Contribution of prostaglandins to exercise-induced vasodilation in humans.
It has been postulated that endothelial release of prostaglandins contributes to exercise-induced vasodilation of skeletal muscle arterioles. To test this hypothesis, 12 normal subjects underwent brachial arterial and venous catheter insertion and instrumentation of their forearm to measure plethysmographic forearm blood flow. Forearm blood flow and arterial and venous 6-ketoprostaglandin F1 alpha (PGF1 alpha) and prostaglandin E2 (PGE2) were then measured during two levels of wrist flexion exercise (0.2 and 0.4 W). In nine of the subjects, exercise was repeated after intra-arterial infusion of indomethacin (0.3 mg/100 ml forearm vol). Exercise increased forearm blood flow (2.0 +/- 0.2 to 12.1 +/- 1.1 ml.min-1.100 ml-1) and forearm release of PGF1 alpha (162 +/- 28 to 766 +/- 193 pg.min-1.100 ml-1) and PGE2 (26 +/- 6 to 125 +/- 46 pg.min-1.100 ml-1) (all P < 0.05). Indomethacin virtually abolished forearm prostaglandin release and reduced forearm blood flow at rest (2.2 +/- 0.2 to 1.7 +/- 0.2 ml.min-1.100 ml-1), at 0.2 W (6.3 +/- 0.7 to 5.4 +/- 0.7 ml.min-1.100 ml-1), and at 0.4 W (12.2 +/- 1.5 to 10.3 +/- 1.3 ml.min-1.100 ml-1) (all P < 0.02). These data suggest that release of vasodilatory prostaglandins contributes to exercise-induced arteriolar vasodilation and hyperemia in skeletal muscle.


Simple Microcontact Printing Technique to Obtain Cell Patterns by Lithography Using Grayscale, Photopolymer Flexographic Mold, and PDMS.
Microcontact printing using PDMS embossing tools and its variations have aroused the interest of a wide spectrum of research fields, hence the feasibility of defining micro and nanoscale patterns. In this work, we have proposed and demonstrated a novel lithography method based on grayscale patterns printed in a flexographic photopolymer mold and transferred to epoxy resin and a single PDMS stamp to obtain different microprint pattern structures. The geometry of the patterns can be modified by adjusting the layout and grayscale of the stamp patterns. The functionality of this contact printing methodology was validated by generating human induced pluripotent stem cells (hiPSC) patterns. These specific micropatterns can be very useful for achieving complex differentiation in cell lines such as hiPSC. Microfabrication through the new technique provides a promising alternative to conventional lithography for constructing complex aligned surfaces; these structures could be used as components of biological patterns or microfluidic devices.


Oncogenic MicroRNA-27a is a target for genistein in ovarian cancer cells.
MicroRNAs (miRNAs) are emerging as important regulators in various pathobiological processes in cancer. Genistein, as a major isoflavonoid isolated from dietary soybean, possesses a wide variety of biological activities particularly in cancer prevention. However, the molecular mechanisms by which genistein elicits its effects on ovarian cancer cells have not been fully elucidated. In this study, we reported that expression of miR-27a was higher in human ovarian cancer relative to benign ovarian tissues. Meanwhile, transfection of SKOV3 cells with the inhibitor of miR-27a suppressed growth and migration of tumor cells. Our study also found that treatment of ovarian cancer cells with genistein caused an inhibition of ovarian cancer cell growth and migration. Further cellular mechanistic studies revealed that genistein down-regulated miR-27a expression, which was accompanied by significantly increased expression of Sprouty2, a putative miR-27a target gene. Taken together, our findings reveal that oncogenic miR-27a plays an important role in ovarian cancer cell growth and metastasis, and genistein, as nontoxic inactivators of miRNA, can block ovarian cancer cell growth and migration, offering novel insights into the mechanisms of genistein therapeutic actions.


Comparison of the causes and clinical features of drug rash with eosinophilia and systemic symptoms and stevens-johnson syndrome.
Drug rash with eosinophilia and systemic symptoms (DRESS) and the Stevens-Johnson syndrome (SJS) are both severe drug reactions. Their pathogenesis and clinical features differ. This study compared the causes and clinical features of SJS and DRESS. We enrolled 31 patients who were diagnosed with DRESS (number=11) and SJS (number=20). We retrospectively compared the clinical and laboratory data of patients with the two disorders. In both syndromes, the most common prodromal symptoms were itching, fever, and malaise. The liver was commonly involved in DRESS. The mucosal membrane of the oral cavity and eyes was often affected in SJS. The most common causative agents in both diseases were antibiotics (DRESS 4/11 (37%), SJS 8/20 (40%)), followed by anticonvulsants (DRESS 3/11 (27%), SJS 7/20 (35%)). In addition, dapsone, allopurinol, clopidogrel, sulfasalazine and non-steroidal anti-inflammatory drugs (NSAIDs) were sporadic causes. The most common causes of DRESS and SJS were antibiotics, followed by anticonvulsants, NSAIDs and sulfonamides. The increase in the use of antibiotics in Korea might explain this finding.


[Genomic medicine : the challenges of information in clinical practice].
The genomic revolution lifts up several potential opportunities in predictive and preventive medicine. Yet, genomic medicine opportunities can lead to clinical utility only if challenges that come with it are understood, anticipated, and faced. This review discusses the challenges that genomic medicine raises for the patients and their physicians, the general population, study participants and investigators. The article presents a program of genomic consultation in general internal medicine in the French-speaking part of Switzerland (MedOmics) that aims to address these challenges in order to optimize the clinical opportunities offered by genomic medicine.


A prospective randomized double-blind study comparing dexmedetomidine vs. combination of midazolam-fentanyl for tympanoplasty surgery under monitored anesthesia care.
Analgesia and sedation are usually required for the comfort of the patient and surgeon during tympanoplasty surgery done under local anesthesia. In this study, satisfaction scores and effectiveness of sedation and analgesia with dexmedetomidine were compared with a combination of midazolam-fentanyl. Ninety patients undergoing tympanoplasty under local anesthesia randomly received either IV dexmedetomidine 1 μg kg(-1) over 10 min followed by 0.2 μg kg(-1)h(-1) infusion (Group D) or IV midazolam 0.06 mg kg(-1) plus IV fentanyl 1 μg kg(-1) over 10 min (Group MF) followed by normal saline infusion at 0.2 ml kg(-1)h(-1). Sedation was titrated to Ramsay sedation score (RSS) of three. Vital parameters, rescue analgesics (fentanyl 1 μg kg(-1)) and sedatives (midazolam 0.01 mg kg(-1)), patient and surgeon satisfaction scores were recorded. Patient and surgeon satisfaction score was better in Group D than Group MF (median interquartile range (IQR) 9 (8-10) vs. 8 (6.5-9.5) and 9 (8.5-9.5) vs. 8 (6.75-9.25), P = 0.0001 for both). Intraoperative heart rate and mean arterial pressure in Group D were lower than the baseline values and the corresponding values in Group MF (P < 0.05). Percentage of patients requiring rescue fentanyl was higher in Group MF than Group D (40% vs. 11.1%, P = 0.01). One patient in Group D while four in Group MF (8.8%) required rescue sedation with midazolam (P > 0.17). Seven patients in Group D had dry mouth vs. none in Group MF (P = 0.006). One patient in Group D had bradycardia with hypotension which was effectively treated. Dexmedetomidine is comparable to midazolam-fentanyl for sedation and analgesia in tympanoplasty with better surgeon and patient satisfaction. Hemodynamics need to be closely monitored.


Neurological manifestations of neurofibromatosis: a review.
Neurofibromatosis type 1(NF1) is a dominantly inherited genetic disorder caused by a mutation in the NF1 tumor-suppressor gene. Patients are prone to develop benign and malignant tumors not only in the central and peripheral nervous system but also in other parts of the body. Apart from tumors, neurofibromatosis may also be associated with neurological symptoms and disorders such as cerebrovascular disease, epilepsy, neuropathy, and headache. This article seeks to review the different neurological manifestations of neurofibromatosis.


Ancient dissolved methane in inland waters revealed by a new collection method at low field concentrations for radiocarbon (14C) analysis.
Methane (CH4) is a powerful greenhouse gas that plays a prominent role in the terrestrial carbon (C) cycle, and is released to the atmosphere from freshwater systems in numerous biomes globally. Radiocarbon (14C) analysis can indicate both the age and source of CH4 in natural environments. In contrast to CH4 present in bubbles released from aquatic sediments (ebullition), dissolved CH4 in lakes and streams can be present in low concentrations compared to carbon dioxide (CO2), and therefore obtaining sufficient aquatic CH4 for radiocarbon (14C) analysis remains a major technical challenge. Previous studies have shown that freshwater CH4, in both dissolved and ebullitive form, can be significantly older than other forms of aquatic C, and it is therefore important to characterise this part of the terrestrial C balance. This study presents a novel method to capture sufficient amounts of dissolved CH4 for 14C analysis in freshwater environments by circulating water across a hydrophobic, gas-permeable membrane and collecting the CH4 in a large headspace volume. The results of laboratory and field tests show that reliable dissolved δ13CH4 and 14CH4 samples can be readily collected over short time periods (∼4-24 h), at relatively low cost and from a variety of surface water types. The initial results further support previous findings that dissolved CH4 may be significantly older than other forms of aquatic C, and is currently unaccounted for in many terrestrial C balances and models. This method is suitable for use in remote locations, and could potentially be used to detect the leakage of unique 14CH4 signatures from point sources into waterways, e.g. coal seam gas and landfill gas.


Cell Aggregation Assays to Evaluate the Binding of the Drosophila Notch with Trans-Ligands and its Inhibition by Cis-Ligands.
Notch signaling is an evolutionarily conserved cell-cell communication system used broadly in animal development and adult maintenance. Interaction of the Notch receptor with ligands from neighboring cells induces activation of the signaling pathway (trans-activation), while interaction with ligands from the same cell inhibits signaling (cis-inhibition). Proper balance between trans-activation and cis-inhibition helps establish optimal levels of Notch signaling in some contexts during animal development. Because of the overlapping expression domains of Notch and its ligands in many cell types and the existence of feedback mechanisms, studying the effects of a given post-translational modification on trans- versus cis-interactions of Notch and its ligands in vivo is difficult. Here, we describe a protocol for using Drosophila S2 cells in cell-aggregation assays to assess the effects of knocking down a Notch pathway modifier on the binding of Notch to each ligand in trans and in cis. S2 cells stably or transiently transfected with a Notch-expressing vector are mixed with cells expressing each Notch ligand (S2-Delta or S2-Serrate). Trans-binding between the receptor and ligands results in the formation of heterotypic cell aggregates and is measured in terms of the number of aggregates per mL composed of >6 cells. To examine the inhibitory effect of cis-ligands, S2 cells co-expressing Notch and each ligand are mixed with S2-Delta or S2-Serrate cells and the number of aggregates is quantified as described above. The relative decrease in the number of aggregates due to the presence of cis-ligands provides a measure of cis-ligand-mediated inhibition of trans-binding. These straightforward assays can provide semi-quantitative data on the effects of genetic or pharmacological manipulations on the binding of Notch to its ligands, and can help deciphering the molecular mechanisms underlying the in vivo effects of such manipulations on Notch signaling.


