What we have learned about cervical ultrasound.
The National Institute of Child Health and Human Development Maternal-Fetal Medicine Units Network has completed 2 prospective, blinded observational studies of cervical ultrasound for the prediction of preterm birth and the identification of high-risk women who might benefit from interventions aimed at preventing spontaneous preterm birth. These reports and other clinical data support the concept that cervical competence is not a dichotomous variable, but more likely functions along a continuum that is reflected by the relationship between cervical length and reproductive outcomes. Because of its safety, availability, patient acceptance and reproducibility, the sonographic evaluation of the uterine cervix has become an important investigational tool that has advanced our understanding of the preterm birth syndrome and should allow a more focused approach to the most persistent and challenging problem in modern obstetrics.


The role of the emergency department in the acute management of chronic or recurrent pain.
Exacerbation of chronic pain is a common presenting problem for patients attending emergency departments (EDs), with many making multiple visits. This paper aims to identify the role of the ED in the acute management of patients with persistent or chronic nonmalignant pain through a review of current literature. Four databases were searched using the MeSH and subject search terms "chronic nonmalignant pain", "persistent pain" and "emergency" and synonyms associated with these terms. Literature related to the underlying causes of suboptimal chronic pain management along with the sequelae associated with treatment or management was extracted. Three main themes emerged: patient expectations and satisfaction, barriers to care, and strategies/principles to improve ED management for this patient group. The presence of these themes appears to be partially due to time limitations for chronic issues in an acute department, accompanied by a lack of clear guidelines. It is evident that the ED is not the ideal setting for managing patients with chronic pain however it is the last resort for many who do present, and who will continue to present should their pain persist. It is time to ensure that the ED provides a consistently supportive, cohesive and integrated approach to managing patients with chronic pain syndromes.


Effects of vaginal seeding on gut microbiota, body mass index, and allergy risks in infants born through cesarean delivery: a randomized clinical trial.
Vaginal seeding-exposure of neonates to maternal vaginal fluids-has been proposed to improve the microbiota of infants born through cesarean delivery, but its impacts on the infants' subsequent health outcomes remain unclear. This study aimed to examine the impacts of vaginal seeding on gut microbiota, growth, and allergy risks in infants born through cesarean delivery. This randomized controlled trial was conducted at Liuyang Maternal and Child Health Care Hospital in Hunan, China. We estimated that a minimum sample size of 106 was needed by assuming a standardized effect size of 0.6 for the primary outcomes, with a statistical power of 80%, a 2-sided type I error of 0.05, and an expected loss to follow-up rate of 15%. Finally, 120 singleton term pregnant women scheduled for cesarean delivery were enrolled from November 2018 to September 2019. Infant follow-up was completed in September 2021. The participants were randomized in a 1:1 ratio to the vaginal seeding group (n=60; infants were swabbed immediately after birth using gauze preincubated in maternal vagina) or the control group (n=60; routine standard care). The first set of primary outcomes was infant body mass index and body mass index z-scores at 6, 12, 18, and 24 months of age. The other primary outcome was the total allergy risk score at 18 months for 20 common allergens (each scored from 0-6 points). Characteristics of gut microbiota, overweight/obesity, and allergic diseases and symptoms were included as secondary outcomes. The main analyses were performed according to the modified intention-to-treat principle. Of 120 infants, 117 were included in the analyses. Infant body mass index and body mass index z-scores did not significantly differ between the 2 groups at any of the 4 time points, with the largest difference in point estimates occurring at 6 months: the mean (standard deviation) body mass index was 17.5 (1.4) kg/m2 and 17.8 (1.8) kg/m2 in the vaginal seeding and control groups, respectively (mean difference, -0.31 kg/m2 [95% confidence interval, -0.91 to 0.28]; P=.30), and body mass index z-score was 0.2 (1.0) and 0.4 (1.1), respectively (mean difference, -0.20 [95% confidence interval, -0.58 to 0.18]; P=.31). The median total allergy risk score was 1.5 (interquartile range, 0.0-4.0) in the vaginal seeding group and 2.0 (interquartile range, 1.0-3.0) in the control group (median difference, 0.00 [95% confidence interval, -1.00 to 1.00]; P=.48). For infants from the vaginal seeding group, the relative abundance of genera Lactobacillus and Bacteroides in the gut microbiota was slightly yet nonsignificantly elevated at birth and 6 months, and the risk of overweight/obesity was lower at 6 months (0/57 vs 6/59; relative risk, 0.03 [95% confidence interval, 0.00-0.57]; P=.03) though not at subsequent time points. Other secondary outcomes did not differ between groups. No adverse events related to the intervention were reported. For infants born through cesarean delivery, vaginal seeding has no significant impacts on the gut microbiota, growth, or allergy risks during the first 2 years of life.


Visible-light promoted degradation of the commercial antioxidants butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT): a kinetic study.
Visible-light photo-irradiation of the commercial phenolic antioxidants (PhAs) butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), in the presence of vitamin B2 (riboflavin, Rf), in methanolic solutions and under aerobic conditions, results in the photo-oxidation of the PhAs. The synthetic dye photosensitiser Rose Bengal was also employed for auxiliary experiments. With concentrations of riboflavin and PhAs of ca. 0.02 mM and < 1 mM, respectively, the excited triplet state of the vitamin (3Rf*) is quenched by BHT in a competitive fashion with dissolved ground state triplet oxygen. From the quenching of 3Rf*, the semireduced form of the pigment is generated through an electron transfer process from BHT, with the subsequent production of superoxide anion radical (O2*-) by reaction with dissolved molecular oxygen. In parallel, the species singlet molecular oxygen, O2(1delta(g)), is also generated. Both reactive oxygen species produce the photodegradation of BHT. In the case of BHA, the lack of any effect exerted by superoxide dismutase drives out a significant participation of a O2(*-)-mediated mechanism. BHA mainly interacts with O2(1delta(g)) and exhibits a desirable property as an antioxidant--a relatively high capacity for O2(1delta(g)) de-activation and a low photodegradation efficiency by the oxidative species. Electrochemical determinations support the proposed photodegradative mechanism.


Isoeugenol destabilizes IL-8 mRNA expression in THP-1 cells through induction of the negative regulator of mRNA stability tristetraprolin.
We previously demonstrated in the human promyelocytic cell line THP-1 that all allergens tested, with the exception of the prohapten isoeugenol, induced a dose-related release of interleukin-8 (IL-8). In the present study, we investigated whether this abnormal behavior was regulated by the AU-rich element-binding proteins HuR and tristetraprolin (TTP) or by the downstream molecule suppressor of cytokine signaling (SOCS)-3. The contact allergens isoeugenol, diethylmaleate (DEM), and 2,4-dinitrochlorobenzene (DNCB), and the irritant salicylic acid were used as reference compounds. Chemicals were used at concentrations that induced a 20% decrease in cell viability as assessed by propidium iodide staining, namely 100 μg/ml (0.61 mM) for isoeugenol, 100 μg/ml (0.58 mM) for DEM, 3 μg/ml (14.8 μM) for DNCB, and 250 μg/ml (1.81 mM) for salicylic acid. Time course experiments of IL-8 mRNA expression and assessment of IL-8 mRNA half-life, indicated a decreased IL-8 mRNA stability in isoeugenol-treated cells. We could demonstrate that a combination and regulation of HuR and TTP following exposure to contact allergens resulted in a different modulation of IL-8 mRNA half-life and release. The increased expression of TTP in THP-1 cells treated with isoeugenol results in destabilization of the IL-8 mRNA, which can account for the lack of IL-8 release. In contrast, the strong allergen DNCB failing to up-regulate TTP, while inducing HuR, resulted in longer IL-8 mRNA half-life and protein release. SOCS-3 was induced only in isoeugenol-treated cells; however, its modulation did not rescue the lack of IL-8 release, indicating that it is unlikely to be involved in the lack of IL-8 production. Finally, the destabilization effect of isoeugenol on IL-8 mRNA expression together with SOCS-3 expression resulted in an anti-inflammatory effect, as demonstrated by the ability of isoeugenol to modulate LPS or ionomycin-induced cytokine release.


Identification and characterization of transcribed sequences on human chromosome 9q32-34.
The gene responsible for the neuromuscular disease idiopathic torsion dystonia (DYT1) has recently been mapped to human chromosome 9q32-34. Our goal is to identify candidate genes for torsion dystonia as well as other neurologically important genes in this region. To accomplish this we have characterized the expression patterns of transcribed sequences identified within a collection of 3000 human 9q32-34-specific clones. Screening of this clone collection with cDNA probes from various brain and peripheral tissues resulted in the identification of 143 clones corresponding to 9q32-34-specific transcripts. Thirty three of these corresponded to transcripts expressed in a brain-specific manner and thus represent preferred candidates for the dystonia gene. None of these candidates were expressed specifically in the putative dystonia target tissue, basal ganglia. The 9q32-34 collection was screened with a subtracted probe enriched in striatal sequences using a directional tag PCR subtraction method. This resulted in the identification of several genes exhibiting preferential expression in the striatum as compared to cerebellum.


Errata in the Report on Continued Fever, by the Editor.
[This corrects the article on p. 129 in vol. 6.].


The value of brachytherapy in the age of advanced external beam radiotherapy: a review of the literature in terms of dosimetry.
Brachytherapy (BT) has long been used for successful treatment of various tumour entities, including prostate, breast and gynaecological cancer. However, particularly due to advances in modern external beam techniques such as intensity-modulated radiotherapy (IMRT), volume modulated arc therapy (VMAT) and stereotactic body radiotherapy (SBRT), there are concerns about its future. Based on a comprehensive literature review, this article aims to summarize the role of BT in cancer treatment and highlight its particular dosimetric advantages. The authors conclude that image-guided BT supported by inverse dose planning will successfully compete with high-tech EBRT in the future and continue to serve as a valuable modality for cancer treatment.


Detection of a rabbit uteroglobin-like protein in human neonatal tracheobronchial washings.
Uteroglobin is a steroid hormone dependent, low molecular weight, secretory protein with many immunomodulatory properties. Immunomodulation by this protein may, at least in part, be related to its inhibitory effects on phospholipase A2 activity. Although uteroglobin is conclusively found in the rabbit, its presence in the human is controversial. Here, we present biochemical and immunological evidence for the detection of a uteroglobin-like protein in the wet epithelial living of the respiratory tract of human neonates. Because inhibition of phospholipase A2 may modulate tissue eicosanoid levels and since many eicosanoids (i.e. prostaglandins and leukotrienes etc.) are well known regulators of smooth muscle contractility, cellular migration and inflammatory processes, the discovery of this protein in the human respiratory tract may have important physiological implications.


