Human adrenomedullin combined with human adrenomedullin binding protein-1 is protective in gut ischemia and reperfusion injury in the rat.
Previous studies have demonstrated that co-administration of rat adrenomedullin (AM) and human AM binding protein-1 (AMBP-1) has various beneficial effects following adverse circulatory conditions. In order to reduce rat proteins to elicit possible immune responses in humans, we determined the effect of human AM combined with human AMBP-1 after intestinal ischemia and reperfusion (I/R). Intestinal ischemia was induced in the rat by occluding the superior mesenteric artery for 90 min. At 60 min after the beginning of reperfusion, human AM/AMBP-1 at 3 different dosages was administered intravenously over 30 min. At 240 min after the treatment, blood and tissue samples were harvested and measured for pro-inflammatory cytokines (i.e., TNF-alpha and IL-6), myeloperoxidase activities in the gut and lungs, and cleaved caspase-3 expression in the lungs, as well as serum levels of hepatic enzymes and lactate. In additional groups of animals, a 10-day survival study was conducted. Results showed that administration of human AM/AMBP-1 reduced pro-inflammatory cytokines, attenuated organ injury, and improved the survival rate in a seemingly dose-response fashion. Co-administration of the highest dose of human AM/AMBP-1 in this study had the optimal therapeutic effect in the rat model of intestinal I/R.


Massive hemorrhage in tumor of tuberous sclerosis.
A massive hemorrhage originating in a giant celled astrocytoma of tuberous sclerosis is reported and pertinent literature is reviewed. No such association has been reported previously.


Correction: Kim et al. Effects of Nursing Simulation Using Mixed Reality: A Scoping Review. Healthcare 2021, 9, 947.
The authors would like to make the following corrections about the published paper [...].


The Uncomplicated Course of COVID-19 in Primary Immunodeficiency Patients: A Report of 14 Common Variable Immunodeficiency Patients.
Coronavirus disease 2019 (COVID-19) affects millions of people worldwide. Clinical manifestations range from asymptomatic to severe viral pneumonia. CVID patients with COVID-19 infection are not adequately studied. In some studies, CVID patients had higher mortality rates, although other studies showed that CVID patients might have an uncomplicated COVID-19 infection. We describe 14 cases of COVID-19 infection in Iranian CVID patients in this study, including clinical manifestations, laboratory findings, and treatment strategies. There were 29% of patients with mild disease, 43% with moderate disease, and 29% with severe disease in this study. A critical case and a death occurred in none of our patients. There were six cases of infection more than two weeks after receiving the second dose of Sinopharm BIBP COVID-19 vaccine; all had mild to moderate disease. Among these patients, Remdesivir was the most frequently prescribed medication. According to this study, most of our patients presented with an uncomplicated disease course.


Flies cope with uncontrollable stress by learned helplessness.
In a wide range of animals, uncontrollable stressful events can induce a condition called "learned helplessness." In mammals it is associated with low general activity, poor learning, disorders of sleep and feeding, ulcers, and reduced immune status, as well as with increased serotonin in parts of the brain. It is considered an animal model of depression in humans. Here we investigate learned helplessness in Drosophila, showing that this behavioral state consists of a cognitive and a modulatory, possibly mood-like, component. A fly, getting heated as soon as it stops walking, reliably resumes walking to escape the heat. If, in contrast, the fly is not in control of the heat, it learns that its behavior has no effect and quits responding. In this state, the fly walks slowly and takes longer and more frequent rests, as if it were "depressed." This downregulation of walking behavior is more pronounced in females than in males. Learned helplessness in Drosophila is an example of how, in a certain situation, behavior is organized according to its expected consequences.


The influence of ESR1 polymorphisms on selected hormonal, metabolic and mineral balance markers in women with hyperandrogenism.
Hyperandrogenism is the most common endocrine disorder in women, characterized by an imbalance in normal estrogen and androgen levels in the blood. Androgens influence bone mineral density, body mass composition, muscle mass, mental state, and the regulation of sexual function.. The aim of the study was to assess the effect of estrogen receptor α gene (ESR1) polymorphisms on selected markers of bone metabolism and hormonal parameters in women with hyperandrogenism. The study group included 80 young women with hyperandrogenism who underwent measurements of bone mineral density (BMD), and determination of hormonal and metabolic parameters. Enzyme immunoassays were used to measure leptin, sRANKL (soluble receptor activator of nuclear factor-kB ligand), osteoprotegerin and 25-OH vitamin D total levels. An analysis of ESR1 gene polymorphisms was performed using the real-time PCR method. A relationship was demonstrated between the concentration of free estradiol (FEI) and the concentration of 17-OH-progesterone, and the ESR1 gene polymorphisms: rs3020314 (p = 0.031, p = 0.026 respectively) and rs1884051 (p = 0.033, p = 0.026 respectively). In conclusion, the ESR gene polymorphisms may be associated with hormonal disturbances in the concentration of estrogens and androgens, in hyperandrogenism in young women which may indirectly affect bone mineral density. However, no statistically significant relationships between the studied polymorphisms and the selected parameters of mineral metabolism have been demonstrated..


Narratives, environments, and decision-making: A fascinating narrative, but one to be completed.
I encourage Johnson et al. to ground Conviction Narrative Theory in more detail in foundational, earlier decision-making research - first and foremost in Herbert Simon's work. Moreover, I wonder if and how further reflections about narratives could aid tackling two interrelated grand challenges of the decision sciences: To describe decision-making environments; to understand how people select among decision-strategies in environments.


[Laparostomy with vacuum pack technique].
The technique of abdominal wall closure by vacuum pack is described. Indications are essentially the abbreviated laparotomy or damage control (especially with abdominal packing), and the post traumatic abdominal compartment syndrome (in the treatment and prevention).


Cell-mediated immunity to mouse adenovirus infection. Macrophage migration inhibition test.
Cell-mediated immunity (CMI) to mouse adenovirus (M-Ad) infection was studied by macrophage migration inhibition test (MMI) as one of in vitro correlates of CMI. Both direct and indirect tests showed clearly that migration of packed peritoneal exudate cells (PEC) (immune mouse or nonimmune guinea pig) was remarkably inhibited; MIF was produced by interactions between immune PEC and infected cell extracts and between immune spleen cells and infected cells or their extracts. The antigen(s) responsible for the above MMI was demonstrated in 6- to 12-hour infected ME cells, and FUdR-treated infected ME cells. Since under these conditions there is S antigen(s) synthesis but not capsid antigen synthesis, the antigen(s) concerned must be an S antigen(s). T cells sensitized to infected cells were shown to be required to induce MMI. The MMI is specific for M-Ad, since no cross MMI was observed between M-Ad and SV40 systems. Time course study of the development of CMI to M-Ad by MMI tests showed that CMI became detectable 4 days post-infection (pi), reached its peak level about 10 days pi, and faded away rapidly in about 10 days thereafter.


Exposure to non-acid fresh meat decontamination washing fluids sensitizes Escherichia coli O157:H7 to organic acids.
To investigate whether Escherichia coli O157:H7 maintains acid tolerance in water meat decontamination washing fluids. A rifampicin-resistant derivative of E. coli O157:H7 strain ATCC 43895 was inoculated (10(5) cfu ml(-1)) in spray-washings from meat sprayed with cold (10 degrees C) or hot (85 degrees C) water, stored at 10 degrees C for up to 14 days, and its acid tolerance was assessed at 2 and 8 days by exposure to broth or new washings adjusted to pH 3.5 or 3.7 with lactic or acetic acid. The pathogen survived in the water washings, but it was outgrown by the natural, Pseudomonas-like flora, and it was sensitized to acid. The acid tolerance of E. coli O157:H7 decreases following exposure to non-acid, but otherwise stressful, conditions prevailing in water meat washings at 10 degrees C. These findings suggest that the more intense use of water-based technologies should be included in meat decontamination strategies because they may contribute to enhanced meat safety by inducing acid sensitization in E. coli O157:H7.


Suicide attempters examined in a Parisian Emergency Department: Contrasting characteristics associated with multiple suicide attempts or with the motive to die.
Among patients examined after a suicide attempt in a Parisian emergency department, we aimed to compare individual characteristics of i) first time and multiple suicide attempters, ii) attempters whose principal motive was "to die" and attempters who had any other motive. Information regarding sociodemographics, clinical characteristics, prior mental health care and outgoing referral was collected in 168 suicide attempters using a standardized form. Associations of these variables with suicide attempt repetition (yes or no) and with the motive underlying the attempt (to die or not) were examined using descriptive statistics and multivariable logistic regression models. Multiple attempters were more likely to have no occupation and to report previous mental health care: mental health follow-up, psychiatric medication or psychiatric hospitalization. The motive to die was not associated with the risk of multiple suicide attempts but related to past suicidal ideation and to some specific precipitating factors, including psychiatric disorder. Patients who intended to die were also more likely to be referred to inpatient than to outpatient psychiatric care. Multiple attempters and attempters who desire to die might represent two distinct high-risk groups regarding clinical characteristics and care pathways. They would probably not benefit from the same intervention strategies.


Mechanistic and structural basis of bioengineered bovine Cathelicidin-5 with optimized therapeutic activity.
Peptide-drug discovery using host-defense peptides becomes promising against antibiotic-resistant pathogens and cancer cells. Here, we customized the therapeutic activity of bovine cathelicidin-5 targeting to bacteria, protozoa, and tumor cells. The membrane dependent conformational adaptability and plasticity of cathelicidin-5 is revealed by biophysical analysis and atomistic simulations over 200 μs in thymocytes, leukemia, and E. coli cell-membranes. Our understanding of energy-dependent cathelicidin-5 intrusion in heterogeneous membranes aided in designing novel loss/gain-of-function analogues. In vitro findings identified leucine-zipper to phenylalanine substitution in cathelicidin-5 (1-18) significantly enhance the antimicrobial and anticancer activity with trivial hemolytic activity. Targeted mutants of cathelicidin-5 at kink region and N-terminal truncation revealed loss-of-function. We ensured the existence of a bimodal mechanism of peptide action (membranolytic and non-membranolytic) in vitro. The melanoma mouse model in vivo study further supports the in vitro findings. This is the first structural report on cathelicidin-5 and our findings revealed potent therapeutic application of designed cathelicidin-5 analogues.


