Analyzing dynamic change in children's socioemotional development using the strengths and difficulties questionnaire in a large United Kingdom longitudinal study.
Many children who suffer from one mental health issue also suffer from at least one co-occurring disorder and a range of developmental psychopathology theories, including developmental cascade and network models, have been proposed to explain this widespread co-occurrence. Autoregressive latent trajectory models with structured residuals (ALT-SR) and multilevel graphical vector autoregression (GVAR) are recently proposed complementary approaches that can help operationalize and test these theories and provide new insights into the reciprocal relations between multiple mental health domains to advance the understanding of the development of co-occurring mental health problems. This study uses ALT-SR and multilevel GVAR models to analyze the temporal, contemporaneous, and between-person relations between key dimensions of child mental health: emotional problems, peer problems, conduct problems, hyperactivity/inattention, and prosociality as measured by the parent-reported Strengths and Difficulties Questionnaire (SDQ) in 17,478 children from the U.K. Millennium Cohort study at ages 3, 5, 7, 11, 14, and 17 years. Children's strengths and difficulties in different domains of psychosocial functioning were dynamically associated with each other over- and within-time. The ALT-SR highlighted that hyperactivity/inattention plays a central role in affecting other domains over developmental time, while the GVAR model highlighted comparably strong bidirectional relations between conduct problems and prosociality as well as between emotional problems and peer problems. This study confirms that mental health difficulties influence one another dynamically over time. The complementary techniques of ALT-SR and GVAR models offer different insights into co-occurring mental health problems and hold promise for supporting the building of more comprehensive developmental psychopathological theories that acknowledge the interconnectedness of different domains of mental health. (PsycInfo Database Record (c) 2022 APA, all rights reserved).


Do furanic and phenolic compounds of lignocellulosic and algae biomass hydrolyzate inhibit anaerobic mixed cultures? A comprehensive review.
Nowadays there is a growing interest on the use of both lignocellulosic and algae biomass to produce biofuels (i.e. biohydrogen, ethanol and methane), as future alternatives to fossil fuels. In this purpose, thermal and thermo-chemical pretreatments have been widely investigated to overcome the natural physico-chemical barriers of such biomass and to enhance biofuel production from lignocellulosic residues and, more recently, marine biomass (i.e. macro and microalgae). However, the pretreatment technologies lead not only to the conversion of carbohydrate polymers (ie cellulose, hemicelluloses, starch, agar) to soluble monomeric sugar (ie glucose, xylose, arabinose, galactose), but also the generation of various by-products (i.e. furfural and 5-HMF). In the case of lignocellulosic residues, part of the lignin can also be degraded in lignin derived by-products, mainly composed of phenolic compounds. Although the negative impact of such by-products on ethanol production has been widely described in literature, studies on their impact on biohydrogen and methane production operated with mixed cultures are still very limited. This review aims to summarise and discuss literature data on the impact of pre-treatment by-products on H2-producing dark fermentation and anaerobic digestion processes when using mixed cultures as inoculum. As a summary, furanic (5-HMF, furfural) and phenolic compounds were found to be stronger inhibitors of the microbial dark fermentation than the full anaerobic digestion process. Such observations can be explained by differences in process parameters: anaerobic digestion is performed with more complex mixed cultures, lower substrate/inoculum and by-products/inoculum ratios and longer batch incubation times than dark fermentation. Finally, it has been reported that, during dark fermentation process, the presence of by-products could lead to a metabolic shift from H2-producing pathways (i.e. acetate and butyrate) to non-H2-producing pathways (i.e. lactate, ethanol and propionate) and whatever the metabolic route, metabolites can be all further converted into methane, but at different rates.


New insights into the Tyrolean Iceman's origin and phenotype as inferred by whole-genome sequencing.
The Tyrolean Iceman, a 5,300-year-old Copper age individual, was discovered in 1991 on the Tisenjoch Pass in the Italian part of the Ötztal Alps. Here we report the complete genome sequence of the Iceman and show 100% concordance between the previously reported mitochondrial genome sequence and the consensus sequence generated from our genomic data. We present indications for recent common ancestry between the Iceman and present-day inhabitants of the Tyrrhenian Sea, that the Iceman probably had brown eyes, belonged to blood group O and was lactose intolerant. His genetic predisposition shows an increased risk for coronary heart disease and may have contributed to the development of previously reported vascular calcifications. Sequences corresponding to ~60% of the genome of Borrelia burgdorferi are indicative of the earliest human case of infection with the pathogen for Lyme borreliosis.


Cellular pharmacology of multi- and duplex drugs consisting of ethynylcytidine and 5-fluoro-2'-deoxyuridine.
Prodrugs can have the advantage over parent drugs in increased activation and cellular uptake. The multidrug ETC-L-FdUrd and the duplex drug ETC-FdUrd are composed of two different monophosphate-nucleosides, 5-fluoro-2'deoxyuridine (FdUrd) and ethynylcytidine (ETC), coupled via a glycerolipid or phosphodiester, respectively. The aim of the study was to determine cytotoxicity levels and mode of drug cleavage. Moreover, we determined whether a liposomal formulation of ETC-L-FdUrd would improve cytotoxic activity and/or cleavage. Drug effects/cleavage were studied with standard radioactivity assays, HPLC and LC-MS/MS in FM3A/0 mammary cancer cells and their FdUrd resistant variants FM3A/TK(-). ETC-FdUrd was active (IC(50) of 2.2 and 79 nM) in FM3A/0 and TK(-) cells, respectively. ETC-L-FdUrd was less active (IC(50): 7 nM in FM3A/0 vs 4500 nM in FM3A/TK(-)). Although the liposomal formulation was less active than ETC-L-FdUrd in FM3A/0 cells (IC(50):19.3 nM), resistance due to thymidine kinase (TK) deficiency was greatly reduced. The prodrugs inhibited thymidylate synthase (TS) in FM3A/0 cells (80-90%), but to a lower extent in FM3A/TK(-) (10-50%). FdUMP was hardly detected in FM3A/TK(-) cells. Inhibition of the transporters and nucleotidases/phosphatases resulted in a reduction of cytotoxicity of ETC-FdUrd, indicating that this drug was cleaved outside the cells to the monophosphates, which was verified by the presence of FdUrd and ETC in the medium. ETC-L-FdUrd and the liposomal formulation were neither affected by transporter nor nucleotidase/phosphatase inhibition, indicating circumvention of active transporters. In vivo, ETC-FdUrd and ETC-L-FdURd were orally active. ETC nucleotides accumulated in both tumor and liver tissues. These formulations seem to be effective when a lipophilic linker is used combined with a liposomal formulation.


Neuroimaging of NREM sleep in primary insomnia: a Tc-99-HMPAO single photon emission computed tomography study.
The objectives of this study were to: 1) demonstrate the feasibility of combining polysomnography and SPECT neuroimaging to study NREM sleep in primary insomnia and 2) evaluate possible functional CNS abnormalities associated with insomnia. Patients with insomnia and good sleeper controls were studied polysomnographically for three nights with a whole brain SPECT Scan of NREM sleep on Night 3. Groups were screened for medical/psychiatric history, substance use, and matched on age, body mass index, and education. Sleep Research Laboratory and Nuclear Medicine Center Nine females, 5 patients with chronic psychophysiologic insomnia and 4 healthy good sleepers (mean age 36 years, SD 12, range 27-55). N/A. Tomographs of regional cerebral blood flow during the 1st NREM sleep cycle were successfully obtained. Contrary to our expectations, patients with insomnia showed a consistent pattern of hypoperfusion across all 8 pre-selected regions of interest, with particular deactivation in the basal ganglia (p=.006). The frontal medial, occipital, and parietal cortices also showed significant decreases in blood flow compared to good sleepers (p<.05). Subjects with insomnia had decreased activity in the basal ganglia relative to the frontal lateral cortex, frontal medial cortex, thalamus, occipital and parietal cortices (p<.05). This study demonstrated the feasibility of combining neuroimaging and polysomnography to study cerebral activity in chronic insomnia. These preliminary results suggest that primary insomnia may be associated with abnormal central nervous system activity during NREM sleep that is particularly linked to basal ganglia dysfunction.


An organ-preserving selective arterial chemotherapy strategy for head and neck cancer.
Squamous cancer of the upper aerodigestive tract is a disheartening disease. Despite our best efforts, the long-term survival rate remains only 15% to 40%, and surgical cures often decrease the quality of life owing to the loss of swallowing and speech organs. A better understanding of tumor dynamics and the discovery that thiosulfate can neutralize cisplatin led us to develop a treatment plan that combines a rapid superselective high-dose intraarterial delivery of cisplatin (CDDP), simultaneous intravenous infusion of its antagonist, thiosulfate, and radiation therapy. Patients with advanced head and neck squamous cancer were entered into the protocol after a multidisciplinary evaluation that included CT or MR imaging. Forty-two patients constituted the first cohort. After baseline angiography, an arterial acceptance test determined the maximum infusion rate that the tumor's nutrient artery would accept. CDDP was then infused at that rate, usually within 3 to 5 minutes, while the antagonist thiosulfate was given intravenously. In the second cohort of 85 patients with stage 3 or 4 previously untreated and unresectable disease, local radiation was added to the treatment plan. The radiation dose (180-200 cGy/d x 35) was delivered regionally on the basis of the known radiosensitizing effect of CDDP. Cohort 1 allowed us to develop the infusion technique and to establish a dose quantity and delivery frequency. When 150 mg/m2 was administered weekly for 4 weeks, no severe toxicity was found. In cohort 2, 72 (92%) of the remaining 78 patients had complete disappearance of their tumor. Seventeen severe toxic events were associated with 323 femoral catheterizations. One patient died of pulmonary embolus, precluding follow-up evaluation. Six patients had neurologic sequelae, three with transient and three with permanent strokes. Rapid superselective chemotherapy with CDDP combined with a circulatory systemic antagonist allowed delivery of an antitumoral drug directly into the lesion while protecting the kidneys and bone marrow from the agent's systemic effects. Use of a dose regimen of 150 mg CDDP/m2 per week for 4 weeks resulted in the disappearance of a large percentage of advanced squamous cancers.


