Acute and chronic paediatric intensive care patients: current trends and perspectives on resource utilization.
Advances in paediatric critical care have resulted in increased survival of critically ill patients, many of whom require long-term ventilation as a means of life support. To determine current trends in resource utilization, and problems in the care of acute and chronic paediatric intensive care patients. Open observational study. We evaluated consecutive admissions (n = 1629) to a 10-bed paediatric intensive care unit (PICU) over a 5-year period. Three previously defined criteria for resource utilization were used: mean length of stay (LOS); length of mechanical ventilation (LOMV); and LOMV/LOS ratio. A total of 10 310 patient bed days and 5223 ventilator days were used. Mean LOS increased from 5.3 +/- 12 days in 1998 to 8.7 +/- 27 days in 2001 (p < 0.05). Although LOMV/LOS ratio (50.7%) was significantly correlated with Paediatric Risk of Mortality score (p < 0.0001), there was no significant change in mortality rate (12.6% vs. 12%). Patients hospitalized for >2 weeks (n = 320, 20%) used 55% of LOS and 57% of LOMV, in contrast to the 1298 (80%) hospitalized for <7 days, who used only 29% of LOS and 20% of LOMV. Patients hospitalized for >3 months (11, 0.7%) consumed 17% of LOS and 23% of LOMV. Five of these (45%) were eventually discharged home, two on ventilators. The increasing trend of occupation of PICU bed and ventilator days by critically ill children may be related to the increasing trend for hospitalization of chronic care patients. Severity scoring systems were predictive of resource consumption, but not of the overall trend in mortality rate.


Hemofiltration for cytokine-driven illnesses: the mediator delivery hypothesis.
Hemofiltration is evolving as an adjunctive therapy for sepsis and other forms of systemic inflammation. Designed as a substitute for lost renal function, it is sometimes employed prior to the onset of renal failure to facilitate the nonspecific clearance of pro-inflammatory mediators. Prevailing theories suggest that hemofiltration attenuates the immune response when a threshold amount of excess cytokine is removed at the semi-permeable membrane. In this article we introduce an alternative hypothesis, in which hemofiltration exerts its effect by reinvigorating lymphatic flow and function. Crystalloid "replacement" solution, as much as 48 to 72 liters daily, is infused to restore intravascular volume lost through production of ultrafiltrate. Partial redistribution into interstitium and lymph mobilizes inflammatory mediators and other proteins, cellular byproducts, excessive ground matrix, fragments of apoptotic cells and free DNA. These substances are then metabolized, scavenged or cleared at multiple sites, including the reticuloendothelial system, liver, kidney, erythrocyte, and hemofilter.


Nitric oxide in gingival crevicular fluid and nitric oxide synthase expression in the gingiva of patients with sickle cell disease.
This study aimed to biochemically measure the production of nitric oxide in gingival crevicular fluid and immunohistochemically measure the expression of inducible nitric oxide synthase in the gingiva of patients with sickle cell disease. Additionally, we aimed to obtain insight into the immunopathology of sickle cell disease by comparing inducible nitric oxide synthase levels in patients with sickle cell disease and controls using gingiva and gingival crevicular fluid. The study included 20 sickle cell disease patients and 20 healthy controls. Immunohistochemical analysis was used to measure inducible nitric oxide synthase expression in gingiva and nitric oxide levels in gingival crevicular fluid were spectrophotometrically measured. Nitric oxide levels in the patients and controls did not differ significantly (21.2±4.5 and 23.1±2.3 μM L-1, respectively, p>0.05). There weren't any statistically significant differences in infiltrated inflammatory cells, density of inflammatory cells that stained with inducible nitric oxide synthase, or nitric oxide expression in gingiva between the patient and control groups (p>0.05). To the best of our knowledge this is the first study to examine the expression of inducible nitric oxide synthase in the gingiva and gingival crevicular fluid in patients with sickle cell disease. Using the gingiva and gingival crevicular fluid we were unable to observe sickle cell disease-associated inducible nitric oxide synthase expression and a difference in nitric oxide levels.


Examination of the gait pattern based on adjusting and resulting components of the stride-to-stride variability: proof of concept.
Stride-to-stride variability may be used as an indicator in the assessment of gait performance, but the evaluation of this parameter is not trivial. In the gait pattern, a deviation in one stride must be corrected within the next strides (elemental variables) to ensure a steady gait (performance variable). The variance in these elemental and performance variables may therefore be evaluated as adjusting and resulting components of variability. We explored this approach to gait evaluation by matching the velocity of one stride to a subsequent stride with four different time lags ranging from 0.5 to 2 strides with 0.5 stride increments. The time lag values corresponded to the following contralateral stride, the following ipsilateral stride, the second following contralateral stride and the second following ipsilateral stride. Twenty asymptomatic young adults walked on an instrumented treadmill at their preferred gait speed. The stride velocity was calculated, and variances in the stride-to-stride differences and in the stride-to-stride sums represented the adjusting and the resulting variances, respectively. A ratio between these values of greater than one indicated a meaningful stride-to-stride interaction. For the four time lags (0.5, 1, 1.5, and 2 strides), the adjusting/resulting variance ratios (mean and CI 95%) were 1.0 (0.8-1.2), 2.9 (2.3-3.6), 1.2 (1.0-1.4) and 1.2 (0.9-1.4), respectively. This new approach to the evaluation of stride-to-stride variability suggests that gait velocity adjustments occurred within one full stride cycle during treadmill walking among asymptomatic young adults. The validity of the approach needs to be tested in over-ground walking.


Location of monovalent cation binding sites in the gramicidin channel.
Six syntheses of gramicidin A have been carried out, each with 90% 13 C enrichment of a single carbonyl carbon these being the formyl, Val-1, Trp-9, Trp-11, Trp-13, and Trp-15 carbonyl carbons. Each gramicidin A was incorporated as the channel state into phospholipid structures, and the chemical shift of the carbonyl carbon resonance was monitored by 13C NMR as a function of ion concentration. Plots of Na+- and Tl+-induced chemical shifts as a function of carbonyl location in the channel indicate two symmetrically related binding sites centered at the tryptophan carbonyls and separated by 23 A. The absence of ion-induced chemical shifts for the formyl and Val-1 carbonyl carbon resonances indicates that there is no binding site midway through the channel but rather a central free-energy barrier for ion transit through the channel. Ion induced chemical shifts of the tryptophan carbonyl carbon resonances at 100 mM Na+ verify that the tight binding constant (Kbt congruent to 70 M-1), observed with 23Na NMR, results from binding within the channel. This observation and the lateral, triangular distribution of the coordinating Trp-9, -11, and -13 carbonyls combine to provide an experimental demonstration that the carbonyls of the walls of the channel directly coordinate the ion, successfully competing with the polar solvent. With the binding sites verified and localized, it is possible to conclude that the transport mechanism for Na+ is well represented by the case of the two-site model [D. W. Urry, Venkatachalam, C. M., Spisni, A., Läuger, P. & Khaled, M. A. (1980) Proc. Natl. Acad. Sci. USA 77, 2028--2032].


Norwegian obstetricians' experiences of the use of ultrasound in pregnancy management. A qualitative study.
To explore obstetricians' experiences and views of the use of obstetric ultrasound in clinical management of pregnancy. A qualitative interview study was undertaken in 2015 with obstetricians (N = 20) in Norway as part of the CROss Country Ultrasound Study (CROCUS). Three categories developed during analyses. 'Differing opinions about ultrasound and prenatal diagnosis policies' revealed divergent views in relation to Norwegian policies for ultrasound screening and prenatal diagnosis. Down syndrome screening was portrayed as a delicate and frequently debated issue, with increasing ethical challenges due to developments in prenatal diagnosis. 'Ultrasound's influence on the view of the fetus' illuminated how ultrasound influenced obstetricians' views of the fetus as a 'patient' and a 'person'. They also saw ultrasound as strongly influencing expectant parents' views of the fetus, and described how ultrasound was sometimes used as a means of comforting women when complications occurred. 'The complexity of information and counselling' revealed how obstetricians balanced the medical and social aspects of the ultrasound examination, and the difficulties of 'delivering bad news' and counselling in situations of uncertain findings. This study highlights obstetricians' experiences and views of ultrasound and prenatal diagnosis in Norwegian maternity care and the challenges associated with the provision of these services, including counselling dilemmas and perceived differences in expectations between caregivers and expectant parents. There was notable diversity among these obstetricians in relation to their support of, and adherence to Norwegian regulations about the use of ultrasound, which indicates that the care pregnant women receive may vary accordingly.


Sparganosis presenting as a conus medullaris lesion: case report and literature review of the spinal sparganosis.
Sparganosis is a rare parasitic infection affecting various organs, including the central nervous system. In rare cases, sparganosis may involve the spinal cord, usually at the thoracic area. We herein report, to our knowledge, the first case of sparganosis presenting as a conus medullaris lesion and review the literature of sparganosis involving the spinal cord. A 42-year-old man presented with progressive perianal paresthesia and sphincter disturbances. Results of enzyme-linked immunosorbent assay of the cerebrospinal fluid and surgical biopsy were consistent with sparganum infection affecting the conus medullaris. We reviewed 7 other cases of spinal sparganosis. Sparganosis may present as a conus medullaris lesion. This possibility should be considered when clinicians encounter patients with a conus medullaris lesion or cauda equina syndrome with uncertain diagnosis.


Toward a Theory of HealthIT Adoption Across the Lifespan: Findings from Five Years in the Community.
Mediated communication enabled by information technology has immense potential to positively affect personal health. Although existing theories of technology use and adoption have advanced our understanding of information technology, they do not fully address voluntary adoption in community settings, adoption across the lifespan, and privacy concerns. Drawing on evidence collected during more than five years of field research, we start to address those issues, especially as they pertain to HealthIT (e.g. mHealth, e-Health, and/or connected health) use. Our goals include advancing theoretical discussions on technology acceptance and offering practical applications useful for medical professionals serving patients of all ages. We discuss our findings related to mandatory adoption learning heuristics, pressured voluntary adoption, digital immigrants' self-reported technology use and skill, perceived versus actual support, concerns about online privacy and information sharing, potential loss of control over personal information, online-offline boundary incongruence, and adoption barriers related to technological features.


