[Ulcerating vulvitis--a rare complication in abdominal typhus].
This article describes the clinical pattern and course of an ulcerating vulvovaginitis occurring within the overall clinical picture of a case of typhus abdominalis as a now rare complication of that severe infectious disease.


Phospholipase D involvement in the plant oxidative burst.
Pathogen-triggered generation of reactive oxidants, termed the oxidative burst, contributes to disease resistance in both plant and animal kingdoms. Since phospholipase D plays a key role in the neutrophil oxidative burst signaling cascade and is highly abundant in plants, we investigated its participation in the plant oxidative burst. Thin layer chromatography of extracted phospholipids revealed no changes in phosphatidic acid levels in soybean cells undergoing oxidant production, and no changes in phosphatidyl-ethanol biosynthesis could be detected when ethanol was present during elicitation. An inhibitor of phosphatidic acid hydrolase, propranolol, did not modify burst parameters or phosphatidic acid levels during the burst, suggesting our inability to detect phosphatidic acid accumulation was not due to rapid elimination. Furthermore, exogenous phosphatidic acid did not elicit a burst or enhance elicitor-stimulated bursts. Finally, ethanol, a substitute nucleophile, did not abrogate the burst. With data showing the presence of phospholipase D in soybean cells, these data argue that soybean phospholipase D does not participate in signaling the oxidative burst. This constitutes the first major difference between the plant and animal oxidative burst signal transduction pathways.


Treatment of closed tibial fractures.
Closed tibial shaft fractures are common injuries that remain challenging to treat because of the wide spectrum of fracture patterns and soft-tissue injuries. Understanding the indications for surgical and nonsurgical treatment of these fractures is essential for good outcomes. Although cast treatment of stable tibial shaft fractures has traditionally been successful and continues to be widely used, recent clinical studies have shown that intramedullary nails may be more advantageous for fracture healing and function than casting. Surgical treatment (intramedullary nailing, plate fixation, or external fixation) of closed tibial shaft fractures varies depending on multiple factors. Metaphyseal fractures are well suited for plates, although newer intramedullary nail designs provide the option of intramedullary nailing of proximal or distal metaphyseal tibia-fibula fractures. External fixators are well suited for skeletally immature patients with unstable fracture patterns or for patients with unacceptably small intramedullary canals. Interlocking intramedullary nails are the treatment of choice for most unstable tibia-fibula shaft fractures.


Transient evoked otoacoustic emissions in patients with normal hearing and in patients with hearing loss.
1) To evaluate transient evoked otoacoustic emission (TEOAE) test performance when measurements are made under routine clinical conditions. 2) To evaluate TEOAE test performance as a function of frequency and as a function of the magnitude of hearing loss. 3) To compare test performance using univariate and multivariate approaches to data analyses. 4) To provide a means of interpreting clinical TEOAE measurements. TEOAEs were measured in 452 ears of 246 patients. All measurements were made after acoustic immittance assessments, which were used to demonstrate that middle-ear function was normal at the time of the TEOAE test. TEOAE amplitudes and signal to noise ratios (SNRs), analyzed into octave bands centered at 1, 2, and 4 kHz, were compared with the pure-tone threshold at the same frequencies. Data were analyzed with clinical decision theory, cumulative distributions, discriminant analyses, and logistic regressions. Using univariate analysis techniques, TEOAEs accurately identified auditory status at 2 and 4 kHz but were less accurate at 1 kHz. Test performance was best when audiometric thresholds between 20 and 30 dB HL were used as the criteria for normal hearing. TEOAE SNR resulted in better test performance than did TEOAE amplitude alone; this effect decreased as frequency increased. Multivariate analysis methods resulted in better separation between normal and impaired ears than did univariate approaches, which relied on only TEOAE amplitude or SNR when test frequency band and audiometric frequency were the same. This improvement in test performance was greatest at 1 kHz, decreased as frequency increased, and was negligible at 4 kHz. TEOAEs can be used to identify hearing loss in children under routine clinical conditions. Univariate tests accurately identified auditory status at mid and high frequencies but performed more poorly at lower frequencies. The decrease in performance as frequency decreases may be a result of increased noise at lower frequencies but also may be due to properties of the measurement paradigm ("QuickScreen," high-pass filter at 0.8 kHz), which would not be ideal for recording energy around 1 kHz. The improvement in test performance when SNR was used and the interaction of this effect with frequency, however, would be consistent with the view that test performance in lower frequencies is at least partially influenced by the level of background noise. Multivariate analysis techniques improved test performance compared with the more traditional univariate approaches to data analysis. An approach is provided that allows one to assign measured TEOAE amplitudes, SNRs, or outputs from multivariate analyses to one of three categories: response properties consistent with normal hearing; results consistent with hearing loss; hearing status undetermined.


Using Gap Charts to Visualize the Temporal Evolution of Ranks and Scores.
To address the limitations of traditional line chart approaches, in particular rank charts (RCs) and score charts (SCs), a novel class of line charts called gap charts (GCs) show entries that are ranked over time according to a performance metric. The main advantages of GCs are that entries never overlap (only changes in rank generate limited overlap between time steps) and gaps between entries show the magnitude of their score difference. The authors evaluate the effectiveness of GCs for performing different types of tasks and find that they outperform standard time-dependent ranking visualizations for tasks that involve identifying and understanding evolutions in both ranks and scores. They also show that GCs are a generic and scalable class of line charts by applying them to a variety of different datasets.


Artificial intelligence and the work-health interface: A research agenda for a technologically transforming world of work.
The labor market is undergoing a rapid artificial intelligence (AI) revolution. There is currently limited empirical scholarship that focuses on how AI adoption affects employment opportunities and work environments in ways that shape worker health, safety, well-being and equity. In this article, we present an agenda to guide research examining the implications of AI on the intersection between work and health. To build the agenda, a full day meeting was organized and attended by 50 participants including researchers from diverse disciplines and applied stakeholders. Facilitated meeting discussions aimed to set research priorities related to workplace AI applications and its impact on the health of workers, including critical research questions, methodological approaches, data needs, and resource requirements. Discussions also aimed to identify groups of workers and working contexts that may benefit from AI adoption as well as those that may be disadvantaged by AI. Discussions were synthesized into four research agenda areas: (1) examining the impact of stronger AI on human workers; (2) advancing responsible and healthy AI; (3) informing AI policy for worker health, safety, well-being, and equitable employment; and (4) understanding and addressing worker and employer knowledge needs regarding AI applications. The agenda provides a roadmap for researchers to build a critical evidence base on the impact of AI on workers and workplaces, and will ensure that worker health, safety, well-being, and equity are at the forefront of workplace AI system design and adoption.


Correlation of macrophage inflammatory protein-2 expression and brain edema in rats after intracerebral hemorrhage.
Brain edema is one of the most frequent and serious complications of intracerebral hemorrhage (ICH), but its underlying mechanism remains largely unknown. In order to understand whether inflammatory mediators released from the blood after cerebral hemorrhage plays a role in brain edema, we investigated the dynamic change of the inflammatory mediator macrophage inflammatory protein-2 (MIP-2) in rat brain after ICH. Our results indicate that the expression of MIP-2 increases 2 hours and peaks 2 days after ICH. The expression of MIP-2 correlates with NF-kappaB activation and brain water content. These results suggest that MIP-2 expression may play an important role in the development of brain edema after ICH in rats.


Leukaemias in Africa.
Until recently, cALL has been uncommon in sub-Saharan Africa, but there is now emerging a peak of incidence at the age 3 to 5 years in west and southern Africa. Prognosis for African patients with cALL is poor because of a multitude of clinical, biological and social factors. AML is seen at high frequency (probably indicating truly high incidence) in male children 5-14 years, of whom up to a quarter present with chloroma. It is predicted that the incidence of AML in adults may rise in the near future, related to cigarette smoking, occupational and environmental exposures to benzene and other pollutants, and the prescription of alkylating agents to young people with malignant disease. CML shows no particular epidemiological features, except for a high frequency in young adults and children, reflecting the age structure of the whole population. There are two forms of B-CLL: one is seen most commonly in women of low socioeconomic status towards the end of the their reproductive life, and is probably related to an initially polyclonal expansion of B-cells in response of recurrent malaria and other infections; the other is seen over the age of 45 years, with men being affected twice as commonly as women, as in the western world.


H1N1: viral pneumonia as a cause of acute respiratory distress syndrome.
To review the literature on novel swine origin influenza A (H1N1 2009) as a cause of respiratory failure and acute respiratory distress syndrome (ARDS). H1N1 2009 was first recognized as a pathogen in March of 2009, when there was a spike in the number of cases of influenza-like illness leading to severe and at times fatal pneumonia. The etiologic agent was then identified as a novel H1N1 influenza A virus, which subsequent spread rapidly throughout the globe. Most countries reported cases of severe viral pneumonitis requiring intensive care unit (ICU) admission. Severe disease was noted to occur more commonly in younger patients than those typically affected by seasonal influenza and obesity and pregnancy were associated with severe disease. The majority of patients requiring ICU admission met criteria for ARDS and case fatality ratio was estimated at less than 0.5%. Chest radiographs and pathology resembled ARDS and most patients were treated with low tidal volume ventilation, high positive end expiratory pressure and at times, rescue therapies. Available evidence suggests that early antiviral treatment improves outcomes from H1N1 2009. H1N1 2009 has emerged as an important cause of ARDS in 2009-2010. Prompt recognition and treatment with antivirals improves outcomes.


Researchers' Individual Publication Rate Has Not Increased in a Century.
Debates over the pros and cons of a "publish or perish" philosophy have inflamed academia for at least half a century. Growing concerns, in particular, are expressed for policies that reward "quantity" at the expense of "quality," because these might prompt scientists to unduly multiply their publications by fractioning ("salami slicing"), duplicating, rushing, simplifying, or even fabricating their results. To assess the reasonableness of these concerns, we analyzed publication patterns of over 40,000 researchers that, between the years 1900 and 2013, have published two or more papers within 15 years, in any of the disciplines covered by the Web of Science. The total number of papers published by researchers during their early career period (first fifteen years) has increased in recent decades, but so has their average number of co-authors. If we take the latter factor into account, by measuring productivity fractionally or by only counting papers published as first author, we observe no increase in productivity throughout the century. Even after the 1980s, adjusted productivity has not increased for most disciplines and countries. These results are robust to methodological choices and are actually conservative with respect to the hypothesis that publication rates are growing. Therefore, the widespread belief that pressures to publish are causing the scientific literature to be flooded with salami-sliced, trivial, incomplete, duplicated, plagiarized and false results is likely to be incorrect or at least exaggerated.


