Factors related to survival from oral cancer in an Andalusian population sample (Spain).
Approximately 3% of malignant tumors originate in the oral cavity. The majority are squamous cell carcinomas, and a small percentage, malignant tumors of the salivary glands, lymphoreticular diseases, bone tumors, melanomas, sarcomas, malignant odontogenic tumors and metastases of tumors from other locations. The prognosis of these pathologies depends on the size, infiltration, and site of the lesion, the presence or absence of metastatic spread, and to a certain degree the differentiation of the tumor. The prognosis of an oral cancer remains generally negative, with 5-year survival figures below 50%, producing high rates of mortality and morbidity. To evaluate the influence of different variables on survival in an oral cancer population. Two-hundred and sixteen patients with oral squamous cell carcinoma were studied over a period of five years, evaluating 42 variables grouped into five data sections: personal, lesion, site, stage, and risk factors. Average survival was 2088 days, with a standard deviation of 98 days. The factors most associated with mortality were: location in the gingiva (p=0.0590), in the trigone (p=0.0104), size (T3-T4) (p=0.0004) and lymph node involvement (N2a-N2b) (p=0.0035). Tobacco and alcohol, nowadays considered to be highly significant in carcinogenesis, had no considerable influence on survival.


Expression of protein-tyrosine phosphatases in Acute Myeloid Leukemia cells: FLT3 ITD sustains high levels of DUSP6 expression.
Protein-tyrosine phosphatases (PTPs) are important regulators of cellular signaling and changes in PTP activity can contribute to cell transformation. Little is known about the role of PTPs in Acute Myeloid Leukemia (AML). The aim of this study was therefore to establish a PTP expression profile in AML cells and to explore the possible role of FLT3 ITD (Fms-like tyrosine kinase 3 with internal tandem duplication), an important oncoprotein in AML for PTP gene expression. PTP mRNA expression was analyzed in AML cells from patients and in cell lines using a RT-qPCR platform for detection of transcripts of 92 PTP genes. PTP mRNA expression was also analyzed based on a public microarray data set for AML patients. Highly expressed PTPs in AML belong to all PTP subfamilies. Very abundantly expressed PTP genes include PTPRC, PTPN2, PTPN6, PTPN22, DUSP1, DUSP6, DUSP10, PTP4A1, PTP4A2, PTEN, and ACP1. PTP expression was further correlated with the presence of FLT3 ITD, focusing on a set of highly expressed dual-specificity phosphatases (DUSPs). Elevated expression of DUSP6 in patients harboring FLT3 ITD was detected in this analysis. The mechanism and functional role of FLT3 ITD-mediated upregulation of DUSP6 was then explored using pharmacological inhibitors of FLT3 ITD signal transduction and si/shRNA technology in human and murine cell lines. High DUSP6 expression was causally associated with the presence of FLT3 ITD and dependent on FLT3 ITD kinase activity and ERK signaling. DUSP6 depletion moderately increased ERK1/2 activity but attenuated FLT3 ITD-dependent cell proliferation of 32D cells. In conclusion, DUSP6 may play a contributing role to FLT3 ITD-mediated cell transformation.


Lunar gravity: the first farside map.
A global lunar gravity field has been determined from data on the long-term motion of the Apollo 15 and Apollo 16 subsatellites and Lunar Orbiter 5. The nearside gravity map resolves major mascon basins and, in general, is in excellent agreemnent with the results of Muller and Sjogren. The farside gravity map is characterized by broad positive gravity in the highland regions with interspersed, localized, negative anomalies corresponding to major ringed basins. A comparison between global gravity and topography indicates that a thicker farside crust could be responsible for these gravitational differences between the two lunar hemispheres.


Visual loss associated with influenza A: a case report and review of literature.
A 24-year-old female presenting with influenza A pneumonia and simultaneous visual loss was hospitalized. A complete ophthalmological examination was performed three weeks later. Best corrected visual acuity was 20/70 (right eye) and 20/30 (left eye). A dilated fundus exam revealed bilateral vitreous cells and marked bilateral optic nerve swelling with associated peripapillary hemorrhages. A submacular hemorrhage was seen in the right eye. Spinal tap opening pressure was 490 mmHg, with normal cerebrospinal fluid cell counts. Eight months after the initial clinical presentation, the patient was asymptomatic, with normal posterior poles and a best corrected visual acuity of 20/30 in the right eye and 20/25 in the left eye. Although papilledema can produce peripheral retinal hemorrhages secondary to extensive retinal venous congestion, the presence of bilateral vitritis and elevated influenza serum titers suggested that the patient might be suffering from influenza retinopathy. Vitreous polymerase chain reaction could potentially aid in the diagnosis of influenza retinopathy.


Adsorption Mechanisms of Dodecylbenzene Sulfonic Acid by Corn Straw and Poplar Leaf Biochars.
Biochar is an eco-friendly, renewable, and cost-effective material that can be used as an adsorbent for the remediation of contaminated environments. In this paper, two types of biochar were prepared through corn straw and poplar leaf pyrolysis at 300 °C and 700 °C (C300, C700, P300, P700). Brunaer-Emmett-Teller N₂ surface area, scanning electron microscope, elemental analysis, and infrared spectra were used to characterize their structures. These biochars were then used as adsorbents for the adsorption of dodecylbenzene sulfonic acid (DBSA). The microscopic adsorption mechanisms were studied by using infrared spectra, 13C-nuclear magnetic resonance spectra, and electron spin resonance spectra. The surface area and pore volume of C700 (375.89 m²/g and 0.2302 cm³/g) were the highest among all samples. Elemental analysis results showed that corn straw biochars had a higher aromaticity and carbon to nitrogen (C/N) ratio than the poplar leaf biochars. High temperature caused the increase of carbon content and the decrease of oxygen content, which also gave the biochars a higher adsorption rate. Pseudo-second order kinetic provided a better fit with the experimental data. Adsorption isotherm experiments showed that the adsorption isotherm of C300 fit the linear model. For other biochars, the adsorption isotherms fitted Langmuir model. Biochars with high temperatures exhibited enhanced adsorption capacity compared with ones at low temperatures. The qmax values of biochars to DBSA followed the order of P700 > C700 > P300. The adsorption mechanisms were complex, including partition, anion exchange, the formation of H bonds, covalent bonds, and charge transfer. The adsorption by covalent bonding might be the key mechanism determining the adsorption capacity of P700.


Mixed methods evaluation of a self-management group programme for patients with neuromuscular disease and chronic fatigue.
To obtain insight into experiences of patients with a neuromuscular disease and chronic fatigue and their healthcare professionals regarding content and delivery of a multidisciplinary outpatient self-management group programme to improve social participation. This will inform future implementation. A mixed method study alongside a randomised controlled trial. University hospital, rehabilitation centre and community health centre. 29 patients with a neuromuscular disease and chronic fatigue and 13 healthcare professionals participated in this mixed methods study. Multidisciplinary group programme, called Energetic, consisted of a 4 months intervention with weekly meetings and covered four modules: (1) individually tailored aerobic exercise training; (2) education about aerobic exercise; (3) self-management training in applying energy conservation strategies and (4) implementation and relapse prevention in daily life. Quantitative data were collected by a questionnaire measuring patients' (n=25, all completed the programme) satisfaction with the perceived results, content and delivery of the programme. Qualitative data were collected by individual and focus group interviews to gain insight in the experiences of patients (n=18), next of kin (n=2) and healthcare professionals (n=13) with facilitators and barriers to programme implementation. Patients were satisfied with the number and length of the sessions, the different modules and the therapists. Analysis of the interviews led to five themes: (1) the combination of modules makes a complete picture, (2) the programme is physically and mentally intensive, (3) the group setting is valuable, (4) small variations in delivery occur in different settings, (5) therapists are coaches. Suggestions for programme improvement include a combination of face to face and e-health, enhancement of therapists' skills in guiding group interventions and inclusion of more booster sessions to evaluate and maintain self-management competencies. The Energetic programme could be implemented in different healthcare settings and group settings, and a combination of modules proved to be a facilitator for improving self-management. NCT02208687.


Diagnostic significance of immunoglobulin M antibodies to Toxoplasma gondii detected after separation of immunoglobulin M from immunoglobulin G antibodies.
Failure to demonstrate immunoglobulin M (IgM) antibodies by indirect immunofluorescence (IgM-IFA) in sera from some patients with acute acquired toxoplasmosis has recently been attributed to an inhibitory effect of high titers of IgG antibodies in these sera (Pyndiah et al. J. Clin. Microbiol. 9:170-174, 1979). To confirm these findings and define their importance for diagnosis, we used gel filtration to separate IgM from IgG antibodies in a series of sera that were negative in the IgM-IFA test. A total of 68 sera were from patients with acquired toxoplasmosis, 13 were from uninfected adults, 13 were from infants with congenital toxoplasmosis, and 7 were from uninfected neonates. Of the 68 sera from patients with acquired toxoplasmosis, IgM preparations (from the separated sera) were positive in the IgM-IFA test in 36 (53%). There was a significant (P = 0.00003) association between high titers of IgM-IFA antibodies in the IgM preparations (corrected for dilution of IgM antibodies by the gel filtration procedure) and recent acquisition of infection. IgM antibodies were also detected in 5 (38%) of the IgM preparations of 13 sera from congenitally infected infants but not in any of the IgM preparations of sera from uninfected neonates. IgG antibodies to Toxoplasma gondii were shown to interfere with demonstration of IgM antibodies in the IgM-IFA test. Treatment of sera with protein A resulted in greater dilution of IgM antibodies and less efficient separation of IgM from IgG antibodies than did separation of sera by gel filtration. Treatment of sera with protein A did not result in increased detection of IgM antibodies to T. gondii. Testing of IgM preparations (obtained by gel filtration) resulted in a significant increase in sensitivity of the IgM-IFA test for the diagnosis of recently acquired and congenital toxoplasmosis.