Dental therapy practice patterns in Minnesota: a baseline study.
A chronic shortage of dentists, the importance of oral health, and the lack of access to care led to the introduction of a new oral health practitioner in Minnesota, the dental therapist. Dental therapy graduates from the University of Minnesota have been in practice since 2012. To date, there has been no formal study of how they have been incorporated into dental practice. The purpose of this study was to obtain baseline knowledge of dental therapists' practice patterns in Minnesota and determine if dentists' patterns of work changed after a dental therapist was employed. Four dental practices were sampled purposefully to obtain various practice types and geographic locations within Minnesota. Secondary data were collected from practice management software databases in each practice between January-March, 2015. Data were used to describe the work undertaken by dental therapists, the types of patients seen and payer mix. Additionally, data from 6 months before and after employment of the dental therapist were collected to determine whether dentists' practice patterns changed after a dental therapist was employed. Dental therapists were employed full-time, seeing an average of 6.8 patients per day. No distinct pattern emerged with regard to ages of patients seen by dental therapists. Dental therapists saw up to 90% of uninsured patients or patients on public assistance. Restorative services across practices comprised an average of 68% of work undertaken by dental therapists. Dentists delegated a full range of procedures within the dental therapy scope of practice indicating trust and acceptance of dental therapists. Dentists in two practices began to take on more complex dental procedures after a dental therapist joined the practice. Dental therapists are treating a high number of uninsured and underinsured patients, suggesting that they are expanding access to dental care in rural and metropolitan areas of Minnesota. Dentists appear to have an adequate workload for dental therapists and are delegating a full range of procedures within their scope of practice. Dentists performed fewer restorative and preventive procedures after a DT was hired.


Calibration of computer-assisted (Respicomp) respiratory inductive plethysmography in newborns.
We investigated the accuracy of a computer-assisted, respiratory inductive plethysmograph (Respicomp) on 50 awake human newborns who were lying supine. Breaths were selected with different rib cage (RC) to pneumotach (PNT) and abdomen (AB) to pneumotach (PNT) values. The equation RC/PNT + AB/PNT = 1 was solved using the least squares method (LSQ) of calculation of calibration factors. Validation of the calibration factors was performed with a range of consecutive breaths between 6 and 22. Of the 1,128 validation or revalidation breaths, 628 (56%) were within 10% of the simultaneously measured PNT volume, 1,024 (91%) were within 20%, and 1,128 (100%) were within 30%. The RC or AB compartment contributions to ventilation changed spontaneously in the awake newborns. This change eliminated the need to wait for varying sleep states to obtain calibration factors and reduced total time required for calibration. (Some loss of accuracy is a compromise with this method; the calibration factors obtained do not remain accurate while the infant is asleep.) This method provided a reliable and rapid calibration and validation technique of the respiratory inductive plethysmograph (Respicomp) on awake newborns.


Combining proteomics, serum biomarkers and bioinformatics to discriminate between esophageal squamous cell carcinoma and pre-cancerous lesion.
Biomarker assay is a noninvasive method for the early detection of esophageal squamous cell carcinoma (ESCC). Searching for new biomarkers with high specificity and sensitivity is very important for the early detection of ESCC. Serum surface-enhanced laser desorption/ionization-time of flight mass spectrometry (SELDI-TOF-MS) is a high throughput technology for identifying cancer biomarkers using drops of sera. In this study, 185 serum samples were taken from ESCC patients in a high incidence area and screened by SELDI. A support vector machine (SVM) algorithm was adopted to analyze the samples. The SVM patterns successfully distinguished ESCC from pre-cancerous lesions (PCLs). Also, types of PCL, including dysplasia (DYS) and basal cell hyperplasia (BCH), and healthy controls (HC) were distinguished with an accuracy of 95.2% (DYS), 96.6% (BCH), and 93.8% (HC), respectively. A marker of 25.1 kDa was identified in the ESCC patterns whose peak intensity was observed to increase significantly during the development of esophageal carcinogenesis, and to decrease obviously after surgery. We selected five ESCC biomarkers to form a diagnostic pattern which can discriminate among the different stages of esophageal carcinogenesis. This pattern can significantly improve the detection of ESCC.


Pyrimidine starvation induced by adenosine in fibroblasts and lymphoid cells: role of adenosine deaminase.
In the presence of 10(-4) to 10(-5) molar adenosine, established cell lines of fibroblastic or lymphoid origin die of pyrimidine starvation. Less than lethal concentrations inhibit cell growth. Over a broad concentration range, the effects of adenosine are prevented by providing a suitable pyrimidine source. We suggest that the recently described immune deficiency disease associated with absence of adenosine deaminase may be the result of pyrimidine starvation induced by adenosine nucleotides in cells of the lymphoid system.


Women's experiences of monitoring the small-for-gestational age fetus by ultrasound: A qualitative study.
To explore experiences among pregnant women diagnosed with a small-for-gestational age (SGA) fetus, and monitored by frequent ultrasounds. We performed a qualitative study at the outpatient clinic of the Gynecology and Obstetrics department of a large academic hospital in Amsterdam. Semi-structured interviews were conducted with fifteen women, diagnosed with an SGA fetus during their pregnancy and having had at least two monitoring ultrasounds since. Themes were identified following analysis of the interview transcripts. Most women experienced the frequent ultrasounds as a source of support providing comfort and a feeling of safety. It was considered necessary, in the best interest of the baby, which outweighed the discomfort caused by having to come to the hospital frequently. Women described anxiety building up prior to each ultrasound, but feeling reassured and relieved afterwards. During the ultrasound a continuous explanation was preferred, which provided confirmation and a feeling of security. Women identified the uncertainty of SGA's cause and prognosis as one of the biggest challenges to cope with, for which they used different strategies. Many women expressed a need for more detailed information and counselling, including non-medical aspects of pregnancy and delivery as well. Lastly, many women reported that seeing different doctors negatively influenced the perceived quality of care. In general, women in this study were satisfied with the ultrasounds for their small-for-gestational age pregnancies. However, women expressed a need for additional information to help cope with a feeling of uncertainty regarding cause and prognosis. Their medical team should preferably provide this in a consistent and continuous manner.


Lesser celandine (pilewort) induced acute toxic liver injury: The first case report worldwide.
Lesser celandine, also known as Ranunculus ficaria, is a herbaceous perennial plant that commonly utilizes piles and is taken either internally or used externally. The causality assessment of several reports provided evidence for the existence of Greater Celandine hepatotoxicity. However, there hasn't been any case report published thus far, about lesser celandine induced liver injury. Here, we present a case of 36-year-old woman admitted to the hospital with acute hepatitis and jaundice on her sclera with no history of drug abuse or alcohol consumption. However, the patient had a recent history of lesser celandine extract consumption for hemorrhoids, for about 10 d, prior to the admission. Viral hepatitis, autoimmune hepatitis, and drug induced toxic hepatitis were ruled out by further imaging studies and laboratory analysis. Using the Council for International Organizations of Medical Sciences scale, the type of liver injury was assumed as hepatocellular and was scored as 7 which shows probable causality. Immediate discontinuation of lesser celandine extract resulted in rapid decrease of the elevated enzymes. Herbs have been reported to cause liver injury and therefore should be suspected in the case of acute hepatitis with an unknown etiology. This case is important to be the first to explain hepatotoxicity caused by lesser celandine. Physicians should consider lesser celandine as a causative agent for hepatotoxicity.


Cognitive impairment and the regional distribution of cerebellar lesions in multiple sclerosis.
Cerebellar lesions are often reported in relapsing-remitting multiple sclerosis (RRMS) and have been associated with impaired motor function and cognitive status. However, prior research has primarily focused on summary measures of cerebellar involvement (e.g. total lesion load, gray/white matter volume) and not on the effect of lesion load within specific regions of cerebellar white matter. Spatially map the probability of cerebellar white matter lesion (CWML) occurrence in RRMS and explore the relationship between cognitive impairment and lesion (CWML) location within the cerebellum. High-resolution structural magnetic resonance imaging (MRI) was acquired on 16 cognitively impaired (CI) and 15 cognitively preserved (CP) RRMS subjects at 3T and used for lesion identification and voxel-based lesion-symptom mapping (VLSM). CI RRMS demonstrated a predilection for the middle cerebellar peduncle (MCP). VLSM results indicate that lesions of the MCP are significantly associated with CI in RRMS. Measures of cerebellar lesion load were correlated with age at disease onset but not disease duration. A specific pattern of cerebellar lesions involving the MCP, rather than the total CWML load, contributes to cognitive dysfunction in RRMS. Cerebellar lesion profiles may provide a biomarker of current or evolving risk for cognitive status change in RRMS.


Inhibition of tetanus tension by elevated extracellular calcium concentration.
Extracellular [Ca2+] in the range of 5-20 mM produces a concentration-dependent reversible reduction in tetanus tension in single frog skeletal muscle fibers. Both peak tension and ability to sustain tension during tetanus is reduced. The effect is unrelated to osmotic effects and independent of stimulation frequency in the range 100-200 Hz. The effect occurs both at 8 and 24 degrees C. Tetanus tension is most strongly inhibited by elevated extracellular [Ca2+] at short muscle lengths, but the effect can be seen at all lengths. Microelectrode recordings during tetanus indicate that action potentials remain undiminished in amplitude and duration throughout the tetanus. The evidence suggests that the inhibition results from a failure of action potentials propagation within the transverse tubular system.


Generalized Noise Study of Solid-State Nanopores at Low Frequencies.
Nanopore technology has been extensively investigated for analysis of biomolecules, and a success story in this field concerns DNA sequencing using a nanopore chip featuring an array of hundreds of biological nanopores (BioNs). Solid-state nanopores (SSNs) have been explored to attain longer lifetime and higher integration density than what BioNs can offer, but SSNs are generally considered to generate higher noise whose origin remains to be confirmed. Here, we systematically study low-frequency (including thermal and flicker) noise characteristics of SSNs measuring 7 to 200 nm in diameter drilled through a 20-nm-thick SiNx membrane by focused ion milling. Both bulk and surface ionic currents in the nanopore are found to contribute to the flicker noise, with their respective contributions determined by salt concentration and pH in electrolytes as well as bias conditions. Increasing salt concentration at constant pH and voltage bias leads to increase in the bulk ionic current and noise therefrom. Changing pH at constant salt concentration and current bias results in variation of surface charge density, and hence alteration of surface ionic current and noise. In addition, the noise from Ag/AgCl electrodes can become predominant when the pore size is large and/or the salt concentration is high. Analysis of our comprehensive experimental results leads to the establishment of a generalized nanopore noise model. The model not only gives an excellent account of the experimental observations, but can also be used for evaluation of various noise components in much smaller nanopores currently not experimentally available.


