extrapontine myelinolysis was confirmed with the identification of typical features on magnetic resonance imaging. The rapid correction of hyponatremia seemed the most likely cause since other biochemical tests including liver function tests were all within normal ranges. The long term clinical outcome was good. It is important to carefully monitor the rate of correction in electrolyte disturbances, and to consider the individual variation in response to therapy.


The Notch pathway regulates the bone gain induced by PTH anabolic signaling.
Parathyroid hormone (PTH) signaling downstream of the PTH 1 receptor (Pth1r) results in both bone anabolic and catabolic actions by mechanisms not yet fully understood. In this study, we show that Pth1r signaling upregulates the expression of several components of the Notch pathway and that Notch signals contribute to the catabolic actions of PTH in bone. We found that constitutive genetic activation of PTH receptor signaling in osteocytes (caPth1rOt ) or treatment with PTH daily increased the expression of several Notch ligands/receptors in bone. In contrast, sustained elevation of endogenous PTH did not change Notch components expression. Deletion of the PTH receptor or sclerostin overexpression in osteocytes abolished Notch increases by PTH. Further, deleting the canonical Notch transcription factor Rbpjk in osteocytes decreased bone mass and increased resorption and Rankl expression in caPth1rOt mice. Moreover, pharmacological bone-targeted Notch inhibition potentiated the bone mass gain induced by intermittent PTH by reducing bone resorption and preserving bone formation. Thus, Notch activation lies downstream of anabolic signaling driven by PTH actions in osteocytes, and Notch pharmacological inhibition maximizes the bone anabolic effects of PTH.


The Combination of icariin and constrained dynamic loading stimulation attenuates bone loss in ovariectomy-induced osteoporotic mice.
Osteoporosis is a disease characterized by low bone mass and progressive destruction of bone microstructure, resulting in increasing the risk of fracture. Icariin (ICA) as a phytoestrogen shows osteogenic effects, and the mechanical stimulation has been demonstrated the improving effect on osteoporosis. The objective of this study was to investigate the effect of ICA in combination with constrained dynamic loading (CDL) stimulation on osteoporosis in ovariectomized (OVX) mice. The serum hormone levels, bone turnover markers, trabecular architecture, ulnar biomechanical properties, and the expression of osteoblast-related gene (alkaline phosphatase, ALP; osteocalcin, OCN; bone morphogenetic protein-2, BMP-2; Collagen I (α1), COL1; osteoprotegerin, OPG) and osteoclast-related genes (receptor activators of NF-κB ligand, RANKL; tartrate-resistant acid phosphatase, TRAP) were analyzed. The results showed that ICA + CDL treatment could increase the osteocalcin (20.85%), estradiol levels (20.61%) and decrease the TRAP activity (26.27%) significantly than CDL treatment. The combined treatment attenuated bone loss and biomechanical decrease more than single use of CDL treatment. ICA + CDL treatment significantly up-regulated the level of osteoblast-related gene expression and down-regulated the osteoclast-related genes expression; moreover, the combined treatment increased the ratio of OPG/RANKL significantly compared to ICA (72.83%) or CDL (65.63%) treatment alone. The present study demonstrates that icariin in combination with constrained dynamic loading treatment may have a therapeutic advantage over constrained dynamic loading treatment alone for the treatment of osteoporosis, which would provide new evidence for the clinical treatment of osteoporosis. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1415-1424, 2018.


Bladder Capacity is a Biomarker for a Bladder Centric versus Systemic Manifestation in Interstitial Cystitis/Bladder Pain Syndrome.
Interstitial cystitis/bladder pain syndrome presents a significant clinical challenge due to symptom heterogeneity and the myriad associated comorbid medical conditions. We recently reported that diminished bladder capacity may represent a specific interstitial cystitis/bladder pain syndrome subphenotype. The objective of this study was to investigate the relationship between anesthetic bladder capacity, and urological and nonurological clinical findings in a cohort of patients with interstitial cystitis/bladder pain syndrome who had undergone therapeutic urinary bladder hydrodistention. This is a retrospective chart review of prospectively collected data on women diagnosed with interstitial cystitis/bladder pain syndrome between 2011 and 2015 who underwent bladder hydrodistention. Assessments in each patient included a detailed history and physical examination, ICPI (Interstitial Cystitis Problem Index), ICSI (Interstitial Cystitis Symptom Index) and PUF (Pelvic Pain and Urgency/Frequency Patient Symptom Scale). Bladder capacity was determined during bladder hydrodistention with the patient under general anesthesia. Mean age was 45.8 years and mean bladder capacity was 857 ml in the 110 enrolled patients. We found a significant inverse correlation between bladder capacity and scores on 3 gold standard interstitial cystitis/bladder pain syndrome metrics, including ICPI (p = 0.0014), ICSI (p = 0.0022) and PUF (p = 0.0009) as well as urination frequency (p = 0.0025). Women with higher bladder capacity were significantly more likely to report depression (p = 0.0059) and irritable bowel syndrome (p = 0.022). Low bladder capacity while under anesthesia was significantly associated with high symptom scores on 3 validated interstitial cystitis/bladder pain syndrome questionnaires as well as with urinary frequency. However, it was not associated with depression or other common systemic pain problems. These results suggest that low bladder capacity is a marker for a bladder centric manifestation of interstitial cystitis/bladder pain syndrome.


Tracheostomy Outcomes in COVID-19 Patients in a Low Resource Setting.
COVID-19 predominately affects safety net hospitals. Tracheostomies improve outcomes and decrease length of stay for COVID-19 patients. Our objectives are to determine if (1) COVID-19 tracheostomies have similar complication and mortality rates as non-COVID-19 tracheostomies and (2) to determine the effectiveness of our tracheostomy protocol at a safety net hospital. Patients who underwent tracheostomy at Los Angeles County Hospital between August 2009 and August 2020 were included. Demographics, SARS-CoV-2 status, body mass index (BMI), Charlson Co-morbidity Index (CCI), length of intubation, complication rates, decannulation rates, and 30-day all-cause mortality versus tracheostomy related mortality rates were all collected. Thirty-eight patients with COVID-19 and 130 non-COVID-19 patients underwent tracheostomies. Both groups were predominately male with similar BMI and CCI, though the COVID-19 patients were more likely to be Hispanic and intubated for a longer time (P = .034 and P < .0001, respectively). Both groups also had similar, low intraoperative complications at 2% to 3% and comparable long-term post-operative complications. However, COVID-19 patients had more perioperative complications within 7 days of surgery (P < .01). Specifically, they were more likely to have perioperative bleeding at their tracheostomy sites (P = .03) and long-term post-operative mucus plugging (P < .01). However, both groups had similar 30-day mortality rates. There were no incidences of COVID-19 transmission to healthcare workers. COVID-19 tracheostomies are safe for patients and healthcare workers. Careful attention should be paid to suctioning to prevent mucus plugging. 3.