[Effect of preliminarily administered aspartate to the body and its combination with a vitamin-coenzyme complex on the catabolism of L-[14C]-aspartate in tissues of various mouse organs in hermetically closed space].
Effect of factors of sealed non-aired space on the organism leads to the enhancement of catabolism of L-4-[14C]-aspartate in the mice encephalon to 14CO2. Preliminary administration of L-aspartate to the organism (100 mg/kg) leads to the intensification of these adaptative reactions and prolongs life of animals under these conditions. Accumulation of the introduced aspartate in the liver and encephalon gets more intensive and its supply to the blood is more rapid under these conditions. Simultaneous (together with L-aspartate) administration of the vitamin-coenzyme complex (pentapyruvate) which includes thiamine pyrophosphate, lipoate, sodium 4-phosphopantotenate, nicotinate and riboflavin-mononucleotide and stimulates the function of the key links of the Krebs cycle to animals has induced intensification of the protective effect of L-aspartate and evoked further activation of the L-aspartate catabolism in the encephalon, mainly at late, preagonal stages of the developing pathological state. The data presented confirm that protective effect of L-aspartate, provided the effect of the closed space factors on the organism, is a result of its quick introduction, into energy mebolism of tissues, in particular, of the nervous tissue.


Computational Investigation of SENP:SUMO Protein-Protein Interaction for Structure Based Drug Design.
SUMO specific proteases (SENPs) are cysteine proteases that carry out the proteolytic processing of SUMO from its pro form as well as its deconjugation from substrate proteins. SENPs have been implicated in various cancers including prostate cancer, thyroid cancer and colon cancer. Therefore, the inhibition of SENPs is an attractive strategy for the treatment of cancer. However, the current SENP inhibitor development strategies target catalytic site and involve the usage of reactive functionalities to facilitate the covalent binding with a catalytic cysteine, which makes them less desirable for therapeutic purposes. Based on the available structural knowledge about the interaction of SENPs with various SUMO paralogues, an alternative approach for inhibiting SENPs could be via targeting SENP:SUMO protein-protein interaction. Here we have investigated the protein-protein interaction between SENP and SUMO as a target for structure based drug design using pocket prediction, ligand binding hotspot mapping, molecular dynamics simulation and in silico alanine mutagenesis. Finally, we have provided recommendations for the structure based design of SENP:SUMO protein-protein interaction inhibitors. Our study indicates that the SENP inhibitors targeting SENP:SUMO protein-protein interaction is a viable alternative strategy to existing inhibitors targeting the enzymatic site.


Developmental changes in speed of information processing in young children.
This study investigated developmental increases in processing speed in young children, relative to adults, with only nonverbal stimuli. R. Kail's (1991) model of the rate of change in processing speed from childhood to adulthood was evaluated. Processing speed was measured in 34 children at 4 years, 37 at 5 years, and 38 at 6 years and in 43 adults, with a battery of 8 computer-administered tests. Results showed clear age-related increases in processing speed that cannot be attributed to increased accuracy and error rate monitoring. Kail's model adequately accounted for the observed rate of developmental change in processing speed; however, the parameter estimates of R. Kail and Y. Park (1992) provided more accurate predictions than did the meta-analytically derived estimates of Kail (1991). Findings support the global developmental trend hypothesis and suggest that this trend extends beyond the range of verbal skills evaluated in previous research.


Conservative treatment of a young patient with thyroid carcinoma in adult ovarian teratoma - case report.
The cystic mature teratomas, including dermoid cysts, are one of the most frequently occurring benign ovarian tumors diagnosed in female patients. The process of neoplastic transformation in mature dermoid cysts is applicable only to 1-2% of cases. In our article, we present a rare case of thyroid carcinoma development in adult teratoma in 21-year-old patient. The young age, certain pathomorphological features and clinical data (small size of neoplastic lesion, correct values of tumour markers, unilateral character, regular levels of thyreoglobulin and absence of any significant deviations in imaging examinations), were the basis for attempting to apply the conservative treatment both in the scope of gynecological surgery and in the supplemental endocrinological therapy. In the patient, the one-sided adnexectomy was performed, considering pathological lesions on the adnexa, as well as the other ovary dermoid cyst was enucleated, without the hysteroctomy procedure. Considering the lack of any morphological lesions and functional changes relating to thyroid gland, the treatment was not radicalised in this scope, either. At present, one year after the primary operation treatment, the patient does not manifest any disease symptoms, whereas the other ovary, in the follow-up ultrasound examinations, shows normal size and echostructure. The thyroid-stimulating hormone (TSH) suppression keeps being applied.


Preventive effects of nutritional doses of polyphenolic molecules on cardiac fibrosis associated with metabolic syndrome: involvement of osteopontin and oxidative stress.
We previously showed that grape extracts enriched in different polyphenolic families were similarly able to prevent reactive oxygen species (ROS) production, although having differential effects on various features of metabolic syndrome when administered at a dose of 21 mg/kg to the fructose (60%)-fed rat (a model of metabolic syndrome). In the present work, we analyzed on the same model the effect of pure polyphenolic molecules (catechin, resveratrol, delphinidin, and gallic acid) administered at a dose of 2.1 mg/kg. Delphinidin and gallic acid prevented insulin resistance, while gallic acid prevented the elevation of blood pressure. All molecules prevented cardiac ROS overproduction and NADPH overexpression. We also showed that fructose feeding was associated with cardiac fibrosis (accumulation of collagen I) and expression of osteopontin, a factor induced by ROS and a collagen I expression inducer. Collagen I and osteopontin expressions were prevented by the administration of all polyphenolic molecules. The potential use of polyphenols in the prevention of cardiac fibrosis should be further explored.


Dental Care and Trauma Management in Children and Adolescents.
Dental health in early childhood is a predictor for oral health as we age, and oral health is an important factor affecting overall health. For this reason, providing good guidance and early intervention is imperative to help set our patients up for success. To do this, providers must be familiar with dental anatomy and development, as well as recommendations for caries prevention, pacifier use, juice consumption, fluoride, and the establishment of a dental home. Aside from general oral health care, providers must also be able to provide guidance regarding dental trauma prevention and management. As health care providers are often the first point of contact after injury, they must be able to provide acute care and appropriate referral as necessary. [Pediatr Ann. 2019;48(1):e3-e8.].


Lysozymes from bacteriophages T3 and T5.
Lysozymes produced in host cells infected with bacteriophages T3 and T5 were found to have the same enzymatic specificity toward the peptidoglycan from Escherichia coli as T7 phage lysozyme, which has been shown to be an N-acetylmuramyl-L-alanine amidase.


Peroxisome proliferator-activated receptors, fatty acid oxidation, steatohepatitis and hepatocarcinogenesis.
Fatty acids are metabolized in the liver by beta-oxidation in mitochondria and peroxisomes and by omega-oxidation in microsomes. Peroxisomal beta-oxidation is responsible for the metabolism of very long chain fatty acids and mitochondrial beta-oxidation is responsible for the oxidation of short, medium and long chain fatty acids. Very long chain fatty acids are also metabolized by the cytochrome P450 CYP4A omega-oxidation system to dicarboxylic acids. Both peroxisomal beta-oxidation and microsomal omega-oxidation lead to the generation of H2O2. The genes encoding peroxisomal, microsomal and some mitochondrial fatty acid metabolizing enzymes in the liver are transcriptionally regulated by peroxisome proliferator-activated receptor alpha (PPAR alpha). Sustained activation of PPAR alpha by peroxisome proliferators has been shown to induce hepatocellular carcinomas in rats and mice. The peroxisome proliferator-induced carcinogenic effect has been attributed to transcriptional activation of PPAR alpha regulated genes and the resulting excessive generation of H2O2. Evidence from mice lacking fatty acyl-CoA oxidase (AOX), PPAR alpha and PPAR alpha/AOX has confirmed the role of PPAR alpha in the development of hepatocellular carcinomas. In addition, mice lacking AOX developed steatohepatitis and provided clues regarding the molecular mechanism responsible for steatosis and steatohepatitis and the role of unmetabolized AOX substrates in the activation of PPAR alpha.


Children's Oncology Group's 2023 blueprint for research: Neuroblastoma.
Neuroblastoma is the most common extra-cranial solid tumor in children and is known for its clinical heterogeneity. A greater understanding of the biology of this disease has led to both improved risk stratification and new approaches to therapy. Outcomes for children with low and intermediate risk disease are excellent overall, and efforts to decrease therapy for such patients have been largely successful. Although survival has improved over time for patients with high-risk disease and treatments evaluated in the relapse setting are now being moved into earlier phases of treatment, much work remains to improve survival and decrease therapy-related toxicities. Studies of highly annotated biobanked samples continue to lead to important insights regarding neuroblastoma biology. Such studies, along with correlative biology studies incorporated into therapeutic trials, are expected to continue to provide insights that lead to new and more effective therapies. A focus on translational science is accompanied by an emphasis on new agent development, optimized risk stratification, and international collaboration to address questions relevant to molecularly defined subsets of patients. In addition, the COG Neuroblastoma Committee is committed to addressing the patient/family experience, mitigating late effects of therapy, and studying social determinants of health in patients with neuroblastoma.


Psychological aspects of individualized choice and reproductive autonomy in prenatal screening.
Probably the main purpose of reproductive technologies is to enable people who choose to do so to avoid the birth of a baby with a disabling condition. However the conditions women want information about and the 'price' they are willing to pay for obtaining that information vary enormously. Individual women have to arrive at their own prenatal testing choices by 'trading off' means and ends in order to resolve the dilemmas facing them. We know very little about how individuals make these trade-offs, so it is difficult to predict how new technologies will affect their choices and preferences. Uptake decisions can be expected to change, especially in the group of women who now are put off by some aspect of the current screening approach, where the avoidance of miscarriage risk may have provided a kind of 'psychological shelter', protecting a lot of people from having to make other decisions. Technologies such as Pre-implantation Genetic Diagnosis may remove a second 'psychological shelter' because they offer the means of avoiding the birth of an affected child without terminating a pregnancy. Even if new technologies will make some decisions easier in terms of their cognitive demands, they will also create new dilemmas and decision making will not necessarily become less stressful in emotional terms. Key challenges concern information and decision-making.


