Exposure to levonorgestrel-based birth control pill in early life and its persistent effects in zebrafish.
The consumption of progestins has increased considerably in recent decades, as has their disposal into the environment. These substances can negatively affect the reproduction, physiology, and behavior of non-target organisms, such as fish. We aimed to evaluate the effects of exposure to environmentally relevant concentrations of levonorgestrel-control birth based (1.3, 13.3, 133, and 1330 ng/L) on the development and behavior of zebrafish (Danio rerio) in terms of mortality, hatching, spontaneous movement, and larval and adult behavioral tests. Exposure caused anxiogenic-like behavior in larvae, which persisted in adults, as demonstrated by the light-dark test. In contrast, it caused anxiolytic-like behavior in the novel tank test. There was a high mortality rate at all tested concentrations and increases in the hormone cortisol at 13.3 ng/L that affected the sex ratio. These changes may lead to an ecological imbalance, emphasizing the risk of early exposure to progestins in the environment.


Classification models for neocryptolepine derivatives as inhibitors of the β-haematin formation.
This paper describes the construction of a QSAR model to relate the structures of various derivatives of neocryptolepine to their anti-malarial activities. QSAR classification models were build using Linear Discriminant Analysis (LDA), Quadratic Discriminant Analysis (QDA), Classification and Regression Trees (CART), Partial Least Squares-Discriminant Analysis (PLS-DA), Orthogonal Projections to Latent Structures-Discriminant Analysis (OPLS-DA), and Support Vector Machines for Classification (SVM-C), using four sets of molecular descriptors as explanatory variables. Prior to classification, the molecules were divided into a training and a test set using the duplex algorithm. The different classification models were compared regarding their predictive ability, simplicity, and interpretability. Both binary and multi-class classification models were constructed. For classification into three classes, CART and One-Against-One (OAO)-SVM-C were found to be the best predictive methods, while for classification into two classes, LDA, QDA and CART were.


Comparison on pore development of activated carbon produced from palm shell and coconut shell.
A series of experiments were conducted to compare the pore development in palm-shell and coconut-shell-based activated carbons produced under identical experimental conditions. Carbonization and activation processes were carried out at 850 degrees C using a fluidized bed reactor. Within the range of burn-off studied, at any burn-off, the micropore and mesopore volumes created in palm-shell-based activated carbon were always higher than those of coconut-shell-based activated carbon. On macropore volume, for palm-shell-based activated carbon, the volume increased with increase in burn-off up to 30% and then decreased. However, for coconut-shell-based activated carbon, the change in macropore volume with burn-off was almost negligible but the absolute macropore volume decreased with burn-off.


A bioenergetic study of a benthic nematode, Plectus palustris de man 1880, throughout its life cycle : I. The respiratory metabolism at different densities of bacterial food.
Respiration rates of the bacterivorous freshwater nematode Plectus palustris were measured during the whole life cycle of the species and for animals grown at two food densities. Covariance analysis showed that small, but significant differences exist in the elevation of the respiration rate-body weight regressions (R=aW b, in nl O2/ind·h and μg wet weight) for different food densities. At a food density of 6-9·108 bacterial cells/ml the level of respiration is 14% lower compared to rates of animals cultured at a ten times higher food density. However, the allometric function, R-aW b, adequately describes the relationship of respiration and body weight only during the larval growth phase and for young females, while respiration rates of newly hatched larvae and mature females at maximal egg production have lower metabolic rates. Cumulated metabolic costs to attain a certain age, size and stage of development have been determined and are used in a subsequent paper (Schiemer et al., 1979) to calculate the energy budgets of the species.


High-Strength, Self-Healable, Temperature-Sensitive, MXene-Containing Composite Hydrogel as a Smart Compression Sensor.
As a new two-dimensional material similar to graphene, MXene has attracted extensive attention in the field of electrochemical materials such as supercapacitors because of its excellent mechanical properties, electrical conductivity, and thermal conductivity. What is better than graphene is that the few-layer MXene material obtained by proper treatment has good water dispersibility and can be used as an ideal nanomaterial to enhance the conductivity of hydrogels. However, the articles about the few-layer MXene material used in the preparation of composite hydrogels are rare. In this paper, MXene was synthesized by Yury mild method. Poly(N-isopropyl acrylamide) (PNIPAM) hydrogel and physical cross-linking hydrogel were used as the matrix to prepare composite hydrogels with temperature sensitivity and stress-sensing properties. The composite hydrogels exhibited excellent mechanical properties: it could be stretched to over 14 times the original length and achieved a 0.4 MPa tensile strength while showing good self-healing ability, which was of great significance for the practical application of hydrogels. The conductivity of the composite hydrogel was 1.092 S/m, which was about 15 times that of the control hydrogel without MXene. The potential of the composite hydrogel as a smart compression sensor was also verified by the conductivity tests.


Norepinephrine is a presynaptic input to visual corpus callosum cells.
The neurochemical identity of presynaptic inputs to cell bodies of corpus callosum fibers (callosal cells) located in visual cortex of the cat was investigated using a double labeling technique. Callosal cells were labeled by horseradish peroxidase applied to the severed ends of callosal fibers, and [3H]norepinephrine (NE) was injected into the crown of the lateral gyrus corresponding to the visual cortical area 17/18 border to label synapses. The tissue surrounding the injection sites was processed for electron microscope autoradiography. The results show that NE can be localized to cortical synapses contacting callosal cells in visual cortex of the cat.


Management of Highly Resistant Gram-Negative Infections in the Intensive Care Unit in the Era of Novel Antibiotics.
Antimicrobial-resistant bacterial infections, particularly those caused by Gram-negative bacteria, are major public health threats globally. Since 2015, several antibiotics with activity against highly antimicrobial-resistant Gram-negative bacteria have been approved, which offer alternatives emerging to previous frontline agents such as polymyxins and aminoglycosides. Despite data that new drugs are more effective and better tolerated than older agents against at least some highly antimicrobial-resistant Gram-negative bacterial infections, clinicians remain uncertain about how best to incorporate them into clinical practice. In this article, we discuss the management of highly resistant Gram-negative bacterial infections in the era of new antibiotics, with particular attention to those caused by AmpC- and extended-spectrum β-lactamase-producing Enterobacterales (which manifest phenotypically as 3rd generation cephalosporin resistance), carbapenem-resistant Enterobacterales, multidrug-resistant Pseudomonas aeruginosa, carbapenem-resistant acinetobacter baumannii, and Stenotrophomonas maltophilia.


Disseminated mycobacteriosis manifesting as paraplegia in two Parma wallabies (Macropus parma) naturally exposed to Mycobacterium avium.
Two captive female Parma wallabies (Macropus parma) died after a history of flaccid paraplegia. On postmortem examination, granulomatous and suppurative osteomyelitis involving the left ischium and the lumbosacral region, with meningeal extension at the cauda equina, and caseonecrotic mastitis were the most significant changes. Multiple small nodules in the liver and spleen, and an enlargement of some lymph nodes with central caseous necrosis were also observed. Microscopically, a disseminated granulomatous inflammation with numerous multinucleate giant cells was seen. Numerous acid-fast bacilli were detected in macrophages, in multinucleated giant cells, and free in the central necrosis and suppurative exudate. After culture, polymerase chain reaction assays were carried out to detect the 65-kDa heat shock protein (Hsp65) and insertion sequences (IS)1245 and IS900. The causative agent was identified as Mycobacterium avium subsp. avium.