Novel antitumor and radioprotective sulfonamides containing pyrrolo [2,3-d]pyrimidines.
Several sulfonamides having pyrrole (5a-c, 8, 11b-19, 23, 24), pyrrolo[2,3-d] pyrimidine (6, 7, 10, 20, 21, 25) and pyrrolo[2,3-b]pyridine (22) were synthesized and evaluated for their antitumor and radioprotective activities. The structure of the synthesized compounds was elucidated by elemental analyses and spectral data. Compounds 5a, 16, 17, 19, and 23 displayed more potent antitumor activities than the reference drug, doxorubicin. On the other hand compounds 19, 23 and 25 exhibited radioprotective activities.


Mechanisms responsible for surfactant changes in sepsis-induced lung injury.
Pulmonary surfactant is altered in sepsis, and these changes contribute to the predisposition of septic lungs to subsequent insults, ultimately leading to acute lung injury. Specifically, the total amount of surfactant is lower in sepsis, mainly due to decreased small aggregate (SA) surfactant pools. The amount of large aggregate (LA) surfactant is not altered. To evaluate the mechanisms responsible for these alterations, trace doses of tritium-labelled dipalmitoylphosphatidylcholine (3H-DPPC)-labelled LA were instilled intratracheally into adult rats 20 hrs after caecal ligation and perforation (CLP) or sham surgery. Animals were sacrificed at 0, 1 and 4 h after instillation and recovery of 3H-DPPC in alveolar macrophages (AM), LA and SA was measured. In separate in vitro experiments, AM isolated from CLP/sham rats were incubated with LA or SA isolated from normal animals to evaluate the uptake of these aggregates into the AM. Results showed increased surfactant radioactivity associated with AM of CLP animals compared with sham animals both in vivo and in vitro. In addition, more 3H-DPPC label remained in LA forms in the CLP animals in vivo compared with sham. These findings indicate that differences in surfactant aggregate uptake and large aggregate conversion occur in septic lungs, resulting in changes in surfactant pools.


Variation of systolic blood pressure in rats exposed to cadmium and nickel.
This research was intended to verify separate and combined effects of cadmium and nickel on blood pressure in rats. After cadmium chloride (CdCl(2)) and nickel chloride (NiCl(2)) were administered individually and combined by intraperitoneal injection to rats daily for a week, systolic blood pressure of the tails were measured at 1, 5, 10, 20, and 30 days after administration. Each substance was injected into rats with 0.1 mg/kg x bw and 1.0 mg/kg x bw concentrations. After 0.1 mg/kg x bw CdCl(2) was injected, statistically significant differences from the control group (only saline) were found at 1, 5, and 10 days. After 0.1 mg/kg x bw NiCl(2) was injected, no statistically significant differences from the control group were found. After 0.1 mg/kg x bw CdCl(2) and 0.1 mg/kg x bw NiCl(2) were injected combined simultaneously, statistically significant differences from the control group were found at 1, 5, and 10 days, compared with the 0.1 mg/kg x bw CdCl(2) group after 5 days and the 0.1 mg/kg x bw NiCl(2) group after 5 and 10 days. After 1.0 mg/kg x bw CdCl(2) was injected, statistically significant differences from the control group were found at 1, 5, 10, and 20 days. After 1.0 mg/kg x bw NiCl(2) was injected, statistically significant differences from the control group were found at 1 and 5 days. After 1.0 mg/kg x bw CdCl(2) and 1.0 mg/kg x bw NiCl(2) were injected combined, statistically significant differences were found at 1, 5, 10, 20, and 30 days, compared with 1.0 mg/kg x bw CdCl(2) at 10, 20, and 30 days and 1.0 mg/kg x bw NiCl(2) at 5, 10, 20, and 30 days. It was found that the effect of CdCl(2) on blood pressure was much more than that of NiCl(2) and the combination of CdCl(2) and NiCl(2) in high concentration delayed recovery of blood pressure.


Assuming a Pharmacy Organization Leadership Position: A Guide for Pharmacy Leaders.
Important and influential pharmacy organization leadership positions, such as president, board member, or committee chair, are volunteer positions and require a commitment of personal and professional time. These positions provide excellent opportunities for leadership development, personal promotion, and advancement of the profession. In deciding to assume a leadership position, interested individuals must consider the impact on their personal and professional commitments and relationships, career planning, employer support, current and future department projects, employee support, and personal readiness. This article reviews these factors and also provides an assessment tool that leaders can use to determine their readiness to assume leadership positions. By using an assessment tool, pharmacy leaders can better understand their ability to assume an important and influential leadership position while achieving job and personal goals.


Heterogeneity of GNAQ/11 mutation inversely correlates with the metastatic rate in uveal melanoma.
To determine whether the GNAQ/11 mutation correlated with the outcome of patients with uveal melanoma (UM) when genetic heterogeneity was considered. We performed a retrospective study of sixty-seven patients with UM. The heterogeneity of GNAQ/11 was examined by using droplet digital PCR. The correlation between metastasis and heterogeneity of the GNAQ/11 mutation was analysed. Disease free survival curves were constructed using the Kaplan-Meier method, and the Wilcoxon log-rank test was used to compare the curves. The GNAQ/11 mutation ratio was varied between each case. Among these patients, 28.35% of them harboured homogeneous mutation of GNAQ/11, 62.69% present heterogeneous mutation and 8.96% didn't present either GNAQ or GNA11 mutation. The tumour with heterogeneous mutation of GNAQ/11 has a higher metastatic rate than that with homogeneous mutation (13/29 vs 1/18, p=0.027). In Kaplan-Meier analysis, metastasis-free survival was not significantly associated with either homogeneous or heterogeneous mutation of GNAQ/11. The mutation ratio of GNAQ/11 in UM was quite variable. The tumour with heterogeneous mutation of GNAQ/11 is more likely to develop a poor prognosis than that with homogeneous mutation of GNAQ/11.


Prescreen evaluation of situs inversus patients.
Situs inversus is a congenital visceral malrotation anomaly that occurs in approximately 2 per 10,000 live births, but it may go unrecognized until discovered during emergency surgery. The differential diagnosis in situs inversus patients may not be readily seen in the emergency setting. Historical symptoms include reversed locations for common physical complaints, whereas physical signs can be used to diagnose and treat these patients. Laboratory data may also be used to diagnose and treat patients with this anomaly. This study was prompted by a postmortem investigation of a patient with situs inversus and dextrocardia. Several other cases of congenital malrotation, with attention to anatomical variants coupled with medical data, provide guidelines in prescreen evaluation and medical/surgical treatment of similar patients. Careful attention to laboratory and radiologic findings are paramount to quality patient care and prevention of complications. Educating these patients about their malrotation would also aid in future treatment.


Analysis of Health Service Utilization and its Influencing Factors among Patients with Pneumoconiosis in China.
Pneumoconiosis, an interstitial lung disease that occurs from breathing in certain kinds of damaging dust particles, is a major occupational disease in China. Patients diagnosed with occupational pneumoconiosis can avail of free medical treatment, whereas patients without a diagnosis of occupational diseases cannot not claim free medical treatment in most provinces from the government before 2019. This study aimed to analyze the priority of medical facility selection and its influencing factors among patients with pneumoconiosis. A total of 1,037 patients with pneumoconiosis from nine provinces in China were investigated. The health service institutions most frequently selected by the patients were county-level hospitals (37.5%). The main reason for the choice was these hospitals' close distance to the patients' homes (47.3%). The factors for the choice of health care institutions were living in the eastern region ( OR = 2.91), living in rural areas ( OR = 2.10), silicosis diagnosis ( OR = 2.44), employment in private enterprises ( OR = 2.91), smoking ( OR = 2.69), and quit smoking ( OR = 3.98). The diagnosis, treatment, and rehabilitation therapy of pneumoconiosis should be enhanced in primary medical institutions.