Structural dynamics in the C-terminal domain of calmodulin at low calcium levels.
Calmodulin undergoes Ca2+-induced structural rearrangements that are intimately coupled to the regulation of numerous cellular processes. The C-terminal domain of calmodulin has previously been observed to exhibit conformational exchange in the absence of Ca2+. Here, we characterize further the conformational dynamics in the presence of low concentrations of Ca2+ using 15N spin relaxation experiments. The analysis included 1H-15N dipolar/15N chemical shift anisotropy interference cross-correlation relaxation rates to improve the description of the exchange processes, as well as the picosecond to nanosecond dynamics. Conformational transitions on microsecond to millisecond time scales were revealed by exchange contributions to the transverse auto-relaxation rates. In order to separate the effects of Ca2+ exchange from intramolecular conformational exchange processes in the apo state, transverse auto-relaxation rates were measured at different concentrations of free Ca2+. The results reveal a Ca2+-dependent contribution due mainly to exchange between the apo and (Ca2+)1 states with an apparent Ca2+ off-rate of approximately 5115 s(-1), as well as Ca2+-independent contributions due to conformational exchange within the apo state. 15N chemical shift differences estimated from the exchange data suggest that the first Ca2+ binds preferentially to loop IV. Thus, characterization of chemical exchange as a function of Ca2+ concentration has enabled the extraction of unique information on the rapidly exchanging and weakly populated (<10 %) (Ca2+)1 state that is otherwise inaccessible to direct study due to strongly cooperative Ca2+ binding. The conformational exchange within the apo state appears to involve transitions between a predominantly populated closed conformation and a smaller population of more open conformations. The picosecond to nanosecond dynamics of the apo state are typical of a well-folded protein, with reduced amplitudes of motions in the helical segments, but with significant flexibility in the Ca2+-binding loops. Comparisons with order parameters for skeletal troponin C and calbindin D9k reveal key structural and dynamical differences that correlate with the different Ca2+-binding properties of these proteins.


Cross talk free fluorescence cross correlation spectroscopy in live cells.
Fluorescence correlation spectroscopy (FCS) is now a widely used technique to measure small ensembles of labeled biomolecules with single molecule detection sensitivity (e.g., low endogenous concentrations). Fluorescence cross correlation spectroscopy (FCCS) is a derivative of this technique that detects the synchronous movement of two biomolecules with different fluorescence labels. Both methods can be applied to live cells and, therefore, can be used to address a variety of unsolved questions in cell biology. Applications of FCCS with autofluorescent proteins (AFPs) have been hampered so far by cross talk between the detector channels due to the large spectral overlap of the fluorophores. Here we present a new method that combines advantages of these techniques to analyze binding behavior of proteins in live cells. To achieve this, we have used dual color excitation of a common pair of AFPs, ECFP and EYFP, being discriminated in excitation rather than in emission. This is made possible by pulsed excitation and detection on a shorter timescale compared to the average residence time of particles in the FCS volume element. By this technique we were able to eliminate cross talk in the detector channels and obtain an undisturbed cross correlation signal. The setup was tested with ECFP/EYFP lysates as well as chimeras as negative and positive controls and demonstrated to work in live HeLa cells coexpressing the two fusion proteins ECFP-connexin and EYFP-connexin.


The incidence of Turner's syndrome in Ibadan, Nigeria.
A study of 22 769 consecutive live births in a Nigerian hospital has revealed the incidence of Turner's syndrome to be 1 in 2745 live females. Shortness of stature and neck, low posterior hair line, broad chest with widely spaced rudimentary nipples, congenital lymphoedema, redundant lax neck skin and hypoplastic nails were the most common clinical features. Birth weight was above 2.5 kg in only five of the fourteen cases in which this measurement was taken. Associated renal and cardiovascular anomalies occurred in 87.5 and 45% of the cases respectively. While neither parental age nor the birth rank of the patients were contributory factors in the causation of the syndrome, ingestion of traditional medicinal concoctions during the pregnancy which appeared to have played a role in four out of the sixteen cases requires further studies.


An integrated study of glutamine alleviates enteritis induced by glycinin in hybrid groupers using transcriptomics, proteomics and microRNA analyses.
Glutamine has been used to improve intestinal development and immunity in fish. We previously found that dietary glutamine enhances growth and alleviates enteritis in juvenile hybrid groupers (Epinephelus fuscoguttatus♀ × Epinephelus lanceolatus♂). This study aimed to further reveal the protective role of glutamine on glycinin-induced enteritis by integrating transcriptome, proteome, and microRNA analyses. Three isonitrogenous and isolipidic trial diets were formulated: a diet containing 10% glycinin (11S group), 10% glycinin diet supplemented with 2% alanine-glutamine (Gln group), and a diet containing neither glycinin nor alanine-glutamine (fishmeal, FM group). Each experimental diet was fed to triplicate hybrid grouper groups for 8 weeks. The analysis of intestinal transcriptomic and proteomics revealed a total of 570 differentially expressed genes (DEGs) and 169 differentially expressed proteins (DEPs) in the 11S and FM comparison group. Similarly, a total of 626 DEGs and 165 DEPs were identified in the Gln and 11S comparison group. Integration of transcriptome and proteome showed that 117 DEGs showed consistent expression patterns at both the transcriptional and translational levels in the Gln and 11S comparison group. These DEGs showed significant enrichment in pathways associated with intestinal epithelial barrier function, such as extracellular matrix (ECM)-receptor interaction, tight junction, and cell adhesion molecules (P < 0.05). Further, the expression levels of genes (myosin-11, cortactin, tenascin, major histocompatibility complex class I and II) related to these pathways above were significantly upregulated at both the transcriptional and translational levels (P < 0.05). The microRNA results showed that the expression levels of miR-212 (target genes colla1 and colla2) and miR-18a-5p (target gene colla1) in fish fed Gln group were significantly lower compared to the 11S group fish (P < 0.05). In conclusion, ECM-receptor interaction, tight junction, and cell adhesion molecules pathways play a key role in glutamine alleviation of hybrid grouper enteritis induced by high-dose glycinin, in which miRNAs and target mRNAs/proteins participated cooperatively. Our findings provide valuable insights into the RNAs and protein profiles, contributing to a deeper understanding of the underlying mechanism for fish enteritis.


Adolescents' sense of coherence and smoking as longitudinal predictors of self-reported gingivitis.
This study sought to determine the influence of sense of coherence (SOC), a personal stress-coping resource, and smoking on the self-reported gingival health of a cohort of rural black South African adolescents. This 18-month study involved a three-wave survey of a representative sample of eighth graders from 11 randomly selected high schools in the Limpopo province, South Africa (n=970). Using a generalized estimating equation model, we examined the correlates of recent gingivitis, defined as self-reporting frequent gingival bleeding (GB). Explanatory variables included baseline socio-economic status, age, gender, plaque levels, toothbrushing frequency, tobacco use status and SOC levels. Among our sample, 74.6% reported experiencing gingivitis at some point during follow-up, while 41.9% reported frequent GB at the last survey. Factors that were positively associated with recent gingivitis include living in poor households [odds ratio (OR)=1.49; p<0.01], having higher plaque levels (OR=1.18; p=0.04) and smoking regularly (OR=1.57; p=0.04). Self-reporting gingivitis was negatively associated with being female (OR=0.76; p=0.02) and having a higher SOC (OR=0.96; p<0.001). Adolescent smoking and SOC levels are independent predictors of self-reported gingivitis. Therefore, in addition to plaque control, smoking prevention and the teaching of stress-coping skills may be important interventions for promoting adolescents' gingival health.


The limits of subfunctionalization.
The duplication-degeneration-complementation (DDC) model has been proposed as an explanation for the unexpectedly high retention of duplicate genes. The hypothesis proposes that, following gene duplication, the two gene copies degenerate to perform complementary functions that jointly match that of the single ancestral gene, a process also known as subfunctionalization. We distinguish between subfunctionalization at the regulatory level and at the product level (e.g within temporal or spatial expression domains). In contrast to what is expected under the DDC model, we use in silico modeling to show that regulatory subfunctionalization is expected to peak and then decrease significantly. At the same time, neofunctionalization (recruitment of novel interactions) increases monotonically, eventually affecting the regulatory elements of the majority of genes. Furthermore, since this process occurs under conditions of stabilizing selection, there is no need to invoke positive selection. At the product level, the frequency of subfunctionalization is no higher than would be expected by chance, a finding that was corroborated using yeast microarray time-course data. We also find that product subfunctionalization is not necessarily caused by regulatory subfunctionalization. Our results suggest a more complex picture of post-duplication evolution in which subfunctionalization plays only a partial role in conjunction with redundancy and neofunctionalization. We argue that this behavior is a consequence of the high evolutionary plasticity in gene networks.


Birth weight, cardiometabolic risk factors and effect modification of physical activity in children and adolescents: pooled data from 12 international studies.
Low and high birth weight is associated with higher levels of cardiometabolic risk factors and adiposity in children and adolescents, and increases the risk of cardiovascular diseases, obesity, and early mortality later in life. Moderate-to-vigorous physical activity (MVPA) is associated with lower cardiometabolic risk factors and may mitigate the detrimental consequences of high or low birth weight. Thus, we examined whether MVPA modified the associations between birth weight and cardiometabolic risk factors in children and adolescents. We used pooled individual data from 12 cohort- or cross-sectional studies including 9,100 children and adolescents. Birth weight was measured at birth or maternally reported retrospectively. Device-measured physical activity (PA) and cardiometabolic risk factors were measured in childhood or adolescence. We tested for associations between birth weight, MVPA, and cardiometabolic risk factors using multilevel linear regression, including study as a random factor. We tested for interaction between birth weight and MVPA by introducing the interaction term in the models (birth weight x MVPA). Most of the associations between birth weight (kg) and cardiometabolic risk factors were not modified by MVPA (min/day), except between birth weight and waist circumference (cm) in children (p = 0.005) and HDL-cholesterol (mmol/l) in adolescents (p = 0.040). Sensitivity analyses suggested that some of the associations were modified by VPA, i.e., the associations between birth weight and diastolic blood pressure (mmHg) in children (p = 0.009) and LDL- cholesterol (mmol/l) (p = 0.009) and triglycerides (mmol/l) in adolescents (p = 0.028). MVPA appears not to consistently modify the associations between low birth weight and cardiometabolic risk. In contrast, MVPA may mitigate the association between higher birth weight and higher waist circumference in children. MVPA is consistently associated with a lower cardiometabolic risk across the birth weight spectrum. Optimal prenatal growth and subsequent PA are both important in relation to cardiometabolic health in children and adolescents.


