[A hemolytic crisis with liver failure as the first manifestation of Wilson's disease].
An 18-year-old woman developed an acute haemolytic anaemia, acute transient renal failure and progressive hepatic failure. Coeruloplasmin and serum copper concentration were normal; a Kayser-Fleischer ring and any neurological symptoms were absent initially. Liver biopsy was contraindicated because of increased bleeding tendency. Wilson's disease was diagnosed only after the acute renal failure had regressed, on the basis of the urinary copper excretion (2890 micrograms/d, rising to 7330 micrograms/d after D-penicillamine administration). Progressive liver failure required transplantation. After it the patient quickly recovered and is now, two years later, free of disease. -This case demonstrates that Wilson's disease may be difficult to diagnose at the time of initial acute manifestation. But it can be recognized early from the pathognomonic low alkaline phosphatase and by calculation of free serum copper.


Identification of hub genes in peripheral blood mononuclear cells for the diagnosis of hepatocellular carcinoma using a weighted gene co-expression network analysis.
Human hepatocellular carcinoma (HCC) is a common malignant tumor of the digestive tract that is prevalent worldwide. Improving diagnosis methods for HCC helps to improve patient survival rate. The present study aimed to identify novel HCC biomarkers for the diagnosis of HCC through analyzing gene changes on peripheral blood mononuclear cells (PBMCs) and verifying these in additional samples. The gene expression profiles GSE49515 (including 10 specimens from normal patients and 10 specimens from patients with HCC) and GSE58208 (including 5 specimens from normal patients and 10 specimens from patients with HCC) were downloaded from the online Gene Expression Omnibus database (GEO). Differentially expressed genes (DEGs) in PBMCs between healthy controls and patients with HCC were identified using R software. A total of 935 DEGs, including 686 upregulated DEGs and 249 downregulated DEGs, were identified in the present study. In order to identify any internal associations, these DEGs were used to construct weighted gene co-expression networks (WGCNA). Gene Ontology (GO) enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis of genes in each module were conducted using the online database DAVID. Furthermore, hub genes with high module membership were identified in a co-expression network and receiver operating characteristic curves were used to verify the diagnostic values of these eight hub genes. Furthermore, the expression and diagnosis value of the eight hub genes were also verified in additional samples. The results of the present study suggested that secreted protein acidic and cysteine rich(SPARC), transmembrane protein 40 (TMEM40), solute carrier family 25 member 44, formyl peptide receptor 2 (FPR2), complement C8 β chain, N-myristoyltransferase 1, protein kinase C δ(PRKCD) and protein phosphatase, Mg2+/Mn2+ dependent 1M(PPM1M) were hub genes. SPARC, TMEM40, FPR2, PRKCD and PPM1M had prominent diagnostic value according to the results from the GEO data and the additional samples. The present study demonstrated that these hub genes may help to improve the diagnosis of HCC.


Crystal structures of the class D beta-lactamase OXA-13 in the native form and in complex with meropenem.
The therapeutic problems posed by class D beta-lactamases, a family of serine enzymes that hydrolyse beta-lactam antibiotics following an acylation-deacylation mechanism, are increased by the very low level of sensitivity of these enzymes to beta-lactamase inhibitors. To gain structural and mechanistic insights to aid the design of new inhibitors, we have determined the crystal structure of OXA-13 from Pseudomonas aeruginosa in the apo form and in complex with the carbapenem meropenem. The native form consisted of a dimer displaying an overall organisation similar to that found in the closely related enzyme OXA-10. In the acyl-enzyme complex, the positioning of the antibiotic appeared to be ensured mainly by (i) the covalent acyl bond and (ii) a strong salt-bridge involving the carboxylate moiety of the drug. Comparison of the structures of OXA-13 in the apo form and in complex with meropenem revealed an unsuspected flexibility in the region of the essential serine 115 residue, with possible consequences for the catalytic properties of the enzyme. In the apo form, the Ser115 side-chain is oriented outside the active site, whereas the general base Lys70 adopts a conformation that seems to be incompatible with the activation of the catalytic water molecule required for the deacylation step. In the OXA-13:meropenem complex, a 3.5 A movement of the backbone of the 114-116 loop towards the side-chain of Lys70 was observed, which seems to be driven by a displacement of the neighbouring 91-104 loop and which results in the repositioning of the side-chain hydroxyl group of Ser115 toward the catalytic centre. Concomitantly, the side-chain of Lys70 is forced to curve in the direction of the deacylating water molecule, which is then strongly bound and activated by this residue. However, a distance of ca 5 A separates the catalytic water molecule from the acyl carbonyl group of meropenem, a structural feature that accounts for the inhibition of OXA-13 by this drug. Finally, the low level of penicillinase activity revealed by the kinetic analysis of OXA-13 could be related to the specific presence in position 73 of a serine residue located close to the general base Lys70, which results in a decrease of the number of hydrogen-bonding interactions stabilising the catalytic water molecule.


[Multistage mechanism of reproductive sympatric isolation of the closely-related species, Ixodes persulcatus and I. Pavloskyi (Ixodidae)].
The closely related species Ixodes persulcatus and I. pavlovskyi are vectors of agents tick-born encephalitis and Lyme disease. These species have two great disjunctive sympatric distribution areas (fig. 1), where both species inhabit the same biotopes, and during the same season. In these conditions there are prerequisites of contacts of opposite sexes of the different species during ambushing the hosts on vegetation. Sequence of "switching on" of the morphological, physiological, and hostparasite factors of reproductive isolation has been established. The features and the range of manifestation of these factors at different combinations of sexes and species of the partners have been revealed. The studied factors, such as precopulative and postcopulative components of the mechanism of reproductive isolation of I. persulcatus and I. pavlovskyi were considered. A hypothesis for sympatric origin of the species as a result of specialization the adults of I. persulcatus to mammals, and I. pavlovskyi to birds is proposed.


Easily manufactured TiO2 hollow fibers for quantum dot sensitized solar cells.
TiO(2) hollow fibers with high surface area were manufactured by a simple synthesis method, using natural cellulose fibers as template. The effective light scattering properties of the hollow fibers, originating from their micron size, were observed by diffuse reflectance spectroscopy. In spite of the micrometric length of the TiO(2) hollow fibers, the walls were highly porous and high surface area (78.2 m(2) g(-1)) was obtained by the BET method. TiO(2) hollow fibers alone and mixed with other TiO(2) pastes were sensitized with CdSe quantum dots (QDs) by Successive Ionic Layer Adsorption and Reaction (SILAR) and integrated as a photoanode in quantum dot sensitized solar cells (QDSCs). High power conversion efficiency was obtained, 3.24% (V(oc) = 503 mV, J(sc) = 11.92 mA cm(-2), FF = 0.54), and a clear correspondence of the cell performance with the photoanode structure was observed. The unique properties of these fibers: high surface area, effective light scattering, hollow structure to facile electrolyte diffusion and the rather high efficiencies obtained here suggest that hollow fibers can be introduced as promising nanostructures to make highly efficient quantum dot sensitized solar cells.


Spiropyrimidinetriones: a Class of DNA Gyrase Inhibitors with Activity against Mycobacterium tuberculosis and without Cross-Resistance to Fluoroquinolones.
Described here is a series of spiropyrimidinetrione (SPT) compounds with activity against Mycobacterium tuberculosis through inhibition of DNA gyrase. The SPT class operates via a novel mode of inhibition, which involves Mg2+-independent stabilization of the DNA cleavage complex with DNA gyrase and is thereby not cross-resistant with other DNA gyrase-inhibiting antibacterials, including fluoroquinolones. Compound 22 from the series was profiled broadly and showed in vitro cidality as well as intracellular activity against M. tuberculosis in macrophages. Evidence for the DNA gyrase mode of action was supported by inhibition of the target in a DNA supercoiling assay and elicitation of an SOS response seen in a recA reporter strain of M. tuberculosis. Pharmacokinetic properties of 22 supported evaluation of efficacy in an acute model of M. tuberculosis infection, where modest reduction in CFU numbers was seen. This work offers promise for deriving a novel drug class of tuberculosis agent without preexisting clinical resistance.


[Cyclophosphamide bolus therapy in lupus nephritis].
A pilot study of 21 patients (17 women; 4 men; mean age 35 [18-59] years), randomized into two groups, was undertaken to test how many cycles of intravenous pulse cyclophosphamide administration were required in lupus nephritis to achieve remission. It was planned that patients randomized to group A should be treated for 3 months, those in group B for over 12 months. In the first cycle the cyclophosphamide dosage was 500 mg/m2, in the subsequent cycles, 4 weeks apart, it was raised by 250 mg/m2 to a maximum of 1,000 mg/m2, if the WBC count was over 2,000/microliters. Three women in group B gave up treatment prematurely after 5-8 cycles, because a remission had occurred. In group A only one patient went into remission after only three cycles. Of the total of 18 patients in both groups whose data could be evaluated, 15 achieved remission after an average of 7.3 cycles and a cumulative total cyclophosphamide dosage of 9.3 g. The disease progressed in two patients, one died. No recurrence has so far been observed after a follow-up period of 1-41 months. Three patients had infections and two had developed leukopenia as side effects. Pulse cyclophosphamide has thus been shown to be an effective treatment in lupus nephritis, but it must be continued for more than 3 months.


Neural G0: a quiescent-like state found in neuroepithelial-derived cells and glioma.
Single-cell RNA sequencing has emerged as a powerful tool for resolving cellular states associated with normal and maligned developmental processes. Here, we used scRNA-seq to examine the cell cycle states of expanding human neural stem cells (hNSCs). From these data, we constructed a cell cycle classifier that identifies traditional cell cycle phases and a putative quiescent-like state in neuroepithelial-derived cell types during mammalian neurogenesis and in gliomas. The Neural G0 markers are enriched with quiescent NSC genes and other neurodevelopmental markers found in non-dividing neural progenitors. Putative glioblastoma stem-like cells were significantly enriched in the Neural G0 cell population. Neural G0 cell populations and gene expression are significantly associated with less aggressive tumors and extended patient survival for gliomas. Genetic screens to identify modulators of Neural G0 revealed that knockout of genes associated with the Hippo/Yap and p53 pathways diminished Neural G0 in vitro, resulting in faster G1 transit, down-regulation of quiescence-associated markers, and loss of Neural G0 gene expression. Thus, Neural G0 represents a dynamic quiescent-like state found in neuroepithelial-derived cells and gliomas.


