Impact of stress and mitigating information on evaluations, attributions, affect, disciplinary choices, and expectations of compliance in mothers at high and low risk for child physical abuse.
The objective is to know if high-risk mothers for child physical abuse differ in their evaluations, attributions, negative affect, disciplinary choices for children's behavior, and expectations of compliance. The effect of a stressor and the introduction of mitigating information are analyzed. Forty-seven high-risk and 48 matched low-risk mothers participated in the study. Mothers' information processing and disciplinary choices were examined using six vignettes depicting a child engaging in different transgressions. A four-factor design with repeated measures on the last two factors was used. High-risk mothers reported more hostile intent, global and internal attributions, more use of power assertion discipline, and less induction. A risk group by child transgression interaction and a risk group by mitigating information interaction were found. Results support the social information-processing model of child physical abuse, which suggests that high-risk mothers process child-related information differently and use more power assertive and less inductive disciplinary techniques.


Supporting health literacy using an interactive app for symptom management during radiotherapy for prostate cancer.
Patients' ability to self-monitor symptoms and engage in self-care activities is dependent upon their level of health literacy. Health literacy and self-care ability was compared in men with prostate cancer undergoing radiotherapy that used an app for symptom management with a control group. Included were an intervention group (n = 66), who used an app for symptom reporting and support for self-care, and a control group (n = 64). Outcomes were Functional Health Literacy, Communicative and Critical Health Literacy and Appraisal of Self-Care Agency (ASA-A). The intervention group had improved regarding "ability to select information needed from a variety of information sources" (p = .020), "ability to determine the information credible" (p = .041), and "being able to plan and decide what to do to improve health" (p = .004). No inter-group difference was found for ASA-A. With the support of an app for reporting and managing symptoms, important advanced health literacy skills of selecting, determining, and judging information credible may improve. Patients undergoing treatment for prostate cancer may benefit from an individualized approach, such as an app, for communication with health care providers and as a source of health information to make decisions about their own health.


Data collection in decision-making: a study in general practice.
In a study of simulated consultations with patients suffering from dyspepsia, the amount and nature of information required by 20 general practitioners to make management decisions about these simulated patients were analysed. The number of items of information required to complete all eight cases ranged from 23 to 128 (median 66). Doctors who consulted more rapidly in actual surgeries required less information in the simulations (P less than 0.01). Two-way analysis of variance showed that both cases and doctors independently influenced the number of items of information collected, but that doctors were a more powerful influence (P less than 0.05). The nature of the information collected by doctors varied widely between individuals. There was no correlation between the professional experience of the doctors studied and the amount or nature of data collected; this is at odds with previous studies and requires an alternative explanation.


The concept of spirituality in the context of Chinese patients with cancer: A scoping review.
To elucidate how the concept of spirituality has been addressed in studies with Chinese people with cancer. A scoping review. Patterns in conceptual definitions of spirituality and indicators for measuring spirituality were analysed. Literature published from inception to August 2022 was searched in five electronic databases (CINAHL, PubMed, Web of Science, PsycINFO and a Chinese database). Using data from 10 qualitative studies, a new taxonomy of concepts of spirituality among Chinese people with cancer was derived, consisting of four categories: Creation of meaning, Connection, Transcendence and Existence. A total of 12 instruments developed outside of Chinese contexts and used to measure dimensions of spirituality across 27 quantitative studies were compared to the taxonomy developed in this review, and patterns were identified according to the dimensions of spirituality. Several instruments required modifications or additional explanations in questions regarding God/Higher Power and religion. The four categories of spirituality classified in the current review are considered universal across all cultural contexts. Spirituality is multidimensional and functional concept, and the components of the instruments differed depending on which dimension of spirituality was being measured. The findings of this study suggest that for measuring spirituality in research and clinical settings with Chinese people with cancer, it is important to use culturally appropriate scales that are consistent with the dimensions of spirituality being measured. Even instruments developed outside of the Chinese context could be used for Chinese people with cancer if appropriately selected for their intended use. This paper adheres to the EQUATOR guidelines and has no direct patient or public contribution.


Evaluation of clinical information modeling tools.
Clinical information models are formal specifications for representing the structure and semantics of the clinical content within electronic health record systems. This research aims to define, test, and validate evaluation metrics for software tools designed to support the processes associated with the definition, management, and implementation of these models. The proposed framework builds on previous research that focused on obtaining agreement on the essential requirements in this area. A set of 50 conformance criteria were defined based on the 20 functional requirements agreed by that consensus and applied to evaluate the currently available tools. Of the 11 initiative developing tools for clinical information modeling identified, 9 were evaluated according to their performance on the evaluation metrics. Results show that functionalities related to management of data types, specifications, metadata, and terminology or ontology bindings have a good level of adoption. Improvements can be made in other areas focused on information modeling and associated processes. Other criteria related to displaying semantic relationships between concepts and communication with terminology servers had low levels of adoption. The proposed evaluation metrics were successfully tested and validated against a representative sample of existing tools. The results identify the need to improve tool support for information modeling and software development processes, especially in those areas related to governance, clinician involvement, and optimizing the technical validation of testing processes. This research confirmed the potential of these evaluation metrics to support decision makers in identifying the most appropriate tool for their organization. Los Modelos de Información Clínica son especificaciones para representar la estructura y características semánticas del contenido clínico en los sistemas de Historia Clínica Electrónica. Esta investigación define, prueba y valida un marco para la evaluación de herramientas informáticas diseñadas para dar soporte en la en los procesos de definición, gestión e implementación de estos modelos. El marco de evaluación propuesto se basa en una investigación previa para obtener consenso en la definición de requisitos esenciales en esta área. A partir de los 20 requisitos funcionales acordados, un conjunto de 50 criterios de conformidad fueron definidos y aplicados en la evaluación de las herramientas existentes. Un total de 9 de las 11 iniciativas identificadas desarrollando herramientas para el modelado de información clínica fueron evaluadas. Los resultados muestran que las funcionalidades relacionadas con la gestión de tipos de datos, especificaciones, metadatos y mapeo con terminologías u ontologías tienen un buen nivel de adopción. Se identifican posibles mejoras en áreas relacionadas con los procesos de modelado de información. Otros criterios relacionados con presentar las relaciones semánticas entre conceptos y la comunicación con servidores de terminología tienen un bajo nivel de adopción. El marco de evaluación propuesto fue probado y validado satisfactoriamente contra un conjunto representativo de las herramientas existentes. Los resultados identifican la necesidad de mejorar el soporte de herramientas a los procesos de modelado de información y desarrollo de software, especialmente en las áreas relacionadas con gobernanza, participación de profesionales clínicos y la optimización de la validación técnica en los procesos de pruebas técnicas. Esta investigación ha confirmado el potencial de este marco de evaluación para dar soporte a los usuarios en la toma de decisiones sobre que herramienta es más apropiadas para su organización.


Hypervirulence and cross-resistance to a clinical antifungal are induced by an environmental fungicide in Cryptococcus gattii.
The increasing human population requires ongoing efforts in food production. This is frequently associated with an increased use of agrochemicals, leading to environmental contamination and altering microbial communities, including human fungal pathogens that reside in the environment. Cryptococcus gattii is an environmental yeast and is one of the etiological agents of cryptococcosis. Benomyl (BEN) is a broad-spectrum fungicide used on several crops. To study the effects of agrochemicals on fungal pathogens, we first evaluated the susceptibility of C. gattii to BEN and the interactions with clinical antifungals. Antagonistic interaction between BEN and fluconazole was seen and was strain- and concentration-dependent. We then induced BEN-resistance by culturing strains in increasing drug concentrations. One strain demonstrated to be more resistant and showed increased multidrug efflux pump gene (MDR1) expression and increased rhodamine 6G efflux, leading to cross-resistance between BEN and fluconazole. Morphologically, BEN-adapted cells had a reduced polysaccharide capsule; an increased surface/volume ratio; increased growth rate in vitro and inside macrophages and also higher ability in crossing an in vitro model of blood-brain-barrier. BEN-adapted strain demonstrated to be hypervirulent in mice, leading to severe symptoms of cryptococcosis, early mortality and higher fungal burden in the organs, particularly the brain. The parental strain was avirulent in murine model. In vivo cross-resistance between BEN and fluconazole was observed, with mice infected with the adapted strain unable to present any improvement in survival and behavior when treated with this antifungal. Furthermore, BEN-adapted cells cultured in drug-free media maintained the hypervirulent and cross-resistant phenotype, suggesting a persistent effect of BEN on C. gattii. In conclusion, exposure to BEN induces cross-resistance with fluconazole and increases the virulence of C. gattii. Altogether, our results indicate that agrochemicals may lead to unintended consequences on non-target species and this could result in severe healthy problems worldwide.


Whole-Genome Sequencing of Xanthomonadaceae Strain Alg18-2.2, Isolated from the Saline Lake Gudzhirganskoe in the Republic of Buryatia, Russia.
A draft genome sequence of the bacterial isolate Alg18-2.2, recovered from the highly saline and alkaline lake Gudzhirganskoe (Buryatia, Russia), was determined. The results of bacterial identification using 16S rRNA gene sequence and whole-genome analyses suggest that the bacterium belongs to a novel genus. Some genomic features are discussed here.


Androgen receptor gene amplification and protein expression in hormone refractory prostate cancer.
This study examined androgen receptor (AR) gene amplification and protein expression in 102 matched paired hormone sensitive and resistant tumours from 51 patients. AR gene amplification and X chromosome copy number were assessed by fluorescent in situ hybridisation, and protein expression was assessed by immunohistochemistry. All tumours were stained for PSA protein expression. Significantly more tumours exhibited AR amplification following the development of hormone resistance (20%, 10 out of 49) compared to matched hormone-sensitive tumours from the same patient (2%, one out of 48) (P=0.0085). The level of AR expression was significantly higher in hormone-resistant tumours compared to matched hormone-sensitive tumours from the same patient (130, interquartile range, 55-167 vs 94.5 interquartile range, 55-120, P=0.019). AR expression levels in hormone-resistant tumours with and without AR amplification were not significantly different. However, an increase in AR expression was seen with the development of AR amplification in paired tumours. The rate of AR gene amplification and/or an increase in AR protein expression during androgen resistant is too low to wholly explain the development of androgen resistance. Alternative mechanisms for modulating the function of the AR, or other signalling pathways, must be considered as key factors in the development of hormone-resistant prostate.