[Protection for noise-induced hearing loss using active hearing protection systems].
Though noise induced hearing loss is no longer the most frequent occupational disease in the Federal Republic of Germany, the environmental pollution by the product "noise" in our technical and industrialized world has not been reduced. On the contrary, the situation is worsened by the rising influence of leisure noise. To avoid occupational hearing loss, the "Noise Injury Prevention Code" issued by the insurers would demand wearing personal ear protection, e.g. ear plugs, if ambient noise levels are above 85 dB(A). But there are working places in which such equipment would have precisely the adverse effect, because one of the reasons for possible damage to hearing is radio communication. In military aircraft cockpits for example noise exposure measurements showed ambient noise levels above 90 dB(A) during regular flight service nearly all the time. To be able to understand radio traffic in spite of the noisy environment, the headphone volume must be raised above the noise of the engines. The use of ear plugs can only be of limited value. Whereas pilots with normal hearing show only little impairment of speech intelligibility, those with noise-induced hearing losses show substantial impairment that varies in proportion to their hearing loss. Communication abilities may be drastically reduced which may compromise the reliability of radio traffic. To avoid compromising air security one has to demand a noise protection system which allows to reduce ambient noise levels without disturbing speech intelligibility in the inevitable radio communication. Nowadays active noise cancelling (ANC) systems by electronic compensation in different ways provide effective protection against noise induced hearing loss.(ABSTRACT TRUNCATED AT 250 WORDS)


The safety of the hepatitis B vaccine. Inactivation of the AIDS virus during routine vaccine manufacture.
In the United States, one hepatitis B vaccine (Heptavax-B) has been licensed for the prevention of hepatitis B virus infections. Even though this vaccine has been shown to be highly effective and well tolerated in controlled trials and has been recommended for use in those at risk for acquiring infection by hepatitis B virus, many individuals have been reluctant to be immunized for fear of contracting acquired immunodeficiency syndrome (AIDS). In this study, we demonstrate that each of the three inactivation steps used in the manufacture of Heptavax-B independently will inactivate the infectivity of high-titered preparations of the AIDS virus; recipients of the hepatitis B vaccine do not develop antibodies to the AIDS virus; the hepatitis B vaccine does not contain detectable levels of nucleic acids related to the AIDS virus. These observations clearly demonstrate that vaccination with the currently available hepatitis B vaccine poses no demonstrable risk for acquiring AIDS.


Supplementation of carnitine leads to an activation of the IGF-1/PI3K/Akt signalling pathway and down regulates the E3 ligase MuRF1 in skeletal muscle of rats.
Recently, it has been shown that carnitine down-regulates genes involved in the ubiquitin-proteasome system (UPS) in muscle of pigs and rats. The mechanisms underlying this observation are yet unknown. Based on the previous finding that carnitine increases plasma IGF-1 concentration, we investigated the hypothesis that carnitine down-regulates genes of the UPS by modulation of the of the IGF-1/PI3K/Akt signalling pathway which is an important regulator of UPS activity in muscle. Male Sprague-Dawley rats, aged four weeks, were fed either a control diet with a low native carnitine concentration or the same diet supplemented with carnitine (1250 mg/kg diet) for four weeks. Components of the UPS and IGF-1/PI3K/Akt signalling pathway in skeletal muscle were examined. Rats fed the diet supplemented with carnitine had lower mRNA and protein levels of MuRF1, the most important E3 ubiquitin ligase in muscle, decreased concentrations of ubiquitin-protein conjugates in skeletal muscle and higher IGF-1 concentration in plasma than control rats (P < 0.05). Moreover, in skeletal muscle of rats fed the diet supplemented with carnitine there was an activation of the PI3K/Akt signalling pathway, as indicated by increased protein levels of phosphorylated (activated) Akt1 (P < 0.05). The present study shows that supplementation of carnitine markedly decreases the expression of MuRF1 and concentrations of ubiquitinated proteins in skeletal muscle of rats, indicating a diminished degradation of myofibrillar proteins by the UPS. The study moreover shows that supplementation of carnitine leads to an activation of the IGF-1/PI3K/Akt signalling pathway which in turn might contribute to the observed down-regulation of MuRF1 and muscle protein ubiquitination.


Development of a PFAS reaction library: identifying plausible transformation pathways in environmental and biological systems.
Perfluoroalkyl and polyfluoroalkyl substances (PFAS) are used in many consumer applications due to their stain repellency, surfactant properties, ability to form water-proof coatings and use in fire suppression. The production, application, transport, use and disposal of PFAS and PFAS-treated products have resulted in their wide-spread occurrence in environmental and biological systems. Concern over exposure to PFAS and their transformation products and metabolites has necessitated the development of tools to predict the transformation of PFAS in environmental systems and metabolism in biological systems. We have developed reaction libraries for predicting transformation products and metabolites in a variety of environmental and biological reaction systems. These reaction libraries are based on generalized reaction schemes that encode the process science of PFAS reported in the peer-reviewed literature. The PFAS reaction libraries will be executed through the Chemical Transformation Simulator, a web-based tool that is available to the public. These reaction libraries are intended for predicting the environmental transformation and metabolism of PFAS only.


Thyroid disorders in chronic hepatitis C virus infection.
The prevalence of thyroid disorders has been evaluated in patients with hepatitis C virus (HCV) infection by many studies. From a review of the published controlled studies, it is possible to observe that: (1) most investigated patients with chronic HCV hepatitis, while a minority evaluated hepatitis C virus antibody (HCVAb)- seropositive patients (the two conditions are not comparable with regards to thyroidal repercussions, in fact, HCVAb-seropositive patients do not necessarily display changes of the immune system present in chronically infected HCV patients); and (2) some authors selected as internal control hepatitis B virus (HBV)-infected patients, while others selected apparently healthy controls or HCVAb-negative subjects. Pooling all data about HCV-positive patients (with chronic hepatitis or HCVAb positivity) and using as control the sum of healthy controls, HBV-infected patients and sera negative for HCVAb, a significant increase of the prevalence has been observed both for thyroid autoimmune disorders (odds ratio [OR] = 1.6; 95% confidence interval = [C]) 1.4-1.9) as well as for hypothyroidism (OR = 2.9; 95% CI = 2.0-4.1). The results of the epidemiologic studies showing an association between HCV infection and thyroid cancer need to be confirmed. The abovementioned evidences seem sufficient to suggest careful thyroid monitoring during the follow-up of patients with HCV infection.


Mast cell-derived TNF-alpha primes sensory nerve endings in a pulmonary hypersensitivity reaction.
TNF-alpha is a cytokine associated with inflammatory diseases, including asthma. Increased levels of TNF-alpha were found in the bronchoalveolar lavage fluid of mice undergoing a dinitrofluorobenzene (DNFB)-induced non-IgE-mediated pulmonary hypersensitivity reaction. We report in this work that TNF-alpha increases the susceptibility of sensory neurons to dinitrobenzene sulfonic acid (DNS) and capsaicin, leading to a tracheal vascular hyperpermeability response in DNFB-sensitized and DNS-challenged mice. mAb against TNF-alpha or the TNFR1 inhibited this hyperpermeability response in DNFB-sensitized and DNS-challenged mice. Furthermore, the hyperpermeability response after DNS challenge was abolished in DNFB-sensitized mast cell-deficient WBB6F(1)-W/W(V) mice. These animals showed a remarked decrease of TNF-alpha bronchoalveolar lavage fluid levels after a single DNS challenge. The hyperpermeability response after DNS challenge was regained in mast cell-deficient mice after mast cell reconstitution. These findings indicate a prominent role for TNF-alpha and its TNFR1 in the DNFB-induced tracheal hyperpermeability response. We propose that a priming effect of mast cell-derived TNF-alpha on the sensory neurons could be the mechanism of action of TNF-alpha in the vascular hyperpermeability response in tracheas of mice undergoing a pulmonary hypersensitivity reaction.


A Case of Biliary Cast Syndrome After Endoscopic and Percutaneous Management of Common Bile Duct Stone.
Biliary cast syndrome is an unusual complication in patients who have previously undergone liver transplantation. It occurs in approximately 5%-18% of such patients. Rare cases of biliary cast syndrome in patients without liver transplants have also been reported. The pathogenesis of biliary cast has not been clearly identified, although etiologic factors including post-transplant bile duct damage, ischemia, biliary infection, and presence of a post-operative biliary drainage tube have been proposed. Here we present a case of biliary cast that developed in a 49-year-old male who underwent a non-liver surgery after endoscopic and percutaneous management of common bile duct stone.


RPL34-Divergent Transcript, a Novel Long NonCoding Ribonucleic Acid, Promotes Migration by Activating Epithelial-Mesenchymal Transition in Glioma.
Glioma is one of the leading causes of death in patients with intracranial tumours. RPL34 divergent transcript (RPL34-DT) is a long non-coding ribonucleic acid that is significantly upregulated in glioma tissues. However, the role of RPL34-DT in glioma behavior remains to be elucidated. Therefore, in this study, we focused on the effect of RPL34-DT on the epithelial-mesenchymal transition in gliomas. Real-time quantitative reverse transcription polymerase chain reaction was used to detect the levels of RPL34-DT in glioma tissue and cell lines. We further used the LN229 and U251 glioma cell lines to assess the role of RPL34-DT. Wound healing and invasion assays were performed to determine the role of RPL34-DT in migration. Changes in protein levels were assessed by western blotting. We found that RPL34-DT was upregulated in glioma tissues and glioma cell lines. Knockdown of RPL34-AS1 blocked migration of glioma cell. This effect occurred through a decrease of epithelial-mesenchymal transition and β-catenin. This study suggests that RPL34-DT affects cell migration in glioma and therefore may serve as a valuable therapeutic target in patients with glioma.


Acceptability of receiving lifestyle advice at cervical, breast and bowel cancer screening.
Cancer screening could be an opportunity to deliver cancer prevention advice, but it is not known how such information would be received. We explored willingness to receive lifestyle advice in the context of the English National Health Service cervical, breast, and bowel (FS; flexible sigmoidoscopy) screening programmes. A population-based survey was conducted in 2016 to collect nationally representative data on willingness to receive lifestyle advice across cervical (n = 768), breast (n = 420) and FS (n = 308) screening programmes. Additional items assessed the impact of lifestyle advice on screening attendance, preference for receiving advice in the event of an abnormal screening result, and timing of advice. Most respondents were willing to receive lifestyle advice around the time of cancer screening (cervical 78.9%, breast 79.4%, FS 81.8%), and if their results were abnormal (cervical 86.3%, breast 83.0%, FS 85.1%). A small proportion indicated it may discourage future attendance (cervical 4.9%, breast 7.0%, FS 8.8%). Most preferred information to be delivered at the screening appointment (cervical 69.8%, breast 72.6%, FS 70.7%). There were no associations between sociodemographic characteristics and willingness to receive lifestyle advice at breast screening. For those intending to attend cervical screening, non-White ethnicity and higher education were associated with increased willingness to receive lifestyle advice. Women were more likely to be willing to receive advice at FS screening than men. Providing lifestyle advice at cancer screening is likely to be acceptable to the general population. The optimal approach for delivery needs careful consideration to minimise potential negative effects on screening attendance.