Crystal-facet-dependent surface transformation dictates the oxygen evolution reaction activity in lanthanum nickelate.
Electrocatalysts are the cornerstone in the transition to sustainable energy technologies and chemical processes. Surface transformations under operation conditions dictate the activity and stability. However, the dependence of the surface structure and transformation on the exposed crystallographic facet remains elusive, impeding rational catalyst design. We investigate the (001), (110) and (111) facets of a LaNiO3-δ electrocatalyst for water oxidation using electrochemical measurements, X-ray spectroscopy, and density functional theory calculations with a Hubbard U term. We reveal that the (111) overpotential is ≈ 30-60 mV lower than for the other facets. While a surface transformation into oxyhydroxide-like NiOO(H) may occur for all three orientations, it is more pronounced for (111). A structural mismatch of the transformed layer with the underlying perovskite for (001) and (110) influences the ratio of Ni2+ and Ni3+ to Ni4+ sites during the reaction and thereby the binding energy of reaction intermediates, resulting in the distinct catalytic activities of the transformed facets.


Developing a high-performance liquid chromatography fast and accurate method for quantification of silibinin.
Silibinin is an antioxidant agent and is shown to have anticancer effects in different cancers including lung, breast, colorectal, liver, prostate, and kidney. There are challenges in the clinical use of silibinin. The main limitation is low solubility, poor oral absorption, and extensive hepatic metabolism. We aim to develop a High-Performance Liquid Chromatography (HPLC) sensitive method for quantification of silibinin in aqueous samples to quantify its concentration in new formulations. A reverse-phase high-performance liquid chromatography (RP-HPLC) composed of C18 column as stationary phase and the mixture of methanol (90%) and water (10%) as mobile phase. The developed method was validated based on the established guidelines. The retention time for silibinin was seen in 2.97 min after injection. The calibration curve was drawn and the established method demonstrated a linear ranged from 10 to 100 µg/ml, with a correlation coefficient of 0.996. The sensitivity of the developed method was 10 µg/ml. The accuracy calculated in the range of 88-105.9% and the precision (as relative standard deviation) was between 2.7 and 10.9%. These results demonstrate that the developed method can be a fast and accurate method for quantification of silibinin in aqueous samples.


Testosterone dose-dependently increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension.
Testosterone supplementation in men increases fat-free mass, but whether measures of muscle performance, such as maximal voluntary strength, power, fatigability, or specific tension, are improved has not been determined. Furthermore, the extent to which these measures of muscle performance are related to testosterone dose or circulating concentration is unknown. To examine the relationship between testosterone dose and muscle performance, 61 healthy, eugonadal young men (aged 18-35 yr) were randomized to 1 of 5 groups, each receiving a long-acting GnRH agonist to suppress endogenous testosterone production plus weekly injections of 25, 50, 125, 300, or 600 mg testosterone enanthate for 20 wk. These doses produced mean nadir testosterone concentrations of 253, 306, 542, 1345, and 2370 ng/dl, respectively. Maximal voluntary muscle strength and fatigability were determined by a seated leg press exercise. Leg power was measured using a validated leg power instrument. Specific tension was estimated by the ratio of one repetition maximum muscle strength to thigh muscle volume determined by magnetic resonance imaging. Testosterone administration was associated with a dose-dependent increase in leg press strength and leg power, but muscle fatigability did not change significantly during treatment. Changes in leg press strength were significantly correlated with total (r = 0.46; P = 0.0005) and free (r = 0.38; P = 0.006) testosterone as was leg power (total testosterone: r = 0.38; P = 0.007; free testosterone: r = 0.35; P = 0.015), but not muscle fatigability. Serum IGF-I concentrations were not significantly correlated with leg strength, power, or fatigability. Specific tension did not change significantly at any dose. We conclude that the effects of testosterone on muscle performance are specific; it increases maximal voluntary strength and leg power, but does not affect fatigability or specific tension. The changes in leg strength and power are dependent on testosterone dose and circulating testosterone concentrations and exhibit a log-linear relationship with serum total and free testosterone. Failure to observe a significant testosterone dose relationship with fatigability suggests that testosterone does not affect this component of muscle performance and that different components of muscle performance are regulated by different mechanisms.


Antiphagocytic Effect of Slime from a Mucoid Strain of Pseudomonas aeruginosa.
Mucoid strains of Pseudomonas aeruginosa produce a viscid slime when grown on the surface of agar media. These strains are known to colonize persistently the tracheobronchial tree of children with cystic fibrosis. Colonization may result from inhibition of phagocytosis due to slime produced by the organism. Slime separated from one mucoid strain was examined to determine whether it possessed antiphagocytic activity in vitro. Cells of P. aeruginosa, Escherichia coli, and Staphylococcus aureus were rapidly phagocytized by rabbit polymorphonuclear leukocytes when mixtures were rotated for 2 hr at 37 C in the absence of slime. The addition of relatively small amounts of slime to bacteria and leukocytes inhibited phagocytosis as measured by phagocytic killing of the organisms. Inhibition was found to be most complete with P. aeruginosa.


Frequency of three polymorphisms of the CCL5 gene (rs2107538, rs2280788 and rs2280789) and their implications for the phenotypic expression of sickle cell anemia in Tunisia.
The pro-inflammatory context of sickle cell disease promotes the liberation of cytokines such as CCL5, encoded by a gene located on chromosome 17. Herein, the occurrence of three variations of CCL5 in sickle cell anemia (SCA) and their relations to two major complications - painful crisis and presence of infections - were investigated. 100 SCA Tunisian patients and 100 healthy subjects were included in the case control study. Then the sample of patients was divided into two groups according to the presence or absence of each complication. The polymorphisms, namely g.-403G>A, g.-28C>G and g.In1.+1T>C, were analyzed by PCR/sequencing. Our findings show the presence of eight genotypes, namely GG, GA and AA of g.-403G>A, CC, CG and GG of g.-28C>G, and TT and TC of g.In1.+1T>C. The frequencies of studied single nucleotide polymorphisms (SNPs) and haplotypes in SCA patients do not differ significantly from healthy control group results. There is also no significant association between the analyzed polymorphisms and complications as for painful crisis and presence of infections (p > 0.05). Altogether, our data support the conclusion that the three polymorphisms of CCL5, namely g.-403G>A, g.-28C>G and g.In1.+1T>C, do not seem to be involved in the clinical variability of SCA in Tunisia.


Does green innovation facilitate firms' access to trade credit?
Employing a large sample of Chinese firms, this study examined the influence of corporate green innovation on firms' access to trade credit. The results indicated a positive association between green innovation and firms' capability to access trade credit, suggesting that suppliers value firms' green innovation capabilities. This relationship was strengthened after the implementation of the new Environmental Protection Law (EPL) in 2015, which enhanced the value of green innovation. The findings remained robust to several robustness tests. The results suggest that green innovation helps firms access trade credit through better environmental, social, and governance (ESG) scores and more state subsidy channels and plays a more pronounced role for financially constrained firms, non-state-owned enterprises, firms with lower bargaining power, and firms located in regions with better intellectual property rights protections. Green innovation is valuable for future corporate growth and shareholder value. Overall, this study reveals the value of green innovation through informal corporate financing.


Mitochondrial hydrogen peroxide production by pyruvate dehydrogenase and α-ketoglutarate dehydrogenase in oxidative eustress and oxidative distress.
Pyruvate dehydrogenase (PDH) and α-ketoglutarate dehydrogenase (KGDH) are vital entry points for monosaccharides and amino acids into the Krebs cycle and thus integral for mitochondrial bioenergetics. Both complexes produce mitochondrial hydrogen peroxide (mH2O2) and are deactivated by electrophiles. Here, we provide an update on the role of PDH and KGDH in mitochondrial redox balance and their function in facilitating metabolic reprogramming for the propagation of oxidative eustress signals in hepatocytes and how defects in these pathways can cause liver diseases. PDH and KGDH are known to account for ∼45% of the total mH2O2 formed by mitochondria and display rates of production several-fold higher than the canonical source complex I. This mH2O2 can also be formed by reverse electron transfer (RET) in vivo, which has been linked to metabolic dysfunctions that occur in pathogenesis. However, the controlled emission of mH2O2 from PDH and KGDH has been proposed to be fundamental for oxidative eustress signal propagation in several cellular contexts. Modification of PDH and KGDH with protein S-glutathionylation (PSSG) and S-nitrosylation (PSNO) adducts serves as a feedback inhibitor for mH2O2 production in response to glutathione (GSH) pool oxidation. PSSG and PSNO adduct formation also reprogram the Krebs cycle to generate metabolites vital for interorganelle and intercellular signaling. Defects in the redox modification of PDH and KGDH cause the over generation of mH2O2, resulting in oxidative distress and metabolic dysfunction-associated fatty liver disease (MAFLD). In aggregate, PDH and KGDH are essential platforms for emitting and receiving oxidative eustress signals.


Serum nerve growth factor concentration and its role in the preclinical stage of dementia.
Nerve growth factor is important for the development and function of the cholinergic basal forebrain. The authors examined the hypothesis that the concentration of nerve growth factor is lower than normal in the preclinical phase of neurodegenerative dementia, especially Alzheimer's disease. The serum nerve growth factor concentration of subjects from the Berlin Aging Study and the Berlin Memory Clinic who later developed Alzheimer's disease were compared with those of subjects who were free of dementia and subjects who were already suffering from Alzheimer's disease. There were 17 subjects in each group, matched for age and sex. The three groups differed in log-10-transformed mean nerve growth factor concentrations: 1.62 (SD=0.59) for the healthy comparison subjects, 0.92 (SD=0.30) for the subjects with preclinical dementia, and 1.44 (SD=0.61) for the subjects with Alzheimer's disease. These results support the hypothesis of disturbed nerve growth factor regulation in the serum of patients with preclinical Alzheimer's disease. Mechanisms by which these disturbances appear are unclear, but they may reflect the situation in the preclinical Alzheimer's disease brain.


Elevated cAMP in intestinal epithelial cells during experimental cholera and salmonellosis.
Cholera and salmonellosis are two diarrheal diseases in which intestinal tissue cyclic adenosine monophosphate (cAMP) concentrations are elevated. Investigations of each experimental disease were initiated to identify the specific intestinal cells containing the elevated cAMP. Epithelial cells were eluted from the mucosa of infected and control intestinal loops of adult rabbits, after which the cAMP content of the epithelial cell fractions and the lamina propria cells was extracted and assayed. The identity of the epithelial cells (in the villus tip-to-crypt cell gradient) was monitored by measuring their intracellular alkaline phosphatase activity, while scanning electron microscopy was used to visualize the effects of infection and cell elution techniques. Clearly, in both experimental cholera and salmonellosis, elevated cAMP levels were associated with crypt epithelial cells. Villus tip epithelial cells from either infection tended to contain less cAMP than those of noninfected control tissue. In Salmonella-infected loops, it was apparent that cAMP was also elevated in lamina propria cell fractions. Lamina propria cells from V. cholerae-infected intestinal loops contained only basal levels of cAMP. In vitro exposure of isolated intestinal cells from normal rabbit intestine to a cell-free lysate of Salmonella resulted in elevation of cAMP in the epithelial cells and lamina propria cells. We conclude that in experimental cholera and salmonellosis, significant elevation of the cAMP levels occurred in intestinal crypt cells, consistent with an enterotoxin-mediated mechanism. In Salmonella-infected loops, it was unclear if the increased concentration of cAMP in lamina propria cells was generated by enterotoxin released from the invasive salmonellae or by prostaglandins formed during the inflammatory response to the bacteria, or by both mechanisms.