Repertory of drugs and medicinal plants used in traditional medicine of Afghanistan.
The traditional uses of plants for medicine were studied in Afghanistan. To date, 215 medicinal plants have been identified and are presented in a table with the vernacular name (in Dari, Pashto and Kati), the geographical and ecological distribution, and the medicinal use. This study of traditional medicine demonstrates a close relationship between the kinds of medicinal plants used and pathology, and thus may serve as an indicator of the major health problems of the people.


Uterine septum and reproductive outcome. From diagnosis to treatment. How, why, when?
Septate uterus is a benign congenital malformation and represents the most common uterine anomaly in women with poor reproductive outcome. To review the available scientific data concerning the biological context of the intrauterine septum and the association with poor reproductive outcome, the best methods for diagnosis and treatment. From July 2020 to October 2020, we searched for relevant free full text articles in PubMed, written in English, and published from the 1st of January 2000 to 31st of July 2020. Association of the pathophysiology of septate uterus with poor reproductive outcome, evaluation of the different classification systems, the accuracy of diagnostic methods and the efficacy of the available treatment options. 259 articles were screened, and 22 articles were finally included in our study. Many theories regarding the pathophysiology of this congenital anomaly and its' association with reproductive problems have been proposed along the recent decades. Combination of diagnostic methods should be used to avoid misclassification of this congenital anomaly. Lack of uniformity in the different classification systems makes the diagnosis of septate uterus challenging as there is no universally accepted definition. Data regarding the reproductive outcome of women with septate uterus are still limited, thus recommendations regarding optimal treatment of these women are biased. According to new insights regarding the pathophysiology of the uterine septum, differences in the underlying embryological defects are associated with changes in the histological composition and vascularisation of septa, as well as in clinical significance.


[Etiology and pathogenesis of age-related macular degeneration].
Age-related macular degeneration (AMD) is the most common cause of blindness in Germany. Due to the demographic development a further increase of affected patients is to be expected. Improved understanding of AMD pathogenesis resulted from the molecular biological approaches in recent years and showed an association of genetic factors with AMD. The complement factor H gene and the second high-risk locus ARMS2 in particular were found to contribute a significant risk for development of the disease. Ageing and environmental factors, such as smoking, modulate the individual genetic risk profile. A detailed understanding of the complex AMD pathogenesis is also relevant in ophthalmological practice to understand new treatment strategies. In this review we aim to give an overview of the interplay of ageing, external environmental factors and genetic risk variants leading to AMD.


Observations on some of the plates used to illustrate the Lymphatics section of Andrew Fyfe's Compendium of the Anatomy of the Human Body, Published in 1800.
An engraving displaying A General View of the Absorbent System was used as one of many plates illustrating the Lymphatics section of Andrew Fyfe's Compendium of the Anatomy of the Human Body published in 1800. It is a scaled-down version of a life-size engraving displayed in the museum of the Department of Anatomy at the University of Edinburgh, and is based on a cadaver specially dissected and injected with mercury in 1788 by Alexander Monro secundus, probably with the assistance of Fyfe, who was his 'dissector'. Only recently has the relationship between these two engravings been established, and the Figure Legend in Fyfe's Compendium now provides the missing key to the features illustrated in the life-size engraving. The source and very variable quality of some of Fyfe's other plates, both in the Lymphatics section and elsewhere in the book, are discussed.


Accuracy of visual prediction of pathology of colorectal polyps: how accurate are we?
Small and diminutive polyps seen at colonoscopy could be left unresected because of a balance of risks between perceived low malignant potential and complications of removing the polyp. This relies on a high accuracy in prediction of the pathology of the polyp. This study was undertaken to determine if experienced endoscopists could determine the histological types of polyps found at colonoscopy. We performed a prospective study at Christchurch Hospital from December 2010 to December 2012. Gastroenterologists and surgeons were asked to fill out a questionnaire at time of colonic polypectomy, predicting pathology of polyp excised. Data were collected on indication for colonoscopy, location, size of polyp and use of narrow band imaging. Predictive accuracy was then calculated. A total of 527 polyps were excised from 258 patients. Ninety-one per cent were less than 1 cm. Predictive accuracy of hyperplastic polyps was 47%. Of the 53% wrong predictions, 82% were adenomas. Predictive accuracy of adenoma was 42%, with 66% of incorrect predictions being hyperplastic polyps. Accuracy was lowest in the right colon, with only 25% of predicted hyperplastic polyps actually being hyperplastic. A patient's age, sex, polyp size and site did not affect prediction accuracy. Overall accuracy of visual prediction of pathology of all colorectal polyps was 45%. Narrow band imaging was used too infrequently to determine how useful it was. Pathology of colorectal polyps cannot be accurately predicted visually alone. All polyps visualized at colonoscopy should be excised for ex vivo histology, regardless of size, location or predicted pathology.


Fine-needle aspiration of scalp masses: A review of 30 cases.
Scalp masses are often the initial presentation of a widely disseminated malignancy. Fine-needle aspiration (FNA) is an optimal method for obtaining an accurate tissue diagnosis, in these patients with initial presentation and those with a known malignancy. We reviewed all FNAs of skin and soft tissue lesions from the scalp at our institution over a period of 31 years (1990-2021). Relevant clinical information was obtained from the review of computerized patient record. The histologic type, presentation, previous diagnoses, and survival after the diagnosis were correlated. Thirty patients with scalp masses were identified. All the patients were males with a median age of 61 years (27-81 years). The scalp masses ranged from 0.4 to 6 cm in size. Ten cases (33%) were benign, but the majority of cases (n = 20, 67%) were malignant. Of the malignant lesions sampled, 1 case was a primary squamous-cell carcinoma (SCC), and the remaining 19 cases were metastatic tumors. Of these, 13 cases (68.4%) had a previously diagnosed malignancy. Most of the 19 metastatic lesions were adenocarcinomas or poorly differentiated carcinomas (n = 12, 63.2%), followed by melanoma (n = 4), SCC (n = 1), alveolar soft part sarcoma (n = 1) and large cell lymphoma (n = 1). The most common site of primary was the gastrointestinal tract (6/19, 31.5%) and lung (6/19, 31.5%). The average survival after the diagnosis of these scalp metastases was around 6.3 months, signifying a poor prognosis. In our patient population, most scalp masses were metastatic tumors. Metastasis to the scalp signals advanced disease and is associated with a very poor prognosis. FNA is an easy, safe, rapid, cost effective and precise modality for diagnosing these masses. It can also yield material for molecular testing for newer directed therapies, if needed.


Everolimus in de novo liver transplant recipients: a systematic review.
Everolimus has no nephrotoxicity and is used to treat patients with post-liver transplant chronic renal insufficiency. The present systematic review was to evaluate the efficacy and safety of everolimus in de novo liver transplant patients. Randomized controlled trials comparing everolimus for de novo liver transplant in PubMed, the Cochrane Library, and ScienceDirect published up to March 31, 2014 were searched by two independent reviewers. Mean differences and 95% confidence interval (95% CI) for renal function, relative risk (RR) and 95% CI for treated biopsy-proven acute rejection (tBPAR), graft loss, death, neoplasms/tumor recurrence, and adverse events were collected. Meta-analyses were performed with RevMan version 5.10. A total of four randomized controlled trials covering 1119 cases were included. The meta-analyses revealed that compared with standard exposure of calcineurin inhibitors (CNIs), everolimus combined with reduced CNIs improved creatinine clearance (calculated with the Cockcroft-Gault formula) by 5.13 mL/min at one year (95% CI: 0.42-9.84; P=0.03), and decreased tBPAR (RR: 0.56; 95% CI: 0.35-0.90; P=0.02). Everolimus initiation with CNIs elimination improved glomerular filtration rate (GFR, measured with the modification of diet in renal disease formula) of 10.42 mL/min/1.73 m2 (95% CI: 3.44-17.41; P<0.01) one year after treatment, but increased tBPAR (RR: 1.71; 95% CI: 1.15-2.53; P<0.01). Everolimus decreased the risk of neoplasms/tumor recurrence after liver transplant (RR: 0.60; 95% CI: 0.34-1.03; P=0.06), but was associated with greater risk of adverse events which resulted in drug discontinuation (RR: 1.98; 95% CI: 1.49-2.64; P<0.01). Early introduction of everolimus combined with low-dose or no CNI in de novo liver transplant significantly improves renal function one year post treatment. Everolimus combined with low-dose CNI decreases the risk of tBPAR one year after liver transplant, but everolimus administered without CNIs increases tBPAR.


Efficient N-Type Organic Electrochemical Transistors and Field-Effect Transistors Based on PNDI-Copolymers Bearing Fluorinated Selenophene-Vinylene-Selenophenes.
n-Type organic electrochemical transistors (OECTs) and organic field-effect transistors (OFETs) are less developed than their p-type counterparts. Herein, polynaphthalenediimide (PNDI)-based copolymers bearing novel fluorinated selenophene-vinylene-selenophene (FSVS) units as efficient materials for both n-type OECTs and n-type OFETs are reported. The PNDI polymers with oligo(ethylene glycol) (EG7) side chains P(NDIEG7-FSVS), affords a high µC* of > 0.2 F cm-1 V-1 s-1 , outperforming the benchmark n-type Pg4NDI-T2 and Pg4NDI-gT2 by two orders of magnitude. The deep-lying LUMO of -4.63 eV endows P(NDIEG7-FSVS) with an ultra-low threshold voltage of 0.16 V. Moreover, the conjugated polymer with octyldodecyl (OD) side chains P(NDIOD-FSVS) exhibits a surprisingly low energetic disorder with an Urbach energy of 36 meV and an ultra-low activation energy of 39 meV, resulting in high electron mobility of up to 0.32 cm2 V-1 s-1 in n-type OFETs. These results demonstrate the great potential for simultaneously achieving a lower LUMO and a tighter intermolecular packing for the next-generation efficient n-type organic electronics.