Raising the cycling stability of aqueous lithium-ion batteries by eliminating oxygen in the electrolyte.
Aqueous lithium-ion batteries may solve the safety problem associated with lithium-ion batteries that use highly toxic and flammable organic solvents, and the poor cycling life associated with commercialized aqueous rechargeable batteries such as lead-acid and nickel-metal hydride systems. But all reported aqueous lithium-ion battery systems have shown poor stability: the capacity retention is typically less than 50% after 100 cycles. Here, the stability of electrode materials in an aqueous electrolyte was extensively analysed. The negative electrodes of aqueous lithium-ion batteries in a discharged state can react with water and oxygen, resulting in capacity fading upon cycling. By eliminating oxygen, adjusting the pH values of the electrolyte and using carbon-coated electrode materials, LiTi(2)(PO(4))(3)/Li(2)SO(4)/LiFePO(4) aqueous lithium-ion batteries exhibited excellent stability with capacity retention over 90% after 1,000 cycles when being fully charged/discharged in 10 minutes and 85% after 50 cycles even at a very low current rate of 8 hours for a full charge/discharge offering an energy storage system with high safety, low cost, long cycling life and appropriate energy density.


Image-guided robotic radiosurgery (CyberKnife) for pancreatic insulinoma: is laparoscopy becoming old?
Insulinomas constitute about 25% of endocrine pancreatic tumors. Laparoscopic surgery is the treatment of choice. However, pancreas-related complications rate is very high, even in experienced hands, ranging up to 37%. Alternative procedures such as embolization with trisacryl have not been accepted by the surgical community. Image-guided robotic radiosurgery or stereotactic radiosurgery (CyberKnife) is a minimally invasive procedure delivering large doses of ionizing radiation to a well-defined target. CyberKnife radiosurgery is successfully used in brain cancer, lung cancer, prostate cancer, liver metastases, kidney cancer, and pancreatic cancer. The authors present the first case to their knowledge of a benign functioning insulinoma successfully treated by a CyberKnife technique with a 3-year follow-up.


Reconstructing embedding spaces of coupled dynamical systems from multivariate data.
A method for reconstructing dimensions of subspaces for weakly coupled dynamical systems is offered. The tool is able to extrapolate the subspace dimensions from the zero coupling limit, where the division of dimensions as per the algorithm is exact. Implementation of the proposed technique to multivariate data demonstrates its effectiveness in disentangling subspace dimensionalities also in the case of emergent synchronized motions, for both numerical and experimental systems.


Comparison of laboratory and in situ sediment bioassays using Corophium volutator.
Bioassays with the marine amphipod Corophium volutator were performed simultaneously in situ and in the laboratory using sediments sampled from the in situ locations. In most cases, the in situ response was significantly higher compared to the laboratory response. This difference was not caused by direct influence of the use of the field chamber on Corophium sp., nor was the difference caused by the overlying water used. Experiments showed homogenization can affect the toxicity of a sediment, but not in such a way that it can completely explain the difference between the response in situ and in the laboratory. Possible explanatory factors are harbor activity, storms, and temperature. To reduce the influence of some of these factors, the best period of the year to perform in situ bioassays with C. volutator is May, June, or September.


Endoventriculoplasty of the Left Ventricle for Congenital Diverticulum.
Congenital left ventricular diverticulum is an extremely rare heart defect. Here, we report a case of successful endoventriculoplasty using a Dacron patch in an infant who was followed up for one year.


[Hand Osteoarthritis].
Hand osteoarthritis Symptomatic hand osteoarthritis (oa) is a highly prevalent disease affecting about 10 % of the general population. It causes pain, stiffness, impaired physical function and quality of life, and aesthetic discomfort. In some patients, the global burden of the disease can be as severe as in rheumatoid arthritis. Guidelines recommend a combina¬tion of pharmacological and non-pharmacological ap¬proaches for managing hand oa.


Metered dose inhaler add-on devices: is the inhaled mass of drug dependent on the size of the infant?
Limited cooperation and low tidal volumes in infants make aerosol therapy difficult. We measured the amount of drug delivered from two baby spacer devices especially developed for use in infants. Designed as a randomized crossover study, aerolized budesonide from a pressurized metered dose inhaler (pMDI) was collected in the inspiratory filter interposed between the face mask and the spacer in 13 infants aged from 2 to 19 months old. The study was performed in connection with pulmonary function testing with a plethysmograph, and the children were sedated with cloral hydrate. Two small-volume baby spacer devices were used: a Babyhaler spacer (GlaxoWellcome, Hertfordshire, UK) made of polycarbonate with a volume of 350 mL and a built-in dead space of 40 mL and a NebuChamber spacer (AstraZeneca, Lund, Sweden) made of stainless steel with a volume of 250 mL and no dead space. Budesonide delivery from the NebuChamber was significantly higher than from the Babyhaler: 38.2% (range, 28.3%-47.5%) of the nominal dose versus 12% (range, 3.3%-21.25%) of the nominal dose of 400 micrograms of budesonide (P = 0.002). The inhaled mass of budesonide from the Babyhaler correlated significantly with skin surface area (r = 0.68, P = 0.018), weight (r = 0.66, P = 0.019), height (r = 0.69; P = 0.017), tidal volume (r = 0.82; P = 0.004), and minute volume (r = 0.67; P = 0.019). No correlations were found between these variables and the inhaled mass of budesonide from the NebuChamber. The results indicate that the design of the NebuChamber spacer affords stable drug delivery in infants and that a large variability in the inhaled mass of drug may be found when infants are inhaling from different baby spacers.


Photophysical properties of quinones and their interaction with the photosynthetic reaction centre.
Photophysical properties of tetramethyl-1,4-benzoquinone (TMBQ) and 2,6-dimethoxy-1,4-benzoquinone (DMOBQ) in solution and their interactions with the photosynthetic reaction centre (RC) isolated from the photosynthetic bacterium Rhodobacter sphaeroides have been investigated in this work. For these two benzoquinone derivatives an efficient ISC process which leads to the population of the lowest triplet state of the molecules upon direct excitation was observed. The presence of RC does not alter the properties of the triplet state of DMOBQ suggesting that interactions are negligible; on the other side RC efficiently quenched the T1 state of TMBQ. The behavior is rationalized in terms of redox potentials of quinones and kinetic characteristics of their transients.