MTMR9 increases MTMR6 enzyme activity, stability, and role in apoptosis.
Myotubularin-related protein 6 (MTMR6) is a catalytically active member of the myotubularin (MTM) family, which is composed of 14 proteins. Catalytically active myotubularins possess 3-phosphatase activity dephosphorylating phosphatidylinositol-3-phoshate and phosphatidylinositol-3,5-bisphosphate, and some members have been shown to form homomers or heteromeric complexes with catalytically inactive myotubularins. We demonstrate that human MTMR6 forms a heteromer with an enzymatically inactive member myotubularin-related protein 9 (MTMR9), both in vitro and in cells. MTMR9 increased the binding of MTMR6 to phospholipids without changing the lipid binding profile. MTMR9 increased the 3-phosphatase activity of MTMR6 up to 6-fold. We determined that MTMR6 is activated up to 28-fold in the presence of phosphatidylserine liposomes. Together, MTMR6 activity in the presence of MTMR9 and assayed in phosphatidylserine liposomes increased 84-fold. Moreover, the formation of this heteromer in cells resulted in increased protein levels of both MTMR6 and MTMR9, probably due to the inhibition of degradation of both proteins. Furthermore, co-expression of MTMR6 and MTMR9 decreased etoposide-induced apoptosis, whereas decreasing both MTMR6 and MTMR9 by RNA interference led to increased cell death in response to etoposide treatment when compared with that seen with RNA interference of MTMR6 alone. Thus, MTMR9 greatly enhances the functions of MTMR6.


Attaching and effacing enteropathogenic Escherichia coli as a cause of infantile diarrhea in Bangkok.
To identify Escherichia coli that cause infantile diarrhea in Bangkok, Thailand, E. coli isolated in a year-long study of infantile diarrhea were examined for O and H serotypes and virulence determinants. Classic enteropathogenic E. coli (EPEC) were isolated from 28 of 509 infants with diarrhea (cases) and 11 of 509 age-matched controls (P = .009; odds ratio [OR], 2.64). Most of this difference was attributable to EPEC adherence factor (EAF)-positive EPEC that produced an attachment and effacement lesion, as identified in the fluorescence actin staining assay, isolated from 13 cases and 1 control (P = .003; OR, 13.3). EAF-EPEC was isolated from 15 cases and 10 controls (P = .418; OR, 1.52) and EAF+ non-EPEC from 17 cases and 10 controls (P = .242; OR, 1.72). EAF+EPEC that caused an attachment and effacement lesion was found in 3% of children less than 6 months old with diarrhea who were studied in an outpatient clinic in Bangkok in 1988.


Renal tubular acidosis following intestinal bypass: an etiological study.
Nine cases of the distal type of renal tubular acidosis (RTA) following intestinal bypass were found. Diagnosis was based on inability to acidify the urine to pH values below 5.40 despite systemic acidosis. Acidosis, if not present, was induced by giving ammonium chloride 0.1 g/kg body weight. Patients were examined for diseases known to cause RTA but no already known etiological factor was found. Hyperoxaluria was found in eight of the nine cases with RTA, while not present in patients without RTA or in obese control patients. A causal relationship between hyperoxaluria and RTA is suggested though not proved. Cases reported in the literature of renal damage following bypass are summarized and discussed in relation to presence of hyperoxaluria and RTA.


A High-Throughput Method for Measuring Drug Residence Time Using the Transcreener ADP Assay.
Analysis of drug-target residence times during drug development can result in improved efficacy, increased therapeutic window, and reduced side effects. Residence time can be estimated as the reciprocal of the dissociation rate ( koff) of an inhibitor from its target. The traditional methods for measuring koff require synthesis of labeled ligands or low-throughput label-free methods. To provide an alternative that is better suited to an automated high-throughput screening (HTS) environment, we adapted a classic "jump dilution" catalytic assay method for determination of koff values for kinase inhibitor drugs. We used the Transcreener ADP2 Kinase assay as a universal, homogenous method to monitor the recovery of kinase activity as the drugs dissociated from preformed inhibitor-kinase complexes. We measured residence times for several drugs that bind the epidermal growth factor receptor (EGFR), ABL1, and Aurora kinases and found that the rank ordering of inhibitor koff values correlated with literature values determined using ligand binding assays. Moreover, very similar results were obtained using the Transcreener assay with fluorescence polarization (FP), fluorescence intensity (FI), and time-resolved Förster resonance energy transfer (TR-FRET) detection modes. This HTS-compatible, generic assay method should facilitate the use of residence time as a parameter for compound prioritization and optimization early in kinase drug discovery programs.


cAMP-responsive element-binding protein (CREB) and cAMP co-regulate activator protein 1 (AP1)-dependent regeneration-associated gene expression and neurite growth.
To regenerate damaged axons, neurons must express a cassette of regeneration-associated genes (RAGs) that increases intrinsic growth capacity and confers resistance to extrinsic inhibitory cues. Here we show that dibutyrl-cAMP or forskolin combined with constitutive-active CREB are superior to either agent alone in driving neurite growth on permissive and inhibitory substrates. Of the RAGs examined, only arginase 1 (Arg1) expression correlated with the increased neurite growth induced by the cAMP/CREB combination, both of which were AP1-dependent. This suggests that cAMP-induced AP1 activity is necessary and interacts with CREB to drive expression of RAGs relevant for regeneration and demonstrates that combining a small molecule (cAMP) with an activated transcription factor (CREB) stimulates the gene expression necessary to enhance axonal regeneration.


Campylobacter jejuni.
This review describes characteristics of the family Campylobacteraceae and traits of Campylobacter jejuni. The review then focuses on the worldwide problem of C. jejuni antimicrobial resistance and mechanisms of pathogenesis and virulence. Unravelling these areas will help with the development of new therapeutic agents and ultimately decrease illness caused by this important human pathogen.


Postoperative trifascicular block complicating tetralogy of fallot repair.
Transient and residual conduction defects, including early and late complete heart block, are not uncommon in children following the intracardiac repair of tetralogy of Fallot. The case of a young girl is described, in whom early, transient complete heart block was found to be due to trifascicular damage. Through serial electrophysiological studies, gradual improvement in the conducting system was documented, although residual trifascicular damage remained. It is believed that all children with evidence of residual trifascicular damage are subject to possibly fatal bradyarrhythmias due to late postoperative complete heart block.


Position statement: start middle and high schools at 8:30 am or later to promote student health and learning.
The Society of Behavioral Medicine recommends school officials start middle and high school classes at 8:30 am or later. Such a schedule promotes students' sleep health, resulting in improvements in physical health, psychological well-being, attention and concentration, academic performance, and driving safety. In this position statement, we propose a four-tiered approach to promote later school start times for middle and high schools.


Time-Resolved Measurement of the ATP-Dependent Motion of the Group II Chaperonin by Diffracted Electron Tracking.
Previously, we demonstrated the ATP-dependent dynamics of a group II chaperonin at the single-molecule level by diffracted X-ray tracking (DXT). The disadvantage of DXT is that it requires a strong X-ray source and also perfect gold nano-crystals. To resolve this problem, we developed diffracted electron tracking (DET). Electron beams have scattering cross-sections that are approximately 1000 times larger than those of X-rays. Thus, DET enables us to perform super-accurate measurements of the time-resolved 3D motion of proteins labeled with commercially available gold nanorods using a scanning electron microscope. In this study, we compared DXT and DET using the group II chaperonin from Methanococcus maripaludis (MmCpn) as a model protein. In DET, the samples are prepared in an environmental cell (EC). To reduce the electron beam-induced protein damage, we immobilized MmCpn on the bottom of the EC to expose gold nanorods close to the carbon thin film. The sample setup worked well, and the motions of gold nanorods were clearly traced. Compared with the results of DXT, the mobility in DET was significantly higher, which is probably due to the difference in the method for immobilization. In DET, MmCpn was immobilized on a film of triacetyl cellulose. Whereas proteins are directly attached on the surface of solid support in DXT. Therefore, MmCpn could move relatively freely in DET. DET will be a state-of-the-art technology for analyzing protein dynamics.


[Laparoscopic management of Meckel's diverticulum].
We present our observations on two young patients with repeated digestive bleeding from hemorrhagic Meckel's diverticulum. In one patient examined by Tc99 scintigraphy, the hemorrhagic area was shown in the lower abdomen. The laparoscopic exploration showed the Meckel's diverticulum at 1 m distance from ileocecal angle. Both cases were treated by resection with a vascular stapler postoperative evolution was favorable.


Effect of bilateral lower limb strengthening exercise on balance and walking in hemiparetic patients after stroke: a randomized controlled trial.
[Purpose] To evaluate the effect of bilateral lower limb strengthening designed to improve balance and walking in stroke patients. [Subjects and Methods] Twenty hemiparetic stroke patients were divided into two groups: a unilateral therapy group (UTG) (n=10) and a bilateral therapy group (BTG) (n=10). The UTG completed strength training only in the paretic lower limb. The BTG completed strength training in the paretic and non-paretic lower limbs. Assessment tools included the functional reach test (FRT), the Berg balance scale (BBS), the timed up and go (TUG) test, and a 10-meter walk test (10MWT). [Results] In both groups, the lower limb strengthening exercise for balance and walking significantly improved the FRT, BBS, TUG, and 10MWT scores. Compared with UTG, the BTG attained significantly improved FRT and BBS scores. [Conclusion] Bilateral therapy using this lower limb strengthening exercise effectively promotes balance in hemiparetic stroke patients.


BEHAVIORAL EVIDENCE FOR HOST-RACE FORMATION IN EUROSTA SOLIDAGINIS.
We report behavioral evidence that Eurosta solidaginis, a stem-galling tephritid fly, has formed host races on its two goldenrod hosts, Solidago altissima and S. gigantea. Previous work has shown that flies from each host plant differ electrophoretically at the level of host races. The two host-associated populations were truly sympatric and were frequently found on host plants of the two species growing interdigitated with each other. Each host-associated population demonstrated a strong preference for ovipuncturing its own host. The S. gigantea-associated population emerged 10 to 14 d earlier than the S. altissima-associated population, contributing to the reproductive isolation between populations. Partial reproductive isolation is also maintained by a preference for mating on the host from which the fly emerged. The populations meet the criteria established for host races, suggesting that they may be in an intermediate stage of sympatric speciation.


Optimal broadband antireflective taper.
We have solved the optimal taper design for minimizing reflection over a broad frequency band for a given tapered length. We believe this work will lead to significant improvement in developing broadband antireflective devices in many areas.