Modification of N-Methyl-N-Nitrosourea initiated bladder carcinogenesis in Wistar rats by terephthalic acid.
The effect of terephthalic acid (TPA) on urinary bladder carcinogenesis was examined. Male Wistar rats were initiated by injection of N-Methyl-N-Nitrosourea (MNU) (20 mg/kg b.w. ip) twice a week for 4 weeks, then given basal diet containing 5% TPA, 5% TPA plus 4% Sodium bicarbonate (NaHCO3) or 1% TPA for the next 22 weeks, and then euthanized. 5% TPA treatment induced a high incidence of urinary bladder calculi and a large amount of precipitate. Though 5% TPA plus 4% Sodium bicarbonate (NaHCO3) and 1% TPA treatment did not induce urinary bladder calculi formation, they resulted in a moderate increase in urinary precipitate. Histological examination of urinary bladder revealed that MNU-5% TPA treatment resulted in a higher incidence of simple hyperplasia, papillary or nodular hyperplasia (PN hyperplasia), papilloma and cancer than MNU control. MNU-5% TPA plus 4% Sodium bicarbonate (NaHCO3) and 1% TPA treatment increased slightly the incidence of simple hyperplasia and PN hyperplasia (not statistically significant). The major elements of the precipitate are phosphorus, potassium, sulfur, chloride, calcium and TPA. The present study indicated that the calculi induced by TPA had a strong promoting activity on urinary bladder carcinogenesis and the precipitate containing calcium terephthalate (CaTPA) may also have weak promoting activity on urinary bladder carcinogenesis.


Imaging Tc-99m-labeled FGF-1 targeting in rats.
Recombinant human acidic fibroblast growth factor (FGF-1) was radiolabeled with (99m)Tc by the HYNIC method. The (99m)Tc-FGF-1 retained its representative molecular mass, heparin affinity, cellular binding to both low (Kd = 9.5 nM) and high (Kd = 125 pM) affinity sites, and mitogenic activity. Gamma camera imaging after intravenous dosing in rats confirmed high liver and kidney binding. Heparin significantly decreased (99m)Tc-FGF-1 liver uptake and increased urinary excretion. These studies illustrate a new method for imaging FGF-1 targeting under various conditions.


Postradiation-associated sclerosing mediastinitis diagnosed in fine needle aspiration specimen: A cytological-pathological correlation.
Sclerosing mediastinitis (SM) is an aggressive fibroproliferative process in the mediastinum that may lead to encasement of mediastinal structures within a dense fibrotic mass. This disease may cause significant clinical complications, morbidity, and even mortality. The etiology and pathogenesis of SM is unclear and in more than one third of cases remains idiopathic. Among the known causes of SM, granulomatous infection is the commonest. Association of SM with radiation therapy has been rarely reported. Herein, we are reporting a case of postradiation sclerosing mediastinitis diagnosed in fine needle aspiration (FNA) specimen. To our knowledge, this is the first reported case of postradiation sclerosing mediastinitis with unusual striking intracytoplasmic glycogen accumulation. Having high index of suspicion and awareness of the fact that this entity may be also associated with radiation therapy, will be helpful in avoiding diagnostic pitfalls in FNA specimens and guiding proper clinical management.


Relation of risk factors for cardiovascular disease to early atherosclerosis detected by ultrasonography in middle-aged normotensive hypercholesterolemic men. PCV Metra Group.
The relations between carotid arteries and/or abdominal aortic plaque and cardiovascular risk factors were investigated by ultrasonography in 161 untreated hypercholesterolemic normotensive men. Of them, 58 had no plaque (NP group), 34 had carotid but not aortic plaque (CP group), 34 had aortic but not carotid plaque (AP group) and 35 had both carotid and aortic plaques (CAP group). Groups significantly differed for age, smoking, blood pressure, and the ratio of total to HDL cholesterol. Age was higher in CAP group than in NP and CP groups and in AP and CP groups than in NP group. Life long smoking dose was higher in CAP group than in CP, AP, and NP groups. Systolic and diastolic pressures were higher in CAP group than in NP group, systolic pressure was higher in CAP group than in CP group, and diastolic pressure was higher in AP group than in CP and NP groups. The ratio of total to HDL cholesterol was higher in CAP group than in AP, CP, and NP groups. Multiple regression analysis showed that carotid plaque was only related to age, while aortic plaque and the number of sites affected by plaque were correlated to age, smoking and diastolic pressure. These findings suggest that in hypercholesterolemia risk factors other than lipids seem to influence arterial plaque and that risk profile differs according to the plaque location.


Spectra of human L cones.
Variations in the amino acid sequences of the human cone opsins give rise to spectrally variant subtypes of L and M cone pigments even in the population with normal color vision. In vitro mutagenesis studies have shown that a limited number of amino acid substitutions produce shifts in the wavelength sensitivity. Presented here are results comparing electrophysiological measurements of single human cones with the expressed cone pigment gene sequences from the same retina. In a sample of eight long-wavelength sensitive cone (L cone) spectra obtained from five donors the precise spectral sensitivities, measured in situ, of the two most commonly occurring spectral variants were determined. The peak sensitivity of the Lser180 cone was 563 nm while that of the Lala180 cone was 559 nm.


Sex-specific relationships between prenatal exposure to metal mixtures and birth weight in a Chinese birth cohort.
Birth weight is an indicator linking intrauterine environmental exposures to later-life diseases, and intrauterine metal exposure may affect birth weight in a sex-specific manner. We investigated sex-specific associations between prenatal exposure to metal mixtures and birth weight in a Chinese birth cohort. The birth weight of 1296 boys and 1098 girls were recorded, and 10 metals in maternal urine samples collected during pregnancy were measured using inductively coupled plasma mass spectrometry. Bayesian Kernel Machine Regression was used to estimate the association of individual metals or metal mixtures and birth weight for gestational age (BW for GA). The model showed a sex-specific relationship between prenatal exposure to metal mixtures and BW for GA with a significant negative association in girls and a non-significant positive association in boys. Cadmium (Cd) and nickel (Ni) were positively and negatively associated with BW for GA in girls, respectively. Moreover, increasing thallium (Tl) concentration lowered the positive association between Cd and BW for GA and enhanced the negative association between Ni and BW for GA in girls. When exposure to other metals increased, the positive association with Cd diminished, whereas the negative association with Ni or Tl increased. Our findings provide evidence supporting the complex effects of intrauterine exposure to metal mixtures on the birth weight of girls and further highlight the sex heterogeneity in fetal development influenced by intrauterine environmental factors.


An exploratory study examining how nano-liquid chromatography-mass spectrometry and phosphoproteomics can differentiate patients with advanced fibrosis and higher percentage collagen in non-alcoholic fatty liver disease.
Non-alcoholic steatohepatitis (NASH) is among the leading causes of liver disease worldwide. It is increasingly recognized that the phenotype of NASH may involve a number of different pathways, of which each could become important therapeutic targets. The aim of this study is to use high resolution mass spectrometry (MS) and phosphoproteomics techniques to assess the serum proteome and hepatic phosphoproteome in subjects with NASH-related fibrosis. Sixty-seven biopsy-proven NAFLD subjects with frozen sera and liver tissue were included. Reverse phase protein microarray was used to quantify the phosphorylation of key signaling proteins in liver and nano-liquid chromatography (LC)-MS was used to sequence target biomarkers in the serum. An image analysis algorithm was used to quantify the percentage of collagen (% collagen) using computer-assisted morphometry. Using multiple regression models, serum proteomes and phosphorylated hepatic proteins that were independently (p ≤ 0.05) associated with advanced fibrosis (stage ≥ 2) and higher % collagen were assessed. Phosphorylated signaling pathways in the liver revealed that apoptosis signal-regulating kinase 1, mitogen-activated protein kinase (ASK1-MAPK pathway involving ASK1 S38 (p < 0.02) and p38 MAPK (p = 0.0002)) activated by the inflammatory cytokine interleukin (IL-10) (p < 0.001), were independently associated with higher % collagen. LC-MS data revealed that serum alpha-2 macroglobulin (α2M) (p = 0.0004) and coagulation factor V (p = 0.0127) were independently associated with higher % hepatic collagen. Simultaneous profiling of serum proteome and hepatic phosphoproteome reveals that the activation of ASK1 S38, p38 MAPK in the liver, and serum α2M and coagulation factor V are independently associated with hepatic collagen deposition in patients with NASH. These data suggest the role of these pathways in the pathogenesis of NASH-related fibrosis as a potential therapeutic target.


The trauma response of children and adolescents. Future directions in research.
Although trauma research in children lags behind that of adults and is often preliminary or unreplicated, current work promises rich understanding of the neurobiologic and psychologic mechanisms underlying the trauma response of the young. Epidemiologic and longitudinal, prospective, controlled studies sensitive to cultural and developmental differences are needed to illuminate the natural history of posttraumatic stress disorder and to show how trauma and its response interact with family, school, and community factors. Promising profound implications for society, such data would enable mental health professionals, educators, and policy makers to develop standards for prevention, detection, and intervention to optimize children's developmental trajectory.


Single-serum diagnosis of recent rubella infection with the use of hemagglutination inhibition test and enzyme-linked immunosorbent assays.
Single-serum diagnosis of recent rubella infection was attempted with the use of hemagglutination inhibition (HI) test and two commercially available enzyme-linked immunosorbent assays (ELISAs). The period during which IgM antibody was detectable by IgM capture ELISA was 4 to 30 days after the onset of rash. Rubella IgG ELISA values relative to HI titer were lower in the sera from the patients with recent infection than in the sera from the subjects with remote infection. IgM ELISA and the combined use of IgG ELISA and HI test are two useful methods of single-serum diagnosis of recent rubella infection.


Ballistic thermophoresis of adsorbates on free-standing graphene.
The textbook thermophoretic force which acts on a body in a fluid is proportional to the local temperature gradient. The same is expected to hold for the macroscopic drift behavior of a diffusive cluster or molecule physisorbed on a solid surface. The question we explore here is whether that is still valid on a 2D membrane such as graphene at short sheet length. By means of a nonequilibrium molecular dynamics study of a test system-a gold nanocluster adsorbed on free-standing graphene clamped between two temperatures [Formula: see text] apart-we find a phoretic force which for submicron sheet lengths is parallel to, but basically independent of, the local gradient magnitude. This identifies a thermophoretic regime that is ballistic rather than diffusive, persisting up to and beyond a 100-nanometer sheet length. Analysis shows that the phoretic force is due to the flexural phonons, whose flow is known to be ballistic and distance-independent up to relatively long mean-free paths. However, ordinary harmonic phonons should only carry crystal momentum and, while impinging on the cluster, should not be able to impress real momentum. We show that graphene and other membrane-like monolayers support a specific anharmonic connection between the flexural corrugation and longitudinal phonons whose fast escape leaves behind a 2D-projected mass density increase endowing the flexural phonons, as they move with their group velocity, with real momentum, part of which is transmitted to the adsorbate through scattering. The resulting distance-independent ballistic thermophoretic force is not unlikely to possess practical applications.


