Characterization of the transcriptional regulatory region of the human WT1 gene.
Specific control of the expression of the Wilms tumor gene WT1 is important for normal development of the kidney. In order to characterise the transcriptional control region of the WT1 gene we have isolated genomic clones spanning the upstream region, the first WT1 exon and the 5' end of the Wit1 gene. DNA sequencing revealed that the WT1 promoter lacks a TATA box or CCAAT motif and has a GC content of 71%. Four transcriptional start sites are clustered within a 32 bp region. GC-boxes are present at nucleotide positions -413, -160, +84 and +158. DNAase I protection assays with purified Sp1 protein revealed the existence of 11 different binding sites in the WT1 promoter. WT1 and Wit1 promoter activities were tested in COS-7 cells with luciferase reporter gene constructs either containing or lacking an SV40 enhancer. WT1 promoter activity was found in a fragment extending from 449 bp upstream to 201 bp downstream of the WT1 start site. It was 26 fold lower in the absence of the SV40 enhancer than in the presence. Cotransfection with a Sp1 expression vector stimulated both constructs 3-4 fold. Wit1 promoter activity was identified in a DNA fragment extending from 200 bp upstream of the putative Wit1 TATA box to 130 bp downstream. Several potential recognition sites for WT1/EGR, Pax-8, and GAGA-like transcription factors are present in the WT1 promoter.


Rare presentation of biliary ascariasis.
Ascariasis is the most common helminthic infection in the world. We present a very rare manifestation of ascariasis in which the worms came out through the T-tube tract of a 36 years old patient who had undergone cholecystectomy with choledocholithotomy.


[The nature of melanin pigments from some micro- and macromycetes].
New inhibitors of melanin formation by micromycetes Aspergillus carbonarius, Alternaria alternata, and Paecilomyces variotii and basidiomycetes Inonotus obliquus and Phellinus robustus were found. Precursors of melanin pigments were isolated and identified. p-Hydroxybenzoic acid was identified among the products of alkaline degradation of melanin formed by micromycetes, whereas in the case of macromycetes this was protocatechuic acid. Therefore, melanins of the former were found to belong to the dihydronaphthalene group, whereas those of the latter belong to catechols.


The Effects of the Passage of Time from the 2011 Tohoku Earthquake on the Public's Anxiety about a Variety of Hazards.
This research investigated whether the Japanese people's anxiety about a variety of hazards, including earthquakes and nuclear accidents, has changed over time since the Tohoku Earthquake in 2011. Data from three nationwide surveys conducted in 2008, 2012, and 2015 were compared to see the change in societal levels of anxiety toward 51 types of hazards. The same two-phase stratified random sampling method was used to create the list of participants in each survey. The results showed that anxiety about earthquakes and nuclear accidents had increased for a time after the Tohoku Earthquake, and then decreased after a four-year time frame with no severe earthquakes and nuclear accidents. It was also revealed that the anxiety level for some hazards other than earthquakes and nuclear accidents had decreased at ten months after the Earthquake, and then remained unchanged after the four years. Therefore, ironically, a major disaster might decrease the public anxiety in general at least for several years.


Microvolt t-wave alternans with exercise in pediatrics and congenital heart disease: limitations and predictive value.
Microvolt t-wave alternans (TWA) in early exercise is a noninvasive marker of life-threatening ventricular arrhythmia in some adult cardiac populations. The incidence and potential significance of sustained TWA in pediatric and congenital heart disease (CHD) populations has not been well defined. TWA treadmill exercise studies in pediatric patients with CHD, myopathy, potential myocardial ischemia, syncope, or history of cardiac arrest were analyzed. Tests were categorized as abnormal for sustained TWA with onset heart rate < 130 beats/min with specific analyses for lower onset heart rates. Patient characteristics were analyzed as possible correlates of TWA. Over 2 years, 318 consecutive TWA exercise studies were performed in 304 patients (60% male, median 14 years, 6-41) for indications of syncope, cardiac arrest, possible ventricular arrhythmia, or evaluation of functional myocardial perfusion. Underlying conditions included apparently normal hearts (45%), CHD (16%), cardiomyopathy (11%), coronary anomalies (11%), electrical myopathy (9%), and transplant (8%). Abnormal TWA was seen in 24 (7%, onset HR 106 +/- 18) and included 19 at high clinical risk for serious events including 3 with cardiac arrest. By multivariate analysis sustained TWA was associated with cardiac arrest, ventricular arrhythmias, and a clinical classification of high risk. TWA is associated with pediatric and CHD diagnoses at high risk of serious events and may contribute, with other diagnostic tools, to management choices. While the absence of TWA has relatively high negative predictive value, it does not completely exclude the potential for serious sustained ventricular arrhythmias. A more robust noninvasive marker for risk stratification in these populations is required.


Growth factors, AGEing, and the diabetes link in Alzheimer's disease.
Diabetes mellitus and Alzheimer's disease (AD) each become increasingly common with age. Diabetes causes many chronic end-organ complications and among them is dementia, which may be due to an underlying vascular cause, as well as being related to AD. The pathogenic mechanisms that lead to diabetes complications include advanced glycation end products (AGEs) and growth factor dysregulation. This review explores the evidence for epidemiological links between diabetes and AD, as well as potential pathogenic mechanisms whereby AGEs, their cellular receptors, and key growth factors may contribute to AD development and progression in diabetes. Directions for future research are also discussed.


Analysis of trace metal humic acid interactions using counterion condensation theory.
Recent extensions of counterion condensation theory, originally developed for well-defined linear polyelectrolytes, enable us to analyze the interaction of trace metals with humic acid. In the present model, the heterogeneity of the macromolecule is taken into account as well as the chemical binding of the considered metal ions to the humic material. Experimentally, potentiometric titrations have been performed for humic acid in solution in the presence of different environmentally important (heavy) metals (Ca, Cd, Cu, Ni, and Pb) at various metal concentrations by titrating with potassium hydroxide without additional salt. From proton release data obtained for the initial point in the titration, it was estimated that the interaction of the different metals with the humic acid in terms of binding strength increased in the order Ca < Cd approximately = Ni < Pb approximately = Cu. These results were confirmed by model analysis. Experimentally obtained apparent dissociation constants were in good agreement for the humic acid systems containing Ca, Cd, and Ni at concentrations ranging from 0 up to 0.75 x 10(-3) mol L(-1) and polymer dissociation degree from about 0.1 up to approximately 0.8. Also for the Cu/humic acid and Pb/humic acid systems, the agreement between experimental data and calculated data was satisfactory atthe lowest metal concentrations over the complete titration curve. For elevated levels of Cu and Pb, the agreement between experimental data and theoretical calculations becomes less satisfactory at low degrees of dissociation of the humic acid. This distortion of the potentiometric curves is probably due to changes in the intrinsic pK of the functional groups due to metal binding. This complex process is not included in present polyelectrolytic models.


Description of Notoglanidium pembetadi new species (Siluriformes: Claroteidae) from the Kouilou-Niari River, Republic of the Congo.
A new claroteid catfish, Notoglanidium peinbetadi, is described from the Kouilou-Niari River basin (Republic of the Congo). This species can be distinguished from all other currently known Notoglanidium species as well as from the very similar Anaspidoglanis boutchangai, to which two specimens have erroneously been attributed in the past, by the following combination of characters: II, 10-13 dorsal-fin rays; long dorsal-fin base (21.1-24.4% SL); short predorsal distance (30.1-33.5% SL); and short prepelvic distance (40.1-45.4% SL).


Activation of the RLR/MAVS Signaling Pathway by the L Protein of Mopeia Virus.
The family Arenaviridae includes several important human pathogens that can cause severe hemorrhagic fever and greatly threaten public health. As a major component of the innate immune system, the RLR/MAVS signaling pathway is involved in recognizing viral components and initiating antiviral activity. It has been reported that arenavirus infection can suppress the innate immune response, and NP and Z proteins of pathogenic arenaviruses can disrupt RLR/MAVS signaling, thus inhibiting production of type I interferon (IFN-I). However, recent studies have shown elevated IFN-I levels in certain arenavirus-infected cells. The mechanism by which arenavirus infection induces IFN-I responses remains unclear. In this study, we determined that the L polymerase (Lp) of Mopeia virus (MOPV), an Old World (OW) arenavirus, can activate the RLR/MAVS pathway and thus induce the production of IFN-I. This activation is associated with the RNA-dependent RNA polymerase activity of Lp. This study provides a foundation for further studies of interactions between arenaviruses and the innate immune system and for the elucidation of arenavirus pathogenesis. Distinct innate immune responses are observed when hosts are infected with different arenaviruses. It has been widely accepted that NP and certain Z proteins of arenaviruses inhibit the RLR/MAVS signaling pathway. The viral components responsible for the activation of the RLR/MAVS signaling pathway remain to be determined. In the current study, we demonstrate for the first time that the Lp of MOPV, an OW arenavirus, can activate the RLR/MAVS signaling pathway and thus induce the production of IFN-I. Based on our results, we proposed that dynamic interactions exist among Lp-produced RNA, NP, and the RLR/MAVS signaling pathway, and the outcome of these interactions may determine the final IFN-I response pattern: elevated or reduced. Our study provides a possible explanation for how IFN-I can become activated during arenavirus infection and may help us gain insights into the interactions that form between different arenavirus components and the innate immune system.


Redundant-interconnection interpattern-association neural network.
We have shown that introducing interconnection redundancy can make a neural network more robust. We describe performances under noisy input and partial input that show that the optimum-redundant interconnection improves both the noise tolerance and the pattern discriminability. Simulated and experimental demonstrations are also provided.


Current research trends on micro- and nano-plastics as an emerging threat to global environment: A review.
Micro-and nano-plastics (MNPs) (size < 5 mm/<100 nm) epitomize one of the emergent environmental pollutants with its existence all around the globe. Their high persistence nature and release of chemicals/additives used in synthesis of plastics materials may pose cascading impacts on living organism across the globe. Natural connectivity of all the environmental compartments (terrestrial, aquatic, and atmospheric) leads to migration/dispersion of MNPs from one compartment to others. Nevertheless, the information on dispersion of MNPs across the environmental compartments and its possible impacts on living organisms are still missing. This review first acquaints with dispersion mechanisms of MNPs in the environment, its polymeric/oligomeric and chemical constituents and then emphasized its impacts on living organism. Based on the existing knowledge about the MNPs' constituent and its potential impacts on the viability, development, lifecycle, movements, and fertility of living organism via several potential mechanisms, such as irritation, oxidative damage, digestion impairment, tissue deposition, change in gut microbial communities' dynamics, impaired fatty acid metabolism, and molecular damage are emphasized. Finally, at the end, the review provided the challenges associated with remediation of plastics pollutions and desirable strategies, policies required along with substantial gaps in MNPs research were recommended for future studies.