Perinatal activity of the hypothalamic-pituitary-gonadal axis in the lamb. IV. Testicular responsiveness to hCG from 1 through 28 days of life.
Previous studies in this laboratory have shown the existence of an early postnatal activation of the hypothalamic-pituitary-gonadal axis (HPGA) in the male lamb which was present at 2 and 4 weeks of age. In order to define more precisely the time sequence of HPGA activity, we have studied the in vivo and in vitro testicular responsiveness to human chorionic gonadotropin (hCG) of the immature lamb at 1, 3, 7, 14, 21 and 28 days of life. Plasma testosterone (T) increments (delta) after hCG were lower in 1-day-old animals than in other age groups. Testicular concentrations of T, dehydroepiandrosterone and 17-hydroxyprogesterone increased from 1 to 14 days. Testicular 17, 20 lyase activity rose significantly with age but was not influenced by hCG. hCG and dibutyryl cyclic AMP increased significantly the T production by enriched interstitial cell preparation at 1, 3, and 7 days, the greatest response being found at 7 days. hCG also increased significantly the T production at 14 days. These data suggest that the lamb testis has the capacity to respond to hCG in vivo and to various stimuli vitro from the 1st day of life and that the response reaches a plateau from 2 to 4 weeks after birth.


Necrotizing fasciitis.
Necrotizing fasciitis is a life-threatening, invasive soft-tissue infection that is characterized by widespread, rapidly developing necrosis of the subcutaneous tissue and fascia. It is more likely to occur in patients with a compromised immune system. In type I necrotizing fasciitis, anaerobes and gram-negative bacteria are predominant; in the type II form, the bacterial etiology is group A beta-hemolytic streptococci. The diagnosis must be made on the basis of clinical grounds and is characterized by rapidly developing, painful erythema that progresses to bullous formation and gangrenous necrosis.


Analysis of the HIV-1 nef gene in five intravenous drug users with long-term nonprogressive HIV-1 infection in Italy.
Great variability in the course of human immunodeficiency virus type 1 (HIV-1) infection results from a complex interplay between host and virus factors. Some of the patients with prolonged nonprogressive infection have been reported to harbor virus variants with gross deletions in the accessory nef gene that has been implicated in in vivo pathogenicity in simian and mouse models. To investigate the role of nef-deleted HIV-1 in long-term nonprogressor (LTNP) drug addicts in Italy the nef sequence from proviral DNA was analyzed from five LTNPs and five rapid progressor controls. Only small (2-12 amino acids) in-frame deletions and insertions were detected in the N-terminal polymorphic and variable regions obtained from three LTNPs and one rapid progressor. There was no evidence of premature termination of the Nef protein and all of the identified functional motifs were well conserved in both groups. Phylogenetic analysis showed interdigitation of nef sequences obtained from LTNPs and rapid progressors. The nef sequence of one LTNP, however, diverged significantly from those of the other patients. Availability of two additional blood DNA samples obtained previously from this subject allowed to detect evolution of nef at 14-17 years of HIV-1 infection, including progressive deletions. Although alterations of nef may be relatively frequent and continue to evolve in LTNPs, this study of a small number of patients does not indicate that gross deletions or loss of functional motifs play a major role in delaying or halting disease progression in infected drug abusers in Italy.


Synthesis, molecular docking, binding free energy calculation and molecular dynamics simulation studies of benzothiazol-2-ylcarbamodithioates as Staphylococcus aureus MurD inhibitors.
A new series of benzothiazol-2-ylcarbamodithioate functional compounds 5a-f has been designed, synthesized and characterized by spectral data. These compounds were screened for their in vitro antibacterial activity against strains of Staphylococcus aureus (NCIM 5021, NCIM 5022 and methicillin-resistant isolate 43300), Bacillus subtilis (NCIM 2545), Escherichia coli (NCIM 2567), Klebsiella pneumoniae (NCIM 2706) and Psudomonas aeruginosa (NCIM 2036). Compounds 5a and 5d exhibited significant activity against all the tested bacterial strains. Specifically, compounds 5a and 5d showed potent activity against K. pneumoniae (NCIM 2706), while compound 5a also displayed potent activity against S. aureus (NCIM 5021). Compound 5d showed minimum IC50 value of 13.37 μM against S. aureus MurD enzyme. Further, the binding interactions of compounds 5a-f in the catalytic pocket have been investigated using the extra-precision molecular docking and binding free energy calculation by MM-GBSA approach. A 30 ns molecular dynamics simulation of 5d/modeled S. aureus MurD enzyme was performed to determine the stability of the predicted binding conformation.


NRF2 activation by reversible KEAP1 binding induces the antioxidant response in primary neurons and astrocytes of a Huntington's disease mouse model.
Oxidative stress has been associated with pathogenesis in several diseases including Huntington's disease (HD), a neurodegenerative disorder caused by a mutation in the huntingtin gene. Oxidative stress induced reactive oxygen species (ROS) are normally controlled at the cellular level by the nuclear factor (erythroid-derived 2)-like 2 (NRF2) a transcription factor that regulates the expression of various antioxidants and detoxifying proteins. Normally NRF2 is largely inactivated in the cytoplasm by the Kelch-like ECH-associated protein 1 (KEAP1)/Cullin-3 (CUL3) mediated ubiquitination and subsequent proteosomal degradation. In the presence of ROS, KEAP1 sensor cysteines are directly or indirectly engaged resulting in NRF2 release, nuclear translocation, and activation of its target genes. Consequently the activation of NRF2 by a small-molecule drug may have the therapeutic potential to control oxidative stress by upregulation of the endogenous antioxidant responses. Here we attempted to validate the use of a reversible non-acidic KEAP1 binder (Compound 2) to activate NRF2 with better cellular activity than similar acidic compounds. When tested head to head with sulforaphane, a covalent KEAP1 binder, Compound 2 had a similar ability to induce the expression of genes known to be modulated by NRF2 in neurons and astrocytes isolated from wild-type rat, wild type mouse and zQ175 (an HD mouse model) embryos. However, while sulforaphane also negatively affected genes involved in neurotoxicity in these cells, Compound 2 showed a clean profile suggesting its mode of action has lower off-target activity. We show that Compound 2 was able to protect cells from an oxidative insult by preserving the ATP content and the mitochondrial potential of primary astrocytes, consistent with the hypothesis that neurotoxicity induced by oxidative stress can be limited by upregulation of innate antioxidant response.


[Vulvovaginitis in young girls].
Vulvovaginitis is the most common cause of gynecological complaints in young girls. Factors which cause vulvovaginitis include, among other things, low level of sexual hormones (hypoestrogenism), the anatomical proximity of the rectum and delicate vulvar skin and vaginal mucosa. Usually vulvovaginitis in young girls is caused by non-specific factors. The aim of the study was to present the most frequent causes of vulvovaginitis in young girls.