Approach-based techniques of CT-guided percutaneous vertebral biopsy.
Magnetic resonance imaging (MRI) plays an important role in the characterization of vertebral lesions. Even if latest improvements in MRI permit to understand and suspect the nature of vertebral lesions and positron emission tomography computed tomography (PET-CT) gives information about lesion metabolism, biopsy is still needed in most cases. CT-guided percutaneous vertebral biopsy is a minimally invasive, safe and accurate procedure for definitive tissue diagnosis of a vertebral lesion. CT-guided vertebral biopsy is often the best alternative to a surgical biopsy. The purpose of this technical note is to discuss the approach-based techniques for CT-guided percutaneous vertebral biopsy.


Cancer epigenomics: DNA methylomes and histone-modification maps.
An altered pattern of epigenetic modifications is central to many common human diseases, including cancer. Many studies have explored the mosaic patterns of DNA methylation and histone modification in cancer cells on a gene-by-gene basis; among their results has been the seminal finding of transcriptional silencing of tumour-suppressor genes by CpG-island-promoter hypermethylation. However, recent technological advances are now allowing cancer epigenetics to be studied genome-wide - an approach that has already begun to provide both biological insight and new avenues for translational research. It is time to 'upgrade' cancer epigenetics research and put together an ambitious plan to tackle the many unanswered questions in this field using epigenomics approaches.


Restoration of tumor suppression in prostate cancer by targeting the E3 ligase E6AP.
Restoration of tumor suppression is an attractive onco-therapeutic approach. It is particularly relevant when a tumor suppressor is excessively degraded by an overactive oncogenic E3 ligase. We previously discovered that the E6-associated protein (E6AP; as classified in the human papilloma virus context) is an E3 ligase that has an important role in the cellular stress response, and it directly targets the tumor-suppressor promyelocytic leukemia protein (PML) for proteasomal degradation. In this study, we have examined the role of the E6AP-PML axis in prostate cancer (PC). We show that knockdown (KD) of E6AP expression attenuates growth of PC cell lines in vitro. We validated this finding in vivo using cell line xenografts, patient-derived xenografts and mouse genetics. We found that KD of E6AP attenuates cancer cell growth by promoting cellular senescence in vivo, which correlates with restoration of tumor suppression by PML. In addition, we show that KD of E6AP sensitizes cells to radiation-induced death. Overall, our findings demonstrate a role for E6AP in the promotion of PC and support E6AP targeting as a novel approach for PC treatment, either alone or in combination with radiation.


Challenges of conducting a randomised placebo-controlled trial of spinal surgery: the SUcceSS trial of lumbar spine decompression.
Although placebo-controlled trials are considered the gold standard for evaluating the efficacy of healthcare interventions, they can be perceived to be controversial and challenging to conduct for surgical treatments. The SUcceSS trial is the first placebo-controlled trial of lumbar decompression surgery for symptomatic lumbar canal stenosis. The SUcceSS trial has experienced common issues affecting the implementation of randomised placebo-controlled surgery trials, accentuated by the COVID-19 pandemic. Using the SUcceSS trial as an example, we discuss key challenges and mitigation strategies specific to the conduct of a randomised placebo-controlled surgical trial. Overall, the key lessons learned were (i) involving key stakeholders early and throughout the trial design phase may increase clinician and patient willingness to participate in a placebo-controlled trial of surgical interventions, (ii) additional resources (e.g. budget, staff time) are likely required to successfully operationalise trials of this nature, (iii) the level of placebo fidelity, timing of randomisation relative to intervention delivery, and nuances of the surgical procedure under investigation should be considered carefully. Findings are based on one example of a placebo-controlled surgical trial; however, researchers may benefit from employing or building from the strategies described and lessons learned when designing or implementing future trials of this nature.


Prevalence, clinical presentations, associated risk factors and recurrence of laryngeal papillomatosis among inpatients attended at a Tertiary Hospital in Northern zone Tanzania.
Although Laryngeal papillomatosis is a rare disease and can be conventionally managed through surgical excision as well as adjuvant therapy yet Laryngeal papillomatosis has high tendency to recur raising its prevalence in the community, airway involvement warrants dangerous complications requiring emergency tracheostomy, especially if clinical course is poorly understood and misdiagnosis is common. The study aims to determine the prevalence, clinical features, risk factors and recurrence of Laryngeal Papillomatosis among patients attending ENT department at KCMC from 2005 to 2015. This was a 10 year experience/ Descriptive hospital based cross-sectional study conducted based on patients' medical record at KCMC. Information was recorded into data collection sheets, entered and analyzed through SPSS version 20, summarized and presented in tables and charts, proportions and percentage used to compare groups. 51 patients were identified over the 10 years study period corresponding to a prevalence of 0.09%. 26 were males and 25 females, ages ranging from 1 to 67 years. The median age of onset was 6 years. Children less than 5 years accounted for 19 (37.3%) and 58.8% had repeated surgeries. Clinical presentation ranged from hoarseness in 43 (84.3%) patients to weight loss 3 (5.9%) and 96.1% showed complete or partial presence of the clinical triad of risk factors. Laryngeal papillomatosis is a rare disease that carries severe morbidity due to its highly recurring nature. It is primarily a paediatric disease, generally affecting more males; its clinical features highly resemble other airway obstructive diseases and therefore a careful thorough clinical evaluation is required in order to correctly diagnose Laryngeal papillomatosis.


Segmental Membranous Glomerulopathy in Adults.
The clinicopathological features of segmental membranous glomerulopathy (SMGN) have not been well characterized. The aim of this study was to investigate the prevalence and clinicopathological features of SMGN in adults. Adult patients with biopsy-confirmed SMGN in the native kidney at our center between January 2017 to September 2020 were identified. The clinicopathological features of SMGN were collected. The glomerular deposition of IgG subclasses, M-type phospholipase A2 receptor 1 (PLA2R), thrombospondin type 1 domain-containing 7A (THSD7A), and neural epidermal growth factor-like 1 protein (NELL1) were tested. Clinical and pathologic features were comparable between NELL1-positive and NELL1-negative SMGN. A total of 167 patients with biopsy-proven SMGN were enrolled. During the same period, 32,640 (33.0%) out of 98,939 renal biopsies were diagnosed with membranous nephropathy (MN) in adults. SMGN accounted for 0.17% of total kidney biopsies and 0.51% of MN in adults. One hundred and fifty (89.8%) cases were isolated SMGN, and 17 (10.2%) cases were complicated with other kidney disease. Clinically, the median age of isolated SMGN patients was 41.5 years, with female (74%) predominance, and 33.1% had full nephrotic syndrome. Pathologically, IgG1 was the dominant subclass (92.5%), followed by IgG4 (45.0%). PLA2R and THSD7A staining were done in 142 and 136 isolated SMGN cases, respectively, in which, all the cases showed negative. NELL1 staining was done in 135 isolated SMGN cases; 58 cases (43.0%) showed positive. Fifty-eight patients (41.1%) had diffuse (≥90%) foot process effacement, and 119 patients (83.8%) had either stage I (38.0%) or stage II (45.8%) membranous alterations in patients with SMGN. Most patients with NELL1-positive SMGN were female. Patients with NELL1-positive SMGN were more likely with lower prevalence of full nephrotic syndrome than NELL1-negative SMGN. SMGN is a relatively rare pathological type. Majority of patients with isolated SMGN were female, with a median age of 41.5 years, 33.1% had full nephrotic syndrome, absence of PLA2R and THSD7A, 43.0% with NELL1-positive, and mainly stage I or II MN (83.8%). NELL1 is the major target antigen of SMGN in adults.


[Functional activity of gonadal glandular cells in patients with testicular dysgenesis].
Results of histochemical study of testicular tissue in 31 patients, aged 2.5 to 31 years, suffering from dysgenesia syndrome of the testis are presented. Enzymes and lipids furnishing synthesis of steroid hormones (3-beta-oxysteroid dehydrogenase, alcohol dehydrogenase, glucose-6-phosphate dehydrogenase. NAD- and NADP-diaphorase, cholesterol and its esters) were revealed in Leydig's cells of pubertal-juvenile and adult patients, in Leydig's cells precursors in children, and also in Sertoli's cells of all these patients. All these cellular elements possessed high activity of the enzymes under study. It is suggested that Sertoli cells and Leydig's cells precursors, along with mature Leydig's cells, provide a sufficiently high functional activity of the gonads in patients with dysgenesia of the testis.


Regulation of the T-box transcription factor Tbx3 by the tumour suppressor microRNA-206 in breast cancer.
The Tbx3 transcription factor is over-expressed in breast cancer, where it has been implicated in proliferation, migration and regulation of the cancer stem cell population. The mechanisms that regulate Tbx3 expression in cancer have not been fully explored. In this study, we demonstrate that Tbx3 is repressed by the tumour suppressor miR-206 in breast cancer cells. Bioinformatics prediction programmes and luciferase reporter assays were used to demonstrate that miR-206 negatively regulates Tbx3. We examined the impact of miR-206 on Tbx3 expression in breast cancer cells using miR-206 mimic and inhibitor. Gene/protein expression was examined by quantitative reverse-transcription-PCR and immunoblotting. The effects of miR-206 and Tbx3 on apoptosis, proliferation, invasion and cancer stem cell population was investigated by cell-death detection, colony formation, 3D-Matrigel and tumorsphere assays. In this study, we examined the regulation of Tbx3 by miR-206. We demonstrate that Tbx3 is directly repressed by miR-206, and that this repression of Tbx3 is necessary for miR-206 to inhibit breast tumour cell proliferation and invasion, and decrease the cancer stem cell population. Moreover, Tbx3 and miR-206 expression are inversely correlated in human breast cancer. Kaplan-Meier analysis indicates that patients exhibiting a combination of high Tbx3 and low miR-206 expression have a lower probability of survival when compared with patients with low Tbx3 and high miR-206 expression. These studies uncover a novel mechanism of Tbx3 regulation and identify a new target of the tumour suppressor miR-206. The present study identified Tbx3 as a novel target of tumour suppressor miR-206 and characterised the miR-206/Tbx3 signalling pathway, which is involved in proliferation, invasion and maintenance of the cancer stem cell population in breast cancer cells. Our results suggest that restoration of miR-206 in Tbx3-positive breast cancer could be exploited for therapeutic benefit.