How we perceive our own retina.
Ever since the days of René Descartes, in the seventeenth century, the search for the relationship between subjective perception and neural activity has been an ongoing challenge. In neuroscience, an approach to the problem via the visual system has produced a paradigm using perceptual suppression, changing with time. Cortical areas in which the neural activity was modulated in temporal correlation with this percept could be traced. Although these areas may lead directly to perception, such temporal correlation of neural activity does not suffice as ultimate proof that they actually do so. In this article, I will use a different method to show that, for the perception of our own retina, any brain area leading directly to this perception also needs to represent the retina without distortion. Furthermore, I will demonstrate that the phenomenon of size constancy must be realized in this area.


Immunological response of three mouse strains to typhoid vaccine and Vi antigen.
Vi-agglutinin, active cutaneous anaphylaxis and protective responses (ed(50)) of three mouse strains (CFW, NIH, and Balb/cAnN) to acetone-inactivated typhoid vaccine and soluble Vi antigen were compared. Seven days after immunization with either typhoid vaccine or Vi antigen the three strains of mice differed with respect to Vi-antibody titers. Significant differences were observed in the protective responses. Each mouse strain was significantly better protected by the intraperitoneal than by subcutaneous route of immunization. Active cutaneous anaphylaxis was more pronounced in showing strain differences in response to Vi antigen. The serological responses to Vi antigen of the strains of mice did not correlate with their protective response.


Identification of Streptomyces coelicolor M145 genomic region involved in biosynthesis of teichulosonic acid-cell wall glycopolymer.
The cell wall of the model actinomycete Streptomyces coelicolor M145 has recently been shown to contain the novel glycopolymer teichulosonic acid. The major building block of this polymer is 2-keto-3-deoxy-D-glycero-D-galacto-nononic acid (Kdn), suggesting initial clues about the genetic control of biosynthesis of this cell wall component. Here, through genome mining and gene knockouts, we demonstrate that the sco4879-sco4882 genomic region of S. coelicolor M145 is necessary for biosynthesis of teichulosonic acid. Specifically, mutants carrying individual knockouts of sco4879, sco4880 and sco4881 genes do not produce Kdn-containing glycopolymer and instead accumulate the minor cell wall component poly(diglycosyl 1-phosphate). Our studies provide evidence that this region is at least partly responsible for biosynthesis of Kdn, whereas flanking genes might control the other steps of teichulosonic acid formation.


Morphology of the endocrine pancreas in cyclosporine-treated glucose-intolerant Wistar rats.
The toxic effect of Cyclosporin A (CS-A) (1.25-50.0 mg/kg body weight) on the endocrine pancreas of Wistar rats was morphologically investigated. The treatment of animals with CS-A doses above 5 mg/kg for 2 weeks resulted in a disturbed glucose tolerance, a reduced B-cell volume density and degranulation, vacuolization and decreased mitotic activity of the B-cells. After withdrawal of the drug the impaired parameters were stepwise normalized, starting with regranulation of pancreatic B-cells, followed by a stimulation of mitotic activity, and increase of B-cell volume density. When continuing the CS-A treatment with doses lower than 5.0 mg/kg for longer periods we observed a decreased body weight gain and reduced pancreatic insulin content.


C.A.S., Belleville v. L.T., 2 April 1987.
The Court held that, under Section 37 of the Child and Family Services Act, in certain circumstances an unborn child can be considered a child in need of protection. It ruled that such a finding is justified when the evidence establishes that the mother is suffering from a mental disorder of a nature and quality that will likely result in serious bodily harm to herself or the child. It ordered the unborn child in question to be made a ward of the Children's Aid Society for three months.


Bond strength between machinable glass-ceramic and dual-cured resin luting cements using silane coupling agents.
To evaluate the shear bond strength of two dual-cured resin luting cements (Linkmax HV and Panavia Fluoro Cement) to machinable glass-ceramics (Decsy Machinable Ceramic) and the effect of three silane coupling agents (Clearfil Porcelain Activator, Ceramic Primer, and Porcelain Liner M) on the bond strength. Disk-shaped specimens fabricated from machinable glass-ceramic blocks using a low-speed cutting saw were either treated or not treated with one of three silane coupling agents and then bonded together with one of two dual-cured resin luting cements. Specimens were stored in water at 37degrees C for 24 hours and/or thermal cycled 50,000 times before shear bond strength testing. Regardless of the resin luting cement and thermal cycling, specimens treated with the Clearfil Porcelain Activator showed the highest shear bond strength among all the treatments. Surface treatment of the Clearfil Porcelain Activator showed significantly greater shear bond strength after 50,000 thermocycles compared with other treatments. However, significant differences in bond strength were observed between 0 and 50,000 thermocycles for all treatments.


Competitor analysis for imaging services.
Managers of radiology and imaging services need to continually question their assumptions about competitors, particularly in highly competitive markets. The systematic collection of information about a competitor's future goals, current strategies, assumptions held and capabilities can improve the accuracy of predictions of a competitor's future behavior. The resources devoted to a competitor analysis should depend on the level of risk which a manager's organization faces. Interviews with selected professionals involved in the day-to-day operations of radiology and imaging services are the most important source of information, but published and unpublished information available to the public can provide essential background information and corroborate the information gained through interviews.


[Uterine rupture: report of 41 cases].
To establish the epidemiological profile, of patients who presented a uterine rupture, as well as the obstetrical follow up, the neonatal outcome and the prognosis factors. A retrospective study of 41 cases of uterine rupture treated in the maternity center of Tunis during a 5-year period. The frequency of uterine rupture was 1.38%@1000 of births. Rupture in scarred uterus was found in 58.5% of the cases against 41.5% in sain uterus. Three risk factors were statistically significant in our series: cesarian section, multiparity and high fetal weight. Uterine rupture is a medico-surgical emergency causing materno-fetal morbidity and mortality.


Single Dose Gonadotropin-Releasing Hormone Agonist Luteal Support in Fresh Embryo Transfer: Variation in Timing, Type, and Dosage.
To evaluate the effects of the addition of single-dose GnRH agonist to the routine progestogens use for luteal phase support on IVF outcome as compared to progestogens only. This is a retrospective case-control study on selected patients who underwent IVF treatment with fresh embryo transfer (ET) under Medically Assisted Conception Unit, University Kebangsaan Malaysia Medical Center for the period of June 2015-June 2018. A higher dose of 0.2 mg subcutaneous Decapeptyl was administered 2 days before fresh ET concurrent with routine progestogen support. Patients with different luteal phase regimes, frozen embryo transfer and medical records with missing data were excluded. Their medical records were reviewed, and data analyzed. The pregnancy outcomes measured included biochemical pregnancy rates, clinical pregnancy rates, live birth rates and miscarriage rates. A total of 786 patients were analyzed. Four hundred forty-four patients were given luteal phase support with progestogens and GnRH agonist, whereas 342 patients served as control were given progestogens only. The study group showed higher biochemical pregnancy rate (47.7 vs. 44.4%,), clinical pregnancy rate (25.7 vs. 23.4%) and livebirth rate (24.3 vs. 22.2%), respectively but not statistically significant. The rate of miscarriage among the study group was lower (4.5% vs 9.4%) compared to the progestogen group alone. Nonetheless, the OHSS rate was slightly increased in the study group (4.5 vs. 3.5%) despite using a mild stimulation protocol. New regime of GnRH agonist luteal support in addition to the standard progestogen support was found to be beneficial in overall IVF outcome.


Prevalence of peripheral arterial disease in type 2 diabetics in Pakistan.
To observe the prevalence of peripheral arterial disease (PAD) and associated factors among people with type 2 diabetes in Pakistan. A multicenter cross-sectional study was carried out at eight centers in all the provinces of Pakistan on people with type 2 diabetes. History of symptoms related to Peripheral arterial disease were noted and anthropometric measurements were recorded. Ankle brachial index (ABI) was measured using Doppler ultrasound; patients with ABI < 0.9 were classified as having low ABI. There were 830 patients in the study, (49% males and 51% females). Females were younger and had a higher body mass index (BMI) (p < 0.001). The prevalence of peripheral arterial disease was 31.6% with a 95% CI of 28.4% to 34.8%. There was no significant difference in the proportion of low ABI between males (30%) and females (33%) (p = 0.29). Patients with low ABI were found to have significantly higher BMI (p = 0.02) and waist circumference (p = 0.001). The most common symptom in the patients with low ABI was pain on walking (84%), followed by numbness of the feet (64%). There was a significant difference in the reporting of all the symptoms (p < 0.05) except for numbness of the feet (p = 0.57) as compared to patients with normal ABI. No association was found between low ABI and duration of diabetes mellitus or cigarette smoking. There was no significant association between cardiovascular conditions and low ABI. Peripheral arterial disease is common among people with type 2 diabetes in Pakistan and needs to be properly evaluated by the medical professionals as early diagnosis can help prevent future complications.


[The influence of aging on the development of rat galactosemic cataract].
In order to investigate the effect of age on the rat galactosemic cataract, 3, 6, 12 and 24-week-old rats were fed with a 50% galactose diet. The cataractous lenses were observed by light microscopy, and the amount of galactitol measured. All rats fed with 50% galactose developed cataracts in the equatorial region. However, the morphological and biochemical development of the galactose cataract in old rats was slower than in young rats. These results suggested that older diabetic patients are less likely to develop diabetic cataract than younger patients.


Shared Variance among Self-Report and Behavioral Measures of Distress Intolerance.
Distress intolerance may be an important individual difference variable in understanding maladaptive coping responses across diagnostic categories. However, the measurement of distress intolerance remains inconsistent across studies and little evidence for convergent validity among existing measures is available. This study evaluated the overlap among self-report and behavioral measures of distress intolerance in four samples, including an unselected sample, a sample of patients with drug dependence, and two samples of cigarette smokers. Results suggested that the self-report measures were highly correlated, as were the behavioral measures; however, behavioral and self-report measures did not exhibit significant associations with each other. There was some evidence of domain specificity, with anxiety sensitivity demonstrating strong associations with somatic distress intolerance, and a lack of association between behavioral measures that elicit affective distress and those that elicit somatic distress. These findings highlight a potential divergence in the literature relative to the conceptualization of distress intolerance as either sensitivity to distress or as the inability to persist at a task when distressed. Further research is needed to elucidate the conceptualization and measurement of distress intolerance to facilitate future clinical and research applications of this construct.