Adhesion-promoting properties of dyes routinely used during fertility surgeries.
With the link between peritoneal adhesions and infertility well established, it is critical that materials used in pelvic surgery be tested for their adhesion-forming properties. The current study examined the adhesion-inducing properties of two dyes routinely used for visualization during pelvic surgery. In vivo and in vitro examination of the effects of the dyes methylene blue and indigo carmine on adhesion formation in a mouse model. A series of three experiments was conducted. In the first, dyes were injected directly into the peritoneal cavity. The mice were then sacrificed at one of two time points and the peritoneal cavity examined for adhesion formation. In addition, because of their purposed role in adhesion formation, macrophages from the cavity were examined for signs of dye-induced activation. Further studies of macrophage activation were then conducted in vitro to determine the effects of dye concentration and exposure time on the activation process. Both methylene blue and indigo carmine appeared to induce adhesion formation as well as macrophage activation in vivo. Further, long-term exposure to visual concentrations of both dyes appeared to induce macrophage activation. However, only those macrophages exposed to methylene blue exhibited signs of activation when the exposure time was limited to times equivalent to those which might be expected during surgery. Of the two dyes tested, indigo carmine might be the dye of choice in surgeries where fertility is to be maintained.


Efficacy and tolerability of once-daily oral telithromycin compared with clarithromycin for the treatment of community-acquired pneumonia in adults.
Telithromycin is a new antibacterial agent of the ketolide class designed to provide optimal treatment against common bacterial respiratory tract pathogens. Telithromycin was derived by structural modification of the basic macrolide molecule to allow tight binding to the bacterial ribosome that enhances potency and minimizes the risk for the development of resistant strains. The aim of this study was to compare the efficacy and tolerability of telithromycin 800 mg once daily with those of high-dose clarithromycin (500 mg twice daily), each for 10 days, in the treatment of adult patients with community-acquired pneumonia (CAP). This randomized, double-blind, double-dummy, parallel-group clinical trial was conducted at 54 centers in the United States, Canada, Argentina, and Chile. Patients aged >or=18 years with acute CAP were randomized to receive 10-day treatment with oral telithromycin 800 mg once daily (administered as two 400-mg encapsulated tablets in the morning) and placebo (administered as 2 encapsulated tablets identical to the telithromycin in the evening) or high-dose clarithromycin (500 mg administered as two 250-mg identical encapsulated tablets twice daily). The primary outcome measure was clinical outcome at the posttherapy, test-of-cure visit (days 17-24 after the completion of therapy) in the clinically assessable per-protocol population. Secondary efficacy variables included bacteriologic outcome at the posttherapy, test-of-cure visit, and clinical and bacteriologic outcomes at the late posttherapy visit (day 31-45). Tolerability was assessed using investigator observation, patient self-reporting, clinical laboratory data, a 12-lead electrocardiogram, and physical examination (including vital signs). A total of 493 patients were enrolled and 448 patients received >or=1 dose of study medication (224 patients/group). A diagnosis of CAP was confirmed in 416 patients (205 men, 211 women; median age, 43 years; telithromycin, n = 204; clarithromycin, n = 212). Clinical cure rates were 88.3% (143/162) in the telithromycin group and 88.5% ( 138/56) in the clarithromycin group. Bacterial eradication rates were comparable between treatment groups (telithromycin, (28/32) [87.5%]; clarithromycin, (29/30) [96.7%]. Both treatment were fairly well tolerated; adverse events were experienced in 57.0% of the patients treated with telithromycin and 49.1% of those treated with clarithromycin; most of these were assessed as mild. In this study of adult patients with CAP, telithromycin 800 mg once daily was an effective and fairly well-tolerated regimen for initial empiric treatment, with clinical and bacteriologic efficacy and tolerability equivalent to therapy with high-dose clarithromycin (500 mg twice daily).


Was Paul Klee's scleroderma an occupational disease? A series of historical and clinical vignettes, part III.
Paul Klee (1879-1940), one of the most influential artists of the 20th century, died at 60 years of age from complications of systemic sclerosis (scleroderma). The precipitating event(s) of Klee's scleroderma, as in most cases, will never be known. Among various potential factors, exposure to heavy metals, crystalline silica, and organic solvents-acting alone or in combination-can now be considered potential factors in the onset of Klee's disease. By altering and modulating epigenetic determinants in a genetically susceptible host, these and other environmental factors may have led to perturbations of self-tolerance and inflammation culminating in Klee's scleroderma.


[A contribution to the stereospecific synthesis of antifungal imidazolyloxime-ethers/Oxiconazole nitrate (Sgd 301-76), a new broadspectrum antifungal agent (author's transl)].
A stereospecific synthesis of antifungal imidazolyloxime-ether derivatives is reported. The compound Sgd 301-76 (oxiconazole nitrate) = (Z)-1-(2,4-dichlorophenyl)-2-(1H-imidazol-1-yl)-O-(2,4-dichlorobenzyl)-ethanoneoxime-nitrate was selected for clinical trials. The (E)- and (Z)-assignments, respectively, were made on the basis of 1-H-NMR-spectral data.


Effect of low-intensity pulsed ultrasound stimulation on gap healing in a rabbit osteotomy model evaluated by quantitative micro-computed tomography-based cross-sectional moment of inertia.
It has been previously demonstrated that low-intensity pulsed ultrasound stimulation (LIPUS) enhances formation of the medullary canal and cortex in a gap-healing model of the tibia in rabbits, shortens the time required for remodeling, and enhances mineralization of the callus. In the current study, the mechanical integrity of these models was confirmed. In order to do this, the cross-sectional moment of inertia (CSMI) obtained from quantitative micro-computed tomography scans was calculated, and a comparison was made with a four-point bending test. This parameter can be analyzed in any direction, and three directions were selected in order to adopt an XYZ coordinate (X and Y for bending; Z for torsion). The present results demonstrated that LIPUS improved earlier restoration of bending stiffness at the healing site. In addition, LIPUS was effective not only in the ultrasound-irradiated plane, but also in the other two planes. CSMI may provide the structural as well as compositional determinants to assess fracture healing and would be very useful to replace the mechanical testing.


Morphologic patterns of noncontrast-enhancing tumor in glioblastoma correlate with IDH1 mutation status and patient survival.
Glioblastomas with a substantial proportion of noncontrast-enhancing tumour (nCET) have a variety of imaging appearances. We aimed to determine whether glioblastomas demonstrating a substantial proportion (>33%) of nCET can be sub-classified by different morphologic pattern of nCET. We then assessed whether this improves the ability of MRI to predict isocitrate dehydrogenase-1 (IDH1) mutation status and whether this has prognostic significance independent of IDH1 mutation status. Pre-operative MRIs of patients with a new diagnosis of glioblastoma were reviewed. Tumours with >33% nCET were sub-classified by the dominant morphologic pattern of nCET: mass-like expansion, white matter dissemination, grey matter dissemination or a combination. IDH1 mutation status (by immunohistochemistry) and survival were compared for each pattern. 153 patients met the inclusion criteria, of whom 34 patients demonstrated >33% nCET. 10 patients had a significant mass-like component, either as the dominant pattern (n=4) or as part of a mixed pattern (n=6). The 10 patients with a significant mass-like component had longer survival than those without (median 387days, compared to 241days), though this was not statistically significant (p=0.242). Three patients had R132H-IDH1 mutations and >33% nCET, and all three had a mass-like component. Using the presence of a mass-like component of nCET for predicting IDH1 mutation status improved the positive predictive value, specificity and overall accuracy of MRI. Classification of nCET by morphologic pattern improves the ability of MRI to predict IDH1 mutations and may provide useful prognostic information.


Relapsed/Refractory T- Acute Lymphoblastic Leukemia - Current Options and Future Directions.
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children. The T-cell subtype (T-ALL) accounts for 10-15% of pediatric ALL cases and has been historically associated with outcomes inferior to those of B-cell ALL (B-ALL). The prognosis of T-ALL has significantly improved with contemporary intensive pediatric regimens. However, most children with relapsed T-ALL have dismal outcomes and fewer therapeutic salvage options than those available for B-ALL. After demonstrating efficacy in relapsed T-ALL, nelarabine is being increasingly incorporated into frontline T-ALL regimens. The development of genomic sequencing has led to the identification of new T-ALL subgroups and potential targeted therapeutic approaches which could improve patients' outcomes and reduce the toxicity associated with current therapy. Immunotherapy and cellular therapy regimens are also under early investigation in T-cell malignancies. This review outlines the clinical and biological characteristics of T-ALL and provides an overview of novel treatment options for refractory and relapsed T-ALL.