Functionalized Membrane Domains: An Ancestral Feature of Archaea?
Bacteria and Eukarya organize their plasma membrane spatially into domains of distinct functions. Due to the uniqueness of their lipids, membrane functionalization in Archaea remains a debated area. A novel membrane ultrastructure predicts that monolayer and bilayer domains would be laterally segregated in the hyperthermophilic archaeon Thermococcus barophilus. With very different physico-chemical parameters of the mono- and bilayer, each domain type would thus allow the docking of different membrane proteins and express different biological functions in the membrane. To estimate the ubiquity of this putative membrane ultrastructure in and out of the order Thermococcales, we re-analyzed the core lipid composition of all the Thermococcales type species and collected all the literature data available for isolated archaea. We show that all species of Thermococcales synthesize a mixture of diether bilayer forming and tetraether monolayer forming lipids, in various ratio from 10 to 80% diether in Pyrococcus horikoshii and Thermococcus gorgonarius, respectively. Since the domain formation prediction rests only on the coexistence of di- and tetraether lipids, we show that all Thermococcales have the ability for domain formation, i.e., differential functionalization of their membrane. Extrapolating this view to the whole Archaea domain, we show that almost all archaea also have the ability to synthesize di- and tetraether lipids, which supports the view that functionalized membrane domains may be shared between all Archaea. Hence domain formation and membrane compartmentalization may have predated the separation of the three domains of life and be essential for the cell cycle.


Improving Osteogenesis Activity on BMP-2-Immobilized PCL Fibers Modified by the γ-Ray Irradiation Technique.
The purpose of this study was to demonstrate the ability of BMP-2-immobilized polycaprolactone (PCL) fibers modified using the γ-ray irradiation technique to induce the osteogenic differentiation of MG-63 cells. Poly acrylic acid (AAc) was grafted onto the PCL fibers by the γ-ray irradiation technique. BMP-2 was then subsequently immobilized onto the AAc-PCL fibers (BMP-2/AAc-PCL). PCL and surface-modified PCL fibers was characterized by evaluation with a scanning electron microscope (SEM), X-ray photoelectron spectroscopy (XPS), and contact angle. The biological activity of the PCL and surface-modified PCL fibers were characterized by alkaline phosphatase (ALP) activity, calcium deposition, and the mRNA expression of osteocalcin and osteopontin in MG-63 cells. Successfully grafted AAc and PCL fibers with immobilized BMP-2 were confirmed by XPS results. The results of the contact angle showed that BMP-2/AAc-PCL fibers have more hydrophilic properties in comparison to PCL fibers. The ALP activity, calcium deposition, and gene expressions of MG-63 cells grown on BMP-2/AAc-PCL fibers showed greatly induced osteogenic differentiation in comparison to the PCL fibers. In conclusion, these results demonstrated that BMP-2/AAc-PCL fibers have the potential to effectively induce the osteogenic differentiation of MG-63 cells.


Clinical characteristics and outcomes in Japanese patients with COPD according to the 2017 GOLD classification: the Ishinomaki COPD Network Registry.
The GOLD report provides a framework for classifying COPD in a way that reflects its clinical impact and allows treatment recommendations. The GOLD 2017 proposes a new classification whereby patients are grouped as A-D according to their symptoms and history of exacerbations. However, the clinical characteristics and outcomes in these patients are not well documented. In this prospective observational study, we analyzed data from the Ishinomaki COPD Network Registry. All patients with stable COPD were classified into the four groups defined by GOLD 2017. The patient demographics, clinical characteristics, number of exacerbations, and mortality rate during 1 year of follow-up were compared between the groups. Four hundred and one patients with stable COPD were identified. There were 240 patients (59.9%) in group A, 122 (30.4%) in group B, 16 (4.0%) in group C, and 23 (5.7%) in group D. Patients in groups B, C, and D had ORs of 2.95, 3.92, and 5.45, respectively, for risk of exacerbation relative to group A. Groups C and D experienced exacerbations more frequently, including exacerbations leading to hospital admission, than groups A and B (both P<0.001) during the 1-year follow-up period. Patients with a high risk of exacerbation (groups C and D) had a lower body mass index, showed more symptoms, used more respiratory medications, and had more severe airflow limitation than patients at low risk of exacerbation (groups A and B). Mortality was not different between the high-risk and low-risk groups. The results of our study provide evidence that the GOLD 2017 classification identifies patients with COPD at risk of exacerbations, including those requiring hospitalization, but has a poor ability to predict mortality.


A Comparative Visual Analytics Framework for Evaluating Evolutionary Processes in Multi-objective Optimization.
Evolutionary multi-objective optimization (EMO) algorithms have been demonstrated to be effective in solving multi-criteria decision-making problems. In real-world applications, analysts often employ several algorithms concurrently and compare their solution sets to gain insight into the characteristics of different algorithms and explore a broader range of feasible solutions. However, EMO algorithms are typically treated as black boxes, leading to difficulties in performing detailed analysis and comparisons between the internal evolutionary processes. Inspired by the successful application of visual analytics tools in explainable AI, we argue that interactive visualization can significantly enhance the comparative analysis between multiple EMO algorithms. In this paper, we present a visual analytics framework that enables the exploration and comparison of evolutionary processes in EMO algorithms. Guided by a literature review and expert interviews, the proposed framework addresses various analytical tasks and establishes a multi-faceted visualization design to support the comparative analysis of intermediate generations in the evolution as well as solution sets. We demonstrate the effectiveness of our framework through case studies on benchmarking and real-world multi-objective optimization problems to elucidate how analysts can leverage our framework to inspect and compare diverse algorithms.


Algal and Cyanobacterial Lectins and Their Antimicrobial Properties.
Lectins are proteins with a remarkably high affinity and specificity for carbohydrates. Many organisms naturally produce them, including animals, plants, fungi, protists, bacteria, archaea, and viruses. The present report focuses on lectins produced by marine or freshwater organisms, in particular algae and cyanobacteria. We explore their structure, function, classification, and antimicrobial properties. Furthermore, we look at the expression of lectins in heterologous systems and the current research on the preclinical and clinical evaluation of these fascinating molecules. The further development of these molecules might positively impact human health, particularly the prevention or treatment of diseases caused by pathogens such as human immunodeficiency virus, influenza, and severe acute respiratory coronaviruses, among others.


Investigation of ocular neovascularization-related genes and oxidative stress in diabetic rat eye tissues after resveratrol treatment.
Changes in vascular endothelial growth factor (VEGF), angiotensin-converting enzyme (ACE), matrix metalloproteinase (MMP)-9, and endothelial nitric oxide synthase (eNOS) mRNA expression profiles and oxidative stress in the eye tissue microenviroment may have important roles in ocular neovascularization and permeability in proliferative diabetic retinopathy. The present study investigated the effects of resveratrol (RSV) treatment on the mRNA expression profile of VEGF, ACE, MMP-9, and eNOS, which are associated with vascular neovascularization, and glutathione, protein carbonyl, and nitrite-nitrate levels, which are markers of oxidative stress in eyes of diabetic rats. Twenty-four Wistar albino male rats were divided into four groups. After diabetes induction with streptozotocin (10 mg/kg/day) RSV was administered to the RSV and diabetes mellitus (DM) + RSV groups for 4 weeks. The mRNA levels were measured by quantitative real-time polymerase chain reaction assay, and biochemical estimations were determined with spectrophotometric assays in eye homogenates. The mRNA expression levels of VEGF, ACE, and MMP-9 were increased in the DM group compared with the control group, and RSV treatment decreased their mRNA levels. Expression of eNOS mRNA was increased in the RSV and DM groups and decreased in the DM + RSV group. Nitrite-nitrate levels and protein carbonyl content were increased and glutathione levels were decreased in the DM group compared with controls. Consequently, these data suggest that RSV suppressed the expression of eNOS, which is actively involved in the inflammation and healing process in chronic diabetes. Although oxidative stress was increased in eye tissue from diabetic rats, mRNA levels of VEGF, MMP-9, and ACE genes associated with vascular remodeling did not change in diabetic eyes.


Calcium-dependent physiological processes in trees.
Among the various plant nutrients, calcium appears to occupy a unique position, acting as an important regulator in many processes related to both growth and responses to environmental stresses. This applies to stomatal function, cell division, cell wall synthesis, signalling functions in plant defence, repair of damage from biotic and abiotic stress and to the structural chemistry and function of woody tissues. The calcium content in the cambium of poplar was shown to rise transiently by as much as 40% in spring, indicating the significant role that calcium plays in the onset of cambial reactivation. Moreover, during bud flush and the beginning of cell division, calcium was reported to increase significantly in the apical meristem. A reduction in calcium supplies also proved to strongly affect wood formation, as evidenced in the pronounced reduction in wood increment, vessel size and fibre length, as well as in reduced carbonyl and methoxy groups from S-lignin. Induced wounding revealed that calcium acts as an intracellular signal and, furthermore, proved its involvement in long-distance electrical signalling. Environmental stimuli such as cold shock or wounding showed that poplar grown under calcium-starved conditions was incapable of responding to this type of stress. The above evidence highlights the important role of calcium in tree functions, both as a signal in minute physiologically active pools within the cytoplasm, and in higher concentrations for its impact on the structural integrity of cell walls and woody tissues.


[Alcohol--a perioperative problem of anaesthesia and intensive care medicine].
Alcohol is a socially tolerated drug. Its consumption is associated with several physiological and pharmacological negative side-effects during anaesthesia and intensive care. The impact of chronic and acute alcoholism on perioperative morbidity and mortality and especially on anaesthetic risk are important, due to pharmacological interactions, pathophysiological changes and direct pharmacological interactivities between alcohol and narcotics. In contrast to opioid withdrawal symptoms of alcohol withdrawal are a serious and potentially life-threatening complication and should be avoided or the risk for occurrence must at least be reduced. Patients with a high risk of developing perioperative symptoms of alcohol withdrawal can be detected by laboratory tests and questionnaires. A prophylaxis of withdrawal should be started preoperatively solely with benzodiazepines or in combination with clonidine. Haloperidol is the drug of choice for emerging symptoms of alcohol withdrawal with productive psychosis. To estimate the pharmacological changes during anaesthesia, it is necessary to differentiate whether the patient is an occasional drinker with acute intoxication, a chronic abuser without limitations of hepatic function or a chronic user with insufficiency of the liver. The most important implication for anaesthesia are the choice of a rapid sequence induction to reduce the risk of aspiration and the maintenance of haemodynamic stability and liver perfusion. For the acute alcoholic providing prolonged postoperative surveillance is necessary, for the chronic alcoholic intensive care seems to be mandatory. For regional anaesthesia the indications and limitations are the same as for other patients (cooperativeness, coagulation, consent, etc.).