Intra-abdominal pressure mechanism for stabilizing the lumbar spine.
Currently, intra-abdominal pressure (IAP) is thought to provide stability to the lumbar spine but the exact principles have yet to be specified. A simplified physical model was constructed and theoretical calculations performed to illustrate a possible intra-abdominal pressure mechanism for stabilizing the spine. The model consisted of an inverted pendulum with linear springs representing abdominal and erector spinae muscle groups. The IAP force was simulated with a pneumatic piston activated with compressed air. The critical load of the model was calculated theoretically based on the minimum potential energy principle and obtained experimentally by increasing weight on the model until the point of buckling. Two distinct mechanisms were simulated separately and in combination. One was antagonistic flexor extensor muscle coactivation and the second was abdominal muscle activation along with generation of IAP. Both mechanisms were effective in stabilizing the model of a lumbar spine. The critical load and therefore the stability of the spine model increased with either increased antagonistic muscle coactivation forces or increased IAP along with increased abdominal spring force. Both mechanisms were also effective in providing mechanical stability to the spine model when activated simultaneously. Theoretical calculation of the critical load agreed very well with experimental results (95.5% average error). The IAP mechanism for stabilizing the lumbar spine appears preferable in tasks that demand trunk extensor moment such as lifting or jumping. This mechanism can increase spine stability without the additional coactivation of erector spinae muscles.


Nimodipine-mediated re-myelination after facial nerve crush injury in rats.
This study aimed to investigate the mechanism of nimodipine-mediated neural repair after facial nerve crush injury in rats. Adult Sprague-Dawley rats were divided into three groups: healthy controls, surgery alone, and surgery plus nimodipine. A facial nerve crush injury model was constructed. Immediately after surgery, the rats in the surgery plus nimodipine group were administered nimodipine, 6 mg/kg/day, for a variable numbers of days. The animals underwent electromyography (EMG) before surgery and at 3, 10, or 20 days after surgery. After sacrifice, nerve samples were stained with hematoxylin and eosin (H&E) and luxol fast blue. The EMG at 20 days revealed an apparent recovery of eletroconductivity, with the surgery plus nimodipine group having a higher amplitude and shorter latency time than the surgery only group. H&E staining showed that at 20 days, the rats treated with nimodipine had an obvious recovery of myelination and reduction in the number of infiltrating cells, suggesting less inflammation, compared with the rats in the surgery only group. Luxol fast blue staining was relatively even in the surgery plus nimodipine group, indicating a protective effect against injury-induced demyelination. Staining for S100 calcium-binding protein B (S-100β) was not evident in the surgery alone group, but was evident in the surgery plus nimodipine group, indicating that nimodipine reversed the damage of the crush injury. After a facial nerve crush injury, treatment with nimodipine for 20 days reduced the nerve injury by mediating remyelination by Schwann cells. The protective effect of nimodipine may include a reduction of inflammation and an increase in calcium-binding S-100β protein.


Transcriptional responses to intermittent hypoxia.
Recurrent apneas are characterized by transient repetitive cessations of breathing (two breaths duration or longer) resulting in periodic decreases in arterial blood PO2 or chronic intermittent hypoxia (IH). Patients with recurrent apneas and experimental animals exposed to chronic IH exhibit cardio-respiratory morbidities. The purpose of this article is to highlight the current information on the transcriptional mechanisms associated with chronic IH. Studies on rodents and cell cultures have shown that IH activates a variety of transcription factors including the hypoxia-inducible factor-1 (HIF-1), c-fos (immediate early gene), nuclear factor of activated T-cells (NFAT), and nuclear factor kB (NF-kB). The signaling pathways associated with transcriptional activation associated with IH differ from continuous hypoxia (CH). Compared to same duration and intensity of CH, IH is more potent in activating HIF-1 and c-fos and also results in long-lasting accumulation of HIF-1alpha and c-fos mRNA, a phenomenon that was not seen with CH. IH-evoked transcriptional activation by HIF-1, c-fos as well as the resulting activator protein-1 (AP-1) requires reactive oxygen species (ROS)-mediated signaling and involves complex feed forward interactions between HIF-1 and ROS. Chronic IH-evoked cardio-respiratory responses are absent in Hif-1alpha+/- mice, and hypertension elicited by chronic IH is absent in mice lacking NFAT3c. These studies indicate that cardiorespiratory responses to chronic IH depend on complex interactions between various transcription factors resulting in alterations in several down stream genes and their protein products.


Successful application of active learning techniques to introductory microbiology.
While the traditional lecture format may be a successful way to teach microbiology to both medical and nursing students, it was not an effective means of learning for many prenursing and preprofessional students enrolled in either of the introductory microbiology courses at Ashland Community College, an open enrollment institution. The structure of both Medical Microbiology and Principles of Microbiology was redesigned to allow students to address the material in an active manner. Daily quizzes, student group discussions, scrapbooks, lab project presentations and papers, and extra credit projects were all added in order to allow students maximum exposure to the course material in a manner compatible with various methods of learning. Student knowledge, course evaluations, and student success rates have all improved with the active learning format.


Semaphorin 3A Is Effective in Reducing Both Inflammation and Angiogenesis in a Mouse Model of Bronchial Asthma.
Semaphorin 3A (sema3A) belongs to the sub-family of the immune semaphorins that function as regulators of immune-mediated inflammation. Sema3A is a membrane associated molecule on T regulatory cells and on B regulatory cells. Being transiently ligated to the cell surface of these cells it is suggested to be a useful marker for evaluating their functional status. In earlier studies, we found that reduced sema3A concentration in the serum of asthma patients as well as reduced expression by Treg cells correlates with asthma disease severity. Stimulation of Treg cells with recombinant sema3A induced a significant increase in FoxP3 and IL-10 expression. To find out if sema3A can be of benefit to asthma patients, we evaluated the effect of sema3A injection in a mouse model of asthma. BALB\c-mice were sensitized using ovalbumin (OVA) + adjuvant for 15 days followed by OVA aerosol inhalation over five consecutive days. Four hours following air ways sensitization on each of the above days- 15 of these mice were injected intraperitoneally with 50 μg per mouse of recombinant human sema3A-FR and the remaining 15 mice were injected with a similarly purified vehicle. Five days later the mice were sacrificed, broncheo-alveolar lavage (BAL) was collected and formalin-fixed lung biopsies taken and analyzed. In sema3A treated mice, only 20% of the bronchioles and arterioles were infiltrated by inflammatory cells as compared to 90% in the control group (p = 0.0079). In addition, eosinophil infiltration was also significantly increased in the control group as compared with the sema3A treated mice. In sema3A treated mice we noticed only a small number of mononuclear and neutrophil cells in the BAL while in the control mice, the BAL was enriched with mononuclear and neutrophil cells. Finally, in the control mice, angiogenesis was significantly increased in comparison with sema3A treated mice as evidenced by the reduced concentration of microvessels in the lungs of sema3A treated mice. To conclude, we find that in this asthma model, sema3A functions as a potent suppressor of asthma related inflammation that has the potential to be further developed as a new therapeutic for the treatment of asthma.


Polarization of water in the first hydration shell of K+ and Ca2+ ions.
Accurate representation of the interactions of water molecules with charges is essential for correct description of biomolecules and their interactions and, hence, is a primary concern in the design of classical force fields. This task is made even more challenging by the fact that the charge distribution of water molecules in liquid is significantly altered by the local environment. To understand how such polarization effects would modify the force fields, we have performed density functional calculations for ion-water clusters using K+ and Ca2+ ions as probes. We find that the dipole moment of water molecules in the first hydration shell decreases with increasing number of waters, which is explained by the suppression of the ion's electric field by those of water dipoles. Adding further water beyond the first shell, the dipole moment of the first shell waters increases because water dipoles are strongly polarized in the presence of hydrogen bond acceptors. Thus the net polarization of water in the hydration shell of an ion is determined by two competing effects, of which only one directly depends on the ion. These observations explain why the dipole moment of waters in the first hydration shell of a K+ ion is smaller compared to those in bulk water while the opposite is true for Ca2+ ions and suggest new constraints to be used in the development of polarizable water models.


In vivo effects of CETP inhibitory peptides in hypercholesterolemic rabbit and cholesteryl ester transfer protein-transgenic mice.
We previously reported that cholesteryl ester transfer protein (CETP) inhibitory peptides (designated P28 and P10) have anti-atherogenic effects in hypercholesterolemic rabbits (Biochim. Biophys. Acta (1998) 1391, 133-144). To further investigate those effects, we studied rabbit plasma that was collected after 30 h of a P28 or P10 injection. We found that there is a strong correlation between the in vivo CETP inhibition effects and alterations of lipoprotein particle size distribution in rabbit plasma, as determined on an agarose gel electrophoresis and gel filtration column chromatography. In vivo effects of the peptide were observed again in C57BL/6 mice that expressed simian CETP. The P28 or P10 peptide (7 microg/g of body weight) that was dissolved in saline was injected subcutaneously into the mice. The P28 injection caused the partial inhibition of plasma CETP activity up to 50%, decreasing the total plasma cholesterol concentration by 30%, and increasing the ratio of HDL/ total-cholesterol concentration by 150% in the CETPtransgenic (tg) mice. The CETP inhibition by the P28 or P10 made alterations that modulated the size re-distribution of the lipoproteins in the blood stream. Particle size of the very low (VLDL) and low density lipoproteins (LDL) from the peptide-injected group was highly decreased compared to the saline-injected group (determined on the gel filtration column chromatography). In contrast, The HDL particle size of the P28-injected group increased compared to the control group (saline-injected). The expression level of the CETP mRNA of the P28-injected CETP-tg mouse appeared lower than the saline-injected CETP-tg mouse. These results suggest that the injection of the CETP inhibitory peptide could affect the CETP expression level in the liver by influencing lipoprotein metabolism.