Post-vaccination anti-HBs testing among healthcare workers: More economical than post-exposure management for Hepatitis B.
to compare the direct cost, from the perspective of the Unified Health System, of assessing the post-vaccination serological status with post-exposure management for hepatitis B among health care workers exposed to biological material. cross-sectional study and cost-related, based on accident data recorded in the System of Information on Disease Notification between 2006 and 2016, where three post-exposure and one pre-exposure management scenarios were evaluated: A) accidents among vaccinated workers with positive and negative serological status tests for hepatitis B, exposed to known and unknown source-person; B) handling unvaccinated workers exposed to a known and unknown source-person; C) managing vaccinated workers and unknown serological status for hepatitis B and D) cost of the pre-exposure post-vaccination test. Accidents were assessed and the direct cost was calculated using the decision tree model. scenarios where workers did not have protective titles after vaccination or were unaware of the serological status and were exposed to a positive or unknown source-person for hepatitis B. the direct cost of hepatitis B prophylaxis, including confirmation of serological status after vaccination would be more economical for the health system.


Giardia duodenalis: dendritic cell defects in IL-6 deficient mice contribute to susceptibility to intestinal infection.
Interleukin (IL)-6 is important in numerous infections. IL-6 can promote T cell survival and differentiation toward Th17 cells, as well as B cell proliferation and differentiation to plasma cells. Giardia duodenalis is a protozoan parasite that replicates in the lumen of the small intestine in humans and many other mammals resulting in diarrhea, cramps and developmental delays in children. IL-6 is required for control of this infection, but it is unclear what its role is or which cells are required to produce this cytokine to generate efficient immunity. We have analyzed infections in a series of chimeric mice in which specific cell types lacked the ability to produce IL-6 in order to determine which sources of IL-6 played an important role in controlling this infection. Analysis of bone marrow chimeras indicate that radiation-sensitive, bone-marrow derived cells must produce IL-6. T cell chimeras show that T cell production of IL-6 is not required. Finally, by transferring dendritic cells from wild-type mice into IL-6 deficient recipients, we show that dendritic cell defects are responsible for the inability of IL-6 deficient mice to respond to Giardia challenge.


Supplementary feeding and jaundice in newborns.
In a survey it was found that the majority of full-term breast fed infants receive supplementary feeds of water, dextrose solution or infant formula during the first few days of life. Breast fed babies receiving water or dextrose supplements had higher plasma bilirubins on the sixth day of life than bottle fed infants. Supplementation with water or dextrose did not reduce the hyperbilirubinaemia of term, breast fed infants. Since it may prejudice the establishment of breast feeding, we suggest that the practice is abandoned.


The development of an augmented reality device for the autonomous management of the electric bed and the electric wheelchair for patients with amyotrophic lateral sclerosis: a pilot study.
The main aim of this Human Centred Design project was to develop the Environment COntrol in Amyotrophic Lateral Sclerosis (ECO-ALS) System, a new device which could improve ALS patient's autonomy in controlling the environment. Moreover, we verified the feasibility and usability of this technology in ALS patients in advanced stages of the disease. Twelve ALS patients in advanced disease stage were recruited, two patients for the development phase and ten patients and their caregivers for the two weeks' trial phase. We evaluated the impact of the ECOALS system by administering the Psychosocial Impact of Assistive Devices Scale (PIADS), the Individual Prioritised Problem Assessment (IPPA), the McGill Quality of Life Questionnaire (MQOL) and the Caregiver Burden Inventory (CBI). In the trial phase, patients were very satisfied for having recovered their autonomy in the management of the EAB, that enabled patients to reduce calls to their caregivers to change their bed position. The IPPA questionnaire showed a significant improvement in patients' participation and management of the system. Moreover, the PIADS questionnaire showed that patients perceived a progress in competence, adaptability and areas of self-esteem, confirming a positive psychosocial impact of the patients' assistance device. The project has collected some useful information for technological system development to face the need for autonomy ALS patients. Patients were satisfied with the tested aids and were interested in the future developments. Further studies are needed to improve the system and overcome some technical problems that occurred during the project.IMPLICATIONS FOR REHABILIATIONThe ECO-ALS system seems to improve the patients' perceived autonomy.The ECO-ALS system seems to improve the patients' perceived progress in competence, adaptability and areas of self-esteem, confirming a positive psychosocial impact of the assistance device.The ECO-ALS system seems to improve the patients' perceived quality of life.Patients were satisfied with the tested aids and were interested in the future developments.


Health-related quality of life in patients with alpha-1 antitrypsin deficiency: the French experience.
The French registry of patients with alpha-1 antitrypsin deficiency (AATD)-associated emphysema was launched in 2006. Here, we aimed to report on the baseline characteristics of these patients, their health-related quality of life (HRQoL) and factors associated with HRQoL. Another goal was to survey the practices of French physicians regarding augmentation therapy. We included 273 patients with AATD, emphysema, obstructive-pattern [forced expiratory volume in 1 sec/forced volume capacity (FEV1/FVC) < 0.7], FEV1 ≤ 80% predicted. Mean (SD) age was 51.8 (11.1) years, 240 (87.9%) of patients were smokers or ex-smokers, mean (SD) FEV1 was 40.5% (15.7) predicted. Mean (SD) SGRQ score was 49.0 (20.0) and was higher for females than males (52.7 [20.7] vs 46.8 [18.2]; p = 0.01). Dyspnea showed the strongest association with SGRQ score (r = 0.65; p < 0.0001), followed by chronic bronchitis (r = 0.33; p < 0.0001) and wheezing (r = 0.32; p < 0.0001). Number of exacerbations in the year before inclusion was also significantly associated with SGRQ score (r = 0.36; p < 0.0001). The SGRQ score was associated with the 6-min walking distance (r = -0.53, p < 0.0001), FEV1 (% predicted, r = -0.53, p < 0.0001) and DLCO (% predicted, r = -0.52, p < 0.0001). It was also associated with the GOLD 2006 (r = 0.53; p < 0.0001) and GOLD 2011 (r = 0.63; p< 0.0001) classifications and with the BODE index (r = 0.37; p < 0.0001). Age, history of tobacco smoking or current smoking did not show any association with SGRQ total scores. On multivariate analysis, a model including age, chronic bronchitis, dyspnea (MRC scale), diffusing lung capacity and 6-min walking distance explained 57% of the variation in the score. The French registry provides important insights into the clinical characteristics of French patients with AATD-related emphysema.


Group B Streptococcus infections in non-pregnant adults: the role of immunosuppression.
Group B Streptococcus (GBS) is a known causative pathogen of neonatal sepsis, but the epidemiology in non-pregnant adults is less studied. Retrospective case-control and cohort analyses of risk factors and outcomes of GBS infections among non-pregnant adults were conducted at the Detroit Medical Center from January 2005 to May 2010. Uninfected controls were matched to cases in a 3:1 ratio. Data were obtained from charts and pharmacy records. Identification of the bacteria and antimicrobial susceptibility testing were determined by MicroScan. Cox regression was used for matched multivariate analyses. Thirty-two patients with GBS infections were identified and were matched and compared to 96 controls. Compared to controls, patients with GBS infection were significantly younger. Immunosuppression, attributable mainly to neutropenia and recent use of glucocorticoids, was an independent predictor for GBS infection (odds ratio 2.7, p=0.03). Nine (28%) of the patients with GBS infection had bacteriological failure despite the administration of appropriate antimicrobial therapy. Of the 10 patients with bloodstream infections (BSI), three had endocarditis and four had central nervous system (CNS) infections. During the study period the incidence of infections decreased, but the rates of resistance to erythromycin and clindamycin increased. GBS, previously considered a genitourinary pathogen, has emerged as a non-nosocomial opportunistic pathogen causing BSI, endocarditis, and CNS infections. Immunosuppression, particularly transient immunosuppressed states, was an independent predictor for GBS BSI. Resistance rates to macrolides and clindamycin continue to increase, and should be closely monitored.


Molecular Basis for the Regulation of Transcriptional Coactivator p300 in Myogenic Differentiation.
Skeletal myogenesis is a highly ordered process which specifically depends on the function of transcriptional coactivator p300. Previous studies have established that Akt/protein kinase B (PKB), a positive regulator of p300 in proliferating cells, is also important for proper skeletal muscle development. Nevertheless, it is not clear as to how the p300 is regulated by myogenic signaling events given that both p300 and Akt are involved in many cellular processes. Our studies revealed that the levels of p300 protein are temporally maintained in ligand-enhanced skeletal myocyte development. Interestingly, this maintenance of p300 protein is observed at the stage of myoblast differentiation, which coincides with an increase in Akt phosphorylation. Moreover, regulation of p300 during myoblast differentiation appears to be mediated by Akt signaling. Blunting of p300 impairs myogenic expression and myoblast differentiation. Thus, our data suggests a particular role for Akt in myoblast differentiation through interaction with p300. Our studies also establish the potential of exploiting p300 regulation and Akt activation to decipher the complex signaling cascades involved in skeletal muscle development.


Use of a double epidural catheter provides effective postoperative analgesia after spine deformity surgery.
Spine deformity surgery is a painful procedure in which pain control is difficult to obtain. The aim of this study was to evaluate the efficacy of double epidural catheters in this setting. Twenty-three patients scheduled for an elective spine deformity surgery were included prospectively. At the end of surgery, the surgeon inserted two epidural catheters, one cranial, one caudal to the surgical field. In the recovery room the catheters were both injected with a bolus of bupivacaine 0.0625%. In the absence of any neurological abnormality a continuous infusion of bupivacaine 0.0625%, fentanyl 2 microg.mL(-1) and clonidine 3 microg.mL(-1) was administered at a rate of 10 mL.hr(-1) through each catheter for 48 hr. Pain score, sedation level, motor block and side-effects were checked regularly. Complete analgesia (VAS=0) was obtained at rest in all patients. During mobilization and physiotherapy four patients (17%) had a VAS 30. No motor block was observed. Four patients (17%) had nausea and vomiting. No excessive sedation, pruritus or respiratory depression were observed. Early mobilization was possible in all patients. Postoperative epidural analgesia by means of a double catheter is an effective technique to control pain after spine deformity surgery and is associated with a low incidence of side-effects.


Glutamate metabolism directs energetic trade-offs to shape host-pathogen susceptibility in Drosophila.
Individual hosts within populations often show inter-individual variation in their susceptibility to bacterial pathogen-related diseases. Utilizing Drosophila, we highlight that phenotypic variation in host-pathogen susceptibility within populations is driven by energetic trade-offs, facilitated by infection-mediated changes in glutamate metabolism. Furthermore, host-pathogen susceptibility is conditioned by life history, which adjusts immunometabolic sensing in muscles to direct vitamin-dependent reallocation of host energy substrates from the adipose tissue (i.e., a muscle-adipose tissue axis). Life history conditions inter-individual variation in the activation strength of intra-muscular NF-κB signaling. Limited intra-muscular NF-κB signaling activity allows for enhanced infection-mediated mitochondrial biogenesis and function, which stimulates glutamate dehydrogenase-dependent synthesis of glutamate. Muscle-derived glutamate acts as a systemic metabolite to promote lipid mobilization through modulating vitamin B enzymatic cofactor transport and function in the adipose tissue. This energy substrate reallocation improves pathogen clearance and boosts host survival. Finally, life history events that adjust energetic trade-offs can shape inter-individual variation in host-pathogen susceptibility after infection.