Psychosocial Suicide Prevention Interventions in the Elderly: A Mini-Review of the Literature.
In Europe the elderly population is projected to increase from 18.5% (93.9 million) in 2014 to 28.7% (149.1 million) by 2080. In the United States it is estimated that by 2030 more than 20% of the population will be aged 65 years or over. This specific population is at high risk of unrecognized or untreated psychiatric illnesses and suicide. It is well known that completed suicide rate increases with age in both men and women. Although elderly people attempt suicide less often than other age groups, they show a higher completion rate. Generally, the methods chosen by elderly are more lethal, the intent is more serious, they are more determined, and they show fewer warning signs than the younger population. A recent systematic review and meta-analysis of psychosocial intervention, following self-harm in adults, found that cognitive behavioral therapy was the most effective therapy in these patients. Unfortunately, there have been few reported trials of other potentially effective interventions. Because the scientific literature on psychosocial suicide prevention interventions in the elderly is still scant, we conducted a mini-review in order to take stock of the situation. Studies were identified through electronic searches of the Cochrane library, MEDLINE, Scopus and the Web of Science databases. PRISMA guidelines were followed and only seven articles met the inclusion criteria. No firm conclusions can be drawn about this topic because there is still very little data and studies use inconsistent outcome measures and designs. Nonetheless, the existing data suggests that psychosocial interventions are promising.


Transition from escaped to decomposed nematic defects, and vice versa.
An escaped radial director profile in a nematic liquid crystal cell can be transformed into a pair of strength m = +1/2 surface defects (and their associated disclination lines) at a threshold electric field. Analogously, a half-integer defect pair can be transformed at a threshold electric field into a director profile that escapes into the third dimension. These transitions were demonstrated experimentally and numerically, and are discussed in terms of topologically discontinuous and continuous pathways that connect the two states. Additionally, we note that the pair of disclination lines associated with the m = +1/2 surface defects were observed to co-rotate around a common point for a sufficiently large electric field at a sufficiently low frequency.


Interaction of melanosomal proteins with melanin.
Melanin is deposited in melanosomes upon a proteinaceous matrix enveloped by a melanosomal membrane. Since melanin is highly detergent insoluble, we hypothesized that the detergent solubility of proteins of the melanosomal matrix might be inversely related to the state of melanosomal melanization. Immunoblotting analyses were performed on extracts of albino and black melanocytes to test this hypothesis. The protein products of the silver (si) and the pink-eyed-dilution (p) loci as well as other matrix constituents were present at twofold higher levels in extracts of albino cells. When black cells were rendered amelanotic by growing cultures in the presence of the tyrosinase inhibitor phenylthiourea, the apparent levels of these proteins were also increased. To obviate the potential role of different levels of synthesis in contributing to these differences, we developed a cell-free melanosomal melanization assay. Upon incubation of a melanosome-rich fraction with the melanin precursor L-3,4-dihydroxyphenylalanine (Dopa) followed by immunoblot analysis, the si locus protein, the p locus protein, and other putative matrix constituents became rapidly insoluble in SDS when compared with the members of the tyrosinase-related family of melanosomal membrane proteins. Our results suggest that melanosomal proteins that interact with melanin may be identified by their relative insolubility in SDS under conditions of increasing melanization. In addition to the si locus protein and other putative melanosomal matrix proteins, the membrane-bound p locus protein may also interact closely with melanin.


Comparison of the NIST and BIPM Standards for Air Kerma in Medium-Energy X-Rays.
A comparison has been made of the air-kerma standards for medium-energy x-rays of the National Institute of Standards and Technology (NIST) and the Bureau International des Poids et Mesures (BIPM). The comparison involved a series of measurements at the BIPM and the NIST using the air-kerma standards and three NIST reference-class transfer ionization chamber standards. Reference beam qualities in the range from 100 kV to 250 kV were used. The results show the standards to be in reasonable agreement within the combined standard uncertainty of the comparison of 0.37 %, although a significant trend with radiation quality is observed and the possible sources discussed.


Comparing undergraduate research experiences before, during, and after the COVID-19 quarantine: The successful adaptation of the BUILD PODER Summer JumpStart program.
In March 2020, the COVID-19 pandemic forced many in person undergraduate research experiences (UREs) to pivot to remote online training. To investigate how the COVID-19 quarantine disrupted student URE outcomes over time, the current study examines Building Infrastructure Leading to Diversity (BUILD) Promoting Opportunities for Diversity in Education and Research (PODER) URE outcomes across different platforms (in-person, remote, and hybrid models) by comparing student survey data from 2019 to 2021. Participants consisted of three cohorts: 2019 (n = 26 students), 2020 (n = 33), 2021 (n = 34). The BUILD PODER Summer JumpStart program (SJS), which aims to increase diversity in Science, Technology, Engineering, and Mathematics (STEM) by recruiting mostly underrepresented students, was conducted in person in 2019, remotely in 2020 and using a hybrid model in 2021. All students completed an online survey on the first and last day of the four-week SJS program. We used one-way and mixed ANOVA models to analyze Cohort, Time (pre-test vs. post-test scores), and interaction of Cohort and Time for Research Self-Efficacy, Sense of Belonging, Mentor Relationship, Mentee Knowledge, Health, Stress, and Student Program Satisfaction measures. Despite the platform changes, student scores increased significantly over time for all measures. There was a significant main effect of Time for Research Self-Efficacy, Sense of Belonging, Mentor Relationship, Mentee Knowledge, Health Assessment, and Stress Management. Findings indicate that URE programs that are implemented remotely and using a hybrid format can provide students with experiences similar to in-person URE programs. In addition, remote UREs may provide added benefits compared to in-person programs. For instance, remote UREs could engage more historically minoritized students, who may experience barriers to access, such as work/family commitments, financial constraints, and geographic limitations.


Effect of curcumin on lung resistance-related protein (LRP) in retinoblastoma cells.
Multidrug resistance to anticancer drugs is a major cause of chemotherapy failure in cancer patients. Lung resistance-related protein (LRP) has been identified as the major vault protein (MVP) in humans, which is associated with multidrug resistance in various cancer cells. Overexpression of LRP is found in many solid tumors and cancer cell lines. In this study, curcumin mixture was used to study the modulation of LRP in Y79 retinoblastoma cell line by Western blot and RT-PCR. RT-PCR and Western blot was carried to determine the expression of LRP mRNA and protein level. Western blot and RT-PCR analysis showed that curcumin inhibited LRP expression in a dose-dependent manner in the Y79 retinoblastoma cell line. These results demonstrate that curcumin modulated the expression of LRP in the Y79 retinoblastoma cell line. Thus, curcumin may be used as a chemosensitizer to make the retinoblastoma cells more sensitive to the effects of chemotherapy.


Novel cytosine deaminase fusion gene enhances the effect of radiation on breast cancer in bone by reducing tumor burden, osteolysis, and skeletal fracture.
Painful breast carcinoma metastases in bone are a common manifestation of malignant disease. Eradication of these tumors can be evasive, and as a result, skeletal morbidity increases with disease progression. The treatment potential of cytosine deaminase (CD) gene therapy combined with radiation treatment was evaluated in vitro and in vivo using a 4T1 murine breast carcinoma model. 4T1 carcinoma cells were transduced with a fusion gene encoding the extracellular and transmembrane domains of the human nerve growth factor receptor and the cytoplasmic portion of the yeast CD gene (NGFR-CD(y)). CD-expressing tumor cells (4TCD(y)) were highly sensitive to treatment by 5-fluorocytosine prodrug (P < 0.0001). 5-Fluorocytosine treatment of 4TCD(y), but not 4T1 cells, enhanced the effects of radiation in vitro (P < 0.0001). 5-Fluorocytosine prodrug treatment also increased the therapeutic potential of radiation in vivo. Mice with 4TCD(y) intrafemoral tumors showed increased effectiveness of radiation based on improved reductions in tumor size, reductions in tumorigenic osteolysis, and a decrease in skeletal fractures (P < 0.01).


Neonatal encephalopathy in foals.
Neonatal encephalopathy is a common central nervous system disorder of neonatal foals and human infants, resulting in clinical signs such as lethargy, inappropriate behavior, seizures, and other neurologic deficits. Although neonatal encephalopathy is frequently seen in equine practice, a paucity of veterinary clinical and basic science research data is available. Therefore, the pathophysiologic mechanisms of this disorder in equids, such as energy deprivation, excess excitatory amino acids, and free radical injury, have been extrapolated from human medicine. Equine veterinarians have used various diagnostic and therapeutic regimens from human medicine with reasonable success in equine patients. Understanding the potential pathophysiologic mechanisms involved in neonatal encephalopathy can facilitate management of affected foals.


Endurance exercise and gut microbiota: A review.
The physiological and biochemical demands of intense exercise elicit both muscle-based and systemic responses. The main adaptations to endurance exercise include the correction of electrolyte imbalance, a decrease in glycogen storage and the increase of oxidative stress, intestinal permeability, muscle damage, and systemic inflammatory response. Adaptations to exercise might be influenced by the gut microbiota, which plays an important role in the production, storage, and expenditure of energy obtained from the diet as well as in inflammation, redox reactions, and hydration status. A systematic and comprehensive search of electronic databases, including MEDLINE, Scopus, ClinicalTrials.gov, ScienceDirect, Springer Link, and EMBASE was done. The search process was completed using the keywords: "endurance", "exercise", "immune response", "microbiota", "nutrition", and "probiotics". Reviewed literature supports the hypothesis that intestinal microbiota might be able to provide a measureable, effective marker of an athlete's immune function and that microbial composition analysis might also be sensitive enough to detect exercise-induced stress and metabolic disorders. The review also supports the hypothesis that modifying the microbiota through the use of probiotics could be an important therapeutic tool to improve athletes' overall general health, performance, and energy availability while controlling inflammation and redox levels. The present review provides a comprehensive overview of how gut microbiota may have a key role in controlling the oxidative stress and inflammatory responses as well as improving metabolism and energy expenditure during intense exercise.