Novel Hybrids of Podophyllotoxin and Coumarin Inhibit the Growth and Migration of Human Oral Squamous Carcinoma Cells.
Oral squamous cell carcinoma is the most common malignancy of oral tumor. In this study, two novel hybrids of podophyllotoxin and coumarin were designed using molecular hybridization strategy and synthesized. Pharmacological evaluation showed that the potent compound 12b inhibited the proliferation of three human oral squamous carcinoma cell lines with nanomolar IC50 values, as well as displayed less toxicity on normal cells. Mechanistic studies indicated that 12b triggered HSC-2 cell apoptosis, induced cell cycle arrest, and inhibited cell migration. Moreover, 12b could disturb the microtubule network via binding into the tubulin. It was noteworthy that induction of autophagy by 12b was associated with the upregulation of Beclin1, as well as LC3-II. Furthermore, 12b significantly stimulated the AMPK pathway and restrained the AKT/mTOR pathway in HSC-2 cells. These results indicated that compound 12b was a promising candidate for further investigation.


A clinico-genomic analysis of soft tissue sarcoma patients reveals CDKN2A deletion as a biomarker for poor prognosis.
Sarcomas are a rare, heterogeneous group of tumors with variable tendencies for aggressive behavior. Molecular markers for prognosis are needed to risk stratify patients and identify those who might benefit from more intensive therapeutic strategies. We analyzed somatic tumor genomic profiles and clinical outcomes of 152 soft tissue (STS) and bone sarcoma (BS) patients sequenced at Stanford Cancer Institute as well as 206 STS patients from The Cancer Genome Atlas. Genomic profiles of 7733 STS from the Foundation Medicine database were used to assess the frequency of CDKN2A alterations in histological subtypes of sarcoma. Compared to all other tumor types, sarcomas were found to carry the highest relative percentage of gene amplifications/deletions/fusions and the lowest average mutation count. The most commonly altered genes in STS were TP53 (47%), CDKN2A (22%), RB1 (22%), NF1 (11%), and ATRX (11%). When all genomic alterations were tested for prognostic significance in the specific Stanford cohort of localized STS, only CDKN2A alterations correlated significantly with prognosis, with a hazard ratio (HR) of 2.83 for overall survival (p = 0.017). These findings were validated in the TCGA dataset where CDKN2A altered patients had significantly worse overall survival with a HR of 2.7 (p = 0.002). Analysis of 7733 STS patients from Foundation One showed high prevalence of CDKN2A alterations in malignant peripheral nerve sheath tumors, myxofibrosarcomas, and undifferentiated pleomorphic sarcomas. Our clinico-genomic profiling of STS shows that CDKN2A deletion was the most prevalent DNA copy number aberration and was associated with poor prognosis.


Asymptomatic Severe Aortic Stenosis and Noncardiac Surgery.
The patient with severe asymptomatic aortic stenosis presenting for elective noncardiac surgery poses a unique challenge. These patients are not traditionally offered surgical aortic valve replacement or transcatheter aortic valve replacement given their lack of symptoms; however, they are at increased risk for postsurgical complications given the severity of their aortic stenosis. The decision to proceed with elective noncardiac surgery should be based on individual and surgical risk factors. However, severity of aortic stenosis is not accounted for in current surgical risk factor assessment scoring; therefore, extensive communication with patients and surgical teams is necessary to minimize a patient's risk. A clear intraoperative plan should be designed to manage the unique hemodynamics of these patients, and a discussion should address postoperative placement.


Exposure to environmental tobacco smoke at work, at home, and during leisure time: a cross-sectional population sample.
Environmental tobacco smoke (ETS) is among the most common environmental health risks, with a striking and immediate biological response and increased disease risk. Exposure studies have looked mostly at worksite or home exposures, whereas total exposure levels at the population level are rarely reported. This study examined ETS exposure at work, at home, and during leisure time in a cross-sectional population sample of working-age adults. Our aim was to monitor changes in ETS exposure from 1992 to 2002. More detailed information on duration of exposure, distribution of exposure sites, and patterns of exposure was obtained in 2002. Data were based on Finland's national population chronic disease risk-factor surveys (conducted every 5 years). Total sample size varied from 8,000 to 13,500. The survey includes a self-administered questionnaire about ETS exposure at different sites. The proportion of nonsmoking persons exposed to ETS declined throughout the study period among both men and women. In 2002, 5.9% of male and 3.6% of female nonsmokers were exposed to ETS 1 hour or more per day, whereas 5.8% of men and 1.7% women were exposed less than 1 hour daily. Worksite exposure was more common among younger age groups of both sexes, but nonsmoking women in older age groups received more exposure at home than at worksites. Policy developments on ETS should aim to protect the whole population from ETS in all environments given that health risks from ETS often persist at home and in leisure environments. Total exposure levels should be studied to assess the health impacts of ETS.


Zyban for smoking cessation in a general practice setting: the response to an invitation to make a quit attempt.
The objective of this study was to assess the feasibility and success of Zyban as part of a moderately supported smoking cessation programme within UK general practice. Treatment was offered to 479 moderately dependent smokers (smoking 15 or more cigarettes per day) who had never used Zyban, and who had taken part in a previous NRT trial (the PATCH study). Main outcome measures were point prevalence and continuous abstinence from smoking at 6 and at 12 months. Two hundred and forty were excluded because of medical reasons or prescribing contraindication. Of the remainder (n=239) only 54 (23%) made an active quit attempt. Thirty percent (16/54) were abstinent at six months, and 22% (12/54) at 12 months (biochemically validated point prevalence rates). Age, socio-economic status, nicotine dependence, and genetic profile appeared to have little impact on success rates, but male quit-attempters were significantly more successful than female (40% vs. 10% at 12 months, p<0.05). In conclusion, a real-world smoking cessation programme using Zyban with moderate support within a general practice setting may achieve satisfactory quit rates without widening existing disparities in cessation.


Temperature preferences of male field crickets ( Gryllus integer) alter their mating calls.
Temperature affects the mating displays of many ectothermic animals, yet almost no information exists on the temperature preferences of ectotherms while they are displaying for mates. This study investigated the preferences of displaying male field crickets ( Gryllus integer) for microhabitats of different temperatures. G. integer males attract sexually receptive females by calling from cracks in the ground. We collected data from the field on the temperature of male calling sites (cracks in the ground), on the amount of herbaceous cover (which affects crack temperature) surrounding calling sites, and on the temporal properties of male calls at different temperatures. Laboratory experiments demonstrated that males prefer warmer sites and confirmed that temperature influences mating calls. We conclude that males of this ectothermic species prefer to call for mates from warmer sites, and that microhabitat choice on the basis of temperature affects their mating calls, and potentially their reproductive success.


Feasibility and Effectiveness of a Preventive Care Program during the Compound Humanitarian Crisis and COVID-19 Pandemic in Venezuela.
Effective preventive care programs are urgently needed during humanitarian crises, as has been especially obvious during the COVID-19 pandemic. A pragmatic trial was designed: hybridized intervention (Diabetes Prevention Program [DPP] + medical nutrition therapy + liquid diet [LD]; LD group) vs. DPP only (DPP group). The participants were adults who were overweight/obese and at high risk of type 2 diabetes mellitus (T2DM). The LD consisted of a "homemade" milk- and fruit-juice-based beverage. Pandemic restrictions delayed the program by nine months, tripled the amount of time required for screening, and reduced the total sample to 60%. Eventually, 127 participants were randomized, and 94/127 participants (74.0%) completed the first phase. Participant dropout was influenced by migration, COVID-19 symptoms, education level, and socioeconomic status. In two months, the LD group lost 2.9 kg (p < 0.001) and the DPP group, 2.2 kg (p < 0.001) (between-group p = 0.170), with improvements in their cardiometabolic risk factors. At this stage, the DPP was shown to be feasible and effective, demonstrating weight loss with the improvement of cardiometabolic risk factors in a primary setting in Venezuela, a middle-income country with a chronic humanitarian crisis, during the COVID-19 pandemic.


An overview of drug combination analysis with isobolograms.
Drugs given in combination may produce effects that are greater than or less than the effect predicted from their individual potencies. The historical basis for predicting the effect of a combination is based on the concept of dose equivalence; i.e., an equally effective dose (a) of one will add to the dose (b) of the other in the combination situation. For drugs with a constant relative potency, this leads to linear additive isoboles (a-b curves of constant effect), whereas a varying potency ratio produces nonlinear additive isoboles. Determination of the additive isobole is a necessary procedure for assessing both synergistic and antagonistic interactions of the combination. This review discusses both variable and constant relative potency situations and provides the mathematical formulas needed to distinguish these cases.


High Affinity to Skeleton Rare Earth Doped Nanoparticles for Near-Infrared II Imaging.
As a newly noninvasive emerging modality, NIR-II fluorescence imaging (1000-1700 nm) has many advantages over conventional visible and NIR-I imaging (700-900 nm). Unfortunately, only a few NIR-II fluorophores are suitable for bone imaging. Here, we report an NIR-II fluorophore based on DSPE-mPEG encapsulated rare earth doped nanoparticles (RENPs@DSPE-mPEG), which shows inherent affinity to bone without linking any targeting ligands, and thus, it provides an alternative noninvasive and nonradiation strategy for skeletal system mapping and bone disease diagnoses. Interestingly, within the NIR-II window, imaging at a longer wavelength (1345 nm) provides a higher resolution and signal-to-noise ratio than imaging at 1064 nm, even though the quantum yield at 1064 nm is 2-fold higher than that at 1345 nm. Besides bone imaging, RENPs@DSPE-mPEG show an imaging application in blood vessels and lymph nodes. Importantly, RENPs@DSPE-mPEG can be internalized by circulating white blood cells. This finding may open a window to increase efficient nanoparticle delivery in the fields such as immunotherapy and improve the diagnostic and therapeutic efficacy of cancer-targeted nanoparticles in clinical applications.


Pre- and early postnatal enriched environmental experiences prevent neonatal hypoxia-ischemia late neurodegeneration via metabolic and neuroplastic mechanisms.
Prenatal and early postnatal periods are important for brain development and neural function. Neonatal insults such as hypoxia-ischemia (HI) causes prolonged neural and metabolic dysregulation, affecting central nervous system maturation. There is evidence that brain hypometabolism could increase the risk of adult-onset neurodegenerative diseases. However, the impact of non-pharmacologic strategies to attenuate HI-induced brain glucose dysfunction is still underexplored. This study investigated the long-term effects of early environmental enrichment in metabolic, cell, and functional responses after neonatal HI. Thereby, male Wistar rats were divided according to surgical procedure, sham, and HI (performed at postnatal day 3), and the allocation to standard (SC) or enriched condition (EC) during gestation and lactation periods. In-vivo cerebral metabolism was assessed by means of [18 F]-FDG micro-positron emission tomography, and cognitive, biochemical, and histological analyses were performed in adulthood. Our findings reveal that HI causes a reduction in glucose metabolism and glucose transporter levels as well as hyposynchronicity in metabolic brain networks. However, EC during prenatal or early postnatal period attenuated these metabolic disturbances. A positive correlation was observed between [18 F]-FDG values and volume ratios in adulthood, indicating that preserved tissue by EC is metabolically active. EC promotes better cognitive scores, as well as down-regulation of amyloid precursor protein in the parietal cortex and hippocampus of HI animals. Furthermore, growth-associated protein 43 was up-regulated in the cortex of EC animals. Altogether, results presented support that EC during gestation and lactation period can reduce HI-induced impairments that may contribute to functional decline and progressive late neurodegeneration.