[Choledocholithiasis and pregnancy. Hybrid laparo-endoscopic treatment in one step].
Complications associated with choledocholithiasis are uncommon during pregnancy. However, when it occurs, the morbidity and mortality related for the product and the mother increases, so a proper treatment is imperative in these patients. A 25-year-old pregnant woman on her second trimester. The current condition was started four days prior to the hospital admission with abdominal pain in the right upper quadrant with nausea and vomit.Twenty-four hours later jaundice and dark urine is observed. Physical examination shows scleral jaundice, right upper quadrant abdominal pain without peritoneal irritation. Uterus at umbilicus level without uterine activity. Uterus at umbilicus level without uterine activity. Laboratory tests showed elevated bilirubin and transaminases without leukocytosis; ultrasound reported live intrauterine unique product, with a heart rate of 128 beats per minute, gallbladder with multiple images inside that cast acoustic shadowing, and a 10 mm common bile duct dilated bile duct with dilatation of intrahepatic bile ducts. It was perform laparoscopic cholecystectomy with intraoperative cholangiography and placement of a transcystic jaguar guide for selective cannulation of the common bile duct. Intraoperative endoscopic retrograde cholangiopancreatography was performed with endoscopic stone extraction. The outcome was satisfactory with a hospital discharge at 48 hours. Current evidence has shown that the combined use of laparoscopy and therapeutic endoscopic cholangiography in one step is effective for the treatment of choledocholithiasis, decreasing the risk of complications associated with cannulation of the bile duct.


Interstitial laser coagulation for management of benign prostatic hyperplasia: long-term follow-up.
We evaluated the long-term results of transurethral interstitial laser coagulation in the treatment of benign prostatic hyperplasia (BPH) with up to 9 years of follow up at the Kurashiki Central Hospital and determined the patient characteristics that predict a favorable outcome. From December 1993 to May 1997, a total of 82 patients were enrolled in the present study. Subjective and objective voiding parameters were collected from medical records and a self-administered questionnaire was sent to the patients. Kaplan-Meier plots were constructed to assess the risk of retreatment. The mean follow-up period was 48.4 months (range, 3-108 months). A total of 59 patients (72%) did not need any additional treatment at 12 months and 30 patients (37%) did not require additional treatment during the entire follow-up period. A total of 29 patients (35%) were retreated during follow-up. Transurethral prostate resection (TURP) was performed in 18 patients (22%). The remaining 11 patients (13%) were offered additional pharmacotherapy. The minimum and median retreatment-free durations were 3 and 14 months, respectively. Seven patients died and 17 were lost to follow-up. Men aged 71 years or older had greater likelihood of requiring retreatment than those younger than 71 years (P = 0.0397). No significant differences were noted in the other baseline characteristics. Among postoperative parameters, a rate of decrease of the International Prostate Symptom Score of the patient of lower than 60% and a rate of decrease in patient quality of life of lower than 50% at 3 months were associated with greater likelihood of retreatment (P = 0.0083 and P = 0.0006, respectively). Interstitial laser coagulation is effective for the treatment of BPH. Good long-term results and an acceptably low retreatment rate render this modality an effective alternative to TURP, especially for younger patients. Short-term improvement of subjective symptoms was predictive of favorable long-term outcome.


Impaired awareness, behavior disturbance, and caregiver burden in Alzheimer disease.
Caregiver burden, the stress experienced as a result of caregiving, is determined by many factors. This study examined the contributions of the patient's awareness of memory deficit and behavioral disturbance to caregiver burden in Alzheimer disease. Participants were 41 patients with Alzheimer disease and their caregivers. Dementia severity, functional impairment, awareness of memory deficit, and behavioral disturbance were measured and examined in relation to caregiver burden. Positive correlations were found between caregiver burden and both impaired awareness of memory deficit and behavioral disturbance. Regression analyses demonstrated that both impaired patient awareness of memory deficit and behavioral disturbance contributed to caregiver burden over and above dementia severity and functional impairment. However, when both were entered together into regression equations, only behavioral disturbance contributed to caregiver burden. Of the problem behaviors, measures of disinhibition contributed most to caregiver burden. These data further our understanding of the multiple contributors to caregiver burden. We conclude that both patient awareness of memory deficit and behavioral disturbance impact caregiver burden, with behavioral disturbance making the greater contribution.


The pathogenesis and biomechanics of turf toe.
Sprain injury to the 1st metatarsophalangeal joint is referred to as turf toe. The incidence of this injury has increased over the years secondary to athletic fields being covered by artificial turf and also by increased flexibility of the toe box in athletic shoes. The pathogenesis of turf toe will be presented in this article.


Exploiting Resistive Matrix Technology to Build a Stretchable Sensorised Sock for Gait Analysis in Daily Life.
We describe the development and preliminary evaluation of an innovative low-cost wearable device for gait analysis. We have developed a sensorized sock equipped with 32 piezoresistive textile-based sensors integrated in the heel and metatarsal areas for the detection of signals associated with the contact pressures generated during walking phases. To build the sock, we applied a sensing patch on a commercially available sock. The sensing patch is a stretchable circuit based on the resistive matrix method, in which conductive stripes, based on conductive inks, are coupled with piezoresistive fabrics to form sensing elements. In our sensorized sock, we introduced many relevant improvements to overcome the limitations of the classical resistive matrix method. We preliminary evaluated the sensorized sock on five healthy subjects by performing a total of 80 walking tasks at different speeds for a known distance. Comparison of step count and step-to-step frequency versus reference measurements showed a high correlation between the estimated measure and the real one.


Internal pressure measurements during burst fracture formation in human lumbar vertebrae.
In a laboratory study, 21 human lumbar spine segments were used to determine whether intraosseous pressure increases occur during axial-compressive loading conditions under two displacement rates. To determine whether an intraosseous pressure rise is associated with burst fracture formation. Burst fractures are high-speed injuries usually associated with neurologic deficit. An internal pressure rise has been implicated as a critical factor in burst fracture formation. The authors hypothesize that the internal pressure increases with increasing input velocity. The internal pressure changes were measured in spine segments using two displacement rates: 10 mm/s (slow speed) and 2500 mm/s (high speed). Failure load and energy absorption were determined for both groups. The resultant fracture types were determined from postinjury radiographs. The initial peak internal pressure decreased from slow- to high-speed tests (P < 0.01). Overall peak pressure, failure load, and energy absorbed at failure were not significantly different. Slow-speed tests resulted in compression fractures, whereas high-speed tests resulted in burst and compression fractures. The current research did not support the current theory of burst fracture formation. There was a decrease in measured internal pressure from the slow- to high-speed groups, and burst fractures still were produced. The theory could be potentially modified to suggest that the nucleus entering the vertebral body acts as a wedge, splitting the vertebral body apart and enabling the bony fragments to be pushed into the canal space.