Early Adverse Reactions to Snake Antivenom: Poison Center Data Analysis.
Antivenom is an essential treatment for snake envenomation; however, early adverse reactions (EARs) are major limitations to its use. We performed a retrospective cross-sectional study using Ramathibodi Poison Center data (January 2016 to December 2017) to clarify the incidence and severity of EARs following different F(ab')2 antivenoms. Among 1006 envenomed patients, 684 (68%) received antivenom therapy with a total of 1157 doses, mostly green pit viper antivenom. The overall EAR incidence and rate were 22. 5% (154/684) and 15% (173/1157), respectively. The EAR rate following each type of antivenom was >10%, except for Russell's viper antivenom (2.9%); the severe reaction rate was 2.6% (30/1157). Malayan pit viper bites caused a high incidence of EARs (37.8%) and the highest EAR rate (22.3%). Fifty-two cases developed anaphylaxis. All EARs occurred within 2 h after treatment initiation. No deaths were attributed to EARs. The duration of administration was significantly different between doses of antivenom that induced EARs and those that did not. In conclusion, all types and every dose of antivenom should be infused for 30−60 min. Preparation of resuscitation equipment and continuous clinical observation are crucial for at least 2 h after administration, and prompt treatment should be provided when EARs occur.


A multi-level analysis of counselor attitudes toward the use of buprenorphine in substance abuse treatment.
Despite evidence that buprenorphine is effective and safe and offers greater access as compared with methadone, implementation for treatment of opiate dependence continues to be weak. Research indicates that legal and regulatory factors, state policies, and organizational and provider variables affect adoption of buprenorphine. This study uses hierarchical linear modeling to examine National Treatment Center Study data to identify counselor characteristics (attitudes, training, and beliefs) and organizational factors (accreditation, caseload, access to buprenorphine, and other evidence-based practices) that influence implementation of buprenorphine for treatment of opiate dependence. Analyses showed that provider training about buprenorphine, higher prevalence of opiate-dependent clients, and less treatment program emphasis on a 12-step model predicted greater counselor acceptance and perceived effectiveness of buprenorphine. Results also indicate that program use of buprenorphine for any treatment purpose (detoxification, maintenance, and/or pain management) and time (calendar year in data collection) was associated with increased diffusion of knowledge about buprenorphine among counselors and with more favorable counselor attitudes toward buprenorphine.


Income dividends and subjective survival in a Cherokee Indian cohort: a quasi-experiment.
Persons with high temporal discounting tend to value immediate gratification over future gains. Low self-reported lifespan (SRL)-an individual's assessment of a relatively short future lifespan-concentrates in low-income populations and may reflect high temporal discounting. We use casino-based cash dividends among the Eastern Band of Cherokee Indians (EBCI) as a quasi-experiment to test whether large income gains among EBCI members translate into increased SRL. We used SRL data for EBCI and White youth, aged 19 to 28, participating in two waves of the Life Time Trajectory of Youth (LTI-Y) survey from 2000 to 2010. We controlled for unobserved confounding across individuals, time, and region through a longitudinal design using a difference-in-difference analytic approach (N = 294). We conducted all analyses separately by gender and by quartile of socioeconomic status. Cash dividends correspond with a 15.23 year increase in SRL among EBCI men below the lowest socio-economic quartile at baseline relative to Whites (standard error = 5.39, p < .01). Results using other socio-economic cut-points support improved SRL among EBCI men (but not women). The large magnitude of this result among EBCI men indicates that a non-trivial cash dividend to a low-income population may confer long-term benefits on perceptions of future lifespan and, in turn, reduce temporal discounting.Abbreviations: EBCI: Eastern Band of Cherokee Indians; SES: Socioeconomic Status; LTI-Y: Life Trajectory Interview for Youth; GSMS: Great Smoky Mountains Study; SRL: Self-Reported Lifespan; SSS: Subjective Social Status.


A laboratory assessment of enamel hypoplasia of teeth with varying severities of dental fluorosis.
The effect of lifelong exposure to drinking-water containing fluoride on tooth enamel microhardness was investigated. Dental fluorosis of teeth from adult subjects, who lived continuously since birth in areas characterized by the hot climate of India, supplied by drinking-water containing between 0.5 and 8.7 parts/10 F, was estimated by the Dean score. Tooth enamel sections were examined from the enamel surface towards the dentino-enamel junction (DEJ) for microhardness. Separated enamel crowns were pulverized and analysed for fluoride. Regarding the distribution of the fluoride concentrations in the drinking-water, we selected a partition below and above 0.8 parts/10 F as a criterion for comparison between the results. Tooth enamel of humans from Israel living in a drinking-water area containing about 0.5 parts/10 F was also examined. Positive associations were evident between fluoride in drinking-water, fluoride concentrations in the bulk enamel and fluorosis selection. A significantly high inverse relationship was evident between the fluoride concentration of the drinking-water and the subsurface enamel microhardness. In similar fluoride-concentration drinking-water areas of India and Israel the microhardness of the subsurface enamel was less for the Indian teeth. The microhardness of the enamel near the DEJ for the three different water fluoride-concentration areas was not significantly different.


Efficacy of home-based exercise programmes for people with chronic heart failure: a meta-analysis.
Home-based programmes may offer an alternative to conventional programmes or as a means of maintaining physical fitness after graduating from centre-based programmes. We sought to examine the effectiveness of home-based exercise programmes on exercise capacity in patients with heart failure compared with usual medical care. Electronic databases were searched to identify randomized controlled trials. Protocols included an initial period of centre-based exercise followed by exercise at home, home-based exercise only and concurrent centre and home-based exercise. Outcome measures included peak oxygen consumption, exercise duration and the six-minute walk test. Nineteen relevant studies were identified for review. The mean improvement in peak oxygen consumption was 2.86 ml/kg per min [95% confidence interval (CI): 1.43-4.29]. Exercise duration increased by 1.94 min (95% CI: 0.89-2.98) and distance on the six-minute walk test was increased by 30.41 m (95% CI: 6.13-54.68). Other reported benefits of home-based programmes include increased quality of life and lowered hospital admission rates. In conclusion, home-based exercise programmes have been shown to benefit people with heart failure in the short term. Further research is required to investigate the long-term effects of home exercise and to determine the optimal strategies for improving exercise adherence in patients with heart failure.


The plasma membrane as radiosensitive target.
The rapidly accumulating knowledge on the structure and function of cell membranes stimulates the relevant radiobiological studies. Several factors rendering the membrane system a radiosensitive target as well as radiation-induced alterations of plasma membrane are reviewed. For understanding subcellular effects the need of projecting physical energy deposition events over the biological scenary in respective volumes is emphasized. The possible role of membrane alterations in the fate of irradiated cell is discussed.


Neurotoxicity Induced by Mephedrone: An up-to-date Review.
Mephedrone is a β-ketoamphetamine belonging to the family of synthetic cathinones, an emerging class of designer drugs known for their hallucinogenic and psychostimulant properties as well as for their abuse potential. The aim of this review was to examine the emerging scientific literature on the possible mephedrone-induced neurotoxicity, yet not well defined due to the limited number of experimental studies, mainly carried on animal models. Relevant scientific articles were identified from international literature databases (Medline, Scopus, etc.) using the keywords: "Mephedrone", "4-MMC," "neurotoxicity," "neuropharmacology", "patents", "monoamine transporters" and "neurochemical effects". Of the 498 sources initially found, only 36 papers were suitable for the review. Neurotoxic effect of mephedrone on 5-hydroxytryptamine (5-HT) and dopamine (DA) systems remains controversial. Although some studies in animal models reported no damage to DA nerve endings in the striatum and no significant changes in brain monoamine levels, some others suggested a rapid reduction in 5-HT and DA transporter function. Persistent serotonergic deficits were observed after binge like treatment in a warm environment and in both serotonergic and dopaminergic nerve endings at high ambient temperature. Oxidative stress cytotoxicity and an increase in frontal cortex lipid peroxidation were also reported. In vitro cytotoxic properties were also observed, suggesting that mephedrone may act as a reductant agent and can also determine changes in mitochondrial respiration. However, due to the differences in the design of the experiments, including temperature and animal model used, the results are difficult to compare. Further studies on toxicology and pharmacology of mephedrone are therefore necessary to establish an appropriate treatment for substance abuse and eventual consequences for public health.


[Autonomic dysreflexia and nursing interventions for patients with spinal cord injury].
This retrospective study, performed in 2009, aimed to identify nursing diagnoses and interventions for the care of patients with spinal cord injury. Data were collected from the nursing records of 465 patients with SCI undergoing rehabilitation. The nursing diagnosis Risk for autonomic dysreflexia was identified in 271 clinical records (58, 3%). Approximately 80 patients developed autonomic dysreflexia, with a predominance in young men around 35.7 years old, who had experienced a trauma as the main cause of the injury. Their neurological injury level was at the sixth thoracic vertebra or above. Nursing interventions were arranged in two groups, one focused on prevention and the other on treatment. An intervention guide was developed and can be used by nurses in their clinical practice of rehabilitation and can be included into information systems. The removal of the stimulus which causes autonomic dysreflexia was identified as the most effective therapy and the best intervention.


Dystonin is an essential component of the Schwann cell cytoskeleton at the time of myelination.
A central role for the Schwann cell cytoskeleton in the process of peripheral nerve myelination has long been suggested. However, there is no genetic or biological evidence as yet to support this assumption. Here we show that dystonia musculorum (dt) mice, which carry mutations in dystonin, a cytoskeletal crosslinker protein, have hypo/amyelinated peripheral nerves. In neonatal dt mice, Schwann cells were arrested at the promyelinating stage and had multiple myelinating lips. Nerve graft experiments and primary cultures of Schwann cells demonstrated that the myelination abnormality in dt mice was autonomous to Schwann cells. In culture, dt Schwann cells showed abnormal polarization and matrix attachment, and had a disorganized cytoskeleton. Finally, we show that the dt mutation was semi-dominant, heterozygous animals presenting hypo- and hyper-myelinated peripheral nerves. Altogether, our results suggest that dt Schwann cells are deficient for basement membrane interaction and demonstrate that dystonin is an essential component of the Schwann cell cytoskeleton at the time of myelination.


Sleep habits and strategies of ultramarathon runners.
Among factors impacting performance during an ultramarathon, sleep is an underappreciated factor that has received little attention. The aims of this study were to characterize habitual sleep behaviors in ultramarathon runners and to examine strategies they use to manage sleep before and during ultramarathons. Responses from 636 participants to a questionnaire were considered. This population was found to sleep more on weekends and holidays (7-8 h to 8-9 h) than during weekdays (6-7 h to 7-8 h; p < 0.001). Work was a mediator of napping habits since 19-25% reported napping on work days and 37-56% on non-work days. There were 24.5% of the participants reporting sleep disorders, with more women (38.9%) reporting sleep problems than men (22.0%; p < 0.005). Mean (±SD) sleepiness score on the Epworth Sleepiness Scale was 8.9 ± 4.3 with 37.6% of respondents scoring higher than 10, reflecting excessive daytime sleepiness. Most of the study participants (73.9%) had a strategy to manage sleep preceding an ultramarathon, with 54.7% trying to increase their opportunities for sleep. Only 21% of participants reported that they had a strategy to manage sleep during ultramarathons, with micronaps being the most common strategy specified. Sub-analyses from 221 responses indicated that sleep duration during an ultramarathon was correlated with finish time for races lasting 36-60 h (r = 0.48; p < 0.01) or > 60 h (r = 0.44; p < 0.001). We conclude that sleep duration among ultramarathon runners was comparable to the general population and other athletic populations, yet they reported a lower prevalence of sleep disorders. Daytime sleepiness was among the lowest rates encountered in athletic populations, which may be related to the high percentage of nappers in our population. Sleep extension, by increasing sleep time at night and daytime napping, was the main sleep strategy to prepare for ultramarathons.