A new protocol for functional analysis of adipogenesis using reverse transfection technology and time-lapse video microscopy.
Since the worldwide increase in obesity represents a growing challenge for healthcare systems, research focusing on fat cell metabolism has become a focal point of interest. Here, we describe a small interfering RNA (siRNA)-technology-based screening method to study fat cell differentiation in human primary preadipocytes that could be further developed towards an automated middle-throughput screening procedure. First, we established optimal conditions for the reverse transfection of human primary preadipocytes demonstrating that an efficient reverse transfection of preadipocytes is technically feasible. Aligning the processes of reverse transfection and fat cell differentiation utilizing peroxisome proliferator-activated receptor gamma (PPAR gamma)-siRNA, we showed that preadipocyte differentiation was suppressed by knock-down of PPAR gamma, the key regulator of fat cell differentiation. The use of fluorescently labelled fatty acids in combination with fluorescence time-lapse microscopy over a longer period of time enabled us to quantify the PPAR gamma phenotype. Additionally, our data demonstrate that reverse transfection of human cultured preadipocytes with TIP60 (HIV-1 Tat-interacting protein 60)-siRNA lead to a TIP60 knock-down and subsequently inhibits fat cell differentiation, suggesting a role of this protein in human adipogenesis. In conclusion, we established a protocol that allows for an efficient functional and time-dependent analysis by quantitative time-lapse microscopy to identify novel adipogenesis-associated genes.


Immunosuppression of experimental autoimmune myasthenia gravis by hydrocortisone and azathioprine.
Experimental autoimmune myasthenia gravis (EAMG), induced in rabbits by injection of acetylcholine receptor (AChR) from Torpedo californica, was suppressed by appropriate treatment with hydrocortisone or with azathioprine. Administration of hydrocortisone in gradually increasing doses, starting at the time of immunization with the receptor, prevented exacerbation of the disease in the early stages of treatment, as was the case when hydrocortisone was administered in high doses from the beginning. Prolonged administration of the antimetabolite azathioprine (Imuran) prevented the appearance of EAMG, for at least 4 months, in rabbits immunized with AChR. Cell-mediated immunity to AChR was demonstrated to be significantly decreased in such treated animals. The effects of hydrocortisone and azathioprine on EAMG support the view that the disease involves an immunologically cell-mediated mechanism and indicate that the experimental disease can serve as a useful model for chemotherapy of the human disease.


Time Course of Radiological Imaging and Variable Interindividual Symptoms in Amyotrophic Lateral Sclerosis and Frontotemporal Dementia Associated with p.Arg487His Mutation in the VCP Gene.
To our knowledge, this is the first study to report the time course of radiological imaging of 3 patients from 2 families with VCP-related amyotrophic lateral sclerosis (ALS) and dementia. Both families shared the same p.Arg487His mutation in the VCP gene encoding valosin-containing protein. The first patient started to have a typical form of ALS, followed by dementia 7 years later. The second patient, a brother of the first one, had frontotemporal dementia and parkinsonism. The third patient had simultaneous ALS and dementia. All patients seemed to have progressive brain atrophy as their clinical symptoms progressed. The common and characteristic finding was atrophy of the temporal lobes including the hippocampi. The relation between imaging findings and symptoms varied considerably among the 3 patients.


Coefficients of variation of ground reaction force measurement in cats.
Gait analysis has been extensively performed in dogs and horses; however, very little is known about feline biomechanics. It was, therefore, the aim of this study to determine the coefficient of variation (CV) among three ground reaction force (GRF) measurements taken for 15 client-owned European shorthaired cats without a training period and a short acclimatisation time. Gait was measured as each cat walked across a pressure-sensitive walkway, and measurements were made three times over a multi-week period (range: 2 to 17 weeks). The parameters evaluated were peak vertical force (PFz), vertical impulse (IFz), stance phase duration (SPD), step length (SL), paw contact area (PCA) and symmetry index (SI%) of the front and hind limbs. After averaging each of the values from the three measurements, the CV and 95% confidence interval (CI) were calculated for all parameters. PFz showed the lowest CV (~ 3%), while IFz showed the highest CV (~11%) when normalised to body mass. When the GRFs were normalised to total force, the CV of PFz dropped to ~2% and that of IFz dropped to ~3%. The CV of SL and PCA were lower (~6% respectively ~5%) compared to the CV for SPD (~10%). The SI% for both PFz and IFz were comparable to the values reported in the gait analysis literature for dogs. Results of the current study indicate that gait analysis of cats using pressure-sensitive walkways produces reliable data and is a promising approach for evaluation of lameness. The results also suggest that PFz may be a more reliable parameter than IFz and that normalisation to percent of total force may aid in interpretation of the evaluated data.


[Trans-ethmoid meningocele diagnosed in adults. Description of one case].
The meningocele and encephalocele are extracranial herniation of single meninges or meninges with brain tissue, through cranial defect. This pathology can be classificated according to contain or localization. The trans-etmoidal encephalocele is the 5% of meningoencephaloceles, and they are the 8-19% of all neural tube dysraphism. We report a 54 year-old woman with a spontaneous rhinorrhea due to an trans-ethmoidal meningocele associate with a recurrent meningitis. The computed tomographic (CT) revealed a trans-ethmoidal meningocele and she was treated with surgery. In presence of a patient with recurrent meningitis is necessary value the possibility of rhinorrhea, and an exhausted radiology study will be fulfill for identify the opening in the skull through leak CSF, and offer the best treatment. The transetmoidal can be a cause of rhinorrhea. The CT scan study of anterior fosa is a good method for diagnostic of this pathology, however, the IRM is the election method.


Expression of prolactin gene in mouse placenta during late pregnancy: detection of mRNA and its translation product.
To examine the existence of PRL messenger ribonucleic acid (mRNA) in the mouse placenta during late pregnancy, reverse transcriptase-polymerase chain reaction (RT-PCR) and Southern blot analysis were carried out followed by nucleotide sequence analysis of cDNA. Total RNA extracted from each tissue was reverse-transcribed, followed by PCR with two oligonucleotide primers specific or a part of mouse PRL (mPRL) cDNA. An amplified RT-PCR product of predicted size was detected in all samples from the placenta of days 16 and 18 pregnant mice. This product was specifically hybridized with a probe overlapping an entire sequence of mPRL cDNA in Southern blot analysis. Nucleotide sequence analysis also provided evidence that the amplified cDNA had a nucleotide sequence completely identical to the mPRL cDNA sequence reported previously. Furthermore, mPRL with a slightly bigger molecular weight than that of pituitary PRL was detected in the placenta of days 12, 14, 16 and 18 pregnancy by immunoblot analysis. These results suggest that PRL mRNA and its translation product are synthesized in mouse placenta during late pregnancy.


Maspin expression in normal and neoplastic salivary gland.
Maspin inhibits cell motility, invasion and metastasis. Loss or reduction in maspin expression has been associated with tumoral progression. The presence of maspin was studied immunohistochemically in salivary gland tumours presenting cells with myoepithelial differentiation in their composition, and in normal salivary gland. Pleomorphic adenoma (PA) presented high expression of maspin, except in the spindle cells and occasional luminal cells. Epithelial-myoepithelial carcinoma and tubular adenoid cystic carcinoma (ACC) showed intense expression in all cells. Cribriform ACC evidenced only few positive cells of the luminal type, while solid subtype showed rare positive cells. Normal salivary gland tissue has shown low levels of maspin positivity. Maspin has small participation in normal salivary gland, is increased in PA, and decreases as the histological malignancy raises. Hence, in salivary gland, its expression is not exclusive of myoepithelial cells; thus, it should not be used as a marker for this cell. Nevertheless, we believe it is an important marker of biological behaviour in these tumours.


Legionellosis in Poland in 2018-2021.
The aim of this study is to compare the epidemiological situation of legionellosis in Poland in 2018-2021 to prior years, taking into account the impact of the COVID-19 pandemic in 2020-2021. The assessment is based on national surveillance data published in the annual bulletin "Infectious Diseases and Poisons in Poland" from 2013 to 2021, as well as data from Legionnaires' disease case reports collected and sent to the Department of Epidemiology of Infectious Diseases and Surveillance NIPH NIH - NRI by sanitary and epidemiological stations or submitted to EpiBase. In Poland, both Legionnaires' disease (an acute infection that progresses to pneumonia) and Pontiac fever (a mild, flu-like sickness) are reported. In 2018-2021, a total of 255 cases of legionellosis were registered, including 236 cases of Legionnaires' disease and 19 cases of Pontiac fever. Each year, there was an increase in the number of notifications compared to the annual median number of cases from 2013-2017. The annual incidence rate in 2019 (0.23 per 100,000 population) was the highest since the start of legionellosis case registration in Poland. It declined again during the years of the COVID-19 pandemic. The notifications occurred throughout the country, but the highest notification rate was observed in the western belt of voivodeships. Pomorskie reported the highest incidence, accounting for more than 20% of all registered cases. The median incidence of Legionnaires' disease in men (0.23 per 100,000) was more than twice that of women (0.10), with the highest incidence (0.58) recorded in men 65 years of age or older. All indigenous cases of Legionnaires' disease were sporadic; all but three patients were hospitalized. State Sanitary Inspection reported 26 fatal cases of Legionnaires' disease (mortality = 11%). Twenty-four cases were linked to contaminated water systems in health-care settings, and 21 cases were likely associated with travel abroad. Although the number of notifications has increased in recent years, Legionnaires' disease is still an infrequently diagnosed respiratory infection in Poland, and the reported incidence remains one of the lowest in the entire EU. The most affected demographic group is men aged 65 and older. Improving the early diagnosis of Legionnaires' disease in healthcare settings remains a priority.


An Experimental and Density Functional Theory Simulation Study of NO Reduction Mechanisms over Fe0 Supported on Graphene with and without CO.
NO reduction over highly dispersed zerovalent iron (Fe0) supported on graphene (G), with and without the presence of CO in the reacting stream, was systematically studied using a fixed-bed reactor, and the reaction mechanism was examined with the aid of in situ Fourier transform infrared (FTIR) spectroscopy and density functional theory (DFT) calculations. The in situ FTIR results showed that NO adsorbed on the Fe0 site is reduced to form active surface oxygen species (O*), which is then reduced by carbon in graphene to form CO2. The presence of CO in the reacting stream helps to reduce the oxidized Fe(O) sites to regenerate Fe0 sites, making NO reduction easier. It was revealed that NO and CO2 are easily adsorbed on the active surface oxygen species (O*) to form nitrate and carbonate, inhibiting their reduction by CO and deactivating the catalyst. The DFT calculations results suggest that the role of Fe is to reduce the energy barrier of the NO adsorption and decomposition, which controls the formation of active surface oxygen species and N2. The combined FTIR and DFT results offer new insights into the possible mechanism of catalytic NO reduction over graphene loaded with Fe, with and without CO.