A microscopic and immunocytochemical study of structural changes in dysfunctional human temporomandibular joint discs.
The central part of 12 articular discs from patients with serious alterations in function of the temporomandibular joint were investigated. The control discs were removed at autopsy from individuals who did not have any such functional defects. The anomalous discs had an increased cellular component; fibrocytes, fibroblasts, numerous myofibroblasts and, less frequently, smooth muscle cells and mast cells were present. The myofibroblasts, which had numerous bundles of thin filaments in the cytoplasm, were positive to the immunocytochemical reaction with antibody to alpha-smooth muscle actin. In one disc only a large part had changed into a mostly fatty tissue. In the majority of the altered discs, the part examined, which usually is neither vascularized nor innervated, was characterized by the presence of numerous blood vessels. Besides the capillary network several larger vessels were present. In one disc, several myelinated and unmyelinated fibres, isolated or in nerve bundles, were also seen. These observations show that the disc fibrous tissue may undergo deep structural modifications that appear to indicate not only a capacity for repair but also an ability to adapt to new functional conditions.


A highly sensitive DNA bead-based suspension array for the detection and species identification of bovine piroplasms.
Piroplasms are among the most harmful tick-borne pathogens for livestock and sensitive and specific diagnostic methods for rapid detection and identification of the different species are needed for effective control. Reverse Line Blot has been the molecular technique of choice but it is laborious, time-consuming and highly susceptible to subjective variation in the interpretation of the hybridisation signal. Here, an oligonucleotide multiplex suspension microarray (Luminex® microsphere system) was developed for bovine piroplasms. Probes previously used in Reverse Line Blot for Babesia divergens, Babesia bovis, Babesia occultans, Babesia bigemina and Theileria buffeli, and a catch-all Theileria and Babesia control probe, were included in the Luminex assay together with newly designed probes for Theileria annulata and Babesia major. An internal amplification control that was detected with a Luminex probe was included to monitor for inhibition. Serially diluted linearised recombinant plasmids of the different species were used to assess the analytical sensitivity and specificity, and the detection limit of the Luminex assay was determined using serial dilutions of infected blood from an animal with a known level of T. annulata parasitaemia. The assay was then validated on 214 bovine blood samples analysed in parallel by Reverse Line Blot and Luminex. The Luminex assay proved to be highly specific and more sensitive than Reverse Line Blot, detecting 0.05 parasites/μl of blood. Technically, the Luminex procedure was rapid, provided high throughput screening, transformed the subjective interpretation of Reverse Line Blot results into numerical objective values, and allowed more flexibility in array preparation than Reverse Line Blot. The method described herein can substantially improve the detection of piroplasm carriers and thus better protect livestock trade and facilitate preventive control programs.


Relaxin-like peptides in male reproduction - a human perspective.
The relaxin family of peptide hormones and their cognate GPCRs are becoming physiologically well-characterized in the cardiovascular system and particularly in female reproductive processes. Much less is known about the physiology and pharmacology of these peptides in male reproduction, particularly as regards humans. H2-relaxin is involved in prostate function and growth, while insulin-like peptide 3 (INSL3) is a major product of the testicular Leydig cells and, in the adult, appears to modulate steroidogenesis and germ cell survival. In the fetus, INSL3 is a key hormone expressed shortly after sex determination and is responsible for the first transabdominal phase of testicular descent. Importantly, INSL3 is becoming a very useful constitutive biomarker reflecting both fetal and post-natal development. Nothing is known about roles for INSL4 in male reproduction and only very little about relaxin-3, which is mostly considered as a brain peptide, or INSL5. The former is expressed at very low levels in the testes, but has no known physiology there, whereas the INSL5 knockout mouse does exhibit a testicular phenotype with mild effects on spermatogenesis, probably due to a disruption of glucose homeostasis. INSL6 is a major product of male germ cells, although it is relatively unexplored with regard to its physiology or pharmacology, except that in mice disruption of the INSL6 gene leads to a disruption of spermatogenesis. Clinically, relaxin analogues may be useful in the control of prostate cancer, and both relaxin and INSL3 have been considered as sperm adjuvants for in vitro fertilization. This article is part of a themed section on Recent Progress in the Understanding of Relaxin Family Peptides and their Receptors. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.10/issuetoc.


Flexibility and dynamics of NhaA Na+/H+-antiporter of Escherichia coli studied by Fourier transform infrared spectroscopy.
NhaA (41,355Da) is a Na(+)/H(+) antiporter of Escherichia coli which plays a central role in regulation of intracellular pH, cellular Na(+) content, and cell volume [E. Padan, S. Schuldiner, J. Exp. Biol. 196 (1994) 443]. Its activity is strongly regulated by pH and increases over 3 orders of magnitude between pH 7 and 8 [A. Rothman, Y. Gerchman, E. Padan, S. Schuldiner, Biochemistry 36 (1997) 14572]. Protein dynamics and flexibility in the activated and inactivated state, respectively, was analysed by probing accessibility in (1)H/(2)H exchange experiments for the wild type and the mutant G338S which is constitutively active independent of pH [A. Rimon, Y. Gerchman, Z. Kariv, E. Padan, J. Biol. Chem. 273 (1998) 26470]. This was studied by ATR-FTIR difference spectroscopy using a home built microvolume (<5 microl) perfusion chamber [E. Agić, O. Klein, W. Mäntele, Proceedings of the 10th European Conference on the Spectroscopy of Biological Molecules, vol. 93, 2003, ISBN 9634826148; S. Gourion-Arsiquaud, S. Chevance, P. Bouyer, L. Garnier, J.-L. Montillet, A. Bondon, C. Berthomieu, Biochemistry 44 (2005) 8652]. The solution or suspension of the target protein is contained in a chamber with sample volumes of below 5 microl. It is in contact with the ATR crystal and separated from the flowing effector molecules by a dialysis membrane. The flow-ATR unit is characterised by high stability, fast response, and high sensitivity for the IR spectroscopic detection of binding-induced conformational changes and reactions. On the basis of (1)H-(2)H exchange of NhaA followed in the amide I and amide II region of the IR spectrum, it is concluded that the accessible fraction of the polypeptide chain of NhaA increases by more than 10% in the active state. For the mutant, no changes in accessibility were observed for different pH values. The increase of Na(+) concentration increases the extent of exchange. The stability of the wild type protein in the active and inactive form was analysed by measuring the temperature profiles of the IR spectra. A decrease of the structural stability of the protein with activation was observed. Together with the results from (1)H/(2)H exchange, the inactive state represents a more compact form whereas activation induces a more open conformation of the protein.


The treatment of ACTH Paraneoplastic syndrome with aminoglutethimide.
A 60-year-old white female with oat-cell carcinoma of the lung presents with a recurrent pulmonary nodule and Cushing syndrome. The tumor is uncontrollable with MeCCNU and cyclophosphamide (Cytoxan), consequently the symptoms of Cushing disease become severe. Cushing syndrome is documented by laboratory examinations. Aminoglutethimide, an anticonvulsant, is used to reverse the symptomatology and also the laboratory values. When aminoglutethimide is discontinued, the laboratory findings return to pretreatment levels.


Starvation and dehydration: effect on hypothalamic monoamines and serum LH and prolactin.
1. Rats submitted to starvation or water deprivation showed a decrease in LH and prolactin serum levels. 2. 5-HT was increased without changes in DA and NA in cerebral cortex of starved rats. 3. Neurotransmitters did not change in hypothalamus of starved rats but water deprivation decreased NA and increased 5-HT.


Laser therapy in a soft-shelled turtle (Pelodiscus sinensis) for the treatment of skin and shell ulceration. A case report.
Skin and shell diseases in aquatic turtles are often associated with several underlying causes. The presented case report describes aetiology including differential diagnoses, diagnostic procedures and therapy of a soft-shelled turtle (Pelodiscus sinensis) suffering from a septicaemic ulcerative dermatitis. Central aspect hereby is the positive curing effect of laser therapy on skin and shell lesions.


Diagnostic value of plasma biochemistry, haematology, radiography and endoscopic visualisation for hepatic disease in psittacine birds.
Hepatic disease in psittacine birds is common but challenging to diagnose. This retrospective study evaluates the diagnostic value of plasma biochemistry, haematology, radiography and endoscopic visualisation in psittaciforms with suspected hepatic disease that underwent endoscopic liver biopsy. Clinical records of 28 companion psittaciforms from a veterinary teaching hospital (2007-2016) were reviewed. Diagnostic results were categorised as abnormal or normal and compared with histopathology for agreement or disagreement. Statistical significance was determined by kappa test for agreement and McNemar's test for disagreement. 11 of 28 psittaciforms (39.3 per cent) had clinical signs considered specific for liver disease. 25 of 28 (89.3 per cent) psittaciforms had histopathological liver lesions. Gross changes radiographically and endoscopically agreed with histopathology in 57.1 per cent and 53.6 per cent of cases, respectively. Aspartate aminotransferase (AST) (48.1 per cent), creatine phosphokinase (73.1 per cent) and albumin by protein electrophoresis (50 per cent) showed the highest agreement. Kappa was not significant for any parameters, while McNemar's test for disagreement was significant for radiography, endoscopy, AST, lactate dehydrogenase, bile acid, total protein (chemistry), cholesterol, triglycerides, uric acid and glucose. Overall, changes on plasma biochemistry, radiography or endoscopy are non-specific and do not consistently agree with histopathology results. Endoscopic liver biopsy is highly recommended if there is clinical suspicion of hepatic disease.


Toward developmentally aware practices in the legal system: Progress, challenge, and promise.
Much research in developmental psychology has implications for practice and policy. In this article, I first describe how initial attempts to understand early social development and embrace multidisciplinary perspectives helped inform more nuanced approaches to the development of parenting plans for children with separating and maltreating parents. Second, I trace the ways in which notorious child abuse cases fostered research on children's testimonial capacities, which, in turn, informed the development of more effective forensic interview techniques. Progress in these domains has, however, been offset by failures to apply similar developmentally sensitive principles when dealing with children classified as suspects rather than victims, with children who testify in court, and with children in the child welfare system.