Thyroid disease in the emergency department. Thyroid function tests and hypothyroidism and myxedema coma.
The recognition of hypothyroidism may not always be easy in the emergency department setting. Laboratory evaluations of thyroid function are not usually performed on a 24-hour basis, and therefore the emergency physician, although suspecting the presence of hypothyroidism, may be unable to confirm the diagnosis while the patient is in the Emergency Department. It is not always the responsibility of the emergency physician to diagnose hypothyroidism, but in some clinical settings it may be important to include thyroid function tests in laboratory evaluation of patients to ensure adequate patient care and followup. Careful attention to nonspecific complaints, myxedematous changes, and signs of dysfunction of any organ system, especially in older female patients, may lead to the ultimate correct diagnosis. Myxedema coma is potentially fatal and must be recognized and treated emergently, usually prior to laboratory confirmation. Ventilatory support and thyroid hormone replacement are the two most important therapeutic maneuvers in the treatment of myxedema coma.


Comment: compulsory licensing of patented pharmaceutical inventions: evaluating the options.
In this Comment, the author traces the relevant legislative history pertaining to compulsory licensing of patented pharmaceuticals from the TRIPS Agreement of 1994 to the 2003 waiver to, and later proposed amendment of, article 31, which enables poor countries to obtain needed medicines from other countries that possess manufacturing capacity. The Comment then evaluates recent, controversial uses of the relevant legislative machinery as viewed from different critical perspectives. The Comment shows how developing countries seeking access to essential medicines can collaborate in ways that would avoid undermining incentives to innovation and other social costs attributed to compulsory licensing. It ends by defending the legality of recent measures taken to promote public health in developing countries, and by reminding developed countries that unilateral retaliation against such measures is demonstratably illegal under WTO foundational law and jurisprudence.


[Role of echography in diagnosis of diseases of cervical lymph nodes].
We studied echograms of lymph nodes and clinically similar tumors of the neck in 194 patients. A complex of echographic signs providing the best diagnostic indicators: a minimal size of the node, volume, maximal to minimal size ratio and form. Accuracy of differential diagnosis of benign and malignant lymphadenopathies was 80.4%, sensitivity -- 94.3%, specificity -- 69.4%. In duration of the disease less than 1 month use of computer processing of echograms raised diagnostic accuracy by 9.5%.


Efficiently train and validate a RapidPlan model through APQM scoring.
The aim of this study was to propose and validate an intuitive method for training and to validate knowledge-based planning (KBP) systems based on a patient-specific plan quality scoring. A sample of 80 clinical plans of prostate cancer patients were ranked on the basis of the Adjusted Plan Quality Metric (APQM%). This quality metric was computed normalizing the Plan Quality Metric (PQM%) score to the best possible OAR sparing estimated by the Feasibility DVH (FDVH) algorithm. Two different plan libraries were created, purging all the plans below the first quartile or below the median the APQM% distribution. These libraries were used to populate and train two RapidPlan models: respectively, the APMQ25% and the APMQ50% models. No further refinements or actions were undertaken on these two models. Their performances were benchmarked against another two RapidPlan models. An Uncleaned model, which was populated and trained with the initial sample of 80 plans, and a Cleaned model, obtained through the standard iterative cleaning and refinement process suggested by the vendor and in literature. The outcomes of a planning test based on 20 patients within the training library (closed loop) and 20 patients outside of the training library (open-loop) were compared through various DVH metrics and the PQM% score. The selection through APQM% thresholding roughly preserves the geometric variety of the Cleaned model; only the APMQ50% model showed a modest broadness reduction. The models generated through APQM% thresholding showed target coverage and OARs sparing equal or superior to the Uncleaned and Cleaned models both for the closed- and the open-loop tests. No significant differences were found between the four models. PQM% analysis ranked the overall plan quality as: 86.5 ± 6.5% APQM50% , 83.1 ± 5.9% APQM25% , 80.39 ± 10.6% Cleaned and 79.4 ± 8.5% Uncleaned in the closed-loop test; 84.9 ± 7.6% APQM50% , 82.6 ± 7.9% APQM25% , 80.39 ± 10.6% Cleaned and 79.4 ± 8.5% Uncleaned in the open-loop test. Forward feeding a RapidPlan model through a thresholding selection based on APQM% is proven to produce equal or better results than a model based on a manually and iteratively refined population. A tighter APQM% threshold turns approximately into a higher average quality of plans generated with RapidPlan. A trade-off must be found between the mean quality of the KBP library and its numerosity. The proposed KBP feeding method helps the KBP user, because it makes the model refinement more intuitive and less time consuming.


Hollow Copper Sulfide Nanosphere-Doxorubicin/Graphene Oxide Core-Shell Nanocomposite for Photothermo-chemotherapy.
A novel core-shell nanostructure, hollow copper sulfide nanosphere-doxorubicin (DOX)/graphene oxide (GO) (CuS-DOX/GO), is constructed for the purpose of controlled drug delivery and improved photothermo-chemotherapeutic effect. The CuS-DOX/GO nanocomposite is configured by employing dual photothermal agents, where the core, hollow CuS nanoparticle, acts as delivery-carrier for doxorubicin, and the shell, PEGylated GO nanosheet, prohibits leakage of the drug. DOX can be efficiently loaded onto the hollow CuS nanoparticles, and its subsequent release from CuS-DOX/GO nanocomposite is triggered in a pH- and near-infrared light-dependent manner. Moreover, integration of the two photothermal agents significantly improves the photothermal performance of this system. Ultimately, the combination of phototherapy and chemotherapy based on this system results in a much higher HeLa cell killing efficacy with respect to that for a single chemotherapy mode, as demonstrated by in vitro cytotoxicity tests.


Farseer-NMR: automatic treatment, analysis and plotting of large, multi-variable NMR data.
We present Farseer-NMR ( https://git.io/vAueU ), a software package to treat, evaluate and combine NMR spectroscopic data from sets of protein-derived peaklists covering a range of experimental conditions. The combined advances in NMR and molecular biology enable the study of complex biomolecular systems such as flexible proteins or large multibody complexes, which display a strong and functionally relevant response to their environmental conditions, e.g. the presence of ligands, site-directed mutations, post translational modifications, molecular crowders or the chemical composition of the solution. These advances have created a growing need to analyse those systems' responses to multiple variables. The combined analysis of NMR peaklists from large and multivariable datasets has become a new bottleneck in the NMR analysis pipeline, whereby information-rich NMR-derived parameters have to be manually generated, which can be tedious, repetitive and prone to human error, or even unfeasible for very large datasets. There is a persistent gap in the development and distribution of software focused on peaklist treatment, analysis and representation, and specifically able to handle large multivariable datasets, which are becoming more commonplace. In this regard, Farseer-NMR aims to close this longstanding gap in the automated NMR user pipeline and, altogether, reduce the time burden of analysis of large sets of peaklists from days/weeks to seconds/minutes. We have implemented some of the most common, as well as new, routines for calculation of NMR parameters and several publication-quality plotting templates to improve NMR data representation. Farseer-NMR has been written entirely in Python and its modular code base enables facile extension.


Human monocyte-derived soluble product(s) has an accessory function in the generation of histamine- and concanavalin A-induced suppressor T cells.
We have analyzed the cellular interactions required for the generation of histamine- and concanavalin A (Con A)-induced suppressor T cells by employing a co-culture assay and techniques for fractionation of human blood mononuclear cells (PBMC). PBMC cultured in the presence of histamine (0.1 mM-1 mM) or Con A (20 micrograms/ml) for 24 h, mitomycin treated and subsequently combined with autologous mitogen-stimulated mononuclear cells, significantly suppressed a subsequent blastogenic response. PBMC fractionated over nylon wool columns and depleted of adherent cells and enriched for T cells (NWNA-T) were unable to generate suppressor activity. However, suppressor cell function by NWNA-T cells was reconstituted by the addition of autologous monocytes. In both the histamine and ConA suppressor systems, the requirement for monocytes in the activation process was enhanced by suspending the NWNA-T population in supernatants derived from allogeneic monocytes stimulated with heat-killed Staphylococcus albus. These crude supernatants contained leukocytic pyrogen (LP) and lymphocyte activating factor (LAF). Sequential purification and separation of the crude supernatants using gel-filtration, immunoadsorption, and isoelectric focusing demonstrated that only those fractions containing LP and LAF were capable to reconstituting NWNA-T cell histamine and Con A-induced suppressor activity. Thus, these studies suggest that the accessory role of supernatants derived from activated monocytes in the generation of suppressor cells may be mediated by LP/LAF. Further studies are in progress to explore the mechanism by which soluble factors stimulate suppressor T cells.


[Intranuclear development of the macrogametes of the coccidian, Tyzzeria parvula].
The fine structure of macrogametes of a goose coccidium Tyzzeria parvula has been studied, intranuclear localization of these being discovered. Unlike other coccidia, macrogametes of T. parvula display only one type of wall-forming bodies. Deep invaginations are formed on the surface of macrogametes, in which fragments of host cell nucleoplasm, separated with the membrane of parasitophorous vacuole, are invaginating. They may be connected with process of parasite's feeding.


Macromolecular synthesis in varicella-zoster virus-infected epithelial and fibroblast cells.
Replication of varicella-zoster virus (VZV) was studied in a range of human cells (Chang conjunctival, HEp2 and Vero) and compared with that in HEL cells. Evidence for virus-specific protein and nucleic acid synthesis was obtained from each of these cell lines. In some cell lines, virus proteins were clearly visible by polyacrylamide gel electrophoresis both with and without immunoprecipitation. Multiple passage of infected cells enhanced both virus-specific protein synthesis and shutoff of host protein synthesis. No qualitative differences in the patterns of VZV-specific protein synthesis were detected. Approximately 2000 copies of the VZV genome were detected per infected HEL cell.