A controlled study of the relationship between Bordetella pertussis infections and sudden unexpected deaths among German infants.
This was a prospective, controlled, multicenter study to investigate the relationship between Bordetella pertussis infections and sudden unexpected deaths among German infants. Between 1995 and 1997, all infants who died at 7 to 365 days of age and for whom autopsies were performed in 1 of 8 participating institutes of legal medicine were enrolled. During a standardized autopsy, nasopharyngeal specimens (NPSs) and tracheal specimens were obtained for polymerase chain reaction (PCR) assays to detect B pertussis. The oligonucleotide primers PTp1 and PTp2, which specifically amplify a 191-base pair DNA fragment of the pertussis toxin operon of B pertussis, were used. Two control subjects (matched according to residence, age, gender, and nationality) were enrolled for each case subject, via a network of pediatricians in private practice, and NPSs were obtained from those infants. Parents of case subjects and control subjects were asked to provide specific information on respiratory illnesses of the child, contact with a known case of pertussis, or close contact with a person with a cough illness during the 4 weeks before death or enrollment, as well as the child's pertussis immunization status. The pathologists performing the autopsies were unaware of the PCR results. Enrolled were 254 infants (66% male) with sudden unexpected deaths and 441 matched control subjects. Autopsies according to protocol were performed for 234 of the case subjects (92%); a diagnosis of sudden infant death syndrome (SIDS) was made for 76%. For the remaining subjects, causes of death were respiratory or other infections (14%), congenital anomalies or organ failures (4%), aspiration (2%), or accidents or traumatic events (4%). PCR results were positive for B pertussis for 12 case subjects (5.1%) (all with SIDS or respiratory infections) and 5.3% of control subjects. Of the 12 case subjects with positive PCR results, 10 (83%) were male. Questionnaires had been returned by the parents of 5 of the 12 infants. Three had experienced a respiratory illness (all with cough), beginning 7, 14, and 19 days before death. None had a known contact with a case of pertussis. Four of 15 control infants (27%) with positive PCR findings for B pertussis had a cough illness, indicating possible pertussis, and 2 of those 4 developed typical symptoms (whooping). Background information was received from 116 parents (46%) of case subjects and from parents of all control subjects. Upper respiratory tract infections within 4 weeks before death were reported for 53% of case subjects and 38% of control subjects. Also, fewer case subjects (33%) than control subjects (68%) had received age-adequate numbers of pertussis vaccine doses. The concept of infection as a factor in SIDS is supported by a number of observations, including the seasonal distribution of the occurrence of SIDS; the high incidence of concurrent upper respiratory tract infections among infants dying as a result of SIDS; the peak age at 3 to 4 months; nicotine use in a child's household, which predisposes children to respiratory infections such as otitis media; and the protective role of breastfeeding. A prominent role might be suspected for B pertussis, for several reasons. 1) B pertussis infections in infancy are frequently associated with apneic spells, which are occasionally life-threatening and, if leading to death, might be reported as SIDS. 2) Epidemiologic evidence from the United Kingdom, Sweden, and Norway indicates that SIDS is associated with B pertussis infection. 3) In a previously published study, we detected B pertussis DNA in the nasopharynx of 9 of 51 consecutive infants (18%) with sudden unexpected deaths. This is the first prospective, controlled study to investigate the possible etiologic role of B pertussis in SIDS. Clinically unrecognized B pertussis infections were relatively frequent (5.3%) among control infants during the course of our study. The rate of infection was similar or perhaps greater for control subjects, compared with case subjects (1.7%), when only NPS results were compared. This may seem surprising but is supported by other studies, in which asymptomatic infections or mild respiratory illnesses were observed among infants exposed to B pertussis. Careful autopsies, including histologic evaluations of organ specimens and use of PCR to detect B pertussis in NPSs and tracheal specimens, represented a strength of this study. Our general findings were as expected. The majority of cases were classified as SIDS. The second largest group included infants for whom respiratory infections were found. The findings of various other diagnoses, which in several instances would have been undiscovered otherwise, emphasize the need for autopsies after unexpected infant deaths. What is the significance of the identified B pertussis infections in 12 cases? Several pieces of evidence support the plausibility of a cause-and-effect relationship. Eight of the 12 case subjects died before 6 months of age, the typical age for death attributable to pertussis. In autopsies, 9 of the subjects were found to have signs of respiratory infections; for 2 infants, the autopsies suggested that death was attributable to a respiratory infection. One additional infant (data not shown) had brain edema (which could have been attributable to hypoxemia during pertussis). Lower rates of completed primary series or age-adequate numbers of pertussis vaccine doses among case subjects than among control subjects may indicate that immunization against pertussis protects children from death attributable to unrecognized B pertussis infection. Moreover, a recent study indicated that immunization with diphtheria-tetanus-pertussis vaccine induces antibodies that cross-react with pyrogenic staphylococcal toxins, which have been implicated in several cases of SIDS. Other microorganisms may be involved in the sudden death of infants, as suggested in this study by the higher rate of a history of concurrent upper respiratory tract infections among case subjects, compared with control subjects. Similarly, in a Scandinavian study, 48% of 244 SIDS case subjects, compared with 31% of 869 control subjects, exhibited symptoms of upper airway infection during the last week before death or interview, respectively. Because SIDS is a diagnosis of exclusion, every attempt should be made to identify a cause of death during autopsy. This should include the search for pathogenic microorganisms in the respiratory tract with the use of PCR and other sensitive tests. In conclusion, B pertussis infection was found for 12 of 234 infants (5.1%) with unexpected deaths, and the infections might have contributed to the deaths.


Significance of cell cycle regulatory proteins as malignant and prognostic biomarkers in ovarian epithelial tumors.
The principal objective of this study was to comprehensively assess the clinicopathologic and prognostic impacts of the expression of various cell cycle regulatory proteins in patients with ovarian epithelial tumors. The tissue microarrays were constructed from formalin-fixed, paraffin-embedded tissues of 205 ovarian epithelial tumors. We investigated 55 benign (20 serous cystadenomas, 17 mucinous cystadenomas, and 18 endometriotic cysts), 72 borderline (26 serous borderline tumors and 46 mucinous borderline tumors), and 78 malignant tumors (45 serous carcinomas, 10 mucinous adenocarcinomas, 15 endometrioid adenocarcinomas, and 8 clear cell carcinomas). Immunohistochemical staining was performed using antibodies to p16(Ink4a), p53, p21(Waf1/Cip1), p27(Kip1), Cyclin D1, Cyclin E, Cyclin A, Cyclin B1, and Cyclin-dependent Kinase2. We noted significantly different levels of p53 and Cyclin B1 expressions between malignant and borderline tumors and between borderline and benign tumors excepting the mucinous type. The p21(Waf1/Cip1) and Cyclin A were significantly overexpressed in malignant tumors compared with borderline tumors. Cyclin A, Cyclin E, and p16(Ink4a) were more pronounced proteins, showing differential expression patterns among the histologic types of ovarian carcinomas. We determined that the overexpression of p16(Ink4a) (P=0.031), Cyclin E (P=0.009), and Cyclin-dependent Kinase2 (P=0.004) were significantly associated with higher tumor grades. Overexpression of p16(Ink4a) was correlated with both lymph node metastasis (P=0.030) and distant metastasis (P=0.034). Overexpression of Cyclin E was associated with advanced stage (P=0.004). Higher tumor grade (P=0.008), advanced stage (P=0.001), mucinous histologic type (P=0.012), low expression levels of p16(Ink4a) (P=0.032), and overexpression of p53 (P=0.032) were associated with poor overall survival on multivariate analysis in patients with ovarian cancer. In serous carcinomas, old age (P=0.005), distant metastasis (P=0.020), low expression of p16(Ink4a) (P=0.047), and overexpression of cytoplasmic p27(Kip1) (P=0.007) and Cyclin A (P=0.031) were all independent predictors of worse overall survival. Our data indicate that the overexpression of p16 and Cyclin E are valuable factors predicting disease progression and metastatic potential. Low p16(Ink4a) expression, overexpression of p53, cytoplasmic p27(Kip1), and Cyclin A are predictive markers for shorter overall survival in ovarian carcinomas.


A cell culture model of the blood-brain barrier.
Endothelial cells that make up brain capillaries and constitute the blood-brain barrier become different from peripheral endothelial cells in response to inductive factors found in the nervous system. We have established a cell culture model of the blood-brain barrier by treating brain endothelial cells with a combination of astrocyte-conditioned medium and agents that elevate intracellular cAMP. These cells form high resistance tight junctions and exhibit low rates of paracellular leakage and fluid-phase endocytosis. They also undergo a dramatic structural reorganization as they form tight junctions. Results from these studies suggest modes of manipulating the permeability of the blood-brain barrier, potentially providing the basis for increasing the penetration of drugs into the central nervous system.


Evaluation of multi-assay algorithms for identifying individuals with recent HIV infection: HPTN 071 (PopART).
Assays and multi-assay algorithms (MAAs) have been developed for population-level cross-sectional HIV incidence estimation. These algorithms use a combination of serologic and/or non-serologic biomarkers to assess the duration of infection. We evaluated the performance of four MAAs for individual-level recency assessments. Samples were obtained from 220 seroconverters (infected <1 year) and 4,396 non-seroconverters (infected >1 year) enrolled in an HIV prevention trial (HPTN 071 [PopART]); 28.6% of the seroconverters and 73.4% of the non-seroconverters had HIV viral loads ≤400 copies/mL. Samples were tested with two laboratory-based assays (LAg-Avidity, JHU BioRad-Avidity) and a point-of-care assay (rapid LAg). The four MAAs included different combinations of these assays and HIV viral load. Seroconverters on antiretroviral treatment (ART) were identified using a qualitative multi-drug assay. The MAAs identified between 54 and 100 (25% to 46%) of the seroconverters as recently-infected. The false recent rate of the MAAs for infections >2 years duration ranged from 0.2%-1.3%. The MAAs classified different overlapping groups of individuals as recent vs. non-recent. Only 32 (15%) of the 220 seroconverters were classified as recent by all four MAAs. Viral suppression impacted the performance of the two LAg-based assays. LAg-Avidity assay values were also lower for seroconverters who were virally suppressed on ART compared to those with natural viral suppression. The four MAAs evaluated varied in sensitivity and specificity for identifying persons infected <1 year as recently infected and classified different groups of seroconverters as recently infected. Sensitivity was low for all four MAAs. These performance issues should be considered if these methods are used for individual-level recency assessments.