Small incision otoplasty for prominent ears.
A 5-cm incision and an elliptical skin excision are part of almost all surgical techniques designed to correct prominent ears. It is proposed that two 0.5-cm incisions be used that give access to the lateral surface of the auricular cartilage, which is thinned with a rasp along the antihelix and concha. The skin is not removed at all. Results obtained with this technique are presented.


Distribution of echinococcosis/hydatidosis in Italy.
Results of an epidemiological survey carried out in 88 slaughterhouses in Italy from 1979 to 1983 are reported. Data have been compared to national surveys previously conducted in 1955 and from 1968 to 1978. Analysis of various factors affecting the incidence of the disease in different areas of the country are reported.


Terminal 7p deletion and 1;7 translocation associated with craniosynostosis.
A female infant with presumptive deletion of the 7p2 region and an unusual translocation between a part of the short arm of chromosome 1 and a deleted chromosome 7 is described. The patient showed congenital craniosynostosis of the coronal and metopic sutures; marked turricephaly; hypotelorism; deeply cleft palate; shallow orbits with prominent bulging eyes; a depressed nasal bridge; anteverted nostrils; short hands with broad thin fingers and elongated thumbs; a mild talipes calcaneovalgus deformity of the feet; a systolic murmur due to a small VSD; and psychomotor retardation. The child died of bronchopneumonia at 10 weeks of age. The parents are chromosomally normal.


Radiotherapy for mucosal melanomas.
Twelve patients who were primarily irradiated at the Princess Margaret Hospital (PMH) for mucosal melanomas of the head and neck and 6 patients irradiated for mucosal melanomas of the vagina and anorectal region are reported. The PMH results of irradiation of mucosal melanomas of the head and neck are combined with the literature results for this type of melanoma. A total of 24 patients who had 25 areas irradiated are considered. The complete remission rate locally is 72% (18 of 25 areas treated). Seven of the 18 patients who achieved complete local remission subsequently relapsed locally (9 to 144 months post treatment); 11 are in maintained complete local remission (9 to 54 months). Four died of intercurrent disease without melanoma, 5 are alive and well post irradiation, one recurred regionally and was salvaged surgically and one died of distant metastases without local or regional relapse. Only 1 of 7 patients who failed to respond to irradiation was salvaged with subsequent surgery, the others all died very rapidly following unsuccessful irradiation. Analysis of local control versus fraction size revealed that 6 of 7 patients treated with a fraction size of 400 rad or more achieved complete remission as compared to 5 of 18 treated with a fraction size of 399 rad or less. The results of primary irradiation for mucosal melanomas of the head and neck are compared with the literature on radical surgery, it is concluded that in view of the poor results of radical surgery that large dose per fraction irradiation should be seriously considered as the initial treatment of choice for primary mucosal melanomas of the head and neck. Four patients with vaginal melanomas were treated at the PMH, all achieved complete remission locally, 2 recurred at 18 and 28 months, one is alive and well at 3 years and one died of intercurrent disease at 1 1/2 years. Two patients with anorectal melanoma had transient palliative benefit from irradiation. Since the treatment of both vaginal and thick (greater than 2 mm) anorectal melanoma is essentially palliative it is suggested that irradiation should be considered as an alternate treatment to radical treatment in these conditions.


Comparison of Mycobacterium tuberculosis isocitrate dehydrogenases (ICD-1 and ICD-2) reveals differences in coenzyme affinity, oligomeric state, pH tolerance and phylogenetic affiliation.
M.tb icd-1 and M.tb icd-2, have been identified in the Mycobacterium tuberculosis genome as probable isocitrate dehydrogenase (ICD) genes. Earlier we demonstrated that the two isoforms can elicit B cell response in TB patients and significantly differentiate TB infected population from healthy, BCG-vaccinated controls. Even though immunoassays suggest that these proteins are closely related in terms of antigenic determinants, we now show that M.tb icd-1 and M.tb icd-2 code for functional energy cycle enzymes and document the differences in their biochemical properties, oligomeric assembly and phylogenetic affiliation. Functionally, both M.tb ICD-1 and ICD-2 proteins are dimers. Zn+2 can act as a cofactor for ICD-1 apart from Mg+2, but not for ICD-2. ICD-1 has higher affinity for metal substrate complex (Km (isocitrate) with Mg++: 10 microM +/- 5) than ICD-2 (Km (isocitrate) with Mg++: 20 microM +/- 1). ICD-1 is active across a wider pH range than ICD-2, retaining 33-35% activity in an acidic pH upto 5.5. Difference in thermal behaviour is also observed with ICD-2 being active across wider temperature range (20 degrees C to 40 degrees C) than ICD-1 (optimum temperature 40 degrees C). The isozymes are NADP+ dependent with distinct phylogenetic affiliations; unlike M.tb ICD-2 that groups with bacterial ICDs, M.tb ICD-1 exhibits a closer lineage to eukaryotic NADP+ dependent ICDs. The data provide experimental evidence to show that the two open reading frames, Rv3339c (ICD-1) and Rv0066c (ICD-2), annotated as probable ICDs are functional TCA cycle enzymes with identical enzymatic function but different physio-chemical and kinetic properties. The differences in biochemical and kinetic properties suggest the possibility of differential expression of the two ICDs during different stages of growth, despite having identical metabolic function.


Spread of flushing-generated fecal aerosols in a squat toilet cubicle: Implication for infection risk.
Toilet flushing generates and spread fecal aerosols, potentially leading to infection transmission risk. Squat toilets are widely used in public restrooms in some Asian countries including China and India, and remain to be studied. Aerosol dispersion while flushing squat toilet in cubicle was visualized, while the aerosol concentrations were measured on different surfaces by monitoring fluorescence intensity through seeding simulated fluorescence feces. Flushing-generated fecal aerosols could spread to the breathing zone, deposit on floor, and partitions in squat toilet cubicles, and spread even beyond to the restroom lobby. A total of 0.24 % and 0.17 % of seeded fecal waste deposits on the floor and partition (lower than 0.20 m) for each flush. Aerosol concentration decays rapidly, with 86.8 ± 2.2 % reduction in the second minute after a previous flush compared to that in the first minute. Public toilet users are recommended to wait for 2 min after the early flush before entering the cubicle.


Purification and gene cloning of alpha-methylserine aldolase from Ralstonia sp. strain AJ110405 and application of the enzyme in the synthesis of alpha-methyl-L-serine.
By screening microorganisms that are capable of assimilating alpha-methyl-DL-serine, we detected alpha-methylserine aldolase in Ralstonia sp. strain AJ110405, Variovorax paradoxus AJ110406, and Bosea sp. strain AJ110407. A homogeneous form of this enzyme was purified from Ralstonia sp. strain AJ110405, and the gene encoding the enzyme was cloned and expressed in Escherichia coli. The enzyme appeared to be a homodimer consisting of identical subunits, and its molecular mass was found to be 47 kDa. It contained 0.7 to 0.8 mol of pyridoxal 5'-phosphate per mol of subunit and could catalyze the interconversion of alpha-methyl-L-serine to L-alanine and formaldehyde in the absence of tetrahydrofolate. Formaldehyde was generated from alpha-methyl-L-serine but not from alpha-methyl-D-serine, L-serine, or D-serine. Alpha-methyl-L-serine synthesis activity was detected when L-alanine was used as the substrate. In contrast, no activity was detected when D-alanine was used as the substrate. In the alpha-methyl-L-serine synthesis reaction, the enzymatic activity was inhibited by an excess amount of formaldehyde, which was one of the substrates. We used cells of E. coli as a whole-cell catalyst to express the gene encoding alpha-methylserine aldolase and effectively obtained a high yield of optically pure alpha-methyl-L-serine using L-alanine and formaldehyde.


Septic arthritis caused by Mycobacterium fortuitum and Mycobacterium abscessus in a prosthetic knee joint: case report and review of literature.
Nontuberculous mycobacterium (NTM) is an infrequent cause of prosthetic knee joint infections. Simultaneous infection with different NTM species in a prosthetic knee joint has not been previously reported. A case of prosthetic knee joint infection caused by Mycobacterium abscessus and M. fortuitum is described in this report. The patient was successfully treated with adequate antibiotics and surgery. The clinical features of sixteen previously reported cases of prosthetic knee joint infection caused by NTM are reviewed.


Role of tryptophan in the active site of plant esterase: chemical modification and fluorometric studies.
Plant esterase extracted from wheat flour play key roles in the spectrophotometric detection of organophosphorus compounds (OPs) for food safety and human health. The purpose of the present study was to investigate the role of tryptophan residues in the activity and structure of plant esterase by chemical modification and fluorometric studies. Active site characterization of purified plant esterase showed the involvement of tryptophan in the catalytic activity. Only one was essential for the enzyme activity by the Tsou's analysis. Substrate protection experiments further confirmed that the tryptophan residue was located at the substrate-binding site. Fluorescence quenching studies elucidated that the tryptophan residues were largely exposed to the solvent, and a smaller fraction of the surface tryptophan residues had electropositively charged amino acids around them. Experimental results obtained here are expected to promote the applications of plant esterase in OPs detection. Further confirmation of the existence of other critical residues and detailed explanation of their functions were also required for the elucidation of the mechanism involved in the detection of OPs.


Pattern-evoked potentials and optic nerve fiber loss in monocular laser-induced glaucoma.
ERG and VEP responses to counterphase checkerboard stimuli were obtained from cynomolgus monkeys with monocular glaucoma induced by laser photocoagulation of the trabecular meshwork. The glaucomatous eyes showed reductions of PERG amplitude that were directly related to the histologically defined nerve damage. VEP amplitudes were also reduced in the glaucomatous eyes, but were more variable and less affected by damage than the PERG responses. An acute increase in eye pressure to 40 mm Hg in eyes without damage had no detectable effect on PERG amplitudes.