Efficacy of Beta1 Integrin and EGFR Targeting in Sphere-Forming Human Head and Neck Cancer Cells.
Resistance to radiotherapy continues to be a limiting factor in the treatment of cancer including head and neck squamous cell carcinoma (HNSCC). Simultaneous targeting of β1 integrin and EGFR was shown to have a higher radiosensitizing potential than mono-targeting in the majority of tested HNSCC cancer models. As tumor-initiating cells (TIC) are thought to play a key role for therapy resistance and recurrence and can be enriched in sphere forming conditions, this study investigated the efficacy of β1 integrin/EGFR targeting without and in combination with X-ray irradiation on the behavior of sphere-forming cells (SFC). HNSCC cell lines (UTSCC15, UTSCC5, Cal33, SAS) were injected subcutaneously into nude mice for tumor up-take and plated for primary and secondary sphere formation under non-adhesive conditions which is thought to reflect the enrichment of SFC and their self-renewal capacity, respectively. Treatment was accomplished by inhibitory antibodies for β1 integrin (AIIB2) and EGFR (Cetuximab) as well as X-ray irradiation (2 - 6 Gy single doses). Further, flow cytometry for TIC marker expression and cell cycling as well as Western blotting for DNA repair protein expression and phosphorylation were employed. We found higher primary and secondary sphere forming capacity of SAS cells relative to other HNSCC cell lines, which was in line with the tumor up-take rates of SAS versus UTSCC15 cells. AIIB2 and Cetuximab administration had minor cytotoxic and no radiosensitizing effects on SFC. Intriguingly, secondary SAS spheres, representing the fraction of surviving SFC upon passaging, showed greatly enhanced radiosensitivity compared to primary spheres. Intriguingly, neither AIIB2 nor Cetuximab significantly altered basal sphere forming capacity and radiosensitivity. While an increased accumulation of G0/G1 phase cells was observable in secondary SAS spheres, DNA double strand break repair indicated no difference on the basis of significantly enhanced ATM and Chk2 dephosphorylation upon irradiation. In the HNSCC model, sphere-forming conditions select for cells, which are unsusceptible to both anti-β1 integrin and anti-EGFR inhibitory antibodies. With regard to primary and secondary sphere formation, our data suggest that both of these SFC fractions express distinct survival strategies independent from β1 integrin and EGFR and that future work is warranted to better understand SFC survival and enrichment before and after treatment to untangle the underlying mechanisms for identifying novel, druggable cancer targets in SFC.


Levels of cell-free DNA and plasma KRAS during treatment of advanced NSCLC.
Non-small cell lung cancer (NSCLC) is one of the most common malignant tumours in the western world and is associated with a poor prognosis. Biomarkers predicting prognosis and therapeutic effects are highly required, and cell-free DNA (cfDNA) may be a feasible option. Genetic mutations can be analysed in plasma and may increase the scientific use of such measurements. In the present study, we investigated: i) the dynamics of cfDNA and plasma mutated KRAS (pmKRAS) during the treatment of patients with advanced NSCLC; and ii) the prognostic value of baseline cfDNA and pmKRAS. Sixty‑nine patients were included in a prospective biomarker trial. Inclusion criteria included advanced NSCLC, candidate for first-line treatment, no previous cancer within the five years prior to this study. Blood samples were drawn at baseline, day 8 and at progression. Analyses of cfDNA and KRAS mutations in plasma were performed using an in-house qPCR assay. Evaluation of the treatment effect and status at follow-up was performed according to RECIST 1.1. The median levels of cfDNA were significantly higher at progression (9,250 alleles/ml) than at baseline (5,450 alleles/ml). Overall survival and progression-free survival were both significantly shorter in patients with high levels of cfDNA (above the 75th percentile) compared to lower levels. Only few patients harboured KRAS mutations in plasma. Two patients had no KRAS mutations in plasma at baseline, but mutations appeared in the subsequent blood samples. High baseline levels of cfDNA indicate a poor prognosis. The level changes during the treatment course with a significant increase at progression, suggesting a possible predictive value of cfDNA. The plasma KRAS status may change during treatment with potential implications for treatment selection.


Debriefing bystanders of out-of-hospital cardiac arrest is valuable.
To explore the concept of debriefing bystanders after participating in an out-of-hospital cardiac arrest resuscitation attempt including (1) bystanders' most commonly addressed reactions after participating in a resuscitation attempt when receiving debriefing from medical dispatchers; (2) their perception of effects of receiving debriefing and (3) bystanders' recommendations for a systematic debriefing concept. Qualitative study based on telephone debriefing to bystanders and interviews with bystanders who received debriefing. Data was analyzed using the phenomenological approach. Six themes emerged from analysis of debriefing audio files: (1) identification of OHCA; (2) emotional and perceptual experience with OHCA; (3) collaboration with healthcare professionals; (4) patients outcome; (5) coping with the experience and (6) general reflections. When evaluating the concept, bystanders expressed positive short term effect of receiving debriefing and a retention of this effect after two months. Recommendations for a future debriefing concept were given. Debriefing by emergency medical dispatchers to OHCA bystanders stimulates reflection, positively influencing the ability to cope with the emotional reactions and the cognitive perception of own performance and motivates improvement of CPR skills. Importantly, it increases confidence to provide CPR in the future. Implementation of telephone debriefing to bystanders at Emergency Medical Dispatch Centres is a low complexity and a low cost intervention though the logistic challenges have to be considered.


Modelling the potential prevention benefits of a treat-all hepatitis C treatment strategy at global, regional and country levels: A modelling study.
The World Health Organization (WHO) recently produced guidelines advising a treat-all policy for HCV to encourage widespread treatment scale-up for achieving HCV elimination. We modelled the prevention impact achieved (HCV infections averted [IA]) from initiating this policy compared with treating different subgroups at country, regional and global levels. We assessed what country-level factors affect impact. A dynamic, deterministic HCV transmission model was calibrated to data from global systematic reviews and UN data sets to simulate country-level HCV epidemics with ongoing levels of treatment. For each country, the model projected the prevention impact (in HCV IA per treatment undertaken) of initiating four treatment strategies; either selected randomly (treat-all) or targeted among people who inject drugs (PWID), people aged ≥35, or those with cirrhosis. The IA was assessed over 20 years. Linear regression was used to identify associations between IA per treatment and demographic factors. Eighty-eight countries (85% of the global population) were modelled. Globally, the model estimated 0.35 (95% credibility interval [95%CrI]: 0.16-0.61) IA over 20 years for every randomly allocated treatment, 0.30 (95%CrI: 0.12-0.53) from treating those aged ≥35 and 0.28 (95%CrI: 0.12-0.49) for those with cirrhosis. Globally, treating PWID achieved 1.27 (95%CrI: 0.68-2.04) IA per treatment. The IA per randomly allocated treatment was positively associated with a country's population growth rate and negatively associated with higher HCV prevalence among PWID. In conclusion, appreciable prevention benefits could be achieved from WHO's treat-all strategy, although greater benefits per treatment can be achieved through targeting PWID. Higher impact will be achieved in countries with high population growth.


Can peak expiratory flow measurements reliably identify the presence of airway obstruction and bronchodilator response as assessed by FEV(1) in primary care patients presenting with a persistent cough?
In general practice airway obstruction and the bronchodilator response are usually assessed using peak expiratory flow (PEF) measurements. A study was carried out in patients presenting with persistent cough to investigate to what extent PEF measurements are reliable when compared with tests using forced expiratory volume in one second (FEV(1)) as the measure of response. Data (questionnaire, physical examination, spirometry, PEF) were collected from 240 patients aged 18-75 years, not previously diagnosed with asthma or chronic obstructive pulmonary disease (COPD), who consulted their general practitioner with cough of at least two weeks duration. The relationship between low PEF (PEF < PEFpred - 1.64RSD) and low FEV(1) (FEV(1) < FEV(1)pred - 1.64RSD) was tested. A positive bronchodilator response after inhaling 400 microg salbutamol was defined as an increase in FEV(1) of > or = 9% predicted and was compared with an absolute increase in PEF with cut off values of 40, 60, and 80 l/min and DeltaPEF % baseline with cut off values of 10%, 15%, and 20%. Forty eight patients (20%) had low FEV(1), 86 (35.8%) had low PEF, and 32 (13.3%) had a positive bronchodilator response. Low PEF had a positive predictive value (PPV) for low FEV(1) of 46.5% and a negative predictive value (NPV) of 95%. DeltaPEF of > or = 10%, > or = 15%, or > or = 20% baseline had PPVs of 36%, 52%, and 67%, respectively, and DeltaPEF of > or = 40, > or = 60, and > or = 80 l/min in absolute terms had PPVs of 39%, 45%, and 57%, respectively, for DeltaFEV(1) > or = 9% predicted; NPVs were high (88-93%). Although PEF measurements can reliably exclude airway obstruction and bronchodilator response, they are not suitable for use in the assessment of the bronchodilator response in the diagnostic work up of primary care patients with persistent cough. The clinical value of PEF measurements in the diagnosis of reversible obstructive airway disease should therefore be re-evaluated.


[Liver transplantation from a living donor: necessity or an alternative?].
Liver transplantations using a part of the liver from a living donor are already being performed around the world. The main arguments for performing such transplantations are the shortage of brain-dead donors and the consequently high mortality rate of patients on the waiting list for a liver transplantation. The disadvantages of this option are the mortality and morbidity risk for the living donor. The shortage of brain-dead donors could also be resolved by the implementation of special techniques such as split-liver and domino-liver transplantations or by using compromised and non-heart-beating donors. Furthermore, measures should be taken to reduce the shortage of brain-dead donors in the Netherlands. If such actions do not lead to an increase in the number of brain-dead donors and a willingness to restrict the indications for transplantation is not forthcoming then donation for liver transplantation by living donors is inevitable. Such a program should satisfy certain conditions and have the requisite medical-ethical and public support.