Molecularly imprinted sensor based on an enzyme amplifier for ultratrace oxytetracycline determination.
A novel strategy for preparing highly sensitive, molecularly imprinted sensors based on enzyme amplifiers was proposed for oxytetracycline (OTC) determination. A molecularly imprinted polymer (MIP) film was used as an artificial antibody to interact with OTC and horseradish peroxidase-labeled OTC (HRP-OTC). Oxytetracycline was determined according to the competition reaction. The molecularly imprinted sensor was characterized by alternating current (ac) impedance spectroscopy, differential pulse voltammetry (DPV), and cyclic voltammetry (CV). The DPV technique was performed to verify the voltammetric behavior of the molecularly imprinted sensor. At the concentration of 0-1 x 10(-7) mol/L, OTC could be determined with a detection limit of 6.49 x 10(-10) mol/L. The MIP artificial immunosensor showed high sensitivity, selectivity, and reproducibility. Determination of OTC in samples showed good recovery.


Antiadrenergic therapy in the control of atrial fibrillation.
Atrial fibrillation (AF) in heart failure develops commonly in older individuals and its prevalence increases as heart failure severity progresses. Because of deteriorating hemodynamics, patients with heart failure are at increased risk for developing AF and, conversely, AF in heart failure patients is associated with adverse hemodynamic changes. AF is believed to increase the mortality risk in heart failure, which may be minimized by treatment that includes the control of ventricular rate, prevention of thrombotic events, and conversion to normal sinus rhythm. Clinical guidelines recommend amiodarone or dofetilide in heart failure patients, but these drugs have certain drawbacks, such as an increased risk for bradyarrhythmias with amiodarone and proarrhythmic reaction with dofetilide. Some but not all clinical trials have suggested that rate control should be the primary therapeutic goal in high-risk heart failure patients with AF and, if unsuccessful, followed by rhythm control. The former is effectively achieved with rate-lowering beta-blockers alone or in combination with digoxin. Recent studies evaluating the effects of combination carvedilol/digoxin therapy demonstrate synergistic effects between the two drugs. This combination therapy decreased heart failure symptoms, effectively reduced ventricular rate, and improved ventricular function to a greater extent compared with that produced by either drug alone. Although digoxin alone is an effective heart failure treatment, its use as a single rate-control therapy is often ineffective in heart failure patients with AF associated with rapid ventricular response. Carvedilol is effective, alone or in combination, with digoxin in such heart failure patients with AF, and has been shown to reduce mortality risk in patients with chronic heart failure during prolonged therapy.


Protein kinase C-alpha and protein kinase C-epsilon are required for Grb2-associated binder-1 tyrosine phosphorylation in response to platelet-derived growth factor.
Grb2-associated binder-1 (Gab1) is an adapter protein related to the insulin receptor substrate family. It is a substrate for the insulin receptor as well as the epidermal growth factor (EGF) receptor and other receptor-tyrosine kinases. To investigate the role of Gab1 in signaling pathways downstream of growth factor receptors, we stimulated rat aortic vascular smooth muscle cells (VSMC) with EGF and platelet-derived growth factor (PDGF). Gab1 was tyrosine-phosphorylated by EGF and PDGF within 1 min. AG1478 (an EGF receptor kinase-specific inhibitor) failed to block PDGF-induced Gab1 tyrosine phosphorylation, suggesting that transactivated EGF receptor is not responsible for this signaling event. Because Gab1 associates with phospholipase Cgamma (PLCgamma), we studied the role of the PLCgamma pathway in Gab1 tyrosine phosphorylation. Gab1 tyrosine phosphorylation by PDGF was impaired in Chinese hamster ovary cells expressing mutant PDGFbeta receptor (Y977F/Y989F: lacking the binding site for PLCgamma). Pretreatment of VSMC with (a specific PLCgamma inhibitor) inhibited Gab1 tyrosine phosphorylation as well, indicating the importance of the PLCgamma pathway. Gab1 was tyrosine-phosphorylated by phorbol ester to the same extent as PDGF stimulation. Studies using antisense protein kinase C (PKC) oligonucleotides and specific inhibitors showed that PKCalpha and PKCepsilon are required for Gab1 tyrosine phosphorylation. Binding of Gab1 to the protein-tyrosine phosphatase SHP2 and phosphatidylinositol 3-kinase was significantly decreased by PLCgamma and/or PKC inhibition, suggesting the importance of the PLCgamma/PKC-dependent Gab1 tyrosine phosphorylation for the interaction with other signaling molecules. Because PDGF-mediated ERK activation is enhanced in Chinese hamster ovary cells that overexpress Gab1, Gab1 serves as an important link between PKC and ERK activation by PDGFbeta receptors in VSMC.


Successful treatment of recurrent malignancy-associated hemophagocytic lymphohistiocytosis with a modified HLH-94 immunochemotherapy and allogeneic stem cell transplantation.
Acquired hemophagocytic lymphohistiocytosis (HLH) triggered by a known or still to be recognized malignancy is a life-threatening hyperinflammatory syndrome due to massive cytokine release from activated lymphocytes and macrophages. Malignancy-associated HLH (M-HLH) often impedes adequate treatment of malignancy and has the worst outcome compared with any other form of HLH. The incidence of M-HLH is unknown, and there are no published treatment recommendations addressed to this HLH form. Here, we report the case of a young woman with recurrent ALK1-positive anaplastic large T-cell lymphoma and M-HLH successfully treated with a modified HLH-94 protocol, allogeneic stem cell transplantation (alloSCT) and donor lymphocyte infusion (DLI). More than 3 years after DLI, the patient is alive, in complete remission from her malignancy and HLH-free, although suffering from extensive chronic graft-versus-host disease. AlloSCT and, if needed, DLI performed to consolidate remission of malignancy and HLH may have a curative impact on both entities. We propose that when discussing possible treatment options for patients with M-HLH, alloSCT should be considered in eligible individuals.


A complex case of a granulosa cell tumour.
This is a case of a 73-year-old woman who first presented in 2020 with a fullness in her abdomen. After several thorough investigations and unforeseen complications, the fullness was diagnosed as a granulosa cell tumour. In 2003, she had been diagnosed with a granulosa cell tumour of the ovary. Complete excision was performed, however she was not given a follow-up appointment after the procedure. This case highlights the importance of frequent follow-up of these tumours, the high recurrence rate, the severe complications which may result and the awareness of possible variations in this tumour's histologic appearance.


Preservation of bone structure and function by Lithothamnion sp. derived minerals.
Progressive bone mineral loss and increasing bone fragility are hallmarks of osteoporosis. A combination of minerals isolated from the red marine algae, Lithothamnion sp. was examined for ability to inhibit bone mineral loss in female mice maintained on either a standard rodent chow (control) diet or a high-fat western diet (HFWD) for 5, 12, and 18 months. At each time point, femora were subjected to μ-CT analysis and biomechanical testing. A subset of caudal vertebrae was also analyzed. Following this, individual elements were assessed in bones. Serum levels of the 5b isoform of tartrate-resistant acid phosphatase (TRAP) and procollagen type I propeptide (P1NP) were also measured. Trabecular bone loss occurred in both diets (evident as early as 5 months). Cortical bone increased through month 5 and then declined. Cortical bone loss was primarily in mice on the HFWD. Inclusion of the minerals in the diet reduced bone mineral loss in both diets and improved bone strength. Bone mineral density was also enhanced by these minerals. Of several cationic minerals known to be important to bone health, only strontium was significantly increased in bone tissue from animals fed the mineral diets, but the increase was large (5-10 fold). Serum levels of TRAP were consistently higher in mice receiving the minerals, but levels of P1NP were not. These data suggest that trace minerals derived from marine red algae may be used to prevent progressive bone mineral loss in conjunction with calcium. Mineral supplementation could find use as part of an osteoporosis-prevention strategy.


Vaccinia virus subverts a mitochondrial antiviral signaling protein-dependent innate immune response in keratinocytes through its double-stranded RNA binding protein, E3.
Skin keratinocytes provide a first line of defense against invading microorganisms in two ways: (i) by acting as a physical barrier to pathogen entry and (ii) by initiating a vigorous innate immune response upon sensing danger signals. How keratinocytes detect virus infections and generate antiviral immune responses is not well understood. Orthopoxviruses are dermatotropic DNA viruses that cause lethal disease in humans. Virulence in animal models depends on the virus-encoded bifunctional Z-DNA/double-stranded RNA (dsRNA)-binding protein E3. Here, we report that infection of mouse primary keratinocytes with a vaccinia DeltaE3L mutant virus triggers the production of beta interferon (IFN-beta), interleukin-6 (IL-6), CCL4, and CCL5. None of these immune mediators is produced by keratinocytes infected with wild-type vaccinia virus. The dsRNA-binding domain of E3 suffices to prevent activation of the innate immune response. DeltaE3L induction of IFN-beta, IL-6, CCL4, and CCL5 secretion requires mitochondrial antiviral signaling protein (MAVS; an adaptor for the cytoplasmic viral RNA sensors RIG-I and MDA5) and the transcription factor IRF3. IRF3 phosphorylation is induced in keratinocytes infected with DeltaE3L, an event that depends on MAVS. The response of keratinocytes to DeltaE3L is unaffected by genetic ablation of Toll-like receptor 3 (TLR3), TRIF, TLR9, and MyD88.


COBRA legislation: complying with ED provisions. Consolidated Omnibus Budget Reconciliation Act of 1985.
With the passage of the COBRA transfer provisions, Congress has put hospitals on notice that patient dumping will no longer be tolerated. It is incumbent on hospitals to provide thorough guidelines of the COBRA requirements to its medical and nursing staff. The wise hospital administrator will ensure that comprehensive transfer procedures will be put into effect that are in accord with the COBRA provisions. Financial triage of patients in the emergency department could prove to be a costly problem for the hospital that misses an emergency condition.