Triglyceride removal from very low density lipoproteins in vivo as a function of their triglyceride content.
Rabbit very low density lipoproteins (VLDL) were fractionated in 3 subfractions differing in density and triglyceride (TG) content. The fraction of total weight represented by triglycerides was: VLDL1 TG = 71%, VLDL2 TG = 62%, VLDL3 TG = 55%. No other difference in composition was observed. After intravenous administration of radioglycerol all subfractions were labelled and the distribution of radioactivity in their glycerolipids was the same. In 5 rabbits, a biologically labelled triglyceride-rich VLDL1 subfraction preparation was administered and the specific activity of triglyceride was determined in all 3 subfractions in serial samples. A precursor--product relationship between VLDL1 TG and VLDL TG in other subfractions was not observed. In another set of experiments the disappearance rates of VLDL TG from subfractions were determined in recipient rabbits. The half-lives were: VLDL1 TG = 9.5 +/- 1.3 min, VLDL2 TG : 16.0 +/- 1.3 min, VLDL3 TG: 26.9 +/- 1.3 min. It is concluded that triglyceride removal from a VLDL subfraction varies inversely with its triglyceride content. A role for partial VLDL lipolysis in this metabolic heterogeneity was not established.


Different kinetic properties of the two mutants, RAS2Ile152 and RAS2Val19, that suppress the CDC25 requirement in RAS/adenylate cyclase pathway in Saccharomyces cerevisiae.
The properties of RAS2Gly19----Val and RAS2Thr152----Ile, two mutants suppressing the CDC25 requirement for the activation of adenylate cyclase in Saccharomyces cerevisiae, were compared with the properties of wild-type RAS2. We examined (a) the guanine nucleotide interaction, (b) the intrinsic GTPase (EC 3.6.1-) activity, and (c) the ability to activate adenylate cyclase in vitro. The low GTPase of RAS2Val19 is associated with an increased stability of the GTP complex. By contrast, RAS2Ile152 shows a strong destabilization of the GDP complex (the dissociation rate constants of the RAS2Ile152.GDP complex is enhanced almost 50 times) and an increased GTPase activity. Remarkably, all the parameters of the interaction with GDP and GTP as well as the catalytic activity are modified by the two mutations in an opposite manner. Our kinetic results show that the functional modifications of RAS2 compensating for the CDC25 inactivation can not only be associated with the presence of a long-lived RAS2.GTP complex, but also with a rapid GDP to GTP exchange reaction. As a striking result, the functional modifications induced by Thr152----Ile activate the adenylate cyclase in vitro much more efficiently than those induced by Gly19----Val. This stresses the importance of a rapid regeneration of the RAS2.GTP complex for the activation of the adenylate cyclase pathway.


Critical care medicine update: essentials for the nonintensivist, part 1.
The intensive care unit (ICU) can be a challenging environment for health care practitioners who are not trained in critical care medicine. A structured approach to patient care is necessary in order to achieve optimal clinical outcomes. The purpose of this two-part article is to review essential highlights of critical care medicine for the nonintensivist. We provide a structured overview of the management of the critically ill patient and focus on problems commonly encountered in the heterogeneous ICU patient population. In Part 1 we review (a) altered states of consciousness and sedation, (b) respiratory failure and ventilators, (c) cardiovascular monitoring and management, and (d) fluid and electrolyte disorders.


Cervical cancer screening programs in Latin America and the Caribbean.
Latin America and the Caribbean (LAC) have a significant burden of cervical cancer. Prophylactic human papillomavirus (HPV) vaccines are an opportunity for primary prevention and new screening methods, such as new HPV DNA testing, are promising alternatives to cytology screening that should be analyzed in the context of regional preventive programs. Cytology-based screening programs have not fulfilled their expectations and coverage does not sufficiently explain the lack of impact on screening in LAC. While improved evaluation of screening programs is necessary to increase the impact of screening on the reduction of incidence and mortality, other programmatic aspects will need to be addressed such as follow-up of positive tests and quality control. The implementation of new technologies might enhance screening performance and reduce mortality in the region. The characteristics, performance and impact of cervical cancer screening programs in LAC are reviewed in this article.


Kinetics of mammary and intestinal IgA-producing cells in the lactating rat.
IgA-producing B lymphocytes in the lactating mouse mammary gland are thought to be derived from lymphoid tissues associated with the small intestine. By contrast, adoptive transfer studies in the rat have failed to confirm a simple entero-mammary migration of IgA plasma cell precursors during lactation. To explain this discrepancy we postulated that recent cIgA+ cell immigrants undergo extensive local proliferation in the rat mammary gland. The present study tested this hypothesis by determining mitotic indices of cIgA+ cells in the gland during lactation. The results did not support this contention and suggest that rat mammary cIgA+ B cells are not derived from the same pool of precursors providing IgA-producing B cells for the small intestine.


The structure of bypass of forespore C, an intercompartmental signaling factor during sporulation in Bacillus.
Sporulation in Bacillus subtilis begins with an asymmetric cell division giving rise to smaller forespore and larger mother cell compartments. Different programs of gene expression are subsequently directed by compartment-specific RNA polymerase sigma-factors. In the final stages, spore coat proteins are synthesized in the mother cell under the control of RNA polymerase containing sigma(K), (Esigma(K)). sigma(K) is synthesized as an inactive zymogen, pro-sigma(K), which is activated by proteolytic cleavage. Processing of pro-sigma(K) is performed by SpoIVFB, a metalloprotease that resides in a complex with SpoIVFA and bypass of forespore (Bof)A in the outer forespore membrane. Ensuring coordination of events taking place in the two compartments, pro-sigma(K) processing in the mother cell is delayed until appropriate signals are received from the forespore. Cell-cell signaling is mediated by SpoIVB and BofC, which are expressed in the forespore and secreted to the intercompartmental space where they regulate pro-sigma(K) processing by mechanisms that are not yet fully understood. Here we present the three-dimensional structure of BofC determined by solution state NMR. BofC is a monomer made up of two domains. The N-terminal domain, containing a four-stranded beta-sheet onto one face of which an alpha-helix is packed, closely resembles the third immunoglobulin-binding domain of protein G from Streptococcus. The C-terminal domain contains a three-stranded beta-sheet and three alpha-helices in a novel domain topology. The sequence connecting the domains contains a conserved DISP motif to which mutations that affect BofC activity map. Possible roles for BofC in the sigma(K) checkpoint are discussed in the light of sequence and structure comparisons.


A history of ventricular neuroendoscopy.
To describe the history of neuroendoscopy through the history of the major neurosurgeons who worked and published in the field. All relevant data described in publications before 1980 about the history of neuroendoscopy and found through OVID MEDLINE searches and related references are reported. Contributions of 14 neurosurgeons who were pioneers in neuroendoscopy are described in chronologic order: Lespinasse, Dandy, Payr, Mixter, Fay, Grant, Volkmann, Putnam, Dereymacker, Scarff, Feld, Guiot, Fukushima, and Griffith. An historical review of ventricular neuroendoscopy remains by essence incomplete. Medical technical progress proceeds by leaps and bounds, related to the ingenuity of surgeons able to understand rapidly the value of a technical change to improve their surgical procedure. The ability to remain attentive to patients and evolving pathologies as well as the evolution of modern technology is required to make further progress in neuroendoscopy.


Insights into molecular therapy of glioma: current challenges and next generation blueprint.
Glioma accounts for the majority of human brain tumors. With prevailing treatment regimens, the patients have poor survival rates. In spite of current development in mainstream glioma therapy, a cure for glioma appears to be out of reach. The infiltrative nature of glioma and acquired resistance substancially restrict the therapeutic options. Better elucidation of the complicated pathobiology of glioma and proteogenomic characterization might eventually open novel avenues for the design of more sophisticated and effective combination regimens. This could be accomplished by individually tailoring progressive neuroimaging techniques, terminating DNA synthesis with prodrug-activating genes, silencing gliomagenesis genes (gene therapy), targeting miRNA oncogenic activity (miRNA-mRNA interaction), combining Hedgehog-Gli/Akt inhibitors with stem cell therapy, employing tumor lysates as antigen sources for efficient depletion of tumor-specific cancer stem cells by cytotoxic T lymphocytes (dendritic cell vaccination), adoptive transfer of chimeric antigen receptor-modified T cells, and combining immune checkpoint inhibitors with conventional therapeutic modalities. Thus, the present review captures the latest trends associated with the molecular mechanisms involved in glial tumorigenesis as well as the limitations of surgery, radiation and chemotherapy. In this article we also critically discuss the next generation molecular therapeutic strategies and their mechanisms for the successful treatment of glioma.


A cost-effectiveness analysis of avelumab plus best supportive care versus best supportive care alone as first-line maintenance treatment for patients with locally advanced or metastatic urothelial carcinoma in Taiwan.
Patients with locally advanced or metastatic urothelial carcinoma have limited treatment options and a poor prognosis. The JAVELIN Bladder 100 trial showed that avelumab as first-line maintenance plus best supportive care significantly prolonged overall survival and progression-free survival versus best supportive care alone in patients with locally advanced or metastatic urothelial carcinoma that had not progressed with first-line platinum-containing chemotherapy. We assessed whether avelumab plus best supportive care is a cost-effective treatment option versus best supportive care alone in this patient group in Taiwan. A partitioned survival model was used to estimate the costs and effects of avelumab plus best supportive care versus best supportive care alone over a 20-year time horizon from the perspective of Taiwan's National Health Insurance Administration. Patient-level data from JAVELIN Bladder 100 on efficacy, safety, utility, and time on treatment were analyzed to provide parameters for the model. Log-normal and Weibull distributions were used for overall survival and progression-free survival, respectively. Costs of healthcare resources, drug acquisition, adverse events, and progression were identified through publicly available data sources and clinician interviews. The model estimated total costs, life years, and quality-adjusted life years. In the modeled base case, avelumab plus best supportive care increased survival versus best supportive care alone by 0.79 life years (2.93 vs. 2.14) and 0.61 quality-adjusted life years (2.15 vs. 1.54). The incremental cost-effectiveness ratio for avelumab plus best supportive care versus best supportive care alone was NT$1 827 680. Most (78%) of the probabilistic sensitivity analyses fell below three times the gross domestic product per capita. Scenario analysis indicated that life year and quality-adjusted life year gains were most sensitive to alternative survival extrapolations for both avelumab plus best supportive care and best supportive care alone. Avelumab first-line maintenance therapy combined with best supportive care was determined as a cost-effective treatment strategy for patients in Taiwan diagnosed with locally advanced or metastatic urothelial carcinoma that had not progressed with platinum-containing chemotherapy.