Profilin-1 overexpression upregulates PTEN and suppresses AKT activation in breast cancer cells.
Profilin-1 (Pfn1), a ubiquitously expressed actin-binding protein, has been regarded as a tumor-suppressor molecule for breast cancer. Since AKT signaling impacts cell survival and proliferation, in this study we investigated whether AKT activation in breast cancer cells is sensitive to perturbation of Pfn1 expression. We found that even a moderate overexpression of Pfn1 leads to a significant reduction in phosphorylation of AKT in MDA-MB-231 breast cancer cells. We further demonstrated that Pfn1 overexpression in MDA-MB-231 cells is associated with a significant reduction in the level of the phosphoinositide regulator of AKT, PIP(3), and impaired membrane translocation of AKT that is required for AKT activation, in response to EGF stimulation. Interestingly, Pfn1-overexpressing cells showed post-transcriptional upregulation of PTEN. Furthermore, when PTEN expression was silenced, AKT phosphorylation was rescued, suggesting PTEN upregulation is responsible for Pfn1-dependent attenuation of AKT activation in MDA-MB-231 cells. Pfn1 overexpression induced PTEN upregulation and reduced AKT activation were also reproducible features of BT474 breast cancer cells. These findings may provide mechanistic insights underlying at least some of the tumor-suppressive properties of Pfn1.


Negative regulation of cytokine signaling and inflammatory diseases.
Immune and inflammatory systems are controlled by multiple cytokines, including interleukins and interferons. These cytokines exert their biological functions through Janus tyrosine kinases and signal transducer and activators of transcription (STATs). The cytokine-inducible SH2 proteins (CIS) and suppressors of cytokine signaling (SOCS) are a family of intracellular proteins, several of which have emerged as key physiological regulators of cytokine responses, including those that regulate the inflammatory system. Several recent advances have been made in this field, including treatment of inflammatory diseases by modulating extracellular and intracellular signaling pathways.


Development of the generic, multidimensional Treatment Expectation Questionnaire (TEX-Q) through systematic literature review, expert surveys and qualitative interviews.
Patients' expectations-as a central mechanism of placebo and nocebo effects-are an important predictor of health outcomes. However, the lack of a way to assess expectations across different settings restricts progress in understanding the role of expectations and to quantify their importance in medical and psychological treatments. The aim of this study was to develop a theory-based, generic, multidimensional measure assessing patient expectations of medical and psychological treatments. The Treatment Expectation Questionnaire (TEX-Q) was developed based on the integrative model of expectations and a systematic literature review of treatment expectation scales. After creating a comprehensive item pool, the scale was further refined by use of expert ratings and patient interviews. Patients were recruited in primary care at two hospitals in Hamburg, Germany. 13 scientific experts participated in the expert survey. 11 patients waiting for psychological or surgical treatments participated in the qualitative interviews. The 2×2×2 multidimensional structure of the TEX-Q assesses two expectation constructs (probabilistic vs value-based) across two outcome domains with two valences (direct benefits and adverse events, broader positive and negative impact), plus process and behavioural control expectations. We examined 583 items from 38 scales identified in the systematic review and developed 78 initial items. Content validity was then rated by experts according to item fit and comprehensibility. The best 53 items were further evaluated for comprehensibility, acceptability, phrasing preference and understanding by interviewing patients prior to treatment using the 'think aloud' technique. This resulted in a first 35-item version of the TEX-Q. The TEX-Q is a generic, multidimensional measure to assess patient expectations of medical and psychological treatments and allows comparison of the impact of multidimensional expectations across different conditions. The final TEX-Q will be available after psychometric validation.


Haemorrhagic bullae induced by oral anticoagulants.
A 77-year-old patient developed haemorrhagic bullae on her fingers 30 months after initiation of anti-coagulation treatment with warfarin sodium for chronic atrial fibrillation and mitral insufficiency. The bullae resolved 10 days after discontinuation of the medication. Two weeks after initiation of sintrom, (3-alpha-(4-nitrophenyl)-beta-acetylethyl-4-hydroxy coumarin), the lesions recurred and resolved again upon cessation of the drug. This adverse skin reaction has not been hitherto reported.


Introduction of an extra tryptophan fluorophore by cataract-associating mutations destabilizes βB2-crystallin and promotes aggregation.
β/γ-Crystallins are predominant structural proteins in vertebrate lens with unique properties of extremely high solubility, long-term stability and resistance to UV damage. Four conserved Trp residues in β/γ-crystallins account for UV absorbance and thereafter fluorescence quenching to avoid photodamage. Herein we found that βB2-crystallin Trp fluorescence was greatly enhanced by the introduction of an extra unquenched Trp fluorophore by cataract-associated mutations S31W and R145W. Both mutations impaired oligomerization, decreased stability and promote thermal aggregation, while S31W was more deleterious. S31W accelerated βB2-crystallin aggregation under UV damaging conditions, whereas R145W delayed. These observations suggested that the introduction of an extra Trp fluorophore had complicated effects on βB2-crystallin stability and aggregation against various stresses. Our findings highlight that the number of Trp fluorophores in β/γ-crystallin is evolutionarily optimized to exquisitely perform their structural roles in the lens.


Infiltration pattern predicts metastasis and progression better than the T-stage and grade in pancreatic neuroendocrine tumors: a proposal for a novel infiltration-based morphologic grading.
The advancing edge profile is a powerful determinant of tumor behavior in many organs. In this study, a grading system assessing the tumor-host interface was developed and tested in 181 pancreatic neuroendocrine tumors (PanNETs), 63 of which were <=2 cm. Three tumor slides representative of the spectrum (least, medium, and most) of invasiveness at the advancing edge of the tumor were selected, and then each slide was scored as follows. Well-demarcated/encapsulated, 1 point; Mildly irregular borders and/or minimal infiltration into adjacent tissue, 2 points; Infiltrative edges with several clusters beyond the main tumor but still relatively close, and/or satellite demarcated nodules, 3 points; No demarcation, several cellular clusters away from the tumor, 4 points; Exuberantly infiltrative pattern, scirrhous growth, dissecting the normal parenchymal elements, 5 points. The sum of the rankings on the three slides was obtained. Cases with scores of 3-6 were defined as "non/minimally infiltrative" (NI; n = 77), 7-9 as "moderately infiltrative" (MI; n = 68), and 10-15 as "highly infiltrative" (HI; n = 36). In addition to showing a statistically significant correlation with all the established signs of aggressiveness (grade, size, T-stage), this grading system was found to be the most significant predictor of adverse outcomes (metastasis, progression, and death) on multivariate analysis, more strongly than T-stage, while Ki-67 index did not stand the multivariate test. As importantly, cases <=2 cm were also stratified by this grading system rendering it applicable also to this group that is currently placed in "watchful waiting" protocols. In conclusion, the proposed grading system has a strong, independent prognostic value and therefore should be considered for integration into routine pathology practice after being evaluated in validation studies with larger series.


Long-term patency of coronary grafts with endoscopically harvested saphenous veins determined by contrast-enhanced electron beam computed tomography.
We determined the long-term patency rates of coronary artery grafts with endoscopically harvested saphenous veins. Patency rates were established in 51 patients with 130 distal saphenous vein grafts using contrast-enhanced electron beam computed tomography at 3.74 +/- 0.65 years after coronary artery bypass grafting. A similar group of 50 patients with 131 distal grafts were studied prospectively using the same methodology at 0.7 +/- 0.19 years after coronary artery bypass grafting. The overall patency rates were 95.4% in the retrospective group and 95.3% in the prospective group. Sequential grafts tended to have a patency advantage over independent grafts. These data compare favorably with reported patency rates for traditionally harvested saphenous veins. Endoscopic saphenous vein harvesting, in addition to previous favorable reports on pain, complications, and costs, is now shown to provide comparable or better patency rates in comparison with traditionally harvested veins.


Clinical responses following inspiratory muscle training in exercise-induced laryngeal obstruction.
Exercise-induced laryngeal obstruction (EILO) is relatively common in young people. Treatment rests on poor evidence; however, inspiratory muscle training (IMT) has been proposed a promising strategy. We aimed to assess laryngeal outcomes shortly after IMT, and to compare self-reported symptoms with a control group 4-6 years later. Two groups were retrospectively identified from the EILO-register at Haukeland University Hospital, Norway; one group had received only information and breathing advice (IBA), and another additionally IMT (IBA + IMT). At diagnosis, all participants performed continuous laryngoscopy during exercise (CLE), with findings split by glottic and supraglottic scores, and completed a questionnaire mapping exercise-related symptoms. After 2-4 weeks, the IBA + IMT-group was re-evaluated with CLE-test. After 4-6 years, both groups were re-assessed with a questionnaire. We identified 116 eligible patients from the EILO-register. Response rates after 4-6 years were 23/58 (40%) and 32/58 (55%) in the IBA and IBA + IMT-group, respectively. At diagnosis, both groups rated symptoms similarly, but laryngeal scores were higher in the IBA + IMT-group (P = 0.003). After 2-4 weeks, 23/32 in the IBA + IMT-group reported symptom improvements, associated with a decrease of mainly glottic scores (1.7-0.3; P < 0.001), contrasting unchanged scores in the 9/32 without symptom improvements. After 4-6 years, exercise-related symptoms and activity levels had decreased to similar levels in both groups, with no added benefit from IMT; however, full symptom resolution was reported by only 8/55 participants. Self-reported EILO symptoms had improved after 4-6 years, irrespective of initial treatment. Full symptom resolution was rare, suggesting individual follow-up should be offered.


Spatial proteomics reveals subcellular reorganization in human keratinocytes exposed to UVA light.
The effects of UV light on the skin have been extensively investigated. However, systematic information about how the exposure to ultraviolet-A (UVA) light, the least energetic but the most abundant UV radiation reaching the Earth, shapes the subcellular organization of proteins is lacking. Using subcellular fractionation, mass-spectrometry-based proteomics, machine learning algorithms, immunofluorescence, and functional assays, we mapped the subcellular reorganization of the proteome of human keratinocytes in response to UVA light. Our workflow quantified and assigned subcellular localization for over 1,600 proteins, of which about 200 were found to redistribute upon UVA exposure. Reorganization of the proteome affected modulators of signaling pathways, cellular metabolism, and DNA damage response. Strikingly, mitochondria were identified as one of the main targets of UVA-induced stress. Further investigation demonstrated that UVA induces mitochondrial fragmentation, up-regulates redox-responsive proteins, and attenuates respiratory rates. These observations emphasize the role of this radiation as a potent metabolic stressor in the skin.