Trans-sialidase genes expressed in mammalian forms of Trypanosoma cruzi evolved from ancestor genes expressed in insect forms of the parasite.
The trans-sialidase of Trypanosoma cruzi mammalian forms transfers sialic acids from host's cell-surface glycoconjugates to acceptor molecules on parasite cell surface. To investigate the mechanism by which the mammalian stages of Trypanosoma cruzi have acquired their trans-sialidase, we compared the nucleotide and predicted amino acid sequences of trans-sialidase genes expressed in different developmental stages and strains of Trypanosoma cruzi with the sialidase gene of Trypanosoma rangeli and the sialidase genes of the prokaryotic genera Clostridium, Salmonella, and Actinomyces. The trans-sialidase gene products of Trypanosoma cruzi have a significant degree of structural and biochemical similarity to the sialidases found in bacteria and viruses, which would hint that horizontal gene transfer occurred in Trypanosoma cruzi trans-sialidase evolutionary history. The comparison of inferred gene trees with species trees suggests that the genes encoding the T. cruzi trans-sialidase of mammalian forms might be derived from genes expressed in the insect forms of the genus Trypanosoma. The branching order of trees inferred from T. cruzi trans-sialidase sequences, the sialidase from Trypanosoma rangeli, and bacterial sialidases parallels the expected branching order of the species and suggests that the divergence times of these sequences are remarkably long. Therefore, a "vertical" inheritance from a hypothetical eukaryotic trans-sialidase gene expressed in insect forms of trypanosomes is more likely to have occurred than the horizontal gene transfer from bacteria, and thus explains the presence of this enzyme in the mammalian infective forms of Trypanosoma cruzi.


Plasma complement C7 as a target in non-small cell lung cancer patients to implement 3P medicine strategies.
Programmed cell death-1 (PD-1)/programmed cell death ligand-1 (PD-L1) immune checkpoint inhibitors (ICIs) significantly affect outcomes in non-small cell lung cancer (NSCLC) patients. However, differences in reactions toward PD-1/PD-L1 ICI among patients impose inefficient treatment. Therefore, developing a reliable biomarker to predict PD-1/PD-L1 ICI reaction is highly necessary for predictive, preventive, and personalized (3P) medicine. We recruited 63 patients from the National Cancer Center (NCC) and classified them into the training and validation sets. Next, 99 patients were recruited for inclusion into the external validation set at the Samsung Medical Center (SMC). Proteomic analysis enabled us to identify plasma C7 levels, which were significantly different among groups classified by their overall response to the RECIST V 1.1-based assessment. Analytical performance was evaluated to predict the PD-1/PD-L1 ICI response for each type of immunotherapy, and NSCLC histology was evaluated by determining the C7 levels via ELISA. Plasma C7 levels were significantly different between patients with and without clinical benefits (PFS ≥ 6 months). Among the groups sorted by histology and PD-1/PD-L1 immunotherapy type, only the predicted accuracy for pembrolizumab-treated patients from both NCC and SMC was greater than 73%. In patients treated with pembrolizumab, C7 levels were superior to those of the companion diagnostics 22C3 (70.3%) and SP263 (62.1%). Moreover, for pembrolizumab-treated patients for whom the PD-L1 tumor proportion score (TPS) was < 50%, the predictive accuracy of C7 was nearly 20% higher than that of 22C3 and SP263. Evaluation of plasma C7 levels shows an accurate prediction of NSCLC patient reactions on pembrolizumab. It demonstrates plasma C7 is an alternative and supportive biomarker to overcome the predictive limitation of previous 22C3 and SP263. Thus, it is clear that clinical use of plasma C7 allows predictive diagnosis on lung cancer patients who have not been successfully treated with current CDx and targeted prevention on metastatic diseases in secondary care caused by a misdiagnosis of current CDx. Reduction of patients' financial burden and increased efficacy of cancer treatment would also enable prediction, prevention, and personalization of medical service on NSCLC patients. In other words, plasma C7 provides efficient medical service and an optimized medical economy followed which finally promotes the prosperity of 3P medicine. The online version contains supplementary material available at 10.1007/s13167-021-00266-x.


Segmental configuration and putative origin of the reassortant orbivirus, epizootic hemorrhagic disease virus serotype 6, strain Indiana.
In 2006, an exotic reassortant orbivirus, epizootic hemorrhagic disease virus serotype 6 (EHDV-6) [strain (Indiana)], was first detected in the United States. To characterize the reassortment configuration of this virus and to conclusively determine the parental virus of each RNA segment, the complete genome of EHDV-6 (Indiana) was sequenced, in addition to the genomes of representative EHDV-6 and EHDV-2 isolates. Based on genomic comparisons to all other EHDV serotypes, we determined that EHDV-6 (Indiana) originated from a reassortment event between the Australian prototype strain of EHDV-6 (CSIRO 753) and the North American topotype of EHDV-2 (Alberta). Additionally, phylogenetic analysis of all EHDV-6 (Indiana) isolates detected in the United States from 2006 to 2010 suggests that the virus may be undergoing continual reassortment with EHDV-2 (Alberta). In 2010, EHDV-6 (CSIRO 753) was detected in Guadeloupe, demonstrating that the parental virus of the reassortment event is circulating in the Caribbean.


Normal coordinate analysis and Nonlinear Optical Response of cross-conjugated system 4,4-Dimethyl Benzophenone.
FT-Raman and IR spectra of the nonlinear optical active crystal, 4,4-Dimethyl Benzophenone (4DMBP) have been recorded and analyzed The equilibrium geometry, harmonic vibrational wavenumbers of 4DMBP investigated with the help of density functional theory (DFT) method. The assignments of the vibrational spectra have been carried out with the help of normal coordinate analysis (NCA) following the scaled quantum mechanical force field methodology (SQMFF). The calculated hyperpolarizability value shows the nonlinear optical activity of the molecule. The value of HOMO-LUMO energy, Mulliken and the natural charges are calculated and analyzed. The Natural bond orbital analysis confirms the occurrence of intramolecular charge transfer interaction.


Cost-Effectiveness Analysis of Transplantation-Ineligible Elderly Patients With Acute Leukemia Harboring a Molecular Target: Ph-Positive Acute Leukemia and FLT3-Mutated Acute Myeloid Leukemia.
Tyrosine kinase inhibitors (TKIs) and FMS-like tyrosine kinase 3 (FLT3) inhibitors are promising agents for Ph-positive acute leukemia (Ph+ AL) and FLT3 mutated acute myeloid leukemia (FLT3-AML), respectively. We examined the cost-effectiveness ratio (CER) of dasatinib and ponatinib for Ph+ AL and the cost-effectiveness of gilteritinib and quizartinib for FLT3-AML in elderly patients. Molecular therapy can fit the elderly population better than chemotherapy (CT). The daily drug cost of dasatinib, ponatinib, gilteritinib, and quizartinib was $240, $170, $524, and $479 in terms of treatment maintenance dose, respectively. Treatment of Ph+ AL with stem cell transplantation (SCT), CT, dasatinib, and ponatinib yielded CERs of $322,375, $34,928, $61,104, and $46,234, respectively. The CERs for FLT3-AML treated with SCT, CT, gilteritinib, and quizartinib were $355,270, $42,717, $94,987, and $90,080, respectively. Treatment of elderly patients with TKIs and FLT3 inhibitors remained expensive and inferior to conventional CT. Although TKIs and FLT3 inhibitors have an inferior CER than does conventional CT, their promising survival benefit with better QOL can offer a profound advantage. TKI or FLT3 inhibitor monotherapy is recommended as an alternative treatment option for unfit (vulnerable) elderly patients with Ph+ AL or FLT3-AML.