Comparison of trunk muscle exercises in supine position during short arm centrifugation with 1 g at centre of mass and upright in 1 g.
Spaceflight is associated with reduced antigravitational muscle activity, which results in trunk muscle atrophy and may contribute to post-flight postural and spinal instability. Exercise in artificial gravity (AG) performed via short-arm human centrifugation (SAHC) is a promising multi-organ countermeasure, especially to mitigate microgravity-induced postural muscle atrophy. Here, we compared trunk muscular activity (mm. rectus abdominis, ext. obliques and multifidi), cardiovascular response and tolerability of trunk muscle exercises performed during centrifugation with 1 g at individual center of mass on a SAHC against standard upright exercising. We recorded heart rate, blood pressure, surface trunk muscle activity, motion sickness and rating of perceived exertion (BORG) of 12 participants (8 male/4 female, 34 ± 7 years, 178.4 ± 8.2 cm, 72.1 ± 9.6 kg). Heart rate was significantly increased (p < 0.001) during exercises without differences in conditions. Systolic blood pressure was higher (p < 0.001) during centrifugation with a delayed rise during exercises in upright condition. Diastolic blood pressure was lower in upright (p = 0.018) compared to counter-clockwise but not to clockwise centrifugation. Target muscle activation were comparable between conditions, although activity of multifidi was lower (clockwise: p = 0.003, counter-clockwise: p < 0.001) and rectus abdominis were higher (clockwise: p = 0.0023, counter-clockwise: < 0.001) during centrifugation in one exercise type. No sessions were terminated, BORG scoring reflected a relevant training intensity and no significant increase in motion sickness was reported during centrifugation. Thus, exercising trunk muscles during centrifugation generates comparable targeted muscular and heart rate response and appears to be well tolerated. Differences in blood pressure were relatively minor and not indicative of haemodynamic challenge. SAHC-based muscle training is a candidate to reduce microgravity-induced inter-vertebral disc pathology and trunk muscle atrophy. However, further optimization is required prior to performance of a training study for individuals with trunk muscle atrophy/dysfunction.


A Clustering Method Unifying Cell-Type Recognition and Subtype Identification for Tumor Heterogeneity Analysis.
The rapid development of single-cell technology has opened up a whole new perspective for identifying cell types in multicellular organisms and understanding the relationships between them. Distinguishing different cell types and subtypes can identify the components of different immune cells and different tumor clones in the tumor microenvironment, which is the basic work of tumor heterogeneity analysis and can help researchers understand the mechanism of tumor immune escape. Existing algorithms treat both cell types and subtypes as populations of cells with specific gene expression patterns, which is not conducive to accurate cell typing. For that, we proposed a cell similarity metric that unifies cell type recognition and subtype identification (UCRSI), with the assumption that selectively expressed genes represent differences in underlying cell type with on/off manner, while differences in expression level represent different cell subtype with more/less manner. Our method calculates these two kinds of differences separately, and then combines them using a consensus adjacency matrix, and finally cell typing is completed using spectral clustering algorithm. The results show that UCRSI can reconstruct expert annotation of single-cell RNA sequencing datasets more robustly than existing methods. And, UCRSI is useful for analyzing tumor heterogeneity and improving visualization of large-scale cell clustering.


Human papillomavirus DNA testing for cervical cancer screening: practical aspects in developing countries.
Cervical cancer is the second most common cancer in women worldwide, and the most common cause of death from cancer in women in the developing world. Cervical cancer represents the only gynecologic cancer that can be prevented through regular screening. Although there are established screening programs in the Western world that have effectively reduced the burden of cervical cancer, these programs have relied on insensitive screening technologies that depend on the long preinvasive phase of cervical carcinogenesis. The developing world faces specific additional challenges in implementing a successful cervical cancer screening program. The association between cervical cancers and human papillomavirus (HPV) make testing for the presence of HPV DNA a valuable screening tool. This review focuses on practical aspects of the implementation and delivery of HPV testing as the primary cervical cancer screening strategy in the developing world, and attempts to offer some solutions to the real-world challenges faced in these regions.


Structural Similarities between Spinach Chloroplast and Cytosolic Class I Fructose 1,6-Bisphosphate Aldolases : Immunochemical and Amino-Terminal Amino Acid Sequence Analysis.
Immunochemical studies using polyclonal antisera prepared individually against highly purified cytosolic and chloroplast spinach leaf (Spinacia oleracea) fructose bisphosphate aldolases showed significant cross reaction between both forms of spinach aldolase and their heterologous antisera. The individual cross reactions were estimated to be approximately 50% in both cases under conditions of antibody saturation using a highly sensitive enzyme-linked immunosorbent assay. In contrast, the class I procaryotic aldolase from Mycobacterium smegmatis and the class II aldolase from yeast (Saccharomyces cerevisiae) did not cross-react with either type of antiserum. The 29 residue long amino-terminal amino acid sequences of the procaryotic M. smegmatis and the spinach chloroplast aldolases were determined. Comparisons of these sequences with those of other aldolases showed that the amino-terminal primary structure of the chloroplast aldolase is much more similar to the amino-terminal structures of class I cytosolic eucaryotic aldolases than it is to the corresponding region of the M. smegmatis enzyme, especially in that region which forms the first "beta sheet" in the secondary structure of the eucaryotic aldolases. Moreover, results of a systematic comparison of the amino acid compositions of a number of diverse eucaryotic and procaryotic fructose bisphosphate aldolases further suggest that the chloroplast aldolase belongs to the eucaryotic rather than the procaryotic "family" of class I aldolases.


Treatment of large HCC: transcatheter arterial chemoembolization combined with percutaneous ethanol injection versus repeated transcatheter arterial chemoembolization.
To compare the efficacy of transcatheter arterial chemoembolization (TACE) combined with percutaneous ethanol injection (PEI) versus repeated TACE in the treatment of large hepatocellular carcinoma (HCC). Fifty-three patients with cirrhosis and a large HCC (main tumor, 3.1-8.0 cm in diameter with no more than two daughter nodules) were enrolled in a prospective, randomized study. Twenty-six patients underwent a single TACE session followed by PEI (TACE-PEI group), whereas 27 patients underwent two to five TACE sessions (TACE group). Both groups of patients were similar with regard to liver function. Follow-up ranged from 8 to 39 months. Complete therapeutic responses were higher (P < .05) and tumor recurrences during follow-up were lower (P < .05) in the TACE-PEI group than in the TACE group. Patients in the TACE-PEI group survived longer than those in the TACE group, although the difference was not significant (P > .1). The rates of survival without recurrence were better in the TACE-PEI group than in the TACE group (P < .05). Use of a single TACE session combined with PEI is more effective than repeated TACE in the treatment of large HCC.


[Experitoneal bladder perforation due to in-dwelling urethral catheter successfully treated by urethral drainage: a case report].
Perforation of the bladder related to long-term indwelling urethral catheter is a rare and serious complication. A 85-year-old man with an indwelling urethral catheter presented severe hematuria, abdominal pain with rebound tenderness and muscular tension over the suprapubic area after the exchange of the urethral catheter. Computed tomography and cystogram revealed experitoneal bladder perforation due to indwelling catheter. Three weeks after the indwelling urethral catheter had been placed, the perforation was closed. In most cases, laparotomy and suprapubic cystostomy are performed. We describe the case of experitoneal bladder perforation successfully treated by urethral drainage.


Perforation of the Meckel's Diverticulum Following Blunt Trauma to the Abdomen.
Meckel's diverticulum (MD) is the most common congenital anomaly of the gastrointestinal tract. Most of the patients are asymptomatic and very few develop symptoms. Hemorrhage, obstruction, perforation, and inflammation are the complications that can occur in an MD. Even though hollow viscus perforation is common, perforation of the MD following blunt abdominal trauma is rare. We report a case of perforation of the MD in a 60-year-old man following a blunt abdominal trauma due to a fall from a bike, which was diagnosed promptly and managed successfully by timely operative intervention.