[Clinical Characteristics and Risk Factors for 30-Day Mortality in Patients with Hematologic Diseases Infected by Carbapenem-Resistant Organisms].
To explore the clinical characteristics of hospitalized patients with hematologic diseases complicated with carbapenem-resistant organisms (CRO) infection and analyze the risk factors of 30-day all-cause mortality. The clinical data and laboratory test data of 77 hospitalized patients with hematologic diseases complicated with CRO infection in department of hematology of the Third Hospital of Shanxi Medical University from January 2015 to December 2020 were retrospectively analysed, the risk factors of 30-day all-cause mortality after CRO infection were analyzed by multivariate logistic regression. Among the total of 77 patients with hematologic diseases complicated with CRO infection, 29 died and 48 survived within 30 days of infection, with a case fatality rate of 37.66%. A total of 93 strains of CRO were isolated from these patients, of which Acinetobacter baumannii had the highest detection rate (25.81%, 24/93), followed by Pseudomonas aeruginosa (18.28%, 17/93). The lung was the most common site of CRO infection. The detected pathogens were highly resistant to carbapenems, and 64.52% (60/93) of the pathogens were resistant to imipenem with minimum inhibitory concentration (MIC)≥16 μg/ml. The results of the univariate analysis showed that albumin concentration <25 g/L (P =0.048), serum creatinine concentration≥120 μmol/L (P =0.023), age-adjusted Charlson comorbidity index (ACCI) (P =0.037) and primary treatments (supportive treatment, immunosuppressive therapy, chemotherapy, HSCT) (P =0.048) were significantly associated with 30-day all-cause mortality after infection. The results of multivariate logistic regression analysis showed that when CRO infection confirmed, albumin concentration <25 g/L (P =0.014, OR=6.171), serum creatinine concentration≥120 μmol/L (P =0.009, OR=10.867) were independent risk factors for 30-day mortality of patients with hematologic diseases complicated with CRO infection. The mortality rate of CRO-infected patients with hematologic diseases is high. The detected pathogenic bacteria are highly resistant to imipenem. The albumin concentration <25 g/L and the serum creatinine concentration≥ 120 μmol/L at diagnosis of CRO infection were independent risk factors for 30-day mortality of the patients with hematologic diseases.


Improved survival after implementation of ultra-radical surgery in advanced epithelial ovarian cancer: Results from a tertiary referral center.
To compare survival rates of surgically treated advanced epithelial ovarian cancer patients before and after a programmatic change in surgical approach from standard surgery towards ultra-radical surgery. 247 patients with FIGO stage IIIB-IV ovarian, tubal, and primary peritoneal carcinoma were operated during 2013-2019 either by primary or interval cytoreduction in Tampere University Hospital, Finland. Group 1 (n = 122) patients were operated during 2013 and February 2016. Group 2 patients (n = 125) were operated between March 2016 and March 2019, when a systematic change in surgical approach towards more extensive surgery was implemented. The complete resection (R0) rate increased significantly from 17.2% (21/122) to 52.0% (65/125) within the study period (p < 0.001). The median progression-free survival (PFS) was 15.6 months vs 19.3 months (p = 0.037), and the median overall survival (OS) was 33.5 months vs 54.5 months in Groups 1 and 2, respectively (p = 0.028). Median OS for stage III patients in Group 1 was 36.1 months (95% CI 27.4-44.8) but could not be reached in Group 2 (p = 0.009). In Stage IV patients, OS was 32.0 months (16.4-47.7) and 39.3 months (24.8-53.8) in Group 1 and 2, respectively (p = 0.691). Multivariable Cox regression analysis revealed that OS was independently affected by the amount of residual tumor and complication grade. The change of surgical approach towards maximal surgical effort improved both progression-free and overall survival. The survival benefit was unquestionable for stage III patients but did not reach statistical significance in stage IV patients.


[Satisfaction and utility of rehabilitative treatment through educational material in patients with COVID-19].
In Madrid, during the pandemic, due to hospital saturation, medicalisation of hotels was required for the transfer of patients infected by SARS-CoV-2 with favourable evolution. Their typical clinical situation was one of fatigue and physical deconditioning, requiring and benefiting from a rehabilitative approach. The Rehabilitation Department developed educational material in paper format on therapeutic exercise adapted to the different functional situations detected. To describe the profile of patients admitted to a medicalised hotel and to analyse the degree of satisfaction, utility and adherence to the exercise prescribed during hospitalisation and at home and the related factors. We conducted a descriptive study of patients admitted to the Hotel Colon during April and May 2020. We analysed the socio-demographic and clinical variables, as well as the responses to the adherence and satisfaction questionnaires about rehabilitation management during admission and at discharge. 100 patients participated in the study with a mean age of 52±14.5 years, where 61% (n=61) were women. 99% (n=99) reported they understood the material with a 90% (n=90) adherence to exercise during admission and 58% (n=58) at discharge. 92% (n=92) were "very satisfied" with the educational material and considered it easy to perform in 100% (n=100) of cases. The use of paper-based educational material of therapeutic exercise appears to be an effective resource in the management of patients with SARS-CoV-2 infection during admission, thus minimising the exposure of healthcare staff.


The Inhibitory Effect on Tumor Cells Proliferation Induced by Arsenic Through DNMTs and its Downstream Molecules: A Systematic Review and Meta-Analysis.
We aimed to systematically evaluate the regulatory effect of arsenic on DNMTs and its downstream molecules in tumor cells and to provide a theoretical framework revealing the specific mechanism of arsenic in the treatment of tumors. Meta-analysis was performed using RevMan 5.3 and Stata 12.0, and differences between groups were described as standardized mean difference. We found out that compared with the control group, the expression of DNMT1, DNMT3a, DNMT3b, MMP-9 & β-catenin decreased and the expression of RECK and E-cadherin increased in the arsenic-treated group. Subgroup analysis showed that high-dose arsenic exposure (> 2 μmol/L) reduced the expression of DNMT1, DNMT3b, MMP-9, and β-catenin and promoted the expression of E-cadherin. Arsenic could decrease the level of DNMT1, MMP-9 & β-catenin and increase the level of E-cadherin with short-time arsenic intervention (≤ 48 h). Arsenic could reduce DNMT1, DNMT3a, DNMT3b & β-catenin in hematological tumor cells; under the effect of arsenic, the expression of DNMT1, DNMT3b, MMP-9 & β-catenin decreased in solid tumor cells. In addition, the regulation of arsenic on DNMT3a was dose-dependent in the range of arsenic concentration from 0 to 5.0 μmol/L. The dose, time, and cell types of arsenic intervention were the variables of heterogeneity. Arsenic could inhibit the proliferation and viability of tumor cells, and its mechanism may be related to the reduction of DNMTs and regulation of the expression of its downstream molecules. Overall, arsenic may be a promising candidate for the treatment of tumors.


[The role of timing factors for the effect of caffeine on heart rhythm variability in healthy humans].
Caffeine upon single administration optimizes the indices of heart rhythm variability in young humans and enhances parasympathotonia. The expression of this reaction depends on the daytime (being more pronounced in the morning than in the evening) and on the chronotype (morningness) of volunteers.


Patient perspectives of pain and function after knee replacement: a systematic review and meta-synthesis of qualitative studies.
Joint replacement surgery typically results in good clinical outcome, although some people experience suboptimal pain relief and functional improvement. Predicting surgical outcome is difficult. There is merit in better understanding patients' perspectives of pain and function to identify avoidable problems perceived to contribute to their outcome, to inform prognostic expectations, and to identify potential cointerventions to sit alongside surgery that might mitigate pain/functional problems. Here, we aimed to synthesise the available literature exploring perspectives of people with knee osteoarthritis about their pain and function following joint replacement. Six electronic databases and 2 websites were searched. Two independent reviewers completed study inclusion, quality assessment, and data extraction. Data were iteratively synthesised using first-, second-, and third-order analyses. Twenty-eight studies were included. Four themes were identified; perceptions of pain and function were inseparable. Theme 1 addressed experiences of recovery after surgery, which often differed from expectations. Theme 2 described the challenges of the pain experience and its functional impact, including the difficulty navigating medication use in context of personal beliefs and perceived stigma. Theme 3 articulated the toll of ongoing problems spanning pain-function-mood, necessitating the need to "endure." Theme 4 encompassed the importance of clinical/social interactions on mood and pain, with reports of concerns dismissed and practical support missing. Together, these findings show that numerous individual considerations beyond the technical aspects of surgery influence experiences of pain and function. A tailored approach addressing these considerations from the patient perspective could provide a basis for improved success of knee replacement surgery.


Management of Nail Disease in Patients With Psoriatic Arthritis: An Updated Literature Review Informing the 2021 GRAPPA Treatment Recommendations.
Nail psoriasis is common, impairs fine motor finger functioning, affects cosmesis, and is associated with a lower quality of life. This review updates the previous Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for nail psoriasis. This systematic literature review of the PubMed, MEDLINE, Embase, and Cochrane databases examined the updated evidence since the last GRAPPA nail psoriasis treatment recommendations published in 2014. Recommendations are based on preformed PICO (Patient/Population - Intervention - Comparison/Comparator - Outcome) questions formulated by an international group of dermatologists, rheumatologists, and patient panel members. Data from this literature review were evaluated in line with Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Overall, there is insufficient evidence to make any recommendation for the use of topical corticosteroids, topical calcipotriol, topical tazarotene, topical cyclosporine, dimethyl fumarates/fumaric acid esters, phototherapy, and alitretinoin. There is a low strength of evidence to support the use of calcipotriol and corticosteroid preparations, topical tacrolimus, oral cyclosporine, oral methotrexate, intralesional corticosteroids, pulsed dye laser, acitretin, Janus kinase inhibitors, and apremilast. The highest strength of supporting evidence is for the recommendation of biologic agents including tumor necrosis factor inhibitors, and interleukin 12/23, 17, and 23 inhibitors.


Modification of the radiation response of pig skin by manipulation of tissue oxygen tension using anesthetics and administration of BW12C.
The importance of tissue oxygen tension on radiosensitivity was studied by examining modifications in the incidence of moist desquamation in pig skin after irradiation with strontium-90 plaques. The effects were analyzed using quantal dose-response data and comparisons were made using ED50 values for moist desquamation. Under standard anesthetic conditions of 2% halothane, approximately 70% oxygen, and approximately 30% nitrous oxide, the ED50 value (+/- SE) for moist desquamation was 27.32 +/- 0.52 Gy with no significant variation in radiosensitivity between dorsal, lateral, and ventral skin sites on the flank. Irradiation with 2% halothane and air increased the ED50 to 31.25 +/- 0.94 Gy, primarily due to an increased radioresistance of the dorsal sites. When combined with BW12C, a drug which binds oxygen selectively to hemoglobin and hence reduced the oxygen availability to tissues, a further increase in the ED50 values was observed. This was approximately 39 Gy with BW12C concentrations of 30 mg/kg and 50 mg/kg b.w. of BW12C, indicating a dose modification factor (DMF) of approximately 1.26. However, when animals were breathing the standard gas mixture, this DMF was reduced to 1.15 for 30 mg/kg of BW12C, indicating that a higher level of oxygen partly counteracted the effects of the drug in these studies with BW12C. The greatest variability in radiosensitivity was seen in the dorsal fields. This suggested complex physiological adaptation, a phenomenon that might also explain the absence of any modification of the radiation response when 100 mg/kg of BW12C was used.