Student Drowsiness During Simulated Solo Flight.
INTRODUCTION: Pilot fatigue is a significant concern in aviation, where efforts are directed at improving rosters, developing models, and improving countermeasures. Little attention has been given to in-flight detection of fatigue/drowsiness. The aims of this research were to determine whether drowsiness is an issue and explore whether infrared reflectance oculography could prove useful for continuous inflight monitoring.METHODS: Nine university-based pilot trainees wore activity monitors and completed diaries, prior to a simulated navigational exercise of approximately 4 h, during the secondary window of circadian low. During the flight they wore a head-mounted device. Oculographic data were collected and converted into a single number, using the Johns Drowsiness Scale (JDS), with increasing values indicating greater drowsiness (range 0.0 to 10.0).RESULTS: Peak JDS values reached 6.5. Values declined from shortly before top of descent, continuing until landing. Two of the nine participants (22.2%), reached drowsiness levels at or above a cautionary warning level, below which is considered safe for driving a motor vehicle.DISCUSSION: The results of this study revealed the timeline and levels of fatigue that might be experienced by student pilots; showing that drowsiness is a potential issue for student pilots operating in flying conditions similar to those in the simulation. Analysis indicated that pilots are likely to experience levels of drowsiness above a cautionary warning level when modeling predicted effectiveness below 90%, indicating a potential drowsiness issue for pilots. It was concluded that oculography is worthy of further investigation for use as an objective fatigue detection tool in aviation.Corbett MA, Newman DG. Student drowsiness during simulated solo flight. Aerosp Med Hum Perform. 2022; 93(4):354-361.


Growth and Structural Characteristics of CuGaSe2 Films Fabricated from Metallic Precursors Followed by an Elemental Se Reaction Process.
We investigated the growth, structural and optical characteristics of CuGaSe2 thin films prepared with the selenium reaction. Metallic precursor layers from Cu0:5Ga0.5 and Cu0.8Ga0.2 alloy targets were prepared on a sodalime glass substrate by using DC magnetron sputtering, and then annealed to form CuGaSe2 in a rapid thermal process (RTP) with selenium radicals generated by a thermal cracker. The base and sputtering pressures were < 5 x 10(-7) Torr and 30 mTorr, respectively. At ambient temperature, the precursors from the Cu0.5Ga0.5 and Cu0.8Ga0.2 targets were deposited at the rates of 42 nm/min. and 45 nm/min., respectively. The film thicknesses were about 300 nm. Selenization was carried out at different annealing temperatures of T(a) = 450 degrees C, 500 degrees C, 550 degrees C, and 600 degrees C for time periods of 15 min., 30 min., and 60 min. We found that high quality CuGaSe2 films of crystal grains (-1 μm in dia.) fabricated with a reaction using elemental Se at temperatures as low as 450 degrees C for 30 min. When T(a) ≤ 350 degrees C, the Se reaction was insufficient to form CuGaSe2. However, the annealing time had little effect on the formation of CuGaSe2 at T(a) ≥ 450 degrees C. For all the samples, the photoluminescence (PL) emission was only from the donor-acceptor interband transition D1A1 for all the composition ratios of the films [Ga]/[Cu] -1.


Cysteine proteases in nodulation and nitrogen fixation.
The cysteine proteinases or cysteine endopeptidases (EC 3.4.22) are known to occur widely in plant cells. They are involved in almost all aspects of plant growth and development including germination, circadian rhythms, senescence and programmed cell death. They are also involved in mediating plant cell responses to environmental stress (such as water stress, salinity, low temperature, wounding, ethylene, and oxidative conditions) and plant-microbe interactions (including nodulation). In the development and function of legume root nodules, cysteine proteases could be involved in several important processes:-(i) a defence response to root invasion by microorganisms; (ii) protein turnover required during the formation of new tissue; (iii) cellular homeostasis and metabolism; (iv) adaptation of host cells to physiological stresses; (v) control of nodule senescence. Because of their central importance to plant physiology, cysteine proteases could serve as important targets for the study of nodule development and functioning at the molecular level. Because of their widespread occurrence in nodulating plants they could also serve as candidate genes for targeted plant breeding programmes.


Clinical Use of High-Intensity Focused Ultrasound (HIFU) for Tumor and Pain Reduction in Advanced Pancreatic Cancer.
Evaluation of ultrasound-guided high-intensity focused ultrasound (HIFU) used for the first time in Germany in patients with inoperable pancreatic cancer for reduction of tumor volume and relief of tumor-associated pain. 15 patients with locally advanced inoperable pancreatic cancer and tumor-related pain symptoms were treated by HIFU (n = 6 UICC stage III, n = 9 UICC stage IV). 13 patients underwent simultaneous standard chemotherapy. Ablation was performed using the JC HIFU system (Chongqing, China HAIFU Company) with an ultrasonic device for real-time imaging. Imaging follow-up (US, CT, MRI) and clinical assessment using validated questionnaires (NRS, BPI) was performed before and up to 15 months after HIFU. Despite biliary or duodenal stents (4/15) and encasement of visceral vessels (15/15), HIFU treatment was performed successfully in all patients. Treatment time and sonication time were 111 min and 1103 s, respectively. The applied total energy was 386 768 J. After HIFU ablation, contrast-enhanced imaging showed devascularization of treated tumor regions with a significant average volume reduction of 63.8 % after 3 months. Considerable pain relief was achieved in 12 patients after HIFU (complete or partial pain reduction in 6 patients). US-guided HIFU with a suitable acoustic pathway can be used for local tumor control and relief of tumor-associated pain in patients with locally advanced pancreatic cancer. • US-guided HIFU allows an additive treatment of unresectable pancreatic cancer.• HIFU can be used for tumor volume reduction.• Using HIFU, a significant reduction of cancer-related pain was achieved.• HIFU provides clinical benefit in patients with pancreatic cancer. Citation Format: • Strunk HM, Henseler J, Rauch M et al. Clinical Use of High-Intensity Focused Ultrasound (HIFU) for Tumor and Pain Reduction in Advanced Pancreatic Cancer. Fortschr Röntgenstr 2016; 188: 662 - 670.


Efficacy and tolerability of BP-C1 in metastatic breast cancer: a Phase II, randomized, double-blind, and placebo-controlled Thai multi-center study.
The aim of this study was to compare the efficacy and tolerability of BP-C1 vs equal-looking placebo in metastatic breast cancer. A randomized, double-blind, placebo-controlled multi-center study with a semicross-over design was performed. Sixteen patients received daily intramuscular injection of 0.035 mg/kg bodyweight of BP-C1 and 15 patients received equal-looking placebo for 32 days. After 32 days, the placebo patients crossed to BP-C1 with the last observation in the placebo period as baseline. The status of receptors including estrogen receptor (ER), progesterone receptor (PtR), and human EGF receptor 2 (HER2) was analyzed prior to inclusion in the study. Thoracoabdominal CT scan was blindly analyzed by the same independent radiologist in accordance with the RECIST criteria 1.1. Toxicity was assessed according to the NCI Bethesda Version 2.0 (CTC-NCI), and the quality of life (QOL) was assessed according to European Organization for the Research and Treatment of Cancer QOL-C30 and QOL-BR23. The sum of target lesion diameters (sum lesions) after 32 days of treatment increased by 8.9% (P=0.08) in the BP-C1 arm compared to 37.6% (P<0.001) in placebo patients. Twelve of the 15 placebo patients subsequently had BP-C1 treatment. The increase in sum lesions was 3.5% in these patients. The sum of CTC-NCI was increased 18.7% in the BP-C1 arm (P=0.38) compared to 50.9% (P=0.04) in placebo patients. Four mild/moderate adverse events (AEs) present in BP-C1. Two mild/moderate AEs and one severe AE present in placebo. The QOL benchmarks "breast cancer problems last week", "sexual interest and activity last 4 weeks", and "breast cancer-related pain and discomfort last week" were stable in the BP-C1 arm but deteriorated in placebo patients. The sum lesions increased significantly in ER+ (P=0.02) and PtR+ (P=0.03) but not in HER2+. The increase in sum lesions significantly decreased (P=0.02) with an increasing number of negative receptors. A total of 32 days of BP-C1 treatment inhibited cancer growth and was well tolerated with few and mainly mild AEs. The efficacy of BP-C1 was superior in receptor-negative patients. NCT03603197.


Social inequality in food consumption between 2008 and 2019 in Brazil.
To analyse the trend of social inequality in food consumption among Brazilians from 2008 to 2019. Time series analyses using cross-sectional annual data from the Telephone Surveillance System (VIGITEL 2008-2019). Food consumption was evaluated through: (1) consumption of five or more portions of fruits and vegetables in ≥5 d/week; (2) consumption of beans in ≥5 d/week and (3) consumption of soft drinks or artificial juices in ≥5 d/week. Absolute inequality was assessed by the slope index of inequality (SII) and relative inequality by the concentration index (CIX). SII and CIX positive values indicate higher prevalence among more educated citizens and negative among less educated ones. Time trend was assessed by linear regression using weighted least squares. 26 Brazilian state capitals and the Federal District. 621 689 individuals ≥18 years. Fruits and vegetable consumption was more prevalent among the more educated citizens, while beans were mostly consumed by the less educated, and soft drinks or artificial juices was more prevalent among individuals with intermediate education. The highest absolute inequality was found for beans (SII2019 -25·9). In 12 years, the absolute inequality increased for fruit and vegetable consumption (from SII2008 12·8 to SII2019 16·2), remained for beans (SII2008 -23·1 to SII2019 -25·9) and reduced for soft drinks or artificial juices (SII2008 8·7 to SII2019 0·4). Relative inequality was low and constant. Despite the advances reducing inequalities in soft drinks or artificial juice consumption, the increase in the social gap for adequate consumption of fruits and vegetables is troublesome.