Short-term isocapnic hypoxia and coagulation activation in patients with sleep apnea.
Hemostatic changes might contribute to the increased risk of cardiovascular and cerebrovascular events in patients with obstructive sleep apnea (OSA). We investigated the effect of a short-term isocapnic hypoxic challenge on coagulation activation markers thrombin/antithrombin III complexes (TAT) and D-dimer in OSA. Thirty-two OSA patients (mean age 48 +/- 11 years) inhaled a gas mixture containing 10% O(2) and 90% N(2) and further adjusted to yield pulse oximetry saturation of 80-85% for 5 minutes. Plasma levels of TAT and D-dimer were measured immediately before and immediately after the hypoxic challenge. The hypoxic challenge provoked a significant increase in TAT (p < 0.001) and in D-dimer (p = 0.037). Mean nocturnal oxygen saturation from the sleep recordings correlated with D-dimer increase (r = -0.37, p = 0.041). Also, OSA patients with a history of hypertensive parents had greater D-dimer increase in response to hypoxia than patients having normotensive parents (p = 0.035). Parental hypertension independently explained 15% of the variance in D-dimer increase after hypoxia (p = 0.035). Oxygen desaturation during sleep may predispose OSA patients, in particular those with a parental history of hypertension, to a hypercoagulable state providing one explanation for the increased risk of atherothrombotic events in this population.


Kit(+) melanocytes seem to contribute to melanocyte proliferation after UV exposure as precursor cells.
Melanogenesis caused by UV exposure is characterized by proliferation and differentiation of functioning melanocytes in epidermis. Recently, the existence of precursor melanocytes in normal skin was proposed immunohistochemically. Thus, this precursor melanocyte seems to proliferate and differentiate into mature pigmented melanocytes after UV exposure. To elucidate how these processes occur, we examined C57BL mouse epidermal sheets after UV exposure immunohistochemically. In normal epidermis, TRP-1(+) cells and Kit(+) cells were easily identified and the cellularities were 41.0 and 31.7 cells per mm(2), respectively. Only a few Mitf(+) cells and no TRP-2(+) cells were observed. On the first day after UV exposure, Mitf(+) cells and TRP-2(+) cells appeared, whereas the numbers of TRP-1(+) cells and Kit(+) cells decreased. Some Kit+ cells also expressed Mitf, but no TRP-1 and Mitf double positive cells were seen. In this period, some Mitf(+) cells were labeled with BrdU. The next day, Mitf(+) cells and TRP-2(+) cells increased to the maximum cellularity, and they decreased thereafter and disappeared on the seventh day. An increase of TRP-1(+) cells was first identified on the fifth day after UV exposure, and reached a cellularity four times as great as that of the normal control on the fourteenth day. The subepidermal injection of Kit antibody attenuated the increase of Mitf+ cells and TRP-1(+) cells. These findings suggested that precursor cells that reside in the skin, first differentiated into Mitf(+) and TRP-2(+) melanocytes by the activation of the Kit receptor, then become mature TRP-1(+) melanocytes after UV exposure.


Coalescence of two growing bubbles in a Hele-Shaw cell.
An understanding of the dynamics of growth-driven coalescence is important in diverse fields across natural science and engineering. Motivated by the bubble coalescence in magma during volcanic eruptions, we study both experimentally and theoretically the coalescence of two growing bubbles in a Hele-Shaw cell. In our system, bubbles grow by gas expansion due to decompression and the diffusional influx of dissolved gas in the liquid. Our experiments show that the evolution of film thickness and bubble shape depends on viscosity, decompression rate, and cell gap. Through a scaling analysis and a perturbation approximation, we find that the hydrodynamic interaction between two bubbles is characterized by a film capillary number [Formula: see text] depending on viscosity [Formula: see text], bubble radius R, growth rate [Formula: see text], interfacial tension [Formula: see text], and cell gap D. The experimental results demonstrate that the film capillary number solely determines the bubble distortion just before coalescence. Under our experimental conditions, bubble coalescence occurs below a critical value of a nominal film capillary number defined as a film capillary number evaluated when two undeformed circular bubbles come into contact.


The use of aztreonam in pediatric patients: a review.
Aztreonam is the first monobactam available for use in this country. A parenteral antibiotic, its antibacterial spectrum is limited to gram-negative aerobic pathogens. The drug's pharmacologic, pharmacokinetic, and toxicologic properties are reviewed. Based on early experience in pediatric patients, certain recommendations can be made for the use of aztreonam.


Custom-made intraoral mandibular distraction as treatment for neonatal airway obstruction.
Hypoplastic mandible related airway obstruction therapy may vary from non-surgical to surgical, depending on the severity of the obstruction. Since its introduction in 1992, distraction osteogenesis (DO) has been used to lengthen the mandible. A new intraoral device is presented here. It has no need of screw fixation, whilst placement and activation are intraoral, leading to simple placement and removal. Seven cases with hypoplastic mandible related airway obstruction were treated between 2001 and 2008 with intraoral DO at the authors' institution. Six patients had a tracheostomy and one received continuous positive airway pressure (CPAP). After the distraction phase, five patients could be decanulated and in one case CPAP was no longer required. In one case the desired effect was not achieved. The findings suggest that early mandibular DO leads to damage to the permanent tooth buds resulting in missing teeth. The effectiveness of mandibular DO regarding early discharge of the patient is shown, leading to an overall cost reduction. Knowledge of alternative modalities such as mandibular DO in case of hypoplastic mandible related airway obstruction in neonatal healthcare should lead to early referral to a dedicated maxillofacial surgeon, possibly avoiding long-term airway support or tracheotomy.


Bat songs as acoustic beacons - male territorial songs attract dispersing females.
Male song in birds and mammals is important for repelling rivals, stimulating mates or attracting them to a specific location. Nevertheless, direct experimental evidence for the mate attraction function of male song is limited to a few studies. Here, we provide strong experimental evidence that male songs attract wild female bats (Saccopteryx bilineata). Playbacks of territorial songs reliably elicited phonotaxis in females but not males. Most females captured during playbacks were subadults searching for new colonies to settle in. In S. bilineata, multiple males sing simultaneously at dawn and dusk, thereby creating a conspicuous chorus which encodes information on colony identity and size. Since territorial songs have a large signalling range, male songs constitute acoustic beacons which enable females to localize new colonies. In our playbacks, females strongly preferred local territorial songs over foreign territorial songs from two different locations, indicating that song familiarity influences phonotaxis. Our study provides the first clear experimental evidence that male song elicits female phonotaxis in a non-human mammal. Bats are an especially promising taxon for studying mammalian song since male song has been described in different species with diverse social organisations and natural histories, thus providing exciting opportunities for phylogenetically controlled comparative studies.


Anti-Epstein-Barr Virus BNLF2b for Mass Screening for Nasopharyngeal Cancer.
Population screening of asymptomatic persons with Epstein-Barr virus (EBV) DNA or antibodies has improved the diagnosis of nasopharyngeal carcinoma and survival among affected persons. However, the positive predictive value of current screening strategies is unsatisfactory even in areas where nasopharyngeal carcinoma is endemic. We designed a peptide library representing highly ranked B-cell epitopes of EBV coding sequences to identify novel serologic biomarkers for nasopharyngeal carcinoma. After a retrospective case-control study, the performance of the novel biomarker anti-BNLF2b total antibody (P85-Ab) was validated through a large-scale prospective screening program and compared with that of the standard two-antibody-based screening method (EBV nuclear antigen 1 [EBNA1]-IgA and EBV-specific viral capsid antigen [VCA]-IgA). P85-Ab was the most promising biomarker for nasopharyngeal carcinoma screening, with high sensitivity (94.4%; 95% confidence interval [CI], 86.4 to 97.8) and specificity (99.6%; 95% CI, 97.8 to 99.9) in the retrospective case-control study. Among the 24,852 eligible participants in the prospective cohort, 47 cases of nasopharyngeal carcinoma (38 at an early stage) were identified. P85-Ab showed higher sensitivity than the two-antibody method (97.9% vs. 72.3%; ratio, 1.4 [95% CI, 1.1 to 1.6]), higher specificity (98.3% vs. 97.0%; ratio, 1.01 [95% CI, 1.01 to 1.02]), and a higher positive predictive value (10.0% vs. 4.3%; ratio, 2.3 [95% CI, 1.8 to 2.8]). The combination of P85-Ab and the two-antibody method markedly increased the positive predictive value to 44.6% (95% CI, 33.8 to 55.9), with sensitivity of 70.2% (95% CI, 56.0 to 81.4). Our results suggest that P85-Ab is a promising novel biomarker for nasopharyngeal carcinoma screening, with higher sensitivity, specificity, and positive predictive value than the standard two-antibody method. (Funded by the National Key Research and Development Program of China and others; ClinicalTrials.gov number, NCT04085900.).


Opposing influences of emotional and non-emotional distracters upon sustained prefrontal cortex activity during a delayed-response working memory task.
Performance in delayed-response working memory (WM) tasks is typically associated with sustained activation in the dorsolateral prefrontal cortex (dlPFC) that spans the delay between the memoranda and the memory probe. Recent studies have demonstrated that novel distracters presented during the delay interval both affect sustained activation and impair WM performance. However, the effect of the performance-impairing distracters upon sustained dlPFC delay activity was related to the characteristics of the distracters: memoranda-confusable distracters increased delay activity, whereas memoranda-nonconfusable emotional distracters decreased delay activity. Because these different effects were observed in different studies, it is possible that different dlPFC regions were involved and the paradox is more apparent than real. To investigate this possibility, event-related fMRI data were recorded while subjects performed a WM task for faces with memoranda-confusable (novel faces) and memoranda-nonconfusable emotional (novel scenes) distracters presented during the delay interval. Consistent with previous findings, confusable face distracters increased dlPFC delay activity, while nonconfusable emotional distracters decreased dlPFC delay activity, and these opposing effects modulated activity in the same dlPFC regions. These results provide direct evidence that specific regions of the dlPFC are generally involved in mediating the effects of distraction, while showing sensitivity to the nature of distraction. These findings are relevant for understanding alterations in the neural mechanisms associated with both general impairment of cognitive control and with specific impairment in the ability to control emotional distraction, such as those observed in aging and affective disorders, respectively.