Quantitative analysis of lead sources in wheat tissue and grain under different lead atmospheric deposition areas.
Due to rapid growth of industrialization and human activities, such as mining and smelting, lead (Pb) has become a major environmental contaminant. As Pb can pose risks to human health, preventing Pb pollution in wheat is important for food safety, requiring accurate verification of pollution sources. Pb concentrations and isotope ratio levels in soil, in the atmosphere, and wheat tissue (root, stem, leaf, grain) in an area of high-Pb deposition (in the vicinity of a Pb smelter in Jiyuan city) and an area of low deposition (the northwest suburb of Zhengzhou city) were examined. The Pb isotope ratio and the binary mixed model were used to quantify the contribution of soil and atmospheric deposition to Pb content in wheat tissues. Results show that Pb content in soil, atmospheric deposition, and wheat in the high deposition area were significantly higher than those in the low deposition area. Pb content in soil, atmospheric deposition, wheat roots, stems, leaves, and grains in the high-deposition area were 355.32 ± 14.78, 5477.90 ± 187.85, 158.72 ± 9.56, 21.36 ± 1.72, 26.49 ± 1.96, and 0.94 ± 0.02 mg kg-1, respectively. Pb content in the low-deposition area were 6.10 ± 0.75, 78.50 ± 4.35, 2.47 ± 0.23, 1.03 ± 0.07, 2.11 ± 0.13, and 0.08 ± 0.01 mg kg-1, respectively. The Pb isotope ratio recorded obvious differences between soil and atmospheric deposition in the two areas. Combined with the significant correlation between Pb isotopes in various tissues of wheat and environmental media, and analysis of the isotopic composition characteristics of wheat and environmental media, in the high-deposition area, the contribution rate of atmospheric deposition in wheat roots, stems, leaves, and grains was 14%, 66%, 84%, and 77%, respectively. And the soil contribution rate was 86%, 34%, 16%, 23%, respectively. In the low-deposition area, the contribution rate of atmospheric deposition in wheat roots, stems, leaves, and grains was 49%, 73%, 93%, and 83%, respectively. And the soil contribution rates were 51%, 27%, 7%, and 17%, respectively. In the low-Pb deposition area, the contribution rate of atmospheric deposition in wheat was higher than that in the high-deposition area. Atmospheric deposition was the main source of Pb in grains, leaves, and stems of wheat in different depositional areas. Pb in wheat roots mainly derives from soil, and the Pb contribution rate of soil to wheat roots in the high-deposition area was significantly higher than that in the low-deposition area.


Selective anti-aggressive properties of DU 27725: ethological analyses of intermale and territorial aggression in the male rat.
The effects of a new anti-aggressive compound, DU 27725, were evaluated in intermale and territorial aggression. Ethological analysis of intermale aggression showed that DU 27725 (1 to 8 mg/kg IP) strongly decreased aggression, while introductory social behaviour was unaffected or enhanced. The offensive character of aggression disappeared and was replaced by a more defensive pattern. No drastic changes occurred in non-social activities. Sedation, muscle relaxation and motor impairment did not occur at any of the doses tested, suggesting that the anti-aggressive effects were not caused by nonspecific actions of the drug. In territorial aggression, DU 27725 (4 and 8 mg/kg IP) also decreased all aspects of aggression; introductory social behaviour was slightly decreased, and defensive behaviour remained unaffected. At the highest dose (8 mg/kg) sedation was observed. DU 27725 reduced both the number of ultrasonic vocalizations and the number of bites inflicted upon the partners.


Supramolecular chirogenesis in zinc porphyrins by enantiopure hemicucurbit[n]urils (n = 6, 8).
Chiral cyclohexanohemicucurbit[n]urils (n = 6, 8) (cycHCs) are able to bind guests through multiple "outer surface interactions", which in the case of planar zinc porphyrins leads to induction of chirality. Crystal structures of complexes of complementary sized hosts revealed social self-sorting, while in the solution phase one cycHC can accommodate up to three porphyrin molecules with log Ktotal 9.


Sudden death of a child because of an intestinal obstruction caused by a large congenital mesenteric defect.
Transmesenteric hernias are internal hernias caused by a congenital defect in the mesentery. They are rare causes of intestinal obstruction, but most commonly affect the small bowel. We report an unexpected death of an infant with a bowel obstruction caused by a congenital mesenteric defect, which was undiagnosed despite visits to three different hospitals. Mesenteric defects are usually 2-3 cm in diameter. At autopsy, we found an oval, 14 × 7 cm congenital defect in the ileal mesentery through which the small bowel had herniated. Diagnosis of such defects remains difficult, even with currently available imaging techniques. Diagnosis is particularly difficult in infants who usually have nonspecific symptoms. Therefore, it is important that sudden unexpected deaths in children undergo full forensic evaluation to establish the precise cause of death. It is also important for forensic physicians to inform clinicians of the risk of such diseases, particularly in emergency situations.


The influence of voltage-gated sodium channels on human gastrointestinal nociception.
Abdominal pain is a frequent and persistent problem in the most common gastrointestinal disorders, including irritable bowel syndrome and inflammatory bowel disease. Pain adversely impacts quality of life, incurs significant healthcare expenditures, and remains a challenging issue to manage with few safe therapeutic options currently available. It is imperative that new methods are developed for identifying and treating this symptom. A variety of peripherally active neuroendocrine signaling elements have the capability to influence gastrointestinal pain perception. A large and growing body of evidence suggests that voltage-gated sodium channels (VGSCs) play a critical role in the development and modulation of nociceptive signaling associated with the gut. Several VGSC isoforms demonstrate significant promise as potential targets for improved diagnosis and treatment of gut-based disorders associated with hyper- and hyposensitivity to abdominal pain. In this article, we critically review key investigations that have evaluated the potential role that VGSCs play in visceral nociception and discuss recent advances related to this topic. Specifically, we discuss the following: (a) what is known about the structure and basic function of VGSCs, (b) the role that each VGSC plays in gut nociception, particularly as it relates to human physiology, and (c) potential diagnostic and therapeutic uses of VGSCs to manage disorders associated with chronic abdominal pain.


Mannose Receptor Is Required for Optimal Induction of Vaccine-Induced T-Helper Type 17 Cells and Resistance to Blastomyces dermatitidis Infection.
We investigated how innate sensing by the mannose receptor (MR) influences the development of antifungal immunity. We demonstrate that MR senses mannan on the surface of attenuated Blastomyces dermatitidis vaccine yeast and that MR(-/-) mice demonstrate impaired vaccine immunity against lethal experimental blastomycosis, compared with wild-type control mice. Using naive Blastomyces-specific transgenic CD4(+) T cells, we found that MR regulates differentiation of naive T cells into T-helper type 17 (Th17) effector cells, which are essential in vaccine immunity against systemic dimorphic fungi. Thus, MR regulates differentiation of Th17 cells and is required to induce vaccine immunity against lethal pulmonary blastomycosis.


Michael adducts--source for biologically potent heterocycles.
A new class of pyrimidinetriones, thioxopyrimidinediones, pyrazolidinediones and isoxazolidinediones were prepared from (E)-1,4-diarylbut-2-ene-1,4-diones. All the new compounds synthesized were screened for antimicrobial activity.


Label-free electrochemical sensor to investigate the effect of tocopherol on generation of superoxide ions following UV irradiation.
Generation of reactive oxygen species (ROS), triggered by ultraviolet radiation (UVR), is associated with carcinogenesis of the skin. UV irradiation induced superoxide anion (O2•-) is the key ROS involved in the cellular damage. The cytoprotective efficacy of an unknown anti-oxidant compound can be evaluated by analyzing the production of O2•- from treated cells. In this study, a glass carbon electrode functionalized with nanotube@DNA-Mn3(PO4)2 composite was applied to quantitative determination of generation of highly unstable O2•- from the melanoma A375 cell line following UVR(UV, UVA and UVB). In addition, the cytoprotective efficacy of anti-oxidant α-tocopherol was evaluated by quantifying the production of O2•-. The results showed that, UVR triggers generation of O2•- in melanoma A375 cells, and α-tocopherol is effective in diminishing the production of O2•- following UV irradiation. By comparing the conventional cell-survival assays results, we found that our simple and quick electrochemical sensing method can quantify O2•- generation through the biological activity of an anti-oxidant compound (α-tocopherol). Our label-free electrochemical quantification method for ROS (O2•- major) in cells facing UVR stress demonstrates its potential application for high-throughput screening of anti-oxidation compounds.


Structure-based design and subsequent optimization of 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) inhibitors of p38 MAP kinase.
A computer-aided drug design strategy leads to the identification of a new class of p38 inhibitors based on the 2-tolyl-(1,2,3-triazol-1-yl-4-carboxamide) scaffold. The tolyl triazole amides provided a potent platform amenable to optimization. Further exploration leads to compounds with greater than 100-fold improvement in binding affinity to p38. Derivatives prepared to alter the physicochemical properties produced inhibitors with IC(50)'s in human whole blood as low as 83 nM.


Airway vascular changes after lung transplant: potential contribution to the pathophysiology of bronchiolitis obliterans syndrome.
Bronchiolitis obliterans syndrome (BOS) remains the primary factor limiting successful lung transplantation. In asthma and lung transplantation BOS-increased sub-mucosal vascularity has been shown to contribute to airflow limitation. Vascularity has 2 components: sprouting angiogenesis (more vessels) and microvascular enlargement (larger vessels). We hypothesized that the lack of a reanastomosed bronchial arterial blood supply at the time of transplant might stimulate angiogenesis and be a risk factor for subsequent BOS. Twenty-seven initially stable lung transplant recipients (BOS 0) were recruited at 148 +/- 80 days post-transplant and underwent clinical and bronchoscopic longitudinal follow-up for at least 3 years. Eight remained stable and BOS developed in 19. Nine normal controls were also recruited. Airway vasculature was examined immunohistochemically in endobronchial biopsy (EBB) specimens with collagen IV antibody, quantified by computer image analysis, and expressed as average vessel size, vessel number, and overall vascularity. The effects of demographic, clinical, bronchoalveolar lavage (BAL), and EBB variables on airway vasculature were analyzed in a multivariate model. No significant differences in airway vascularity were found between stable and BOS lung transplant recipients cross-sectionally or longitudinally. However, both lung transplant groups at baseline showed significantly greater airway vascularity compared with normal controls (p < .05). Multivariate analysis suggested that the percentage of BAL CD3+ cells and acute rejection are the most influential variables on airway vasculature. This study suggests early and persistent airway vasculature changes occur in lung transplant recipients, mainly manifested as microvascular enlargement. Potentially this baseline change contributes to airway obstruction and also puts all lung transplant recipients at risk for further exponential loss of airway caliber with any subsequent airway inflammatory insult.