Different roles for CD4+ and CD8+ T lymphocytes and macrophage subsets in the control of a generalized virus infection.
The importance of T-lymphocyte subsets in the control of poxvirus infections is controversial. To determine the relative contribution of lymphocyte subsets important for recovery from infection with ectromelia virus (EV), a natural murine poxvirus pathogen, C57BL/6 (B6) mice lacking functional CD8+ T cells because of disruption of the beta2-microglobulin gene or lacking functional CD4+ T cells because of disruption of the I-(A)beta gene, acutely depleted of CD8+ or CD4+ T cells with monoclonal antibody, or depleted of macrophage subsets by the macrophage suicide technique were used. Recovery from infection was strictly dependent on the effector functions of CD8+ T cells, in the absence of which 100% mortality resulted. This lymphocyte population had demonstrable antiviral activity early in the infection process even before class I major histocompatibility complex (MHC)-restricted CD8+ cytotoxic T-lymphocyte (CTL) activity was detectable. CD4+ T cells were found to be necessary for the generation of an optimal virus-specific, class I MHC-restricted CD8+ CTL response and contributed to virus clearance not involving cytolytic mechanisms. In both models of CD4+ T-cell deficiency, virus clearance was incomplete and persisted at low levels in most organs and at very high levels in the skin, but the animals did not die. The elimination of macrophage subpopulations impeded virus clearance, impaired the generation of class I MHC-restricted antiviral CTL response, and resulted in 100% mortality. These findings establish an absolute requirement for CD8+ and CD4+ T lymphocytes and macrophage subsets in the elimination of a natural murine poxvirus infection and support the idea that macrophages may be essential accessory cells for the generation of class I MHC-restricted antiviral CTL responses.


DHRS3, a retinal reductase, is differentially regulated by retinoic acid and lipopolysaccharide-induced inflammation in THP-1 cells and rat liver.
Both retinoid status and inflammation have been shown to control the level of expression of retinoid homeostatic genes. In the present study, DHRS3, previously shown to possess retinal reductase activity, was identified by microarray analysis of THP-1 monocytes as a possible gene target of all-trans-retinoic acid (RA). In these cells, DHRS3 mRNA increased 30- to 40-fold after treatment with ≤20 nM RA for 24 h, while DHRS3 protein also increased. Of several synthetic retinoids tested, only Am580, a RA receptor-α-selective retinoid, increased DHRS3 mRNA expression. The full-length DHRS3 cDNA was cloned from rat liver and subjected to in vitro transcription-translation. Two major ∼30- and 35-kDa proteins were detected. In adult rat tissues, DHRS3 mRNA was most abundant in the adrenal gland, liver, and ovary. In the liver, DHRS3 is expressed in hepatocytes and possibly in all liver cells. To evaluate whether DHRS3 is regulated in the liver by RA and/or inflammatory stimuli, we treated rats for 6 h with RA or LPS or both. DHRS3 mRNA was doubled by RA but reduced by >90% after treatment with LPS in the absence and presence of RA. On the basis of our results, DHRS3 mRNA expression is regulated by RA in a tissue- or cell-type specific manner; the RA-induced increase in DHRS3 may contribute to retinoid storage; and a reduction of DHRS3 expression in the liver during inflammation may contribute to the perturbation of whole body vitamin A metabolism that has previously been shown to occur in conditions of inflammatory stress.


The association of malocclusion and trumpet performance.
To determine whether trumpet performance skills are associated with malocclusion. Following institutional review board approval, 70 university trumpet students (54 male, 16 female; aged 20-38.9 years) were consented. After completing a survey, the students were evaluated while playing a scripted performance skills test (flexibility, articulation, range, and endurance exercises) on their instrument in a soundproof music practice room. One investigator (trumpet teacher) used a computerized metronome and a decibel meter during evaluation. A three-dimensional (3D) cone-beam computerized tomography scan (CBCT) was taken of each student the same day as the skills test. Following reliability studies, multiple dental parameters were measured on the 3D CBCT. Nonparametric correlations (Spearman), accepting P < .05 as significant, were used to determine if there were significant associations between dental parameters and the performance skills. Intrarater reliability was excellent (intraclass correlations; all r values > .94). Although associations were weak to moderate, significant negative associations (r ≤ -.32) were found between Little's irregularity index, interincisal inclination, maxillary central incisor rotation, and various flexibility and articulation performance skills, whereas significant positive associations (r ≤ .49) were found between arch widths and various skills. Specific malocclusions are associated with trumpet performance of experienced young musicians.


Transcriptomics analysis unveils key potential genes associated with brain development and feeding behavior in the hypothalamus of L-citrulline-fed broiler chickens.
High ambient temperature is a major environmental stressor affecting poultry production, especially in the tropical and subtropical regions of the world. Nutritional interventions have been adopted to combat thermal stress in poultry, including the use of amino acids. L-citrulline is a nonessential amino acid that is involved in nitric oxide generation and thermoregulation, however, the molecular mechanisms behind L-citrulline's regulation of body temperature are still unascertained. This study investigated the global gene expression in the hypothalamus of chickens fed either basal diet or L-citrulline-supplemented diets under different housing temperatures. Ross 308 broilers were fed with basal diet (CON) or 1% L-citrulline diet (LCT) from day-old, and later subjected to 2 environmental temperatures in a 2 by 2 factorial arrangement as follows; basal diet-fed chickens housed at 24°C (CON-TN); L-citrulline diet-fed chickens housed at 24°C (LCT-TN); basal diet-fed chickens housed at 35°C (CON-HS), and L-citrulline diet-fed chickens housed at 35°C (LCT-HS) from 22 to 42 d of age. At 42-days old, hypothalamic tissues were collected for mRNA analyses and RNA sequencing. A total of 1,019 million raw reads were generated and about 82.59 to 82.96% were uniquely mapped to genes. The gene ontology (GO) term between the CON-TN and LCT-TN groups revealed significant enrichments of pathways such as central nervous system development, and Wnt signaling pathway. On the other hand, GO terms between the CON-HS and LCT-HS groups revealed enrichments in the regulation of corticosteroid release, regulation of feeding behavior, and regulation of inflammatory response. Several potential candidate genes were identified to be responsible for central nervous system development (EMX2, WFIKKN2, SLC6A4 Wnt10a, and PHOX2B), and regulation of feed intake (NPY, AgRP, GAL, POMC, and NMU) in chickens. Therefore, this study unveils that L-citrulline can influence transcripts associated with brain development, feeding behavior, energy metabolism, and thermoregulation in chickens raised under different ambient temperatures.


Shape and deposition angle control of silver film-over-nanosphere SERS substrates.
Thin metallic films on dielectric nanospheres are demonstrated to have a high potential for the fabrication of cost-effective SERS substrates. In addition to the morphological advantages that nanospheres offer for attaining a high density of hot spots, possessing shape adjustability by uncomplicated thermal treatment makes them an attractive platform for tuneable SERS substrates. Furthermore, when combined with the oblique angle metal deposition technique, adjustable gaps at a high density and adjustable shape of metal films, such as Ag films, can be achieved on nanospheres. Applying small changes in deposition angle can provide means for fine adjustment of the Raman enhancement factor (EF), resulting in EF up to 108measured using crystal violet dye molecule as a Raman analyte. This practice paves the way for the fabrication of high EF SERS substrates at a reasonable cost using a monolayer of self-organized nanosphere patterns. An ultra-thin Ag film coated at 5° tilt is shown to be an excellent substitute for a film deposited at 0° with double the thickness. There is a strong agreement between the experimental results and finite-elements-method-based Maxwell simulations exhibiting expected field enhancements up to 109at a tilt angle of 5°.


Intraspecific variation in male mating strategies in an African ground squirrel (Xerus inauris).
Male mating strategies respond to female availability such that variation in resources that affect spatial distribution can also alter cost-benefit tradeoffs within a population. In arid-adapted species, rainfall alters reproduction, behavior, morphology, and population density such that populations differing in resource availability may also differ in successful reproductive strategies. Here, we compare two populations of Cape ground squirrels (Xerus inauris), a sub-Saharan species with year-round breeding and intense mating competition. Unlike most mammals where males resort to aggressive interactions over females, male X. inauris are tolerant of one another, relying instead on other nonaggressive pre- and postcopulatory strategies to determine reproductive success. Our findings suggest that differences in resource availability affect female distribution, which ultimately leads to intraspecific variation in male reproductive tactics and sexual morphology. Sperm competition, assessed by reproductive morphometrics, was more pronounced in our high resource site where females were distributed evenly across the landscape, whereas dominance seemed to be an important determinant of success in our low resource site where females were more aggregated. Both sites had similar mating intensities, and most males did not sire any offspring. However, our low resource site had a higher variance in fertilization success with fewer males siring multiple offspring compared with our high resource site where more individuals were successful. Our results lend support to resource models where variations in female spatial distribution attributed to environmental resources ultimately impact male reproductive behaviors and morphology.


ESX/type VII secretion systems of mycobacteria: Insights into evolution, pathogenicity and protection.
Pathogenesis of Mycobacterium tuberculosis depends on the secretion of key virulence factors, such as the 6 kDa early secreted antigenic target ESAT-6 (EsxA) and its protein partner, the 10 kDa culture filtrate protein CFP-10 (EsxB), via the ESX-1 secretion system. ESX-1 represents the prototype system of the recently named type VII secretion systems that exist in a range of actinobacteria. The M. tuberculosis genome harbours a total of five gene clusters potentially coding for type VII secretion systems, designated ESX-1 - ESX-5, with ESX-4 being the most ancient system from which other ESX systems seem to have evolved by gene duplication and gene insertion events. The five ESX systems show similarity in gene content and gene order but differ in function. ESX-1 and ESX-5 are both crucial virulence determinants of M. tuberculosis, but with different mechanisms. While ESX-1 is implicated in the lysis of the host cell phagosomes, ESX-5 is involved in secretion of the mycobacteria specific PE and PPE proteins and cell wall stability. Research on type VII secretion systems has thus become a large and competitive research topic that is tightly linked to studies of host-pathogen interaction of pathogenic mycobacteria. Insights into this matter are of relevance for redrawing the patho-evolution of M. tuberculosis, which might help improving current strategies for prevention, diagnostics and therapy of tuberculosis as well as elucidating the virulence mechanisms employed by this important human pathogen.


Safety, Costs, and Efficacy of Rapid Drug Desensitizations to Chemotherapy and Monoclonal Antibodies.
Rapid drug desensitization (RDD) is used to address hypersensitivity reactions to chemotherapeutics and monoclonal antibodies, allowing patients to be treated with optimal pharmacological agents. RDD protocols are tailored to each individual patient's reaction and needs, and protect against anaphylaxis, but overall risks, costs, and benefits have not been determined. We investigated the safety, efficacy, costs, and life expectancy of patients in a large population undergoing RDD. We analyzed 2177 RDD procedures performed in 370 patients with cancer, vasculitis, and hematological and connective tissue diseases who presented 402 reactions. A subgroup of carboplatin allergic patients with ovarian cancer treated with RDD was analyzed for costs and life expectancy and compared with a nonallergic control group. RDD allowed all patients to receive safely the full dose of the medication to which they were reactive. A gradual increase in the fraction of outpatient desensitizations from 81% to 98% was achieved through risk stratification. Of the 2177 desensitizations, 93% had no or mild reactions whereas 7% had moderate to severe reactions, which did not preclude the completion of the treatment, and there were no deaths. Overall health costs in the carboplatin allergic group were not higher than those in the nonallergic group treated with standard of care. Administration of carboplatin through RDD was as effective as standard administration with a nonsignificant increase in life expectancy in desensitized patients as compared with nonallergic, nondesensitized controls. RDD is cost effective and safe for allergic patients with cancer and chronic disease to remain on first line therapy.