Gait and six-minute walk performance in persons with multiple sclerosis.
The six-minute walk (6 MW) has been established as a clinic-based, performance measure of walking endurance that reflects community ambulation in multiple sclerosis (MS). Consequently, identifying the contribution of variables to 6 MW performance may provide targets for improving real-life walking in MS, and these variables may differ as a function of disability. This study examined cadence and stride length as gait variables that explain differences in 6 MW performance between persons with MS and controls, and by level of disability. 256 community-residing persons with MS and 49 non-MS controls performed a standard 6 MW test and completed 2 trials of comfortable walking on an electronic walkway for quantifying gait. Regression analyses indicated that cadence and stride length explain differences in 6 MW performance between MS and controls, and by level of disability in MS. The contribution of cadence and stride length to walking endurance differed as a function of disability, such that cadence and to a greater extent stride length explained variance in 6 MW performance in mild MS, whereas cadence and stride length explained approximately an equivalent amount of variance in 6 MW performance in moderate-to-severe MS. We provide evidence for intervention strategies that are specific to disability level to improve walking endurance in MS.


Sinu virus, a novel and divergent orthomyxovirus related to members of the genus Thogotovirus isolated from mosquitoes in Colombia.
The genome and structural organization of a novel insect-specific orthomyxovirus, designated Sinu virus, is described. Sinu virus (SINUV) was isolated in cultures of C6/36 cells from a pool of mosquitoes collected in northwestern Colombia. The virus has six negative-sense ssRNA segments. Genetic analysis of each segment demonstrated the presence of six distinct ORFs encoding the following genes: PB2 (Segment 1), PB1, (Segment 2), PA protein (Segment 3), envelope GP gene (Segment 4), the NP (Segment 5), and M-like gene (Segment 6). Phylogenetically, SINUV appears to be most closed related to viruses in the genus Thogotovirus.


[Urological follow-up and development of cancer after renal transplantation].
The number of renal transplant recipients is rising, as well as graft and recipient survival. The mainstay of urological follow-up is to ensure urine transport and voiding function; also, the diagnosis and treatment of urological malignancies following renal transplantats is growing in importance. As urological malignancies are one of the three most common tumors following renal transplantation (RT), meticulous and regular urological evaluation is a central part of follow-up care after RT. Urological evaluation following RT must ensure correct urine transport and voiding function. Transplant ureter strictures, relevant ureteral reflux and voiding dysfuntion (e.g., neurologic dysfunction, benign prostate hypeplasia) must be excluded or treated. Urinary tract infection (UTI), which can be life threatening in the immunosuppressed transplant recipient, must be diagnosed and treated consequently and for an adequate period of time. Prophylaxis of UTIs is indicated in patients with recurrent symptomatic UTI as well as in the initial 6 months following renal transplantation. Asymptomatic bacteriuria must not necessarily be treated. The incidence of urological malignancies like renal cell carcinoma, urothelial cancer of the bladder, and penile carcinoma is increased following RT, while the incidence of prostate and testis cancer is the same as in the nontransplant population. Surgical and nonsurgical treatment options do not differ from the normal population. Adaptation, cessation, or switching of the immunosuppressive regimen in case of urologic malignancy must be decided on the individual recipient basis.


Role of resection margins in patients treated with breast conservation surgery.
After breast conservation therapy (BCT), margin status is routinely evaluated to select patients who need reexcision. The aim of this study was to investigate how margin status and other clinicopathologic factors correlate with the presence of residual tumor at reexcision. A series of 431 breast cancer patients who underwent BCT followed by reexcision were considered because they had positive or close (< or =3 mm) margins. At univariate and multivariate analysis the frequency of residual tumor in the reexcision specimens was associated with the status and width of resection margins and with a series of other clinicopathologic factors. Of the 382 evaluable patients, 253 had positive and 129 close margins. Residual tumor was found at reexcision in 51.8% positive-margin patients and 34.1% close-margin patients (P = .001). In the latter group tumor-margin distance (range, 0.08 to 3 mm) was not associated with the incidence of residual tumor (P = .134). On univariate analysis age < or =45 years (P = .006), intraductal histotype (P = .005), size > 2 cm (P = .010), positive axillary nodes (P = .031), and timing of reexcision (P = .044) were significantly associated with a higher frequency of residual tumor. All these factors, except tumor size, maintained a significant predictive value on multivariate analysis. In the presence of positive margins, relevant residual disease cannot be ruled out and further surgery is indicated. Close margins do not mandate reexcision because they may indicate either that the tumor has been radically excised or the presence of residual foci of a multifocal tumor, which are usually effectively treated by radiotherapy.


Infliximab Does Not Worsen Outcomes During Flare-ups Associated with Cytomegalovirus Infection in Patients with Ulcerative Colitis.
Immunosuppressive therapies used for treating ulcerative colitis are known to favor chronic and latent viral diseases. This study aimed at evaluating prospectively the association between colonic cytomegalovirus (CMV) reactivation and anti-tumor necrosis factor (TNF) monoclonal antibodies (mabs) by comparison to azathioprine (AZA) in a series of flare-ups occurring in consecutive ulcerative colitis patients. A total of 109 flare-ups were recorded in 73 patients receiving a maintenance therapy by anti-TNF mabs (n = 69) or AZA (n = 40). The CMV DNA load in colonic tissue was determined by reverse transcription polymerase chain reaction on a pair of biopsies. The number of CMV reactivation was of 35% and 38% in patients receiving anti-TNF mabs and AZA, respectively. The median of CMV DNA load was 378 [10-29,800] and 8300 [10-3,25,000] copies/mg of tissue in patients treated by anti-TNF mabs and AZA, respectively (P = 0.11 by Mann-Whitney U test). In a subgroup of 45 patients under anti-TNF mabs requiring an optimized treatment by infliximab, clinical remission (partial Mayo score <3) was not significantly impacted by the presence of CMV reactivation at the time of flare-up (P = 0.52). Twenty of these patients underwent a second colonic biopsy 8 weeks after the initiation of flare-up therapy; except for 3 patients, the colonic CMV DNA load was stable or decreased. Patients under anti-TNF maintenance therapy are not at higher risk of CMV reactivation in case of flare-up. No reciprocal adverse influence was observed between anti-TNF mabs and CMV infection, suggesting that these drugs must be considered for treating flare-ups associated to CMV reactivation.


Recombinant porcine interferon-gamma activates in vitro porcine adherent mononuclear cells to produce interleukin 1.
The effect of recombinant porcine interferon-gamma (rPoIFN gamma) on in vitro production of interleukin 1 (IL-1) by porcine blood monocytes was studied. Three-day-old cultures of porcine adherent blood mononuclear cells were treated by doses of rPoIFN gamma for 3 or 6 days before lipopolysaccharide (LPS)-induction. While rPoIFN gamma alone had no effect, a combined treatment by rPoIFN gamma and LPS enhanced the IL-1 secretory potential of adherent mononuclear cells and, to a lesser extent, the level of cell-associated IL-1. The IL-1 activity was neutralized by anti porcine IL-1 alpha and beta antisera. These results demonstrate that rPoIFN gamma has immunomodulatory effects in vitro on porcine monokine production.


A fetal respiratory epithelial cell line for studying some problems of transplacental carcinogenesis in Syrian golden hamsters.
Using repeated cloning and treatment with cis-HPL (200 micrograms/ml), an analogue of a procollagen precursor inhibitory to the growth of collagen-synthesizing cells of mesenchymal origin, clonally premature epithelial cell lines were isolated from fetal SGH lungs cultured on the 15th day of gestation. One of the cell lines, M3E3/C3, which has been extensively studied for biological characterization, developed poorly differentiated carcinomas in injected hamsters after transformation by MNNG. Moreover, when grown on collagen gel, this cell line indicated an obvious potency for in vitro differentiation in response to vitamin A by developing activated Golgi regions, well developed rER and a number of mucus-like granules. Since such a differentiative responses is expected to be definable in the light of respiratory epithelium developing in utero, this cell line may be useful for studying mechanisms of differentiation-dependent sensitivity of fetal organs to transplacental carcinogen exposure.


Disseminated fusarium infection after allogeneic hematopoietic stem cell transplantation after CART: A case report.
Fusarium is a conditional pathogen that can cause invasive infection in patients with hematological diseases under immune function. A case of recurrent and refractory Philadelphia chromosome-positive acute lymphoblastic leukemia was treated with allogeneic hematopoietic stem cell transplantation after chimeric antigen receptor-modified T cells treatment. During transplantation, disseminated Fusarium infection occurred, involving the skin, liver, spleen and central nervous system, and the patient eventually died. Early identification of Fusarium infection based on the characteristic rash and timely antifungal treatment can improve the cure rate.


Recording morphogen signals reveals origins of gastruloid symmetry breaking.
When cultured in three dimensional spheroids, mammalian stem cells can reproducibly self-organize a single anterior-posterior axis and sequentially differentiate into structures resembling the primitive streak and tailbud. Whereas the embryo's body axes are instructed by spatially patterned extra-embryonic cues, it is unknown how these stem cell gastruloids break symmetry to reproducibly define a single anterior-posterior (A-P) axis. Here, we use synthetic gene circuits to trace how early intracellular signals predict cells' future anterior-posterior position in the gastruloid. We show that Wnt signaling evolves from a homogeneous state to a polarized state, and identify a critical 6-hour time period when single-cell Wnt activity predicts future cellular position, prior to the appearance of polarized signaling patterns or morphology. Single-cell RNA sequencing and live-imaging reveal that early Wnt-high and Wnt-low cells contribute to distinct cell types and suggest that axial symmetry breaking is driven by sorting rearrangements involving differential cell adhesion. We further extend our approach to other canonical embryonic signaling pathways, revealing that even earlier heterogeneity in TGFβ signaling predicts A-P position and modulates Wnt signaling during the critical time period. Our study reveals a sequence of dynamic cellular processes that transform a uniform cell aggregate into a polarized structure and demonstrates that a morphological axis can emerge out of signaling heterogeneity and cell movements even in the absence of exogenous patterning cues.