Association of the protein Z ATG haplotype with symptomatic nonvascular stroke or thromboembolism in white children: a family-based cohort study.
To clarify the role of protein Z (PZ) in children with stroke/thromboembolism (TE), the present haplotype (HT)-based family study was performed. We genotyped 365 pediatric stroke/TE families (stroke n = 216; TE n = 149) for 4 single nucleotide polymorphisms (SNPs; rs3024718, rs3024731, rs3024772, and rs3024778) to assess the association between genetic variation within a conserved block of linkage disequilibrium harboring the PZ gene and pediatric TE. Association was assessed with use of the transmission disequilibrium test (TDT), corrected for multiple testing (permutation testing: HAPLOVIEW). In addition, PZ antigen was determined and correlated with carriership of PZ haplotypes and the FV G1691A mutation. Rs3024718, rs3024731, and rs3024772 are in tight linkage disequilibrium (LD) and define 4 haplotypes, capturing 97% of the genetic variation for this LD block. HT1 (ATG) was significantly overtransmitted from parents to affected offspring (HT frequency 73.5%, T:U 122:80, chi(2) = 8.791, P = .003). The ATG risk haplotype was significantly correlated with greater PZ antigen levels. Multivariate analysis adjusted for age, sex, established thrombophilias, smoking, fibrinogen, and PZ levels revealed a significant association of the ATG haplotype and TE in children (odds ratio [OR] 1.4; 95% confidence interval [95% CI] 1.08-1.93). Our results suggest that the ATG haplotype of the PZ gene is a genetic marker for symptomatic TE in white German children.


[Application of physiobalneotherapeutic factors in the combined rehabilitative treatment of patients with chronic bacterial prostatitis complicated by erectile dysfunction].
Patients with chronic bacterial prostatitis complicated by erectile dysfunction received combined rehabilitative treatment based on the use of various combinations of physiobalneotherapeutic factors, such as ultrasound, local negative pressure, white and yellow turpentine or sodium chloride baths, supplemented by basal medicamentous therapy in the form of rectal suppositories. Efficiency of therapy involving sodium chloride, white and yellow turpentine baths was estimated at 85, 60, and 75% respectively.


Analysis of Altered Flowering Related Genes in a Multi-Silique Rapeseed (Brassica napus L.) Line zws-ms Based on Combination of Genome, Transcriptome and Proteome Data.
Based on previous researches, we further investigated the multi-silique trait in rapeseed (Brassica napus L.) line zws-ms. In this study, we used a relatively comprehensive list of flowering related genes in rapeseed and compared them between zws-ms and its near-isogenic line (NIL) zws-217. Genes were studied on genome, transcriptome and proteome levels and then we focused on genes with non-synonymous single nucleotide polymorphism (SNP) or frame-shift insertion-deletion (InDel), finding some genes on the list which changes their sequences. Then, combined with their annotation and the information of their orthologs, certain genes such as BnaA09g05900D, ortholog of AGAMOUS-LIKE 42 (AGL42), which encodes an MADS-box protein, were assumed as probably responsible for the multi-silique trait. Also, we analyzed the Differentially Accumulated Proteins (DAPs) between zws-ms and zws-217, revealing some genes involved in homologous recombination and mismatch repair pathways. Since the development of flowers/siliques is crucial to crops and it influences the yield of rapeseed, this study paved a way to deeply understand the mechanism of the multi-pistil flower formation, which may facilitate researches on rapeseed production in future.


Sulfur Compounds in Regulation of Stomatal Movement.
Sulfur, widely present in the soil and atmosphere, is one of the essential elements for plants. Sulfate is a dominant form of sulfur in soils taken up by plant roots. In addition to the assimilation into sulfur compounds essential for plant growth and development, it has been reported recently that sulfate as well as other sulfur containing compounds can also induce stomatal movement. Here, we first summarized the uptake and transport of sulfate and atmospheric sulfur, including H2O and SO2, and then, focused on the effects of inorganic and organic sulfur on stomatal movement. We concluded all the transporters for different sulfur compounds, and compared the expression level of those transporters in guard cells and mesophyll cells. The relationship between abscisic acid and sulfur compounds in regulation of stomatal movement were also discussed.


Heart rate recovery after treadmill electrocardiographic exercise stress test and 24-hour heart rate variability in healthy individuals.
Heart rate recovery after treadmill electrocardiographic exercise stress test is modulated by the autonomic nervous system. Analysis of heart rate variability can provide useful information about autonomic control of the cardiovascular system. The aim of the study was to test the hypothesis of association between heart recovery after treadmill electrocardiographic exercise test and heart rate variability. We studied 485 healthy individuals aged 42+/- 12.1 (range 15-82) years, 281(57.9%) women, submitted to treadmill electrocardiographic exercise stress tests and heart rate variability evaluations over time (SDNN, SDANN, SDNNi, rMSSD, pNN50) and frequency (LF, HF, VLF, LF/HF ratio) domains in 24-hour ambulatory electrocardiographic monitoring. Heart rate recovery was 30+/- 12 beats in the 1st minute and 52+/- 13 beats in the 2nd minute after exercise. Younger individuals recovered faster from the 2nd to the 5th minute after exercise (r= 0.19-0.35, P< 0.05). Recovery was faster in women than in men (4+/- 1.1 beats lower in the 1st minute, p<0.001; 5.7+/- 1.2 beats lower in the 2nd minute, p<0.01; 4.1+/- 1.1 beats lower in the 3rd minute, p<0.001). There was no significant correlation between heart rate recovery and heart rate variability in 1st and 2nd minutes after exercise. SDNN, SDANN, SDNNi, rMSSD, and pNN50 indices demonstrated a significant correlation with heart rate recovery only at the 3rd and 4th minutes. The hypothesis of association between heart rate recovery and 24-hour heart rate variability in the first two minutes after exercise was not substantiated in this study. Heart rate recovery after exercise was associated with age and gender.


Influence of polyethyleneglycol modification on phagocytic uptake of polymeric nanoparticles mediated by immunoglobulin G and complement activation.
The purpose of this study is to investigate the influence of polyethyleneglycol (PEG) modification on in vitro phagocytic uptake of polymeric nanoparticles (NPs) mediated by immunoglobulin G (IgG) and complement activation. A series of PEG-modified poly (D, L-lactide-co-glycolide) nanoparticles (PEG-PLGA-NPs) were incubated in pure serum protein or whole serum, and their capacity for adsorbing albumin and the serum total proteins was measured by a bicinchoninic acid (BCA) protein assay. The adsorption of serum total IgG and complement activation was investigated by enzyme-linked immunosorbent assay (ELISA). To measure in vitro uptake, various fluorescently labeled (Nile red) PEG-PLGA-NPs were opsonized by different pre-treated sera and subsequently incubated with phagocytes. The uptake of NPs by macrophages was then measured by fluorescence spectrometry. Longer chain length and appropriate content PEG reduced the adsorption of serum proteins and complement activation by NPs via both the classical and the alternative pathways. The phagocytosis of PEG-PLGA-NPs by murine peritoneal macrophages (MPMs) involved both serum-independent and serum-dependent phagocytosis. PEG modification was shown only to reduce serum-dependent phagocytosis, mainly by inhibiting IgG adsorption and complement activation on NP surfaces, and the effect of complement activation was greater than that of IgG. The results of this study provided new information that may assist in the design of more efficient nano drug carriers for medical applications.


Trends in Tuberculosis Incidence in the Australian-Born in Victoria: Opportunities and Challenges to Elimination.
Australia is a low tuberculosis incidence country. In the setting of increasing migration, we aimed to investigate the epidemiology and trends of tuberculosis in the Australian-born population in the state of Victoria between 1992 and 2017. We performed a retrospective descriptive analysis of demographic, clinical and outcome data extracted from a centralized notifiable disease database. The mean incidence of tuberculosis was 1.19 cases per 100,000 population per year with a small but significant reduction of 0.98% per year. The median age of cases decreased from 67.5 years in 1994 to 17 years in 2017. Among 0⁻14 year-olds, there was an increase from 0.13 cases per 100,000 population in 1996 to 2.15 per 100,000 population in 2017. Data for risk factors were available from 2002 onwards. The most common risk factor in the 0⁻14 year age group was a household contact with tuberculosis (85.1%), followed by having a parent from a high tuberculosis incidence country (70.2%). We found the rate of tuberculosis in the Australian-born population in Victoria is low. However, there has been an increase in incidence in children, particularly among those with links to countries with high tuberculosis incidence. This could threaten progress towards tuberculosis elimination in Australia.


Current monitoring in a microchannel with repeated constrictions for accurate detection of sample location in isotachophoresis.
We present a new method for accurate detection of sample location in peak mode isotachophoresis (ITP). The technique is based on the design of a microchannel with multiple constrictions and on detecting the passage of the ITP interface through these constrictions. We achieve this by monitoring the electric current across the channel, which exhibits sharp decreases as the ITP interface moves more rapidly through the higher current density constrictions. We show that cross-correlation between the electric current signal and a predefined step function is an effective method for detecting changes in the slope of the electric current curve in real-time and is robust to changes in the composition of the buffers. We demonstrate the use of the technique to deliver sample to a designated location in the channel with an accuracy as low as 50 μm. Importantly, the method does not require the use of any optics and thus can be used to monitor the location of unlabeled species for application in a variety of ITP assays.


[Usefulness of transvaginal echography in the study of organic pathology of the female urethra].
The Authors describe their experience about the use of vaginal ultrasound in the diagnosis of some organic disease of the female urethra. The ultrasonography was performed with the 5 Mhz endocavitary probe and patients in lithotomy position and filled bladder. With this method has been possible value the urethral and peri-urethral echostructure and urethral calibre during micturition. the Authors visualized 20 urethral diverticula, 6 stenosis, 2 carcinomas and 1 leiomyoma. They show the great reliability of this investigation and argue that it may be present as a first instrumental approach in the clinical suspicion of an organic pathology of the female urethra.


A unique case of a typical carcinoid of the middle mediastinum: en bloc surgical resection on cardiopulmonary bypass.
We report a unique case of a 67-year-old man with a typical carcinoid of the middle mediastinum that adhered tightly to the pericardium, the posterior part of the ascending aorta and the pulmonary trunk, that was radically resected with the patient on cardiopulmonary bypass by clamping, sectioning and suturing the ascending aorta.


Rolling circle amplification, a powerful tool for genetic and functional studies of complete hepatitis B virus genomes from low-level infections and for directly probing covalently closed circular DNA.
Complete characterization of the biological properties of hepatitis B virus (HBV) variants requires the generation of full-length genomes. The aim of this study was to develop new tools for the efficient full-length genome amplification of virus from samples with low viral loads. Rolling circle amplification (RCA) was used to amplify full-length HBV genomes from both sera and liver biopsy samples from chronic HBV carriers. Serum-derived relaxed circular HBV DNA could be amplified only after completion and ligation of plus-strand DNA. Covalently closed circular DNA (cccDNA) from liver biopsies could be amplified directly from as few as 13 copies, using RCA, followed by a full-length HBV PCR. Three serial liver biopsy samples were obtained from a lamivudine-resistant patient who cleared detectable serum HBV after adefovir dipivoxil was added to the lamivudine therapy and then seroconverted to anti-HBs. Only the genomes from the last biopsy specimen obtained after the emergence of lamivudine resistance contained the lamivudine resistance-associated mutations rtL180M and rtM204V ("rt" indicates reverse transcriptase domain). Defective genomes were also found in this biopsy sample. Genomes cloned from the liver biopsy specimens were transfected into HuH7 cells to study their replication competence and their susceptibility to lamivudine. RCA is a powerful tool for amplifying full-length HBV genomes and will be especially useful for the study of occult or inactive HBV infections and patients undergoing antiviral treatment. It can also be used to probe HBV cccDNA, the crucial intermediate in viral persistence and the archive of resistance mutations.