Purification of a factor inducing differentiation in murine myelomonocytic leukemia cells. Identification as granulocyte colony-stimulating factor.
A naturally occurring inducer of terminal differentiation in a murine myelomonocytic leukemia cell line (WEHI-3B) was purified to apparent homogeneity from medium conditioned by lungs from mice injected with bacterial endotoxin. The factor was purified over 400,000-fold by sequential fractionation using salting out chromatography, chromatography on phenyl-Sepharose, gel filtration on Bio-Gel P-60 in 1 M acetic acid, reverse-phase high performance liquid chromatography on a phenyl-silica column, and high performance liquid chromatography on a gel filtration column. During the first two steps, the differentiation-inducing factor was separated completely from a known proliferative regulator for normal myeloid cells, granulocyte-macrophage colony-stimulating factor, but it co-purified through all remaining steps with a distinct granulocyte-specific colony-stimulating factor. The purified factor showed a single protein band of Mr = 24,000-25,000 on sodium dodecyl sulfate-polyacrylamide gels coincident with both differentiation-inducing and granulocyte colony-stimulating activity. The granulocyte-specific colony-stimulating factor was active on WEHI-3B cells and normal granulocytic progenitor cells in vitro at the same half-maximally active concentration of 3 X 10(-12) M.


Creation and testing of the Domiscore-a tool to characterize the impact of housing on health and well-being.
Despite evidence of the major impact housing carries on health, many individuals still live in unhealthy dwellings. In France, the Domiscore has been proposed as a tool to assess the quality of dwellings with regard to their health impact, to allow for a better detection of unsafe housing and to improve dwellings. The aim of this paper is to present the method used to construct the Domiscore and test its relevance and usability. The Domiscore grid, inspired by the Nutriscore, consists of 46 variables-such as air quality, light or outdoor view. Each variable is scored on a four-point scale using in situ observation, mandatory diagnostics and open access data. The sum of each variable's score results in an overall risk score for the dwelling. The Domiscore was tested in two phases. During the first testing phase, 11 real estate professionals, health professionals and social workers used the Domiscore for on-site visits in different geographic areas of France. They then participated in a semi-structured qualitative interview. The second phase consisted in a public consultation with diverse stakeholders such as public authorities, housing activists and social workers, using an online survey to collect their opinions on the Domiscore's relevance, understandability and usability. The Domiscore was tested on 28 homes. Variables completion rates were high irrespective of tester profile for all home visits (91%, SD = 4.7%). The mean time needed to fill in the grid was 1.5 h. The public consultation returned 151 responses. The Domiscore was deemed easy to understand, relevant, and rather easy to fill out. Most participants found the Domiscore useful for information gathering, awareness raising, detecting at-risk situations and agreed that it could contribute to enhance housing conditions. Its length was noted, although the inclusion of additional variables was also suggested. The results of this study suggest that the Domiscore is accessible to housing specialists and other professionals for the evaluation of a dwelling's health impacts and the standardized detection of dangerous situations. The testing process allowed for improvements in the grid and training materials for future users.


Investigation of catalytic activity of metal doped nanocages (Ni-C72 and Ni-Al36P36) for ozone decomposition to oxygen molecules.
The potential of Ni-C72 and Ni-Al36P36 as effective catalysts for O3 decomposition is examined by LH and ER mechanisms. The activation barrier energy and Gibbs free energy of reaction steps for O3 decomposition on Ni-C72 and Ni-Al36P36 are calculated. The ∆Eformation of Ni-C72 and Ni-Al36P36 are negative values and these structures are stable nano-catalysts. The Ni atoms are catalytic positions to adsorb the O3 and other important species of O3 decomposition by LH and ER mechanisms. The Ni-Al36P36 for O3 decomposition has lower Eacivation and more negative ∆Greaction than Ni-C72. The Eacivation value of rate-determining step for O3 decomposition by LH mechanism is lower than ER mechanism. The Ni-C72 and Ni-Al36P36 can catalyze the reaction steps of O3 decomposition by LH and ER mechanisms. The structures of Ni-C72 and Ni-Al36P36 nanocages and their complexes with O3 and other important species of are optimized by PW91PW91/6-311 + G (2d, 2p) model and M06-2X/cc-pVQZ model in GAMESS software. The strcutures of nanocages and their complexes with important species of O3 decomposition by LH and ER mechanisms are optimized and their frequencies are calculated in order to demonstrate that these structures are real minima on the potential energy surface.


Comparison of Two Corticosteroid Pre-Infusion Regimens for Pegloticase in the United States: A Retrospective Analysis in Community Rheumatology Practices.
Pegloticase is a recombinant porcine-like uricase enzyme that is FDA-approved for the treatment of chronic refractory gout in adults. Some patients receiving pegloticase develop anti-drug antibodies, which leads to both loss of pegloticase efficacy and an increased risk for infusion reactions. In the pivotal trials, all patients received pre-infusion medications before each pegloticase dose, including intravenous (IV) hydrocortisone. In clinical practice, many clinicians use methylprednisolone for pre-infusion therapy with pegloticase; however, the efficacy of methylprednisolone compared with hydrocortisone as a pre-infusion medication for pegloticase has not been established. The aim of this study was to compare the efficacy of methylprednisolone versus hydrocortisone as a pre-infusion medication for pegloticase. Data were retrospectively collected from 92 qualifying patients treated with pegloticase and administered pre-infusion prophylaxis with either intravenous hydrocortisone or methylprednisolone. Patient demographics, steroid type and dose, duration of pegloticase therapy, overall number of infusions, and number of infusion reactions were assessed. Patients treated with methylprednisolone as a pre-infusion medication received on average 8.5 pegloticase infusions versus 4.9 infusions for patients who were treated with hydrocortisone (p < 0.001). In addition, a significantly lower proportion of patients receiving methylprednisolone had their course of therapy terminated early due to infusion reactions (8.2%) versus patients receiving hydrocortisone (41.9%, p < 0.01). In this retrospective chart-review project, patients were able to have a longer duration of pegloticase therapy, received a significantly greater number of infusions, and experienced fewer infusion reactions when methylprednisolone was used as the corticosteroid for pre-infusion prophylaxis compared with hydrocortisone.


In vitro and in vivo immunocytochemistry for the distribution of mineralocorticoid receptor with the use of specific antibody.
To examine the distribution of mineralocorticoid receptor (MR) and the interactions with glucocorticoid receptor (GR) in the brain, we raised a polyclonal antibody against the transcriptional modulation domain of rat MR using the GST-fusion system. Immunoblotting analysis revealed that this antibody recognized a band with the molecular mass of MR in MR-transfected COS-1 cells and in a homogenate of rat hippocampus, and showed no cross-reactivity with GR. In vitro immunocytochemistry of both primary cultured hippocampal neurons and MR-transfected cells revealed immunoreactivity detected by this antibody in both the cytoplasm and nucleus in the absence of aldosterone (ALD), a specific agonist of MR. After 1 h of treatment with 10(-7) M ALD, the MR-immunoreactivity was accumulated in the nuclear region. In the case of GR-transfected cells, our anti-MR antibody either detected no immunopositive cells in the presence or absence of GR agonist. In our in vivo study, MR-immunoreactivity was observed in the rat hippocampus, where cell nuclei showed immunopositive reactions. These results suggest that our antibody against rat MR shows high specificity for the receptor both in liganded and unliganded forms, with no cross-reactivity to GR, and will be useful for cell biological and neuroanatomical investigations of MR.


Computed tomography angiography-derived fractional flow reserve (CT-FFR) for the detection of myocardial ischemia with invasive fractional flow reserve as reference: systematic review and meta-analysis.
A method named computed tomography angiography-derived fractional flow reserve (FFRCT) is an alternative method for detecting hemodynamically significant coronary stenosis. We carried out a meta-analysis to derive reliable assessment of the diagnostic performances of FFRCT and compare the diagnostic accuracy with CCTA using FFR as reference. We searched PubMed, EMBASE, The Cochrane Library, and Web of science for relevant articles published from January 2008 until May 2019 using the following search terms: FFRCT, noninvasive FFR, non-invasive FFR, noninvasive fractional flow reserve, non-invasive fractional flow reserve, and CCTA. Pooled estimates of sensitivity and specificity with the corresponding 95% confidence intervals (CIs) and the summary receiver operating characteristic curve (sROC) were determined. Sixteen studies published between 2011 and 2019 were included with a total of 1852 patients and 2731 vessels. The pooled sensitivity and specificity for FFRCT at the per-patient level was 89% (95% CI, 85-92%) and 71% (95% CI, 61-80%), respectively, while on the per-vessel basis was 85% (95% CI, 82-88%) and 82% (95% CI, 75-87%), respectively. No apparent difference in the sensitivity at per-patient and per-vessel level between FFRCT and CCTA was observed (0.89 versus 0.93 at per-patient; 0.85 versus 0.88 at per-vessel). However, the specificity of FFRCT was higher than CCTA (0.71 versus 0.32 at per-patient analysis; 0.82 versus 0.46 at per-vessel analysis). FFRCT obtained a high diagnostic performance and is a viable alternative to FFR for detecting coronary ischemic lesions. • Noninvasive FFRCThas higher specificity for anatomical and physiological assessment of coronary artery stenosis compared with CCTA. • Noninvasive FFRCTis a viable alternative to invasive FFR for the detection and exclusion of coronary lesions that cause ischemia.


[Phantom limb pain syndrome: therapeutic approach using mirror therapy in a Geriatric Department].
The clinical use of mirror visual feedback was initially introduced to alleviate phantom pain by restoring motor function through plastic changes in the human primary motor cortex. It is a promising novel technique that gives a new perspective to neurological rehabilitation. Using this therapy, the mirror neuron system is activated and decrease the activity of those systems that perceive protopathic pain, making somatosensory cortex reorganization possible. This paper reports the results of the mirror therapy in three patients with phantom limb pain after recent lower limb amputation, showing its analgesic effects and its benefits as a comprehensive rehabilitation instrument for lower limb amputee geriatric patients.


Immunofluorescence test with antigen-loaded erythrocytes: detection of influenza virus specific IgG, IgA, and IgM antibodies.
An immunofluorescence test (IFT) for the detection of influenza virus antibodies was established to supplement the standard serological diagnostical complement fixation test (CFT). Current strains (A/Philippines/2/82, A/Brazil/11/78, B/Singapore/222/79) were loaded on formalinized chicken erythrocytes. In contrast to CFT, we can distinguish specific immunoglobulin classes against influenza virus. Unlike CFT, IFT is subtype-specific. A recent infection can be distinguished from a past infection by the differentiation of specific immunoglobulin classes. Anticomplementary factors and hemolytic sera do not influence the result of the IFT. IFT does not require cell cultures and is easy to read.


[The threatening influenza pandemic: a national store ofoseltamivir is a waste of money].
In the treatment of confirmed influenza, neuraminidase inhibitors yield only a limited reduction in the duration of disease and are neither efficacious nor cost-effective. Neuraminidase inhibitors would be cost-effective if a deadly influenza virus that is highly sensitive to oseltamivir causes a pandemic soon. If not, then the money invested in establishing a store of oseltamivir is wasted and lost to the health-care sector.