The effects of intracellular and exosomal ncRNAs on cancer progression.
Altered gene expression as well as mislocalization of a gene's encoded product (proteins or noncoding RNAs (ncRNAs)) can lead to disease and cancer formation. Multiple studies have indicated that exosomes and their contents act as cell-to-cell communicators and play a key role in cancer progression. Moreover, exosomes contain several functional molecules, including ncRNAs. NcRNAs function as master regulators to coordinate cell growth, cell motility and drug resistance. However, intracellular ncRNAs, which can be transferred to recipient cells via exosomes (exosomal ncRNAs), mediate common/distinct downstream molecules, signaling pathways and functions that are less emphasized concepts in cancer development research. In this study, by using exosomes as a model, we comprehensively discuss the current knowledge regarding (1) the functional role of ncRNAs, both their intracellular and exosomal forms, in cancer progression, (2) the possible mechanism of ncRNA incorporation into exosomes and (3) the therapeutic applications and limitations of exosomes based on current knowledge.


Impact of 5 years of hepatitis C testing and treatment in the North East of England prisons.
Hepatitis C virus infection (HCV) is prevalent in prisons. Therefore, effective prison HCV services are critical for HCV elimination programmes. We aimed to evaluate the efficacy of a regional HCV prison testing and treatment programme. Between July 2017 and June 2022, data were collected prospectively on HCV test offer and uptake rates, HCV Antibody (HCV-Ab) and HCV-RNA positivity, treatment starts and outcomes for new inmates incarcerated in three prisons. Rates of HCV-Ab and RNA positivity at reception, incidence of new HCV infections and reinfection following treatment were determined. From a total of 39,652 receptions, 33,028 (83.3%) were offered HCV testing and 20,394 (61.7%) completed testing. Including all receptions, 24.5% of tests (n = 4995) were HCV-Ab positive and 8.4% of tests (n = 1713) were HCV-RNA positive. When considering the first test for each individual (median age 34 years; 88.1% male), 14.8% (n = 1869) and 7.2% (n = 905) were HCV-Ab and HCV-RNA positive, respectively. The incidence of new HCV-Ab and RNA positivity was 5.1 and 3.3 per 100 person-years, respectively. Of 1145 HCV viraemic individuals, 18 died within 6 months and 150 were rapidly transferred out of area, leaving 977 individuals with outcomes. Of these, 835 (85.5%) received antivirals and 47 spontaneously cleared the infection, leaving 95 (9.7%) untreated. 607 (72.7%) achieved SVR. 95 patients had reinfection post-treatment (rate 10.1 cases per 100 person-years). Testing for HCV has increased in our prisons and the majority with viraemia are initiated on antiviral treatment. Reassuringly, a significant fall in frequency of HCV-RNA positivity at prison reception was observed suggesting progress towards HCV elimination.


A Genetic Lab-on-Phone Test for Point-of-Care Diagnostic of Lactose Intolerance near Patient and in less than 90 Minutes.
The -13910 C/T single nucleotide polymorphism located within the MCM6 gene, an enhancer region located upstream of the lactase-phlorizin hydrolase gene, is associated with lactase persistence/non-persistence traits among the Caucasian population. The performance of a new point-of-care CE-IVD (In Vitro Diagnostic) marked isothermal lab-on-phone lactose intolerance assay, using crude samples, was assessed in comparison with Sanger sequencing using purified DNA, as reference method. The study was conducted following a non-probability sampling using direct buccal swab (n = 63) and capillary blood (n = 43) clinical samples from a total of 63 volunteers. A 3 × 3 confusion matrix/contingency table was used to evaluate the performance of the isothermal lab-on-phone lactose intolerance assay. The isothermal lab-on-phone lactose intolerance assay successfully detected the -13910 C/T variant with a limit of detection of 5 cells/assay and demonstrated an overall accuracy of 98.41% (95% CI, 91.47%-99.96%) for buccal swab samples and 100% (95% CI, 91.19%-100%) for capillary blood, taking just 90 min from sample to result, with only 2 min hands-on. The lab-on-phone pocket-sized assay displayed good performance when using direct buccal swab and capillary blood samples, enabling a low-cost, real-time, and accurate genotyping of the -13910 C/T region for the rapid diagnosis of primary lactose intolerance at point-of-care, which enables a prompt implementation of appropriate diet habits and/or intolerance therapies. To our knowledge, this is the first point-of-care genetic test for lactose intolerance to be made available on the market.


The solo nurse practitioner: a private practice model.
This article discusses the experience of one NP through 4 years of an independent private practice. Suggestions are offered for those considering the option. Personal, practical, and financial factors should be carefully considered. Business training and a business plan are essential. Expected and unexpected outcomes are shared with the reader.


Optical constants of HNO3/H2O and H2SO4/HNO3/H2O at low temperatures in the infrared region.
The complex index of refraction of liquid HNO3/H2O and H2SO4/HNO3/H2O has been obtained at different temperatures and acid concentrations. FT-IR specular reflectance spectra were obtained for 30, 54, and 64 wt % aqueous HNO3 and for four different H2SO4/HNO3/H2O mixtures in the temperature region from 293 to 183 K. The complex index of refraction was obtained from the reflectance spectra with the Kramers-Kronig transformation. The optical constants of the binary and ternary mixtures vary with the acid concentration and the temperature. The results demonstrate that vibrational bands originating from the sulfate species are more sensitive to changes in temperature than the bands originating from vibrations in the nitrate species; only minor changes in the nitrate vibrational bands are observed as the temperature decreases below 248 K.


Altered cardiac excitation-contraction coupling in mutant mice with familial hypertrophic cardiomyopathy.
Excitation-contraction coupling in cardiac muscle of familial hypertrophic cardiomyopathy (FHC) remains poorly understood, despite the fact that the genetic alterations are well defined. We characterized calcium cycling and contractile activation in trabeculae from a mutant mouse model of FHC (Arg403Gln knockin, alpha-myosin heavy chain). Wild-type mice of the same strain and age ( approximately 20 weeks old) served as controls. During twitch contractions, peak intracellular Ca2+ ([Ca2+]i) was higher in mutant muscles than in the wild-type (P < 0.05), but force development was equivalent in the two groups. Ca2+ transient amplitude increased dramatically in both groups as stimulation rate increased from 0.2 to 4 Hz. Nevertheless, developed force fell at the higher stimulation rates in the mutants but not in controls (P < 0.05). The steady-state force-[Ca2+]i relationship was less steep in mutants (Hill coefficient, 2.94 +/- 0.27 vs. 5.28 +/- 0.64; P > 0.003), with no changes in the [Ca2+]i required for 50% activation or maximal Ca2+-activated force. Thus, calcium cycling and myofilament properties are both altered in FHC mutant mice: more Ca2+ is mobilized to generate force, but this does not suffice to maintain contractility at high stimulation rates.


Next steps in the development of ecological soil clean-up values for metals.
This special series in Integrated Environmental Assessment Management presents the results from 6 workgroups that were formed at the workshop on Ecological Soil Levels-Next Steps in the Development of Metal Clean-Up Values (17-21 September 2012, Sundance, Utah). This introductory article presents an overview of the issues assessors face when conducting risk assessments for metals in soils, key US Environmental Protection Agency (USEPA) documents on metals risk assessment, and discusses the importance of leveraging from recent major terrestrial research projects, primarily to address Registration, Evaluation, Authorization and Restriction of Chemical Substances (REACH) requirements in Europe, that have significantly advanced our understanding of the behavior and toxicity of metals in soils. These projects developed large data sets that are useful for the risk assessment of metals in soil environments. The workshop attendees met to work toward developing a process for establishing ecological soil clean-up values (Eco-SCVs). The goal of the workshop was to progress from ecological soil screening values (Eco-SSLs) to final clean-up values by providing regulators with the methods and processes to incorporate bioavailability, normalize toxicity thresholds, address food-web issues, and incorporate background concentrations. The REACH data sets were used by workshop participants as case studies in the development of the ecological standards for soils. The workshop attendees discussed scientific advancements in bioavailability, soil biota and wildlife case studies, soil processes, and food-chain modeling. In addition, one of the workgroups discussed the processes needed to frame the topics to gain regulatory acceptance as a directive or guidance by Canada, the USEPA, or the United States.


Public health strategies adopted to manage the increase of accesses to vaccination services, as a result of the application of the law 119/2017.
In response to the alarming reduction of vaccination coverage rates, Italian Ministry of Health approved the law number 119/2017, which has extended the number of mandatory vaccinations, for school attendance, from four to ten. The present study aims to evaluate accesses to the vaccination services of the Palermo Local Health Unit (LHU) and the variation of the vaccination coverage rates for hexavalent and measles, mumps, rubella and varicella (MMRV) vaccines, after the implementation of the law 119/2017. An extent of opening hours and an involvement of other health-care professionals in the vaccination services of the Palermo LHU have been adopted to manage the excess of accesses after the introduction of 119/2017 law and to limit the discomfort of general population. Vaccination accesses and coverage rates were calculated from the electronic immunization registers. An overall increase of about 15% of single vaccination accesses was observed in the three semester after the introduction of the law in the LHU of Palermo. A peak of 35,516 accesses was observed during the second semester of 2017 (+ 30% compared to the same semesters of 2016 and 2018). From 2016 to 2018, coverage rates for full hexavalent cycle and first dose of MMRV, at 24 and 36 months, and for full MMRV cycle and fourth dose of diphtheria, tetanus, pertussis, poliomyelitis (DTPa+IPV), among 6 years old children, showed considerable increases. Law 199/2017 demonstrated a high efficacy in increase vaccination coverage rates also in Sicily. The synergy established between the LHU and the University of Palermo allowed an excellent management of the accesses to vaccination services, making it possible to respond to the public health needs of the general population.