PIM1 is responsible for IL-6-induced breast cancer cell EMT and stemness via c-myc activation.
Interleukin-6 (IL-6) has been demonstrated to be a critical factor for breast cancer malignancy. However, the molecular mechanisms by which IL-6 induce breast cancer cells epithelial-mesenchymal-transition (EMT) and stemness remain elusive. Breast cancer cell lines T47D and MCF7 were exposed to IL-6, the expression of PIM1 was examined by quantitative real-time PCR (qRT-PCR) and western blot. Luciferase reporter assay was used to determine the transcriptional modulation of PIM1 by IL-6 and STAT3 inhibitor. Transwell assay was used to detect the invading ability of breast cancer cells induced by IL-6 or PIM1. The expressions of EMT and stemness markers were determined by qRT-PCR. IL-6 promoted PIM1 expression in a dose- and time-dependent manner, and this induction could be abrogated by inhibiting STAT3 activation, subsequently suppressing the transcriptional level of PIM1. Moreover, we noticed that knocking down of PIM1 in cells which was exposed to IL-6 significantly impaired the invasion ability and the expression of EMT and stemness markers. On the contrary, overexpression of PIM1 promoted cell invasion and upregulated the expression of EMT and stemness markers. In addition, we demonstrated that c-myc, the cofactor of PIM1, involved in the pro-oncogenic roles of PIM1. Knocking down of c-myc attenuated the PIM1-induced cell EMT and stemness. This study proposed the upregulation of PIM1 by IL-6 contributed to breast cancer cell aggressiveness and targeting PIM1 or c-myc could be novel approaches for breast cancer treatment.


Phospholipase-C and Na-K ATPase activation by cyclosporine and FK506 in LLC-PK1, cells. Possible implications in blood pressure regulation.
Enhanced Na+ and water reabsorption by proximal tubular epithelial cells plays an important role in the development of systemic hypertension associated with cyclosporine immunosuppression. Since such Na+ reabsorption is subserved by sodium-potassium adenosine triphosphatase (Na-K ATPase), the current study compared the acute effects of hydrocortisone (H), cyclosporine, and FK506 on cultured LLC-PK1 cell viability and on Na-K ATPase activity. Phospholipase-C (PL-C) activity was also investigated because of its possible regulatory effect on Na-K ATPase activity. Culture medium containing low (5 nM, 4.1 ng/ml) or high (10 nM) concentrations of FK506 plus cyclosporine at 415 microM (500 ng/ml) resulted in cell death, whereas cyclosporine concentrations of 83 microM plus 5 nM or 10 nM FK506, or isolated use of the two drugs at high dosages, did not affect cell viability. As compared with controls, cyclosporine increased Na-K ATPase activity, particularly with addition of H (P less than 0.01). In contrast, FK506 reduced the specific activity of both PL-cyclosporine and Na-K ATPase (P less than 0.001-0.01); addition of H to FK506 resulted in an even greater fall in both the enzyme activities (P less than 0.001). Na-K ATPase activity increased in cell homogenates briefly incubated with cyclosporine in the ATPase reaction mixture (P less than 0.05) while FK506 reduced such enzyme activity (P less than 0.05), suggesting a direct effect of these agents on pump activity. These data in LLC-PK1 cells pocessing proximal tubular epithelial cell characteristics indicate that the combined use of cyclosporine plus FK506 may be very deleterious to viability in such cells. The opposing effects of cyclosporine and FK506 on PL-cyclosporine and Na-K ATPase activities and the possible potentiating effect of H on such responses are speculated to affect Na+ and water homeostasis in a manner that may explain differences in systemic blood pressure due to these agents.


Evidence for CP violation in B+ → ppK+ decays.
Three-body B+ → ppK+ and B(+) → ppπ(+) decays are studied using a data sample corresponding to an integrated luminosity of 3.0 fb(-1) collected by the LHCb experiment in proton-proton collisions at center-of-mass energies of 7 and 8 TeV. Evidence of CP violation in the B(+) → ppK(+) decay is found in regions of the phase space, representing the first measurement of this kind for a final state containing baryons. Measurements of the forward-backward asymmetry of the light meson in the pp rest frame yield A(FB)(ppK(+),m(pp)<2.85 GeV/c(2)) = 0.495 ± 0.012 (stat) ± 0.007 (syst) and A(FB)(ppπ(+),m(pp) <2.85 GeV/c(2)) = -0.409 ± 0.033 (stat) ± 0.006 (syst). In addition, the branching fraction of the decay B(+) → Λ(1520)p is measured to be B(B(+) → Λ(1520)p) = (3.15 ± 0.48 (stat) ± 0.07 (syst) ± 0.26 (BF)) × 10(-7), where BF denotes the uncertainty on secondary branching fractions.


Contributions of T-type voltage-gated calcium channels to postsynaptic calcium signaling within Purkinje neurons.
Low threshold voltage-gated T-type calcium channels have long been implicated in the electrical excitability and calcium signaling of cerebellar Purkinje neurons although the molecular composition, localization, and modulation of T-type channels within Purkinje cells have only recently been addressed. The specific functional roles that T-type channels play in local synaptic integration within Purkinje spines are also currently being unraveled. Overall, Purkinje neurons represent a powerful model system to explore the potential roles of postsynaptic T-type channels throughout the nervous system. In this review, we present an overview of T-type calcium channel biophysical, pharmacological, and physiological characteristics that provides a foundation for understanding T-type channels within Purkinje neurons. We also describe the biophysical properties of T-type channels in context of other voltage-gated calcium channel currents found within Purkinje cells. The data thus far suggest that one specific T-type isoform, Ca(v)3.1, is highly expressed within Purkinje spines and both physically and functionally couples to mGluR1 and other effectors within putative signaling microdomains. Finally, we discuss how the selective potentiation of Ca(v)3.1 channels via activation of mGluR1 by parallel fiber inputs affects local synaptic integration and how this interaction may relate to the overall excitability of Purkinje neuron dendrites.


Respiratory tract infections increase susceptibility to neurogenic inflammation in the rat trachea.
This study reveals that respiratory tract infections make the tracheal mucosa of rats more susceptible to neurogenic inflammation, which is a type of inflammation mediated by neuropeptides released from sensory nerves. Neurogenic inflammation was produced in the tracheas of 2 groups of Long-Evans rats by electrical stimulation of the vagus nerve (5 V, 1 ms, 20 Hz for 5 min) or by an injection of capsaicin (15 to 200 micrograms/kg i.v.) or substance P (0.05 to 5.0 micrograms/kg i.v.). Rats of one group were pathogen-free; the others had serologic evidence of naturally occurring airway infections caused by Sendai virus, coronavirus, and Mycoplasma pulmonis. The stimuli produced neurogenic inflammation in both groups of rats, but the magnitude of this inflammation was much greater in the infected rats. The susceptibility of the infected rats to neurogenic inflammation was manifested by a 2.0 to 3.1 times larger increase in vascular permeability to Monastral blue, 5 times larger increase in number of neutrophils adhering to the endothelium of venules, and conspicuous morphologic changes in the tracheal epithelium. When pathogen-free rats acquired respiratory tract infections, they too became susceptible to neurogenic inflammation. Other experiments showed that infection by Sendai virus was essential for the change, although infection by M. pulmonis or coronavirus may also be necessary. The susceptibility to neurogenic inflammation outlasted the transient pathologic changes caused in the airway mucosa by the viral infections and may have been permanent.