MiR-137 promotes TLR4/NF-κB pathway activity through targeting KDM4A, inhibits osteogenic differentiation of human bone marrow mesenchymal stem cells and aggravates osteoporosis.
As the global population ages rapidly, osteoporotic fractures have become an important public health problem. Previous studies have suggested that miR-137 is involved in the regulation of bone formation, but its specific regulatory mechanism remains unclear. In this study, we aimed to explore the expression, role, and regulatory mechanism of miR-137 in the osteogenic differentiation of human bone marrow mesenchymal stem cells (hBMSCs). hBMSCs were induced into osteoblasts at first, and the expression level of miR-137 at different time points was detected. After knockdown and overexpression of miR-137, the effect of miR-137 on the osteogenic differentiation of hBMSCs was examined through alkaline phosphatase (ALP) staining and Alizarin Red staining. Western blotting was performed to detect the expression of runt-related transcription factor 2 (Runx2), osteocalcin (OCN), and toll-like receptor 4 (TLR4)/nuclear factor-κB (NF-κB) pathway. Bioinformatics websites were used to predict the target binding sites for miR-137 and KDM4A, and the results were validated using luciferase reporter gene experiments. Moreover, the ALP activity, calcium nodule formation, and activation of Runx2, OCN, and TLR4/NF-κB pathways were observed after knockdown of KDM4A. The expression of miR-137 decreased during osteogenic differentiation. Knockdown of miR-137 expression increased the osteogenic ability of hBMSCs, while overexpression of it weakened the ability. Through the activation of the TLR4/NF-κB pathway, miR-137 inhibited osteogenic differentiation. KDM4A was identified as a predicted target gene of miR-137. After knocking down KDM4A expression, the osteogenic ability of hBMSCs was diminished, and the TLR4/NF-κB pathway was activated. Furthermore, the osteogenic ability of hBMSCs was partially restored and the activation level of TLR4/NF-κB was reduced after miR-137 knockdown. MiR-137 enhances the activity of the TLR4/NF-κB pathway by targeting KDM4A, thereby inhibiting the osteogenic differentiation of hBMSCs and exacerbating osteoporosis.


Long-term effects of physical exercise during rehabilitation in patients with severe burns.
We have reported that a 12-week exercise program is beneficial for the exercise performance of severely burned children. It is not known, however, whether the beneficial effects remain at 2 years postburn. Severely burned children who received no long-term anabolic drugs were consented to this Institutional Review Board-approved study. Patients chose between a voluntary exercise program (EX-group) and no exercise (NoEX-group) after discharge from the acute burn unit. Peak torque per lean leg mass, maximal oxygen consumption, and percent predicted peak heart rate were assessed. In addition, body mass index percentile and lean body mass index were recorded. Both groups were compared for up to 2 years postburn using mixed multiple analysis of variance. A total of 125 patients with a mean age of 12 ± 4 years were analyzed. Demographics between the EX-group (N = 82) and NoEX-group (N = 43) were comparable. In the EX-group, peak torque per lean leg mass, percent predicted peak heart rate, and maximal oxygen consumption increased significantly with exercise (P < .01). Between discharge and 12-24 months, body mass index percentile increased significantly in the EX-Group (P < .05) but did not change in the NoEX-group. There were no significant differences between groups in body mass index percentile, lean body mass index, peak torque per lean leg mass, and maximal oxygen consumption at 24 months postburn. Exercise significantly improves the physical performance of burned children. The benefits are limited to early time points, however, and greatly narrow with further recovery time. Continued participation in exercise activities or a maintenance exercise program is recommended for exercise-induced adaptations to continue.


Energy utilization and pyruvate as determinants of pyruvate dehydrogenase in norepinephrine-stimulated heart.
The quantitative effects of norepinephrine (NE) on the active form of the cardiac pyruvate dehydrogenase complex (PDCa) and the rate of oxidative decarboxylation of pyruvate (MVPyr) were compared with those of pyruvate (Pyr). Isolated working guinea pig hearts metabolized pyruvate alone or in combination with alternative energy-providing substrates (ketone bodies, octanoate, glucose). NE produced proportional increases in PDCa and myocardial oxygen uptake (MVO2). Total PDC activity (PDC1) remained constant. The PDCa/PDC1 ratios in NE depleted hearts (reserpine pretreatment) compared well with those in hearts containing endogenous NE, provided myocardial substrate supply and MVO2 were also comparable. No evidence was obtained indicating that NE or perfusate Ca2+ can dissociate PDCa or MVPyr from MVO2, even in presence of the alternative cosubstrates. In contrast, 0.2-10 mM Pyr produced stepwise but only submaximum increases in PDCa and MVPyr, with MVO2 remaining constant. Thus, at all Pyr concentrations tested, NE stimulations of myocaridal energy utilization and MVO2 were followed by further increases in PDCa and MVPyr. Evidently, pyruvate, and particularly cellular respiration are important determinants in the regulation of cardiac PDC, also during adrenergic stimulation of the heart.


Recurrent haemarthrosis of knee joint due to arterio-venous malformation of the superficial femoral artery.
Recurrent haemarthrosis involving the knee joint is commonly due to bleeding, a coagulation disorder or previous surgery. We have recently encountered a case of recurrent haemarthrosis involving the left knee joint of a 72 year old man due to arterio-venous malformation of the superficial femoral artery. Vascular malformations in patients with recurrent haemarthrosis without previous history of operation and a normal bleeding and clotting screen, should be considered a possible cause.


Film drainage and interfacial instabilities in polymeric systems with diffuse interfaces.
We report an experimental investigation on the effect of mutual diffusion in polymeric systems on film drainage between two captive drops. The main objective is to study the influence of diffuse interfaces on film drainage. This is done by using material combinations with different interfacial properties and interferometric visualization of the film between two interacting drops. For highly diffusive systems film drainage is observed to be, in contrast to immiscible systems, non-axisymmetric and unstable immediately after the film formation (at a few micrometers film thickness). Depending on whether the total thickness of the diffusion layers in the film is smaller or larger than the thickness of the film, Marangoni convection is found to enhance or delay film drainage. Enhanced film drainage is determined to be in order of 100 times faster than predicted by the current models, while delayed film drainage is observed after a drainage period where experimental and predicted results (assuming, a partially mobile interface) are in close agreement.


Supporting pharmacy students' preparation for an entry-to-practice OSCE using video cases.
Objective structured clinical examinations (OSCEs) are widely used, including in licensure examinations. OSCEs assess diverse skills in a structured manner, but can be stressful for students and have a significant organisational burden for faculty. Case-based video OSCE preparation resources were developed for students preparing for a licensure OSCE. The study aimed to examine student engagement, compare scores awarded by students to performances at specific competence standards with faculty scores, and examine usability, usefulness, and acceptability of the video cases. Final year pharmacy students (n = 149) enrolled in an integrated master of pharmacy programme in Ireland were invited to participate. Six sets of recorded OSCE-based video cases were developed, comprising multiple recordings of the same case scenario, with each pitched at a different level of performance. Students watched and scored the video cases. Usability, usefulness, and acceptability were evaluated via questionnaire. One or more video cases were accessed by 70.5% of students. Score ratings awarded by the students, when compared to faculty ratings, showed an overall trend towards inter-rater agreement between students and faculty. Students felt positively in terms of the usability, usefulness, and acceptability of the videos. Video cases designed to support OSCE preparation for a high-stakes national pharmacy licensure examination were widely used by students and were perceived to be usable, useful, and acceptable. Such video cases may be a feasible alternative to additional mock OSCEs to support student preparation.