Frigen II improves the reliability of measurement of interleukin-1 related substances in amniotic fluid.
To investigate the role of interleukin-1 related substances in amniotic fluid in normal term labor without intrauterine infection. Amniotic fluid samples were collected from forty-one patients with various backgrounds. A novel pre-assay treatment using Frigen II was introduced to improve the recovery rates of cytokines, i.e., interleukin-1alpha, interleukin-1beta and interleukin-1 receptor antagonist, prior to ELISA assay. Urine samples from newborn infants were also tested. The concentrations of interleukin-1alpha, interleukin-1beta and interleukin-1ra were significantly higher in samples from normal vaginal delivery. The higher levels of interleukin-1alpha were also observed in samples from preterm labor without infection. Preterm infants produced more of interleukin-1 receptor antagonist in urine compared with term infants. This study provides evidence of the possible involvement of interleukin-1 related substances in labor without signs of infection. The data from newborn urine suggests that amniotic interleukin-1ra originates from the fetus. However, amniotic fluid interleukin-1alpha and interleukin-1beta may be derived from maternal tissue, such as decidua.


[Distribution of radioactive tetanus toxin at the subcellular level].
Experiments were carried out on rabbits for detecting the distribution of radioactive tetanotoxin between subcellular fractions of tissues of the central nervous system. It has been found out that a parenteral administration of tetanotoxin-35S results in a quick rise of the tissue radioactivity. The radioactivity of the free ribosome fraction remained most constant and high, which might be an indication of a high acceptory capacity of these organelles to tetanotoxin. For some periods of an acute tetanus intoxication, a rather high tropism of tetanotoxin of synaptosome, microsome and myelinic fragments was found.


Advances in Controllable Release Essential Oil Microcapsules and Their Promising Applications.
Essential oils (EOs) have emerged as natural and popular ingredients used in the preparation of safe and sustainable products because of their unique characteristics, such as antibacterial and antioxidant activity. However, due to their high volatility, poorly solubility in water, and susceptibility to degradation and oxidation, the application of EOs is greatly limited. One of the promising strategies for overcoming these restrictions is encapsulation, which involves in the entrapment of EOs inside biocompatible materials to utilize their controllable release and good bioavailability. In this review, the microencapsulation of the controllable release EOs and their applications are investigated. The focus is on the antimicrobial mechanism of various EOs on different bacteria and fungi, release mechanism of microencapsulated EOs, and preparation research progress of the controllable EOs microcapsules. In addition, their applications are introduced in relation to the food, textiles, agriculture, and medical fields.


Liver injury following normothermic ischemia in steatotic rat liver.
The influence of normothermic ischemia on steatotic liver was compared with that on healthy liver in rats. Steatotic liver was induced with 4 wk of a choline-deficient diet. We used a procedure of subcutaneous spleen transposition to develop portosystemic collaterals to avoid splanchnic stasis during total hepatic vascular occlusion. One-week survival rates after 30, 45, and 60 min of normothermic ischemia were 75%, 20% and 0% in the steatotic liver group and 100%, 90% and 70% in the control group, respectively. Significantly poor restoration of energy metabolism was observed in the steatotic liver group. After 1 hr of reflow following 45 and 60 min of ischemia, ATP was restored to 74% and 50%, respectively, of the preischemic level in healthy liver but to only 44% and 27% respectively, in steatotic liver. Microscopically, focal hemorrhage, disruption of the sinusoidal microvasculature and occasional spotty necrosis of hepatocytes were demonstrated after 1 hr of reflow following ischemia in steatotic liver, but no significant changes were evident in healthy liver. This microcirculatory alteration seems to be responsible for the loss of organ viability in steatotic liver. We suggest that steatotic liver is more vulnerable than healthy liver to normothermic ischemia in the rat.


A systematic review on reminder systems in physical therapy.
The main goal of physical therapy is to help the patient gain a better health status. Several studies have investigated the use of reminders to prevent such failures on the patients' side. This article presents a systematic review of the literature concerning reminders in physical therapy. Databases were searched until May 2017 and literatures were found from April 1992 until 2017. The literature recruitment strategy was based on applying several keywords and Medical Subject Heading (MeSH) combination running against title and abstract, including concepts such as reminder, physical therapy. The finally selected articles were categorized through reminder aspects such as how, who feedback. Data were extracted according to PRISMA guidelines. In 47% of studies, the reminder was sent to the patients, 29% to the physical therapists and 12% to the caretaker team. In 24% of the studies, paper-based letters were main medium for reminders while the rest were various types of media like emails and SMS mobile text messages. 35% of the articles showed positive effects of the reminders. Many reminder methods consisted of SMS, phone calls, letters, emails and notices on the wall were used in physical therapy. Reminders may be used to improve patients' adherence to exercise programs.


Basal and adenosine receptor-stimulated levels of cAMP are reduced in lymphocytes from alcoholic patients.
Alcoholism causes serious neurologic disease that may be due, in part, to the ability of ethanol to interact with neural cell membranes and change neuronal function. Adenosine receptors are membrane-bound proteins that appear to mediate some of the effects of ethanol in the brain. Human lymphocytes also have adenosine receptors, and their activation causes increases in cAMP levels. To test the hypothesis that basal and adenosine receptor-stimulated cAMP levels in lymphocytes might be abnormal in alcoholism, we studied lymphocytes from 10 alcoholic subjects, 10 age- and sex-matched normal individuals, and 10 patients with nonalcoholic liver disease. Basal and adenosine receptor-stimulated cAMP levels were reduced 75% in lymphocytes from alcoholic subjects. Also, there was a 76% reduction in ethanol stimulation of cAMP accumulation in lymphocytes from alcoholics. Similar results were demonstrable in isolated T cells. Unlike other laboratory tests examined, these measurements appeared to distinguish alcoholics from normal subjects and from patients with nonalcoholic liver disease. Reduced basal and adenosine receptor-stimulated levels of cAMP in lymphocytes from alcoholics may reflect a change in cell membranes due either to chronic alcohol abuse or to a genetic predisposition unique to alcoholic subjects.


A suggested model for potato MIVOISAP involving functions of central carbohydrate and amino acid metabolism, as well as actin cytoskeleton and endocytosis.
We have recently found that microbial species ranging from Gram-negative and Gram-positive bacteria to different fungi emit volatiles that strongly promote starch accumulation in leaves of both mono- and di-cotyledonous plants. Transcriptome and enzyme activity analyses of potato leaves exposed to volatiles emitted by Alternaria alternata revealed that starch over-accumulation was accompanied by enhanced 3-phosphoglycerate to Pi ratio, and changes in functions involved in both central carbohydrate and amino acid metabolism. Exposure to microbial volatiles also promoted changes in the expression of genes that code for enzymes involved in endocytic uptake and traffic of solutes. With the overall data we propose a metabolic model wherein important determinants of accumulation of exceptionally high levels of starch include (a) upregulation of ADPglucose-producing SuSy, starch synthase III and IV, proteins involved in the endocytic uptake and traffic of sucrose, (b) down-regulation of acid invertase, starch breakdown enzymes and proteins involved in internal amino acid provision, and (c) 3-phosphoglycerate-mediated allosteric activation of ADPglucose pyrophosphorylase.


Antigen-specific CD8+ T cell feedback activates NLRP3 inflammasome in antigen-presenting cells through perforin.
The connection between innate and adaptive immunity is best exemplified by antigen presentation. Although antigen-presenting cells (APCs) are required for antigen receptor-mediated T-cell activation, how T-cells feedback to APCs to sustain an antigen-specific immune response is not completely clear. Here we show that CD8+ T-cell (also called cytotoxic T lymphocytes, CTL) feedback activates the NLRP3 inflammasome in APCs in an antigen-dependent manner to promote IL-1β maturation. Perforin from antigen-specific CTLs is required for NLRP3 inflammasome activation in APCs. Furthermore, such activation of NLRP3 inflammasome contributes to the induction of antigen-specific antitumour immunity and pathogenesis of graft-versus-host diseases. Our study reveals a positive feedback loop between antigen-specific CTLs and APC to amplify adaptive immunity.


Quality improvement of medical records in a teaching hospital.
The aim of this study was to evaluate the quality of the MR compilation in some Operative Units of the "Azienda Ospedaliera Universitaria--II Università di Napoli" (AOU- SUN)-Italy, before and after an intervention of quality improvement, underlining the potential differences in the behaviour of different specialists (physicians vs. surgeons). Two random samples of 660 MRs were reviewed. A four-step program was developed: (1) first assessment of the MR; (2) implementation of the MR quality, sending a letter with the purpose of the study, the results obtained in the first step from that ward, the guidelines to correctly fill out the MR; (3) follow-up step four months later; (4) comparison of the data before and after the distribution of the guidelines using indicators of completeness of all sections of MR, clarity of handwriting and presence and clarity of signature. The main concerns were related to the signature of the duty physician (present in 2.0% and legible in only 15.4%), the presence of the letter of discharge (18.0%) and the clarity of the days of hospital stay (32.0%). After the intervention the improvement of the quality of compilation was modest and regarded mainly medical rather than surgical wards. The improvement was not satisfying since from a medical and a legal point of view the indicators should reach 100% of clarity and completeness. A further study is being carried out to improve the involvement of health care professional, so that such requirements will be perceived as a common goal, not as mere bureaucratic initiatives.


Insecticidal characteristics of two commercial Spodoptera exigua nucleopolyhedrovirus strains produced on different host colonies.
The insecticidal characteristics of two Spodoptera exigua multiple nucleopolyhedrovirus (SeMNPV) strains produced on two different S. exigua colonies were measured using the same two host colonies. These strains constitute the active ingredients of the biological insecticides Vir-ex and Spexit and were produced on insect colonies from Spain and Switzerland. Demographic characteristics of insects from each colony were examined before infection. Larval developmental time, larval survival, and adult sex ratio did not differ between the colonies, whereas mean pupal weight was significantly higher in the Spanish colony insects. After infection, susceptibility to virus occlusion bodies (OBs), time to death, larval weight at death, and total production of OBs/larva varied significantly depending on virus strain and the colony used. Vir-ex OBs produced in Spanish colony larvae had improved insecticidal characteristics in terms in lethal dose and speed of kill metrics than other strain-colony combinations. OB production was significantly higher in Spanish colony insects infected with Spexit compared with Vir-ex infected insects from the Swiss colony, with intermediate values for the other two strain-colony combinations. Virus strain and host colony origin were highly influential in determining the insecticidal characteristics of OBs and should be considered as key parameters that require optimization during the production of SeMNPV-based insecticides.


Submicroscopic Malaria in Migrants from Sub-Saharan Africa, Spain.
In a screening program, we detected submicroscopic malaria in 8.9% of recent migrants to Spain from sub-Saharan Africa. Hemoglobinopathies and filarial infection occurred more frequently in newly arrived migrants with submicroscopic malaria than in those without. Our findings could justify systematic screening in immigrants and recent travelers from malaria-endemic areas.