Unnatural amino acids: promising implications for the development of new antimicrobial peptides.
The increasing incidence and rapid spread of bacterial resistance to conventional antibiotics are a serious global threat to public health, highlighting the need to develop new antimicrobial alternatives. Antimicrobial peptides (AMPs) represent a class of promising natural antibiotic candidates due to their broad-spectrum activity and low tendency to induce resistance. However, the development of AMPs for medical use is hampered by several obstacles, such as moderate activity, lability to proteolytic degradation, and low bioavailability. To date, many researchers have focussed on the optimization or design of novel artificial AMPs with desired properties. Unnatural amino acids (UAAs) are valuable building blocks in the manufacture of a variety of pharmaceuticals, and have been used to develop artificial AMPs with specific structural and physicochemical properties. Rational incorporation of UAAs has become a very promising approach to endow AMPs with strong and long-lasting activity but no toxicity. This review aims to summarize key approaches that have been used to incorporate UAAs to develop novel AMPs with improved properties and better performance. It is anticipated that this review will guide future design considerations for UAA-based antimicrobial applications.


The relationship of depression and disease stage to patient perceptions of Parkinson's disease.
The present study aimed to perform an in-depth exploration of perceptions of Parkinson's disease (PD) and their relationship to depression and disease stage using semi-structured interviews. 37 participants with PD formed four groups: depressed and non-depressed with either mild or moderate-severe stage PD. Interviews were analysed using Framework Analysis. Moderate-severe stage patients reported a greater variety of perceptions than those with mild symptoms. Depressed and non-depressed patients differed in their perceptions of the consequences, treatment control and emotional reaction to PD. Helping patients to adjust life goals to accommodate PD and employ adaptive coping strategies may help to relieve depressive symptoms in PD.


Thrombopoietin, the ligand for the Mpl receptor, synergizes with steel factor and other early acting cytokines in supporting proliferation of primitive hematopoietic progenitors of mice.
Recently, the ligand for the Mpl receptor (ML) was identified to be thrombopoietin, the principal regulator of megakaryocytopoiesis and thrombopoiesis. We examined the effects of ML, as a single factor or in combinations with early acting factors such as steel factor (SF), interleukin (IL)-3, IL-1, IL-6, and granulocyte colony-stimulating factor (G-CSF), on colony formation from primitive progenitors of mice. Cells enriched for cell cycle dormant primitive progenitors were isolated from bone marrow cells of 5-fluorouracil (5-FU)-treated mice by a combination of Nycodenz density gradient separation, immunomagnetic selection for lineage-negative cells, and fluorescence-activated cell sorter (FACS) sorting for Ly-6A/E+Kit+ cells. ML, in the presence of erythropoietin, could support the formation of only a few megakaryocyte colonies. However, ML acted synergistically with SF or IL-3 to support the formation of multiple types of hematopoietic colonies including multilineage colonies. Effects of the combination of ML and SF on multipotential progenitors were not mediated through other cells, as demonstrated by micromanipulation of individual progenitors. In suspension culture, the combination of ML and SF increased the number of multipotential progenitors. ML also acted synergistically with IL-11, IL-6, or G-CSF to support colony formation in serum-containing, but not in serum-free, cultures. However, the multilineage colony formation seen in serum-containing culture was completely abrogated by addition of ACK2, a neutralizing antibody to Kit protein. Serial observation (mapping studies) of colony development from multipotential progenitors suggested that ML triggers the cell division of dormant progenitors. Based on these observations, we propose that ML can function as an early acting cytokine and stimulate the proliferation of cell cycle dormant progenitors by shortening their G0 period.


Evaluation of aliphatic acid metabolism in bladder cancer with the goal of guiding therapeutic treatment.
Urothelial bladder cancer (BLCA) is a common internal malignancy with a poor prognosis. The re-programming of lipid metabolism is necessary for cancer cell growth, proliferation, angiogenesis and invasion. However, the role of aliphatic acid metabolism genes in bladder cancer patients has not been explored. The samples' gene expression and clinicopathological data were obtained from the Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Univariate, multivariate, and LASSO Cox regression were used to develop a BLCA prognostic model. GSVA was used to assess function, whereas pRRophetic was used to assess chemotherapeutic drug sensitivity. The twelve-gene signature may define the tumor immune milieu, according to the risk score model. We compared the expression of aliphatic acid metabolism genes in malignant and non-cancerous tissues and chose 90 with a false discovery rate of 0.05 for The Cancer Genome Atlas cohort. The prognostic risk score model can effectively predict BLCA OS. A nomogram including age, clinical T stage, gender, grade, pathological stage, and clinical M stage was developed as an independent BLCA prognostic predictor. The halfmaximal inhibitory concentration (IC50) was used to assess chemotherapeutic medication response. Sorafenib and Pyrimethamine were used to treat patients with low risk scores more sensitively than patients with high risk scores. Immunotherapy candidates with CMS1 exhibited higher risk ratings. The aliphatic acid prognostic risk score model can assess metabolic trends. Clinical stage and molecular subtype may be used to categorize individuals using the risk score.With this new paradigm, future cancer treatment and immunotherapy may be tailored to the patient's exact requirements.


PSpice modeling of the pulsed electroacoustic method for dispersive polymer sample application.
In space applications, space charge inside dielectric materials can lead to unwanted phenomena such as breakdown and electrostatic discharge. To prevent such incidents, the pulsed electroacoustic (PEA) device is employed to measure the space charge of dielectric samples. Unfortunately, most of the current PEA signal processing methods are inaccurate in studying the dielectric materials that attenuate and disperse the acoustic wave, as well as studying multi-layer or thin samples. A model under the PSpice software is developed in this work with the aim of improving the PEA signal processing. This model is an evolution of previous works, including the attenuation and dispersion of a polymer sample using the nearly local Kramers-Kronig relation. This model of the polymer sample is implemented into PSpice as a frequency dependent transmission line using Branin's method of characteristics model. A comparison of a model simulation and an experimental PEA signal obtained from a PTFE sample is presented.


Comparative analysis of nanobody sequence and structure data.
Nanobodies are a class of antigen-binding protein derived from camelids that achieve comparable binding affinities and specificities to classical antibodies, despite comprising only a single 15 kDa variable domain. Their reduced size makes them an exciting target molecule with which we can explore the molecular code that underpins binding specificity-how is such high specificity achieved? Here, we use a novel dataset of 90 nonredundant, protein-binding nanobodies with antigen-bound crystal structures to address this question. To provide a baseline for comparison we construct an analogous set of classical antibodies, allowing us to probe how nanobodies achieve high specificity binding with a dramatically reduced sequence space. Our analysis reveals that nanobodies do not diversify their framework region to compensate for the loss of the VL domain. In addition to the previously reported increase in H3 loop length, we find that nanobodies create diversity by drawing their paratope regions from a significantly larger set of aligned sequence positions, and by exhibiting greater structural variation in their H1 and H2 loops.