Synergistic interactions of cytarabine-adavosertib in leukemic cell lines proliferation and metabolomic endpoints.
Drug synergy allows reduced dosing, side effects and tolerance. Optimization of drug synergy chemotherapy is fundamental in acute lymphocytic leukemia and other cancers. This study aimed to analyze the pharmacodynamic synergy between the anti-metabolite cytarabine and WEE1 inhibitor adavosertib on acute leukemia cell lines CCRF-CEM and Jurkat. In both cell lines analysis of concentration-inhibition curves of adavosertib-cytarabine combinations and synergy matrixes supported mutually synergistic drug interactions. Overall mean ( ± SD) synergy scores were higher in Jurkat than CCRF-CEM: Jurkat, ZIP 22.51 ± 1.1, Bliss 22.49 ± 1.1, HSA 23.44 ± 1.0, Loewe 14.16 ± 1.2; and, CCRF-CEM, ZIP 9.17 ± 1.9, Bliss 8.13 ± 2.1, HSA 11.48 ± 1.9 and Loewe 4.99 ± 1.8. Jurkat also surpassed CCRF-CEM in high-degree synergistic adavosertib-cytarabine interactions with mean across-models synergy values of ∼89.1% ± 2.9 for 63 nM cytarabine-97 nM adavosertib (91.4% inhibition synergy barometer). Combination sensitivity scores scatter plots confirmed combination's synergy efficacy. This combined approach permitted identification and prioritization of 63 nM cytarabine-97 nM adavosertib for multiple endpoints analysis. This combination did not affect PBMC viability, while exhibiting Jurkat selective synergy. Immunoblots also revealed Jurkat selective synergistically increased γH2AX phosphorylation, while CDC2 phosphorylation effects were attributed to adavosertib's WEE1 inhibition. In conclusion, the high synergistic efficacy combination of cytarabine (63 nM) and adavosertib (97 nM) was associated with remarkable alterations in metabolites related to the Krebs cycle in Jurkat. The metabolic pathways and processes are related to gluconeogenesis, amino acids, nucleotides, glutathione, electron transport and Warburg effect. All above relate to cell survival, apoptosis, and cancer progression. Our findings could pave the way for novel biomarkers in treatment, diagnosis, and prognosis of leukemia and other cancers.


Genomic variations combined with epigenetic modifications rewire open chromatin in rice.
Cis-regulatory elements (CREs) fine-tune gene transcription in eukaryotes. CREs with sequence variations play vital roles in driving plant or crop domestication. However, how global sequence and structural variations (SVs) are responsible for multilevel changes between indica and japonica rice (Oryza sativa) is still not fully elucidated. To address this, we conducted multiomic studies using MNase hypersensitivity sequencing (MH-seq) in combination with RNA sequencing (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and bisulfite sequencing (BS-seq) between the japonica rice variety Nipponbare (NIP) and indica rice variety 93-11. We found that differential MNase hypersensitive sites (MHSs) exhibited some distinct intrinsic genomic sequence features between NIP and 93-11. Notably, through MHS-genome-wide association studies (GWAS) integration, we found that key sequence variations may be associated with differences of agronomic traits between NIP and 93-11, which is partly achieved by MHSs harboring CREs. In addition, SV-derived differential MHSs caused by transposable element (TE) insertion, especially by noncommon TEs among rice varieties, were associated with genes with distinct functions, indicating that TE-driven gene neo- or subfunctionalization is mediated by changes of chromatin openness. This study thus provides insights into how sequence and genomic SVs control agronomic traits of NIP and 93-11; it also provides genome-editing targets for molecular breeding aiming at improving favorable agronomic properties.


Crystal arthritis.
Diagnostic and classification criteria have the purpose of separating patients with a certain disease from those without the condition and from normal subjects. Specific identification of the different microcrystals establishes the definite diagnosis of crystal arthritides. The diagnostic criteria for gouty arthritis set up by the American Rheumatism Association in 1975 function well; both their sensitivity and specificity are satisfactory. Unfortunately, we have had no data on the real value of the diagnostic criteria used in CPPD or in hydroxyapatite deposition disease. Status or ranking criteria for stratifying patients by state of disease, such as activity or damage, have not been developed as yet in any type of crystal induced arthropathies. Reliable prognostic criteria sets and outcome criteria are clearly needed to indicate the course of the diseases at the onset, as well as to define the overall impact, of crystal deposition diseases.


Synaptopodin-2: a potential tumor suppressor.
Initially identified as an actin-binding protein containing a PSD95-DLG-ZO1 Domain (PZD domain), Synaptopodin 2 (SYNPO2) has long been considered a structural protein ubiquitously expressed in muscular tissues. However, emerging evidence suggests that SYNPO2 performs diverse functions in cancers in addition to its role in microfilament assembly. In most cancers, high SYNPO2 expression is positively correlated with a good prognosis, suggesting its role as a novel tumor suppressor. Abnormal SYNPO2 expression affects autophagy generation, particularly mitophagy induced by low oxidation or viral infection, as well as chaperone-mediated autophagy triggered by microfilament damage. Mechanically, SYNPO2 regulates tumor growth, metastasis, and invasion via activating the PI3K/AKT/mTOR signal and Hippo signaling pathways. Moreover, the subcellular localization, promoter methylation and single nucleotide polymorphism (SNP) of SYNPO2 have been associated with cancer progression and clinical outcomes, highlighting its potential as a prognostic or diagnostic target for this patient population. This review focuses on the role of SYNPO2 in cancer, including its generation, epigenetic modification, subcellular localization, and biological function.


The effect of various topical peri-implantitis antiseptics on Staphylococcus epidermidis, Candida albicans, and Streptococcus sanguinis.
Although peri-implantitis has presented an ever increasing problem in modern dentistry, satisfying therapeutic strategies or scientifically based treatment recommendations are still not available. The main object of the present study was to evaluate the antibacterial efficacy of six different topical antiseptics on three test microorganisms attached to titanium implant specimens. For biofilm formation, plane titan specimens were incubated either in Candida albicans, Streptococcus sanguinis, or Staphylococcus epidermidis for 2h. The specimens were then treated with different topical antiseptics for 60s (sodium hypochlorite 1.0%, hydrogen peroxide 3.0%, chlorhexidine gluconate 0.2%, citric acid 40.0%, Plax, or Listerine) and with sterile saline as control. Remaining vital fungi were quantified by means of a bioluminometric assay and the bacterial load and the viability of adhering S. epidermidis and S. sanguinis by live or dead cell labelling in combination with fluorescence microscopy. Sodium hypochlorite was effective against all three species, whereas hydrogen peroxide was solely effective against C. albicans. CHX and Listerine showed antimicrobial activity against S. sanguinis and C. albicans and citric acid and Plax against both tested bacteria. None of the tested antimicrobial agents, except for sodium hypochlorite, showed a significant in vitro effect on all three test microbes. Considering the possible toxicity of sodium hypochlorite, none of the tested - and so far widely used - antiseptics showed any broad-spectrum antimicrobial effect and could therefore not be recommended for the topical disinfection and detoxification of infected implant surfaces.


Preoperative statin therapy is not associated with a decrease in the incidence of delirium after cardiac operations.
Delirium after cardiac operations is associated with significant morbidity and death. Statins have been recently suggested to exert protective cerebral effects. This study investigated whether preoperative statins were associated with decreased incidence of postoperative delirium in patients undergoing coronary artery bypass grafting. The study enrolled 4,659 consecutive patients (21% women; age, 67.8±9.2 years) undergoing coronary artery bypass grafting. A propensity score-based optimal-matching algorithm was used to match 1,577 patients receiving preoperative statins with a control group (1:1). Patients were screened for delirium in the intensive care unit according to the Confusion Assessment Method for the intensive care unit. Delirium affected 89 patients (3%), and preoperative statin administration was not multivariably associated with a decreased incidence of delirium (odds ratio, 1.52; 95% confidence interval, 0.97 to 2.37; p=0.18) and was also unrelated to a delirium decrease in patient subgroups undergoing isolated coronary artery bypass grafting (odds ratio, 1.31; 95% confidence interval, 0.68 to 2.52; p=0.51) or combined valvular procedures (odds ratio, 1.72; 95% confidence interval, 0.96 to 3.07, p=0.08). Similar results were observed for age groups and cardiopulmonary bypass durations. Patients affected by postoperative delirium experienced a longer hospital stay (25th to 75th percentile) of 11 (7 to 18 days) vs 7 days (7 to 8 days, p<0.001) and 12% hospital mortality vs 1% (p<0.001). Preoperative statins were not associated with a decreased incidence of delirium in patients undergoing coronary revascularization.


Amiloride sensitivity of proton-conductive pathways in gastric and intestinal apical membrane vesicles.
Passive proton permeability of gastrointestinal apical membrane vesicles was determined. The nature of the pathways for proton permeation was investigated using amiloride. The rate of proton permeation (kH+) was determined by addition of vesicles (pHi = 6.5) to a pH 8.0 solution containing acridine orange. The rate of recovery of acridine orange fluorescence after quenching by the acidic vesicles ranged from 4 x 10(-3) (gastric parietal cell stimulation-associated vesicles; SAV) and 5 x 10(-3) (duodenal brush-border membrane vesicles; dBBMV) to 11 x 10(-3) sec-1 (ileal BBMV; iBBMV). Amiloride, 0.03 and 0.1 mM, significantly reduced the rate of proton permeation in dBBMV and iBBMV, but not gastric SAV. The decreases in kH+ were proportionately greater in iBBMV as compared with dBBMV. The presence of Na+/H+ exchange was demonstrated in both dBBMV and iBBMV by proton-driven (pHi less than pHo) 22Na+ uptake. Evidence was also sought for the conductive nature of pathways for proton permeation. Intravesicular acidification, again determined by quenching of acridine orange fluorescence, was observed during imposition of K(+)-diffusion potential ([K+]i much much greater than [K+]o). In dBBMV and iBBMV, intravesicular acidification was enhanced in the presence of the K(+)-ionophore valinomycin, indicating that the native K+ permeability is rate limiting. In the presence of valinomycin, the K(+)-diffusion potential drove BBMV intravesicular acidification to levels close to the electrochemical potential. In gastric SAV, acidification was not limited by the K+ permeability. Valinomycin was without effect, but the K+/H+ ionophore nigericin enhanced acidification in gastric SAV, illustrating the low proton permeability of these membranes.(ABSTRACT TRUNCATED AT 250 WORDS)


Dietary arachidonate in milk replacer triggers dual benefits of PGE2 signaling in LPS-challenged piglet alveolar macrophages.
Respiratory infections challenge the swine industry, despite common medicinal practices. The dual signaling nature of PGE2 (supporting both inflammation and resolution) makes it a potent regulator of immune cell function. Therefore, the use of dietary long chain n-6 PUFA to enhance PGE2 effects merits investigation. Day-old pigs (n = 60) were allotted to one of three dietary groups for 21 d (n = 20/diet), and received either a control diet (CON, arachidonate = 0.5% of total fatty acids), an arachidonate (ARA)-enriched diet (LC n-6, ARA = 2.2%), or an eicosapentaenoic (EPA)-enriched diet (LC n-3, EPA = 3.0%). Alveolar macrophages and lung parenchymal tissue were collected for fatty acid analysis. Isolated alveolar macrophages were stimulated with LPS in situ for 24 h, and mRNA was isolated to assess markers associated with inflammation and eicosanoid production. Culture media were collected to assess PGE2 secretion. Oxidative burst in macrophages was measured by: 1) oxygen consumption and extracellular acidification (via Seahorse), 2) cytoplasmic oxidation and 3) nitric oxide production following 4, 18, and 24 h of LPS stimulation. Concentration of ARA (% of fatty acids, w/w) in macrophages from pigs fed LC n-6 was 86% higher than CON and 18% lower in pigs fed LC n-3 (P < 0.01). Following LPS stimulation, abundance of COX-2 and TNF-α mRNA (P < 0.0001), and PGE2 secretion (P < 0. 01) were higher in LC n-6 PAM vs. CON. However, ALOX5 abundance was 1.6-fold lower than CON. Macrophages from CON and LC n-6 groups were 4-fold higher in ALOX12/15 abundance (P < 0.0001) compared to LC n-3. Oxygen consumption and extracellular acidification rates increased over 4 h following LPS stimulation (P < 0.05) regardless of treatment. Similarly, increases in cytoplasmic oxidation (P < 0.001) and nitric oxide production (P < 0.002) were observed after 18 h of LPS stimulation but were unaffected by diet. We infer that enriching diets with arachidonic acid may be an effective means to enhance a stronger innate immunologic response to respiratory challenges in neonatal pigs. However, further work is needed to examine long-term safety, clinical efficacy and economic viability.