Habitat restoration opportunities, climatic niche contraction, and conservation biogeography in California's San Joaquin Desert.
A recent global trend toward retirement of farmland presents opportunities to reclaim habitat for threatened and endangered species. We examine habitat restoration opportunities in one of the world's most converted landscapes, California's San Joaquin Desert (SJD). Despite the presence of 35 threatened and endangered species, agricultural expansion continues to drive habitat loss in the SJD, even as marginal farmland is retired. Over the next decades a combination of factors, including salinization, climate change, and historical groundwater overdraft, are projected to lead to the retirement of more than 2,000 km2 of farmland in the SJD. To promote strategic habitat protection and restoration, we conducted a quantitative assessment of habitat loss and fragmentation, habitat suitability, climatic niche stability, climate change impacts, habitat protection, and reintroduction opportunities for an umbrella species of the SJD, the endangered blunt-nosed leopard lizard (Gambelia sila). We use our suitability models, in conjunction with modern and historical land use maps, to estimate the historical and modern rate of habitat loss to development. The estimated amount of habitat lost since the species became protected under endangered species law in 1967 is greater than the total amount of habitat currently protected through public ownership and conservation easement. We document climatic niche contraction and associated range contraction away from the more mesic margins of the species' historical distribution, driven by the anthropogenic introduction of exotic grasses and forbs. The impact of exotic species on G. sila range dynamics appears to be still unfolding. Finally, we use NASA fallowed area maps to identify 610 km2 of fallowed or retired agricultural land with high potential to again serve as habitat. We discuss conservation strategies in light of the potential for habitat restoration and multiple drivers of ongoing and historical habitat loss.


Genotypes of Pneumocystis jiroveci isolates obtained in Harare, Zimbabwe, and London, United Kingdom.
Isolates of Pneumocystis jiroveci from sulfa-exposed and nonexposed patients from London, United Kingdom, and Harare, Zimbabwe, were genotyped. At the dihydropteroate synthase (DHPS) locus, there was evidence of selection pressure from sulfa drug exposure, and reversal of DHPS genotype ratios occurred when selection pressure was absent or was removed.


[Principles of immunotherapy in insulin-dependent diabetes mellitus].
There is now convincing evidence that insulin-dependent (Type 1) diabetes mellitus is an immunological disease. This is derived from observations of a genetically determined predisposition, an association of recent-onset diabetes with viral infections, an inflammatory cell infiltrate affecting the islets of Langerhans, autoantibodies against islet cells, insulin, insulin receptors, and other organ-specific or non-organ-specific antigens, as well as abnormalities of cell-mediated immunity and of non-antigen specific mediators. Finally, recurrent diabetes in cases of pancreas transplantation in monozygotic twins discordant for insulin-dependent diabetes underlines the influence of an autoimmune insulitis. The current concept of the aetiopathogenesis of most cases of insulin-dependent diabetes is that in genetically susceptible individuals any form of damage to beta cells by viral, toxic, dietary or other environmental factors may initiate beta cell destruction and/or aberrant antigen expression, followed by a self-perpetuating, mostly cell-mediated autoimmune destruction of the insulin-producing cells. Successful immunoprevention in autoimmune diabetes models, on the basis of these recent concepts, led to the assumption that immunotherapy by means of immunomodulative or immunosuppressive drugs might be a possible tool in the treatment of patients with recent onset insulin-dependent (Type 1) diabetes mellitus.


Phase III study comparing exemestane with tamoxifen as first-line hormonal treatment of metastatic breast cancer in postmenopausal women: the European Organisation for Research and Treatment of Cancer Breast Cancer Cooperative Group.
This phase III randomized open-label clinical trial was designed to evaluate the efficacy and safety of the steroidal aromatase inactivator exemestane versus the antiestrogen tamoxifen as first-line treatment for metastatic breast cancer (MBC) in postmenopausal women. The study was conducted at 81 centers and enrolled postmenopausal patients with measurable hormone-sensitive metastatic or locally advanced breast cancer. Prior adjuvant chemotherapy and/or tamoxifen were allowed. One previous chemotherapy regimen and no prior hormone therapy for advanced disease were permitted. Patients were randomly assigned to receive exemestane 25 mg or tamoxifen 20 mg orally once daily until disease progression or unacceptable toxicity occurred. A total of 371 patients enrolled at 79 sites (182 exemestane, 189 tamoxifen) were included in the analysis. Both treatments were generally well tolerated without major toxicity. Overall response rate was greater for exemestane than for tamoxifen treatment (46% v 31%; odds ratio = 1.85; 95% CI, 1.21 to 2.82; P = .005). Median progression-free survival (PFS) was longer with exemestane (9.9 months; 95% CI, 8.7 to 11.8 months) than with tamoxifen (5.8 months; 95% CI, 5.3 to 8.1 months). However, these early differences (Wilcoxon P = .028) did not translate to a longer-term benefit in PFS, the primary study end point (log-rank P = .121). There was also no difference in survival between both study arms. Exemestane is an effective and well-tolerated first-line hormonal treatment for postmenopausal women with MBC and offers significant early improvement in time to tumor progression when compared with tamoxifen.


e-Health for COVID-19 Epidemic: The Arizona Poison and Drug Information Center Experience.
Background: A significant challenge of the COVID-19 epidemic was the dissemination of accurate and timely information to the public, health care providers, and first responders. We describe the expansion of the Arizona Poison and Drug Information Center (APDIC) to fill such a need for residents of Arizona. Methodology: The original mission of the APDIC was recognition and management of chemical exposure, poisoning, envenomation, and drug-related medical problems. In response to COVID-19, APDIC expanded its personnel and facilities to accommodate telephone calls and teleconsults regarding COVID-19. Thirteen different topics dealing with COVID-19 were addressed and tracked and included: testing information, isolation, prevention, personal protective equipment, travel, vaccines, therapies, antibody testing, contact tracing, exposure to the virus and what to do in businesses, at work or at school regarding isolation and quarantine. Results: Responding to the public health needs, APDIC accepted >320,000 telephone calls and completed 48,346 teleconsults from March 3, 2020 to March 3, 2021. This represented a 15-fold increase in calls and twice the number of consults over 2019. Upon release of the vaccine, calls increased sharply with >7,000 calls in 1 day (February 7, 2021). Conclusion: In conclusion, the APDIC, rapidly expanded to address urgent public health information needs surrounding COVID-19 while still accomplishing its founding mission.


Oxygen Debt as Predictor of Mortality and Multiple Organ Dysfunction Syndrome in Severe COVID-19 Patients: A Retrospective Study.
Background: Oxygen debt (DEOx) represents the disparity between resting and shock oxygen consumption (VO2) and is associated with metabolic insufficiency, acidosis, severity, and mortality. This study aimed to assess the reliability of DEOx as an indirect quantitative measure for predicting multiple organ dysfunction syndrome (MODS) and 28-day mortality in patients admitted to the intensive care unit (ICU) with respiratory syndrome severe acute coronavirus type 2 (SARS-CoV-2) infection, in comparison to the Acute Physiology and Chronic Health Evaluation II (APACHE II), sepsis-related organ failure assessment (SOFA), and 4C scores. Methods: A retrospective cohort study was conducted, including ICU patients with SARS-CoV-2 infection between 2020 and 2021. Clinical data were extracted from the EPIMED Monitor Database®. APACHE II, SOFA, and 4C scores were calculated upon ICU admission, and their accuracy in predicting 28-day mortality and MODS was compared to DEOx. Multivariate logistic regression analysis was performed to analyze the outcome variables. Results: 708 patients were included, with a mortality rate of 44.4%. DEOx value was 11.16 ml O2/kg. The mean age was 58.7 years. Multivariate analysis showed that DEOx was independently associated with mortality, intubation, and renal injury. Each point increase in creatinine was associated with a higher risk of MODS. To determine the precision of the scores, area under the receiver operating characteristic curves (AUROC) analysis was performed with weak discrimination and similar behavior for the primary outcomes. The most accurate scale for mortality and MODS was 4C with an AUC of 0.683 and APACHE II with an AUC of 0.814, while that of the AUROC of DEOx was 0.612 and 0.646, respectively. Conclusions: DEOx showed similar predictive value to established scoring systems in critically ill patients with SARS-CoV-2 infection. The correlation of DEOx with these scores may facilitate early intervention in critically ill patients.


Functional organization of the second cortical visual area in primates.
The functional organization of the second cortical visual area was examined with three different anatomical markers: 2-[14C]deoxy-D-glucose, cytochrome oxidase, and various myelin stains. All three markers revealed strips running throughout the area, parallel to the cortical surface. The boundaries of these strips provide an anatomical criterion for defining the borders of this extrastriate region. Further, the demonstration of these strips allows a functional and anatomical analysis of modules in the area, just as the recent demonstration of spots in the primary visual cortex has allowed an analysis of modules there. The strips differ structurally and functionally from interstrip regions and these differences are similar to those seen between the spots and the interspot regions in the primary visual cortex. In the macaque the strips and spots differ with regard to binocular organization.


Celecoxib treatment alleviates cerebral injury in a rat model of post-traumatic epilepsy.
An important factor contributing to the development and occurrence of post-traumatic epilepsy (PTE) is neuroinflammation and oxidative stress. The effects of celecoxib include inhibiting inflammatory reactions and antioxidant stress and reducing seizures, making it a potential epilepsy treatment solution. To observe the effect of celecoxib on early epilepsy in post-traumatic epilepsy rats. Methods: Twenty-four adult healthy male Sprague-Dawley rats were randomly assigned to three groups: sham-operated, PTE, and celecoxib. A rat model of PTE was established by injecting ferrous chloride into the right frontal cortex. Afterward, the behavior of rats was observed and recorded. 3.0T superconducting magnetic resonance imaging (MRI) was used to describe the changes in ADC values of the brain. HE and Nissl staining were also used to detect the damage to frontal lobe neurons. Furthermore, the expression of COX-2 protein in the right frontal lobe was detected by Western blot. Moreover, the contents of IL-1 and TNF-α in the right frontal lobe were detected by enzyme-linked immunosorbent assay. Compared with the PTE group, the degree of seizures in rats treated with celecoxib declined dramatically (P < 0.05). Celecoxib-treated rats had significant decreases in tissue structural damage and cell death in the brain. The results of the MRI showed that celecoxib reduced the peripheral edema zone and ADC value of the cortex around the damaged area of the right frontal lobe in the celecoxib-treatment group, which was significantly decreased compared with the PTE group (P < 0.05). Furthermore, celecoxib decreased the expression of COX-2, IL-1β, and TNF-α in brain tissue (P < 0.05). In PTE rats, celecoxib significantly reduced brain damage and effectively reduced seizures. As a result of celecoxib's ability to inhibit inflammation, it can reduce the edema caused by injury in rat brain tissue.