Real-Time Imaging of a Single Gene Reveals Transcription-Initiated Local Confinement.
Genome dynamics are intimately linked to the regulation of gene expression, the most fundamental mechanism in biology, yet we still do not know whether the very process of transcription drives spatial organization at specific gene loci. Here, we have optimized the ANCHOR/ParB DNA-labeling system for real-time imaging of a single-copy, estrogen-inducible transgene in human cells. Motion of an ANCHOR3-tagged DNA locus was recorded in the same cell before and during the appearance of nascent MS2-labeled mRNA. We found that transcription initiation by RNA polymerase 2 resulted in confinement of the mRNA-producing gene domain within minutes. Transcription-induced confinement occurred in each single cell independently of initial, highly heterogeneous mobility. Constrained mobility was maintained even when inhibiting polymerase elongation. Chromatin motion at constant step size within a largely confined area hence leads to increased collisions that are compatible with the formation of gene-specific chromatin domains, and reflect the assembly of functional protein hubs and DNA processing during the rate-limiting steps of transcription.


Diagnostic value of core needle biopsy for determining HER2 status in breast cancer, especially in the HER2-low population.
The status of human epidermal growth factor receptor 2 (HER2) is important for treatment decision-making of breast cancer and was commonly determined by core needle biopsy (CNB). The concordance of CNB with surgical excision biopsy (SEB) has been verified, but remain unclear according to the newly developed classification of HER2 status. Our study aimed to re-evaluate the diagnostic value of CNB for determining HER2 status in breast cancer, especially in the HER2-low population. Eligible breast cancer patients in West China Hospital between January 1, 2007 and December 31, 2021 were enrolled consecutively and data were extracted from the Hospital Information System. The agreement of HER2 status between CNB and SEB was calculated by concordance rate and κ statistics, as well as the sensitivity, specificity, positive, and negative predictive values (PPV & NPV). Logistic models were used to explore potential factors associated with the discordance between both tests. Of 1829 eligible patients, 1097 (60.0%) and 1358 (74.2%) were consistent between CNB and SEB by pathological and clinical classifications, respectively, with κ value being 0.46 (0.43-0.49) and 0.57 (0.53-0.60). The sensitivity (50.9%-52.7%) and PPV (50.5%-55.2%) of CNB were especially low among IHC 1+ and 2+/ISH - subgroups by pathological classifications; however, it showed the highest sensitivity (77.5%) and the lowest specificity (73.9%) in HER2-low population by clinical classifications. Advanced N stages might be a stable indicator for the discordance between both tests. The diagnostic value of CNB was limited for determining HER2 status in breast cancer, especially in HER2-low population.


High-resolution continuum source graphite furnace molecular absorption spectrometry compared with ion chromatography for quantitative determination of dissolved fluoride in river water samples.
In addition to beneficial health effects, fluoride can also have adverse effects on humans, animals, and plants if the daily intake is strongly elevated. One main source of fluoride uptake is water, and thus several ordinances exist in Germany that declare permissible concentrations of fluoride in, for example, drinking water, mineral water, and landfill seepage water. Controlling the fluoride concentrations in aqueous matrices necessitate valid and fast analytical methods. In this work an alternative method for the determination of fluoride in surface waters based on high-resolution continuum source graphite furnace molecular absorption spectrometry (HR-CS-GFMAS) was applied. Fluoride detection was made possible by the formation of a diatomic molecule, GaF, and detection of characteristic molecular absorption. On HR-CS-GFMAS parameter optimization, the method was adapted to surface water sample analysis. The influence of potential main matrix constituents such as Na+, Ca2+, Mg2+, and Cl- as well as surface water sampling/storage conditions on the molecular absorption signal of GaF was investigated. Method validation demonstrated a low limit of detection (8.1 μg L-1) and a low limit of quantification (26.9 μg L-1), both sufficient for direct river water sample analysis after 0.45-μm filtration. The optimized HR-CS-GFMAS method was applied for the analysis of real water samples from the rivers Rhine and Moselle. For method validation, samples were also analyzed by an ion chromatography (IC) method. IC and HR-CS-GFMAS results both agreed well. In comparison with IC, HR-CS-GFMAS has higher sample throughput, a lower limit of detection and a lower limit of quantification, and higher selectivity, and is a very suitable method for the analysis of dissolved fluoride in river water. Graphical abstract High-resolution continuum source graphite furnace molecular absorption spectrometry (HR-CS-GFMAS) was applied for the quantitative analysis of dissolved fluoride in river water samples from the Rhine and the Moselle. Fluoride detection was made possible by the addition of Ga for GaF formation and analysis of characteristic molecular absorption at 211.248 nm. Good agreement between HR-CS-GFMAS and ion chromatography (IC) results was obtained. In comparison with IC, HR-CS-GFMAS had a faster sample throughput and lower limit of detection and limit of quantification.


Nicotiana glauca: another plant species containing vitamin D(3) metabolites.
Vitamin D(3)-related compounds have been detected in various plant species, mostly belonging to the Solanaceae. In this work we show that Nicotiana glauca, a widespread member of this taxonomic family, contains 7-dehydrocholesterol, vitamin D(3) and hydroxylated derivatives bearing precursor-product metabolic relationships in vertebrates. Leaves collected in the field and callus cultures were used. By means of specific radioreceptor binding assays and mass spectrometry of purified fractions obtained from plant tissue lipid extracts by Sephadex LH-20 and Sep-Pak C18 chromatography followed by HPLC, we established the presence of 7-dehydrocholesterol, vitamin D(3), 25(OH)-vitamin D(3) and 1alpha,25(OH)(2)-vitamin D(3) (1alpha,25(OH)(2)D(3)), the latter being a hormonally relevant metabolite in animals. These results indicate that N. glauca may represent a useful species in which to characterize the biosynthetic pathway and physiological functions of vitamin D(3) compounds in plants. In addition, tissue culture of N. glauca could become a significant tool for biotechnological production of 1alpha,25(OH)(2)D(3).


Esophageal motor dysfunction in systemic lupus erythematosus. Two cases with unusual features.
Two patients with systemic lupus erythematosus had intermittent episodes of dysphagia associated with severe nonpleuritic chest pain. Esophageal manometry disclosed abnormalities characteristic of diffuse esophageal spasm. The findings suggest that diffuse spasm should be considered in the differential diagnosis of unexplained chest pain and dysphagia in patients with lupus.


Common, nonsexual masochistic preferences are positively associated with antisocial personality traits.
Based on prior research linking masochism and antisocial behavior to sensation seeking, we hypothesized that masochistic and antisocial preferences are positively correlated. Besides sensation seeking, we tested whether disgust sensitivity (due to its inhibitory function) and shared social values (e.g., stimulation) accounted for the masochistic-antisocial link. We additionally examined the link in relation to broad personality factors. Six online and laboratory studies (N = 2,999) with US-American and European samples. We consistently found positive correlations between masochistic enjoyment (e.g., enjoying the burn of spicy food, disgusting jokes, pounding heart, painful massage) and antisocial traits such as subclinical psychopathy, everyday sadism, and low Honesty-Humility. We observed behavioral correlations in that experienced pleasure of a painful event was positively related to causing another person to feel pain. Shared sensation seeking, low disgust sensitivity, and endorsement of social values such as social power, hedonism, and a stimulating life partially accounted for the masochistic-antisocial link. The extent to which a person enjoys threatening stimuli on the self is reliably related to how much a person enjoys and evokes others' suffering. Future research could explore the common core that underlies common masochistic and antisocial preferences beyond the mediators tested here.