Enhanced antibacterial activity of silver nanoparticles/halloysite nanotubes/graphene nanocomposites with sandwich-like structure.
A sandwich-like antibacterial reagent (Ag/HNTs/rGO) was constructed through the direct growth of silver nanoparticles on the surface graphene-based HNTs nanosheets. Herein, various nanomaterials were combined by adhesion effect of DOPA after self-polymerization. Ag/HNTs/rGO possess enhanced antibacterial ability against E. coli and S. aureus compared with individual silver nanoparticles, rGO nanosheets or their nanocomposites.


Frontal lobe γ-aminobutyric acid levels during adolescence: associations with impulsivity and response inhibition.
The brain undergoes major remodeling during adolescence, resulting in improved cognitive control and decision-making and reduced impulsivity, components of behavior mediated in part by the maturing frontal lobe. γ-Aminobutyric acid (GABA), the main inhibitory neurotransmitter system, also matures during adolescence, with frontal lobe GABA receptors reaching adult levels late in adolescence. Thus, the objective of this study was to characterize in vivo developmental differences in brain GABA levels. Proton magnetic resonance spectroscopy was used at 4 T to acquire metabolite data from the anterior cingulate cortex (ACC) and the parieto-occipital cortex (POC) in adolescents (n=30) and emerging adults (n = 20). ACC GABA/creatine (Cr) levels were significantly lower in adolescents relative to emerging adults, whereas no age differences were observed in the POC. Lower ACC GABA/Cr levels were significantly associated with greater impulsivity and worse response inhibition, with relationships being most pronounced for ACC GABA/Cr and No-Go response inhibition in adolescent males. These data provide the first human developmental in vivo evidence confirming frontal lobe GABA maturation, which was linked to impulsiveness and cognitive control. These findings suggest that reduced GABA may be an important neurobiological mechanism in the immature adolescent brain, contributing to the reduced yet rapidly developing ability to inhibit risky behaviors and to make suboptimal decisions, which could compromise adolescent health and safety.


Latitudinal allozymic variability in natural populations of Zaprionus indianus from India.
Twelve natural populations of Z. indianus from India, collected along lines of latitude, were analyzed electrophoretically and the geographical pattern of variation was compared at 15 allozyme loci. Except for Mdh-2, all the loci revealed extensive polymorphism. The allele frequency variation revealed a statistically significant correlation as well as regression coefficients with the latitude. The populations revealed extensive clinical variation at all the polymorphic loci, which depicted moderate to higher FST values. Thus, the observed genetic divergence in colonizing populations of Z. indianus shows the role of natural selection that varies spatially along the north-south axis of the Indian subcontinent.


Innovative Surgical Concept for Septic Sternoclavicular Arthritis: Case Presentation of a Simultaneous Joint Resection and Stabilization with Gracilis Tendon Graft Including Literature Review.
Septic arthritis of the sternoclavicular joint (SCJ) is a rarity in everyday surgical practice with 0.5 - 1% of all joint infections. Although there are several risk factors for the occurrence of this disease, also healthy people can sometimes be affected. The clinical appearance is very variable and ranges from unspecific symptoms such as local indolent swelling, redness or restricted movement of the affected shoulder girdle to serious consequences (mediastinitis, sepsis, jugular vein thrombosis). Together with the low incidence and the unfamiliarity of the disease among practicing doctors in other specialties, this often results in a delay in the diagnosis, which in addition to a significant reduction in the quality of life can also have devastating consequences for the patient. According to a stage-dependent procedure, the therapy strategies range from antibiotic administration only to radical resection of the SC joint and other affected structures of the chest wall in severe cases with the following necessity for flap reconstruction. The aspect of possible post-interventional instability after resection of the SCJ receives little or no attention in the current literature. In the present case report of a 51-year-old, otherwise healthy gentleman with isolated monoarthritis of the right SCJ with Escherichia coli (E. coli) shortly after two prostatitis episodes, the possibility of a new surgical approach with a one-stage eradication and simultaneous stabilization of the SCJ is presented. Therefore, a joint resection including extensive debridement is performed while leaving the posterior joint capsule and inserting an antibiotic carrier. In the same procedure, the SCJ is then stabilized with an autologous gracilis tendon graft by using the "figure of eight" technique, which has become well established particularly for anterior instabilities of the SCJ in recent years. One year after operative therapy, the patient presented symptom-free with an excellent clinical result (SSV 90%, CS89 points, CSM 94 points, TF 11 points, DASH 2.5 points). It is concluded that in selected cases with an infection restricted to the SCJ without major abscessing in the surrounding soft tissues, the demonstrated procedure leads to good and excellent clinical results with stability of the joint. If the focus of infection and germ are known, stabilization using an autologous graft can be carried out under antibiotic shielding. To the best of the authors' knowledge, this surgical procedure has not yet been described in the current literature. Depending on the extent of the resection, an accompanying stabilization of the SCJ should be considered to achieve stable conditions and an optimal clinical outcome.


The anti-bacterial poly(caprolactone)-poly(quaternary ammonium salt) as drug delivery carriers.
Anti-bacterial materials play significant role in biomedical field. Researches and applications of new anti-bacterial materials are necessary. Novel linear and star-shaped copolymers of poly(caprolactone)-poly(quaternary ammonium salt) (PCL-PJDMA) were synthesized by a combination of ring-opening polymerization and atom transfer radical polymerization. The structures of the copolymers were confirmed by nuclear magnetic resonance ((1)H-NMR) and Fourier transform infrared spectroscopy. The copolymers self-assembled into ball-shaped micelles with low critical micelle concentration (10(-4) ∼ 10(-3) mg/ml). An anti-bacterial drug, triclosan, was chosen as a model drug to investigate the potential application of the copolymers in drug-controlled release. The anti-bacterial experiments against Escherichia coli indicated that all the copolymer micelles had anti-bacterial ability and drug-loaded star-shaped PCL-PJDMA micelles were the best. The slow release of the drug from the drug-loaded micelles prolonged anti-bacterial effect. Therefore, PCL-PJDMA themselves have not only anti-bacterial ability but also the copolymer micelles can be used as carriers for anti-bacterial drugs.


High resolution Orbitrap mass spectrometry analysis of oxidized hydrocarbons found in freshwater following a simulated spill of crude oil.
Negative ion electrospray Orbitrap mass spectrometry was used to analyze water samples taken from a pilot-scale spill tank test of conventional crude oil on freshwater. A 56-day spill test was performed, and water samples were taken at regular intervals throughout the test to determine what changes in water chemistry occur with time. Orbitrap mass spectrometry was used to measure oxidized species in water samples, and oxidized species are analyzed by carbon number, double bond equivalent and hydrocarbon class. Emphasis is placed on changes with time over the course of the spill test, to examine changes by weathering processes that could occur naturally in a field spill scenario. Results demonstrate that while the concentrations of polycyclic aromatic hydrocarbons decrease in the water phase over time, the concentrations of total organic carbon and oxidized species in the water increase with time, where quantities of O2 and O3 species have the highest abundance. Measurement of increasing concentrations and changing relative abundances of these oxidized compounds can be used to assess how oil behaves in a freshwater aquatic environment after a spill.


Biochemical markers of bone turnover. II: Diagnosis, prophylaxis, and treatment of osteoporosis.
Osteoporosis is a major health problem and is becoming increasingly important in our aging society. In many of the Western countries, patients with hip fracture occupy more hospital beds than patients with any other disease. Measures to combat osteoporosis are urgently needed, but the best way of doing so is uncertain. Osteoporosis prevention can be targeted at a subgroup of the population at high risk of disease. Alternatively, the intervention can be aimed at the entire population. Both preventive strategies have been proposed for osteoporotic fractures. Some researchers advocate population programs to increase weight-bearing exercise and calcium intake or to reduce smoking, but there is little direct evidence of their effectiveness. The most widespread opinion is that bone mass measurement is the most accurate predictor of fracture risk. Prediction of fracture risk may mean treatment for several years with drugs with not only effects, but also adverse effects. This encourages attempts to optimize the diagnostic procedures.


The organization of cell populations within lymph nodes: their origin, life history and functional relationships.
The normal lymph node comprises a superficial cortex, a deep cortex or paracortex and a medulla. In each of these regions there are three kinds of spaces: an intralymphatic space, an intravascular space and an extravascular space or interstitium. Both the vascular endothelium and the lymphatic endothelium are specialized in these different regions. The cell types in lymph nodes comprise lymphoid cells, accessory or non-lymphoid cells and stromal cells, and within these cell types a number of different sub-types can now be identified by means of enzyme- and immunocytochemistry. Based predominantly on experimental studies, the origin, migratory patterns, localization, inter-relationships and interactions between these various cells are reviewed.


Altered touch perception and associated risk factors in individuals with diabetes mellitus.
To evaluate the prevalence of altered touch perception in the feet of individuals with diabetes mellitus and the associated risk factors. Cross-sectional study with 224 individuals with diabetes mellitus conducted in an endocrinology clinic at a public hospital in Campina Grande, Paraíba. The evaluation used touch sensitivity and perception, and a descriptive and multivariate analysis with Poisson regression was performed. We found the prevalence of altered touch perception to be 53.1%. The risk factors that had a significant and joint impact on its occurrence were: female gender; previous ulcer; diabetes mellitus type 2; burning sensation, cracks, fissures, calluses, and Charcot foot. This study found a high prevalence of altered perception of touch, and this should support the planning of actions aimed at preventing the problem. The study showed the relevance of the phenomenon as a nursing diagnosis that could be included in NANDA-International.