Addressing gender inequality and intimate partner violence as critical barriers to an effective HIV response in sub-Saharan Africa.
In Africa, women and girls represent 57% of people living with HIV, with gender inequality and violence being an important structural determinant of their vulnerability. This commentary draws out lessons for a more effective combination response to the HIV epidemic from three papers recently published in JIAS. Hatcher and colleagues present qualitative data from women attending ante-natal clinics in Johannesburg, describing how HIV diagnosis during pregnancy and subsequent partner disclosure are common triggers for violence within relationships. The authors describe the challenges women face in adhering to medication or using services. Kyegombe and colleagues present a secondary analysis of a randomized controlled trial in Uganda of SASA! - a community violence prevention programme. Along with promising community impacts on physical partner violence, significantly lower levels of sexual concurrency, condom use and HIV testing were reported by men in intervention communities. Remme and her colleagues present a systematic review of evidence on the costs and cost-effectiveness of gender-responsive HIV interventions. The review identified an ever-growing evidence base, but a paucity of accompanying economic analyses, making it difficult to assess the costs or value for money of gender-focused programmes. There is a need to continue to accumulate evidence on the effectiveness and costs of different approaches to addressing gender inequality and violence as part of a combination HIV response. A clearer HIV-specific and broader synergistic vision of financing and programming needs to be developed, to ensure that the potential synergies between HIV-specific and broader gender-focused development investments can be used to best effect to address vulnerability of women and girls to both violence and HIV.


Midair collisions in U.S. civil aviation 2000-2004: the roles of radio communications and altitude.
Midair collisions are destructive to aircraft and often fatal to occupants, with the additional possibility of death and destruction on the ground. We sought to determine the characteristics of civil aviation mid-air collisions in U.S. airspace with focus on the altitudes at which the collisions took place and radio communications prior to the collisions. Accident reports published by the National Transportation and Safety Board for the period 2000-2004 were analyzed using descriptive statistics. Additional information was extracted from the narrative report of each accident. During the 5-yr period, 48 collisions in U.S. civil aviation occurred with 78 fatalities and 7 persons severely injured. There were 46 aircraft destroyed and 37 substantially damaged. In 14 cases no radio communication was reported. In 19 cases there appeared regular radio communication with a tower or other aircraft. Midair collisions resulted in fewer severe injuries at lower altitudes. Visibility and weather were not contributing factors. Radio communication is recommended to assist aircraft where practical, but pilots need to be made aware of the limitations of radio communication for the avoidance of midair collisions.


The second finger of Urbs1 is required for iron-mediated repression of sid1 in Ustilago maydis.
The urbs1 gene encodes a transcriptional regulator of siderophore biosynthesis in Ustilago maydis. Biological and DNA-binding activities of the two putative zinc-finger motifs of Urbs1 were studied by analyzing mutants containing altered finger domains. The mutated urbs1 alleles from three previously described N'-methyl-N'-nitro-N-nitrosoguanidine (NTG) mutants were mapped and cloned by a gap-repair procedure. Sequence analyses revealed single amino acid substitutions in two of the NTG mutants. Both mutations (G-507 to D in urbs1-1 and P-491 to L in urbs1-3), which are located in the Urbs1 C-terminal finger domain, reduced DNA-binding activity by 10-fold and were sufficient to confer a urbs1-minus phenotype. The third NTG urbs1 mutant (urbs1-2) also contained a mutation in one of the conserved amino acids (P-518 to S) in the C-terminal finger domain, but this mutation alone was not sufficient to confer a urbs1-minus phenotype. A second frame shift mutation was identified in urbs1-2 and is necessary for the urbs1-minus phenotype. In an analysis of the function of the N-terminal finger of Urbs1, the conserved amino acid Arg-350 was mutated to leucine. A Urbs1 protein with this mutation complemented a urbs1 null mutant strain. By contrast, a similar mutation in the C-terminal domain abolished the ability of Urbs1 to regulate siderophore biosynthesis and greatly reduced its ability to bind target DNA.


Radiation impedance of condenser microphones and their diffuse-field responses.
The relation between the diffuse-field response and the radiation impedance of a microphone has been investigated. Such a relation can be derived from classical theory. The practical measurement of the radiation impedance requires (a) measuring the volume velocity of the membrane of the microphone and (b) measuring the pressure on the membrane of the microphone. The first measurement is carried out by means of laser vibrometry. The second measurement cannot be implemented in practice. However, the pressure on the membrane can be calculated numerically by means of the boundary element method. In this way, a hybrid estimate of the radiation impedance is obtained. The resulting estimate of the diffuse-field response is compared with experimental estimates of the diffuse-field response determined using reciprocity and the random-incidence method. The different estimates are in good agreement at frequencies below the resonance frequency of the microphone. Although the method may not be of great practical utility, it provides a useful validation of the estimates obtained by other means.


E2F8 exerts cancer-promoting effects by transcriptionally activating RRM2 and E2F8 knockdown synergizes with WEE1 inhibition in suppressing lung adenocarcinoma.
Ribonucleotide reductase (RR) is a rate-limiting enzyme that facilitates DNA replication and repair by reducing nucleotide diphosphates (NDPs) to deoxyribonucleotide diphosphates (dNDPs) and is thereby crucial for cell proliferation and cancer development. The E2F family of transcription factors includes key regulators of gene expression involved in cell cycle control. In this study, E2F8 expression was significantly increased in most cancer tissues of lung adenocarcinoma (LUAD) patients and was correlated with the expression of RRM2 through database and clinical samples analysis. The protein expression of E2F8 and RRM2 were positively correlated with tumor-node-metastasis (TNM) pathological stage, and high expression of E2F8 and RRM2 predicted a low 5-year overall survival rate in LUAD patients. Overexpression and knockdown experiments showed that E2F8 was essential for LUAD cell proliferation, DNA synthesis, and cell cycle progression, which were RRM2-dependent. Reporter gene, ChIP-qPCR, and DNA pulldown-Western blot assays indicated that E2F8 activated the transcription of the RRM2 gene by directly binding with the RRM2 promoter in LUAD cells. Previous studies indicated that inhibition of WEE1 kinase can suppress the phosphorylation of CDK1/2 and promote the degradation of RRM2. We further showed here that the combination of E2F8 knockdown with MK-1775, an inhibitor of WEE1 being evaluated in clinical trials, synergistically suppressed proliferation and promoted apoptosis of LUAD cells in vitro and in vivo. Thus, this study reveals a novel role of E2F8 as a proto-oncogenic transcription activator by activating RRM2 expression in LUAD, and targeting both the transcription and degradation mechanisms of RRM2 could produce a synergistic inhibitory effect for LUAD treatment in addition to conventional inhibition of RR enzyme activity.


[Surgery for rectum carcinoma in the very aged (author's transl)].
There are no principal restrictions concerning surgery of the large bowel in the very aged. Report on 212 patients more than 75 ys. old, who had to undergo surgery for rectum-carcinoma. Results on morbidity and lethality and considerations about the quality of life in the remaining short time of the old patients life are referred. There is no borderline of age for operations of palliative nor curative intention in large gut surgery of the aged to be accepted. Instead one should follow the simple rules of tumor surgery, where there is an absolute indication for radical surgery if there are no general nor local contraindications on the tumorectomy.


Comments on how child protective services investigators decide to substantiate mothers for failure-to-protect in sexual abuse cases.
This commentary discusses the decisions of child protective service (CPS) investigators to substantiate mothers for failure to- protect (FTP) in child sexual abuse cases. Four areas are identified in which the scientific literature remains inadequate to fully inform child maltreatment researchers, CPS practitioners and child welfare policymakers on models and outcomes for FTP substantiation decisions. Attention is called to the need for more information about how differences in statutory definitions, common guidelines, and professional education and training influence FTP substantiation decisions. Current gaps in the knowledge base on FTP and nonoffending caregivers are highlighted. doi:10.1300/J070v15n04_05.


Deep learning-based predictive biomarker of pathological complete response to neoadjuvant chemotherapy from histological images in breast cancer.
Pathological complete response (pCR) is considered a surrogate endpoint for favorable survival in breast cancer patients treated with neoadjuvant chemotherapy (NAC). Predictive biomarkers of treatment response are crucial for guiding treatment decisions. With the hypothesis that histological information on tumor biopsy images could predict NAC response in breast cancer, we proposed a novel deep learning (DL)-based biomarker that predicts pCR from images of hematoxylin and eosin (H&E)-stained tissue and evaluated its predictive performance. In total, 540 breast cancer patients receiving standard NAC were enrolled. Based on H&E-stained images, DL methods were employed to automatically identify tumor epithelium and predict pCR by scoring the identified tumor epithelium to produce a histopathological biomarker, the pCR-score. The predictive performance of the pCR-score was assessed and compared with that of conventional biomarkers including stromal tumor-infiltrating lymphocytes (sTILs) and subtype. The pCR-score derived from H&E staining achieved an area under the curve (AUC) of 0.847 in predicting pCR directly, and achieved accuracy, F1 score, and AUC of 0.853, 0.503, and 0.822 processed by the logistic regression method, respectively, higher than either sTILs or subtype; a prediction model of pCR constructed by integrating sTILs, subtype and pCR-score yielded a mean AUC of 0.890, outperforming the baseline sTIL-subtype model by 0.051 (0.839, P = 0.001). The DL-based pCR-score from histological images is predictive of pCR better than sTILs and subtype, and holds the great potentials for a more accurate stratification of patients for NAC.


Scientific support for preparing an EU position in the 54th Session of the Codex Committee on Pesticide Residues (CCPR).
The European Commission asked EFSA to provide support in the framework of Article 43 of Regulation (EC) No 396/2005 for the preparation of the EU position for 54th Session of the Codex Committee on Pesticide Residues (CCPR). In the current report, EFSA provided comments and recommendations on the Codex maximum residue level (MRL) proposals derived by the Joint Meeting on Pesticide Residues (JMPR) that will be discussed in the upcoming CCPR meeting. The current report should serve as the basis for deriving the EU position for the CCPR meeting.