Biochar Nanozyme from Silkworm Excrement for Scavenging Vapor-Phase Free Radicals in Cigarette Smoke.
Serious lung diseases and other health problems caused by tobacco consumption are becoming more and more prominent all over the world. Scavenging the excessive harmful free radicals in cigarette smoke is proven to be an effective method in reducing the above problems. Carbon-based nanozymes have been widely studied due to their ability of scavenging free radicals. Accordingly, the biochar derived from silkworm excrement was reported as a nanozyme with free radical scavenging ability. The biochar nanozyme calcination at 900 °C with better free radical scavenging abilities was loaded into commercial cigarette filters for the following free radical scavenging verification in tobacco smoke. Mouse model results reveal the lung tissue could be improved by the addition of biochar nanozyme. This work not only provides an effective approach to reduce the harm caused by tobacco but also provides potential applications to rationally realize low-cost, ease of production, and a wide variety of biochar sources.


The Defining Moment: Children's Conceptualization of Race and Experiences with Racial Discrimination.
This paper examines whether children of marginalized racial/ethnic groups have an awareness of race at earlier ages than youth from non-marginalized groups, documents their experiences with racial discrimination, and utilizes a modified racism-related stress model to explore the relationship between perceived racial discrimination and self-esteem. Data were collected for non-Hispanic black, non-Hispanic white, and Hispanic children aged 7 - 12 using face-to-face interviews (n = 175). The concept of race was measured by assessing whether children could define race, if not a standard definition was provided. Racial discrimination was measured using the Williams Every-day-Discrimination Scale, self-esteem was measured using the Rosenberg Scale, and ethnic identity was assessed using the Multi-group Ethnic Identity Measure. Non-Hispanic black children were able to define race more accurately, but overall, Hispanic children encountered more racial discrimination, with frequent reports of ethnic slurs. Additionally, after accounting for ethnic identity, perceived racial discrimination remained a salient stressor that contributed to low self-esteem.


Association of Clara cell 10-kDa protein, spontaneous regression and sarcoidosis.
Sarcoidosis is a systemic granulomatous disorder with a high rate of spontaneous regression. Clara cell 10-kDa protein (CC10), the predominant product of nonciliated bronchiolar epithelial cells, is a potent immunoregulatory and anti-inflammatory agent. CC10 levels were measured in sera and bronchoalveolar lavage (BAL) fluids from 31 sarcoidosis patients (nine progressive disease and 22 regressive disease) and their relevance to spontaneous regression investigated. The inhibitory effects of recombinant CC10 on interferon gamma (IFN-gamma) production were examined using lipopolysaccharide (LPS)-stimulated sarcoid BAL fluid cells, and the blocking effects of monoclonal antibody TY-5, directed against CC10, on CC10 function were also tested. Serum and BAL fluid CC10 levels in the regressive disease group were significantly higher than those in the progressive disease group (serum, p<0.05; BAL fluid, p<0.005) and healthy subjects (serum, p<0.0001; BAL fluid, p<0.005). CC10 inhibited, in part, IFN-gamma production from LPS-stimulated sarcoid BAL fluid cells (CC10 inhibition: 1,000 ng x mL(-1), 30%; 100 ng x mL(-1), 14%). TY-5 restored IFN-gamma production by blocking CC10 function. Sarcoidosis patients with regressive disease showed increased Clara cell 10-kDa protein levels in their sera and bronchoalveolar lavage fluids. Clara cell 10-kDa protein may be a regulator of the inflammatory process in sarcoidosis.


Intrauterine growth restriction alters term fetal baboon hypothalamic appetitive peptide balance.
Neurons controlling appetite are located in the hypothalamic arcuate nuclei (ARH). Offspring appetite regulation has been shown to be modified by dysregulation of ARH nuclear development. Most ARH developmental studies have been in altricial rodents whose hypothalamic development is predominantly postnatal. In primates including humans, much development of hypothalamic appetite regulatory centers occurs before birth. We hypothesized that i) appetitive peptides are abundantly expressed by 90 percent gestation (0.9G), ready for postnatal function; ii) by 0.9G, intrauterine growth restriction (IUGR) increases the orexigenic:anorexigenic peptide ratio; iii) IUGR increases fetal glucocorticoid receptor (GR) expression; and iv) IUGR decreases STAT3, which signals inhibition of appetite. We developed a fetal baboon IUGR model resulting from reduced maternal nutrition. Pregnant baboons were fed ad libitum, controls (CTR; n=24), or 70% CTR diet to produce IUGR (n=14). C-section was performed at 0.9G. In CTR (n=7) and IUGR (n=6) fetal brains, ARH appetite regulatory peptides (neuropeptide Y (NPY) and proopiomelanocortin (POMC)) were quantified immunohistochemically. Fetal plasma cortisol was raised in IUGR fetuses. We observed that NPY and POMC were well expressed by 0.9G. IUGR increased NPY, GR, and active phosphorylated GR and decreased POMC and phosphorylated form of STAT3. We conclude that IUGR dysregulates ARH development in ways that will reset the appetitive neuropeptide balance in favor of increased appetite drive in postnatal life. We postulate that changes in peptide abundance are in part due to increased fetal cortisol and ARH GR. These changes may contribute to predisposition to obesity in IUGR offspring.


Mammary fat of breast cancer: gene expression profiling and functional characterization.
Mammary fat is the main composition of breast, and is the most probable candidate to affect tumor behavior because the fat produces hormones, growth factors and adipokines, a heterogeneous group of signaling molecules. Gene expression profiling and functional characterization of mammary fat in Chinese women has not been reported. Thus, we collected the mammary fat tissues adjacent to breast tumors from 60 subjects, among which 30 subjects had breast cancer and 30 had benign lesions. We isolated and cultured the stromal vascular cell fraction from mammary fat. The expression of genes related to adipose function (including adipogenesis and secretion) was detected at both the tissue and the cellular level. We also studied mammary fat browning. The results indicated that fat tissue close to malignant and benign lesions exhibited distinctive gene expression profiles and functional characteristics. Although the mammary fat of breast tumors atrophied, it secreted tumor growth stimulatory factors. Browning of mammary fat was observed and browning activity of fat close to malignant breast tumors was greater than that close to benign lesions. Understanding the diversity between these two fat depots may possibly help us improve our understanding of breast cancer pathogenesis and find the key to unlock new anticancer therapies.


Plasmid replicon typing.
To facilitate the study of plasmids and their roles in human and animal health, environmental processes, and microbial adaptation and evolution, plasmid classification has been an important focus of plasmid biologists over the years. Initial schemes were based on the ability of a plasmid to inhibit F fertility, but due to certain limitations, these methods were superseded by incompatibility or Inc typing. Inc typing classifies plasmids by their ability to stably coexist with other plasmids in the same bacterial strain, a trait that is dependent on their replication machinery. Coresident plasmids are incompatible when they share the same replication mechanisms. Since plasmid replicon type determines Inc group, the terms Inc and Rep type to describe plasmid types are used interchangeably. Initially, Inc typing relied on introduction of a plasmid into a strain carrying another plasmid and determining whether both plasmids were stably maintained in the progeny. However, physical Inc typing is time consuming and not easily used in large-scale applications. Some of these shortcomings were addressed through development of a classification scheme based on identification of basic replicons using DNA hybridization and of a polymerase chain reaction (PCR)-based method of replicon typing enabling plasmid typing on a large scale. Here, we elaborate on a recently described PCR-based typing method that streamlines the typing of plasmids occurring among the Enterobacteriaceae; we believe the method will prove applicable to the study of plasmids on a large scale.


Intrafascial abdominal and vaginal hysterectomy: a reappraisal.
This study was designed to provide anatomic and physiologic evaluation of the intrafascial approach to hysterectomy. Anatomy of the pericervical fascia and its relationship to the fascial and muscular layers of the vagina and the cardinal and sacrouterine ligaments were studied in human and nonhuman primates. The effect of hysterectomy on the length, configuration, and axis of the vagina was evaluated using vaginal casts. Intrafascial abdominal and vaginal hysterectomies have many advantages. Damage to the urinary tract and bowel is minimized. Separation and later closure of the pericervical fascia may allow more effective hemostasis, obliterate dead space, decrease the area of raw surfaces, and separate the vaginal cuff from the retroperitoneal space. These are the principal factors in the prevention of postoperative infection. Intrafascial hysterectomy preserves the complex anatomic relationships between the endopelvic fascia and the vagina. It provides good vaginal support and preserves or improves the length, configuration, and axis of the vagina. Intrafascial hysterectomy is indicated only for treatment of benign disease.


Low temperature atomic layer deposition of cobalt using dicobalt hexacarbonyl-1-heptyne as precursor.
In this work, we present the development of an atomic layer deposition (ALD) process for metallic cobalt. The process operates at low temperatures using dicobalt hexacarbonyl-1-heptyne [Co2(CO)6HC≡CC5H11] and hydrogen plasma. For this precursor an ALD window in the temperature range between 50 and 110 °C was determined with a constant deposition rate of approximately 0.1 Å/cycle. The upper limit of the ALD window is defined by the onset of the decomposition of the precursor. In our case, decomposition occurs at temperatures of 125 °C and above, resulting in a film growth in chemical vapour deposition mode. The lower limit of the ALD window is around 35 °C, where the reduction of the precursor is incomplete. The saturation behaviour of the process was investigated. X-ray photoelectron spectroscopy measurements could show that the deposited cobalt is in the metallic state. The finally established process in ALD mode shows a homogeneous coating at the wafer level.


Apoptotic cell instillation after bleomycin attenuates lung injury through hepatocyte growth factor induction.
Apoptotic cell clearance by macrophages and neighbouring tissue cells induces hepatocyte growth factor (HGF) secretion. HGF plays a key role in alveolar epithelial regeneration and reconstruction after lung injury. Direct in vivo exposure to apoptotic cells enhances HGF production, resulting in attenuation of pulmonary injury. We investigated the direct effect of in vivo exposure to apoptotic cells in bleomycin-stimulated lungs (2 days old) on HGF induction. Furthermore, sequential changes of bleomycin-induced HGF production following apoptotic cell instillation related to the changes in inflammatory and fibrotic responses were assessed. At 2 h after apoptotic cell instillation into bleomycin-stimulated lungs, the levels of HGF mRNA and protein production, and apoptotic cell clearance by alveolar macrophages were enhanced. Furthermore, HGF induction persistently increased following apoptotic cell instillation up to 21 days after bleomycin treatment. Apoptotic cell instillation attenuated bleomycin-induced pro-inflammatory mediator production, inflammatory cell recruitment and total protein levels. Apoptotic cell instillation also induced antiapoptotic and antifibrotic effects. These anti-inflammatory and antiapoptotic effects could be reversed by co-administration of HGF-neutralising antibody. These findings indicate that in vivo exposure to apoptotic cells enhances transcriptional HGF production in bleomycin-stimulated lungs, resulting in attenuation of lung injury and fibrosis.