Peer review to ensure quality in forensic mental health publication.
Peer reviewers have been called the gatekeepers of science. For journal publications in forensic psychiatry, as well as other disciplines, the purposes of peer review are to assist in the selection of manuscripts to publish, improve the quality of manuscripts before their publication, and promote the fairness of the process. In this article, we examine, in particular, characteristics of high-quality peer reviewers, selection of peer reviewers, recruitment and retention of peer reviewers, desired quality of peer-reviewer ratings, and the value of peer review. We conclude with specific, albeit largely untested, recommendations for improvements in peer review of forensic mental health publications.


New concepts of radiologic preoperative evaluation of anterior shoulder instability: on-track and off-track lesions.
The shoulder is the most frequently dislocated joint in the body due to a larger range of motion and a small area of articulation between the humeral and glenoid surfaces. Traumatic shoulder dislocations, especially those associated with injury to the labroligamentous or bony stabilizers of the joint, lead to further reduction of articular surface contact with resultant glenohumeral instability and recurrent shoulder dislocations. Imaging plays an increasingly important role in the preoperative evaluation of patients with traumatic shoulder instability by evaluating glenohumeral bone loss (uni- or bipolar), assessing soft tissue injuries and identifying patients at risk of postoperative recurrence. Quantification of bone loss is key to differentiate engaging vs. non-engaging Hill-Sachs lesions, while newer concepts of "on-track" vs. "off-track" lesions are being discussed that can determine the required surgical approaches. In this article, we review the preoperative imaging approaches, traditional treatments, outline the bone loss measurement strategies and review these new tracking concepts with relevant case examples.


Demonstration of a genotype-phenotype correlation in the polymorphic color vision of a non-callitrichine New World monkey, capuchin (Cebus apella).
Color-vision polymorphism in New World monkeys occurs because of an allelic polymorphism of the single-copy red-green middle-to-long-wavelength-sensitive (M/LWS) opsin gene on the X chromosome. Because color-vision types can readily be estimated from allelic types of the M/LWS opsin gene, this polymorphic system offers researchers an excellent opportunity to study the association between vision and behavior. As a prerequisite for such studies, genetically determined color-vision types must be concordant with phenotypes determined directly by behavioral criteria (e.g., by a color discrimination test). However, such correlations between genotypes and phenotypes have been studied only for callitrichine species. Using genetic, electrophysiological, and behavioral approaches, we evaluated the color vision of brown capuchin monkeys (Cebus apella), a representative non-callitrichine model animal for physiology and behavior. Two allelic M/LWS opsins-P545 and P530-were identified in the studied captive population. Females had one or both of the alleles, and males had either one. The retinal sensitivity in P530 dichromats was short-wave shifted relative to that in P545 dichromats, whereas that in P530/P545 trichromats was between the two groups. In a discrimination task using Ishihara pseudo-isochromatic plates, P530/P545 trichromats were successful in discriminating stimuli that P530 and P545 dichromats were unable to discriminate. In a food-search task, P530/P545 trichromats were able to locate red targets among green distracters as quickly as among white distracters, whereas both types of dichromats took longer. These results demonstrate the mutual consistency between genotypes and phenotypes of color vision, and provide a solid genetic basis on which the ecology and evolution of color vision can be investigated.


Hepatitis C virus-specific T-cell response correlates with hepatitis activity and donor IL28B genotype early after liver transplantation.
It is not known how the immune system targets hepatitis C virus (HCV)-infected HLA-mismatched hepatocytes under immune-suppressed conditions after orthotopic liver transplantation (OLT). In addition, the relationship between the HCV-specific immune response and IL28B variants as predictors of HCV clearance has not been well-characterized. We determined the IL28B polymorphisms for 57 post-OLT HCV carriers, and we assessed the HCV-specific immune responses by measuring the peripheral blood mononuclear cell-derived HCV-specific interferon-gamma (IFN-γ) response using an enzyme-linked immunospot assay. At 1-3 years after OLT, patients with no active hepatitis showed higher total spots on the immunospot assay. At>3 years after OLT, patients with resolved HCV showed higher levels of core, NS3, NS5A, and total spots compared to the chronic hepatitis patients. The IL28B major genotype in the donors correlated with higher spot counts for NS5A and NS5B proteins at 1-3 years after OLT. In the post-OLT setting, the HCV-specific immune response could be strongly induced in patients with no active hepatitis with an IL28B major donor or sustained virological response. Strong immune responses in the patients with no active hepatitis could only be maintained for 3 years and diminished later. It may be beneficial to administer IFN treatment starting 3 years after OLT, to induce the maximum immunological effect.


[Determination of air volume in the entotracheals tube cuff].
The aim of this study is to determine the best regulation of air volume to be inflated into cuffs of different endotracheal canula diameters of high residual volume and low pressure. Maintaining the pressure exercised by a balloon in the trachea mucous membrane between preconized limits of 20 to 30 mmHg (less than the trachea capillary pressure). Therefore, 10 ml of air have been inflated into the canular cuff of intubed patients with different internal diameters (7.0-7.5- 8.0-8.5-9.0) one by one, measuring each millilitre of inflated air, the corresponding to pressure of the cuff in the trachea mucous membrane. The monitoring of the pressure has been made by a previously calibrated manometer. The procedure has been performed in 25 adult patients of both sexes, grouped in numbers of 5 for each internal tube diameter. The results have been analysed through linear regression analysis which has shown a close relationship between ml of inflated air and pressure in the cuff by tube diameter. After analysing the results, the author indicated, by means of graphic representation, the quantity of air to be inflated in the cuff and respective exercised pressure on the trachea mucous membrane, by tube meter, in a way to offer a contribution to the staff who provides assistance to intubed patients, in the sense of minimising the possible injuries and complications and assure a better respiratory ventilation.


Kinetic mechanism of octopus hepatopancreatic glutathione transferase in reverse micelles.
Octopus glutathione transferase (GST) was enzymically active in aerosol-OT [sodium bis-(2-ethylhexyl)sulphosuccinate]/iso-octane reverse micelles albeit with lowered catalytic constant (kcat). The enzyme reaction rate was found to be dependent on the [H2O]/[surfactant] ratio (omega(o)) of the system with maximum rate observed at omega(o) 13.88, which corresponded to vesicles with a core volume of 64 nm3. According to the physical examinations, a vesicle of this size is barely large enough to accommodate a monomeric enzyme subunit. Dissociation of the enzyme in reverse micelles was confirmed by cross-linking of the associated subunits with glutaraldehyde and separation of the monomers and dimers with electrophoresis in the presence of SDS. The kinetic properties of the enzyme were investigated by steady-state kinetic analysis. Both GSH and 1-chloro-2,4-dinitrobenzene (CDNB) showed substrate inhibition and the Michaelis constant for CDNB was increased by 36-fold to 11.05 mM in reverse micelles. Results on the initial-velocity and product-inhibition studies indicate that the octopus GST conforms to a steady-state sequential random Bi Bi mechanism. The results from a log kcat versus pH plot suggest that amino acid residues with pKa values of 6.56 0.07 and 8.81 0.17 should be deprotonated to give optimum catalytic function. In contrast, the amino acid residue with a pKa value of 9.69 0.16 in aqueous solution had to be protonated for the reaction to proceed. We propose that the pKa1 (6.56) is that for the enzyme-bound GSH, which has a pKa value lowered by 1.40-1.54 pH units compared with that of free GSH in reverse micelles. The most probable candidate for the observed pKa2 (8.81) is Tyr7 of GST. The pKa of Tyr7 is 0.88 pH unit lower than that in aqueous solution and is about 2 pH units below the normal tyrosine. This tyrosyl residue may act as a base catalyst facilitating the dissociation of enzyme-bound GSH. The possible interaction of GST with plasma membrane in vivo is discussed.


Descriptive data on cancerous lung lesions detected by auto-fluorescence bronchoscope: A five-year study.
Auto-fluorescence bronchoscopy (AFB) has been used for the identification and localization of intra-epithelial pre-neoplastic and neoplastic lesions within the bronchus. To determine the applicability of AFB for the detection and localization of precancerous and cancerous lesions, in addition to analyzing the morphologic presentation, their association to histological type and the variation between genders. A five-year study involving 4983 patients, who underwent routine bronchoscopy [B] examination in a local tertiary teaching hospital, was done. The B examination was performed under intratracheal lidocaine, and samples were obtained using suitable approach. One thousand four hundred and eighty-five pathologically confirmed lung cancer patients were included in the study. The following parameters were studied: Morphological presentation, biopsy sites, histology. Differences between the groups were analyzed using Chi square test. One thousand four hundred and eighty-five patients who had hyperplasia or neoplastic lesions were further confirmed as lung cancer pathologically. Lung cancer was more commonly found in the right lung (51.58% vs. 42.82%). The lesion occurred more frequently in the upper lobe than the lower lobe (44.17% vs. 22.42%). Male patients with squamous cell carcinoma showed upper lobe involvement more commonly, while the left main bronchus was more commonly involved in female patients. Adenocarcinoma mostly involved lesion of the upper lobe. Squamous cell carcinoma and small cell carcinoma were the major proliferative types (80.15% and 76.16% respectively). AFB is efficient in the detection of pre-invasive and invasive lung lesions. The morphological presentation is associated to the histological type. There is variation in the presentation and histology of cancerous lung lesions between genders.


X-ray-induced P-selectin localization to the lumen of tumor blood vessels.
P-selectin is a cell adhesion molecule that is sequestered in Weibel-Palade storage reservoirs within the vascular endothelium and alpha granules in platelets. P-selectin is rapidly translocated to the vascular lumen after tissue injury to initiate the adhesion and activation of platelets and leukocytes. We studied the histological pattern of P-selectin expression in irradiated tumor blood vessels. We observed that P-selectin was localized within the endothelium of tumor vessels prior to treatment. At 1-6 h following irradiation, P-selectin was mobilized to the lumen of blood vessels. To determine whether radiation-induced vascular lumen localization of P-selectin was tumor type specific or species specific, we studied tumors in rats, C3H mice, C57BL6 mice, and nude mice. P-selectin localization to the vascular lumen was present in all tumors and all species studied. Irradiated intracranial gliomas showed P-selectin localization to the vascular lumen within 1 h, whereas blood vessels in normal brain showed no P-selectin staining in the endothelium and no localization to the irradiated vascular lumen. Radiation-induced P-selectin localization to the vascular lumen increased in time-dependent manner, until 24 h after irradiation. P-selectin in platelets may account for the time-dependent increase in staining within the vascular lumen after irradiation. We therefore used immunohistochemistry for platelet antigen GP-IIIa to differentiate between endothelial and platelet localization of P-selectin. We found that GP-IIIa staining was not present at 1 h after irradiation, but it increased at 6 and 24 h. P-selectin localization to the vascular lumen at 6-24 h was, in part, associated with platelet aggregation. These findings indicate that radiation-induced P-selectin staining in the vascular lumen of neoplasms is associated with aggregation of platelets. Radiation-induced localization of P-selectin to the vascular lumen is specific to the microvasculature of malignant gliomas and is not present in the blood vessels of the irradiated normal brain.