[Nutritional therapy in children during perioperative period].
The efficiency of nutritive therapy was analyzed in cases of 37 patients with gastrointestinal pathologies. Group 1 comprised 12 patients with fistulas of different etiologies and localizations; and group 2 comprised 15 patients with esophageal pathologies, including 7 children with esophageal atresia and 8 children with post-burn cicatricial stenosis of the esophagus. A method of nutrition-status correction by means of both enteral and parenteral feeding is suggested on the basis of examination findings comprising both clinical and laboratory-and-instrumental data. Preparations for parenteral feeding, i.e. 10-20% fatty emulsions, 10% amino acids solutions and 15-20% glucose solutions, were made use of. Enteral diets: semi-element oligopeptide solutions, like Nutrilon pepti TSC, Alphare. Balanced mixtures: sour-milk Nan, AL 110, Nutrizon, Nutridrink. Practical recommendations were defined, on the basis of study results, as to the therapeutic feeding schemes during the in-hospital treatment stages.


Frontal Intermittent Rhythmic Delta Activity (FIRDA) in the Neurological Intensive Care: Prevalence, Determinants, and Clinical Significance.
Frontal intermittent rhythmic delta activity (FIRDA), a transient rhythmic slow wave pattern over the anterior EEG leads, has been reported in a wide variety of cerebral lesions and different metabolic disturbances. Few authors have analyzed the frequency and clinical significance of FIRDA in the critical care setting. We aimed to better understand these issues in our intensive care cohort and if possible, try to delineate its underlying mechanisms. Video-EEG reports of consecutive adult patients in the neurological intensive care unit (NICU) since 2009 were retrospectively reviewed to identify cases with FIRDA. Demographic, clinical, and laboratory data were obtained from EEG reports and patient charts. Age- and sex-matched patients with acute stroke, hospitalized in NICU and no FIRDA on video-EEG monitoring served as the control group. Among 162 patients who underwent video-EEG monitoring, FIRDA was documented in 17%. Female prevalence was 50% and age ranged from 23 to 82 years. Twenty-three (82%) of patients with FIRDA had a diagnosis of stroke. Comparison of demographic characteristics, EEG findings, metabolic disturbances and prognoses revealed no differences between stroke cases with and without FIRDA, except for higher frequency of acute and chronic isolated posterior circulation infarcts in patients with FIRDA. FIRDA is more commonly encountered in the neurocritical care setting as compared with outpatient EEG clinics. Our findings in stroke patients indicate that involved vascular territories may be related to the generation of FIRDA.


Non-oncologist Physician Knowledge of Radiation Therapy at an Urban Community Hospital.
Radiation therapy (RT) is a crucial part of cancer care, but previous work suggests that many non-radiation oncologist physicians are uncomfortable referring for RT. To evaluate training and understanding of RT, the authors sent invitations to complete an online questionnaire to all physicians at a community hospital in Bronx, NY, which asked about oncology training and self-rated and objective knowledge of RT. Out of 247 invited participants, 87 responded (35%). Among responders, 19 were attending physicians (22%) and 66 (76%) were residents. Seventy-two percent of respondents reported caring for > 5 cancer patients in the past month, but 54% reported never referring patients for RT. Sixty-nine percent of respondents stated they received no radiation oncology training in medical school, and 36% reported no general oncology training. Approximately half believed themselves to be "somewhat knowledgeable" about RT indications (48%), benefits (53%), and side effects (55%). Objective assessment mean score was 6.2/12 (median 7) for all respondents; Respondents with internal medicine specialization scored higher than others (mean 7.7 vs 3.5; p < 0.01). Scores did not differ between attending and resident physicians, resident post-graduate levels, or receiving oncology training in medical school. The factors most commonly cited as affecting RT referral decisions were type of cancer, patient wishes, family wishes, poor functional status, and life expectancy. Many physicians are unaware of RT effectiveness or indications, which may affect referral patterns. Previous oncology training was not associated with higher knowledge scores.


Unlocking the therapeutic potential of artificial metalloenzymes.
In order to harness the functionality of metals, nature has evolved over billions of years to utilize metalloproteins as key components in numerous cellular processes. Despite this, transition metals such as ruthenium, palladium, iridium, and gold are largely absent from naturally occurring metalloproteins, likely due to their scarcity as precious metals. To mimic the evolutionary process of nature, the field of artificial metalloenzymes (ArMs) was born as a way to benefit from the unique chemoselectivity and orthogonality of transition metals in a biological setting. In its current state, numerous examples have successfully incorporated transition metals into a variety of protein scaffolds. Using these ArMs, many examples of new-to-nature reactions have been carried out, some of which have shown substantial biocompatibility. Given the rapid rate at which this field is growing, this review aims to highlight some important studies that have begun to take the next step within this field; namely the development of ArM-centered drug therapies or biotechnological tools.


A comprehensive school-based clinic: university and community partnership.
To describe the evolution and current status of a university and community partnership engaged in operating an urban elementary school-based clinic (SBC) POPULATION: The children at the school who are eligible to receive care at the SBC include 500 elementary students and 200 adolescents who attend a magnet junior high school housed in the same building. The vast majority of the children attending the school are from families whose incomes are below the national poverty level. Eighty-five percent of the children are black. Fifteen percent are Hispanic, non-white. A variety of services and programs are offered to the children and their families for the promotion of health and the prevention of mental disorders. Service, education, and research occur simultaneously to achieve the multiple goals of the partners and participants. Advanced practice nurses can provide quality health and mental health care services for school-age children and their families through SBCs. Institutional partnerships, capitalizing on each other's strengths, can expand the availability of SBC offerings.


Dry period management and optimization of post-partum reproductive management in dairy cattle.
Dry period and early post-partum management are decisive factors for fertility in lactating dairy cows. Previous studies have shown that decreased dry matter intake (DMI) and increased non-esterified fatty acids (NEFA) negatively affect fertility and subsequent milk production. The traditional dry period decreases DMI prior to parturition, resulting in a decrease in energy intake. A negative energy balance increases NEFA concentration, and increased NEFA may impair the immune system, especially by decreasing neutrophil function prior to parturition. Earlier studies have shown that post-partum health disorders, including retained placenta and metritis, were correlated with periparturient neutrophil function. In addition, decreased DMI is also linked to a reduced body condition score (BCS) in dairy cows. These events in the periparturient period negatively affect fertility. Some manipulation, such as shortening the dry period, may be a solution to increased DMI in the periparturient period, preventing post-partum disorders and subsequent fertility issues. This article aims to explain the effects of shortening the dry period on reproduction and early post-partum treatments to improve fertility. In addition, timed artificial insemination protocols will be discussed for use during the post-partum period to improve fertility in dairy cows.


Prognostic factors and outcome of treatment in Perthes' disease: a prospective study of 368 patients with five-year follow-up.
This nationwide prospective study was designed to determine prognostic factors and evaluate the outcome of different treatments of Perthes' disease. A total of 28 hospitals in Norway were instructed to report all new cases of Perthes' disease over a period of five years and 425 patients were reported and followed for five years. Of these, 368 with unilateral disease were included in the present study. The hips were classified radiologically according to a modified two-group Catterall classification and the lateral pillar classification. A total of 358 patients (97%) attended the five-year follow-up, when a modified three-group Stulberg classification was used as a radiological outcome measure. For patients over six years of age at diagnosis and with more than 50% necrosis of the femoral head (152 patients), the surgeons at the different hospitals had chosen one of three methods of treatment: physiotherapy (55 patients), the Scottish Rite abduction orthosis (26), and proximal femoral varus osteotomy (71). Of these hips, 146 (96%) were available for the five-year follow-up. The strongest predictor of outcome was femoral head involvement of more or less than 50% (odds ratio (OR) = 7.76, 95% confidence interval (CI) 2.82 to 21.37), followed by age at diagnosis (OR = 0.98, 95% CI 0.92 to 0.99) and the lateral pillar classification (OR = 0.62, 95% CI 0.40 to 0.98). In children over six years at diagnosis with more than 50% of femoral head necrosis, proximal femoral varus osteotomy gave a significantly better outcome than orthosis (p = 0.001) or physiotherapy (p = 0.001). There was no significant difference between the physiotherapy and orthosis groups (p = 0.36), and we found no difference in outcome after any of the treatments in children under six years (p = 0.73). We recommend proximal femoral varus osteotomy in children aged six years and over at the time of diagnosis with hips having more than 50% femoral head necrosis. The abduction orthosis should be abandoned in Perthes' disease.


Growth hormone receptor expression in the nucleus and cytoplasm of normal and neoplastic cells.
Growth hormone (GH) exerts its regulatory functions in controlling metabolism, balanced growth and differentiated cell expression by acting on specific receptors which trigger a phosphorylation cascade, resulting in the modulation of numerous signalling pathways dictating gene expression. A panel of five monoclonal antibodies was used in mapping the presence and somatic distribution of the GH receptor by immunohistochemistry in normal and neoplastic tissues and cultured cells of human, rat and rabbit origin. A wide distribution of the receptor was observed in many cell types. Not all cells expressing cytoplasmic GH receptors displayed nuclear immunoreactivity. In general, the relative proportion of positive cells and intensity of staining was higher in neoplastic cells than in normal tissue cells. Immunoreactivity showed subcellular localisation of the GH receptor in cell membranes and was predominantly cytoplasmic, but strong nuclear immunoreaction was also apparent in many instances. Intense immunoreactivity was also observed in the cellular Golgi area of established cell lines and cultured tissue-derived cells in exponential growth phase, indicating cells are capable of GH receptor synthesis. The presence of intracellular GH receptor, previously documented in normal tissues of mostly animal origin, is the result of endoplasmic reticulum and Golgi localisation. Heterogeneity of immunoreactivity was found in normal and neoplastic tissue with a variable range of positive cells. The nuclear localisation of immunoreactivity is the result of nuclear GH receptor/binding protein, identically to the cytosolic and plasma GH-binding protein, using a panel of five monoclonal antibodies against the GH receptor extracellular region. The expression of GH receptors, not only on small proliferating tumour cells such as lymphocytes, but also on well differentiated cells including keratinocytes, suggests that GH is necessary not only for differentiation of progenitor cells, but also for their subsequent clonal expansion, differentiation and maintenance.