Analysis of telomere length in Dolly, a sheep derived by nuclear transfer.
We have used a (TTAGGG) oligonucleotide probe to demonstrate that ovine telomeres are composed of (TTAGGG) repeat arrays and to compare the terminal restriction fragment lengths of sheep derived by natural mating and nuclear transfer. Here we show that ovine somatic telomeres decrease in length with age, and that Dolly, derived by the transfer of 6-year-old adult somatic nucleus, exhibits diminished terminal restriction fragment lengths. The decrease is consistent with the age of the donor tissue and telomere erosion during in vitro culture. Nuclear transfer does not restore telomere lengths. Dolly otherwise appears physiologically and phenotypically normal for her breed and age. We further report on apparent telomere lengthening in sheep, occurring during the first year in naturally derived lambs.


Sentient cells as basic units of tissues, organs and organismal physiology.
Cells evolved some 4 billion years ago, and since then the integrity of the structural and functional continuity of cellular life has been maintained via highly conserved and ancient processes of cell reproduction and division. The plasma membrane as well as all the cytoplasmic structures are reproduced and inherited uninterruptedly by each of the two daughter cells resulting from every cell division. Although our understanding of the evolutionary emergence of the very first cells is obscured by the extremely long timeline since that revolutionary event, the generally accepted position is that the de novo formation of cells is not possible; all present cells are products of other prior cells. This essential biological principle was first discovered by Robert Remak and then effectively coined as Omnis Cellula e Cellula (every cell of the cell) by Rudolf Virchow: all currently living cells have direct structural and functional connections to the very first cells. Based on our previous theoretical analysis, all cells are endowed with individual sentient cognition that guides their individual agency, behaviour and evolution. There is a vital consequence of this new sentient and cognitive view of cells: when cells assemble as functional tissue ecologies and organs within multicellular organisms, including plants, animals and humans, these cellular aggregates display derivative versions of aggregate tissue- and organ-specific sentience and consciousness. This innovative view of the evolution and physiology of all currently living organisms supports a singular principle: all organismal physiology is based on cellular physiology that extends from unicellular roots.


Cohesive and anisotropic vascular endothelial cell motility driving angiogenic morphogenesis.
Vascular endothelial cells (ECs) in angiogenesis exhibit inhomogeneous collective migration called "cell mixing", in which cells change their relative positions by overtaking each other. However, how such complex EC dynamics lead to the formation of highly ordered branching structures remains largely unknown. To uncover hidden laws of integration driving angiogenic morphogenesis, we analyzed EC behaviors in an in vitro angiogenic sprouting assay using mouse aortic explants in combination with mathematical modeling. Time-lapse imaging of sprouts extended from EC sheets around tissue explants showed directional cohesive EC movements with frequent U-turns, which often coupled with tip cell overtaking. Imaging of isolated branches deprived of basal cell sheets revealed a requirement of a constant supply of immigrating cells for ECs to branch forward. Anisotropic attractive forces between neighboring cells passing each other were likely to underlie these EC motility patterns, as evidenced by an experimentally validated mathematical model. These results suggest that cohesive movements with anisotropic cell-to-cell interactions characterize the EC motility, which may drive branch elongation depending on a constant cell supply. The present findings provide novel insights into a cell motility-based understanding of angiogenic morphogenesis.


Altered gut microbiome compositions are associated with the severity of asthma.
Despite substantial evidence on the contribution of the diversity of the gut microbiome to the pathogenesis of asthma and allergic diseases, little is known about their relationship with asthma severity and/or clinical phenotypes. We analyzed the difference in composition of the gut microbiome between subjects with asthma and healthy subjects and explored its role in the development of asthma. Fecal samples from 15 subjects with severe asthma (SA), 14 with non-severe asthma (NSA), and 15 healthy subjects were assessed by 16S ribosomal RNA gene sequencing methods to identify the gut bacterial composition. Compared with those in the NSA group, patients in the SA group had a higher dose of inhaled corticosteroids, and there were more atopic subjects (60% vs. 35.7%, respectively). No significant differences were found at the phylum level either in operational taxonomic unit numbers or in diversity scores among the SA, NSA, and healthy groups. However, at the family level, the relative abundance of Acidaminococcaceae in the SA group was remarkedly lower than that in the group with healthy subjects (P<0.05). Furthermore, Veillonellaceae and Prevotellaceae were significantly more common in samples from the SA group than in those from the NSA group (P<0.05). In the SA group, positive correlations were observed between the relative abundance of Veillonellaceae and mid-expiratory flow 25% (MEF25%) predicted (r=0.538, P=0.047), as well as between the relative abundance of Acidaminococcaceae and body mass index (r=0642, P=0.010). Principal component analysis suggested that the relative abundances of Acidaminococcaceae and Prevotellaceae were associated with severe asthma. Moreover, we found that class Betaproteobacteria, order Burkholderiales, and family Alcaligenaceae were significantly different among the groups defined by serum immunoglobulin E (IgE) levels. Our findings suggest that altered gut microbiome compositions are involved in the severity of asthma and that there are specific bacteria related to different asthma phenotypes in terms of serum IgE levels.


Complications after endovascular treatment of thoracic aortic aneurysms.
To retrospectively determine the value of stent-graft repair of descending thoracic aortic aneurysms by analyzing the results and complications. From May 1997 to July 2002, 45 patients (33 men; mean age 69 years, range 31-88) received endovascular treatment for thoracic aortic aneurysms. In 11 patients, emergency treatment was necessary for a contained rupture. The medical records of these patients were reviewed to gather data on the procedures, immediate results, complications, mortality, and survival in follow-up. In all cases, the stent-grafts were successfully implanted. In 15 (33%) cases, the subclavian artery was covered by the stent-graft without complications. There was no paraparesis/paraplegia; 2 (4.4%) patients suffered a stroke intraoperatively. The in-hospital mortality was 2.2% (n=1); 3 (6.7%) patients died within 30 days. Primary endoleaks occurred in 8 (17.8%) cases. Procedural success (technical success without endoleak or death) was 80% (93.3% after primary endoleak repair). During follow-up, 2 (4.4%) secondary endoleaks developed. All endoleaks were treated successfully or sealed spontaneously (n=2). At a mean 24-month follow-up (range 1-62), 84% of patients were alive. The endovascular treatment of thoracic aortic aneurysms appears to be safe and effective, with lower morbidity and mortality than in conventional open operations. For these reasons, endovascular treatment should be administered whenever possible.


HLA-DRB1 Alleles as Genetic Risk Factors for the Development of Anti-MDA5 Antibodies in Patients with Dermatomyositis.
Patients with polymyositis/dermatomyositis (PM/DM) who express anti-melanoma differentiation associated protein 5 (anti-MDA5) antibodies frequently present with interstitial lung disease (ILD). The aim of this study was to investigate the association of HLA-DRB1 with anti-MDA5 expression in PM/DM. The frequency of DRB1 alleles was compared among 70 patients with PM, 104 patients with DM, and 400 healthy controls in a Han Chinese population. Frequencies of DRB1*04:01 [17.0% vs 1.3%, corrected p value (pc) = 3.8 × 10-8, OR 16.2, 95% CI 6.6-39.7] and *12:02 (42.6% vs 19.3%, pc = 0.008, OR 3.1, 95% CI 1.7-5.7) were significantly higher in anti-MDA5-positive patients with PM/DM compared with the controls. The frequencies of DRB1*04:01 (p = 5.2 × 10-6, OR 17.1, 95% CI 5.3-54.9) and *12:02 (p = 3.8 × 10-4, OR 3.1, 95% CI 1.7-5.7) in anti-MDA5-positive patients with DM-ILD were higher than in the controls, whereas the frequencies of DRB1*04:01 and *12:02 did not differ between the anti-MDA5-negative patients with DM-ILD and controls. No difference in the frequency of DRB1 alleles, other than *04:01, carrying the "shared epitope" (SE), i.e., *01:01, *01:02, *04:05, and *10:01, was observed between the controls and patients with DM stratified by the presence of anti-MDA5 and ILD. DRB1*04:01 and *12:02 confer susceptibility to anti-MDA5 antibody production in DM, which cannot be explained by the SE hypothesis.


Phylogeny of the Schisandraceae based on cpDNA mat-K and rpL16 intron data.
The chloroplast mat-K region and rpL16 intron region were sequenced for 14 species of Schisandraceae, representing both genera Kadsura Kaempf. ex Juss. and Schisandra Michx, to discuss the phylogeny of this family. Analyses were performed both in separate and combined sequence data sets (including the rbc-L sequence), with Illicium angustispealum A. C. Smith as the out-group. The results showed that the Schisandraceae are monophyletic. In all the analyses, Schisandra propinqua var. chinensis Oliva and Schisandra plena A. C. Smith were nested within Kadsura, which implies that the genera Kadsura and Schisandra are closely related. They might have originated from a common ancestor, but then evolved via different routes. The result inferred from the combined data showed a greater resolution within Schisandra than those from the two separate data sets. High bootstrap values supported the monophyly of most subgenera according to Law's system (1996). A combination of morphological, anatomical, and chemical analyses indicates that S. chinensis and S. rubriflora may be the primitive taxa in Schisandra.


Serological and Molecular Analysis of Leishmania Infection in Healthy Individuals from Two Districts of West Bengal, India, Endemic for Visceral Leishmaniasis.
AbstractSeveral epidemiological studies have indicated the presence of asymptomatic infections with Leishmania donovani in the Indian subcontinent, where parasite transmission is considered anthroponotic. In India, such asymptomatic Leishmania cases have been identified in the state of Bihar. We explored here, the presence of asymptomatic Leishmania infection among healthy individuals living in two districts in the state of West Bengal, India, using serological and molecular tests. Blood samples of 246 healthy individuals were collected from nine villages of Malda and Murshidabad districts in West Bengal, considered endemic for visceral leishmaniasis (VL). Real-time quantitative polymerase chain reaction (qPCR) was performed for the quantification of parasite load in the blood. In addition, two serological tests were carried out to demonstrate anti-Leishmania antibodies: rK39 strip test and anti-total soluble Leishmania antigen IgG using enzyme-linked immunosorbent assay method. Nearly one-fifth (53/246) of the screened population was positive in qPCR as against 10.97% (27/246) positive in rK39 strip test. A range of parasite load was observed in the blood of identified asymptomatic Leishmania cases with a median value of 7.7 parasites/mL (range = 1-65). There was poor agreement between qPCR and serological tests (κ = 0.089, P = 0.13), and 29.62% and 20.54% of the population were qPCR positive in seropositive and seronegative groups, respectively. Combined molecular and serological tests enhanced the capacity to detect asymptomatic Leishmania infection in healthy individuals residing in the endemic areas of VL. A significant proportion of asymptomatic Leishmania individuals was detected in the examined endemic regions of West Bengal that might play a role in promoting VL transmission.