Precancerous lesions of the mouth.
Leukoplakia is the only important precancerous lesion of the mouth. The epidemiology of oral leukoplakia has been well established in white adults in the United States. There is a hole in the epidemiologic literature, however, on leukoplakia in American minority populations. Recent literature has begun to address the issue of the pathophysiology of leukoplakia, its causes and treatment, and predicting its malignant transformation. Computerized image analysis, retinoid compounds, beta-carotene, and laser surgery are contributing to advances in these lines of research. Though leukoplakia is often seen in patients who use smokeless tobacco products, it is usually benign and reversible if use of the tobacco product is discontinued. The direction of current research in leukoplakia studies eventually should lead to an understanding of the nature and cure of this ubiquitous lesion.


Attenuating effect of Ginsenoside Rb1 on LPS-induced lung injury in rats.
Sepsis causes neutrophil sequestration in the lung which leads to acute lung injury (ALI). Radix Ginseng (RG), a traditional herb used as herbal remedy in eastern Asia for thousands of years, which has been traditionally used in China to improve blood circulation and ameliorate pathological hemostasis. This study investigated whether Ginsenoside Rb1, the main components of RG, can attenuate ALI induced by LPS. In vivo, 30 male Wistar rats were divided into three groups (n = 10 each groups) on the basis of the reagent used, which were subjected to LPS injection with or without Ginsenoside Rb1 (5 mg/kg) treatments to induce ALI model. Lung injury was assessed by pulmonary histology, lung wet-weight to dry-weight (W/D) ratio, the number of myeloperoxidase (MPO) positive cells, immunohistochemical analysis of intercellular adhesion molecule-1 (ICAM-1), gene expression of ICAM-1, ultrastructure changes of pulmonary microvasculature, concentration of inflammatory markers and in plasma. In vitro, pulmonary microvascular endothelial cells (PMVECs) were stimulated with LPS in the presence and absence of Ginsenoside Rb1 (50 mM), nuclear factor-κB (NF-κB) p65 was measured by immunocytochemistry staining and western blotting. Infusion of LPS induced lung injury, in vivo, as demonstrated by pulmonary edema with infiltration of neutrophils and hemorrhage, the increase in lung W/D ratio, the number of MPO positive cells, the level of inflammatory markers such as TNF-α, MCP-1 and IL-8, enhanced expression of ICAM-1 and ICAM-1 gene. Moreover, resulted in the changes of intercellular junctions in the endothelial cells of pulmonary microvasculature. In vitro, the significant increased release of NF-κB p65 and its subsequent translocation into the nucleus in PMVECs were observed. In contrast, Ginsenoside Rb1 treatment significantly ameliorated the LPS-induced lung injury, as judged by the marked improvement in all these indices. These results indicate that Ginsenoside Rb1 attenuated LPS-induced lung injury through an inhibition of the inflammatory signaling pathway, besides the direct inhibitory effect on proinflammatory molecules.


Detection of Phenylarsine Oxide in Drinking Water Using an Impedimetric Electrochemical Sensor with Gelatin-Based Solid Electrolyte Enriched with Mercaptoethanol: A Novel Prospective Green Biosensor Methodology.
A simple, inexpensive, rapid, and label-free detection of phenylarsine oxide (PAO) in the field is a significant and unmet need because of its fatally acute and chronic effects on human health. A simple, fast, sensitive, and relatively low-cost arsenic detection system with an eco-friendly sensor could fill this gap. To monitor arsenic in situ, a reliable, portable impedimetric electrochemical sensor is the most suitable platform, which is real-time, fast, low-cost, and easy to design and use and has high sensitivity at low detection limits in the nanogram per mL range. The detection system in this study has a patent-applied green sensor with minimum harm to nature and the potential to dissolve in nature. The electrode containing 15 mL of distilled water (DIW) + 2 g gelatin + 1.75 g glycerol was determined to be the most suitable for determining the amount of inorganic arsenic in the range of 1-100 ng/mL using a gelatin-based solid electrochemical sensor enriched with 2-mercaptoethanol. Impedance measurements were performed to analyze the stability of the sensor in both deionized water and drinking water, as well as for arsenic detection. Among the procedures examined, the procedure prepared with 15 mL DIW + 2 g glycerol + 1.75 g gelatin resulted in the best stability in aqueous medium and in sensitivity with resistance changes (-ΔR ct (%)) of 12% (±0.62%), 26% (±2.3%), and 40% (±3.8%) for the concentrations of 1, 10, and 100 ng/mL PAO in drinking water, respectively. With this detection methodology, there is the potential to detect not only arsenic but also other heavy metals in waters and different biomarkers in human fluids.


Assessing negative cognitive style: Development and validation of a Short-Form version of the Cognitive Style Questionnaire.
The Cognitive Style Questionnaire (CSQ) is a frequently employed measure of negative cognitive style, associated with vulnerability to anxiety and depression. However, the CSQ's length can limit its utility in research. We describe the development of a Short-Form version of the CSQ. After evaluation and modification of two pilot versions, the 8-item CSQ Short Form (CSQ-SF) was administered to a convenience sample of adults (N = 278). The CSQ-SF was found to have satisfactory internal reliability and test-retest reliability. It also exhibited construct validity by demonstrating predicted correlations with measures of depression and anxiety. Results suggest that the CSQ-SF is suitable for administration via the Internet.


A Simplified HAART Regimen with Raltegravir and Lamivudine, and Pharmacokinetic Interactions with a Combined Immunosuppressive Therapy with Tacrolimus and Everolimus in an HIV/HCV/HBV/HDV Patient after Liver Transplantation.
In this case report, we examine the impact of a simplified two-drug highly active antiretroviral therapy (HAART) regimen of raltegravir and lamivudine in a patient co-infected with human immunodeficiency virus (HIV) and hepatitis C, D and B viruses (HCV/HDV/HBV) under immunosuppressive therapy after liver transplantation. Pharmacokinetic interactions between integrase inhibitors and immunosuppressant drugs are described. Raltegravir, the first integrase inhibitor, associated with lamivudine, was introduced because its metabolism does not interfere with immunosuppressant therapy. During post-orthotopic liver transplantation follow-up, the patient's transaminases level increased and his antiretroviral therapy (HAART) of tenofovir/emtricitabine and fosamprenavir was changed, due to suspected drug toxicity. After seven months of follow-up, the patient showed good tolerance, good viro-immunological control with undetectable HIV viraemia and stable concentrations of immunosuppressive drugs. This case indicates that the combination of raltegravir and lamivudine is an optimal and effective strategy because it resulted in an important reduction of hepatic transaminases in a patient with very critical clinical conditions.


An Effector from the Cyst Nematode Heterodera schachtii Derepresses Host rRNA Genes by Altering Histone Acetylation.
Cyst nematodes are plant-pathogenic animals that secrete effector proteins into plant root cells to alter host gene expression and reprogram these cells to form specialized feeding sites, known as syncytia. The molecular mechanisms of these effectors are mostly unknown. We determined that the sugar beet cyst nematode (Heterodera schachtii) 32E03 effector protein strongly inhibits the activities of Arabidopsis thaliana histone deacetylases including the HDT1 enzyme, which has a known function in the regulation of rRNA gene expression through chromatin modifications. We determined that plants expressing the 32E03 coding sequence exhibited increased acetylation of histone H3 along the rDNA chromatin. At low 32E03 expression levels, these chromatin changes triggered the derepression of a subset of rRNA genes, which were conducive to H. schachtii parasitism. By contrast, high levels of 32E03 caused profound bidirectional transcription along the rDNA, which triggered rDNA-specific small RNA production leading to RNA-directed DNA methylation and silencing of rDNA, which inhibited nematode development. Our data show that the 32E03 effector alters plant rRNA gene expression by modulating rDNA chromatin in a dose-dependent manner. Thus, the 32E03 effector epigenetically regulates plant gene expression to promote cyst nematode parasitism.


Regulating genome editing technologies: a comparison of expert recommendations in the U.K. and in the U.S.A.
The present paper aims to inform the bioethical debate on the regulation of human genome editing technologies with a specific focus on the role of scientific experts and their interactions with the general public in the formulation of policy. It reviews and compares two of the major contributions to this debate in the U.K. and in the U.S.A., comparing expert approaches towards regulation on genome editing technologies. The results of this analysis offer important lessons that should be appreciated in building an international regulatory framework. On the basis of these results, I conclude that the experts should embrace a socially responsible approach and encourage active public engagement.


Donor-derived mesenchymal stem cells suppress alloreactivity of kidney transplant patients.
Human mesenchymal stem cells (MSC) have immunosuppressive capacities. Although their efficacy is currently studied in graft-versus-host disease, their effect on alloreactivity in solid organ transplant patients is unknown. In this study, the immunosuppressive effect of MSC on recipient anti-donor reactivity was examined before and after clinical kidney transplantation. Anti-donor reactivity was established in pretransplant and posttransplant mixed lymphocyte reactions (MLR) of 14 living-kidney donor-recipient pairs. MSC from donors and third-party controls were added to the MLR in a ratio of 1:5. MSC were isolated from donor perirenal fat and showed multilineage differentiation potential and the capacity to inhibit lymphocyte proliferation. The immunosuppressive effect of MSC was dose dependent and mediated by cell-membrane contact and soluble factors, including interleukin-10 and indoleamine 2,3-dioxygenase.Donor-derived MSC significantly inhibited the recipient anti-donor reactivity before and 1 month after transplantation. This effect was independent of human leukocyte antigen background of MSC. Flow cytometric analysis showed that MSC inhibited the proliferation of CD4+ and CD8+ T-lymphocyte subsets in pretransplant and posttransplant donor-directed MLR, whereas MSC had no effect on B- or natural killer-cell proliferation. Donor MSC significantly inhibited the proliferation of alloactivated recipient T cells before and after kidney transplantation. We believe these findings should encourage MSC-based intervention in clinical organ transplantation.


Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma.
Targeting RAS is one of the greatest challenges in cancer therapy. Oncogenic mutations in NRAS are present in over 25% of melanomas and patients whose tumors harbor NRAS mutations have limited therapeutic options and poor prognosis. Thus far, there are no clinical agents available to effectively target NRAS or any other RAS oncogene. An alternative approach is to identify and target critical tumor vulnerabilities or non-oncogene addictions that are essential for tumor survival. We investigated the consequences of NRAS blockade in NRAS-mutant melanoma and show that decreased expression of the telomerase catalytic subunit, TERT, is a major consequence. TERT silencing or treatment of NRAS-mutant melanoma with the telomerase-dependent telomere uncapping agent, 6-thio-2'-deoxyguanosine (6-thio-dG), led to rapid cell death, along with evidence of both telomeric and non-telomeric DNA damage, increased ROS levels, and upregulation of a mitochondrial antioxidant adaptive response. Combining 6-thio-dG with the mitochondrial inhibitor Gamitrinib attenuated this adaptive response and more effectively suppressed NRAS-mutant melanoma. Our study uncovers a robust dependency of NRAS-mutant melanoma on TERT, and provides proof-of-principle for a new combination strategy to combat this class of tumors, which could be expanded to other tumor types.


Characterizing the effects of tonic 17β-estradiol administration on spatial learning and memory in the follicle-deplete middle-aged female rat.
17β-estradiol (E2)-containing hormone therapy is a safe, effective way to alleviate unwanted menopause symptoms. Preclinical research has focused upon the role of E2 in learning and memory using a surgically menopausal rodent model whereby the ovaries are removed. Given that most women retain their reproductive tract and undergo a natural menopause transition, it is necessary to understand how exogenous E2 impacts a structurally intact, but follicle-deplete, system. In the current study, 8 month old female rats were administered the ovatoxin 4-vinylcyclohexene diepoxide (VCD), which accelerates ovarian follicular depletion, to model the human menopause transition. After follicular depletion, at 11 months old, rats were administered Vehicle or tonic E2 treatment for 12 days prior to behavioral evaluation on spatial working and reference memory tasks. Results demonstrated that E2 had both enhancing and impairing effects on taxed working memory depending upon the learning or retention phases of the water radial-arm maze, with no impact on reference memory. Relationships between memory scores and circulating estrogen levels were specific to follicle-depleted rats without E2 treatment. Collectively, findings demonstrate the complexity of E2 administration in a follicle-depleted background, with cognitive effects specific to working memory; furthermore, E2 administration altered circulating hormonal milieu and relationships between hormone profiles and memory. In sum, menopausal etiology impacts the parameters of E2 effects on cognition, complementing prior work with other estrogen compounds. Deciphering estrogenic actions in a system wherein the reproductive tract remains intact with follicle-depleted ovaries, thus modeling the majority or menopausal women, is critical for translational perspectives.


Azithromycin: The First Broad-spectrum Therapeutic.
The Strategic Plan for Biodefense Research by the U.S. Department of Health and Human Services demarcates the need for drugs which target multiple types of pathogens to prepare for infectious threats. Azithromycin is one such broad-spectrum therapeutic that is both included in the University of Oxford's RECOVERY and excluded from the World Health Organization's SOLIDARITY trials. Here we review azithromycin's broad antibiotic, antimalarial, antiviral pharmacology and contextualise it against a broader history as the most repositioned therapeutic of the macrolide class; we further evaluate azithromycin's clinical and socio-economic propriety for respiratory pandemics and delineate a model for its combinatorial mechanism of action against COVID-19 pneumonia.


Novel method of isolating nuclei of human oligodendrocyte precursor cells reveals substantial developmental changes in gene expression and H3K27ac histone modification.
Oligodendrocyte precursor cells (OPCs) generate differentiated mature oligodendrocytes (MOs) during development. In adult brain, OPCs replenish MOs in adaptive plasticity, neurodegenerative disorders, and after trauma. The ability of OPCs to differentiate to MOs decreases with age and is compromised in disease. Here we explored the cell specific and age-dependent differences in gene expression and H3K27ac histone mark in these two cell types. H3K27ac is indicative of active promoters and enhancers. We developed a novel flow-cytometry-based approach to isolate OPC and MO nuclei from human postmortem brain and profiled gene expression and H3K27ac in adult and infant OPCs and MOs genome-wide. In adult brain, we detected extensive H3K27ac differences between the two cell types with high concordance between gene expression and epigenetic changes. Notably, the expression of genes that distinguish MOs from OPCs appears to be under a strong regulatory control by the H3K27ac modification in MOs but not in OPCs. Comparison of gene expression and H3K27ac between infants and adults uncovered numerous developmental changes in each cell type, which were linked to several biological processes, including cell proliferation and glutamate signaling. A striking example was a subset of histone genes that were highly active in infant samples but fully lost activity in adult brain. Our findings demonstrate a considerable rearrangement of the H3K27ac landscape that occurs during the differentiation of OPCs to MOs and during postnatal development of these cell types, which aligned with changes in gene expression. The uncovered regulatory changes justify further in-depth epigenetic studies of OPCs and MOs in development and disease.


Proteomics and metabolomics of Arabidopsis responses to perturbation of glucosinolate biosynthesis.
To understand plant molecular networks of glucosinolate metabolism, perturbation of aliphatic glucosinolate biosynthesis was established using inducible RNA interference (RNAi) in Arabidopsis. Two RNAi lines were chosen for examining global protein and metabolite changes using complementary proteomics and metabolomics approaches. Proteins involved in metabolism including photosynthesis and hormone metabolism, protein binding, energy, stress, and defense showed marked responses to glucosinolate perturbation. In parallel, metabolomics revealed major changes in the levels of amino acids, carbohydrates, peptides, and hormones. The metabolomics data were correlated with the proteomics results and revealed intimate molecular connections between cellular pathways/processes and glucosinolate metabolism. This study has provided an unprecedented view of the molecular networks of glucosinolate metabolism and laid a foundation towards rationale glucosinolate engineering for enhanced defense and quality.


Toxic shock syndrome associated with TSST-1 producing coagulase-negative staphylococci.
Coagulase-positive staphylococci have been isolated from more than 95% of cases of toxic shock syndrome (TSS). Toxic shock syndrome toxin-1 (TSST-1) is produced in more than 90% of cases. A case is described of recurrent TSS in which a coagulase-negative staphylococcus was isolated from the vagina and produced TSST-1. No coagulase-positive staphylococci were isolated. Coagulase-negative staphylococci should be considered as causative agents in cases of TSS. Assay for TSST-1 should be performed on coagulase-negative staphylococci obtained from the appropriate clinical sites if no coagulase-positive staphylococci are isolated.


Reprogramming Synthetic Cells for Targeted Cancer Therapy.
Advances in synthetic biology enable the reprogramming of bacteria as smart agents to specifically target tumors and locally release anticancer drugs in a highly controlled manner. However, the bench-to-bedside translation of engineered bacteria is often impeded by genetic instability and the potential risk of uncontrollable replication of engineered bacteria inside the patient. SimCells (simple cells) are chromosome-free bacteria controlled by designed gene circuits, which can bypass the interference of the native gene network in bacteria and eliminate the risk of bacterial uncontrolled growth. Here, we describe the reprogramming of SimCells and mini-SimCells to serve as "safe and live drugs" for targeted cancer therapy. We engineer SimCells to display nanobodies on the surface for the binding of carcinoembryonic antigen (CEA), which is an important biomarker found commonly in colorectal cancer cells. We show that SimCells and mini-SimCells with surface display of anti-CEA nanobody can specifically bind CEA-expressing Caco2 cancer cells in vitro while leaving the non-CEA-expressing SW80 cancer cells untouched. These cancer-targeting SimCells and mini-SimCells induced cancer cell death in vitro by compromising the plasma membrane of cancer cells. The cancer-killing effect can be further enhanced by an aspirin/salicylate inducible gene circuit that converts salicylate into catechol, a potent anticancer. This work highlights the potential of SimCells and mini-SimCells for targeted cancer therapy and lays the foundation for the application of synthetic biology to medicine.


Translation-competent extracts from Saccharomyces cerevisiae: effects of L-A RNA, 5' cap, and 3' poly(A) tail on translational efficiency of mRNAs.
Yeast genetics has proven fruitful in the identification of key players that are involved in translational initiation. However, the exact roles of many translation initiation factors in translation initiation remain unknown. This has been due to lack of a suitable in vitro translation system in which the mode of action of certain translation factors can be studied. This report describes the preparation of cell-free Saccharomyces cerevisiae lysates that can mediate the translation of exogenously added mRNAs. Optimal translation required the absence of viral L-A RNA in the lysate and the presence of both a 5' cap and a 3' poly(A) tail on the mRNAs. A cooperative effect of cap and poly(A) tail on translation initiation was observed, a property that has been found to operate in intact yeast cells as well. In addition, the yeast lysates mediated translational initiation through several viral internal ribosome entry sites, demonstrating that the yeast translation apparatus can perform internal initiation. Thus, these lysates may be useful in the biochemical analysis of cap-dependent and cap-independent translation events.


Ontogeny of the male femur: Geometric morphometric analysis applied to a contemporary Spanish population.
To describe the morphological changes of the male femur during the adolescent growth spurt and to compare the pattern obtained with that reported previously for females. Two hundred and forty males from a Spanish population aged between 9 and 16 years were analysed, based on telemetries. Size and shape variation of the femur was quantified by 22 2D-landmarks and analysed using geometric morphometric methods. Likewise, the variation of neck-shaft and bicondylar angles were also determined and evaluated by Student's t-test. Sexual differences were analysed by comparing results here obtained on boys with those corresponding to girls reported in a previous study. In males, both size and shape varied significantly with age, with males having larger dimensions than females. In general terms, these changes are generally characterised by an increase in robustness of the femur and shape modifications in the epiphyses. During growth, the neck-shaft angle decreases and the size of the greater and lesser trochanters increase. A significant increase of distal epiphyseal dimensions was recorded, mainly in the medial condyle. The angular remodeling of both the neck and the bicondylar regions of the male femur continues until 16 and 15 years, respectively. Female and male femur each followed divergent growth trajectories. Males showed a greater variability in neck-shaft and bicondylar angles than females. The timing, morphology and growth trajectories provided on the femur during development can be very helpful in anthropological, paleoanthropological and evolution studies.