Identification of a human monoclonal natural IgM antibody that recognizes early apoptotic cells and promotes phagocytosis.
Efficient clearance of cells undergoing apoptotic death is crucial for normal tissue homeostasis and for the prevention of autoimmunity. Engulfment of apoptotic cells is finely regulated by a highly redundant system of receptors and bridging molecules. We developed a rapid and efficient method for the identification of human natural IgM antibodies and isolated some natural human monoclonal IgM antibodies specific to the apoptotic cells. Among them, AC34 IgM bound to early apoptotic cells and promoted phagocytosis of apoptotic Jurkat cells by human monocyte-derived macrophage (HMDM). AC34 IgM recognized phosphatidylserine (PS), which means PS might be a possible molecule recognized by AC34 IgM on the surface of apoptotic cells and AC34 IgM might be a possible candidate of bridging molecules between the PS and phagocytes. The sequences of V(H) and V(L) of AC34 were almost the same with their germline counterpart. Our experiments suggest a role of natural IgM as an opsonin in the clearance of early apoptotic cells.


In vitro activity of novel dual action MDR anthranilamide modulators with inhibitory activity at CYP-450.
Synthesis and in vitro cytotoxicity assays of new anthranilamide MDR modulators have been performed to assess their inhibition potency of the P-glycoprotein (P-gp) transporter. The aromatic spacer group between nitrogen atoms (N1 and N2) in the known inhibitor XR9576 was replaced with a flexible alkyl chain of 2 to 6 carbon atoms in length. 6,7-Dimethoxy-1,2,3,4-tetrahydroisoquinoline and their open-chain N-methylhomoveratrylamine counterparts were shown to be potent P-gp inhibitors. The maximal inhibition was obtained when using an ethyl or propyl spacer. Several compounds were more potent than verapamil and intrinsically less cytotoxic than XR9576. In addition, in vitro metabolism studies of 23a with a subset of human CYP-450 isoforms revealed that, unlike XR9576, 23a inhibited CYP3A4, an enzyme that colocalizes with P-gp in the intestine and contributes to tumor cell chemoresistance by enhancing the biodisposition of anticancer drugs such as paclitaxel toward metabolism. In this context, 22a might be a suitable candidate for further drug development.


Molecular cloning, characterization, and expression profiles of the Sox3 gene in Chinese loach Paramisgurnus dabryanus.
A number of studies have established that in vertebrates, Sox3 is involved in a wide range of developmental processes, including sex differentiation and neurogenesis. However, the exact functions of the Sox3 gene have not been documented so far in teleosts. Here, we cloned the full length cDNA of Sox3 from the teleost fish, Paramisgurnus dabryanus, which we designated PdSox3. Sequence analysis revealed that PdSox3 encodes a hydrophilic protein, and shares high homology with Sox3 in other species, ranging from mammals to fishes. Quantitative real-time reverse transcription PCR, and in situ hybridization showed that PdSox3 is consistently expressed during embryogenesis, mainly localized in the developing central nervous system. Tissue distribution analyses revealed that PdSox3 is abundant in the adult brain, especially in particle cell layer. Furthermore, PdSox3 expression was higher in gonads, in primary spermatocyte cells, primary oocytes, and previtellogenic oocyte cells. All of these results suggest that PdSox3 plays an important role in early embryonic development, in particular the formation and development of the nervous system, and gonad development, similarly to other vertebrates. This is the first report describing Sox3 gene expression from this species, and the results are necessary to provide fundamental information on both the functional and evolutionary role of Sox3 across different species.


De-epithelialised anterior (anterolateral and anteromedial) thigh flaps for dead space filling and contour correction in head and neck reconstruction.
Anterior (anterolateral and anteromedial) thigh flaps based on the descending branch of the lateral circumflex femoral vessels provide a long vascular pedicle and a large flap without sacrificing main vessels and muscles. Twenty-eight de-epithelialized anterior thigh flaps were transferred for reconstruction of head and neck defects following tumour ablation. Two flaps were lost in patients that had previously undergone high-dose radiotherapy following free tissue transfer. Vascularised fibula, vascularised iliac bone and other tissues were combined with anterior thigh flaps in 13 cases utilising the distal end or derivative branches of the vascular pedicle. Salivary fistula was seen in only one case, although there were many minor and major complications. In five cases, double skin flaps were harvested from the ipsilateral thigh. One of these flaps was used for coverage of intraoral defects, while the other was placed in the submandibular area to fill dead space. Compared with other methods, this multi-flap method is considered to be most suitable for dead space filling and contour correction.


Pulmonary hypertension in thoracic surgical patients.
Literature about thoracic surgery in patients with pulmonary hypertension is scarce. Perceived high risk has appropriately discouraged any unnecessary operation. However, the medical therapy for pulmonary hypertension has made great advances during the last decade. It is likely that future advances in survival and possibly the need for diagnostic procedures will increase the anesthesiologist's exposure to such patients. Understanding the unique physiology as well as new therapeutic agents will facilitate safe care for these challenging patients. Since 1998, there have been three World Heath Organization symposiums on pulmonary hypertension. The most recent meeting in 2008 at Dana Point included revisions of the classification scheme and updates on new trials and therapies. New drugs have been utilized in cardiac, lung, or liver transplant operations to treat pulmonary hypertension. It is also recognized that one-lung ventilation presents unique problems for the patient with pulmonary hypertension. Inhalation use of the new pulmonary vasodilator drugs represents a new frontier for intraoperative pharmacology. Here, the various types of pulmonary hypertension, physiologic changes, and new drug therapies are reviewed. Clinical experience with patients with pulmonary hypertension undergoing both nonthoracic and thoracic procedures is also reviewed. By identifying potential problem areas and application of new pharmacology, an approach to the patient with pulmonary hypertension is synthesized.


Benzyl viologen-mediated counteraction of diquat and paraquat phytotoxicities.
There was reason from bacterial and algal systems to expect that pretreatments with a paraquat analog might confer tolerance against a subsequent paraquat treatment. Thus, a series of compounds were tested for protective activity against bipyridinium herbicides. These included other bipyridinium compounds and derivatives, as well as compounds having similar or more positive redox potentials than paraquat and compounds known to increase or maintain high superoxide dismutase activity levels in plants.Only treatments with benzyl viologen, a benzyl analog of paraquat, protected Spirodela oligorrhiza (Kurz) Hegelm. colonies from otherwise damaging levels of diquat.NADP photoreduction by isolated thylakoids was inhibited by the same concentrations of paraquat, diquat, and benzyl viologen given separately. Thus, the benzyl viologen-mediated tolerance against the bipyridinium herbicides is probably not due to a direct interaction at the thylakoid level.Superoxide dismutase activity was about 50% higher in broken plastids of benzyl viologen-treated plants compared to controls, which may partly explain the observed tolerance.


The phzI gene of Pseudomonas aureofaciens 30-84 is responsible for the production of a diffusible signal required for phenazine antibiotic production.
The production of phenazine (Ph) antibiotics in Pseudomonas aureofaciens (Pau) 30-84 is positively regulated by PhzR, a protein belonging to the LuxR family of transcriptional activators. We have now identified phzI, a second gene required for PH production. The product of phzI is a member of the LuxI family of N-acyl-homoserine lactone (N-acyl-HSL) synthases. Inactivation of phzI results in the loss of Ph production in Pau 30-84. The presence of phzI in Escherichia coli is sufficient for the production of a diffusible signal which activates phzB expression in Pau 30-84 and traA expression in a N-acyl-HSL-dependent reporter strain of Agrobacterium tumefaciens. In addition, synthetic N-(3-oxohexanoyl)-L-HSL induces phzB expression in Pau 30-84. These results suggest that Pau 30-84 produces a N-acyl-HSL signal that regulates Ph production, and that phzI plays a central role in this signaling pathway.


Environment, mitochondria, and Parkinson's disease.
Parkinson's disease (PD) is a common and disabling neurodegenerative disease marked by progressive motor dysfunction, which results from selective degeneration of the nigrostriatal pathway. Epidemiological studies indicate that exposure to pesticides, rural living, farming, and drinking well water are associated with an increased risk of developing PD. Rare cases of PD are caused by mutations in nuclear genes, and there is increasing evidence for susceptibility genes that alter disease risk. Parkinson's disease is also associated with a systemic defect in mitochondrial complex I activity. Animal models indicate that exposure to inhibitors of mitochondrial complex I, including pesticides, is sufficient to reproduce the features of PD, but genetic factors clearly modulate susceptibility. Complex I defects may result in oxidative stress and increase the susceptibility of neurons to excitotoxic death. In this way, environmental exposures and mitochondrial dysfunction may interact and result in neurodegeneration.


Fast Bayesian Variable Screenings for Binary Response Regressions with Small Sample Size.
Screening procedures play an important role in data analysis, especially in high-throughput biological studies where the datasets consist of more covariates than independent subjects. In this article, a Bayesian screening procedure is introduced for the binary response models with logit and probit links. In contrast to many screening rules based on marginal information involving one or a few covariates, the proposed Bayesian procedure simultaneously models all covariates and uses closed-form screening statistics. Specifically, we use the posterior means of the regression coefficients as screening statistics; by imposing a generalized g-prior on the regression coefficients, we derive the analytical form of their posterior means and compute the screening statistics without Markov chain Monte Carlo implementation. We evaluate the utility of the proposed Bayesian screening method using simulations and real data analysis. When the sample size is small, the simulation results suggest improved performance with comparable computational cost.