Use of Fc-Engineered Antibodies as Clearing Agents to Increase Contrast During PET.
Despite promise for the use of antibodies as molecular imaging agents in PET, their long in vivo half-lives result in poor contrast and radiation damage to normal tissue. This study describes an approach to overcome these limitations. Mice bearing human epidermal growth factor receptor type 2 (HER2)-overexpressing tumors were injected with radiolabeled ((124)I, (125)I) HER2-specific antibody (pertuzumab). Pertuzumab injection was followed 8 h later by the delivery of an engineered, antibody-based inhibitor of the receptor, FcRn. Biodistribution analyses and PET were performed at 24 and 48 h after pertuzumab injection. The delivery of the engineered, antibody-based FcRn inhibitor (or Abdeg, for antibody that enhances IgG degradation) results in improved tumor-to-blood ratios, reduced systemic exposure to radiolabel, and increased contrast during PET. Abdegs have considerable potential as agents to stringently regulate antibody dynamics in vivo, resulting in increased contrast during molecular imaging with PET.


Myalgic encephalomyelitis/chronic fatigue syndrome: From pathophysiological insights to novel therapeutic opportunities.
Myalgic encephalomyelitis (ME) or chronic fatigue syndrome (CFS) is a common and disabling condition with a paucity of effective and evidence-based therapies, reflecting a major unmet need. Cognitive behavioural therapy and graded exercise are of modest benefit for only some ME/CFS patients, and many sufferers report aggravation of symptoms of fatigue with exercise. The presence of a multiplicity of pathophysiological abnormalities in at least the subgroup of people with ME/CFS diagnosed with the current international consensus "Fukuda" criteria, points to numerous potential therapeutic targets. Such abnormalities include extensive data showing that at least a subgroup has a pro-inflammatory state, increased oxidative and nitrosative stress, disruption of gut mucosal barriers and mitochondrial dysfunction together with dysregulated bioenergetics. In this paper, these pathways are summarised, and data regarding promising therapeutic options that target these pathways are highlighted; they include coenzyme Q10, melatonin, curcumin, molecular hydrogen and N-acetylcysteine. These data are promising yet preliminary, suggesting hopeful avenues to address this major unmet burden of illness.


MicroRNA-126 suppresses the invasion of trophoblast-model JEG-3 cells by targeting LIN28A.
Inadequate trophoblast invasion and impaired trophoblast-induced vascular remodeling are features of preeclampsia. In this context, an angiogenesis-related microRNA, miR-126, is abnormally expressed in preeclampsia placentas, but its role in trophoblast development remains unclear. The purpose of this study was to investigate the roles of miR-126 in the proliferation, migration, and invasion processes of trophoblast cells using the human choriocarcinoma-derived JEG-3 cell line as a model. The mRNA expression profiling of JEG-3 cells with and without miR-126 overexpression, in combination with bioinformatics analysis, identified LIN28A as a putative target of miR-126. The results of real-time RT-PCR and luciferase assay were consistent with this idea. Overexpression of miR-126 in JEG-3 cells decreased the invasive ability of the cells without affecting proliferation or migration. The invasiveness of JEG-3 cells was significantly reduced to a similar extent by knockdown of LIN28A with siRNA and by miR-126-overexpression-induced downregulation of LIN28A, although the level of LIN28A protein was much lower in the siLIN28A-transfected cells. These results indicate that miR-126 suppresses JEG-3 cell invasion by targeting LIN28A, and suggest that miR-126-mediated downregulation of LIN28A might contribute to the onset/deterioration of preeclampsia.


Effect of free versus liposomal-complexed pentamidine isethionate on biological characteristics of Acanthamoeba castellanii in vitro.
Acanthamoeba is an opportunistic protozoan pathogen that can cause blinding keratitis and a rare but fatal encephalitis involving the central nervous system with a very poor prognosis. This is due to limited availability of effective anti-acanthamoebic drugs. Here, we tested whether the use of liposomes can improve the potency of pentamidine isethionate, an anti-amoebic compound. The liposomes consisted of l-alpha-phosphatidylcholine and cholesterol or ergosterol in a molar ratio of 1 : 5. Pentamidine isethionate was incorporated to achieve a final drug to lipid ratio of 1 : 5. At a drug concentration of 10 microg ml(-1), the liposomal drug was >12 times more effective than the free drug at preventing Acanthamoeba binding to human cells and significantly more effective in reducing parasite-mediated human cell cytopathogenicity, compared with the drug alone. Both the free and liposomal drug blocked Acanthamoeba encystation.


Focused-helium-ion-beam blow forming of nanostructures: radiation damage and nanofabrication.
Targeted irradiation of nanostructures by a finely focused ion beam provides routes to improved control of material modification and understanding of the physics of interactions between ion beams and nanomaterials. Here, we studied radiation damage in crystalline diamond and silicon nanostructures using a focused helium ion beam, with the former exhibiting extremely long-range ion propagation and large plastic deformation in a process visibly analogous to blow forming. We report the dependence of damage morphology on material, geometry, and irradiation conditions (ion dose, ion energy, ion species, and location). We anticipate that our method and findings will not only improve the understanding of radiation damage in isolated nanostructures, but will also support the design of new engineering materials and devices for current and future applications in nanotechnology.


A comparison of two modalities of stereotactic body radiation therapy for peripheral early-stage non-small cell lung cancer: results of a prospective French study.
This prospective, observational, non-randomized multicentric study was conducted to compare efficiency and toxicity using different modalities of stereotactic body radiation therapy (SBRT) in early-stage peripheral non-small cell lung cancer (NSCLC). From 9 April to 11 December, 106 patients were treated according to the local equipment availability for peripheral NSCLC with SBRT: 68 by linear accelerator equipped for SBRT and 38 by Cyberknife®. Multivariate analysis and propensity score analysis using Inverse Probability Treatment Weighting (IPTW) were undertaken in an effort to adjust for potential bias due to non-randomization. 2-year local control rates were 97.0% (95% CI: [90.6%; 99.4%]) with SBRT by Linac vs 100% (95% CI: ([100%; 100%]) with Cyberknife® (p = 0.2839). 2-year PFS and 2-year OS rates were 52.7% (95% CI [39.9%;64.0%]) versus 54.1% (95% CI [36.8; 68.6%]) (p = 0.8582) and 65.1% (95% CI: [51.9%; 75.5%] versus 83.9% (95% CI: [67.5%; 92.4%] (p = 0.0831) using Linac and Cyberknife® respectively. Multivariate regression analysis indicates no significant effect of SBRT treatment type on PFS or OS. Local relapse could not be modeled due to the small number of events (n = 2). Acute and late toxicity rates were not significantly different. After IPTW adjustment, results were unchanged. No difference in efficiency or toxicity was shown after SBRT of peripheral NSCLC treatment using Linac or Cyberknife®. This is the first large prospective non-randomized study focusing on peripheral localized NSCLC comparing SBRT using an appropriately equipped linac with Cyberknife®. No significant difference in efficiency or toxicity was shown in this situation.


A prospective analysis of office-based breast ultrasound.
To determine the usefulness of office-based breast ultrasound. Prospective, nonrandomized study. Academic-affiliated community teaching hospital. Among 653 consecutive patients seen in our office during a 30-month period, we performed 660 ultrasound examinations. The presenting complaint included a palpable mass in 53%, abnormal mammogram in 39%, and nipple discharge or retraction in 3%. Ultrasound examination was performed using a handheld 7.5-MHz linear array transducer. Findings and pertinent clinicopathologic data were recorded prospectively in our Breast Ultrasound Registry. Contribution of breast ultrasound to diagnosis and treatment. The sonogram was normal in 201 cases (30%), showed duct ectasia in 20 cases (3%), a simple cyst or seroma in 101 cases (15%), and a focal complex or solid abnormality in 338 cases (51%). Among the last group, 114 (97%) of 118 lesions thought to be benign on ultrasonography proved to be benign, whereas 13 (12%) of 111 indeterminate and 72 (75%) of 96 sonographically suspicious lesions proved to be cancer (including 13 cases with normal mammograms). Ultrasonographic features of malignancy included an anteroposterior-to-lateral dimension ratio of 1 or greater, heterogeneous hypoechoicity, irregular shadowing, and fuzzy and/or jagged margins. Ultrasound-guided needle biopsy accurately diagnosed 46 benign nonpalpable lesions and 20 malignant nonpalpable lesions. These data suggest that ultrasonography is a useful adjunct to clinical and mammographic evaluation of breast disease. Breast ultrasound identifies cysts, aids in differentiating benign from malignant lesions, and facilitates office needle biopsy of nonpalpable abnormalities, permitting timely and cost-effective patient care.


Biorelevant Weakly Coordinating Directing Group Assisted C-H Alkenylation with Cyclopropanols via Sequential C-H/C-C Activation.
A weakly coordinating biorelevant intrinsic directing group (DG) assisted site-selective C-H alkenylation via sequential C-H/C-C bond activation has been accomplished under Ru(II)-catalysis using readily accessible cyclopropyl alcohol as an alkenyl surrogate. Utilization of an intrinsic DG, exclusive regioselectivity, functional group diversity, late-stage natural product and drug mutations are the important practical features.


Transjugular intrahepatic portosystemic shunt with or without variceal embolization to prevent variceal rebleeding: an updated meta-analysis.
Transjugular intrahepatic portosystemic shunt (TIPS) is an established treatment for portal hypertension complications. Still, the role of adjuvant variceal embolization is a matter of debate. Thus, we aim to evaluate the efficacy and safety of TIPS with variceal embolization versus TIPS alone to prevent variceal rebleeding. We used PubMed, CENTRAL, and OVID to search for all randomized controlled trials (RCTs) and comparative observational studies up to 17 June 20221117 June 2022. We pooled binary outcomes using risk ratios (RRs) presented with 95% confidence intervals (CIs) using RevMan 5.4. We included 11 studies (two RCTs and nine observational studies) with 1024 patients. Pooled RR favored TIPS with embolization in preventing variceal rebleeding (RR 0.58, 95% CI: 0.44, 0.76); however, there was no difference between the two groups regarding shunt dysfunction (RR 0.92, 95% CI: 0.68, 1.23), encephalopathy (RR 0.88, 95% CI: 0.70, 1.11), and death (RR 0.97, 95% CI: 0.77, 1.22). TIPS with embolization can be an effective strategy for preventing variceal rebleeding; however, our results should be interpreted cautiously as most data were observational and the technical quality of the embolization is questionable. Further RCTs are required using the proper techniques of embolization and comparing TIPS with embolization with other treatment modalities such as endoscopic ligation, and balloon-occluded retrograde transvenous obliteration.


Fluctuations of the heat exchanged between two quantum spin chains.
The statistics of the heat exchanged between two quantum XX spin chains prepared at different temperatures is studied within the assumption of weak coupling. This provides simple formulas for the average heat and its corresponding characteristic function, from which the probability distribution may be computed numerically. These formulas are valid for arbitrary sizes and therefore allow us to analyze the role of the thermodynamic limit in this nonequilibrium setting. It is found that all thermodynamic quantities are extremely sensitive to the quantum phase transition of the XX chain.