Stereotactic radiosurgery using the Leksell Gamma Knife Perfexion unit in the management of patients with 10 or more brain metastases.
To better establish the role of stereotactic radiosurgery (SRS) in treating patients with 10 or more intracranial metastases, the authors assessed clinical outcomes and identified prognostic factors associated with survival and tumor control in patients who underwent radiosurgery using the Leksell Gamma Knife Perfexion (LGK PFX) unit. The authors retrospectively reviewed data in all patients who had undergone LGK PFX surgery to treat 10 or more brain metastases in a single session at the University of Pittsburgh. Posttreatment imaging studies were used to assess tumor response, and patient records were reviewed for clinical follow-up data. All data were collected by a neurosurgeon who had not participated in patient care. Sixty-one patients with 10 or more brain metastases underwent SRS for the treatment of 806 tumors (mean 13.2 lesions). Seven patients (11.5%) had no previous therapy. Stereotactic radiosurgery was the sole prior treatment modality in 8 patients (13.1%), 22 (36.1%) underwent whole-brain radiation therapy (WBRT) only, and 16 (26.2%) had prior SRS and WBRT. The total treated tumor volume ranged from 0.14 to 40.21 cm(3), and the median radiation dose to the tumor margin was 16 Gy. The median survival following SRS for 10 or more brain metastases was 4 months, with improved survival in patients with fewer than 14 brain metastases, a nonmelanomatous primary tumor, controlled systemic disease, a better Karnofsky Performance Scale score, and a lower recursive partitioning analysis (RPA) class. Prior cerebral treatment did not influence survival. The median survival for a patient with fewer than 14 brain metastases, a nonmelanomatous primary tumor, and controlled systemic disease was 21.0 months. Sustained local tumor control was achieved in 81% of patients. Prior WBRT predicted the development of new adverse radiation effects. Stereotactic radiosurgery safely and effectively treats intracranial disease with a high rate of local control in patients with 10 or more brain metastases. In patients with fewer metastases, a nonmelanomatous primary lesion, controlled systemic disease, and a low RPA class, SRS may be most valuable. In selected patients, it can be considered as first-line treatment.


Effects of Citric Acid on the Healing Process of Chronic Wound due to Leprosy.
Objective: The aim was to describe the effects of the use of citric acid in the healing process of chronic leprosy wounds. Approach: This is a case series, carried out with 5 people with chronic leprosy wounds, under continuous care in an outpatient center wound care in the center-south region of Brazil. The intervention protocol consisted of topical application of 3% citric acid (ointment), on the wound bed, in a thin layer of approximately 2 mm, on alternate days, and followed up for a total period of 8 weeks and secondary coverage rayon and gauze. The cases were analyzed regarding wound dimensions, histology and clinical observation. Results: It was observed in all cases better aspect of the wound bed, presence of granulation tissue and decrease of the inflammatory process with predominance of lymphocytes, reduction of bacterial colonies, increase and verticalization of type I collagen fibers, reduction of type III collagen and increased areas of epithelialization. Innovation: There was also a reduction in the level of pain and exudation after the treatment protocol. Conclusions: Therefore, the use of citric acid in leprosy neuropathic wounds is promising and may be a treatment option, considering its cost, clinical management and possible effect on the chronic inflammatory process.


Molecular analysis of neurofibromatosis type 1 in Turkish families using polymorphic markers.
Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder characterized by multiple neurofibromas, café-au-lait spots, and Lisch nodules of iris. The NF1 gene is located on chromosome 17q11.2 and encodes an 11-13 kb mRNA containing 60 exons. The NF1 gene product neurofibromin is a large protein of 2818 amino acids which acts as a negative regulator in the ras signal transduction pathway. The disease has a high mutation rate and a wide range of expression. Because of the size and complexity of the gene, the variety of mutations and the need to identify the specific mutation in each family, indirect diagnosis using linked markers has an important part in genetic counseling. We analyzed 10 Turkish families with a total of 28 affected individuals and 34 non-affected relatives using polymorphic sequences, four intragenic and five flanking markers. Intragenic microsatellite markers were highly informative for all families. As a result, prenatal and presymptomatic diagnoses for familial cases are being made available.


Ataxia telangiectasia mutated kinase mediates NF-κB serine 276 phosphorylation and interferon expression via the IRF7-RIG-I amplification loop in paramyxovirus infection.
Respiratory syncytial virus (RSV) is a primary etiological agent of childhood lower respiratory tract disease. Molecular patterns induced by active infection trigger a coordinated retinoic acid-inducible gene I (RIG-I)-Toll-like receptor (TLR) signaling response to induce inflammatory cytokines and antiviral mucosal interferons. Recently, we discovered a nuclear oxidative stress-sensitive pathway mediated by the DNA damage response protein, ataxia telangiectasia mutated (ATM), in cytokine-induced NF-κB/RelA Ser 276 phosphorylation. Here we observe that ATM silencing results in enhanced single-strand RNA (ssRNA) replication of RSVand Sendai virus, due to decreased expression and secretion of type I and III interferons (IFNs), despite maintenance of IFN regulatory factor 3 (IRF3)-dependent IFN-stimulated genes (ISGs). In addition to enhanced oxidative stress, RSV replication enhances foci of phosphorylated histone 2AX variant (γH2AX), Ser 1981 phosphorylation of ATM, and IKKγ/NEMO-dependent ATM nuclear export, indicating activation of the DNA damage response. ATM-deficient cells show defective RSV-induced mitogen and stress-activated kinase 1 (MSK-1) Ser 376 phosphorylation and reduced RelA Ser 276 phosphorylation, whose formation is required for IRF7 expression. We observe that RelA inducibly binds the native IFN regulatory factor 7 (IRF7) promoter in an ATM-dependent manner, and IRF7 inducibly binds to the endogenous retinoic acid-inducible gene I (RIG-I) promoter. Ectopic IRF7 expression restores RIG-I expression and type I/III IFN expression in ATM-silenced cells. We conclude that paramyxoviruses trigger the DNA damage response, a pathway required for MSK1 activation of phospho Ser 276 RelA formation to trigger the IRF7-RIG-I amplification loop necessary for mucosal IFN production. These data provide the molecular pathogenesis for defects in the cellular innate immunity of patients with homozygous ATM mutations. RNA virus infections trigger cellular response pathways to limit spread to adjacent tissues. This "innate immune response" is mediated by germ line-encoded pattern recognition receptors that trigger activation of two, largely independent, intracellular NF-κB and IRF3 transcription factors. Downstream, expression of protective antiviral interferons is amplified by positive-feedback loops mediated by inducible interferon regulatory factors (IRFs) and retinoic acid inducible gene (RIG-I). Our results indicate that a nuclear oxidative stress- and DNA damage-sensing factor, ATM, is required to mediate a cross talk pathway between NF-κB and IRF7 through mediating phosphorylation of NF-κB. Our studies provide further information about the defects in cellular and innate immunity in patients with inherited ATM mutations.


[Percutaneous treatment of a ruptured sinus Valsalva aneurysm with double orifices].
An aneurysm of the sinus of Valsalva (SVA) may rupture into the cardiac cavities and cause abnormal connections between these cavities and the aorta. The right atrium and/or right ventricle are the cavities into which the SVA is most commonly observed to rupture. A 30-year-old patient presented to our cardiology clinic with the complaint of dyspnea. His physical examination revealed a thrill localized in the 5th intercostal space on the right edge of the sternum and systolic-diastolic murmur beginning from the aortic focus and spreading to the neck and back along the right edge of the sternum. The echocardiographic and invasive examinations revealed two defects leading to a passage from the right sinus Valsalva to the right ventricle. While the left-to-right shunt ratio was calculated as 3.8, the anatomic locations and dimensions of the defects were found to be eligible for percutaneous closure. Using the Amplatzer Duct Occluder I device, the defects were closed in two sessions. Although the classical treatment method of ruptured SVA is surgical repair, percutaneous closure devices may be used as a reliable alternative method in suitable patients.


Injecting drug use: implications for skin and wound management.
This article, the first of two parts, introduces the difficulties facing nurses working with injecting drug users with skin problems. Drug abuse is increasing globally, and has huge implications for healthcare practitioners. Increasing numbers of tissue viability nurses are also encountering drug injection-induced wounds in their practice, but there is a lack of evidence for management of chronic skin problems in this patient group. Together with rising numbers of injecting drug users, there are increased health implications such as bacteraemia, septicaemia, amputation and skin breakdown. Abscesses and chronic wounds as well as prolonged leg ulceration are common. Drug users may demonstrate chaotic lifestyles, which may inhibit access to usual healthcare provision. Issues relating to healing of these wounds are explored. The second part, which will appear in the next Tissue Viability Supplement, will describe the development of a specialist wound care clinic for homeless drug users.


Bystander interventions and survival after exercise-related sudden cardiac arrest: a systematic review.
To evaluate the provision of bystander interventions and rates of survival after exercise-related sudden cardiac arrest (SCA). Systematic review. MEDLINE, EMBASE, PubMed, CINAHL, SPORTDiscus, Cochrane Library and grey literature sources were searched from inception to November/December 2020. Observational studies assessing a population of exercise-related SCA (out-of-hospital cardiac arrests that occurred during exercise or within 1 hour of cessation of activity), where bystander cardiopulmonary resuscitation (CPR) and/or automated external defibrillator (AED) use were reported, and survival outcomes were ascertained. Among all included studies, the median (IQR) proportions of bystander CPR and bystander AED use, as well as median (IQR) rate of survival to hospital discharge, were calculated. A total of 29 studies were included in this review, with a median study duration of 78.7 months and a median sample size of 91. Most exercise-related SCA patients were male (median: 92%, IQR: 86%-96%), middle-aged (median: 51, IQR: 39-56 years), and presented with a shockable arrest rhythm (median: 78%, IQR: 62%-86%). Bystander CPR was initiated in a median of 71% (IQR: 59%-87%) of arrests, whereas bystander AED use occurred in a median of 31% (IQR: 19%-42%) of arrests. Among the 19 studies that reported survival to hospital discharge, the median rate of survival was 32% (IQR: 24%-49%). Studies which evaluated the relationship between bystander interventions and survival outcomes reported that both bystander CPR and AED use were associated with survival after exercise-related SCA. Exercise-related SCA occurs predominantly in males and presents with a shockable ventricular arrhythmia in most cases, emphasising the importance of rapid access to defibrillation. Further efforts are needed to promote early recognition and a rapid bystander response to exercise-related SCA.