A Gut Feeling in Amyotrophic Lateral Sclerosis: Microbiome of Mice and Men.
Amyotrophic lateral sclerosis (ALS) is a severely debilitating disease characterized by progressive degeneration of motor neurons. ALS etiology and pathophysiology are not well understood. It could be the consequences of complex interactions among host factors, microbiome, and the environmental factors. Recent data suggest the novel roles of intestinal dysfunction and microbiota in ALS etiology and progression. Although microbiome may indeed play a critical role in ALS pathogenesis, studies implicating innate immunity and intestinal changes in early disease pathology are limited. The gastrointestinal symptoms in the ALS patients before their diagnosis are largely ignored in the current medical practice. This review aims to explore existing evidence of gastrointestinal symptoms and progress of microbiome in ALS pathogenesis from human and animal studies. We discuss dietary, metabolites, and possible therapeutic approaches by targeting intestinal function and microbiome. Finally, we evaluate existing evidence and identify gaps in the knowledge for future directions in ALS. It is essential to understanding the microbiome and intestinal pathogenesis that determine when, where, and whether microbiome and metabolites critical to ALS progression. These studies will help us to develop more accurate diagnosis and better treatment not only for this challenging disease, but also for other neurodegenerative diseases.


His-Tag Immobilization of Cutinase 1 From Thermobifida cellulosilytica for Solvent-Free Synthesis of Polyesters.
For many years, lipase B from Candida antarctica (CaLB) was the primary biocatalyst used for enzymatic esterification and polycondensation reactions. More recently, the need for novel biocatalysts with different selectivity has arisen in the biotechnology and biocatalysis fields. The present work describes how the catalytic potential of Thermobifida cellulosilytica cutinase 1 (Thc_Cut1) was exploited for polyester synthesis. In a first step, Thc_Cut1 was immobilized on three different carriers, namely Opal, Coral, and Amber, using a novel non-toxic His-tag method based on chelated Fe(III) ions (>99% protein bounded). In a second step, the biocatalyzed synthesis of an array of aliphatic polyesters was conducted. A selectivity chain study in a solvent-free reaction environment showed how, in contrast to CaLB, Thc_Cut1 presents a certain preference for C6 -C4 ester-diol combinations reaching monomer conversions up to 78% and Mw of 878 g mol-1 when the Amber immobilized Thc_Cut1 was used. The synthetic potential of this cutinase was also tested in organic solvents, showing a marked activity decrease in polar media like that observed for CaLB. Finally, recyclability studies were performed, which showed an excellent stability of the immobilized Thc_Cut1 (retained activity >94%) over 24 h reaction cycles when a solvent-free workup was used. Concerning a practical application of the biocatalyst's preparation, the production of oligomers with Mn values below 10 kDa is usually desired for the production of nanoparticles and for the synthesis of functional pre-polymers for coating applications that can be crosslinked in a second reaction step.


γH2AX responses in human buccal cells exposed to ionizing radiation.
DNA double strand breaks are induced by ionizing radiation (IR), leading to the phosphorylation of the core histone protein H2AX (termed γH2AX). The understanding of the γH2AX responses in irradiated human buccal cells is still very limited. We used visual scoring and laser scanning cytometry (LSC) methods to investigate γH2AX signaling following exposure of human buccal cells (from six individuals) to ionizing radiation at 0-4 Gy. The frequency of nuclei containing 15-30 γH2AX foci was significantly elevated 30 min post-IR exposure (by visual scoring). Concomitantly, there was a significant decrease in the frequency of cells without foci following exposure to IR. IR-induced γH2AX signal as determined by laser scanning cytometry (which included γH2AX integral and MaxPixel value) increased significantly in all individual's 2N nuclei 30 min post-IR and was similar for all three nuclear shapes identified. Individuals with the lowest baseline γH2AX integral (i.e., in nonirradiated cells) showed the greatest fold stimulation of γH2AX and significant dose-responses to IR doses of 1, 2, and 4 Gy. In 5 out of 6 individuals, the frequency of visually scored γH2AX in nuclei showed a strong correlation (up to r = 0.999) with LSC scored γH2AX integrals. The γH2AX response and subsequent decline varied between individuals but remained elevated above baseline levels 24 h post IR exposure. γH2AX response in irradiated human buccal cells has potential to be used as an index of baseline DNA damage in population studies. The variable response to IR exposure between individuals should be taken into consideration when using the γH2AX assay for radiation biodosimetry.


Effectiveness and feasibility of concurrent chemoradiotherapy using simultaneous integrated boost-intensity modulated radiotherapy with and without induction chemotherapy for locally advanced pancreatic cancer.
To evaluate the effectiveness and feasibility of chemoradiotherapy (CRT) using simultaneous integrated boost-intensity modulated radiotherapy (SIB-IMRT) in locally advanced pancreatic cancer (LAPC) patients. Between January 2011 and May 2015, 47 LAPC patients received CRT using SIB-IMRT. Prior to SIBIMRT, 37 patients (78.7%) received induction chemotherapy (IC-CRT group) and remaining 10 patients (21.3%) did not received induction chemotherapy (CRT group). During SIB-IMRT, all patients received concomitant chemotherapy, with gemcitabine (n = 37) and capecitabine (n = 10). At the time of analysis, 45 patients had died and 2 patients remained alive and the median follow-up time was 14.2 months (range, 3.3 to 51.4 months). For all patients, the median times of local progression-free survival (LPFS), progression-free survival (PFS), and overall survival (OS) were 18.1, 10.3, and 14.2 months, respectively. The median time of LPFS between IC-CRT and CRT groups was similar (18.1 months vs. 18.3 months, p = 0.711). IC-CRT group had a higher trend in PFS (10.9 months vs. 4.1 months, p = 0.054) and had significantly higher OS (15.4 months vs. 9.5 months, p = 0.007) than CRT group. In multivariate analysis, the use of induction chemotherapy and tumor response were significant factors associated with OS (p < 0.05, each). During SIBIMRT, toxicity of grade ≥3 was observed in 7 patients (14.9%) in all patients. CRT using SIB-IMRT is feasible and promising in LAPC patients.


Neonatal treatment with 192 IgG-saporin produces long-term forebrain cholinergic deficits and reduces dendritic branching and spine density of neocortical pyramidal neurons.
The role of basal forebrain-derived cholinergic afferents in the development of neocortex was studied in postnatal rats. Newborn rat pups received intraventricular injections of 192 IgG-saporin. Following survival periods ranging from 2 days to 6 months, the brains were processed to document the cholinergic lesion and to examine morphological consequences. Immunocytochemistry for choline acetyltransferase (ChAT) and in situ hybridization for ChAT mRNA demonstrate a loss of approximately 75% of the cholinergic neurons in the medial septum and nucleus of the diagonal band of Broca in the basal forebrain. In situ hybridization for glutamic acid decarboxylase mRNA reveals no loss of basal forebrain GABAergic neurons. Acetylcholinesterase histochemistry demonstrates a marked reduction of the cholinergic axons in neocortex. Cholinergic axons are reduced throughout the cortical layers; this reduction is more marked in medial than in lateral cortical areas. The thickness of neocortex is reduced by approximately 10%. Retrograde labeling of layer V cortico-collicular pyramidal cells reveals a reduction in cell body size and also a reduction in numbers of branches of apical dendrites. Spine densities on apical dendrites are reduced by approximately 20-25% in 192 IgG-saporin-treated cases; no change was detected in number of spines on basal dendrites. These results indicate a developmental or maintenance role for cholinergic afferents to cerebral cortical neurons.


Novel function of pregnancy-associated plasma protein A: promotes endometrium receptivity by up-regulating N-fucosylation.
Glycosylation of uterine endometrial cells plays important roles to determine their receptive function to blastocysts. Trophoblast-derived pregnancy-associated plasma protein A (PAPPA) is specifically elevated in pregnant women serum, and is known to promote trophoblast cell proliferation and adhesion. However, the relationship between PAPPA and endometrium receptivity, as well as the regulation of N-fucosylation remains unclear. We found that rhPAPPA and PAPPA in the serum samples from pregnant women or conditioned medium of trophoblast cells promoted endometrium receptivity in vitro. Moreover, rhPAPPA increased α1,2-, α1,3- and α1,6-fucosylation levels by up-regulating N-fucosyltransferases FUT1, FUT4 and FUT8 expression, respectively, through IGF-1R/PI3K/Akt signaling pathway in human endometrial cells. Additionally, α1,2-, α1,3- and α1,6-fucosylation of integrin αVβ3, a critical endometrium receptivity biomarker, was up-regulated by PAPPA, thereby enhanced its adhesive functions. Furthermore, PAPPA blockage with antibody inhibited embryo implantation in vivo, mouse embryo adhesion and spreading in vitro, as well as N-fucosylation level of the endometrium in pregnant mice. In summary, this study suggests that PAPPA is essential to maintain a receptive endometrium by up-regulating N-fucosylation, which is a potential useful biomarker to evaluate the receptive functions of the endometrium.


Effect of physical activity on breast cancer risk: findings of the Japan collaborative cohort study.
This study aimed to examine prospectively the association between physical activity and breast cancer risk in a non-Western population. We analyzed data from the Japan Collaborative Cohort Study, which included 30,157 women, ages 40 to 69 years at baseline (1988-1990), who reported no previous history of breast cancer, and provided information on their walking and exercise habits. The subjects were followed prospectively from enrollment until 2001 (median follow-up period, 12.4 years). Breast cancer incidence during this period was confirmed using records held at population-based cancer registries. The Cox proportional hazards model was used to estimate the hazard ratio (HR) for the association of breast cancer incidence with physical activity. During the 340,055 person-years of follow-up, we identified 207 incident cases of breast cancer. The most physically active group (who walked for > or = 1 hour per day and exercised for > or = 1 hour per week) had a lower risk of breast cancer (HR, 0.45; 95% confidence interval, 0.25-0.78) compared with the least active group after adjusting for potential confounding factors. The inverse association of exercise on breast cancer was stronger among those who walked for > or = 1 hour per day than those who walked for <1 hour per day (P = 0.042). These results were not significantly modified by menopausal status or body mass index (BMI). Our analysis provided evidence that physical activity decreased the risk of breast cancer. Walking for 1 hour per day and undertaking additional weekly exercise both seemed to be protective against breast cancer, regardless of menopausal status or BMI.