The adhesive interaction between polymorphonuclear leukocytes and endothelial cells in vitro.
The results of this investigation indicate an adhesive specificity between PMN and cultured endothelial cells. This was monitored by the mono-layer collection assay and by direct cell counts using the scanning electron microscope. Both techniques showed that significantly more PMN attached to endothelial cells than to a variety of other cell types. The interaction can be modulated by divalent cations and neuraminidase, implying a role for surface charge. In the presence of chemotactic agents, the number of PMN adhering to endothelial cells increases. This system presents a good model for studying the process of PMN margination which occurs in vivo during the acute inflammatory response.


Epidemiology and characteristics of emergency department utilization by patients with amyotrophic lateral sclerosis in Korea from 2016 to 2020: A nationwide study.
Patients with amyotrophic lateral sclerosis (ALS) inevitably visit the emergency department (ED) due to their increased risk of respiratory failure and mobility limitations. However, nationwide data on ED visits by patients with ALS are limited. This study investigated the characteristics of patients with ALS-related ED visits. We conducted a cross-sectional study from 2016 to 2020, utilizing a nationwide ED database. The total number of patients with ALS who visited the ED and their primary reasons for visiting/diagnoses were analyzed. In total, 6036 visits to the ED were made by patients with ALS. Of these, 41.8% arrived by ambulance and 27.7% spent >9 h in the ED. Following ED treatment, 57.4% were hospitalized, including 19.3% admitted to the intensive care unit (ICU) and 5.4% who died in the hospital. The primary reasons for ALS-related ED visits were dyspnea (35.2%), feeding tube problems (10.1%), fever (7.8%), and mental status changes (3.6%). The most common diagnoses were pneumonia (14.5%), respiratory failure (5.7%), dyspnea (5.5%), aspiration pneumonia (4.3%), and tracheostomy complications (3.4%). Reasons for ED visits for patients with ALS include acute respiratory distress, as well as concerns related to tube feeding and tracheostomy. To reduce the risk of patients with ALS requiring ED visits, it is essential to ensure the provision of timely respiratory support and high-quality home-based medical care teams that can support and address patients before their condition deteriorates.


Daily runoff prediction based on the adaptive fourier decomposition method and multiscale temporal convolutional network.
The non-linearity and non-stationarity of runoff series pose significant challenges to runoff forecasting, and conventional single forecasting models struggle to accurately capture the internal dynamics of the series. To address this issue, we propose a runoff prediction model named AFDM-MTCN, which combines the adaptive Fourier decomposition method (AFDM) and multiscale temporal convolutional network (MTCN). AFDM-MTCN consists of two stages: adaptive decomposition and multi-scale feature extraction. In the adaptive decomposition stage, the improved Fourier decomposition method (IFDM) is optimized using the Sparrow Search Algorithm to enhance its ability to extract temporal patterns. In the multi-scale feature extraction stage, improvements are made to the temporal convolutional network (TCN) through the use of multi-scale convolution kernels, skip connections, and depth-wise separable convolution, to capture information from multiple angles, enhance information propagation, and reduce training parameters. The model was applied to two hydrological stations in the Weihe River Basin and compared with state-of-the-art methods to assess its accuracy and feasibility. The results demonstrate that AFDM-MTCN exhibits satisfactory performance in runoff prediction. Furthermore, compared to other decomposition techniques, AFDM demonstrates stronger capability in extracting patterns from non-stationary runoff data.


[Diagnostic image (343). A neonate with a red, swollen umbilicus].
A male neonate had fecal loss from a patent omphalomesenteric duct.


Seasonal variability of mercury and heavy metals in roe deer (Capreolus capreolus) kidney.
The seasonal variability of Hg, Pb, Cd and Zn was determined in the kidney of 164 roe deer, shot in three areas of Slovenia in 1998. We found a strong seasonal influence on Hg and Pb levels, which were significantly higher in late summer and early autumn. Cd and Zn levels showed a similar seasonal pattern, although not so pronounced; for these elements differences among periods were probably not a consequence of season per se. Seasonal variability in metal levels in roe deer kidney originated in both quantitative and qualitative differences in nutrition of the species. Since the seasonal peaks for the majority of metals appeared in a very narrow summer autumnal period (August-September), it seems that some plant taxons, such as fungi, might represent an important pathway for heavy metal intake into the mammalian organism. The season of sample collection has to be considered whenever using wildlife as an accumulative bioindicator of environmental pollution. Moreover, the influence of the season should be born in mind whenever a hazard due to accumulation of heavy metals along the food chain is assessed.


[Villonodular synovitis of the knee. Analysis of a series of 17 cases and review of the literature].
Pigmented villonodular synovitis is a rare pathology found predominantly in the knee. We report management and treatment of 17 cases of pigmented villonodular synovitis of the knee. The mean follow-up was 9 years (maximum: 17 years). The diagnosis was always confirmed at histopathology. There were 12 women and 5 men. The average age at the initial symptoms was 28 years. Six cases were diffuse, 7 localized and 4 cases were mixed. First treatment was only arthroscopic in 8 cases, and open synovectomy in 6 cases and mixed in 2 cases. Six patients had a recurrence, one had more than one recurrence. The mean delay for recurrence was 2 years and 5 months. Loss of range of motion was noted in 6 cases. For these 6 cases, flexion was always greater than 90 degrees and flessum always inferior to 10 degrees. Ethiopathogeny of this disease is unclear and no etiopathogenic theory is defined. Magnetic resonance imaging is useful for diagnosis, and absolutely necessary for preoperative tumor localization, and also for survey. In localized types, arthroscopic synovectomy can be performed with success but in diffuse or mixed form an open synovectomy must be performed according to the high rate or recurrence observed after incomplete synovectomy. Synoviorthesis with Yttrium 90 seems to be a good adjuvant for the treatment of recurrent pigmented villonodular synovitis. Arthroscopy is the treatment of choice for localized forms. We propose a mixed concept with an anterior and parameniscal arthroscopic synovectomy (without meniscectomy), an open synovectomy for the posterior localization, and an open anterior synovectomy when the tumor mass is too voluminous.


Perceived constraints to private veterinary practice in India.
We used an exploratory study in two districts of West Bengal State, India to find out the constraints of private veterinary practice. Privatization of veterinary services is being seen as an alternative to government-sponsored veterinary services to livestock. In December 2000 to February 2001, 50 private veterinary practitioners were interviewed from the districts. Their opinion was that weak regulations about competition from illegal practitioners and the use of veterinary drugs, competition by animal-health technicians (who are likely to charge less than veterinarians), absence of efficient diagnostic-laboratory support, and lack of commercial livestock farming were the main constraints faced.


Tumor cell toxicity of stable gallium nitrate: enhancement by transferrin and protection by iron.
The cytotoxicity of citrated gallium nitrate (NSC 15200) to EMT-6/UW mouse sarcoma cells growing in vitro was assayed as growth inhibition in treated cultures as well as cell survival (colony-forming ability) after acute or chronic exposure to graded doses. Gallium nitrate is both cytostatic and lethal to cells, with some growth inhibition occurring after chronic exposure to low doses (10 micrograms/ml) which kill essentially no cells. Cell kill and growth inhibition were both observed if cells were exposed for 24 hr or more to doses greater than 50 micrograms/ml. The growth inhibitory and lethal effects of gallium nitrate were enhanced by the addition of human transferrin to the medium. This enhanced toxicity was consistent with, and proportional to, the increased gallium uptake in the presence of transferrin rather than a direct effect of this iron transport protein. The addition of ferric citrate greatly reduced the toxic effect of the gallium salt. Cells in stationary plateau phase cultures appear to be as sensitive to gallium nitrate as exponentially growing cells. Ga3+ may mimic Fe3+ in some aspects of cellular metabolism, and competition between the two metals occurs at the initial uptake step, binding to transferrin, and possibly at other points in cell metabolism.


The development of alpha-emitting radionuclide lead 212 for the potential treatment of ovarian carcinoma.
alpha-Emitting radionuclides may be an effective alternative treatment against ovarian carcinoma because they have short half-lives and are densely ionizing, with high linear energy transfer to a depth of several cell diameters without requiring cellular oxygenation. One radionuclide that has been generated and tested in our laboratory in vitro and in vivo is lead 212 (212Pb). Intraperitoneal instillation of 212Pb prolonged survival and totally eradicated tumor in 24% of mice inoculated with the extremely virulent Ehrlich ascites-producing tumor. In vitro 212Pb was two to four times more effective in killing human ovarian cancer cells than x-rays. Irradiation with 212Pb increased the radiosensitivity and chromosomal aberrations of cells. In dogs, intraperitoneal instillation of 2.6 mCi of ferrous hydroxide tagged with 212Pb caused no significant toxicity. It appears that alpha-emitting radionucides such as 212Pb have the potential to be a new and potent treatment of ovarian carcinoma and could be effective in cases that are resistant to conventional chemotherapy or x-ray therapy.


Adverse and unconventional reactions related to immune checkpoint inhibitor therapy for cancer.
Immunotherapy is an emerging method for the treatment of cancer. Immune checkpoint inhibitors (ICIs) are monoclonal antibodies that block immune checkpoint pathways and release the body's anti-tumor immunity. They consist mainly of antibodies against cytotoxic T lymphocyte associated antigen-4 (CTLA-4), programmed death receptor 1 (PD-1), and programmed death ligand 1 (PD-L1). Although ICI therapy has been shown to be effective at treating cancer, it can also destroy immune tolerance and lead to organ toxicity. These unwanted side effects are known as immune related adverse events (irAEs). ICI treatment can also cause unconventional reactions such as pseudoprogression and hyperprogression. Pseudoprogression looks like an increase in the tumor parenchyma but is actually a temporary inflammation in the tumor; hyperprogression refers to the acceleration of tumor growth after the start of immunotherapy. Understanding the mechanisms of these two phenomena and distinguishing their differences are necessary for the effective prevention and treatment of unconventional reactions.