Role of gastrin in gastrointestinal adaptation after small bowel resection.
Gastrin is a trophic hormone for the mucosa of the oxyntic gland area of the stomach, the proximal small intestine, and the colon. It also has trophic effects on the pancreas. All these tissues undergo hyperplasia to some extent following distal small bowel resection. This study evaluates the role of gastrin in postresectional hyperplasia by examining the growth of these tissues in antrectomized rats following intestinal resection. Antrectomy itself caused atrophy of the oxyntic gland mucosa, colonic mucosa, and the pancreas but had no effect on ileal mucosa. Resection by itself stimulated growth of all tissues and significantly increased serum gastrin levels. After resection in antrectomized animals, all tissues underwent an adaptational response. The increase in total DNA content after resection in antrectomized rats was as great in all tissues, except the colon, as it was in animals with intact antrums and normal gastrin levels. These results indicate that gastrin plays no role in the postresectional hyperplasia observed in the various tissues of the gastrointestinal tract.


Phytochemical screening studies on Melia orientalis by GC-MS analysis.
Melia orientalis (MO) is an important Ayurvedic medicinal plants. The plant part such as leaves and roots are traditionally used for the treatment of diabetes, edema, traumatic swelling, skin diseases, oligospermia and bleeding disorders. To investigate the phytochemical identification of ethanol leaf extract of MO. The fresh leaves of MO (1000g) were collected and shade dried at room temperature for 30 days and the dried leaves were made into a fine powder. The ethanol leaf extract obtained was dried and used for phytochemical identification by GC-MS analysis. The phytochemical screening studies have been carried out and identified ten chemical constituents present in the leaf extract of MO. Thus, our results show that MO possess important phytocomponents such as phytol, squalene and stigmasterol.


Adaptation of bulk constitutive equations to insoluble monolayer collapse at the air-water interface.
A constitutive equation based on stress-strain models of bulk solids was adapted to relate the surface pressure, compression rate, and temperature of an insoluble monolayer of monodendrons during collapse at the air-water interface. A power law relation between compression rate and surface pressure and an Arrhenius temperature dependence of the steady-state creep rate were observed in data from compression rate and creep experiments in the collapse region. These relations were combined into a single constitutive equation to calculate the temperature dependence of the collapse pressure with a maximum error of 5 percent for temperatures ranging from 10 degrees to 25 degrees C.


Increased prevalence of transfusion-transmitted diseases among people with tattoos: A systematic review and meta-analysis.
Whether having a tattoo increases the risk of transfusion-transmitted diseases (TTDs) is controversial. Although a few studies have suggested a strong association between having tattoos and TTDs, other studies have not shown the significance of the association. In addition, previous studies mainly focused only on hepatitis C viral infections. The objective of our study was to identify the prevalence and risk of TTDs in people with tattoos as compared with the non-tattooed population. A systematic review of the studies published before January 22, 2021, was performed using the Pubmed, Embase, and Web of Science databases. Observational studies on hepatitis C virus (HCV), hepatitis B virus (HBV), human immunodeficiency virus (HIV), and syphilis infections in people with and without tattoos were included. Studies that reported disease status without serological confirmation were excluded. A total of 121 studies were quantitatively analyzed. HCV (odds ratio [OR], 2.37; 95% confidence interval [CI], 2.04-2.76), HBV (OR, 1.55; 95% CI, 1.31-1.83), and HIV infections (OR, 3.55; 95% CI, 2.34-5.39) were more prevalent in the tattooed population. In subgroup analyses, the prevalence of HCV infection was significantly elevated in the general population, hospital patient, blood donor, intravenous (IV) drug user, and prisoner groups. IV drug users and prisoners showed high prevalence rates of HBV infection. The prevalence of HIV infection was significantly increased in the general population and prisoner groups. Having a tattoo is associated with an increased prevalence of TTDs. Our approach clarifies in-depth and supports a guideline for TTD screening in the tattooed population.


How is mechanical ventilation employed in the intensive care unit? An international utilization review.
A 1-d point-prevalence study was performed with the aim of describing the characteristics of conventional mechanical ventilation in intensive care units ICUs from North America, South America, Spain, and Portugal. The study involved 412 medical-surgical ICUs and 1,638 patients receiving mechanical ventilation at the moment of the study. The main outcome measures were characterization of the indications for initiation of mechanical ventilation, the artificial airways used to deliver mechanical ventilation, the ventilator modes and settings, and the methods of weaning. The median age of the study patients was 61 yr, and the median duration of mechanical ventilation at the time of the study was 7 d. Common indications for the initiation of mechanical ventilation included acute respiratory failure (66%), acute exacerbation of chronic obstructive pulmonary disease (13%), coma (10%), and neuromuscular disorders (10%). Mechanical ventilation was delivered via an endotracheal tube in 75% of patients, a tracheostomy in 24%, and a facial mask in 1%. Ventilator modes consisted of assist/control ventilation in 47% of patients and 46% were ventilated with synchronized intermittent mandatory ventilation, pressure support, or the combination of both. The median tidal volume setting was 9 ml/kg in patients receiving assist/control and the median setting of pressure support was 18 cm H(2)O. Positive end-expiratory pressure was not employed in 31% of patients. Method of weaning varied considerably from country to country, and even within a country several methods were in use. We conclude that the primary indications for mechanical ventilation and the ventilator settings were remarkably similar across countries, but the selection of modes of mechanical ventilation and methods of weaning varied considerably from country to country.


Thymosin beta-10 gene overexpression correlated with the highly malignant neoplastic phenotype of transformed thyroid cells in vivo and in vitro.
A subtractive thyroid cDNA library was constructed from two human thyroid carcinoma cell lines originating from an anaplastic carcinoma and a papillary thyroid carcinoma. The library was used to identify genes correlated with the progression to a highly malignant phenotype. The thymosin beta-10 gene was isolated and found to be expressed at much higher levels in the anaplastic cell line than in the papillary cells. The thymosin beta-10 gene was overexpressed in five carcinoma cell lines compared with normal thyroid tissue and normal thyroid primary culture cells. The highest expression occurred in the most malignant cell lines. Thymosin beta-10 gene expression was also increased in surgically removed human thyroid carcinomas and was highest in the anaplastic carcinomas. Thymosin beta-10 gene expression was correlated with the degree of the malignant phenotype also in rat thyroid cells transfected with cellular and viral oncogenes of different tumorigenicity. These results show that thymosin beta-10 overexpression is a general event of thyroid cell neoplastic transformation and suggest that the gene is involved in the progression of thyroid carcinogenesis. Finally, the thymosin beta-10 gene was located on chromosome 2q37 by fluorescence in situ hybridization analysis.


Assessing the Clinical Utility of SNP Microarray for Prader-Willi Syndrome due to Uniparental Disomy.
Maternal uniparental disomy (UPD) 15 is one of the molecular causes of Prader-Willi syndrome (PWS), a multisystem disorder which presents with neonatal hypotonia and feeding difficulty. Current diagnostic algorithms differ regarding the use of SNP microarray to detect PWS. We retrospectively examined the frequency with which SNP microarray could identify regions of homozygosity (ROH) in patients with PWS. We determined that 7/12 (58%) patients with previously confirmed PWS by methylation analysis and microsatellite-positive UPD studies had ROH (>10 Mb) by SNP microarray. Additional assessment of 5,000 clinical microarrays, performed from 2013 to present, determined that only a single case of ROH for chromosome 15 was not caused by an imprinting disorder or identity by descent. We observed that ROH for chromosome 15 is rarely incidental and strongly associated with hypotonic infants having features of PWS. Although UPD microsatellite studies remain essential to definitively establish the presence of UPD, SNP microarray has important utility in the timely diagnostic algorithm for PWS.


Minor depression in adolescence: phenomenology and clinical correlates.
Depressions that fail to meet the diagnostic criteria for major depressive disorder (MDD) may be underdiagnosed and undertreated in adolescent population. Traditionally, they are not considered as serious conditions and the phenomenological nature and clinical correlates of these disorders are largely unknown. In the present study, we used a large, representative and age-standardized sample of adolescents to examine the phenomenology and clinical correlates of minor depression, a poorly understood condition included in the category of Depressive Disorder Not Otherwise Specified in Diagnostic and Statistical Manual of Mental Disorders-Fourth Edition-Text Revised (DSM-IV-TR). 909 girls and 945 boys, with mean age of 14, were interviewed by professionals using the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Although clearly milder condition than MDD, minor depression was associated with marked suicidal thoughts, plans and attempts, recurrences and a high degree of comorbidity. At this early age, despite that 14% of adolescents under 15 had suffered from depressive conditions with severe clinical implications, most of them failing to meet the diagnostic threshold for MDD, only 1.7% had received any psychiatric treatment. 40% of depressive adolescents who had attempted suicide had no contact with mental health services. Analyzed in a cross-sectional setting, no conclusions about long-term implications could be made. The results highlight the clinical and public health significance of non-MDD depressions, e.g. minor depression, which need to be more carefully identified and treated at early age.


Further observations on the occurrence of nexuses in benign and malignant human cervical epithelium.
An estimate is made of the frequency of occurrence of nexuses ("gap junctions") in a spectrum of human cervical epithelia, ranging from normal to malignant, since a deficiency of nexuses may be important in abnormal cell-to-cell communication in malignant tissues. The normal cervical epithelium has approximately ten nexuses per cell in the basal layer of proliferating cells and 200 nexuses per cell in the more differentiated intermediate zone. Nexuses are rare between invasive malignant epithelial cells (carcinoma cells). In many areas of cell proliferation near the edge of the tumor mass, fewer than one nexus per cell is present. However, up to four nexuses per cell can be found in some well differentiated regions of invasive carcinoma. Preinvasive malignant epithelia (severe dysplasia and carcinoma-in situ) have as few nexuses as invasive carcinoma. In abnormal but benign epithelia (squamous metaplasia and mild dysplasia), nexuses are abundant. The data indicate that a decrease in number of nexuses correlates with the severity of the morphological alteration in the dysplastic epithelium. Also the deficiency of nexuses in groups of carcinoma cells can occur many cell generations before the development of invasion of the malignant epithelium into the connective tissue. The diminution of nexuses before invasion suggests that a deficiency of nexuses may be one of the important factors in eventually permitting the development of the diffusely infiltrating type of invasion which is characteristic of highly malignant tumors such as squamous carcinomas.