[Halitosis--Part 1: epidemiology and pathogenesis].
From an epidemiologic perspective halitosis concerns a large section of the population. Reports from affected people go back to ancient times. The causes may be both oral and non-oral changes. Oral causes are predominantly the coat of the tongue as well as marginal periodontitis. The non-oral causes include disorders in the field of the ear, nose and throat specialist, some general disorders, several drugs, smoking, special nutritional habits as well as disorders in the gastro-intestinal tract. Psychosomatic causes play an important role. Bacterial decomposition processes are decisively responsible for the development of halitosis.The occurring volatile sulphur compounds increase the permeability of oral mucosa, for example for endotoxins, and damage the periodontal tissue.


Compliance with health protocols in the banking sector facing Covid-19.
The spread of the coronavirus has become one of the current challenges in the world. Implementing health protocols in the workplace along with informing people who face them, has become a vital issue. The purpose of this study was to determine the level of compliance with health protocols and measure the level of awareness, attitude and performance of bank employees while facing Covid-19. The data collection tool included a checklist and two questionnaires (demographic information and the other on the awareness, attitude and performance of bank staff) regarding the coronavirus. A total of 199 bank employees from 25 bank branches participated in the study. The results showed that in 24% of the bank branches, the staff did not use face masks. And 100% of the studied bank branches lacked proper ventilation. The mean awareness scores of female employees (94.3) were significantly higher than those of male employees (87.7). Also, the performance of female employees (93.2) was significantly better than male employees (87.2). The results showed that to achieve proper performance in controlling and reducing the covid-19 disease among bank employees and other workers, these items are noteworthy: (1) Providing and training the correct use of protective equipment including face masks. (2) Monitoring for strict implementation of health protocols. Therefore, it is necessary to keep training and information up-to-date due to the new phenomena of this disease.


Enhancing the regenerative effectiveness of growth factors by local inhibition of interleukin-1 receptor signaling.
Although growth factors (GFs) are key molecules for regenerative medicine, their use has been limited by issues associated with suboptimal delivery systems and incomplete understanding of their signaling dynamics. Here, we explored how proinflammatory signals affect GF regenerative potential. Using bone regeneration in mouse, we found that the regenerative capacity of two clinically relevant GFs (BMP-2 and PDGF-BB) is impaired by interleukin-1 receptor (IL-1R1). Mechanistically, IL-1R1 activation in bone-forming cells desensitizes them to GFs and accelerates senescence. Moreover, administration of the GFs triggers IL-1 release by macrophages. To provide localized and sustained IL-1R1 inhibition, we engineered IL-1R antagonist (IL-1Ra) to bind the extracellular matrix (ECM) very strongly and demonstrate that codelivering GFs with ECM-binding IL-1Ra induces superior regeneration. Thus, we highlight that GF regenerative activity is hindered by proinflammatory signals, and GF-based therapies should integrate immunomodulation. Particularly, ECM-binding IL-1Ra holds clinical translational potential by enhancing efficacy of GF therapies.


Subcutaneous Infusion of rhPTH1-34 During Pregnancy and Nursing in a Woman With Autosomal Dominant Hypoparathyroidism 1.
We report a successful pregnancy in a young woman with autosomal dominant hypoparathyroidism type 1 (ADH1) due to an activating mutation of the calcium sensing receptor (CASR) (c.2519C>T; p.Ala840Val) who was treated with recombinant human parathyroid hormone (rhPTH)1-34 delivered via continuous subcutaneous infusion using an OmniPod pump. She experienced no tetany or hospitalizations during the pregnancy. Serum calcium levels ranged from 7.2 to 9.8 mg/dL. Due to mild preeclampsia, her infant was delivered at 37 weeks. There were no physical anomalies. The patient continued pump therapy while nursing her daughter, who was ultimately confirmed to have the same CASR mutation. Breastfeeding appeared to protect the infant from significant hypocalcemia without the need for calcium or calcitriol supplementation until weaning at a year of age. A role for parathyroid hormone-related protein (PTHrP) is suggested.


Imaging Aspects of Palatal Torus in Cone Beam Computed Tomography and Magnetic Resonance: Case Report.
The torus palatinus is a unilocular or multilocular exostosis that occurs in the midline of the hard palate. It is considered a common clinical finding. Magnetic resonance imaging (MRI) is not commonly used in dentistry and descriptions of the torus by this imaging method are therefore rare in the literature. This case study reports on a female patient referred to the dentist to elucidate a bone enlargement detected by MRI, which was requested by the physician who accompanied the patient for migraine treatment. Additional routine dental imaging exams were performed for the planning of different treatments. Here is a description of the torus palatinus along with MRI in order to provide a complete representation of the clinical finding.


Distribution, cellular localization, and colocalization of several peptide neurotransmitters in the central nervous system of Aplysia.
Neuropeptides are widely used as neurotransmitters in vertebrates and invertebrates. In vertebrates, a detailed understanding of their functions as transmitters has been hampered by the complexity of the nervous system. The marine mollusk Aplysia, with a simpler nervous system and many large, identified neurons, presents several advantages for addressing this question and has been used to examine the roles of tens of peptides in behavior. To screen for other peptides that might also play roles in behavior, we observed immunoreactivity in individual neurons in the central nervous system of adult Aplysia with antisera raised against the Aplysia peptide FMRFamide and two mammalian peptides that are also found in Aplysia, cholecystokinin (CCK) and neuropeptide Y (NPY), as well as serotonin (5HT). In addition, we observed staining of individual neurons with antisera raised against mammalian somatostatin (SOM) and peptide histidine isoleucine (PHI). However, genomic analysis has shown that these two peptides are not expressed in the Aplysia nervous system, and we have therefore labeled the unknown peptides stained by these two antibodies as XSOM and XPHI There was an area at the anterior end of the cerebral ganglion that had staining by antisera raised against many different transmitters, suggesting that this may be a modulatory region of the nervous system. There was also staining for XSOM and, in some cases, FMRFamide in the bag cell cluster of the abdominal ganglion. In addition, these and other studies have revealed a fairly high degree of colocalization of different neuropeptides in individual neurons, suggesting that the peptides do not just act independently but can also interact in different combinations to produce complex functions. The simple nervous system of Aplysia is advantageous for further testing these ideas.


How "regular" is sentence comprehension in Broca's aphasia? It depends on how you select the patients.
Grodzinsky, Piñango, Zurif, and Drai (1999) argue that a statistical analysis of pooled sentence comprehension data from published studies of Broca's aphasic patients supports the dominance of a differential pattern of performance on active and passive voice structures. They argue that these results counter a previous study in which individual patient data from published studies were analyzed. However, Grodzinsky et al. have not carried out a true test of their hypothesis, but have biased the outcome by selecting samples for analysis that support their claims.


Efficacy for lung metastasis induced by the allogeneic bEnd3 vaccine in mice.
The mouse brain microvascular endothelial cell line bEnd.3 was used to develop a vaccine and its anti-tumor effect on lung metastases was observed in immunized mice. Mouse bEnd.3 cells cultured in-vitro and then fixed with glutaraldehyde was used to immunize mice; mice were challenged with the metastatic cancer cell line U14, and changes in metastatic cancer tissues were observed through hematoxylin and eosin staining. Carboxyfluorescein succinimidyl amino ester (CSFE) and propidium iodide (PI) were used to detect cytotoxic activity of spleen T lymphocytes; the ratio of CD3+ and CD8+ T-cell sub-sets was determined by flow cytometry. Enzyme-linked immunosorbent assay (ELISA), immunocytochemistry and immunoblot were used to examine the specific response of the antisera of immunized mice. The number of metastatic nodules in bEnd.3 and human umbilical vein endothelial cell (HUVEC) vaccine groups was less than NIH3T3 vaccine group and phosphate buffered saline (PBS) control group. The bEnd.3-induced and HUVEC-induced cytotoxic T-lymphocytes (CTLs) showed significant lytic activity against bEnd.3 and HUVEC target cells, while the antisera of mice in bEnd.3 and HUVEC vaccine groups showed specific immune responses to membrane proteins and inhibited target cell proliferation in-vitro. Immunoblot results showed specific bands at 180KD and 220KD in bEnd.3 and at 130 kD and 220 kD in HUVEC lysates. Allogeneic bEnd.3 vaccine induced an active and specific immune response to tumor vascular endothelial cells that resulted in production of antibodies against the proliferation antigens VEGF-R II, integrin, Endog etc. Immunization with this vaccine inhibited lung metastasis of cervical cancer U14 cells and prolonged the survival of these mice.


Newly identified adverse events of enzalutamide using the food and drug administration adverse event reporting system.
Enzalutamide, a second-generation anti-androgen drug, is an androgen receptor inhibitor developed to overcome resistance to first-generation anti-androgens, such as bicalutamide. This study aimed to identify previously undisclosed adverse events associated with enzalutamide. Adverse reactions following enzalutamide administration were extracted from the Food and Drug Administration Adverse Event Reporting System (FAERS) database, and the data obtained were from 2014 to 2023. Four algorithms, namely ROR, PRR, BCPNN, and EBGM, were used to detect signs of adverse reactions associated with enzalutamide use. This study determined several adverse reactions in the nervous system, including hypogeusia, ageusia, dysgeusia, normal-pressure hydrocephalus, dementia, amnesia, balance disorders, and seizure-like phenomena. The mental aspects manifested as laziness, confusion, and eating disorders. Gastrointestinal system-related adverse reactions included dysphagia, constipation, fecal hardening, and abdominal discomfort. We identified several previously unreported adverse reactions, including normal-pressure hydrocephalus, dementia, balance disorders, eating disorders, and dysphagia. Our study revealed novel adverse events associated with enzalutamide, particularly in the nervous system, that have not been previously documented. These findings have important implications for future clinical medication guidelines.


Childhood craniopharyngioma.
Craniopharyngiomas (CP) are partly cystic embryogenic malformations of the sellar and parasellar region. With an overall incidence of 0.5-2.0 new cases/million population/year, approximately 30-50 % of all cases represent childhood CP. Typical manifestations at diagnosis are headache, visual impairment, polyuria/polydypsia, growth retardation, puberty development disturbances, and significant weight gain. Therapy of choice in children with favorable tumor localization is complete resection with the intention to maintain optic nerve and hypothalamic-pituitary functions. In children with unfavorable tumor localization (hypothalamic involvement), a limited resection followed by local irradiation is recommended. Although overall surgical survival rates are high (92 %), recurrence after complete resection and progression after incomplete resection are typical post-surgical events. Particularly troublesome for the pediatric patient are the disturbances to their pubescent development and overall growth. Accordingly, the appropriate time point of irradiation after incomplete resection is under investigation in a randomized multinational trial (KRANIOPHARYNGEOM 2007). Quality of life is substantially reduced in approximately 50 % of long-term survivors due to sequelae, notably morbid hypothalamic obesity. CP should be recognized as a chronic disease requiring constant monitoring of the early life as well as post-pubescent consequences and appropriate medical resources for treatment in order to provide optimal quality of survival for patients.