Two Glycosyl 1-Phosphate Polymers and Teichulosonic Acid from Glutamicibacter protophormiae VKM Ac-2104T Cell Wall.
Two glycosyl 1-phosphate polymers containing monoglycosyl 1-phosphate, -6)-α-D-Glcp-(1-P-, and diglycosyl 1-phosphate, -6)-α-D-GalpNAc-(1→6)-α-D-GlcpNAc-(1-P-, in the repeating unit were identified in the cell wall of Glutamicibacter protophormiae VKM Ac-2104T (formerly, Arthrobacter protophormiae). The structures of these polymers were described for the first time in prokaryotes. Teichulosonic acid, the third identified polymer, with 3-deoxy-D-glycero-α-D-galacto-non-2-ulopyranosonic acid (Kdn) and β-D-glucopyranose residues in the main chain, →6)-β-D-Glcp-(1→8)-α-Kdn-(2→, has been previously detected in a number of actinobacteria. The structures of these glycopolymers were established based on the results of chemical analysis and one-dimensional 1H, 13C, and 31P NMR spectroscopy using two-dimensional homonuclear (1H,1H COZY, TOCSY, ROESY) and heteronuclear (1H,13C HSQC, HSQC-TOCSY, HMBC, and 1H,31P HMBC) techniques.


[Interhemispheric asymmetry of homotopic transcallosal responses of the auditory cortex in the cat].
In majority of 29 immobilized cats under study, the potentials in the right hemisphere had a greater amplitude and shorter latencies than in the left hemisphere when comparing 150-170 symmetrical points in the auditory cortex. The interhemispheric asymmetry depended on the sex of the animals: it was more obvious in females. The maximal asymmetry was observed in pregnant females. The described polarity of transcallosal influences in the auditory cortex seems to be associated with the predominant role of the right hemisphere in organization of spatial hearing.


Purification and characterization of membrane-bound peroxidase from date palm leaves (Phoenix dactylifera L.).
Peroxidase from date palm (Phoenix dactylifera L.) leaves was purified to homogeneity and characterized biochemically. The enzyme purification included homogenization, extraction of pigments followed by consecutive chromatographies on DEAE-Sepharose and Superdex 200. The purification factor for purified date palm peroxidase was 17 with 5.8% yield. The purity was checked by SDS and native PAGE, which showed a single prominent band. The molecular weight of the enzyme was approximately 55 kDa as estimated by SDS-PAGE. The enzyme was characterized for thermal and pH stability, and kinetic parameters were determined using guaiacol as substrate. The optimum activity was between pH 5-6. The enzyme showed maximum activity at 55 °C and was fairly stable up to 75 °C, with 42% loss of activity. Date palm leaves peroxidase showed K m values of 0.77 and 0.045 mM for guaiacol and H2O2, respectively. These properties suggest that this enzyme could be a promising tool for applications in different analytical determinations as well as for treatment of industrial effluents at low cost.


Well-being in the Intensive Care Unit: Looking Beyond COVID-19.
Burnout among critical care personnel has increased due to the additional psychological and physical demands of caring for critically ill patients with limited resources. Factors that increase the risk of burnout include compassion fatigue, lack of control over the work environment, difficult interpersonal relationships, and constant exposure to end-of-life issues. Organizational commitment to physician wellbeing depends on improving workplace efficiency, recognizing stressors in the critical care environment, and providing resources to help manage staffing shortages. Community building, training in communication, and team-building strategies are important steps in building collaboration and camaraderie in the workplace.


Time-dependent AI-Modeling of the anticancer efficacy of synthesized gallic acid analogues.
Main objective of this study is mapping of the anticancer efficacy of synthesized gallic acid analogues using modeling and artificial intelligence (AI) over a large range of concentrations and exposure times to explore the underline mechanisms of drug action and draw careful inferences regarding drug response heterogeneity. Two series of gallic acid derivatives i.e. esters and amides have been synthesized and characterized by FTIR, NMR and mass spectrometry. The compounds have been tested in vitro for their anticancer activity against wild type human ovarian cancer cell line A2780, prostate cancer cell line PC3 and normal human fibroblast cells 3T3. To completely characterize optimal anticancer activity, a comprehensive model using piecewise recursive Hill model is used to quantitatively assess the in vitro anticancer effect of the tested compounds as a function of concentration and exposure time for periods ranging from 24 to 72 h. A robust artificial intelligence approach i.e. the "Support Vector Machine (SVM) Learning Algorithm" is adopted to utilize the data obtained at different temporal values, to identify compounds that trail forecasting algorithm. All the synthesized analogues were found biocompatible. Significantly low EC50 values indicated that tested compounds have potent anticancer activity against A2780 cell line in comparison to PC3 cells where only few compounds generated same impact at almost 200 times high dose. On the basis of EC50 values, compounds 7 h, 7 m, 9c, 9b, 7c, 7b and 7 g were identified as the most active anticancer agent against A2780. Three major patterns of drug response heterogeneity were observed for different compounds in the form of multiple Hill graphs and shallow slopes. The anticancer efficiency of the compounds was verified using Machine learning SVM regression learner algorithm. For compounds 7a, 7b, 7e, 7 g, 7o, 7 r, 9b, 9e-9 g higher accuracy was found in predicted and experimentally obtained end point potency in terms of % viability. Pharmacodynamics modeling of anticancer potential of the synthesized compounds revealed that drug efficacy and response heterogeneity could be modulated by changing the exposure time to optimize therapeutic impact. Combining experimental results with AI based drug action forecasting, compounds 7b, 7 g, and 9b may be tested further as potent anticancer agent for in vivo studies. This approach may serve a useful tool for extrapolation of in vitro results for generating lead compounds in in vivo and preclinical studies.


The IN-MIDAZ study - Intranasal midazolam in aborting seizures - An epilepsy monitoring unit based randomized controlled trial for efficacy.
To compare efficacy and safety of Intranasal and Intramuscular routes of midazolam administration in terminating seizures. This was an open label Randomized controlled trial (RCT). People with drug resistant epilepsy (DRE) undergoing Video Electroencephalogram (VEEG) monitoring, were randomized in a 1:1 ratio to receive either Intranasal (IN) or Intramuscular (IM) midazolam, for prolonged seizures: longer than 5 min for focal, and longer than 2 min for focal to bilateral tonic-clonic. Outcome assessor was blinded to the allocation arm. Primary outcome was time to electrographic seizure termination after administration of midazolam. All adverse events in both the groups were noted. A total of 1108 seizures were recorded in 130 subjects, of which 110 (65 seizures in 23 subjects in IN group; 45 seizures in 18 subjects in IM group) seizures required midazolam administration and were included in final analysis. Mean time to electrographic seizure termination after midazolam administration was 45.1 ± 23.8 s in the IM group and 90.4 ± 59.0 s in the IN group (p = 0.0014); mean time to clinical seizure termination was 53.9 ± 25.8 s in IM group and 104.3 ± 66.4 s in the IN group (p = 0.002). Local side effects were more in IN group; hypotension as serious adverse event was noted in the IM group. Though mean time to electrographic and clinical seizure termination was significantly lesser in Intramuscular group for both adults and pediatric population, it was still under 2 min in the Intranasal midazolam group.IN midazolam is a useful option for terminating seizures.


Spatial distribution of pesticides, organochlorine compounds, PBDEs, and metals in surface marine sediments from Cartagena Bay, Colombia.
Cartagena Bay is an estuarine system located in the Caribbean Sea (Colombia, South America), that receives fresh water from Canal del Dique, which is connected to the Magdalena River, the most important river of Colombia, with some of the most prominent Colombian cities located in its watershed, which has a high sediment yield. An analysis of persistent organic pollutants and heavy metals was carried out on marine sediments from Cartagena Bay. Cartagena Bay sediments deployed the occurrence of total levels of pesticides (thiocarbamates, bromacil, triazines, organochlorines, and organophosphorus), polybrominated diphenyl ethers (PBDEs), and polychlorinated biphenyls (PCBs), in sediments ranging from 0.83-33.67 ng/g dry-weight, 0.05-0.34 ng/g dry-weight, and 0.06-19.58 ng/g dry-weight, respectively. Their concentrations were lower than those reported in NOAA Screening Quick Reference Tables. DDTs and PCBs are banned organochlorine compounds, since, even at low levels, their presence in sediments represents a threat to aquatic organisms and, therefore, to human health through the trophic chain. Sediments showed high concentrations of strontium (50-959.6 mg/kg). All metals evaluated in the marine sediments were found in the S6 sampling point; this was near tannery and hydrocarbon industries (Pb 37.1 mg/kg, Cr 137.2 mg/kg, Cd 1.7 mg/kg, Cu 64.4 mg/kg, As 13.1 mg/kg, Sr 318.9 mg/kg); these results exceeded the accepted values of threshold effect levels (TEL) used as an indicator of their potential risk on marine life.


Neonatal periventricular leukomalacia without evidence of twin-to-twin transfusion syndrome following discordance in nuchal translucency: a case report.
We describe a case of neonatal periventricular leukomalacia (PVL) without evidence of twin-to-twin transfusion syndrome (TTTS) following discordance in nuchal translucency (NT). A 34-year-old woman with monochorionic twins after in-vitro fertilization and embryo transfer was referred to our hospital. At gestational week 11, fetus A showed increased NT (7.0 mm) and normal crown-rump length (CRL) (34.3 mm). Fetus B had normal values, with a NT of 1.3 mm and a CRL of 32.3 mm. Both twins maintained growth throughout pregnancy, with no evidence of TTTS. During the antepartum period, daily fetal heart rate monitoring showed a reassuring pattern. Cesarean delivery was performed in gestational week 32. Neonates A and B weighed 2,071 and 1,617 g, respectively (discordancy rate 21.9%), each with an Apgar score of 8 at 1 min. Soon after birth, brain ultrasonography of neonate A revealed high-echoic periventricular lesions bilaterally, and brain magnetic resonance imaging on day 7 revealed PVL. Neonate B showed completely unremarkable results.


Two-wheel drive-based DNA nanomachine and its sensing potential for highly sensitive analysis of cancer-related gene.
With the biological significance and important advances of nano-scale DNA devices, scientific activities have been directed toward developing molecular machinery. In this work, we present a novel two-wheel drive-based DNA nanomachine composed of one signaling recognition probe (SRP), one label-free recognition probe (LRP), and one driving primer (DP). Target DNA hybridization can activate LRP-based wheel driving by resorting to DP-mediated polymerization/nicking/displacement cycles. This in turn results in the accumulation of nicked strand 1 (NS1) that can initiate extended SRP-based wheel driving. As a result, the hairpin structure of SRP is stretched and pre-quenched fluorescence is restored. Meanwhile, lots of nicked strand 2 (NS2) are produced, which could hybridize perfectly with SRP and lead to further fluorescence amplification. It is worth noting that, because the nanomachine operation relies strongly on inputted target trigger, the unwanted background is completely eliminated. The detection limit of 1 pM and an excellent capability to recognize the single-base mutation were achieved. Significantly, the interrogating of target trigger extracted from cancer cells is already available, reflecting the potential for practical applications. As a proof-of-concept building, the unique analytical properties would significantly benefit the DNA nanomachines and reveal great promise in biochemical and biomedical studies.