Heart Transplantation in Adults With Congenital Heart Disease: 100% Survival With Operations Performed by a Surgeon Specializing in Congenital Heart Disease in an Adult Hospital.
Cardiac transplantation in adult patients with congenital heart disease poses numerous challenges. The optimal operative and postoperative management strategies remain unclear. The purpose of our study was to (1) characterize the adult patient with a congenital heart condition undergoing transplantation, the operation, and the postoperative course; (2) report the survival after heart transplantation at our center; and (3) discuss issues surrounding the unique setting we provide for the operative and postoperative care of this complex patient cohort. We performed a retrospective cohort study of 12 consecutive adult patients with a prior history of congenital heart disease who underwent heart transplantation at a single, large, academic center between September 1, 2005, and September 1, 2013. The operations were performed by a surgeon specializing in congenital heart disease in an adult hospital. Postoperative care was provided jointly by that surgeon and the adult cardiac transplantation team. At operation, the median age and weight were 41 years (range, 16 to 72 years) and 65 kg (range, 45 to 104 kg), and 100% of patients had undergone previous operations. The median donor ischemic time was 197 minutes (range, 137 to 282 minutes). The median cardiopulmonary bypass time was 210 minutes (range, 175 to 457 minutes), and the median total operating time was 582 minutes (range, 389 to 968 minutes). Three patients required mechanical support to be weaned from cardiopulmonary bypass. Postoperatively, 3 patients required the addition of mechanical support in the intensive care unit, and 3 patients required tracheostomy for prolonged ventilation. The majority of patients had a complicated postoperative course (66%). The median number of noncardiac consultants required to help care for these patients was four (range, two to 12). The mortality was 0%. Cardiac transplantation in adults with congenital cardiac disease is challenging, is fraught with adverse events, and requires meticulous care and teamwork for success. A surgeon specializing in congenital heart conditions may be best to handle the operative challenges, and an adult hospital with access to certain technology and consultant services may be best to handle the postoperative challenges in this difficult patient population.


Medicaid reimbursement, prenatal care and infant health.
This paper evaluates the impact of state-level Medicaid reimbursement rates for obstetric care on prenatal care utilization across demographic groups. It also uses these rates as an instrumental variable to assess the importance of prenatal care on birth weight. The analysis is conducted using a unique dataset of Medicaid reimbursement rates and 2001-2010 Vital Statistics Natality data. Conditional on county fixed effects, the study finds a modest, but statistically significant positive relationship between Medicaid reimbursement rates and the number of prenatal visits obtained by pregnant women. Additionally, higher rates are associated with an increase in the probability of obtaining adequate care, as well as a reduction in the incidence of going without any prenatal care. However, the effect of an additional prenatal visit on birth weight is virtually zero for black disadvantaged mothers, while an additional visit yields a substantial increase in birth weight of over 20 g for white disadvantaged mothers.


Potential mechanism of Taohong Siwu Decoction in uterine fibroid treatment based on integrated strategy of network pharmacology and experimental verification.
Taohong Siwu Decoction (THSWD) is a widely prescribed Traditional Chinese Medicine (TCM) for treating gynecological diseases. It is used to treat uterine fibroids (UF) in China, while its potential therapeutic effects and mechanism are unknown. The present study used network pharmacology to identify PI3K/AKT as one of the main THSWD signaling pathways that can be targeted to treat UF. The potential binding sites of miR-21-5p to PTEN were predicted using online databases. We were able to establish a UF rat model successfully. We selected the 15% THSWD serum after preparing THSWD drug-containing serum to culture tumor tissue-derived cells. These studies enabled us to assess the role of THSWD in UF improvement. In vivo, we observed that low, medium, and high doses of THSWD improved histological changes in UF rats by increasing the expression levels of PTEN and miR-21-5p in their uterus while decreasing the expression levels of p-PI3K, p-AKT, and miR-21-5p. Treatment with THSWD medicated serum (15%) effectively inhibited the proliferation of cells derived from human UF and promoted apoptosis in vitro. PI3K phosphorylation, Akt phosphorylation, and miR-21-5p expression were decreased, while PTEN and cleaved caspase-3 were increased. These findings were reversed by administering 740 Y-P (a PI3K/Akt pathway agonist) and a miR-21-5p mimic. In addition, the double luciferase reporter gene assay confirmed the targeted binding relationship between miR-21-5p and PTEN. THSWD inhibited the expression and activation of the PI3K/AKT and miR-21-5p/PTEN pathways, resulting in anti-UF activity in leiomyoma cell models. Our findings suggest that THSWD could be used to treat UF.


Intrathecal baclofen bolus reduces exaggerated extensor coactivation during pre-swing and early-swing of gait after acquired brain injury.
To characterize the concurrent activation of rectus femoris (RF) and medial gastrocnemius (MG) muscles (extensor coactivation) during gait in subjects with pronounced resting hypertonia after acquired brain injury (ABI) and examine changes after intrathecal baclofen (ITB) bolus injection. Magnitude and duration of extensor coactivation during different phases of gait were assessed by recording gait kinematics and activity in bilateral RF and MG muscles in 18 controls and 18 ABI subjects before and at 2, 4, and 6h after a 50-μg ITB injection. Compared to controls, the magnitude of extensor coactivation was significantly increased in all phases of gait except the single support (p≤0.005), while the duration was significantly prolonged throughout (p≤0.001) in both legs of ABI subjects. After ITB bolus, only the duration of extensor coactivation significantly shortened in the more-affected leg during the late double-support and early swing (p≤0.026). Extensor coactivation is bilaterally exaggerated during gait in ABI subjects. ITB bolus effectively shortens the extensor coactivation in the more-affected leg during the pre-swing and early swing phases of gait. Shortening of the prolonged extensor coactivation during gait may serve as an index of neurophysiological response to ITB bolus injection in subjects with ABI.


A 13-week subchronic toxicity study of a Dioscorea Rhizome water extract in rats.
Dioscorea Rhizome is widely used as a traditional herbal medicine to treat asthma, diarrhea, cough, bronchitis, spermatorrhea, leukorrhea, and rheumatoid arthritis. This study investigated the potential subchronic toxicity of a D. Rhizome water extract (DRWE) after repeated oral administration at 0, 800, 2000, and 5000 mg/kg/day in rats for 13 weeks. During the study period, clinical signs, mortality, body weight, food consumption, water consumption, urinalysis, ophthalmoscopy, hematology, serum biochemistry, gross pathology, organ weights, and histopathology were examined. The 13-week repeated oral administration of DRWE to rats resulted in an increased incidence of zona glomerulosa hypertrophy and hyperplasia in the adrenal gland at dose levels of ≥2000 mg/kg/day in both sexes. However, these findings are considered as non-adverse adaptive changes because of minimal histological changes in the lesions, which were not accompanied by any corresponding alterations in serum electrolytes and adrenal gland weight. No treatment-related adverse effects on clinical signs, body weight, food and water consumption, ophthalmic examination, urinalysis, hematology, serum biochemistry, necropsy findings, and organ weights were observed at any dose tested. Under the present experimental conditions, the no-observed-adverse-effect level of the DRWE was considered to be 5000 mg/kg/day in both sexes, and no target organs were identified.


Determination of plasma testosterone using a simple liquid chromatographic method.
A simple and sensitive high-performance liquid chromatographic (HPLC) method using ultraviolet detection was developed for the determination of testosterone in human plasma. Testosterone and the internal standard, griseofulvin, were extracted from 0.50 ml plasma sample using a mixture of dichloromethane-2,2,4-trimethylpentane (3:2, v/v). The mobile phase, consisted of 0.02 M sodium dihydrogenphosphate-acetonitrile-methanol (51:47:2, v/v) adjusted to pH 3.1 and delivered to a C(18) analytical column (150 x 4.6 mm I.D., 4 microm particles) at a flow-rate of 1 ml/min while the detection wavelength was set at 240 nm with a sensitivity range of 0.005 a.u.f.s. The method has a quantification limit of 1.6 ng/ml. Recoveries of testosterone were all greater than 92% over the linear concentration range of 1.6-400 ng/ml while that of griseofulvin was approximately 95%. The within- and between-day RSD values were all less than 8% while the accuracy values ranged from 96.0 to 106.0% over the concentration range studied. The method was applied to the analysis of early morning plasma testosterone levels of 12 healthy human male volunteers. The levels were found to range from 3.1 to 8.4 ng/ml, within the normal range reported in the literature.


Effect of high dietary copper on weight gain and neuropeptide Y level in the hypothalamus of pigs.
An experiment was performed to examine the effect of dietary copper supplementation on weight gain, neuropeptide Y (NPY) concentration and NPY mRNA expression level in the hypothalamus of pigs. Forty-five crossbred pigs were randomly assigned to three groups of 15 pigs, each comprising five replicates of 3 animals. Pigs were allocated to diets that contained 10mg/kg (as a control), 125 and 250 mg/kg copper as CuSO4. Live weight gain and feed conversion efficiency was determined at the end of the experiment and five pigs, selected at random from each group, were slaughtered and the hypothalami collected for determination of NPY concentration and NPY mRNA expression level. The results showed that average daily gain (ADG) and average daily feed intake (ADFI) were higher and feed:gain (F:G) ratio was lower in pigs fed the diets with 125 and 250 mg/kg copper (P<0.05), respectively, than in pigs fed a diet with 10 mg/kg copper, but that there was no statistically significant difference in growth performance between animals of the 125 mg/kg and the 250 mg/kg copper groups. Furthermore, pigs fed diets with 125 and 250 mg/kg copper had higher NPY concentrations and NPY mRNA expression levels in their hypothalamus than control animals. The data indicated that 125 and 250 mg/kg copper gave similar responses in terms of weight gain, whilst high dietary copper could enhance NPY concentration and NPY mRNA expression level in the hypothalamus of pigs. High dietary copper appears to increase feed intake and promote weight gain by enhancing NPY concentration and NPY mRNA expression level in the hypothalamus of pigs.


A observational study of the efficacy and safety of capecitabine versus bolus infusional 5-fluorouracil in pre-operative chemoradiotherapy for locally advanced rectal cancer.
This study is to evaluate the safety and efficacy of preoperative radiotherapy (RT) combined with bolus infusional 5-fluorouracil (5-FU) or oral capecitabine in patients with locally advanced rectal cancer (LARC). Seventy-four patients were retrospectively analyzed. Twenty-seven patients were treated with 5-FU (350 mg/m(2) i.v. bolus) and leucovorin (20 mg/m(2) i.v. bolus) for 5 days/week during week 1 and 5 of RT. Forty-seven patients were treated with capecitabine (850 mg/m(2), twice daily for 5 days/week). Both groups received the same RT course (45-50.4 Gy/25 fractions, 5 days/week, for 5 weeks). Patients underwent surgery in 6 weeks after completion of the chemoradiotherapy. Data of the observational study were collected. Grade 3 or 4 toxicities occurred in 40.7% (5-FU) and 19.1% (capecitabine) of the patients (P = 0.044). Six patients in the 5-FU group (22.2%) and six patients in the capecitabine group (14%) achieved complete response. Primary tumor (T) downstaging were achieved in 51.9% (5-FU) and 69.8% (capecitabine) of the patients. The pathological ypT0-2 stage was 40.7% (5-FU) and 67.4% (capecitabine) (P = 0.028). In consideration of the better ypT0-2 downstaging rate, less severe toxicities, and no need for indwelling intravenous device on oral capecitabine regimen, the administration of oral capecitabine with RT may be a more favorable option in the neoadjuvant treatment for LARC.