Parkinson's disease with late Pick's dementia.
We report a case in which typical clinical features of idiopathic Parkinson's disease existed for seven years prior to the development of significant behavioral and cognitive changes and severe dementia. The patient presented with right-sided resting tremor, bradykinesia, and rigidity, which were highly responsive to levodopa. Serial neuropsychological evaluation revealed no evidence of dementia until late in the disease. The patient deteriorated rapidly eight years into the disease, requiring full care. She died 16 years after symptom onset and post-mortem neuropathological analysis revealed Lewy body Parkinson's disease and Pick's disease. To our knowledge, this is the first non-familial case with this combination of clinical history and pathologically confirmed disease to be reported in the literature. The absence of a family history of any neurological disease sets this case apart from the recently described genetic cases of frontotemporal dementia with Parkinsonism linked to chromosome 17. In addition, the relatively late onset of dementia in frontotemporal dementia is atypical. While there is considerable debate regarding the cause of dementia in idiopathic Parkinson's disease, our case illustrates that Pick's disease is one such cause.


Biochemical and ultrastructural evidence for the association of basic fibroblast growth factor with cardiac gap junctions.
Basic fibroblast growth factor (bFGF) is a ubiquitous and multifunctional polypeptide that is believed to have a role in tissue repair and to act as a morphogen in embryonic development. Here, we have used immunohistochemical and biochemical methods with antibodies directed against the amino-terminal domain of bFGF, designated IS2, which recognize native and denatured bFGF, to demonstrate that in addition to its known intracellular and extracellular localization in heart, bFGF is also associated with cardiomyocyte gap junctions. In tissue sections, IS2 labeled regions of intercalated discs, producing an immunofluorescence pattern virtually indistinguishable from that obtained with antibodies against the heart gap junction protein connexin-43. By electron microscopy, gap junctions but not other regions of plasma membrane were heavily immunolabeled with this antibody. By solid phase immunoassay, bFGF was found to be more concentrated in a fraction enriched in cardiac gap junctions than in whole sarcolemmal preparations. Finally, an 18-kDa protein was recognized by several different antibodies specific for bFGF on Western blots of heart subcellular fractions enriched in gap junctions. We suggest that bFGF-like peptides are either an integral part of, or exist in close association with, cardiac gap junctions and thus may play a role in modulating gap junctional intercellular communication.


Chemical sensing with 2D materials.
During the last decade, two-dimensional materials (2DMs) have attracted great attention due to their unique chemical and physical properties, which make them appealing platforms for diverse applications in opto-electronic devices, energy generation and storage, and sensing. Among their various extraordinary properties, 2DMs possess high surface area-to-volume ratios and ultra-high surface sensitivity to the environment, which are key characteristics for applications in chemical sensing. Furthermore, 2DMs' superior electrical and optical properties, combined with their excellent mechanical characteristics such as robustness and flexibility, make these materials ideal components for the fabrication of a new generation of high-performance chemical sensors. Depending on the specific device, 2DMs can be tailored to interact with various chemical species at the non-covalent level, making them powerful platforms for fabricating devices exhibiting a high sensitivity towards detection of various analytes including gases, ions and small biomolecules. Here, we will review the most enlightening recent advances in the field of chemical sensors based on atomically-thin 2DMs and we will discuss the opportunities and the challenges towards the realization of novel hybrid materials and sensing devices.


Sensitivity and Specificity of the Modified Epworth Sleepiness Scale in Children With Craniopharyngioma.
Children with craniopharyngioma are at risk for excessive daytime sleepiness (EDS). Multiple Sleep Latency Testing (MSLT) is the gold standard for objective evaluation of EDS; however, it is time and resource intensive. We compared the reliability, sensitivity, and specificity of the modified Epworth Sleepiness Scale (M-ESS) and MSLT in monitoring EDS in children with craniopharyngioma. Seventy patients (ages 6 to 20 years) with craniopharyngioma completed the M-ESS and were evaluated by polysomnography and MSLT. Evaluations were made after surgery, if performed, and before proton therapy. MSLT revealed that 66 participants (81.8%) had EDS, as defined by a mean sleep latency (MSL) < 10 minutes, with only 28.8% reporting EDS on the M-ESS by using a cutoff score of 10. The M-ESS demonstrated adequate internal consistency and specificity (91.7%) but poor sensitivity (33.3%) with the established cutoff score of 10. A cutoff score of 6 improved the sensitivity to 64.8% but decreased the specificity to 66.7%. Patients with craniopharyngioma are at high risk for EDS, as documented objectively on the MSLT, but they frequently do not recognize or accurately report their sleepiness. Future sleep studies should investigate whether specific items or alternative self- and parent-reported measures of sleepiness may have greater clinical utility in monitoring sleepiness in this population.


Imprecision nutrition? Duplicate meals result in unreliable individual glycemic responses measured by continuous glucose monitors across four dietary patterns in adults without diabetes.
Continuous glucose monitors (CGMs) are being used to characterize postprandial glycemic responses and thereby provide personalized dietary advice to minimize glycemic excursions. However, the efficacy of such advice depends on reliable CGM responses. To explore within-subject variability of CGM responses to duplicate meals in an inpatient setting. CGM data were collected in two controlled feeding studies ( NCT03407053 and NCT03878108 ) in 30 participants without diabetes capturing 1056 meal responses in duplicate ~1 week apart from four dietary patterns. One study used two different CGMs (Abbott Freestyle Libre Pro and Dexcom G4 Platinum) whereas the other study used only Dexcom. We calculated the incremental area under the curve (iAUC) for each 2-h post-meal period and compared within-subject iAUCs using the same CGM for the duplicate meals using linear correlations, intra-class correlation coefficients (ICC), Bland-Altman analyses, and compared individual variability of glycemic responses to duplicate meals versus different meals using standard deviations (SDs). There were weak to moderate positive linear correlations between within-subject iAUCs for duplicate meals (Abbott r=0.47, p<0.0001, Dexcom r=0.43, p<0.0001), with low within-participant reliability indicated by ICC (Abbott 0.31, Dexcom 0.14). Bland-Altman analyses indicated wide limits of agreement (Abbott -31.3 to 31.5 mg/dL, Dexcom -30.8 to 30.4 mg/dL) but no significant bias of mean iAUCs for duplicate meals (Abbott 0.1 mg/dL, Dexcom -0.2 mg/dL). Individual variability of glycemic responses to duplicate meals was similar to that of different meals evaluated each diet week for both Abbott (SD duplicate = 10.7 mg/dL , SD week 1 =12.4 mg/dL, SD week 2 =11.6 mg/dL, p=0.38) and Dexcom (SD duplicate = 11.1 mg/dL, SD week 1 = 11.5 mg/dL, SD week 2 =11.9 mg/dL, p=0.60). Individual postprandial CGM responses to duplicate meals were unreliable in adults without diabetes. Personalized diet advice based on CGM measurements in adults without diabetes requires more reliable methods involving aggregated repeated measurements.


Risk factors for a phacodonesis surprise during cataract surgery in patients with pseudoexfoliation.
To evaluate the association of different pre-operative parameters with surprise phacodonesis during cataract surgery among patients with pseudoexfoliation (PXF). This is a retrospective charts review of all PXF patients who underwent cataract surgery between the years 2013 and 2018. Pre-operative parameters (demographics, biometry, intraocular pressure (IOP), endothelial cell count, pupil size, cataract density, glaucoma status, cup to disc ratio, number of glaucoma medications, prior intra-vitreous injections, risk for intraoperative floppy iris syndrome) were compared between patients with and without surprise phacodonesis. Binary logistic regression was used to calculate the predictive value of each parameter. Out of 396 surgical cases with computerized pre-operative assessment, we included 127 eyes of 120 PXF patients without evidence of phacodonesis preoperatively. The mean age was 77.8 ± 12.0 years, 63 (52.7%) were male, and 106 (84.2%) underwent phacoemulsification surgery. We identified 10 cases of surprise phacodonesis during surgery (8.2%). Compared to PXF cases without intraoperative phacodonesis, they had higher pre-operative IOP (23.0 ± 11.0 mmHg vs. 14.9 ± 3.8 mmHg, p < 0.001) and a higher rate of B scan use due to dense cataract obscuring posterior pole evaluation [4 (40%) vs. 15 (12.8%), p = 0.04]. Multivariant binary logistic regression confirmed that only baseline IOP contributed to the prediction of surprise phacodonesis (OR 1.22 CI 1.04-1.43, p = 0.014). Among patients with PXF undergoing cataract surgery, elevated IOP and poor posterior segment visibility requiring B scan use were associated with zonular instability putting these patients at risk for intra-operative complications.


Functional Impairment in Older Adults With Bipolar Disorder.
Data describing bipolar disorder in older adults people are scarce, particularly with regard to functional status. This observational, comparative study assessed psychosocial functioning in 33 euthymic older adults with bipolar disorder compared with 30 healthy controls. In addition, we evaluated the association between clinical variables and poor functioning in the patient group. The mean age of the group was 68.70 years. Patients with bipolar disorder experienced poorer psychosocial functioning (19.15 ± 11.36) than healthy controls (5.17 ± 3.72; p = 0.0001), as assessed using the Functioning Assessment Short Test. Significant differences between the groups were found for specific domains of functioning: autonomy, occupational functioning, cognitive functioning, financial issues, and interpersonal relationships (p = 0.0001, respectively). The largest variation was observed in overall functioning (Cohen's d = 0.63). The number of previous hospitalizations was strongly associated with poor overall functioning (F = 7.217, p = 0.002). Older patients with bipolar disorder had a greater functional impairment than the healthy control group. Implementation of novel rehabilitation models is critical to help patients manage their illness.


Neurologic soft signs in schizophrenia and character disorders. Organicity in schizophrenia with premorbid asociality and emotionally unstable character disorders.
Previous studies indicated that for two subgroups of patients, schizophrenics with premorbid asociality (SPA) and individuals with emotionally unstable character disorders (EUCD), central nervous system damage may have etiologic significance. It was hypothesized that these two patient groups would also have an increased number of neurologic soft signs. The relationship of neurologic examination, tests of auditory-visual integration, and intelligence quotient, and diagnoses was studied for 350 patients. Tests of reliability and persistence for all observed signs were performed. The EUCD and SPA groups had increased evidence of neurologic soft signs. Differences in patterns of IQ scores also suggest that different forms of brain damage may be present in these two groups. When the two groups were removed from the larger patient sample, those patients with other types of schizophrenia and character disorder did not exhibit evidence of neurologic impairment. This study of neurologic soft signs adds to the validity of considering SPA and EUCD as separate diagnostic entities.