Bacillus subtilis DisA helps to circumvent replicative stress during spore revival.
The mechanisms that allow to circumvent replicative stress, and to resume DNA synthesis are poorly understood in Bacillus subtilis. To study the role of the diadenylate cyclase DisA and branch migration translocase (BMT) RadA/Sms in restarting a stalled replication fork, we nicked and broke the circular chromosome of an inert mature haploid spore, damaged the bases, and measured survival of reviving spores. During undisturbed ripening, nicks and breaks should be repaired by pathways that do not invoke long-range end resection or genetic exchange by homologous recombination, after which DNA replication might be initiated. We found that DNA damage reduced the viability of spores that lacked DisA, BMT (RadA/Sms, RuvAB or RecG), the Holliday junction resolvase RecU, or the translesion synthesis DNA polymerases (PolY1 or PolY2). DisA and RadA/Sms, in concert with RuvAB, RecG, RecU, PolY1 or PolY2, are needed to bypass replication-blocking lesions. DisA, which binds to stalled or reversed forks, did not apparently affect initiation of PriA-dependent DNA replication in vitro. We propose that DisA is necessary to coordinate responses to replicative stress; it could help to circumvent damaged template bases that otherwise impede fork progression.


Pathophysiology of disk-related low back pain and sciatica. II. Evidence supporting treatment with TNF-alpha antagonists.
Strong evidence suggests that TNF-alpha may be among the chemical factors involved in disk-related sciatica. TNF-alpha is involved in the genesis of nerve pain in animal models and may promote pain-signal production from nerve roots previously subjected to mechanical deformation. In animal experiments, TNF-alpha has been identified in nucleus pulposus and Schwann cells. Local production of endogenous TNF-alpha may occur early in the pathogenic process. Exposure to exogenous TNF-alpha induces electrophysiological, histological, and behavioral changes similar to those seen after exposure to nucleus pulposus, and these changes are more severe when mechanical compression is applied concomitantly. TNF-alpha antagonists diminish or abolish abnormalities in animal models. Other cytokines may be involved also, as suggested by the potent inhibitory effects of compounds such as doxycycline. Two open-label studies in humans suggest dramatic efficacy of TNF-alpha antagonists in alleviating disk-related sciatica. In contrast, the results of the only controlled study available to date do not support a therapeutic effect of TNF-alpha antagonists. Thus, whether TNF-alpha antagonist therapy is warranted in patients with disk-related sciatica remains an open question, and further randomized controlled studies are needed.


Hearing testing in baby health centres: pilot scheme for evaluation of a new method.
A new method of hearing testing has been evaluated on a trial basis in the Baby Health Centres of the Sydney Inner Metropolitan and Illawarra Health Regions, of New South Wales. This consists of earlier and more frequent testing with a newly devised range of auditory stimuli presented in front of the child, rather than behind the child. The reason for the change is that earlier detection leads to earlier treatment and improved speech. The new method will assess whether there is adequate hearing for speech development.


Foliar Application of Low Concentrations of Titanium Dioxide and Zinc Oxide Nanoparticles to the Common Sunflower under Field Conditions.
Nano-fertilisers have only recently been introduced to intensify plant production, and there still remains inadequate scientific knowledge on their plant-related effects. This paper therefore compares the effects of two nano-fertilisers on common sunflower production under field conditions. The benefits arising from the foliar application of micronutrient-based zinc oxide fertiliser were compared with those from the titanium dioxide plant-growth enhancer. Both the zinc oxide (ZnO) and titanium dioxide (TiO2) were delivered by foliar application in nano-size at a concentration of 2.6 mg·L-1. The foliar-applied nanoparticles (NPs) had good crystallinity and a mean size distribution under 30 nm. There were significant differences between these two experimental treatments in the leaf surfaces' trichomes diversity, ratio, width, and length at the flower-bud development stage. Somewhat surprisingly, our results established that the ZnO-NPs treatment induced generally better sunflower physiological responses, while the TiO2-NPs primarily affected quantitative and nutritional parameters such as oil content and changed sunflower physiology to early maturation. There were no differences detected in titanium or zinc translocation or accumulation in the fully ripe sunflower seeds compared to the experimental controls, and our positive results therefore encourage further nano-fertiliser research.


Myocardial deformation assessment in patients with precapillary pulmonary hypertension: A cardiac magnetic resonance study.
The purpose of this study was to investigate right atrial and ventricular strain parameters on cardiac magnetic resonance (CMR) in patients with precapillary pulmonary hypertension (PPH) and whether they can aid in the assessment of PPH prognosis. Adult patients with groups 1 and 4 PPH were invited to participate in the study. Age- and sex-matched healthy volunteers were also recruited as controls. At baseline, patients underwent clinical examination, N-terminal pro-B-type natriuretic peptide measurement and CMR with feature tracking post-processing (CMR-FT). Healthy controls underwent only CMR-FT. The study's primary endpoint was clinical failure, defined as death, hospitalization or demonstrable clinical deterioration during follow-up. Patients who were unable to perform 6-minute walking test due to musculoskeletal disorders were excluded from the study. Thirty-six patients (8 men, 28 women; mean age, 50.6±13.8 [SD] years [range: 18.6-78.5years]) and 12 healthy control subjects (5 mean, 7 women; mean age, 40.6±13.5 [SD] years [range: 23.1-64.4years]) were recruited. Right ventricular global longitudinal strain (GLS) was significantly impaired in PPH patients (-20.2±5.3 [SD] % [range: -28.8 to -9.1%] vs. -28.4±3.1% [-33.7 to -22.7%] respectively, P<0.001). The right atrial GLS was significantly impaired in PPH compared to healthy controls (-19.9±4.5% [range: -28.6 to -3.6%] vs. -26.5±4.2% [range: -32.8 to -15.8%] respectively) (P<0.001). Clinical failure occurred in 19 (19/36, 53%) of patients. Right ventricular GLS predicted clinical failure most reliably among CMR parameters (-22.6±3.8 [SD] % [range: -27.6 to -12.7%] for patients without clinical failure vs. -18±5.6 [SD] % [range: -28.8 to -9.1%] for patients with clinical failure; hazard ratio [HR]=1.85; P=0.007; area under the AUC curve=0.75). Lower absolute right atrial GLS was significantly associated with clinical failure (-22.7±3.0 [SD] % [range: -28.6 to -17.7%] for patients without clinical failure vs. -16.9±5.8 [SD] % [range: -24.2 to -3.6%] for patients with clinical failure) (HR=1.53; P=0.035). CMR feature tracking-derived myocardial strain parameters of both the right atrium and ventricle can assist clinicians in the prognosis of PPH.


Nurses' perspectives on shift-to-shift handovers in relation to person-centred nursing home care.
The aim of this study was to gain insight into nurses' perspectives on the shift-to-shift handover in relation to providing Person-centred care (PCC) in nursing homes. PCC is perceived as the gold standard for nursing home care. To preserve the continuity of PCC, an adequate handover during the nurses' shift change is essential. There is, however, little empirical evidence for what constitutes best shift-to-shift nursing handover practices in nursing homes. An exploratory qualitative descriptive study. Nine nurses were selected purposively and through snowball sampling from five Dutch nursing homes. Semi-structured face-to-face and telephone interviews were conducted. Analysis relied on Braun and Clarke's thematic analysis. Four main themes were identified related to enabling PCC informed handovers: (1) knowing the resident to be enable to provide PCC was key, (2) the actual handover, (3) additional ways of information transfer and (4) nurses' knowledge of the resident prior to start shift. The shift-to-shift handover is one way that nurses become informed about residents. Knowing the resident is essential to enable PCC. The fundamental underlying question is to what extent nurses have to know the resident in order to enable PCC. Once that level of detail has been established, in-depth research is needed to determine the best method for conveying this information to all nurses. Only then can we start to rethink the role of the shift-to-shift handover in conveying PCC-driven information. No Patient or Public Contribution.


[Profile and management of patients consulting for a non severe exacerbation of chronic obstructive pulmonary disease (Pragma survey)].
To evaluate, in patients with chronic obstructive pulmonary disease (COPD), stage 0 or 1, the percentage of patients who had spirometry, and to study their sociodemographic, clinical and epidemiological characteristics. An epidemiological survey was conducted with 2389 general practitioners concerning 4769 patients with early COPD, consulting for the first time for exacerbation of COPD, presumed to be bacterial. Spirometry under stable conditions was performed in only 30% of patients. When the physician does not have access to this examination to guide antibiotic prescription for an exacerbation presumed to be bacterial, recent guidelines have established a correlation between dyspnoea and the degree of severity of COPD (GOLD classification). This correlation was not confirmed by the present study: 34% of patients with stage 0 or 1 COPD complained of dyspnoea and 52% of patients with stage 2 or 3 COPD did not complain of dyspnoea. The main criterion in favour of a bacterial cause of exacerbation, frank purulent sputum, observed in one out of three patients, did not influence the decision to prescribe antibiotics, given to 98% of patients. Therapy used bronchodilators (73%), even in patients with no signs of obstruction, and inhaled steroids (72%), although, according to guidelines, they are only indicated in the most serious forms (stage 3). This survey illustrates the effort needed to ensure better concordance between guidelines and practice, by taking into account the difficulties encountered by practitioners.