Synthesis, and biological evaluation of pyrazole matrine derivatives as an insecticide against Spodoptera frugiperda.
As one of the major threats to global food security, Spodoptera frugiperda (S. frugiperda) is highly gaining consideration due to its severe damage. Matrine is a widely and effectively used botanical insecticide in controlling S.frugiperda but lacks a rapidly available effect. To further improved the insecticidal activity of matrine based on combination principles, this work synthesized five new pyrazole matrine derivatives (PMDs) using Michael addition and investigated insecticidal activity against 2nd instar larvae of S. frugiperda(in vivo) and its isolated cell(in vitro). Our result demonstrated that PMDs show higher pesticidal activity than that matrine in both in vitro and in vivo assays. The most toxic derivatives in vitro and in vivo are PMD-3 and PMD-1, with IC50 of 2.49 mM and LC50 of 22.76 mg/L respectively. This research also investigates the anti-proliferation mechanism of PMDs based on isolated cells. PMDs decrease mitochondria membrane potential, arrested cell cycle at the G2/M phase, and upregulated Caspase 3, Caspase 9, and Apaf-1 to induce Caspase-dependent apoptosis. For Caspase-independent apoptosis, AIF and Endo G were found to be upregulated. Besides, pro-apoptotic factors like p53, IBM-1, and anti-apoptotic factors like IAP were upregulated. Moreover, we supposed that there was a linkage between lysosomes and PMD-induced apoptosis according to increased apoptosis rate, activated lysosomes, and upregulated Cathepsin B. This research provides new ideas for the synthesis of matrine derivatives and further demonstrated the anti-proliferation mechanism of PMDs.


Hairy-cell leukemia. Morphologic, cytochemical, and immunologic features.
Hairy-cell leukemia is a unique lymphoproliferative disorder that has fascinated clinicians and researchers for nearly 3 decades. It can, in most cases, be diagnosed correctly on the basis of a bone marrow biopsy specimen, and the diagnosis is supported by the demonstration of tartrate-resistant acid phosphatase activity in the leukemic cells. Nevertheless, as outlined, rare "variant" cases may pose diagnostic problems, and other lymphoproliferative disorders may have features that closely mimic those of HCL. In virtually all cases of HCL, the hairy cells are of B-cell lineage, representing a relatively mature B cell that is closely related to plasma cells. Treatment of HCL with splenectomy, IFN-alpha, or 2' deoxycorformycin has led to excellent responses in most cases. Much of the progress in our understanding of the nature of this rare leukemia has been made possible through the cooperation of community physicians with referral institutions, or groups of institutions, that are interested in studying HCL. Despite the remarkable advances in the treatment of this disorder over the last 5 years, and the ready availability of IFN-alpha, much remains to be learned regarding the biology of hairy cells, and further advances in therapy still must be made. The needed information can be obtained only through continued referral of patients to centers with expertise and an interest in HCL.


[The influence of fluothane and hexobarbital on the cerebral cortex and spinal cord centers].
Tests set up on 17 cats demonstrated by using methods of evoked potentials that the reflex activity of the spinal cord centers is inhibited after introduction of 2.3 +/- 0.2 ml of fluothane, whereas the functional performance capacity of the large hemispheres cortex is suppressed following administration of 3,2 +/- 0,8 ml of the drug. The restitution of excitability and conductivity of the cortex in the post-anesthetization period proceeds at the rate 1.7 times faster than the restoration of the spinal cord centers. With deepening of the hexobarbital anesthesia complete inhibition of the spinal reflex activity supervenes after introduction of 56.3 +/- 12.3 ml/kg and that of the cortex following introduction of 115.0 +/- 23.2 ml/kg of hexobarbital.


Trigeminal projections to thalamus and subthalamus in the hedgehog tenrec.
The objective of the present study was the identification and characterization of the trigemino-diencephalic target areas in the Madagascan lesser hedgehog tenrec in order to get a more comprehensive view on the mammalian somatosensory thalamus, its evolution and representation in different species. Such an analysis has been considered important because in lower mammals the head and face are relatively well represented, but their ascending trigeminal projections have scarcely been analysed. Following injections of different tracer substances into the rostral and caudal portions of the trigeminal nuclear complex the most prominent area of termination was found in the medial ventroposterior nucleus. These projections were patchy and scarcely overlapped the region previously shown to receive spinal and dorsal column nuclear afferents. On the basis of the laterality and the intensity of the projections, two subdivisions were distinguished, the principal portion and the accessory portion receiving a dense contralateral and a weak bilateral input, respectively. They were considered equivalents to the magnocellular and parvocellular subdivisions of the medial ventroposterior nucleus in more differentiated mammals. In the latter species, however, the overlap between trigeminal and parabrachial fibres appears less extensive than in the tenrec. In addition, a weak bilateral projection was shown from the caudal trigeminal nucleus to the caudal and dorsal subdivision of the nucleus submedius. There was little, if any evidence for a trigeminal projection to the intralaminar nuclei and we failed to identify a correlate to the posterior nuclear complex of higher mammals. On the other hand, there was a distinct contralateral projection to the ventral portion of the zona incerta. This projection was of similar strength as the projection to the medial ventroposterior nucleus; it supports the notion that the zona incerta may play a crucial role in relaying trigeminal information.


EphrinB-EphB receptor signaling contributes to neuropathic pain by regulating neural excitability and spinal synaptic plasticity in rats.
Bidirectional signaling between ephrins and Eph receptor tyrosine kinases was first found to play important roles during development, but recently has been implicated in synaptic plasticity and pain processing in the matured nervous system. We show that ephrinB-EphB receptor signaling plays a critical role is induction and maintenance of neuropathic pain by regulating neural excitability and synaptic plasticity in the dorsal root ganglion (DRG) and the spinal dorsal horn (DH). Intrathecal application of blocking reagents for EphB-receptors, EphB1-Fc and EphB2-Fc chimeras inhibits the induction and maintenance of nerve injury-induced thermal hyperalgesia and mechanical allodynia. These blockers also prevent and suppress the nerve injury-induced hyperexcitability of nociceptive small DRG neurons, sensitization of DH neurons and long-term potentiation (LTP) of synapses between C fibers and DH neurons. In naïve, uninjured animals intrathecal administration of EphB-receptor activators ephrinB1-Fc and ephrinB2-Fc, respectively, induces thermal hypersensitivity and lowers the threshold for LTP, while EphB1-Fc prevents induction of the LTP. Western Blot analysis shows that nerve injury triggers an upregulation of the ephrinB1 and EphB1 receptor proteins in DRG and the spinal cord. These results indicate that, by regulating excitability of nociceptive-related neurons in DRG and DH and the synaptic plasticity at the spinal level, ephrinB-EphB receptor signaling contributes to neuropathic pain. This novel role for ephrinB-EphB receptor signaling suggests that these molecules may be useful therapeutic targets for treating pain after nerve injury.


Oxygen intervention in the regulation of gene expression: the photosynthetic bacterial paradigm.
The means by which oxygen intervenes in gene expression has been examined in considerable detail in the metabolically versatile bacterium Rhodobacter sphaeroides. Three regulatory systems are now known in this organism, which are used singly and in combination to modulate genes in response to changing oxygen availability. The outcome of these regulatory events is that the molecular machinery is present for the cell to obtain energy by means that are best suited to prevailing conditions, while at the same time maintaining cellular redox balance. Here, we explore the dangers associated with molecular oxygen relative to the various metabolisms used by R. sphaeroides, and then present the most recent findings regarding the features and operation of each of the three regulatory systems which collectively mediate oxygen control in this organism.


Pharmacological modulators of the circadian clock as potential therapeutic drugs: focus on genotoxic/anticancer therapy.
The circadian clock is an evolutionary conserved intrinsic timekeeping mechanism that controls daily variations in multiple biological processes. One important process that is modulated by the circadian clock is an organism's response to genotoxic stress, such as that induced by anticancer drug and radiation treatments. Numerous observations made in animal models have convincingly demonstrated that drug-induced toxicity displays prominent daily variations; therefore, undesirable side effects could be significantly reduced by administration of drugs at specific times when they are better tolerated. In some cases, these critical times of the day coincide with increased sensitivity of tumor cells allowing for a greater therapeutic index. Despite encouraging results of chronomodulated therapies, our knowledge of molecular mechanisms underlying these observations remains sketchy. Here we review recent progress in deciphering mechanistic links between circadian and stress response pathways with a focus on how these findings could be applied to anticancer clinical practice. We discuss the potential for using high-throughput screens to identify small molecules that can modulate basic parameters of the entire circadian machinery as well as functional activity of its individual components. We also describe the discovery of several small molecules that can pharmacologically modulate clock and that have a potential to be developed into therapeutic drugs. We believe that translational applications of clock-targeting pharmaceuticals are twofold: they may be developed into drugs to treat circadian-related disorders or used in combination with existing therapeutic strategies to improve therapeutic index of a given genotoxic treatment via the intrinsic clock mechanism.


A detailed description of the distress trajectory from pre- to post-treatment in breast cancer patients receiving neoadjuvant chemotherapy.
To characterize the distress trajectory in patients with newly diagnosed, non-metastatic breast cancer from pre-neoadjuvant chemotherapy until 12 months after onset of treatment and to identify demographic and clinical predictors of distress in these patients. In a retrospective, longitudinal study, chart review data were abstracted for 252 eligible patients treated at a comprehensive cancer care center. The center screens for distress at least monthly with the distress thermometer; the highest distress score per month was included in the analyses. The growth trajectory was established using mixed modeling and predictors were added to the initial growth model in subsequent models. Distress showed a cubic growth trajectory with highest distress prior to treatment onset followed by a steep decline in the first three months of treatment. A slight increase in distress was apparent over months 6-10. Being Hispanic was associated with a stronger increase in distress in the second half of the year (p = 0.012). NACT was associated with lower distress and surgery with higher distress (both: p < 0.001). Distress is at its peak prior to treatment onset and rapidly decreases once treatment has started. Oncologist should be aware that both completion of NACT and undergoing surgery are associated with increases in distress and Hispanic patients may be more at risk for an increase in distress at these times; this suggests that careful monitoring of distress during the treatment trajectory and in Hispanic patients in particular in order to provide timely support.