Molecular cloning of the structural gene for exopolygalacturonate lyase from Erwinia chrysanthemi EC16 and characterization of the enzyme product.
The ability of Erwinia chrysanthemi to cause soft-rot diseases involving tissue maceration in many plants has been linked to the production of endo-pectate lyase E. chrysanthemi EC16 mutant UM1005, however, contains deletions in the pel genes that encode the known endopectate lyases, yet still macerates plant tissues. In an attempt to identify the remaining macerating factor(s), a gene library of UM1005 was constructed in Escherichia coli and screened for pectolytic activity. A clone (pPNL5) was identified in this library that contained the structural gene for an exopolygalacturonate lyase (ExoPL). The gene for ExoPL was localized on a 3.3-kb EcoRV fragment which contained an open reading frame for a 79,500-Da polypeptide. ExoPL was purified to apparent homogeneity from Escherichia coli DH5 alpha (pPNL5) and found to have an apparent molecular weight of 76,000 with an isoelectric point of 8.6. Purified ExoPL had optimal activity between pH 7.5 and 8.0 and could utilize pectate, citrus pectin, and highly methyl-esterified Link pectin as substrates. A PL- ExoPL- mutant of EC16 was constructed that exhibited reduced growth on pectate, but retained pathogenicity on chrysanthemum equivalent to that of UM1005. The results indicate that ExoPL does not contribute to the residual macerating activity of UM1005.


Diarrhea-associated HIV-1 APIs potentiate muscarinic activation of Cl- secretion by T84 cells via prolongation of cytosolic Ca2+ signaling.
Aspartyl protease inhibitors (APIs) effectively extend the length and quality of life in human immunodeficiency virus (HIV)-infected patients, but dose-limiting side effects such as lipodystrophy, insulin resistance, and diarrhea have limited their clinical utility. Here, we show that the API nelfinavir induces a secretory form of diarrhea in HIV-infected patients. In vitro studies demonstrate that nelfinavir potentiates muscarinic stimulation of Cl(-) secretion by T84 human intestinal cell monolayers through amplification and prolongation of an apical membrane Ca(2+)-dependent Cl(-) conductance. This stimulated ion secretion is associated with increased magnitude and duration of muscarinically induced intracellular Ca(2+) transients via activation of a long-lived, store-operated Ca(2+) entry pathway. The enhanced intracellular Ca(2+) signal is associated with uncoupling of the Cl(-) conductance from downregulatory intracellular mediators generated normally by muscarinic activation. These data show that APIs modulate Ca(2+) signaling in secretory epithelial cells and identify a novel target for treatment of clinically important API side effects.


Structure and dissolution of silicophosphate glass.
P2O5-SiO2-Na2O-CaO glasses are promising therapeutic ion-releasing materials. Herein, we investigated the state of silicon (Si) in P2O5-SiO2-Na2O-CaO glass using a model with a composition of 55.0P2O5-21.3SiO2-23.7Na2O (mol%), incorporating a six-fold-coordinated silicon structure ([6]Si). The model was constructed using a classical molecular dynamics method and relaxed using the first-principles method. Further, we experimentally prepared glasses, substituting Na2O for CaO, to investigate the dissolution of glass with varying [6]Si and PO4 tetrahedra (Q P n ) distributions (n = number of bridging oxygens (BOs) to neighboring tetrahedra). [6]Si in the glass model preferentially coordinated with Q P 3. When Si was surrounded by phosphate groups, phosphorus (P) induced the formation of [6]Si by elongating the Si-O distance, and [6]Si acted like a glass network former (NWF). Na+ coordinated with [6]Si-O-P bonds via electrostatic interactions with BO. 31P and 29Si magic-angle-spinning-nuclear-magnetic-resonance spectra of three experimental glass samples with the compositions of 55.0P2O5-21.3SiO2-xCaO-(23.7 - x)Na2O (mol%, x = 0, 12.4, and 23.7) showed that Q P 3 and [6]Si increased with increasing Na2O. When each glass powder was immersed in a tris-HCl buffer solution at 37 °C, the dissolution of NWF ions and network modifier (NWM) ions increased almost monotonically with time for all samples, indicating that the solubility of the samples was suppressed by the coexistence of CaO and Na2O, attributed to the delocalization of the electron distribution of P in the [6]Si-coordinated Q P 3 units compared to that in the P- or [4]Si-coordinated Q P 3 units, which reduces hydrolysis.


Vasopressin, ACTH, and blood pressure during hypoxia induced at different rates.
We decreased arterial PO2 at three different rates and measured blood pressure (BP), vasopressin (AVP), ACTH, and corticosteroid levels in nonsurgically stressed, anesthetized, paralyzed dogs. PaO2 was lowered to 28 Torr in 2 (fast), 10 (moderate), and 20 min (slow). The fast dPO2/dt produced a large spike in BP. Increases in AVP, ACTH, and corticosteroids were similar regardless of the dPO2/dt. When the spike in BP during the fast dPO2/dt was prevented with nitroprusside, hormone levels increased more quickly and were higher during the first 20-30 min of hypoxia. By 60 min, hormone levels were not different between experiments. The data suggest that 1) faster decreases in PO2 produce larger increases in BP, 2) increases in AVP, ACTH, and corticosteroids are primarily sensitive to the level of steady-state PaO2, and 3) increases in BP inhibit stress-induced increases in AVP and ACTH.


Interaction Between Catalase Gene Promoter Polymorphisms and Indoor Environmental Exposure in Childhood Allergic Rhinitis.
Allergic rhinitis (AR) is a highly prevalent chronic inflammatory disease affecting nearly 40% of the children in Taiwan. Genetic susceptibility may interact with specific environmental factors leading to allergic disease development. To assess the interactions between catalase gene promoter polymorphisms and environmental factors on the risk of AR, we conducted a case-control study in Taiwan. Data on AR and environmental factors were collected from 800 children using the ISSAC questionnaire. The case group consisted of 263 children with AR, and the control group consisted of =537 healthy children. Genotyping was performed for rs1001179 and rs769214 polymorphisms, and environmental exposure was assessed using four indicators including dwelling visible molds, mold odor, moisture on surfaces, and water damage. We found that the presence of visible molds, mold odor, and moisture was associated with AR. An apparent joint effect of the GG genotype and mold odor, compared with the AA and AG combined genotypes and without any exposure indicator (adjusted odds ratio [OR] = 1.95 [95% confidence interval (CI) = 1.20, 3.18]; interaction adjusted odds ratio = 2.59 [95% CI = 1.27, 5.30]), was observed. Our findings suggest that gene-environment interactions between the catalase polymorphism rs769214 and mold odor may play an important role in childhood AR development.


The arsenic-lowering effect of inulin-type prebiotics in end-stage renal disease: a randomized crossover trial.
Background: Circulatory imbalance of trace elements is frequent in end-stage renal disease (ESRD), leading to a deficiency of essential elements and excess of toxic elements. The present study aimed to investigate whether inulin-type fructans (ITFs) could ameliorate the circulatory imbalance by modulating gut microbiota and regulating the absorption and elimination of trace elements. Methods: Peritoneal dialysis patients were enrolled in a randomized crossover trial, undergoing interventions with ITFs (10 g d-1) and maltodextrin (placebo) over a 9-month period (with a 3-month washout). The primary outcomes included essential elements Mn, Fe, Co, Cu, Zn, Se, Sr, and Mo and potential toxic elements V, Cr, Ni, As, Cd, Ba, Tl, Pb, Th, and U in plasma. Secondary outcomes included the gut microbiome, short chain fatty acids (SCFAs), bile acids (BAs), and daily removal of trace elements through urine, dialysate and feces. Results: Among the 44 participants initially randomized, 29 completed the prebiotic, placebo or both interventions. The daily dietary intake of macronutrients and trace elements remained consistent throughout the study. The administration of 10 g d-1 ITFs significantly reduced plasma arsenic (As) by 1.03 μg L-1 (95%CI: -1.74, -0.33) (FDR-adjusted P = 0.045) down from the baseline of 3.54 μg L-1 (IQRs: 2.61-4.40) and increased the As clearance rate by urine and dialysis (P = 0.033). Positive changes in gut microbiota were also observed, including an increase in the Firmicutes/Bacteroidetes ratio (P = 0.050), a trend towards higher fecal SCFAs (P = 0.082), and elevated excretion of primary BAs (P = 0.035). However, there were no significant changes in plasma concentrations of other trace elements or their daily removal by urine, dialysis and feces. Conclusions: The daily administration of 10 g d-1 ITFs proved to be effective in reducing the circulating retention of As but demonstrated to be ineffective for other trace elements in ESRD. These sentences are ok to include but as "The clinical trial registry number is ChiCTR-INR-17013739 (https://www.chictr.org.cn/showproj.aspx?proj=21228)".


Nuclear Factor Erythroid 2-Related Factor 2 Activation Might Mitigate Clinical Symptoms in Friedreich's Ataxia: Clues of an "Out-Brain Origin" of the Disease From a Family Study.
Friedreich's ataxia (FRDA) is the most frequent autosomal recessive ataxia in western countries, with a mean age of onset at 10-15 years. Patients manifest progressive cerebellar and sensory ataxia, dysarthria, lower limb pyramidal weakness, and other systemic manifestations. Previously, we described a family displaying two expanded GAA alleles not only in the proband affected by late-onset FRDA but also in the two asymptomatic family members: the mother and the younger sister. Both of them showed a significant reduction of frataxin levels, without any disease manifestation. Here, we analyzed if a protective mechanism might contribute to modulate the phenotype in this family. We particularly focused on the transcription factor nuclear factor erythroid 2-related factor 2 (NRF2), the first line of antioxidant defense in cells, and on the glutathione (GSH) system, an index of reactive oxygen species (ROS) detoxification ability. Our findings show a great reactivity of the GSH system to the frataxin deficiency, particularly in the asymptomatic mother, where the genes of GSH synthesis [glutamate-cysteine ligase (GCL)] and GSSG detoxification [GSH S-reductase (GSR)] were highly responsive. The GSR was activated even in the asymptomatic sister and in the proband, reflecting the need of buffering the GSSG increase. Furthermore, and contrasting the NRF2 expression documented in FRDA tissues, NRF2 was highly activated in the mother and in the younger sister, while it was constitutively low in the proband. This suggests that, also under frataxin depletion, the endogenous stimulation of NRF2 in asymptomatic FRDA subjects may contribute to protect against the progressive oxidative damage, helping to prevent the onset of neurological symptoms and highlighting an "out-brain origin" of the disease.