[Basic principles of after care following autoplastic reconstruction of the cruciate ligament].
Since 1984 we avoided immobilization after reconstruction of the anterior and/or posterior cruciate ligament. Principles of kinematics were taken in consideration during aftertreatment. Results were very satisfactory in anterior cruciate ligament reconstruction. Subjective assessment of knee function (Lysholm score), objective measurement of anterior-posterior knee stability (KT-1000 arthrometer) and clinical follow-up results were good without immobilization.--This cannot be said for the posterior cruciate ligament, because the number of patients was too small. Our current concept of rehabilitation after reconstruction of the posterior cruciate ligament may yet serve as a reasonable but still unproven approach to the problem.


Sodium-glucose cotransporter 2 inhibitors in heart failure with preserved ejection fraction: A protocol for meta-analysis.
Nearly half of patients with heart failure (HF) have preserved ejection fraction (EF) and the mortality and morbidity of patients with HF with preserved EF (HFpEF) are high. Patients with HFpEF are often elderly and their primary chronic symptom is severe exercise intolerance that results in a reduced quality of life. Thus, improvement of exercise capacity presents another important clinical outcome in HFpEF patients. Recent randomized controlled trials (RCTs) and meta-analyses of RCTs reported that sodium-glucose cotransporter 2 (SGLT-2) inhibitors improved cardiovascular outcomes in patients with HF with reduced EF. Although the effects of SGLT-2 inhibitors in HFpEF patients have been examined in multiple RCTs, the results are inconsistent due partly to limited power. The purpose of this meta-analysis is to evaluate the efficacy and safety of SGLT-2 inhibitors in HFpEF patients. This meta-analysis will include RCTs examining the effects of SGLT-2 inhibitors on HF severity and health-related quality of life in HFpEF patients. Information of studies will be collected from electronic databases. The primary outcome will be HF severity (plasma B-type natriuretic peptide levels and exercise capacity assessed as 6-minute walk distance). The secondary outcome will be health-related quality of life. The safety outcomes will be all-cause death, HF hospitalization, hypotension, acute renal failure, diabetic ketoacidosis, and urinary tract infection. This meta-analysis will evaluate the efficacy and safety of SGLT-2 inhibitors in HFpEF patients, providing evidence to the clinical use of SGLT-2 inhibitors in these patients. INPLASY2021120033.


Tacrine. A cause of fatal hepatotoxicity?
Tacrine, an acetyl cholinesterase inhibitor used in the treatment of Alzheimer's disease, often causes reversible abnormalities in liver enzymes, but significant hepatotoxicity is uncommon. We describe fatal hepatic failure associated with tacrine administration. A 75-year-old woman with Alzheimer's disease, taking tacrine for 14 months, developed progressive jaundice. Liver function abnormalities developed during tacrine treatment and led to hepatic failure and death. An extensive evaluation for other etiologies of liver disease was negative. Other potentially hepatotoxic medicines had been administered for at least 2 years before beginning tacrine, and postmortem examination of the liver was consistent with drug-induced hepatotoxicity. Approximately half the patients treated with tacrine have liver enzyme abnormalities develop, primarily in the first 12 weeks of therapy, that resolve with discontinuation of drug or dosage adjustment. Our case of tacrine-associated hepatotoxicity 14 months after the initiation of treatment despite regular biochemical evaluation suggests the potential for delayed and fatal hepatotoxicity with tacrine.


The impetus for the development of hospital in the home (HITH) programs: a literature review.
Alternative health care delivery models such as Hospital in the Home (HITH) are proliferating in Australia and in most Western countries. Such models facilitate patients who would otherwise be hospitalised to be cared for in their own homes. This paper reports a review of the literature related to the development of HITH programs. It reveals that the driving force behind the implementation of acute care programs comes from political and managerial aims to reduce health care spending. Home is clearly an appropriate care option for certain acute patients however, there is no strong evidence to suggest that it suits everyone. Very little attention has been given to the patient's experience of home care and the ethical and social consequences are largely ignored.


Perioperative changes in radiographic density in erector spinae muscle and mortality after lung transplantation.
The radiographic density of the erector spinae muscle (ESM) is often decreased early after lung transplantation (LTx). The prognostic impact of this change has not been elucidated. To investigate whether the decrease in the radiographic density of ESMs early after LTx is associated with a poor prognosis. This study is a single center retrospective cohort study. Routine follow-up chest computed tomography scan data just before and 12 weeks after LTx were retrospectively retrieved for adult patients who underwent primary LTx at Kyoto University Hospital. The radiographic density of ESM was quantitatively evaluated as the mean attenuation of the ESM (ESMct), and the impact of the decreased ESMct during the 12 weeks after LTx on overall survival (OS) was examined by Cox proportional hazard regression. A total of 151 recipients (94 cadaveric LTx, 57 living-donor lobar LTx) were included in this study. The median duration of postoperative observation was 4.4 years, during which time 39 recipients (26%) died. Decreased postoperative ESMct was significantly associated with poor OS (HR, 1.64; 95% CI, 1.14-2.35, P = 0.008 per 1 Z score decrease) in the multivariate model adjusted for age, sex, episodes of acute rejection, and preoperative ESMct. Similar results were obtained when the subjects were limited to those with cadaveric LTx. A decreased perioperative ESMct was strongly associated with a poor prognosis after LTx in addition to low preoperative ESMct. Maintaining postoperative muscle radiographic density, which reflects muscle quality, may be important for a better prognosis after LTx.


Comparison of feline leukemia virus-infected and normal cat T-cell lines in interleukin 2-conditioned medium.
Following mitogen stimulation (phytohemagglutinin or concanavalin A), feline lymphocytes were maintained in medium containing feline interleukin 2. Lymphocyte lines derived from the blood of feline leukemia virus-infected cats contained cells 50 to 90% of which expressed virus antigens, but lymphocyte lines derived from uninfected cats remained virus free. Leukemia virus-positive and -negative lymphocyte lines retained total dependence upon the presence of interleukin 2 for finite life spans of 20 to 40 cell divisions. Cell-doubling times and surface properties (membrane immunoglobulin negative, guinea pig red cell rosette positive) of all T-cell lines were similar. All cat lymphocyte lines rapidly developed strong but nonspecific cytotoxic effects against a variety of established cat target lines, including normal and leukemia virus-infected fibroblasts and virus-producing lymphomas. Attempts to infect virus-negative lymphocytes with leukemia virus in vitro produced lines containing 1 to 4% of infected cells; subsequently, this level of infection remained constant. Within observation limits, the characteristics of feline leukemia virus-infected and normal cat T-cells were similar. Leukemia virus infection did not predispose target lymphocytes to exhibit properties in vitro that might be associated with preneoplastic change, such as rapid or infinite cell division or development of independence from interleukin 2 regulation.


Isolation and in vitro translation of messenger RNA from the American cockroach.
Total RNA was extracted from the whole body of American cockroach (Periplaneta americana) using chaotropic salt guanidine isothiocyanate in the presence of 2-mercaptoethanol (2-ME). Polyadenylated mRNA was isolated by oligothymidylic acid-cellulose chromatography and mRNA was translated using a rabbit reticulocyte lysate system. The translation, as judged by the incorporation of 35S-methionine, was obtained with poly(A)+ RNA, where an approximately 9.5-fold increase in label incorporation over control was achieved. Analysis of translation products by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) in combination with autoradiography showed that many proteins with apparent molecular weights ranging from 12 to 200 kD were synthesized, and no labelled proteins were found with negative RNA control and poly(A)- RNA. Immunoprecipitation studies performed using polyclonal and monoclonal antibodies revealed that synthesized proteins of MW 90, 78, 72, 49, 45, and 26 kD corresponded with previously identified principal and major allergens of American cockroach from our laboratory. In addition, the allergenicity of the translation mixtures was also confirmed by fluoroallergosorbent test (FAST) inhibition studies with IgE antibodies of human reaginic serum pool.


Phase II clinical trial of interleukin-12 in patients with relapsed and refractory non-Hodgkin's lymphoma and Hodgkin's disease.
The purpose of this study was to evaluate the clinical activity and toxicity of recombinant human Interleukin (IL)-12 in patients with relapsed and refractory non-Hodgkin's lymphoma (NHL) or Hodgkin's disease (HD). Forty-two previously treated patients (32 patients with NHL and 10 patients with HD) were enrolled on the study. Patients were treated with either intravenous (n = 11) or subcutaneous (n = 31) administration of IL-12. The patients had received a median of three prior treatment regimens, and 16 patients had undergone prior autologous stem cell transplantation. All patients were assessable for toxicity, and 39 of 42 (93%) patients were assessable for response. Six of 29 (21%) patients with NHL had a partial or complete response, whereas none of the 10 patients with HD responded. Furthermore, 15 patients had stable disease that lasted for up to 54 months. Progression-free survival in patients with indolent NHL, aggressive NHL, and HD was 6, 2, and 2.5 months, respectively. Treatment was well tolerated, and the most common toxicity was flu-like symptoms. Reversible grade 3 hepatic toxicity was observed in three patients requiring dose reduction. IL-12 therapy increased the median number of peripheral blood CD8 T lymphocytes from 423/microl to 576/microl (P = 0.0019). Furthermore, IL-12 therapy decreased serum vascular endothelial growth factor and basic fibroblast growth factor concentrations in 37% of the patients. The ability of recombinant human IL-12 therapy to increase the number of circulating CD8+ cells and induce clinical remissions in patients with relapsed NHL warrants further investigation of the drug.


[State of antioxidant defense and L-arginin-nitrogen oxide system in blood of patients with urogenital chlamydiosis].
The system L-arginine-nitrogen oxide plays a significant role in maintenance of the anti-infectious protection of an organism. A condition of the given system and activity of a enzymatic part of antiradical protection in the blood of patients with chlamydiosis has been studied. Obtained data specify an intensification of processes of an oxidizing way of recycling of arginine in an organism of patients. Substantial increase of NO-synthase activity and insignificant activity of arginase in the blood is revealed. The level of nitrite-anion in blood cells of patients authentically increases: 1.7 times in erythrocytes, and 1.4 times in lymphocytes. It is shown, that in patients with chlamydiosis glutathione system is intensified, that is evidenced by an increase glutathione-peroxidase activity and authentic increase of glutathione level. It is assummed that the established features of nitrogen oxide exchange play a significant role in formation of a pathological condition at urogenital chlamydia infections.