Lymphatics and vascular channels; the differences behind similarity.
Although sharing many features and functions, there is a mounting body of evidence to suggest that there are subtle differences between lymphatics and vascular channels. New data suggest that Ets-1 and Ets-1-target MMP genes are differentially expressed in lymphatic and vascular channels. Since it is generally accepted that the Ets family of transcription factors play a significant role in the regulation of the expression of angiogenic factors, the finding that Ets-1 is apparently not involved in lymphangiogenesis may highlight one aspect where angiogenesis and lymphangiogenesis are differently regulated.


Ultrasound-guided contrast-enhanced sentinel node biopsy of the head and neck in a porcine model.
To test the feasibility of contrast-enhanced ultrasound (CEUS)-guided sentinel lymph node biopsy (SNB) of the head and neck in a porcine model. In this prospective, nonrandomized study, methylene blue and Sonazoid were injected into the lateral tongue or floor of mouth (FOM) of four swine. Real-time CEUS was used to identify contrast in the lymphatic channels flowing to the sentinel lymph node (SLN). Endoscopic or open SNB was performed. Neck dissection was then performed, and the residual nodal packet was examined for remaining contrast-enhancing or blue dye-stained nodes. In all eight procedures, the SLN was visualized with ultrasound and blue dye. Seven procedures identified a single SLN, and one identified two SLNs. Subsequent neck dissections revealed no other nodes containing methylene blue or contrast in the nodal specimen or operative bed. CEUS-guided SNB of the head and neck in swine is feasible, with success comparable to blue dye-guided SNB. This technique may offer several advantages over traditional techniques, and warrants further study.


Goals of palliative cancer therapy: scope of the problem.
This article describes some of the problems of palliative cancer therapy and proposes possible solutions. The topics discussed include the reasons for death in cancer patients, the definition of intermediate and indirect as opposed to direct and measurable goals of treatment, the insufficient outcomes of palliative therapies and the problems associated with the separation of palliative treatment and palliative care. As a solution to these problems, a concept of Tumor versus Host Disease (TvHD) is discussed, and different end points for palliation are defined for daily oncology practice and oncology research. Finally, a way to collect data outside randomized trials is proposed, and the need for data collection is emphasized.


Carbamoylating chemoresistance induced by cobalt pretreatment in C6 glioma cells: putative roles of hypoxia-inducible factor-1.
1. We tested whether pretreatment of reagents known to induce hypoxia-inducible factor-1 (HIF-1) may confer chemoresistance against cytotoxicity of 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) to rat C6 glioma cells. We also studied which cytotoxic mechanism(s) of chloroethylnitrosoureas could be neutralized by cobalt preconditioning. 2. Preconditioning of rat C6 glioma cells with cobalt chloride (300 microm, 2 h) induced HIF-1 binding activity based on electrophoretic mobility shift assay (EMSA). Results from Western blotting confirmed a heightened HIF-1alpha level upon cobalt chloride exposure (300-400 microm, 2 h). Cobalt chloride (300 microm) pretreatment for 2 h substantially neutralized BCNU toxicity, leading to increases in glioma cell survival based on MTT assay. In addition, pre-exposure of C6 cells with desferrioxamine (DFO; 400 microm, 3 h), an iron chelator known to activate HIF-1, also induced HIF-1 binding and rendered the glioma cells resistant to cytotoxicity of BCNU. 3. Pre-incubation with cobalt chloride abolished the cytotoxicity of several carbamoylating agents including 2-chloroethyl isocyanate and cyclohexyl isocyanate, the respective carbamoylating metabolites of BCNU and 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea. The protective effect of cobalt exposure, however, was not observed when cells were challenged with alkylating agents including temozolomide. 4. Cadmium chloride (50 microm) effectively reversed cobalt-induced HIF-1 activation. Correspondingly, cadmium chloride suppressed carbamoylating chemoresistance mediated by cobalt chloride pretreatment. Furthermore, both double-stranded oligodeoxynucleotide (ODN) decoy with HIF-1 cognate sequence and antisense phosphorothioate ODNs against HIF-1alpha partially abolished the carbamoylating chemoresistance associated with cobalt preconditioning. 5. Our results suggest that cobalt- or DFO-preconditioning may enhance glioma carbamoylating chemoresistance that is dependent, at least in part, on induction of HIF-1.


Bipolar spectrum disorder: What evidence for pharmacological treatment? A systematic review.
Bipolar spectrum disorder (BSD) is an extended concept of bipolar disorder (BD) that includes conditions that do not fulfill the criteria. There is no recommendation today about its treatment. We reviewed relevant literature focusing on pharmacological treatments, looking for high-strength evidence leading to guidelines. A literature search was conducted using MedLine / PubMed database and Google Scholar up to September 2018. Search words were related to BSD and pharmacological treatment. The literature search yielded 621 articles. Out of these, 35 articles met our selection criteria. There was limited high quality data. Only one randomized control trial (RCT) and one randomized open label trial were found. Most studies used different definition of BSD. There is a considerable lack of data and no evidence supporting efficacy of pharmacological treatment for BSD. There is a need for a consensus on the definition of BSD and more evidence studies to evaluate drug's effectiveness in this condition.


Red cell autoantibody production in utero: a case report.
Autoantibody production by the fetus is thought to be extremely unlikely. Only one possible case of in utero autoantibody production against red cells by the fetus has previously been described. A case of apparent red cell IgG autoantibody production in utero is reported. This was established by a positive direct antiglobulin test in a newborn infant without evidence of maternal alloantibodies or autoantibodies. There was no evidence of clinically significant hemolysis at the infant's birth. After 6 weeks, his direct antiglobulin test remained strongly positive. The infant thrived without evidence of hemolysis, and after 6 months the direct antiglobulin test was negative. The production of autoantibodies to red cells in utero is possible, though rare. This did not result in apparent hemolysis in this patient.


Determination of risedronate in human urine by column-switching ion-pair high-performance liquid chromatography with ultraviolet detection.
An HPLC assay for the determination of risedronate in human urine was developed and validated. Risedronate and the internal standard were isolated from 5-ml urine samples in a two-part procedure. First, the analytes were precipitated from urine along with endogenous phosphates as calcium salts by the addition of CaCl(2) at alkaline pH. The precipitate was then dissolved in 0.05 M ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid and subjected to ion-pair solid-phase extraction using a Waters HLB cartridge (1 ml, 30 mg) with 1-octyltriethylammonium phosphate as the ion-pair reagent. Following extraction, the analytes were initially separated from the majority of co-extracted endogenous components on a Waters X-Terra RP18 (4.6 x 50 mm, 3.5 microm) column. The effluent from the X-Terra was "heart-cut" onto a Phenomenex Synergi Polar RP (4.6 x 150 mm, 4 microm) column for final separation. UV detection (lambda=262 nm) was used to quantitate risedronate in the concentration range of 7.5-250 ng/ml. Mean recovery was 83.3% for risedronate and 86.5% for the internal standard. The intra-day precision of the assay, as assessed by replicate (n=5) standard curves, was better than 6% RSD for all points on the standard curve. Within-day accuracy for the standards ranged from 96.3 to 106.1% of nominal. Inter-day precision for quality controls assayed over a 3-week period was better than 5%, while inter-day accuracy was within 90% of nominal. The assay was employed to analyze samples collected during a clinical pharmacokinetics study.


US Immigration Is Associated With Rapid and Persistent Acquisition of Antibiotic Resistance Genes in the Gut.
Little is known about the effect of human migration on gut microbiome antibiotic resistance gene (ARG) carriage. Using deep shotgun stool metagenomics analysis, we found a rapid increase in gut microbiome ARG richness and abundance in women from 2 independent ethnic groups relocating from Thailand to the United States.


The use of an oral fluid immunoglobulin G ELISA for the detection of Helicobacter pylori infection in children.
Enzyme linked immunosorbent assay (ELISA) evaluation of oral fluid immunoglobulin G (IgG) antibodies to Helicobacter pylori is a unique approach for both epidemiological studies and the diagnosis of infection, especially in children. The use of oral fluid sampling to evaluate specific H. pylori IgG antibodies has advantages over serum, including reduced biohazard risk and noninvasive collection. Oral fluid sampling is fast and involves minimal patient discomfort. Since children facilitate transmission of H. pylori infection, a simple, accurate, noninvasive diagnostic test is necessary for large epidemiologic studies. The aim of our study was to evaluate a new oral fluid ELISA for detection of IgG antibodies to H. pylori in children. We compared this new oral fluid ELISA with the HM-CAPTM serum ELISA and gastric biopsy histology using 779 oral fluid samples from children collected at 11 clinical sites across the United States. This cohort included 315 children symptomatic for abdominal pain and 464 asymptomatic. All samples were evaluated in a double blind manner. The oral fluid ELISA demonstrated a sensitivity of 76.2% and a specificity of 94.0% in children 2 months old to 201/2 years, as compared with the HM-CAPTM serologic assay. The assay's sensitivity improved to 81.3% in children aged 5 or greater and the specificity remained at 94.0%. When compared with gastric biopsy histology in the same age group, the oral fluid ELISA demonstrated a sensitivity of 71.7% and a specificity of 90.4%. This new oral fluid ELISA is moderately sensitive and offers a very specific method for detecting H. pylori infection in older children, but it is of little value in children under the age of 5 years. Overall, we conclude that this oral fluid ELISA does not appear to be a helpful clinical tool for the diagnosis of H. pylori infection in children.


Management of pulmonary complications in neuromuscular disease.
The clinician working with patients with neuromuscular disease should be aware of the effects of muscle weakness on the respiratory system. Symptoms may present insidiously and can result in progressive loss of function, respiratory failure, and even death. A number of techniques, including several forms of mechanical ventilation as well as physical aids to assist airway hygiene, are available and are effective in improving symptoms and survival in appropriately selected patients with neuromuscular disease.