Dynamic coherent backscattering mirror.
The phase of multiply scattered light has recently attracted considerable interest. Coherent backscattering is a striking phenomenon of multiple scattered light in which the coherence of light survives multiple scattering in a random medium and is observable in the direction space as an enhancement of the intensity of backscattered light within a cone around the retroreflection direction. Reciprocity also leads to enhancement of backscattering light in the spatial space. The random medium behaves as a reciprocity mirror which robustly converts a diverging incident beam into a converging backscattering one focusing at a conjugate spot in space. Here we first analyze theoretically this coherent backscattering mirror (CBM) phenomenon and then demonstrate the capability of CBM compensating and correcting both static and dynamic phase distortions occurring along the optical path. CBM may offer novel approaches for high speed dynamic phase corrections in optical systems and find applications in sensing and navigation.


5-(3,4,5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) targets tubulin and DNA to induce anticancer activity and overcome multidrug resistance in colorectal cancer cells.
Colorectal cancer (CRC) is one of the most common malignancies, and multidrug resistance (MDR) reduces the efficiency of anticancer drugs. Therefore, the development of novel anticancer drugs that are highly active against CRC with MDR is urgently needed. Our previous study showed that 5-(3,4,5-trimethoxybenzoyl)-4-methyl-2-(p-tolyl) imidazol (BZML) is not a P-glycoprotein (P-gp) substrate and has a potent anticancer effect against paclitaxel -sensitive or -resistant non-small-cell lung cancer (NSCLC) in vitro and in vivo. In the present study, we found that BZML exhibited strong anticancer activity not only in sensitive CRC cells (SW480 and HCT-116 cells) but also in intrinsically drug-resistant CRC cells (Caco2 cells). In addition, by targeting the colchicine binding site, BZML inhibited tubulin polymerization, which induced G2/M phase arrest, and it caused DNA damage by directly targeting DNA or producing ROS. Further, BZML induced apoptosis through the time-dependent ROS-mediated mitochondrial apoptotic pathway in the CRC cells. Additionally, BZML inhibited P-gp-mediated drug efflux and enhanced the inhibition of the cell growth that had been induced by paclitaxel or doxorubicin in Caco2 cells. In summary, BZML is a multi-targeted anticancer drug that targets tubulin and DNA, and the mechanisms underlying its potent anticancer activity involve disrupting microtubule assembly, causing DNA damage, inducing cell cycle arrest and eventually activating the ROS-mediated mitochondrial apoptotic pathway in SW480, HCT-116 and Caco2 cells. Therefore, the novel compound BZML is a promising anticancer drug that has tremendous potential for CRC treatment, especially for the treatment of drug-resistant CRC.


CDK2 suppression synergizes with all-trans-retinoic acid to overcome the myeloid differentiation blockade of AML cells.
A characteristic feature of leukemia cells is a blockade of differentiation in cellular maturation. All-trans-retinoic acid (ATRA) has been successfully applied for the treatment of M3-type AML (APL, 10 %), but it fails to demonstrate a significant efficacy on the remaining patients with non-APL AML (90 %). Therefore, the research for strategies to extend the efficacy of ATRA-based therapy to non-APL AML is a key avenue of investigation. Here, we evaluate the synergetic effect of CDK2 inhibition and ATRA in AML both in vitro and in vivo. We have determined that both the CDK2 depletion and pharmacological inhibitor of CDK2 significantly sensitize three subtypes of AML cells (including two non-APL cells) to ATRA-induced cell differentiation. RNA-sequence results indicate that transcription activation of differentiation and maturation pathways plays an important role in this synergetic effect. Furthermore, the down-regulation of CDK2 sensitized AML cells to ATRA-induced engraftment prevention of leukemia cells in NOD-SCID mice and promotes the primary AML blasts differentiation when combined with ATRA. Thus, our work not only provides relevant experimental evidence for further validating CDK2 as a target for differentiation therapy, but also uncovers the future clinical application of CDK2 inhibitors in ATRA-based differentiation therapeutics for AML.


Vitamin E Acetate Determination in Vaping Liquids and Non-targeted Analysis of Vaping Emissions of Diluents of Concern, Vitamin E Acetate and Medium-Chain Triglycerides Oil.
During the summer of 2019, cases of lung injury associated with vaping emerged in North America, including among individuals who reported exclusive use of nicotine vaping liquids. Once vitamin E acetate was identified as a potential causative agent a quantitative method based on a simple sample dilution, separation by gas chromatography and analysis by triple quadrupole mass spectrometry (GC MSMS) was developed. Method detection limit (MDL) and limit of quantification (LOQ) were determined at 0.159 µg/mL and 0.505 µg/mL, respectively. The analysis was performed on a subset of 203 commercially sourced nicotine containing vaping liquids of various flavour profile and nicotine range (nicotine free-59 mg/mL) from an internal inventory. The target analyte, Vitamin E Acetate, was not detected in any samples analyzed, as expected, given the reported detection in literature and high association of the chemical with cannabis and not nicotine containing vaping products.


Differential expression of low molecular weight form of Gs-alpha in neostriatum and cerebellum: correlation with expression of calmodulin-independent adenylyl cyclase.
Adenylyl cyclase of neostriatal plasma membranes is far less responsive to stimulation by Ca2+/calmodulin than is the enzyme from cerebellum. When these tissues were investigated with antibodies against known G-proteins, no difference could be detected in any G-protein species, other than Gs. Whereas the cerebellum expressed predominantly the large form of Gs-alpha, the neostriatum expressed mainly lower molecular weight forms. The possibility is considered that there is selective association between lower molecular weight forms of Gs and calmodulin-independent forms of adenylyl cyclase.


Chitin synthesis during in planta growth and asexual propagation of the cellulosic oomycete and obligate biotrophic grapevine pathogen Plasmopara viticola.
PCR amplification of two CHS gene fragments of the obligate biotroph Plasmopara viticola, the causal agent of downy mildew of grapevine, is described. While one fragment shows homology to fungal class IV chitin synthases, the other fragment groups with other oomycete chitin synthases to form a novel class of chitin synthases most closely related to class I-III. RT-PCR experiments indicate that PvCHS1 is constitutively expressed, whereas PvCHS2 is specifically transcribed in sporangiophores and sporangia. Analyses of wheat germ agglutinin labeling patterns by confocal laser scanning microscopy show that chitin is present on the surface of hyphal cell walls during in planta growth, and of sporangiophores and sporangia.


Arterio-arterial vascular anastomoses in monochorionic twin placentas with and without twin anemia-polycythemia sequence.
We performed a matched case-control study to analyze the placental angioarchitecture, in particular the diameter of arterio-arterial (AA) anastomoses in monochorionic placentas from pregnancies with spontaneous twin anemia-polycythemia sequence (TAPS) compared to a control group of uncomplicated monochorionic placentas. Placental angioarchitecture was analyzed using colored dye injection. AA anastomoses were detected in 20% (3/15) of spontaneous TAPS placentas. The median diameter of AA anastomoses in the group with and without TAPS was 0.4 mm and 2.2 mm, respectively (p = 0.01). In conclusion, AA anastomoses are rarely detected in TAPS placentas. When present, the AA anastomosis is very small, preventing equilibration of hemoglobin levels between both twins.


Detection rates of missing microsurgical needles using intra-operative imaging.
Unintentional retention of foreign bodies in surgery is uncommon but potentially serious. Published data regarding the consequence of retained surgical needles is sparse. We aimed to characterize lost surgical needles at our institution. Secondarily, we aimed to determine whether or not retained microsurgical needles can be reliably detected. Reports of missing surgical needles at our institution were reviewed. Surgical needles of relevant sizes were scattered across an anthropomorphic model at representative anatomical locations. Fluoroscopic images of the field were acquired using two resolution settings. Medical staff in our department attempted to locate needles in these images. A total of 46 323 procedures were performed in the main theatres in the 2.5-year period. Sixty-two needles were reported as missing. No patient harm was documented. Needles of chord length 16 mm (5-0) or greater were always detected. High-resolution fluoroscopy improves detection of needles with chord lengths of 9.3 (7-0) or 6.6 mm (9-0). Needles are consistently better detected in the lower limb for needles of chord length greater than 6.6 mm (9-0). Senior observers under ideal conditions can detect 7.1% of smaller needles. When a needle is lost during surgery, consider the following before ordering fluoroscopy. Needles of chord length greater than 13 mm (6-0) should be reliably detected whilst 3.8 mm (10-0) needles will not. For sizes in between, ideal conditions for detection may include an operating field in the lower limb, high-resolution fluoroscopy and a senior observer. It may not be necessary or cost effective to identify microsurgical needles with fluoroscopy.