Correspondence between the electronic structure and phase separation in a K-doped FeSe system.
Phase separated potassium intercalated FeSe thin films have been synthesized by pulsed laser deposition. The coexistence of FeSe phase and 245 phase was investigated both by x-ray photoemission spectroscopy (XPS) and x-ray diffraction. The volume ratio of these two phases is sensitive to temperatures and amount of extra potassium dosing. The XPS and ultraviolet photoelectron spectroscopy results indicated that these two phases shows the different hybridization strength between adjacent Fe layer and Se layer. We infer that the layered electronic structure is the necessary condition of superconductivity in potassium-doped FeSe system, and the phase separation is driven by competition between quasi-2D and 3D bonding mode within FeSe layer. Similar competition may also be able to interpret the phase seperation in K x Fe2-y Se2 bulk single crystal.


Profiling of primary and phytonutrients in edible mahlab cherry (Prunus mahaleb L.) seeds in the context of its different cultivars and roasting as analyzed using molecular networking and chemometric tools.
Prunus mahaleb L. (mahlab cherry) is a deciduous plant that is native to the Mediterranean region and central Europe with a myriad of medicinal, culinary and cosmetic uses. The present study explored different cultivars of mahlab (white from Egypt and Greece, red from Egypt and post roasting). UPLC-MS led to the detection of 110 primary and secondary metabolites belonging to different classes including phenylpropanoids (hydroxy cinnamates, coumaroyl derivatives), organic acids, coumarins, cyanogenic glycosides, flavonoids, nitrogenous compounds, amino acids and fatty acids, of which 39 are first time to be detected in Prunus mahaleb L. A holistic assessment of metabolites was performed for further analysis of dataset using principal component analysis (PCA) among mahlab cultivars to assess variance within seeds. The results revealed that phenolic acids (coumaric acid-O-hexoside, ferulic acid-O-hexoside, ferulic acid-O-hexoside dimer, dihydrocoumaroyl-O-hexoside dimer and ferulic acid), coumarins (coumarin and herniarin) and amino acids (pyroglutamic acid) were abundant in white mahlab cultivars (cvs.) from different locations. In contrast, red mahlab and its roasted seeds were more rich in organic acids (citric and malic acids), amygdalin derivative and sphingolipids. Orthogonal projections to latent structures discriminant analysis (OPLS-DA) revealed for markers in red mahlab and in response to roasting, where red mahlab was rich in nitrogenous compounds viz. nonamide, deoxy fructosyl leucine, glutaryl carnitine and isoleucine, while roasted product (REM) was found to be enriched in choline.


EVOLUTIONARY DIVERGENCE AND CHARACTER DISPLACEMENT IN TWO PHENOTYPICALLY-VARIABLE, COMPETING SPECIES.
Theoretical studies of character displacement lead to the view that evolutionary divergence depends primarily on incomplete utilization of available resources. Those models which incorporate constraints preventing complete utilization of resources, even in the absence of competitors, all predict character displacement. Those models which allow greater flexibility of resource use within a species predict correspondingly less divergence. Indeed, Matessi and Jayakar (1980, 1981) based their conditions for occurrence of character displacement on underutilization of resources. I extend a model used by Slatkin (1980, 1983) and Taper and Case (1985) which allows each species to fully utilize its resources in the absence of competitors. I concentrate on the biologically reasonable case in which the species, though similar, differ in their ecological characteristics. As a result of this greater biological realism, I arrive at a different conclusion regarding the conditions which lead to character displacement. The presence of a variety of biological differences between species-including as a subset those which result from resource underutilization-leads to divergence with respect to a quantitatively inherited character, due to interspecific competitive interactions. The resulting displacement can be large and depends little on the parameters chosen. The only exception, involving a character with very low heritability, occurs when the non-interactive phenotypic differences are much greater than those associated with studies of character displacement in natural populations. Thus, under conditions comparable to those encountered in the field, involving similar yet not identical species, evolutionary divergence is a consequence of interspecific competition.


Particle density stratification in transient sedimentation.
Theoretical predictions for the scaling of particle velocity fluctuations with container size in homogeneous Stokes suspensions are not consistent with experimental observations. Several explanations have been advanced, including the formation of stratification in bounded systems, such as those used in experiments. Numerical simulations of transient Stokes sedimentation in bounded cells are presented here for several cell sizes. The simulated cells have top and bottom wall boundaries and periodic boundaries in the horizontal. Throughout the course of the simulations the number and distribution of particles in the cell evolve, with impacts on the bulk mean particle velocity, velocity fluctuations, and particle density gradient. Initially the sedimentation follows the classical description, with a sharp front and uniform particle concentration below, but this is not sustained. A layer of higher particle concentration develops below the front. This is unstable and there is a large-scale overturning of the fluid. As a consequence, there is a redistribution of the particles, leaving behind a mass loading of the particles, which is stably stratified (subject to small density fluctuations between horizontal levels). The mean velocity and fluctuations of the particles initially grow and then decay once stable stratification has developed.


Functional interactions of meiotic recombination factors Rdh54 and Dmc1.
Genetic studies in budding and fission yeasts have provided evidence that Rdh54, a Swi2/Snf2-like factor, synergizes with the Dmc1 recombinase to mediate inter-homologue recombination during meiosis. Rdh54 associates with Dmc1 in the yeast two-hybrid assay, but whether the Rdh54-Dmc1 interaction is direct and the manner in which these two recombination factors may functionally co-operate to accomplish their biological task have not yet been defined. Here, using purified Schizosaccharomyces pombe proteins, we demonstrate complex formation between Rdh54 and Dmc1 and enhancement of the recombinase activity of Dmc1 by Rdh54. Consistent with published cytological and chromatin immunoprecipitation data that implicate Rdh54 in preventing the non-specific association of Dmc1 with chromatin, we show here that Rdh54 mediates the efficient removal of Dmc1 from dsDNA. These functional attributes of Rdh54 are reliant on its ATPase function. The results presented herein provide valuable information concerning the Rdh54-Dmc1 protein pair that is germane for understanding their role in meiotic recombination. The biochemical systems established in this study should be useful for the continuing dissection of the action mechanism of Rdh54 and Dmc1.


[DNA methylation-mediated epigenetic silencing of miR-720 contributes to leukemogenesis in acute myeloid leukemia].
To investigate the expression level and regulation mechanism of miR-720 as well as the association of miR-720 expression with leukemia biological characteristics. Expression and promoter methylation of miR-720 were determined by quantitive PCR and pyrosequencing in 38 patients with AML and 20 normal controls. Lentivirous-mediated miR-702 overexpression was constructed in AML cell line kasumi-1. The cell proliferation, apoptosis, cycle, colony formation, migration and P53-mediated apoptosis pathway were determined. AML patients showed significantly lower miR-720 expression compared with normal controls (0.69±0.09 vs 3.00±0.46, P<0.01); The methylation level of miR-720 promoter region in AML patients were significantly higher than normal controls [(75.56±2.35)% vs (47.65±2.78)%, P<0.01]. miR-720 overexpression in kasumi-1 cells induced significantly increased cell apoptosis (P=0.017), elevated apoptosis sensitivity to etoposide (P=0.004), and reduced cell proliferation (P<0.01). miR-720 overexpression also induced reduced colony formation (P=0.005), cell cycle arrest in G(1)/G(0) phase and decreased migration ability in kasumi-1 cells. In addition, overexpression of miR-720 significantly induced increased cell apoptosis-related proteins including P53 and Bax, and activation of NF-κB signal transduction pathway. After kasumi-1 cells were treated with 1uM decitabine for 48 hours, miR-720 promoter methylation reduced significantly, and miR-720 expression significantly increased. The expression of miR-720 in AML patients reduced significantly, and DNA methylation-mediated epigenetic silencing of miR-720 contributed to maintain the malignant characteristics of AML.


Clinical characteristics and coronary anatomy in refractory unstable angina pectoris leading to coronary artery bypass grafting. The Kuopio experience.
One hundred patients with high-risk unstable and medication-resistant angina pectoris underwent coronary artery by-pass grafting. In 35 cases the angina was of early post-infarction type, in 60 it was progressive after previous stability and in five it was of recent onset. All had abnormal ECG in association with anginal attacks (ST depression in 76, ST elevation in 5, T-wave inversion in 15 and left bundle branch block in 4). The left main coronary artery was stenosed in 33 patients, and the respective figures for three-vessel, two-vessel and one-vessel disease were 53, 9 and 5. The average number of inserted peripheral grafts/patient was 4.6. The perioperative mortality rate was 1%. Seven patients had confirmed or probable perioperative myocardial infarction and two had late infarction during the hospital stay, but none had angina pectoris on discharge. Of 60 patients re-examined after 1 year, 47 were angina-free. Five had NYHA class III angina, but all were improved. In refractory unstable angina pectoris there is severe coronary artery involvement, but bypass grafting can give good results.


Primary kidney disease modifies the effect of comorbidities on kidney replacement therapy patients' survival.
Comorbidities are associated with increased mortality among patients receiving long-term kidney replacement therapy (KRT). However, it is not known whether primary kidney disease modifies the effect of comorbidities on KRT patients' survival. An incident cohort of all patients (n = 8696) entering chronic KRT in Finland in 2000-2017 was followed until death or end of 2017. All data were obtained from the Finnish Registry for Kidney Diseases. Information on comorbidities (coronary artery disease, peripheral vascular disease, left ventricular hypertrophy, heart failure, cerebrovascular disease, malignancy, obesity, underweight, and hypertension) was collected at the start of KRT. The main outcome measure was relative risk of death according to comorbidities analyzed in six groups of primary kidney disease: type 2 diabetes, type 1 diabetes, glomerulonephritis (GN), polycystic kidney disease (PKD), nephrosclerosis, and other or unknown diagnoses. Kaplan-Meier estimates and Cox regression were used for survival analyses. In the multivariable model, heart failure increased the risk of death threefold among PKD and GN patients, whereas in patients with other kidney diagnoses the increased risk was less than twofold. Obesity was associated with worse survival only among GN patients. Presence of three or more comorbidities increased the age- and sex-adjusted relative risk of death 4.5-fold in GN and PKD patients, but the increase was only 2.5-fold in patients in other diagnosis groups. Primary kidney disease should be considered when assessing the effect of comorbidities on survival of KRT patients as it varies significantly according to type of primary kidney disease.