A human cytomegalovirus mutant resistant to the nucleoside analog 9-([2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine (BW B759U) induces reduced levels of BW B759U triphosphate.
We have isolated a human cytomegalovirus mutant that is resistant to the antiviral drug 9-([2-hydroxy-1-(hydroxymethyl)ethoxy]methyl)guanine (BW B759U), yet exhibits wild-type sensitivity to inhibitors of herpesvirus DNA polymerases such as phosphonoformic acid and aphidicolin. Cells infected with the mutant accumulate approximately equal to 1/10th the amount of drug triphosphate as do those infected with the wild-type parent. This reduction in drug triphosphate could not be attributed to altered drug uptake or to reduced stability of the triphosphate, once formed. The induction of normal nucleoside and deoxynucleoside triphosphates and certain cellular nucleoside kinases was comparable in mutant and wild-type virus infections. These results provide strong evidence for the importance of phosphorylation in the selectivity of this antiviral compound and raise the possibility that human cytomegalovirus encodes a nucleoside kinase. The mutant may identify the existence of a cytomegalovirus function whose properties could facilitate genetic analysis of this important pathogen.


Chapter 15: Allergic rhinitis.
Allergic rhinitis affects 60 million of the U.S. population, 1.4 billion of the global population, and its prevalence appears to be increasing. The duration and severity of allergic rhinitis symptoms place a substantial burden on patient's quality of life, sleep, work productivity, and activity. The health impact of allergic rhinitis is compounded by associated complications and comorbidities including asthma, otitis media, sinusitis, and nasal polyps. Allergic rhinitis symptoms result from a complex, allergen-driven mucosal inflammatory process, modulated by immunoglobulin E (IgE), and caused by interplay between resident and infiltrating inflammatory cells and a number of vasoactive and proinflammatory mediators, including cytokines. This allergic response may be characterized as three phases: IgE sensitization, allergen challenge, and elicitation of symptoms. A thorough allergic history is the best tool for the diagnosis of allergic rhinitis, the establishment of which is achieved by correlating the patient's history and physical exam with an assessment for the presence of specific IgE antibodies to relevant aeroallergens determined by skin testing or by in vitro assay. Management of allergic rhinitis includes modifying environmental exposures, implementing pharmacotherapy, and, in select cases, administering allergen-specific immunotherapy. Intranasal therapeutic options include antihistamines, anticholinergic agents, corticosteroids (aqueous or aerosol), mast cell stabilizers, saline, and brief courses of decongestants. Selection of pharmacotherapy is based on the severity and chronicity of symptoms with the most effective medications being intranasal corticosteroids and intranasal antihistamines, which can be used in combination (separately or in fixed dose) for more difficult to control allergic rhinitis.


Mechanism-based fluorescent labeling of beta-galactosidases. An efficient method in proteomics for glycoside hydrolases.
(4-N-5-Dimethylaminonaphthalene-1-sulfonyl-2-difluoromethylphenyl)-beta-d-galactopyranoside was synthesized and successfully tested on beta-galactosidases from Xanthomonas manihotis (Wong-Madden, S. T., and Landry, D. Glycobiology (1995) 5, 19-28 and Taron, C. H., Benner, J. S., Hornstra, L. J., and Guthrie, E. P. (1995) Glycobiology 5, 603-610), Escherichia coli (Jacobson, R. H., Zhang, X. J., DuBose, R. F., and Matthews, B. W. (1994) Nature 369, 761-766), and Bacillus circulans (Fujimoto, H., Miyasato, M., Ito, Y., Sasaki, T., and Ajisaka, K. (1988) Glycoconj. J. 15, 155-160) for the rapid identification of the catalytic site. Reaction of the irreversible inhibitor with enzymes proceeded to afford a fluorescence-labeled protein suitable for further high throughput characterization by using antidansyl antibody and matrix-assisted laser desorption ionization time-of-flight/time-of-flight (MALDI-TOF/TOF). Specific probing by a fluorescent aglycon greatly facilitated identification of the labeled peptide fragments from beta-galactosidases. It was demonstrated by using X. manihotis beta-galactosidase that the Arg-58 residue, which is located within a sequence of 56IPRAYWKD63, was labeled by nucleophilic attack of the guanidinyl group. This sequence including Arg-58 (Leu-46 to Tyr-194) was similar to that (Met-1 to Tyr-151) of Thermus thermophilus A4, which is the first known structure of glycoside hydrolases family 42 (Hidaka, M., Fushinobu, S., Ohtsu, N., Motoshima, H., Matsuzawa, H., Shoun, H., and Wakagi, T. (2002) J. Mol. Biol. 322, 79-91). A catalytic glutamic acid (Glu-537) of E. coli beta-galactosidase was proved to be labeled by the same procedure, suggesting that the modification site with this irreversible substrate might depend both on the nucleophilicity of the amino acids and their spatial arrangement in the individual catalytic cavity. Similarly, a Glu-259 in 257TLEE260 was selectively labeled using B. circulans beta-galactosidase, indicating that Glu-259 is one of the nucleophiles in the active site. The present method can be readily extended to other glycosidases and should greatly aid the high throughput proteomics of many glycoside hydrolases showing both retaining- and inverting-type mechanisms.


Pretreatment with hydromorphone, a mu-opioid agonist, does not alter the acute behavioral and physiological effects of ethanol in humans.
Endogenous opioid systems are thought to mediate at least some of the behavioral effects of ethanol. Opioid antagonists, like naloxone and naltrexone, decrease ethanol self-administration under a variety of conditions in different species of laboratory animals (e.g., rodents and nonhuman primates). Opioid agonists, like morphine, also alter ethanol consumption. However, the dose-response functions for opioid agonists are complex in that low doses increase ethanol self-administration, whereas moderate to high doses decrease ethanol self-administration. The results of prospective human laboratory studies that assessed the behavioral effects of ethanol after pretreatment with an opioid antagonist are mixed. The aim of the present study was to assess the acute subject-rated effects of ethanol (0, 0.5, and 1 g/kg) after pretreatment with hydromorphone, a mu-opioid agonist. In the present experiment, the acute subject-rated, performance-impairing, and physiological effects of ethanol (0, 0.5, and 1 g/kg) were examined after pretreatment with hydromorphone (0, 1, and 2 mg), a mu-opioid agonist, in nine healthy volunteers. Volunteers received one of the nine possible ethanolhydromorphone combinations during each of nine experimental sessions. Ethanol produced prototypical subject-rated drug effects (e.g., dose dependently increased ratings of "high"), impaired performance, and increased heart rate. Hydromorphone pretreatment generally did not significantly alter the subject-rated, performance-impairing, or physiological effects of ethanol. The results of the present experiment suggest that hydromorphone pretreatment does not significantly affect the subject-rated effects of ethanol. Future human laboratory studies should test higher doses of hydromorphone. Future studies also might use more sophisticated behavioral procedures like self-administration, or perhaps drug discrimination, to determine if opioid agonists can modulate the behavioral effects of ethanol in humans.


An Evaluation of Shared Mental Models and Mutual Trust on General Medical Units: Implications for Collaboration, Teamwork, and Patient Safety.
This study examines nurse-physician teamwork and collaboration, a critical component in the delivery of safe patient care, on general medical units. To that end, we assess shared mental models and mutual trust, 2 coordinating mechanisms that help facilitate teamwork, among nurses and physicians working on general medical units. Data were collected from 37 nurses and 42 physicians at an urban teaching medical center in the Northeastern United States. Shared mental model questionnaire items were iteratively developed with experts' input to ensure content validity. Mutual trust items were adapted from an existing scale; items were reliable. Data were analyzed using χ and independent 2-tailed t tests. Physicians and nurses reported significant differences in their perceptions of the professional responsible for a variety of roles (e.g., advocating for the patient [P = 0.0007], identifying a near miss/error [P = 0.003]). Medication reconciliation is only role for which nurses perceive less responsibility than physicians perceive nurses have. Regarding mutual trust, both groups reported significantly more trust within their own professions; both groups reported similar levels of trust in physicians, with physicians reporting significantly less trust in their nursing colleagues than nurses perceive (P < 0.0001). Although many efforts have been directed at improving nurse-physician collaboration, more work is needed. To that end, we propose increasing knowledge about their respective roles, providing opportunities for nurse and physician collaboration through rounding or committee work and enhancing the preparedness and professionalism of interactions.


[Benign intracranial hypertension in childhood following mastoiditis (author's transl)].
Case report concerning a three years old boy with benign intracranial hypertension. The typical symptoms are results of increased intracranial pressure, associated with headache, vomiting, choked disk, occasionally dehiscence of cranial sutures and sixth nerve paresis. In computed tomography there were no tumor signs. In childhood a possible cause in thrombosis of the lateral sinus following an occult mastoiditis after antibiotic therapy. Mastoidectomy, intensive antibiotic therapy as well as serial lumbar punctures led to complete recovery in most cases.


The proportion of patients with non-specific low back pain and neural compromise.
Lack of sensitivity in clinical evaluation and imaging techniques often result in the potential misdiagnosis of the nerve root compromise in patients with non specific low back pain (NSLBP). H-reflex is reliable, valid, and sensitive electrophysiological procedure in detecting neural impingement in patients with low back pain of neurological origin and, thus, could be used to detect nerve root compromise in NSLBP To date, this has not been studied. The purpose of this study was to estimate the proportion of patients with NSLPB and neural compromise using the soleus H-reflex. Soleus H-reflex was measured bilaterally in 30 NSLBP patients with no radicular symptoms during prone lying and standing upright relaxed postures. Five traces were measured and averaged. Side-to-side amplitude (HIH) ratios were then calculated. Inference statistic estimated the proportion and 95% confidence intervals of patients with NSLBP and neural involvement. Soleus H-reflex asymmetry was detected in 17% and 20% of patients with NSLBP during lying and standing, respectively. In some patients, NSLBP may be associated with small degree of nerve root compromise, although the neural compromise is insufficient to cause distal radiculopathy. For these patients, treatment strategies to address such possible underlying mechanism of pain should be considered.


Micropuncture needles combined with ultrasound guidance for unusual central venous cannulation: desperate times call for desperate measures--a new trick for old anesthesiologists.
Central vascular access can be a very challenging task in patients with skeletal deformities such as ankylosing spondylitis, kyphosis, and chin-on-chest deformity. The use of traditional methods of accessing the central venous circulation in these patients can require multiple attempts and may lead to significant complications such as bleeding, pneumothorax, and vascular injury. Ultrasound-guided central venous access has become a very common procedure in the United States and Europe; its efficacy and safety have been demonstrated, and together with the use of micropuncture needles, the technique can facilitate central venous access in complicated cases.