Implant-associated anaplastic large cell lymphoma: beyond breast prostheses.
Anaplastic large cell lymphoma (ALCL) is a rare form of non-Hodgkin T-cell lymphoma potentially associated with silicone-shelled breast implants. The low incidence of ALCL has prevented establishment of causality. Many implantable devices are constructed with biomaterials similar to those used in breast prostheses. The purpose of this paper is to identify reports of ALCL in association with other types of implantable devices. A literature review was conducted using PubMed to identify reports of non-Hodgkin lymphoma in association with various implantable devices. One case of ALCL was identified in association with a stainless steel internal fixation plate. Diffuse large B-cell lymphoma was widely reported in association with various implantable biomaterials and chronic inflammation. The neoplastic response associated with breast prostheses appears substantively different from other implantable devices. Physicians caring for patients with silicone elastomer-containing implants should have increased suspicion for implant-associated ALCL and report all pertinent cases in the literature.


Tripterygium glycosides reverse chemotherapy resistance in ovarian cancer by targeting the NRF2/GPX4 signal axis to induce ferroptosis of drug-resistant human epithelial ovarian cancer cells.
Cisplatin resistance is the main cause of postoperative recurrence and difficulty in the treatment of ovarian cancer. It is urgently needed to identify therapeutic drugs with unique functions to overcome the current challenges in the treatment of ovarian cancer. In this study, we found that TG promoted the accumulation of ROS and MDA in A2780/DDP cells and downregulated the expression of key antioxidant molecules. In vivo, the survival rate of tumor-bearing nude mice was prolonged by TG without significant hepatotoxic reaction. The expression of key antioxidant molecules in tumor tissues was consistent with that in vitro. These findings revealed that TG disrupted homeostasis of redox reactions and induced ferroptosis in A2780/DDP cells, thereby enhancing cisplatin chemosensitivity of ovarian cancer. Overall, TG may be a novel potential therapeutic option for reversing resistance to cisplatin chemotherapy.


Correction: Tandem Prins cyclization for the synthesis of indole fused spiro-1,4-diazocane scaffolds.
Correction for 'Tandem Prins cyclization for the synthesis of indole fused spiro-1,4-diazocane scaffolds' by Chandrashekhar Rapelli et al., Org. Biomol. Chem., 2020, 18, 6710-6715, DOI: 10.1039/D0OB01384F.


Two-tiered immunoreactive trypsinogen-based newborn screening for cystic fibrosis in Colorado: screening efficacy and diagnostic outcomes.
To examine immunoreactive trypsinogen (IRT)-based screening for cystic fibrosis (CF) for recall rate, genotype distribution, and "borderline" sweat test results. CF newborn screening in Colorado began in 1982, and >1,153,000 infants were screened through 2002 with an IRT-based screen (IRT/IRT). We have identified 313 infants with CF, giving an overall incidence of 1 in 3684 and a Hispanic incidence of 1 in 6495. Fifty-five infants with meconium ileus (17.6%) were excluded from analysis. Fourteen infants with false-negative results were identified (5.4%). The average recall rate was 0.6%, with a positive predictive value of 4.7%. Ninety-three percent of the infants had at least 1 DeltaF508 mutation, and 98% of the infants had at least 1 mutation from the American College of Medical Genetics recommended panel. Six infants had hypertrypsinogenemia and borderline results on sweat tests (30-60 mmol/L). Increased variability in sweat chloride levels were seen in these infants compared with infants with homozygous DeltaF508. Three children with initial borderline results on sweat tests had CF diagnosed. The recall and false-negative rates of our IRT/IRT CF screening program are reported. Additionally, genotypes of the patients identified mirror the CF population genotypes, reflecting similar disease severity in the screened population. Finally, infants with persistent hypertrypsinogenemia and borderline sweat test results need long-term follow-up.


Short-term antibiotic exposure affected the type and resistance of uropathogens similar to long-term antibiotic prophylaxis in children hospitalised for urinary tract infections.
We investigated the impact of any antibiotic exposure on unusual and resistant pathogens in children with a urinary tract infection (UTI). This was a retrospective cohort study of 695 children (54% female) hospitalised with 711 UTI episodes at Heraklion University Hospital, Greece, from January 2007 to December 2017. Three groups were studied: no previous antibiotic exposure, ongoing prophylaxis and short-term exposure to antibiotics in the last six months. The median age at hospitalisation was 0.8 years (range 25 days to 15.9 years). Previous short-term exposure and prophylaxis were important determinants of non-Escherichia coli (E. coli) (OR 2.05, 95% CI 1.25-3.36, P = .0017 and OR 3.84, 95% CI 2.32-6.34, P < .0001, respectively) and extended-spectrum beta-lactamase-positive uropathogens (OR 2.43, 95% CI 1.36-4.32, P = .0025 and OR 2.63, 95% CI 1.31-5.33, P = .0070, respectively). Short-term antibiotics in the last 30 days or intravenous antibiotics were mostly associated with non-E. coli pathogens (OR 6.71 and OR 2.55, respectively). The most important determinants of E. coli resistance were short-term antibiotics for ampicillin (OR 2.58) and prophylaxis for cotrimoxazole (OR 2.64). Recent short-term exposure to antibiotics and ongoing prophylaxis both had a significant impact on the type and resistance of uropathogens.


Design of pH/reduction dual-responsive nanoparticles as drug delivery system for DOX: Modulating controlled release behavior with bimodal drug-loading.
pH/Reduction dual-responsive P(FPA-co-PEGMA-co-MAA) (PFPM) nanoparticles were designed for tumor-specific intracellular triggered release of anticancer drug DOX by emulsion copolymerization of 4-formylphenyl acrylate (FPA), methacrylic acid (MAA), and poly(ethylene glycol) methyl ether methacrylate (PEGMA), with N,N-bis(acryloyl)cystamine (BACy) as crosslinker. Then three drug delivery systems (DDSs) with average hydrodynamic diameter around 200nm and drug-loading capacity (DLC) of >35% were obtained via the noncovalent interaction of DOX with the carboxyl and aldehyde groups in MAA and FPA units, covalently conjugating DOX onto the FPA units via acid-labile imine bond, or both the two modes. The in vitro release profiles showed that all the three DDSs exhibited good tumor intracellular triggered release characteristic whitout burst release. And the bimodal drug-loaded one (DOX/PFPMC+N), which had the highest DLC of >54%, possessed the middle drug release rate, faster than the one via covalent conjugation (DOX/PFPMC) but slower than the one via noncovalent interaction (DOX/PFPMN). The results demonstrated that the controlled release behavior of such functional nanoparticles could be tailored with drug-loading modes.


Cocaine Use in Adolescents and Young Adults.
Cocaine use by adolescents and young adults continues to be a significant public health issue and the cause of medical and psychological morbidity and mortality. Although use rates are lower than those seen with alcohol, tobacco, and other illicit substances such as marijuana, cocaine is highly addictive and presents significant acute and long-term medical and psychological effects. This article reviews the epidemiology of cocaine use among adolescents and young adults, discusses the pharmacology and neurobiology of cocaine use and dependence, provides information regarding acute intoxication and systemic effects seen with more chronic use, and describes current assessment and treatment approaches.