HPE cells: a clonal endothelial cell line established from human parathyroid tissue (human parathyroid cell line).
We report the culture and cloning of human endothelial cells derived from parathyroid tissue surgically removed from a patient affected by Multiple Endocrine Neoplasia Type 1 syndrome. These cells, known as HPE, have been isolated and maintained in culture by serial passages for more than 15 months. The clonal cell line grows in a medium containing serum substitutes which favour endothelial cell growth. HPE cells replicate with a mean doubling time of 120 h, showing typical functional and morphological features of endothelial cells, such as uptake of acetylated low density lipoprotein and positive reaction for Factor VIII-Related Antigen. Basic fibroblast growth factor, vascular endothelial growth factor, insulin-like growth factor type I and ascorbic acid stimulate cell proliferation, whereas transforming growth factor beta and heparin act as inhibitory factors. Prostaglandin E2, secretin and epinephrine increased cAMP production, while human parathyroid hormone, histamine and glucagon were inert. Cells were found to express pro-collagen alpha 1 (type I) mRNA. In HPE cells Restriction Fragments Length Polymorphism and PCR analysis did not show allelic loss at chromosome 11q12-13, known to be a typical feature of MEN 1 parathyroid tumors. These cells are the first example of an established normal human clonal cell line with an endothelial phenotype.


Pulmonary Smooth Muscle in Vertebrates: A Comparative Review of Structure and Function.
Although the airways of vertebrates are diverse in shape, complexity, and function, they all contain visceral smooth muscle. The morphology, function, and innervation of this tissue in airways is reviewed in actinopterygians, lungfish, amphibians, non-avian reptiles, birds, and mammals. Smooth muscle was likely involved in tension regulation ancestrally, and may serve to assist lung emptying in fishes and aquatic amphibians, as well as maintain internal lung structure. In certain non-avian reptiles and anurans antagonistic smooth muscle fibers may contribute to intrapulmonary gas mixing. In mammals and birds, smooth muscle regulates airway caliber, and may be important in controlling the distribution of ventilation at rest and exercise, or during thermoregulatory and vocal hyperventilation. Airway smooth muscle is controlled by the autonomic nervous system: cranial cholinergic innervation generally causes excitation, cranial non-adrenergic, non-cholinergic innervation causes inhibition, and spinal adrenergic (SA) input causes species-specific, often heterogeneous contractions and relaxations.


Characterization of In Vitro Resistance to Linezolid in Mycobacterium abscessus.
Single-step selection of Mycobacterium abscessus mutants resistant to linezolid yielded high-level resistance at a low frequency that was associated with mutations in 23S rRNA or the ribosomal protein L3. Surprisingly, linezolid-resistant rRNA mutations conferred cross-resistance to several unrelated antibiotics. Low-level linezolid-resistant mutants were isolated at a higher frequency and were due to loss-of-function mutations in the transcriptional regulator MAB_4384, the repressor of the drug efflux pump MmpL5-MmpS5. IMPORTANCE The protein synthesis inhibitor linezolid is used for the treatment of lung disease caused by Mycobacterium abscessus. However, many strains of the bacterium show poor susceptibility to the antibiotic. For most clinical isolates, resistance is not due to mutations in the target of the drug, the ribosome. The mechanism responsible for non-target-related, indirect linezolid resistance is unknown. Here, we analyzed the development of linezolid resistance in the M. abscessus reference strain in vitro. We found, as expected, resistance mutations in the ribosome. In addition, we identified mutations in a system that involves a drug pump, suggesting drug efflux as a mechanism of resistance to linezolid. This finding may inform the analysis of clinical resistance to linezolid. Surprisingly, a subset of linezolid-resistant ribosome mutations conferred cross-resistance to several structurally and mechanistically unrelated drugs, uncovering a novel multidrug resistance mechanism.


Sensory neuropathy and nociception in rodent models of Parkinson's disease.
Parkinson's disease (PD) often manifests with prodromal pain and sensory losses whose etiologies are not well understood. Multiple genetic and toxicity-based rodent models of PD partly recapitulate the histopathology and motor function deficits. Although far less studied, there is some evidence that rodents, similar to humans, develop sensory manifestations of the disease, which may precede motor disturbances and help to elucidate the underlying mechanisms of PD-associated pain at the molecular and neuron circuit levels. The present Review summarizes nociception and other sensory functions in frequently used rodent PD models within the context of the complex phenotypes. In terms of mechanisms, it appears that the acute loss of dopaminergic neurons in systemic toxicity models (MPTP, rotenone) primarily causes nociceptive hyperexcitability, presumably owing to a loss of inhibitory control, whereas genetic models primarily result in a progressive loss of heat perception, reflecting sensory fiber neuropathies. At the molecular level, neither α-synuclein deposits alone nor failure of mitophagy alone appear to be strong enough to result in axonal or synaptic pathology of nociceptive neurons that manifest at the behavioral level, and peripheral sensory loss may mask central 'pain' in behavioral tests. Hence, allostatic combinations or additional challenges and novel behavioral assessments are needed to better evaluate PD-associated sensory neuropathies and pain in rodents.


Progressive loss of the proliferative response of senescing WI-38 cells to platelet-derived growth factor, epidermal growth factor, insulin, transferrin, and dexamethasone.
Normal human diploid cell lines such as WI-38 display a progressive loss of responsiveness to the mitogenic components in serum. Using a serum-free, hormone-growth factor supplemented medium for WI-38 cells (Phillips & Cristofalo, 1980, 1981), we examined the dose-response relationships of cells to the individual growth factor at various in vitro ages. Although as cultures senesced, they became progressively less responsive to mitogenic stimulation, the concentration of epidermal growth factor (25 ng/ml), insulin (5 micrograms/ml), transferrin (5 micrograms/ml), and dexamethasone (55 ng/ml) that elicited the maximum proliferative response did not change as a function of age. As cultures age they may require increasing amounts of platelet-derived growth factor to elicit the maximum mitogenic response.


Exploration of the Regulatory Pathways and Key Genes Involved in the Response to Saline-Alkali Stress in Betula platyphylla via RNA-Seq Analysis.
The pH of saline-alkali soil is high because of carbonate salts, and the deleterious effects of saline-alkali soil on the growth of plants are greater than those of saline soil. Few studies have examined the saline-alkali tolerance of Betula platyphylla at the molecular level. To clarify the regulatory mechanism underlying saline-alkali tolerance in B. platyphylla, RNA sequencing analysis of B. platyphylla seedlings treated with NaHCO3 was conducted. Differences in gene expression in the roots of B. platyphylla seedlings under saline-alkali stress (induced via NaHCO3) for 3 h and 6 h were characterized, and a total of 595 and 607 alkali stress-responsive genes were identified, respectively. Most differentially expressed genes were involved in stress, signal transduction, secondary metabolic process, regulation of jasmonic acid, and the abiotic stimulus signaling pathway. The single nucleotide polymorphism loci in the differentially expressed genes were associated with the alkaline-salt tolerance in birch germplasm. In addition, birch plants overexpressing WRKY70 and NAC9 were obtained using the A. tumefaciens-mediated transient transformation method, and these two genes were found to play key roles in saline-alkali tolerance. Additional study revealed that WRKY70 and NAC9 can increase resistance to saline-alkali stress by enhancing reactive oxygen species scavenging and inhibiting cell death in birch plants. The results of this study enhance our understanding of the saline-alkali stress tolerance of B. platyphylla at the molecular level, and provide several key genes that could be used in the breeding of birch plants in the future.


The Geras virtual frailty rehabilitation program to build resilience in older adults with frailty during COVID-19: a randomized feasibility trial.
The Coronavirus (COVID-19) pandemic has exacerbated the risk for poor physical and mental health outcomes among vulnerable older adults. Multicomponent interventions could potentially prevent or reduce the risk of becoming frail; however, there is limited evidence about utilizing alternative modes of delivery where access to in-person care may be challenging. This randomized feasibility trial aimed to understand how a multicomponent rehabilitation program can be delivered remotely to vulnerable older adults with frailty during the pandemic. Participants were randomized to either a multimodal or socialization arm. Over a 12-week intervention period, the multimodal group received virtual care at home, which included twice-weekly exercise in small group physiotherapy-led live-streamed sessions, nutrition counselling and protein supplementation, medication consultation via a videoconference app, and once-weekly phone calls from student volunteers, while the socialization group received only once-weekly phone calls from the volunteers. The RE-AIM (Reach, Effectiveness, Adoption, Implementation and Maintenance) framework was used to evaluate the feasibility of the program. The main clinical outcomes were change in the 5-times sit-to-stand test (5 × STS) and Depression, Anxiety and Stress Scale (DASS-21) scores. The feasibility outcomes were analyzed using descriptive statistics and expressed as frequencies and mean percent with corresponding confidence intervals (CI). Analysis of covariance (ANCOVA) was used for the effectiveness component. The program enrolled 33% (n = 72) of referrals to the study (n = 220), of whom 70 were randomized. Adoption rates from different referral sources were community self-referrals (60%), community organizations (33%), and healthcare providers (25%). At the provider level, implementation rates varied from 75 to 100% for different aspects of program delivery. Participant's adherence levels included virtual exercise sessions 81% (95% CI: 75-88%), home-based exercise 50% (95% CI: 38-62%), protein supplements consumption 68% (95% CI: 55-80%), and medication optimization 38% (95% CI: 21-59%). Most participants (85%) were satisfied with the program. There were no significant changes in clinical outcomes between the two arms. The GERAS virtual frailty rehabilitation study for community-dwelling older adults living with frailty was feasible in terms of reach of participants, adoption across referral settings, adherence to implementation, and participant's intention to maintain the program. This program could be feasibly delivered to improve access to socially isolated older adults where barriers to in-person participation exist. However, trials with larger samples and longer follow-up are required to demonstrate effectiveness and sustained behavior change. ClinicalTrials.gov NCT04500366. Registered August 5, 2020, https://clinicaltrials.gov/ct2/show/NCT04500366.