Transformation of organic matter in a Barents Sea sediment profile: coupled geochemical and microbiological processes.
Process-based, mechanistic investigations of organic matter transformation and diagenesis directly beneath the sediment-water interface (SWI) in Arctic continental shelves are vital as these regions are at greatest risk of future change. This is in part due to disruptions in benthic-pelagic coupling associated with ocean current change and sea ice retreat. Here, we focus on a high-resolution, multi-disciplinary set of measurements that illustrate how microbial processes involved in the degradation of organic matter are directly coupled with inorganic and organic geochemical sediment properties (measured and modelled) as well as the extent/depth of bioturbation. We find direct links between aerobic processes, reactive organic carbon and highest abundances of bacteria and archaea in the uppermost layer (0-4.5 cm depth) followed by dominance of microbes involved in nitrate/nitrite and iron/manganese reduction across the oxic-anoxic redox boundary (approx. 4.5-10.5 cm depth). Sulfate reducers dominate in the deeper (approx. 10.5-33 cm) anoxic sediments which is consistent with the modelled reactive transport framework. Importantly, organic matter reactivity as tracked by organic geochemical parameters (n-alkanes, n-alkanoic acids, n-alkanols and sterols) changes most dramatically at and directly below the SWI together with sedimentology and biological activity but remained relatively unchanged across deeper changes in sedimentology. This article is part of the theme issue 'The changing Arctic Ocean: consequences for biological communities, biogeochemical processes and ecosystem functioning'.


Conversion preparation.
In reply to Paul Mangan's letter (Nursing Standard, week ending June 24) in which he asks for reasons why EN's with experience cannot be simply verted to first level status, I feel, as an EN presently on a 'conversion course', that I should put forward my views on the subject.


Preparation of nurses who precept baccalaureate nursing students: a descriptive study.
Clinical preceptorship is employed by baccalaureate nursing education programs as a capstone experience and a means of initiating the professional socialization of senior-level students who will shortly be new graduates. This quantitative, descriptive study explored the perceptions about preceptor preparation among nurses who precept baccalaureate nursing students. Mercer's Role Attainment Theory was the theoretical framework for this study, in which 75 participants from two hospitals in the Midwest completed a survey. Two key findings emerged from the data: All preceptors of senior-level nursing students want to know what their responsibilities are with regard to the student and the preceptorship experience, and nurses in critical care areas identified learning how to teach critical thinking to senior-level students as more essential than did nurses in other areas.


Adenoidectomy and otitis media.
Adenoid enlargement has traditionally been considered a factor in otitis media; adenoid size, however, does not appear to be correlated with otitis media occurrence. Presence of pathogenic bacteria in the adenoids of children with otitis media has been shown, and adenoidectomy appears to affect the middle ear primarily by removal of the source of infection in the nasopharynx. Three recent randomized, controlled studies showed the efficacy of adenoidectomy in the treatment of chronic secretory otitis media. In one study comparing no treatment, adenoidectomy, and adenotonsillectomy, a significant benefit was seen with adenoidectomy that was not enhanced by tonsillectomy. Another study that compared adenoidectomy, tympanostomy tubes, and a combination of the two showed a significant reduction in effusion time and less surgical retreatment over 2 years in the two adenoidectomy groups. The third study demonstrated the effect of adenoidectomy in children with recurrent chronic otitis media with effusion after failure of tympanostomy tube insertion. All three studies showed that the effect of adenoidectomy was independent of adenoid size. This review discusses current concepts of adenoid physiology and pathology, the major adenoidectomy studies, and indications for the procedure.


Pertussis toxin-sensitive factor differentially regulates lipopolysaccharide-induced tumor necrosis factor-alpha and nitric oxide production in mouse peritoneal macrophages.
It has been established that LPS, the major constituent of the outer membrane of gram negative bacteria, stimulates macrophages to produce numerous inflammatory mediators, including TNF-alpha and nitric oxide (NO). Both TNF-alpha and NO are important in the macrophage-mediated cytotoxicity against invading microorganisms and tumor cells. Although many LPS-dependent immune responses have been well characterized phenomenologically, the precise signal transduction pathways in LPS-induced macrophage activation are not clear. We reported that 1) pretreatment of C3HeB/FeJ mouse peritoneal macrophages with pertussis toxin (PT) markedly enhanced LPS-induced TNF-alpha production but inhibited LPS-dependent NO production under the same conditions; 2) kinetics of the PT effects on these LPS-responses were correlated with PT-mediated ADP-ribosylation of a 41-kDa protein(s); and 3) PT pretreatment did not correct the refractory states of C3H/HeJ macrophages to wild type smooth-LPS. These results suggest that LPS stimulates TNF-alpha and NO production in mouse peritoneal macrophages through different biochemical pathways, and that the signal transduction for both pathways is regulated by a PT-sensitive factor. It is possible that this factor is a guanine nucleotide-binding regulatory protein(s). Finally our data indicate that it is unlikely that the defect of the C3H/HeJ macrophages in response to LPS is at the level of this PT-sensitive factor.


Percentile growth charts for head circumference in Punjabi infants.
Percentile growth charts for head circumference of Punjabi infants (male 86 and female 68) measured serially at monthly intervals during the first year of life are presented. Besides, constancy of sample size and strict adherence to time tolerance limit of +/- 3 days, on the day of monthly measurements other factors considered responsible for the natural smooth course of the percentile grids are highlighted. The presented data would enable easy detection of infants with abnormal course of head growth.


Lymphoid and myeloid lineage commitment in multipotent hematopoietic progenitors.
Hematopoietic stem cells (HSCs) continuously replenish all classes of blood cells through a series of lineage restriction steps that results in the progressive loss of differentiation potential to other cell lineages. This review focuses on the recent advances in understanding one of the earliest differentiation steps in HSC maturation, which involves the diversification of the lymphoid and myeloid cell lineages, the two major branches of hematopoietic cells. We discuss progress in the identification and characterization of progenitor populations downstream of HSCs, which has been a key to understanding the sequential biological events that take place along the course of differentiation into a certain hematopoietic cell type. We also discuss the importance of bone marrow microenvironment in lymphoid and myeloid lineage choice.


The role of the sports physical therapist-marathon events.
The role of the Sports physical therapist (PT) as a part of the sports medical team at marathon-type events varies widely. The PT can assume the role of an emergency medical responder (EMR) whose primary role is the management of the athlete in emergency type situations. The role of the EMR extends beyond the care of the athlete to the care and safety of the spectators. In this role, the PT must be prepared to handle any type of emergency situation, which may occur from medical conditions to acute orthopedic/sports injuries, to medical conditions which may be found in the participants of the race or the spectators. Additional roles of the PT can be in pre-race education, pre-participation screening/physicals, and other concerns by the participant related to injury prevention. Regardless of the role assumed by the PT, prior planning is essential for the safety, security, and maximal performance of the participant and to make the race enjoyable and safe for everyone. 5.


Neurological symptoms associated with acute multifocal placoid pigment epitheliopathy: treatment dilemma and diagnostic issues.
Acute multifocal placoid pigment epitheliopathy (AMPPE) is thought to be caused by vasculitis of the choroid. Central nervous system involvement is rare. We report a case of a 28-year-old male who developed blurred vision (6/12 OD, 6/24 OS). Past medical history involved non-specific viral meningitis treated with intravenous antibiotics and antivirals. Subsequently, the patient complained of recurrent headaches. Based on typical clinical findings and fluorescein angiogram, he was diagnosed with AMPPE. Visual disturbance resolved without any systemic treatment. Six months later, visual symptoms recurred and resolved spontaneously, but his headache continued. A few months later, the patient developed acute progressive neurological signs and symptoms necessitating inpatient admission. Lacunar infarcts in the CNS were found, which had not been noted in previous neuro-imaging studies. Cerebral vasculitis associated with AMPPE was diagnosed and treated with systemic steroids and immune suppression. Currently, the patient remains asymptomatic under joined care of an ophthalmologist and a neurologist.


Update on biologics in juvenile idiopathic arthritis.
The purpose of this review is to summarize the recent data on biologic therapies in juvenile rheumatoid arthritis. The armamentarium for treatment of juvenile idiopathic arthritis is expanding at a rapid rate, and improved physical and functional outcomes are anticipated. New data from large prospective randomized trials have demonstrated efficacy of anti-tumor necrosis factor agents and a costimulator signal inhibitor. The results of a pivotal trial of infliximab in polyarticular juvenile idiopathic arthritis suggested efficacy, but the primary outcome was not significantly different from placebo. Important information regarding dosing in children was obtained, however. A pivotal trial of adalimumab did prove efficacy, and resulted in U.S. Food and Drug Administration (FDA) approval. The monoclonal antibodies to tumor necrosis factor appear to be more effective in treating chronic uveitis associated with juvenile idiopathic arthritis than etanercept. Anti-IL-1 and anti-IL-6 therapy, particularly for systemic disease patients, looks very promising, as well. The costimulation modifier abatacept was shown to be effective and relatively well tolerated in the short term, also resulting in FDA approval this year. Continued experience with these agents and appropriate systems-based methods such as formal registries, to complement existing FDA procedures for monitoring safety, will improve our ability to identify short-term and long-term toxicities of these new agents. As experience is gained, and longer-term safety is demonstrated, it is likely that biologics will be introduced as therapy earlier in the course of patients who inadequately respond to conventional disease-modifying antirheumatic drugs.


Crystal Structure of the Core Module of the Yeast Paf1 Complex.
The highly conserved multifunctional polymerase-associated factor 1 (Paf1) complex (PAF1C), which consists of five core subunits: Ctr9, Paf1, Leo1, Cdc73, and Rtf1, acts as a diverse hub that regulates all stages of RNA polymerase II-mediated transcription and various other cellular functions. However, the underlying mechanisms remain unclear. Here, we report the crystal structure of the core module derived from a quaternary Ctr9/Paf1/Cdc73/Rtf1 complex of S. cerevisiae PAF1C, which reveals interfaces between the tetratricopeptide repeat module in Ctr9 and Cdc73 or Rtf1, and find that the Ctr9/Paf1 subcomplex is the key scaffold for PAF1C assembly. Our study demonstrates that Cdc73 binds Ctr9/Paf1 subcomplex with a very similar conformation within thermophilic fungi or human PAF1C, and that the binding of Cdc73 to PAF1C is important for yeast growth. Importantly, our structure reveals for the first time that the extreme C-terminus of Rtf1 adopts an "L"-shaped structure, which interacts with Ctr9 specifically. In addition, disruption of the binding of either Cdc73 or Rtf1 to PAF1C greatly affects the normal level of histone H2B K123 monoubiquitination in vivo. Collectively, our results provide a structural insight into the architecture of the quaternary Ctr9/Paf1/Cdc73/Rtf1 complex and PAF1C functional regulation.


The status of hyperopic laser-assisted in situ keratomileusis.
The development of excimer laser technology, coupled with advances in lamellar corneal surgery, has heralded a new era in the treatment of refractive errors. This paper discusses the current status of hyperopic laser-assisted in situ keratomileusis. This surgical modality is at a relatively early stage of investigation but appears to offer promise for the surgical correction of hyperopia. This paper considers the evolution of the technique, analyzes the current literature, and discusses the current indications, limitations, and possible future developments.