MAPK/ERK1/2 and PI3-kinase signalling pathways are required for vitreous-induced lens fibre cell differentiation.
Lens epithelial cells withdraw from the cell cycle to differentiate into secondary fibre cells in response to vitreal factors. Fibroblast growth factor (FGF) in the vitreous has been shown to induce lens fibre differentiation in vivo and in vitro through the activation of defined intracellular signalling, namely via MAPK/ERK1/2 and PI3-K/Akt pathways. To better understand the role of these growth factor-activated signalling pathways in lens fibre differentiation, FGF- and vitreous-induced lens fibre differentiation was examined in primary rat lens epithelial cell explants. The induction of cell elongation and fibre specific beta- and gamma-crystallin expression in lens explants was accompanied by distinct phosphorylation profiles for ERK1/2 and Akt. Using selective inhibitors (U0126 and LY294002) in blocking studies, these pathways were shown to be required for different aspects of lens fibre differentiation. Furthermore, a short 'pulse' treatment of explants with FGF showed that the activation of ERK1/2 over 24 h was not sufficient for the progression of lens fibre differentiation and that cyclic ERK1/2 phosphorylation was required throughout the extended differentiation process. In conclusion, these results support a key role for both ERK1/2 and PI3-kinase/Akt signalling pathways in FGF- and vitreous-induced lens fibre differentiation.


Moving Forward the State of the Art in Prostate Cancer Treatment: Targeted Focal Therapy.
The diagnosis and treatment of prostate cancer have changed dramatically in the prostate specific antigen era. We are now faced with the clinical dilemma of over diagnosis and overtreatment. Targeted focal therapy offers a potential middle ground between the binary choices of active surveillance and the whole gland treatments of radical prostatectomy or radiotherapy. A PubMed® search was performed using the terms "targeted focal therapy," "focal therapy," "hemiablation" and "transperineal mapping biopsy" to locate studies and reviews published after 2000 pertaining to targeted focal therapy of the prostate. Key articles were selected and included in this review, which covers the practical aspects of targeted focal therapy for prostate cancer. Three international, multidisciplinary consensus statements were located which provide best practice for patient selection in ongoing and future trials of targeted focal therapy. Other studies located for the review elaborate on the best techniques to properly stage a case of histologically confirmed prostate cancer under consideration for focal therapy and summarize outcomes reported to date in the literature. Phase I and II studies of targeted focal therapy for prostate cancer have demonstrated safety and efficacy. With improved imaging and standardized patient selection criteria, phase III study is under way, perhaps setting the stage for a new era of prostate cancer therapy for many individuals.


High prevalence of infections and autoimmunity in patients with thymoma.
The thymus selects T cells, thus ensuring T cell tolerance. Thymoma can be associated with immune dysregulation manifesting as autoimmunity and/or immunodeficiency. Immune dysregulation in thymoma patients has only been described in case reports and small case series. The current study was a retrospective single-center study, covering the period 1/2000 to 12/2010. Clinical data were collected by chart review. We identified 29 patients with thymoma. The median age at diagnosis was 60 years (range: 23-87). Median follow-up time was 1,326 days (range: 15-3,710), and 20 patients (69%) were alive at last follow-up. Overall, in 13 of 29 patients (45%) autoimmunity and infection were observed in 7 of 29 (24%) and 3 of 29 patients (10%) infection and autoimmunity only was observed, respectively. Both opportunistic and nonopportunistic infections were recorded. Myasthenia gravis (10 of 29 patients) was the most frequent autoimmune disease. Additional entities included pemphigus, pure red cell aplasia, lichen planus, Sjögren's syndrome, systemic lupus erythematosus (n = 2 each), and cutaneous lupus erythematosus, sarcoidosis, vitiligo, polymyositis, and chronic inflammatory demyelinating polyradiculoneuropathy (n = 1 each). Six of 29 patients (21%) had more than 1 autoimmune disorder. In thymoma patients, infection, autoimmunity, and in particular a combination of both pose a challenge to treating physicians. Prospective multicenter studies are required to more precisely define the thymoma-associated immune dysregulation syndrome.


Seizures in pregnancy: diagnosis and management.
Most seizures during pregnancy occur in women who already have epilepsy. During pregnancy most women will continue their previous level of seizure control, although 15-30% may experience an increase in seizures. Pregnancy-induced changes in antiepileptic drug pharmacokinetics are a major factor affecting changes in seizure control during pregnancy, although compliance is also a significant factor. Status epilepticus occurs in only 1-2% of pregnancies, and if treated appropriately and aggressively carries a fairly low risk of morbidity and mortality. Structural and metabolic changes may precipitate new-onset seizures during pregnancy. The structural causes include intracranial hemorrhage of multiple types, cerebral venous sinus thrombosis, and ischemic stroke. Metabolic causes include hyperemesis gravidarum; acute hepatitis (due to fatty liver of pregnancy or viral hepatitis); metabolic diseases, such as acute intermittent porphyria; infections, such as malaria; and eclampsia.


Genetic analysis of human clinical isolates of Lactococcus garvieae: Relatedness with isolates from foods.
Lactococcus garvieae is a Gram-positive bacterium well-known as an important pathogen in aquaculture, and it is also a human pathogen of increasing clinical significance. Forty-three human L. garvieae isolates from clinical specimens were characterized by Multilocus Sequence Typing (MLST). Twenty-six different sequence types (STs) were identified among the human isolates, of which 20 were novel STs. Most human isolates clustered into four clonal complexes, with a predominance of CC3. Within CC3, ST10 was the most common genotype, indicating the existence of a circulating genetic lineage among the human isolates analyzed. The four CCs also grouped L. garvieae strains isolated from meat, dairy and fish, indicating a genetic overlap between isolates from human and these foods. Genetic relatedness among human and food L. garvieae isolates was confirmed by phylogenetic analysis based on the concatenated sequences of the seven MLST genes. These results represent the first evidence of genetic relatedness between isolates of L. garvieae of human and those isolated meat, milk and dairy products and suggest that, in addition to fish and seafood, these foods might represent important sources of human L. garvieae infections.


Ambiguous melanocytic lesions: A retrospective cohort study of incidence and outcome of melanocytic tumor of uncertain malignant potential (MELTUMP) and superficial atypical melanocytic proliferation of uncertain significance (SAMPUS) in the Netherlands.
Melanocytic tumor of uncertain malignant potential (MELTUMP) and superficial atypical melanocytic proliferation of uncertain significance (SAMPUS) are descriptive and provisional terms for melanocytic tumors with ambiguous histopathological features that are not easily classified as either benign or malignant. To investigate the incidence and clinical outcome of MELTUMP and SAMPUS in the Netherlands. In this retrospective cohort study, we reviewed all diagnoses of MELTUMP and SAMPUS from the Dutch Nationwide Pathology Databank from 1991 to October 1, 2021. Clinical outcome was studied for cases diagnosed until October 1, 2018. A total of 1685 MELTUMP and 1957 SAMPUS were identified with an annual incidence of 150 to 300 cases. Metastatic behavior was seen in 0.7% of all initially diagnosed MELTUMP. All SAMPUS remained free of metastases. Reassessment of pathology slides and confirmation of clonality between primary and metastatic lesions remained outside the scope of this study. Despite the 'uncertainty' in the nomenclature, our results demonstrate a low malignant potential for MELTUMP and no malignant potential for SAMPUS. We emphasize the importance of consultation for ambiguous melanocytic lesions and to limit the MELTUMP/SAMPUS terminology to legitimately uncertain or unclassifiable cases.


The genetic susceptibility analysis of TAAR1 rs8192620 to methamphetamine and heroin abuse and its role in impulsivity.
Abnormal genetic polymorphism of trace amine-associated receptor 1 (TAAR1) rs8192620 site has been confirmed to induce methamphetamine (MA) use and drug craving. However, the genetic susceptibility difference between MA addicts and heroin addicts is unknown. This study evaluated genetic heterogeneity of TAAR1 rs8192620 between MA and heroin addicts and elucidated whether rs8192620 genotypes associated with discrepancy in emotional impulsivity, which would help to instruct individualized treatment in addiction via acting on TAAR1 and evaluate risk of varied drug addiction. Participants consisting of gender-matched 63 MA and 71 heroin abusers were enrolled in the study. Due to mixed drug usage in some MA addicts, MA users were further subdivided into 41 only-MA (only MA taking) and 22 mixed-drug (Magu composed of about 20% MA and 70% caffeine) abusers. Via inter-individual single nucleotide polymorphism (SNP) analysis and two-sample t tests, respectively, the genotypic and Barratt Impulsiveness Scale-11 (BIS-11) scores differences between groups were completed. With following genotypic stratification, the differences in BIS-11 scores between groups were analyzed through two-sample t test. Individual SNP analysis showed significant differences in alleles distribution of rs8192620 between MA and heroin subjects (p = 0.019), even after Bonferroni correction. The TT homozygotes of rs8192620 dominated in MA participants, while C-containing genotypes in heroin (p = 0.026). There was no association of genotypes of TAAR1 rs8192620 with addicts' impulsivity. Our research indicates that the TAAR1 gene polymorphism might mediate the susceptibility discrepancy between MA and heroin abuse.


Data on plasma levels of apolipoprotein E, correlations with lipids and lipoproteins stratified by APOE genotype, and risk of ischemic heart disease.
Data on correlations of plasma apoE with levels of lipids and lipoproteins stratified by APOE genotypes as well as data exploring the association between plasma levels of apoE and risk of ischemic heart disease (IHD) are wanted. The present data on 91,695 individuals from the general population provides correlations between plasma levels of apoE and lipids and lipoproteins for the three APOE genotypes ε33, ε44 and ε22, representing each of the three apoE isoforms. Further, data on extreme groups of plasma apoE (highest 5%) versus lower levels of apoE at enrollment explores risk of IHD and myocardial infarction (MI) and is given as hazard ratios. In addition, IHD and MI as a function of apoE/high-density lipoprotein (HDL) cholesterol ratio, as well as data on lipids, lipoproteins and apolipoproteins are given as hazard ratios. Data is stratified by gender and presented for the Copenhagen General Population Study and the Copenhagen City Heart Study combined.


The role of insurance data in setting priorities for netball injury prevention strategies.
The aim of this study was to investigate insurance records for a one-year period to determine the injury frequencies and costs associated with different age groups in netball. The insurance records for all netball claims made during 1999 in Victoria were obtained from the insurer and entered into a database. The overall injury rate was 9.49 injuries per 1000 players, with 829 claims for injuries filed with the insurance company. Of all injuries claimed for, 85.3% were to the lower limb, 8.7% to the upper limb, 3.1% to the spine/torso and 2.9% to the head and face. Lower limb injuries accounted for 85.4% of costs, upper limb injuries 10.7% and head/neck/torso injuries 3.9% of total injury costs. Knee injuries accounted for 56.9% of total costs, with ankle and calf/Achilles injuries costing 12.7 and 11.8% of total costs, respectively. Injury prevention strategies should therefore be directed to three main injuries taking into account costs and incidence. These injuries were: ankle sprains, knee ligament sprains and Achilles tendon strains. Specifically, the prevention program for Achilles injuries should be directed to the >25 years age groups.