A cleavable self-assembling tag strategy for preparing proteins and peptides with an authentic N-terminus.
Recombinant protein expression and purification remains a central need for biotechnology. Herein, the authors report a streamlined protein and peptide purification strategy using short self-assembling peptides and a C-terminal cleavage intein. In this strategy, the fusion protein is first expressed as an aggregate induced by the self-assembling peptide. Upon simple separation, the target protein or peptide with an authentic N-terminus is then released in the solution by intein-mediated cleavage. Different combinations of four self-assembling peptides (ELK16, L6 KD, FK and FR) with three inteins (Sce VMA, Mtu ΔI-CM and Ssp DnaB) were explored. One protein and two peptides were used as model polypeptides to test the strategy. The intein Mtu ΔI-CM, which has pH-shift inducible cleavage, was found to work well with three self-assembling peptides (L6 KD, FR, FK). Using this intein gave a yield of protein or peptide comparable with that from other more established strategies, such as the Trx-strategy, but in a simpler and more economical way. This strategy provides a simple and efficient method by which to prepare proteins and peptides with an authentic N-terminus, which is especially effective for peptides of 30-100 amino acids in length that are typically unstable and susceptible to degradation in Escherichia coli.


Chemical Synthesis of d-glycero-d-manno-Heptose 1,7-Bisphosphate and Evaluation of Its Ability to Modulate NF-κB Activation.
d-glycero-d-manno-Heptose 1,7-bisphosphate (HBP) is the precursor for heptose residues found in Gram-negative bacterial membrane surface glycoproteins and glycolipids. HBP β-anomer was recently reported to be a pathogen-associated molecular pattern (PAMP) that regulates TIFA-dependent immunity. Herein, we report the chemical synthesis of HBP α- and β-anomers, which highlights a C-7 carbon homologation via the Corey-Chaykovsky reaction, and the introduction of a phosphate group at the anomeric position using the Mitsunobu reaction. Furthermore, NF-κB reporter assaying revealed that HBP β-anomer activates the NF-κB signaling pathway.


Plant defense and density dependence in the population growth of herbivores.
Long-standing theory has predicted that plant defensive and nutritional traits contribute to the population dynamics of insect herbivores. To examine the role of plant variation in density dependence, I took a comparative approach by conducting density manipulation experiments with the specialist aphid, Aphis nerii, on 18 species of milkweed (Asclepias spp.). The strength of density dependence varied on the plant species. Variation in plant secondary compounds (cardenolides), trichomes, leaf carbon and nitrogen concentrations, and seed mass of the milkweed species predicted the R(max) of aphid populations, while specific leaf weight, carbon concentration, latex, water content, and trichome density were significant predictors of the strength of density dependence. Thus, plant traits that probably evolved for primary and defensive functions contribute to the ecological dynamics of herbivore populations.


Fetal antigens in the precursor stages of gastric cancer.
Gastric epithelial cells, identified in biopsy specimens from individuals with varying degrees of gastritis and cellular atypia, were classified according to morphology and reactivity with an adult tissue-absorbed rabbit antibody to 2nd trimester human fetal tissue. Sections of stomach from normal individuals and patients with superficial gastritis were generally unreactive with this antibody as determined by immunoperoxidase microscopy. However, a progressive increase in the frequency of antigen-positive gastric epithelial cells was observed during the transition from superficial gastritis to mature metaplasia to dysplasia. Adjunct immunohistologic subclassification of gastric lesions, thus, appears to be possible using a suitably prepared antibody probe. This approach may provide additional parameters necessary for assessment of preneoplastic syndromes and contribute to clinical staging of gastric disease.


MPEG-hexPLA micelles as novel carriers for hypericin, a fluorescent marker for use in cancer diagnostics.
Ovarian cancer is the most common gynecological cancer diagnosed in Western countries. Detection of micrometastases at an early stage of the disease could lead to a cure rate of 90% by limiting the spread of the disease outside the ovaries. In this article, hypericin (Hy), a hydrophobic photosensitizer used for the photodynamic diagnosis (PD) of ovarian cancer, was efficiently incorporated into a core of micelles made from methoxy-poly(ethylene glycol) and hexyl-substituted poly(lactides) copolymers. The fate of these micelles following intravenous injection was studied in vivo in two ovarian tumor-bearing animal models. In the chick embryo chorioallantoic membrane model, 17 times more Hy accumulated in tumor nodules when Hy was delivered with micelles than when Hy was delivered as an ethanol solution. Studies of the biodistribution of Hy in Fisher rats revealed escape of these nanosized micelles (<32 nm) from the mononuclear phagocyte system. Hy-loaded micelles showed maximal accumulation in tumors and demonstrated the best tumor/muscle contrast visible 3 h after injection in the rat model. The rapid and highly selective accumulation of Hy in tumors that we demonstrated in this study suggests that these micelle formulations could be used for the PD of ovarian cancer in the future.


Associations between drugs and small-bowel mucosal bleeding: Multicenter capsule-endoscopy study.
Although several drugs may induce small-bowel mucosal injuries, it is unclear whether these injuries contribute to overt small-bowel bleeding. This study was designed to evaluate the associations between drug use and small-bowel mucosal injury and between these mucosal injuries and overt bleeding in a disease-relevant population. We retrospectively studied patients with suspected small-bowel diseases who underwent capsule endoscopy between 2010 and 2013. Drug exposure, Charlson Comorbidity Index, smoking, and alcohol consumption were assessed before capsule endoscopy. Adjusted odds ratios (AOR) and confidence intervals (CI) were estimated for small-bowel mucosal injury and small-bowel overt bleeding. In total, 850 patients were analyzed during the study period. Median age was 64 years, and 544 patients (64.0%) were men. Among the patients with small-bowel mucosal injury (n = 60) and without mucosal injury (n = 705), use of non-steroidal anti-inflammatory drugs (NSAIDs) (AOR 1.8, 95% CI 1.01-3.31) was significantly associated with an increased risk of small-bowel mucosal injury compared with non-use. Patients with small-bowel mucosal injury with overt bleeding (n = 85) and without overt bleeding (n = 60) were compared, and no significant difference between the groups in the usage rates for NSAIDs, thienopyridine, other antiplatelets, anticoagulants, acetaminophen, tramadol hydrochloride, or steroids was revealed, even after adjusting for confounders. Although the use of NSAIDs was significantly associated with an increased risk of small-bowel mucosal injury, no significant associations were observed between the use of such drugs and small-bowel overt bleeding.


Capillary electrophoresis-mass spectrometry of proteins at medium pH using bilayer-coated capillaries.
The feasibility of using noncovalently bilayer-coated capillaries for capillary electrophoresis-mass spectrometry (CE-MS) of acidic proteins was investigated using background electrolytes (BGEs) of medium pH. The capillary was coated by successively rinsing the capillary with solutions of the oppositely charged polymers polybrene (PB) and poly(vinyl sulfonic acid) (PVS). Volatile BGEs containing ammonium formate and/or N-methyl morpholine were tested at pH 7.5 and 8.5. Overall, these BGEs provided relatively fast protein separations (analysis times of ca. 12 min) and showed high efficiencies (70,000-300,000 plates) when the ionic strength was sufficiently high. Migration-time reproducibilities were very favorable with RSDs of less than 1.0%. Infusion experiments showed satisfactory MS responses for studied proteins dissolved in ammonium formate (pH 8.5), however, high concentrations of N-methyl morpholine appeared to seriously suppress the MS protein signals. Evaluation of the CE-MS system was performed by analyzing a mixture of intact proteins yielding efficient separations and good-quality mass spectra. CE-MS analysis of a reconstituted formulation of the biopharmaceutical recombinant human growth hormone (rhGH) which was stored for a prolonged time, revealed one degradation product which was provisionally identified as desamido rhGH. Based on the MS responses the amount of degradation was estimated to be ca. 25%.


Relationship between alterations in atrial and ventricular histamine content and cardiac function during cardiac anaphylaxis of isolated guinea pig hearts.
Antigen-induced histamine release from sensitized cardiac tissue has been shown to contribute significantly to the increases in atrial rate, atrioventricular nodal conduction, and ventricular contractile force that occur during cardiac anaphylaxis. These findings suggest that there might be a strong negative correlation between changes in these variables and the residual histamine content in the tissue after the anaphylactic reaction. In the present study using isolated hearts of passively sensitized guinea pigs, antigen challenge evoked transient increases in atrial automaticity, P-R intervals, vascular resistance, and left ventricular pressure. The histamine content of atrial and ventricular tissue from antigen-challenge hearts (1,475 +/- 296 and 4,543 +/- 360 ng/g, respectively) was significantly less than that of nonchallenged hearts (2,652 +/- 335 and 6,298 +/- 251 ng/g, respectively). Significant correlations found were between the residual histamine content of the ventricular tissue or the total histamine released and the magnitude of the antigen-induced increase in left ventricular systolic pressure. These findings suggest that antigen-induced increases in left ventricular systolic pressure can be used as an index of the local ventricular histamine release. The lack of significant correlations between local residual histamine levels and changes in atrial rate, P-R intervals, or coronary vascular resistance suggests that complicated interactions between histamine and other mediators or factors may be involved in the antigen-induced chronotropic, dromotropic, and vasoconstrictive alterations in these preparations.


Evidence that DNase I hypersensitive site 5 of the human beta-globin locus control region functions as a chromosomal insulator in transgenic mice.
We have previously reported that DNase I hypersensitive site 5 (5'HS5) of the human beta-globin locus control region functions as a chromatin insulator in stable transfection assays. In this report we show that a 3.2 kb DNA fragment containing the entire 5'HS5 region can protect a position-sensitive (A)gamma-globin gene against position effects in transgenic mice. Bracketing is required for function of 5'HS5 as an insulator. The 5'HS5 insulator operates in adult as well as in embryonic murine erythroid cells. The insulator has no significant stimulatory effects of its own. These results indicate that 5'HS5 can function as a chromatin insulator in vivo.


Chemical and structural stability of zirconium-based metal-organic frameworks with large three-dimensional pores by linker engineering.
The synthesis of metal-organic frameworks with large three-dimensional channels that are permanently porous and chemically stable offers new opportunities in areas such as catalysis and separation. Two linkers (L1=4,4',4'',4'''-([1,1'-biphenyl]-3,3',5,5'-tetrayltetrakis(ethyne-2,1-diyl)) tetrabenzoic acid, L2=4,4',4'',4'''-(pyrene-1,3,6,8-tetrayltetrakis(ethyne-2,1-diyl))tetrabenzoic acid) were used that have equivalent connectivity and dimensions but quite distinct torsional flexibility. With these, a solid solution material, [Zr6 O4 (OH)4 (L1)2.6 (L2)0.4 ]⋅(solvent)x , was formed that has three-dimensional crystalline permanent porosity with a surface area of over 4000 m(2) g(-1) that persists after immersion in water. These properties are not accessible for the isostructural phases made from the separate single linkers.