The role of Pygo2 for Wnt/ß-catenin signaling activity during intestinal tumor initiation and progression.
Pygo2 acts as a co-activator of Wnt signaling in a nuclear complex with ß-catenin/BCL9/BCL9-2 to increase target gene transcription. Previous studies showed that Pygo2 is upregulated in murine intestinal tumors and human colon cancer, but is apparently dispensable for normal intestinal homeostasis. Here, we have evaluated the in vivo role of Pygo2 during intestinal tumorigenesis using Pygo2 deficient mice. We analyzed chemically induced colon tumor development and conditional intestine specific mouse models harboring either Apc loss-of-function (LOF) or Ctnnb1 gain-of-function (ß-catenin GOF). Remarkably, the number and size of chemically induced tumors was significantly reduced in Pygo2 deficient mice, suggesting that Pygo2 has a tumor promoting function. Furthermore, loss of Pygo2 rescued early tumorigenesis of Ctnnb1 GOF mutants. In contrast, Pygo2 ablation was not sufficient to prevent tumor development of Apc LOF mice. The effect on tumor formation by Pygo2 knockout was linked to the repression of specific deregulated Wnt target genes, in particular of c-Myc. Moreover, the role of Pygo2 appears to be associated with the signaling output of deregulated Wnt signaling in the different tumor models. Thus, targeting Pygo2 might provide a novel strategy to suppress tumor formation in a context dependent manner.


European guideline (EuroGuiDerm) on atopic eczema - part II: non-systemic treatments and treatment recommendations for special AE patient populations.
The evidence- and consensus-based guideline on atopic eczema was developed in accordance with the EuroGuiDerm Guideline and Consensus Statement Development Manual. Four consensus conferences were held between December 2020 and July 2021. Twenty-nine experts (including clinicians and patient representatives) from 12 European countries participated. This second part of the guideline includes recommendations and detailed information on basic therapy with emollients and moisturizers, topical anti-inflammatory treatment, antimicrobial and antipruritic treatment and UV phototherapy. Furthermore, this part of the guideline covers techniques for avoiding provocation factors, as well as dietary interventions, immunotherapy, complementary medicine and educational interventions for patients with atopic eczema and deals with occupational and psychodermatological aspects of the disease. It also contains guidance on treatment for paediatric and adolescent patients and pregnant or breastfeeding women, as well as considerations for patients who want to have a child. A chapter on the patient perspective is also provided. The first part of the guideline, published separately, contains recommendations and guidance on systemic treatment with conventional immunosuppressive drugs, biologics and janus kinase (JAK) inhibitors, as well as information on the scope and purpose of the guideline, and a section on guideline methodology.


Cytotoxic and DNA-Damaging Effects of Aronia melanocarpa, Cornus mas, and Chaenomeles superba Leaf Extracts on the Human Colon Adenocarcinoma Cell Line Caco-2.
Aronia melanocarpa, Cornus mas, and Chaenomeles superba leaf extracts contain large amounts of bioactive compounds-mainly polyphenols, which possess many health benefits including anti-cancer properties. Here, we investigate the biological effects of A. melanocarpa, C. mas, and C. superba leaf extracts on the human colon adenocarcinoma cell line Caco-2. The antiproliferative activity of the extracts was measured using the MTT assay. The most cytotoxic extract was C. mas (IC50 = 0.60%). The extracts caused morphological changes in the Caco-2 cells, including partial detachment of cells, necrotic cells, chromatin condensation, cytoplasmic vacuolization, cell nuclei lysis, and nucleus fragmentation. The DNA damage in the Caco-2 cells after exposure to the leaf extracts was measured using the alkaline comet assay. The extracts increased DNA damage in a concentration dependent manner. However, at lower non-cyto- and non-genotoxic (IC0) concentrations the extracts induced DNA repair in Caco-2 cells after exposure to hydrogen peroxide. In conclusion, the results of these studies suggest that A. melanocarpa, C. mas and C. superba leaf extracts can show anticancer activity. However, further research is required on the mechanisms of anti-cancer activity by these extracts, with the application of more advanced and wide-ranging techniques including in vivo experiments.


Superwoman's kryptonite: The superwoman schema and perceived barriers to weight management among U.S. Black women.
The role that the superwoman schema (SWS) plays in U.S. Black women's perceptions of barriers (biological, psychological, and sociological) to healthy weight management is unknown. This exploratory study examined whether 122 women classified as normal weight, overweight or obese differed in their perceptions of types of barriers and if the SWS predicted perceived barriers to weight management. Women classified as obese reported more barriers than those classified as normal weight. The SWS uniquely positively predicted perceived psychological and sociological barriers. Our findings suggest that the SWS may play a vital role in the self-management of weight in U.S. Black women.


A study comparing hyoscine hydrobromide and glycopyrrolate in the treatment of death rattle.
This study looked at the efficacy of drug treatment in managing death rattle in a 30-bedded specialist palliative care unit. The study was conducted in two phases. In the first, patients received hyoscine hydrobromide as the antimuscarinic; glycopyrrolate was used in the second phase. The patients in the two phases were well matched for diagnosis, age, sex and duration of death rattle. A noise score scale of 0-3 was used, which was separately validated using a verbal rating scale and noise-meter readings. Noise scores were taken at the start; 30 min after an antimuscarinic drug was administered; an hour after the initial injection if a repeat dose was given at 30 min; and 4-hourly thereafter. Drug charts of all patients with death rattle were analysed to ascertain the amount of each drug given and the cost. The incidence of death rattle was 44% in phase I, and 36% in phase II. The percentage of patients with reduced noise scores 30 min after one injection of hyoscine was significantly greater than after one dose of glycopyrrolate (56% vs 27%, P = 0.002). The need for a second injection after 30 min was less using hyoscine (33% vs 50%, P = 0.03). There was no statistically significant difference in improvement at 1 h, or at the last recorded score before death. A comparison of the cost of drug treatment using hyoscine or glycopyrrolate was made, and the potential reduction in cost per patient in the glycopyrrolate group was largely offset by increased expenditure on other drugs, especially diamorphine, midazolam and levomepromazine. The results of this study suggest that: (1) glycopyrrolate 0.2 mg is less effective at reducing death rattle than hyoscine hydrobromide 0.4 mg when assessed at 30 min, (2) the use of glycopyrrolate may lead to an increased need for other sedative or anti-emetic medication such as diamorphine, midazolam or levomepromazine, and (3) the cost benefit of using glycopyrrolate over hyoscine hydrobromide is a small part of the total drug budget, and may be less than anticipated due to the increased need of these other drugs.


Functional analysis of the YopE GTPase-activating protein (GAP) activity of Yersinia pseudotuberculosis.
YopE of Yersinia pseudotuberculosis inactivates three members of the small RhoGTPase family (RhoA, Rac1 and Cdc42) in vitro and mutation of a critical arginine abolishes both in vitro GTPase-activating protein (GAP) activity and cytotoxicity towards HeLa cells, and renders the pathogen avirulent in a mouse model. To understand the functional role of YopE, in vivo studies of the GAP activity in infected eukaryotic cells were conducted. Wild-type YopE inactivated Rac1 as early as 5 min after infection whereas RhoA was down regulated about 30 min after infection. No effect of YopE was found on the activation state of Cdc42 in Yersinia-infected cells. Single-amino-acid substitution mutants of YopE revealed two different phenotypes: (i) mutants with significantly lowered in vivo GAP activity towards RhoA and Rac1 displaying full virulence in mice, and (ii) avirulent mutants with wild-type in vivo GAP activity towards RhoA and Rac1. Our results show that Cdc42 is not an in vivo target for YopE and that YopE interacts preferentially with Rac1, and to a lesser extent with RhoA, during in vivo conditions. Surprisingly, we present results suggesting that these interactions are not a prerequisite to establish infection in mice. Finally, we show that avirulent yopE mutants translocate YopE in about sixfold higher amount compared with wild type. This raises the question whether YopE's primary function is to sense the level of translocation rather than being directly involved in downregulation of the host defence.


Systematic Toxicity Evaluations of High-Performance Carbon "Quantum" Dots.
Carbon dots (CDots) in a general structure of small carbon nanoparticles with various surface passivation schemes have emerged to represent a new class of carbon nanomaterials in now a rapidly advancing and expanding research field. Among various synthesis methods, the use of pre-processed and selected small carbon nanoparticles for deliberate chemical functionalization of the particle surface with organic molecules have produced high-performance and structurally better defined CDots. Specifically, small organic molecules 2,2'-(ethylenedioxy)bis(ethylamine) and 3-ethoxypropylamine were used for the effective surface passivation of the carbon nanoparticles via chemical functionalization to yield CDots that are brightly fluorescent and also structurally ultra-compact, amenable to various desired cell imaging applications. Thus, a systematic evaluation of these CDots on their cytotoxicity profiles is necessary, and performed in this study by using a diverse selection of cell lines. Also for fluorescence imaging, CDots were modified with their encapsulating selected organic dyes for much enhanced red/near-IR fluorescence emissions. These modified CDots with the dyes as guest were also evaluated for their cytotoxicity profiles. The results suggest that the CDots without and with the guest dyes are generally nontoxic to the selected cell lines, further supporting the notion that CDots can be used as high-performance yet nontoxic bioimaging agents.


Erythropoietin receptor expression in biopsy specimens from patients with uterine cervix squamous cell carcinoma.
Hypoxia, an important mechanism of radioresistance, is a strong stimulus for erythropoietin (EPO) production. The stimulatory effects of EPO are mediated through the activation of its receptors, EPO receptors (EPORs). The objective of this study is to determine whether EPORs are expressed in biopsy specimens of patients with squamous cell carcinoma of the cervix. Eighteen biopsy specimens were studied after obtaining Institutional Review Board-approved consent. Standard immunohistochemistry techniques were utilized. Expression of EPORs was present in 16 out of 18 (88.9%) specimens. The intensity (qualitative) and the frequency (semiquantitative) of EPORs expression showed a statistically significant correlation (P= 0.00379). Statistical analysis was performed to determine whether EPORs expression is related to other parameters such as age, FIGO stage, histologic grade, and hemoglobin levels. Only age showed a statistically significant correlation with EPORs frequency of expression (P= 0.00878). Currently, work is in progress in our laboratory to study the radiobiologic effects of EPO on the radiation response of cultured cancer cell lines in vitro.