Mechanism of selective induction of apoptosis of HCT116 tumor cells in circulating blood by riboflavin photochemistry.
The removal or inactivation of circulating tumor cells (CTCs) can prevent distant metastasis by hematogenous route, but there is still a lack of mature and effective technical means. In the previous research, our team has initially established a method of riboflavin photosensitized treatment (RPT) for continuous treatment of peripheral blood in vitro for the inactivation of CTCs. The core of this technology is that it can selectively induce apoptosis of CTCs (HCT116 cells) without damaging immunocyte (mainly Peripheral Blood Mononuclear Cells,PBMCs) under specific parameters. To clarify the specific mechanism, firstly, the enrichment of riboflavin in HCT116 cells and PBMCs was observed under fluorescence microscope. Secondly, the apoptotic signaling pathways in HCT116 cells and PBMCs in response to RPT treatment were analyzed by transcriptomics. Finally, the mitochondrial damage in HCT116 cells and PBMCs before and after RPT treatment was observed under electron microscope. The results showed that under the same treatment conditions, HCT116 cells were significantly enriched in riboflavin compared with PBMCs. Besides, RPT treatment reduced the expression of long non﹣coding RNA (lncRNA) NEAT1, an effector gene of HCT116 cells, which further down-regulated the expression of target gene PAX2 and promoted the expression of Bax, leading to mitochondrial outer membrane permeabilization (MOMP), and consequently increased the release of pro-apoptotic factors such as cytochrome c(Cyt C), high-temperature requirement protein A2(HTRA2), apoptosis-inducing factor (AIF), endonuclease G(ENDOG), finally leading to apoptosis of HCT116 cells. In contrast, lncRNA NEAT1 remained unchanged in PBMCs before and after RPT treatment, and was unable to stimulate the PBMCs apoptotic signaling pathway. The results of the study indicated that under the specific treatment conditions, RPT technology could selectively induce apoptosis of HCT116 cells by activating the mitochondrial apoptosis pathway, which would further provide a theoretical and technical support for the effective inactivation of CTCs by RPT technology, thereby reducing the risk of recurrence of malignant tumors and improving the cure rate of malignant tumors.


Promoting evidence-based nursing through journal clubs: an integrative review.
The journal club has been proposed as a tool to fill the gap between theory and practice. The present research is an integrative review of studies focussing on journal clubs. An integrative review. We searched the databases during 2010-2019 to find papers using the keywords journal club, nursing, evidence-based practice. The modified version of Cooper's five-stage integrative review was applied. The results are presented in two sections - the benefits and challenges of nursing journal clubs and an outline of presentation guidelines. We also discuss the effectiveness of journal clubs in the promotion of evidence-based nursing. The purpose of the nursing journal club is to review existing literature, discuss the latest information and evidence and identify practical changes required to ultimately improve patient outcomes. Further studies are needed to evaluate the effectiveness of journal clubs in patient care.


Testing for association between RNA-Seq and high-dimensional data.
Testing for association between RNA-Seq and other genomic data is challenging due to high variability of the former and high dimensionality of the latter. Using the negative binomial distribution and a random-effects model, we develop an omnibus test that overcomes both difficulties. It may be conceptualised as a test of overall significance in regression analysis, where the response variable is overdispersed and the number of explanatory variables exceeds the sample size. The proposed test can detect genetic and epigenetic alterations that affect gene expression. It can examine complex regulatory mechanisms of gene expression. The R package globalSeq is available from Bioconductor.


Tyrannosaur life tables: an example of nonavian dinosaur population biology.
The size and age structures for four assemblages of North American tyrannosaurs-Albertosaurus, Tyrannosaurus, Gorgosaurus, and Daspletosaurus-reveal a pronounced, bootstrap-supported pattern of age-specific mortality characterized by relatively high juvenile survivorship and increased mortality at midlife and near the maximum life span. Such patterns are common today in wild populations of long-lived birds and mammals. Factors such as predation and entrance into the breeding population may have influenced tyrannosaur survivorship. This survivorship pattern can explain the rarity of juvenile specimens in museum collections.


Anomalous behaviour of the STAT3 binding site in the human c-myc P2 promoter.
The Signal Transducer and Activator of Transcription 3 (STAT3) is necessary for ES cell renewal, plays critical roles during vertebrate development, and has oncogenic potential. STAT3 also mediates cytokine responses notably in the induction of acute phase response genes in the liver. Thus STAT3 is a pleiotropic regulator during cell proliferation and a cell-specific mediator of pro-inflammatory responses. How STAT3 fulfils both roles is unclear. To address this question we attempted to characterise pre-initiation complexes (PICs) on STAT3-responsive promoters containing the c-myc P2 promoter element (P2E) or c-fos Serum-Inducible Element (SIE). Although both promoters mediated cytokine responses in HepG2 cells, poor binding of STAT1 and STAT3 in vitro precluded isolation of active promoter complexes on the P2E. The inability of STAT3 to bind the P2E in vitro correlated with failure of the P2E to mediate cytokine-responsive gene expression in several other cell types. Thus the c-myc P2E behaves as a dual-purpose STAT3 element with anomalous characteristics in HepG2 cells.


A simple, reproducible technique for establishing leptomeningeal tumors in nude rats.
The incidence of leptomeningeal carcinomatosis is on the rise and current treatment modalities have limited efficacy. The development of new treatment strategies has been hampered by the lack of an appropriate animal model that accurately parallels the clinical condition. We have developed a new surgical technique for the establishment of leptomeningeal tumors in rats. Our technique is simple, reproducible and associated with low morbidity and mortality. Tumor implantation resulted in a defined neurological endpoint and a reproducible time course of disease progression using both human medulloblastoma and breast carcinoma cell lines. This animal model provides an appropriate system for testing conventional and new biologic therapies in both early and late stages of leptomeningeal disease.


Raman spectroscopy of captopril crystals under low-temperature conditions.
The polymorphism is a characteristic of several active principles, and can affect the bioavailability of a drug. Among the drugs used in the treatment of heart diseases, captopril is one of the most widely used in the world. Despite the knowledge of vibrational properties of captopril under high temperature and under high pressure, a lack of information impedes the understanding of the substance in the crystal form at low temperatures. In this research, we investigated the vibrational properties of captopril crystals under cryogenic conditions in the 300-8 K interval using Raman spectroscopy. By observing the behavior of the inter- and intra-molecular vibrations it was possible to infer that the captopril molecules suffered a rearranging into the unit cell due slight orientational changes mainly involving CH⋯O hydrogen bonds. The phenomenon occurs in a large temperature range. However, the observed changes do not suggest the occurrence of a structural phase transition and the Raman spectra indicate that the trans conformation is recorded down to the lowest temperature available in the experiments.


Capillary electrophoresis analysis of hydrogen peroxide induced apoptosis in PC12 cells.
Apoptosis is a highly regulated and controlled process of cell death that plays a fundamental role in many biological processes. Abnormal apoptosis of cells is closely related to some diseases such as cancer. Development of a simple and effective method to detect apoptosis is of great importance. In the present paper, capillary electrophoresis (CE) method was applied to distinguish cell apoptosis and necrosis of rat pheochromocytoma (PC12) cells treated by hydrogen peroxide by characterizing the DNA fragmentation. Firstly, effects of separation conditions (voltage, polymer concentration, temperature and injection time) on DNA separation were studied using 100 bp DNA ladders as the analyte. Under optimal separation condition (polyacrylamide coated capillaries: 57.5 cm x 75 microm i.d., effective length: 50 cm; running buffer: 1x TBE containing 2% PVP and 1.2% HEC; separation voltage: 5 kV; temperature: 25 degrees C; electrokinetic injection: 10 kV x 10 s), CE was used to monitor the progress of hydrogen peroxide induced apoptosis of PC12 cells by analyze DNA fragmentation. It was found that normal, apoptotic and neurotic cells had distinct DNA fragmentation patterns analyzed by CE. The results by CE were tested by other current methods (DAPI nuclei staining, flow cytometry analysis and TUNEL) to detect apoptosis and correlated well with those methods. Results show that CE can distinguish cell apoptosis and necrosis, quantify the degree of apoptosis in cells and have advantages of high efficiency, fast sample analysis speed, minute sample consumption and reliable results, which provides an accessorial method in the research of multiple diseases with abnormal apoptosis such as cancer and neurodegenerative diseases.


Multiplex analysis of cytokines in exhaled breath condensate.
To improve monitoring of lung diseases, we analyzed cytokines in exhaled breath condensate (EBC). The main challenge in measurement of cytokines in EBC is the low protein content, which requires concentration steps that conflict with the need for excessive fluid required by most commonly used kits. Here, a multiplex bead array for the detection of interleukins (IL) -1beta, -6, -8, -10, TNF-alpha, and IL-12p70 was modified and validated for analysis in EBC samples. Furthermore, 33 healthy volunteers and 11 patients with acute lung injury were investigated. In patients with inflammatory lung diseases, cytokine levels for all investigated cytokines were higher in comparison to healthy smokers or healthy volunteers. Multiplexed immunoassays in highly sensitive approaches allow for cytokine detection in EBC. We found significant differences between patients and controls for all investigated cytokines.


Retracted: Information Dissemination Model in Rural Live Broadcasting under Blockchain in the Era of Artificial Intelligence.
[This retracts the article DOI: 10.1155/2022/4590578.].


Identification of the first nonsense CDSN mutation with expression of a truncated protein causing peeling skin syndrome type B.
Peeling skin disease (PSD), a generalized inflammatory form of peeling skin syndrome, is caused by autosomal recessive nonsense mutations in the corneodesmosin gene (CDSN). To investigate a novel mutation in CDSN. A 50-year-old white woman showed widespread peeling with erythema and elevated serum IgE. DNA sequencing, immunohistochemistry, Western blot and real-time polymerase chain reaction analyses of skin biopsies were performed in order to study the genetics and to characterize the molecular profile of the disease. Histology showed hyperkeratosis and acanthosis of the epidermis, and inflammatory infiltrates in the dermis. DNA sequencing revealed a homozygous mutation leading to a premature termination codon in CDSN: p.Gly142*. Protein analyses showed reduced expression of a 16-kDa corneodesmosin mutant in the upper epidermal layers, whereas the full-length protein was absent. These results are interesting regarding the genotype-phenotype correlations in diseases caused by CDSN mutations. The PSD-causing CDSN mutations identified heretofore result in total corneodesmosin loss, suggesting that PSD is due to full corneodesmosin deficiency. Here, we show for the first time that a mutant corneodesmosin can be stably expressed in some patients with PSD, and that this truncated protein is very probably nonfunctional.