Atrial natriuretic peptide and the kidney.
Studies addressing the mechanisms of atrial natriuretic peptide (ANP) action within the kidney are reviewed. The magnitude of the natriuretic response to ANP initially suggested inhibition of renal sodium transport. It now appears, however, that the renal response to ANP is largely dependent on ANP-induced alterations in renal hemodynamics. At the glomerulus, ANP-induced afferent arteriolar dilatation and efferent arteriolar constriction produce a rise in the glomerular capillary hydraulic pressure and thus an increase in the filtration fraction and glomerular filtration rate. Furthermore, angiotensin II-induced increments in renal perfusion pressure markedly augment ANP-induced NaCl excretion, whereas increments in peritubular oncotic pressure or reductions in renal perfusion pressure nearly abolish this natriuretic effect, thereby suggesting that changes in the peritubular physical factors, which govern tubule fluid reabsorption, are required to elicit the natriuretic action of ANP. In addition, increments in papillary vasa recta hydraulic pressures during ANP infusion argue for an important influence of ANP on fluid exchange in the renal papilla. There also is recent evidence to suggest that ANP directly inhibits papillary collecting duct NaCl reabsorption. This action of ANP is thought to contribute to the enhanced renal excretion of sodium-rich urine in response to ANP. Finally, in two models of chronic extracellular volume expansion, namely, mineralocorticoid excess and a reduction in nephron number with a high sodium intake, endogenous plasma ANP levels increased significantly above control levels.(ABSTRACT TRUNCATED AT 250 WORDS)


Antidiabetic thiazolidinediones inhibit invasiveness of pancreatic cancer cells via PPARgamma independent mechanisms.
Thiazolidinediones (TZD) are a new class of oral antidiabetic drugs that have been shown to inhibit growth of some epithelial cancer cells. Although TZD were found to be ligands for peroxisome proliferators activated receptor gamma (PPARgamma) the mechanism by which TZD exert their anticancer effect is currently unclear. Furthermore, the effect of TZD on local motility and metastatic potential of cancer cells is unknown. The authors analysed the effects of two TZD, rosiglitazone and pioglitazone, on invasiveness of human pancreatic carcinoma cell lines in order to evaluate the potential therapeutic use of these drugs in pancreatic adenocarcinoma. Expression of PPARgamma in human pancreatic adenocarcinomas and pancreatic carcinoma cell lines was measured by reverse transcription polymerase chain reaction and confirmed by western blot analysis. PPARgamma activity was evaluated by transient reporter gene assay. Invasion assay was performed in modified Boyden chambers. Gelatinolytic and fibrinolytic activity were evaluated by gel zymography. TZD inhibited pancreatic cancer cells' invasiveness, affecting gelatinolytic and fibrinolytic activity with a mechanism independent of PPARgamma activation and involving MMP-2 and PAI-1 expression. TZD treatment in pancreatic cancer cells has potent inhibitory effects on growth and invasiveness suggesting that these drugs may have application for prevention and treatment of pancreatic cancer in humans.


Cognitive impact of traumatic axonal injury (TAI) and return to work.
Axonal injury (AI) after traumatic brain injury (TBI) is often overlooked as an explanation for cognitive complaints when no damage is detected by computed tomography. The purpose was to assess cognition during the 12 months following a TBI and suspected traumatic axonal injury (TAI). The sample included 17 patients younger than 65 years old, however one died. In the acute phase and at 6 and 12 months, cognition, reaction time, psychomotor performance and finger tapping speed were assessed. Working memory and work status were added at 12 months. Acute MRI findings were recorded. After 1 year, all patients still showed cognitive dysfunction. A recovery had been noted at 6 months, but a cognitive decline was indicated for the majority at 12 months. The sick-listed patients had TAI located in the corpus callosum and the brainstem. They were cognitively more impaired and in more areas than the four patients who had returned to work. Cognitive screening can identify the long-term impact of TAI identified by conventional MRI, used as a routine clinical technique. For rehabilitation and for insurance-related matters, these injuries must be taken seriously, as a deterioration over time might occur. Further research is needed.


The role of protein C deficiency in the etiology of Perthes disease.
Recent reports support the hypothesis that thrombophilia plays an important role in the pathogenesis of Perthes disease (PD) and the objective of this report is to show evidence of the role of protein C deficiency in the etiology of PD, based on a meta-analysis of current scientific literature. Studies were selected in all languages over the last twenty years (1986 to 2006) in MEDLINE, LILACS and EMBASE data bases. The inclusion criteria involved controlled studies, those that presented protein C as a continuous variable, and studies conducted in children with Perthes disease. The fixed effect model for continuous data was used; differences between groups were assessed by the t-test, Z-test and Cochran Q test for independent data and the level of significance was p < 0.05. The selected studies involved 175 patients and 193 control subjects. The selected studies were shown to be heterogeneous, but there were no statistically significant differences in protein C levels between groups. The authors' findings were unable to support the hypothesis that protein C deficiency is associated with Perthes disease and that it may play an important role in the ethiopathogenesis of avascular necrosis of the femoral head in childhood.


Reactive oxygen species, antioxidant systems and nitric oxide in peroxisomes.
Peroxisomes are subcellular organelles with an essentially oxidative type of metabolism. Like chloroplasts and mitochondria, plant peroxisomes also produce superoxide radicals (O2*(-)) and there are, at least, two sites of superoxide generation: one in the organelle matrix, the generating system being xanthine oxidase, and another site in the peroxisomal membranes dependent on NAD(P)H. In peroxisomal membranes, three integral polypeptides (PMPs) with molecular masses of 18, 29 and 32 kDa have been shown to generate radicals O2*(-). Besides catalase, several antioxidative systems have been demonstrated in plant peroxisomes, including different superoxide dismutases, the ascorbate-glutathione cycle, and three NADP-dependent dehydrogenases. A CuZn-SOD and two Mn-SODs have been purified and characterized from different types of peroxisomes. The four enzymes of the ascorbate-glutathione cycle (ascorbate peroxidase, monodehydroascorbate reductase, dehydroascorbate reductase, and glutathione reductase) as well as the antioxidants glutathione and ascorbate have been found in plant peroxisomes. The recycling of NADPH from NADP(+) can be carried out in peroxisomes by three dehydrogenases: glucose-6-phosphate dehydrogenase, 6-phosphogluconate dehydrogenase, and isocitrate dehydrogenase. In the last decade, different experimental evidence has suggested the existence of cellular functions for peroxisomes related to reactive oxygen species (ROS), but the recent demonstration of the presence of nitric oxide synthase (NOS) in plant peroxisomes implies that these organelles could also have a function in plant cells as a source of signal molecules like nitric oxide (NO*), superoxide radicals, hydrogen peroxide, and possibly S-nitrosoglutathione (GSNO).


Salvianolic acid B protects from pulmonary microcirculation disturbance induced by lipopolysaccharide in rat.
The aim of the present study was to examine the effect and possible mechanism of salvianolic acid B (SalB) on pulmonary microcirculation disturbance induced by lipopolysaccharide (LPS) in rat. Male Sprague-Dawley rats were subjected to thoracotomy under continuous anesthesia and mechanical ventilation. Albumin leakage from pulmonary capillary and the numbers of leukocytes adherent to the pulmonary capillary wall were determined for 60 min by an upright microscope upon LPS (2 mg · kg(-1) · h(-1)) infusion with or without administration of SalB (5 mg · kg(-1) · h(-1)). Pulmonary tissue wet-to-dry weight ratio, tumor necrosis factor α, and interleukin 8 in plasma and bronchoalveolar lavage fluid were measured. In addition, the expressions of E-selectin, intercellular adhesion molecule 1, and myeloperoxidase in pulmonary tissue were assessed by immunohistochemistry. The expressions of aquaporin 1 (AQP-1), AQP-5, metalloproteinase 2 (MMP-2), and MMP-9 were assessed by Western blot assay. Pretreatment with SalB significantly attenuated LPS-induced pulmonary microcirculatory disturbance, including the increase in leukocyte adhesion and albumin leakage. In addition, LPS increased pulmonary tissue wet-to-dry weight ratio and tumor necrosis factor α and interleukin 8 levels in plasma and bronchoalveolar lavage fluid enhanced the expression of E-selectin, intercellular adhesion molecule 1, myeloperoxidase, MMP-2, and MMP-9, whereas it decreased the expression of AQP-1 and AQP-5 in pulmonary tissue, all of which were attenuated by SalB pretreatment. Salvianolic acid B pretreatment improves pulmonary microcirculation disturbance and lung injury on LPS exposure. More studies are required to evaluate the potential of SalB as an option for protecting lung from endotoxemia.


[Preliminary Study on the Effect of Silencing Nucleostemin Com- bined with Rapamycin on Autophagy and Apoptosis of HL-60 Cells].
To investigate the effects of knocking down nucleostemin ( NS) combined with rapamycin (RAPA) on autophagy and apoptosis in HL-60 cells , and to explore its role in HL-60 cells . The expression of NS protein was detected using Western blot , after transfection of HL-60 cells was achieved by the recombinant lentviral vector NS -RNAi-GV248 . Flow cytometry was used to detect changes in cells apoptosis after NS silencing/ rapamycin for 24 , 48 hours , and the expressions of NS , LC3 , p62 , BCL-2 and Bax proteins in cells were detected by Western blot. The expression of NS in HL-60 cells was successfully down-regulated by recombinant lentiviral vector. After treatment with rapamycin for 24 and 48 h , the apoptosis rate of cells in each group increased (P < 0.05) , and the apoptosis was more obvious at 48 hours . Compared with the NS silencing group or rapamycin group , after treated with NS down-regulation combined with rapamycin for 48 hours , the apoptosis of HL-60 cells was significantly increased ( P < 0.05 ) , LC3 -II/LC3 -I ratio was significantly increased ( P < 0.05 ) , p62 protein expression was significantly decreased (P < 0.05) , and BCL-2/Bax ratio was significantly decreased ( P < 0.05) . NS down-regulation combined with rapamycin can enhance the apoptosis and autophagy of HL-60 cells , and the induction of apoptosis of HL-60 cells may be related to the expression of BCL-2 and Bax proteins .


How Should Organizations Be Held Accountable for Promoting Environments That Foster Social Connection?
Growing familiarity with health risks of loneliness and isolation underscores the importance of social connection in patients' lived environments and communities. Deficits in social connection are linked to poor cognitive, mental, and physical health and premature death. Design interventions for physical environments-structures, spaces, and soundscapes, for example-can foster social connection, support, and resilience. This article canvasses urban interventions that can support human health investment and development. This article also suggests that designers of community policies, programs, structures, and spaces should be accountable for promoting social connection to help generate measurable health outcomes, such as longevity.