Adolescents' Lived Experiences While Hospitalized After Surgery for Ulcerative Colitis.
Adolescents are in a transitional phase of life characterized by major physical, emotional, and psychological challenges. Living with ulcerative colitis is experienced as a reduction of their life quality. Initial treatment of ulcerative colitis is medical, but surgery may be necessary when medical treatment ceases to have an effect. No research-based studies of adolescents' experience of the hospital period after surgery for ulcerative colitis exist. The objective of the study was to identify and describe adolescents' lived experiences while hospitalized after surgery for ulcerative colitis. This qualitative study was based on interviews with eight adolescents. Analysis and interpretation were based on a hermeneutic interpretation of meaning. Three themes were identified: Body: Out of order; Seen and understood; and Where are all the others? The adolescents experience a postoperative period characterized by physical and mental impairment. Being mentally unprepared for such challenges, they shun communication and interaction. The findings demonstrate the importance of individualized nursing care on the basis of the adolescent's age, maturity, and individual needs. Further study of adolescent patients' hospital stay, focusing on the implications of being young and ill at the same time, is needed.


Hypopituitarism Presenting as Adrenal Insufficiency and Hypothyroidism in a Patient with Wilson's Disease: a Case Report.
Wilson's disease typically presents symptoms associated with liver damage or neuropsychiatric disturbances, while endocrinologic abnormalities are rare. We report an unprecedented case of hypopituitarism in a patient with Wilson's disease. A 40-year-old woman presented with depression, general weakness and anorexia. Laboratory tests and imaging studies were compatible with liver cirrhosis due to Wilson's disease. Basal hormone levels and pituitary function tests indicated secondary hypothyroidism and adrenal insufficiency due to hypopituitarism. Brain MRI showed T2 hyperintense signals in both basal ganglia and midbrain but the pituitary imaging was normal. She is currently receiving chelation therapy along with thyroid hormone and steroid replacement. There may be a relationship between Wilson's disease and hypopituitarism. Copper deposition or secondary neuronal damage in the pituitary may be a possible explanation for this theory.


Voluntary Exercise Preconditioning Activates Multiple Antiapoptotic Mechanisms and Improves Neurological Recovery after Experimental Traumatic Brain Injury.
Physical activity can attenuate neuronal loss, reduce neuroinflammation, and facilitate recovery after brain injury. However, little is known about the mechanisms of exercise-induced neuroprotection after traumatic brain injury (TBI) or its modulation of post-traumatic neuronal cell death. Voluntary exercise, using a running wheel, was conducted for 4 weeks immediately preceding (preconditioning) moderate-level controlled cortical impact (CCI), a well-established experimental TBI model in mice. Compared to nonexercised controls, exercise preconditioning (pre-exercise) improved recovery of sensorimotor performance in the beam walk task, as well as cognitive/affective functions in the Morris water maze, novel object recognition, and tail-suspension tests. Further, pre-exercise reduced lesion size, attenuated neuronal loss in the hippocampus, cortex, and thalamus, and decreased microglial activation in the cortex. In addition, exercise preconditioning activated the brain-derived neurotrophic factor pathway before trauma and amplified the injury-dependent increase in heat shock protein 70 expression, thus attenuating key apoptotic pathways. The latter include reduction in CCI-induced up-regulation of proapoptotic B-cell lymphoma 2 (Bcl-2)-homology 3-only Bcl-2 family molecules (Bid, Puma), decreased mitochondria permeabilization with attenuated release of cytochrome c and apoptosis-inducing factor (AIF), reduced AIF translocation to the nucleus, and attenuated caspase activation. Given these neuroprotective actions, voluntary physical exercise may serve to limit the consequences of TBI.


Identification of CDK2-Related Immune Forecast Model and ceRNA in Lung Adenocarcinoma, a Pan-Cancer Analysis.
Tumor microenvironment (TME) plays important roles in different cancers. Our study aimed to identify molecules with significant prognostic values and construct a relevant Nomogram, immune model, competing endogenous RNA (ceRNA) in lung adenocarcinoma (LUAD). "GEO2R," "limma" R packages were used to identify all differentially expressed mRNAs from Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases. Genes with P-value <0.01, LogFC>2 or <-2 were included for further analyses. The function analysis of 250 overlapping mRNAs was shown by DAVID and Metascape software. By UALCAN, Oncomine and R packages, we explored the expression levels, survival analyses of CDK2 in 33 cancers. "Survival," "survminer," "rms" R packages were used to construct a Nomogram model of age, gender, stage, T, M, N. Univariate and multivariate Cox regression were used to establish prognosis-related immune forecast model in LUAD. CeRNA network was constructed by various online databases. The Genomics of Drug Sensitivity in Cancer (GDSC) database was used to explore correlations between CDK2 expression and IC50 of anti-tumor drugs. A total of 250 differentially expressed genes (DEGs) were identified to participate in many cancer-related pathways, such as activation of immune response, cell adhesion, migration, P13K-AKT signaling pathway. The target molecule CDK2 had prognostic value for the survival of patients in LUAD (P = 5.8e-15). Through Oncomine, TIMER, UALCAN, PrognoScan databases, the expression level of CDK2 in LUAD was higher than normal tissues. Pan-cancer analysis revealed that the expression, stage and survival of CDK2 in 33 cancers, which were statistically significant. Through TISIDB database, we selected 13 immunodepressants, 21 immunostimulants associated with CDK2 and explored 48 genes related to these 34 immunomodulators in cBioProtal database (P < 0.05). Gene Set Enrichment Analysis (GSEA) and Metascape indicated that 49 mRNAs were involved in PUJANA ATM PCC NETWORK (ES = 0.557, P = 0, FDR = 0), SIGNAL TRANSDUCTION (ES = -0.459, P = 0, FDR = 0), immune system process, cell proliferation. Forest map and Nomogram model showed the prognosis of patients with LUAD (Log-Rank = 1.399e-08, Concordance Index = 0.7). Cox regression showed that four mRNAs (SIT1, SNAI3, ASB2, and CDK2) were used to construct the forecast model to predict the prognosis of patients (P < 0.05). LUAD patients were divided into two different risk groups (low and high) had a statistical significance (P = 6.223e-04). By "survival ROC" R package, the total risk score of this prognostic model was AUC = 0.729 (SIT1 = 0.484, SNAI3 = 0.485, ASB2 = 0.267, CDK2 = 0.579). CytoHubba selected ceRNA mechanism medicated by potential biomarkers, 6 lncRNAs-7miRNAs-CDK2. The expression of CDK2 was associated with IC50 of 89 antitumor drugs, and we showed the top 20 drugs with P < 0.05. In conclusion, our study identified CDK2 related immune forecast model, Nomogram model, forest map, ceRNA network, IC50 of anti-tumor drugs, to predict the prognosis and guide targeted therapy for LUAD patients.


Low level of extra-pair paternity between nearest neighbors results from female preference for high-quality males in the yellow-rumped flycatcher (Ficedula zanthopygia).
Extra-pair copulation is considered to be a means by which females can modify their initial mate choice, and females might obtain indirect benefits to offspring fitness by engaging in this behavior. Here, we examined the patterns of extra-pair paternity and female preferences in the yellow-rumped flycatcher (Ficedula zanthopygia). We found that female yellow-rumped flycatchers are more likely to choose larger and relatively highly heterozygous males than their social mates as extra-pair mates, that the genetic similarity of pairs that produced mixed-paternity offspring did not differ from the similarity of pairs producing only within-pair offspring, and that extra-pair offspring were more heterozygous than their half-siblings. These findings support the good genes hypothesis but do not exclude the compatibility hypothesis. Most female yellow-rumped flycatchers attained extra-pair paternity with distant males rather than their nearest accessible neighboring males, and no differences in genetic and phenotypic characteristics were detected between cuckolded males and their nearest neighbors. There was no evidence that extra-pair mating by female flycatchers reduced inbreeding. Moreover, breeding density, breeding synchrony and their interaction did not affect the occurrence of extra-pair paternity in this species. Our results suggest that the variation in extra-pair paternity distribution between nearest neighbors in some passerine species might result from female preference for highly heterozygous males.


Conidiobolus, a hitherto unidentified pathogen in microbial keratitis.
Fungal infections are a significantly increasing cause of ocular and systemic morbidity; the vast majority of cases being ascribed to a handful of species. Fungal keratitis, unlike systemic infections, usually occur in immunocompetent individuals. Rarely, systemic infections can be associated with ocular involvement (e.g., Candida, Mucor, Pythium), or a fungus that predominantly causes systemic disease can affect the eye. One such fungus is Conidiobolus which is known to cause muco-cutaneous infections. We report the identification and successful treatment of a case of Conidiobolus corneal ulcer in an immunocompetent individual, who had no co-existing muco-cutaneous disease. Identification of this particular fungus and awareness of its potential to cause systemic disease is especially relevant, given its potential for chronic indolent infection of the subcutaneous tissues. To the best of our knowledge, this is the first reported case of a Conidiobolus corneal ulcer.


Secondary metabolism in Penicillium expansum: Emphasis on recent advances in patulin research.
The plant pathogenic fungus Penicillium expansum is a major concern of the global food industry due to its wide occurrence and ability to produce various mycotoxins, of which the most significant is patulin. Relatively less highlighted in the literature, in comparison with the other food-borne mycotoxins, patulin is one of the main factors in economic losses of vegetables and fruits. Otherwise, patulin is a health hazard which results in both short-term and long-term risks. This review includes knowledge on the biosynthetic mechanisms used for secondary metabolite production in P. expansum, with special emphasis on patulin biosynthesis. The abiotic factors triggering the production of patulin and the strategies developed to reduce or prevent the contamination by this mycotoxin are comprehensively discussed. The database presented in this review would be useful for the prioritization and development of future research.


Predation of nitritation-anammox biofilms used for nitrogen removal from wastewater.
Predation is assumed to be a major cause of bacterial mortality in wastewater treatment plants (WWTP). Grazing on the slowly growing autotrophic ammonia oxidizing bacteria (AOB) and anaerobic ammonium oxidizing bacteria (AMX) may result in loss of biomass, which could compromise nitrogen removal by the nitritation-anammox process. However, predation, particularly of anaerobic AMX, is unknown. We investigated the presence of protozoa, AOB and AMX and the possible predation in nitritation-anammox biofilms from several WWTPs. By fluorescence in situ hybridization (FISH) and confocal laser scanning microscopy (CLSM), predator and prey were localized in intact biofilm cryosections. Different broad morphological types of protozoa were found at different biofilm depths. Large variations in abundance of protozoa were seen. One reactor showed a predation event of amoeba-like protozoa, forming grazing fronts reaching deep biofilm regions that were dominated by the anaerobic AMX. Both AOB and AMX were grazed by the amoeba, as revealed by FISH-CLSM. Hence, even AMX, living in the deeper layers of stratified biofilms, are subjected to predation. Interestingly, different colocalization was observed between the amoeba-like protozoa and two different Ca. Brocadia AMX sublineages, indicating different grazing patterns. The findings indicate that predation pressure can be an important factor regulating the abundance of AOB and AMX, with implications for nitrogen removal from wastewater.