Tracheal agenesis.
Tracheal agenesis is a rare cause of respiratory distress in the neonatal period. Temporary survival depends on ventilation through the esophagus. Thirty-eight case reports of tracheal agenesis (including one from this institution) have appeared in the literature. In this paper, we present the case reports of our 2 patients and review the literature. Tracheal agenesis is associated with a wide variety of congenital anomalies, the most frequent being ventricular septal defect. A new classification encompassing seven types of tracheal agenesis is described.


rGO supported self-assembly of 2D nano sheet of (g-C3N4) into rod-like nano structure and its application in sonophotocatalytic degradation of an antibiotic.
Graphitic carbon nitride (g-C3N4) is an analog of graphite due to its unique electronic structure. g-C3N4 based materials have been used in photocatalytic applications. However, pure g-C3N4 suffers from major shortcomings which include poor disparity, low surface area and a high recombination rate of photo generated electron-hole pairs that significantly reduce its photocatalytic activity. In this work, self-assembly of g-C3N4 sheet into rod shaped g-C3N4 was developed via a simple polymerisation method. A composite made of g-C3N4 nanorods and rGO (rGO-RCN) was also prepared. The band gap g-C3N4 was shifted from 2.77 to 2.6 eV evidented by UV-DRS data. As a result, rGO-RCN showed a relatively high absorption in the visible region. Moreover, a fast electron transfer rate was observed with rGO-RCN composite as conformed from PL analysis and photocurrent measurement. The formation of nanorod and sheet morphologies was confirmed via TEM analysis. The photocatalytic activities of prepared sheet-g-C3N4 (SCN), Rod g-C3N4 (RCN), reduced graphene oxide supported sheet-g-C3N4 (rGO-SCN) and reduced graphene oxide supported Rod-g-C3N4 (rGO-RCN) were evaluated using a commonly used antibiotic (tetracycline). Among these catalysts, rGO-RCN nanocomposite showed sonophotocatalytic activity 3 times higher compared to pure g-C3N4. This superior sonophotocatalytic activity could be due to enhanced visible light absorption of the material, active sites generated by ultrasound, and the high electron transport property of rGO.


Influence of experimental hypoxia on content and composition of free fatty acids in cerebral white matter.
The content and spectrum of free fatty acids were studied in the cerebral white matter, on Wistar rats exposed to acute hypoxia (2% of oxygen in a respiratory mixture) for 3 min. The total content of fatty acids, especially of tetraenoic ones, rose sharply already 4 min after hypoxia and persisted elevated even 2 months after the hypoxia. The results showed that the degradation of phospholipids-containing biological membranes in the nervous tissue of the white matter starts immediately after hypoxia, and is continued for months.


Smart nanomaterials for cancer diagnosis and treatment.
Innovations in nanomedicine has guided the improved outcomes for cancer diagnosis and therapy. However, frequent use of nanomaterials remains challenging due to specific limitations like non-targeted distribution causing low signal-to-noise ratio for diagnostics, complex fabrication, reduced-biocompatibility, decreased photostability, and systemic toxicity of nanomaterials within the body. Thus, better nanomaterial-systems with controlled physicochemical and biological properties, form the need of the hour. In this context, smart nanomaterials serve as promising solution, as they can be activated under specific exogenous or endogenous stimuli such as pH, temperature, enzymes, or a particular biological molecule. The properties of smart nanomaterials make them ideal candidates for various applications like biosensors, controlled drug release, and treatment of various diseases. Recently, smart nanomaterial-based cancer theranostic approaches have been developed, and they are displaying better selectivity and sensitivity with reduced side-effects in comparison to conventional methods. In cancer therapy, the smart nanomaterials-system only activates in response to tumor microenvironment (TME) and remains in deactivated state in normal cells, which further reduces the side-effects and systemic toxicities. Thus, the present review aims to describe the stimulus-based classification of smart nanomaterials, tumor microenvironment-responsive behaviour, and their up-to-date applications in cancer theranostics. Besides, present review addresses the development of various smart nanomaterials and their advantages for diagnosing and treating cancer. Here, we also discuss about the drug targeting and sustained drug release from nanocarriers, and different types of nanomaterials which have been engineered for this intent. Additionally, the present challenges and prospects of nanomaterials in effective cancer diagnosis and therapeutics have been discussed.


Toward a new paradigm of cell plasticity.
The standard paradigm of embryologic development and adult tissue reconstitution posits unidirectional, hierarchical lineages. The presumed mechanisms underlying these differentiative pathways are gene restrictions, such as methylation and heterochromatin formation, which are commonly described as irreversible. However, recent discoveries regarding multi-organ stem cells demonstrate that 'true plasticity' exists, with cells of one organ turning into cells of other organs, including differentiative transformations that cross barriers between tissues derived from different primitive germ layers. These findings, along with earlier experiments into heterokaryon formation and longstanding recognition of reactive and neoplastic lesions in humans and animals, suggest that lineage pathways are not, in fact, unidirectional. Moreover, physiologic mechanisms of reversal of gene restrictions have been recognized. Therefore, in response to these observations, we suggest a new paradigm of cell plasticity, elucidating three guiding principles of 'genomic completeness', 'uncertainty of cell characterization', and 'stochastic nature of cell origins and fates'. These principles imply a change in the way data can be interpreted and could alter subsequent hypothesis formation. This new paradigm will hopefully lead us forward to a more flexible and creative exploration of the potential of adult vertebrate cells.


CPR in children.
CPR has not been well studied in children and little is known about factors predictive of outcome. We conducted a study with three goals: longitudinal determination of demographic and laboratory data characterizing pediatric arrest victims; identification of factor(s) predictive of outcome; and determination of the prevalence of ionized hypocalcemia in pediatric arrest victims. All resuscitation efforts were documented during a one-year period in a 240-bed tertiary care children's hospital. Patients were classified into two groups--respiratory arrest (RA, requiring only assisted ventilation), and cardiac arrest (CA, absence of palpable cardiac activity requiring closed-chest CPR). Collected data and laboratory tests were analyzed using a step-wise discriminant analysis to determine which factors were predictive of outcome. There were 113 arrests in 93 children; 53 were CA victims and 40 were RA victims. CA had a high in-hospital mortality (90.6%) compared to RA (32.5%). The population was young (55% less than 1 year old) and 87% had at least one chronic underlying disease. No laboratory or demographic value was significantly associated with eventual outcome. The number of doses of epinephrine in CA victims, or bicarbonate in RA victims, was associated with eventual outcome. None of 31 CA victims receiving more than two doses of epinephrine survived to discharge. Low ionized calcium concentrations (less than 3.5 mg/dL) were identified in ten patients; septic shock was present in seven, and chronic renal failure in two.(ABSTRACT TRUNCATED AT 250 WORDS)


Diagnostic performance of MRI for prediction of muscle-invasiveness of bladder cancer: A systematic review and meta-analysis.
To review the diagnostic performance of ≥1.5-T MRI for local staging of bladder cancer. MEDLINE and EMBASE were searched up to February 21, 2017. We included diagnostic accuracy studies published since 2000 that used ≥1.5-T MRI for local staging (≥T2 [muscle-invasive]) in patients with bladder cancer, using pathology as the reference standard. The methodological quality was assessed using Quality Assessment of Diagnostic Accuracy Studies-2. Sensitivity and specificity were pooled and plotted in a hierarchical summary receiver operating characteristics plot. Sensitivity analyses using several clinically relevant covariates were performed. 24 studies (1774 patients) were included. Pooled sensitivity was 0.92 (95% CI 0.88-0.95) with specificity of 0.87 (95% CI 0.78-0.93). Sensitivity analyses showed that sensitivity estimates were comparable and consistently high across all subgroups, but specificity estimates were variable. Studies using 3-T scanners had higher specificity (0.93 [95% CI 0.86-0.98]) than those using 1.5-T scanners (0.83 [95% CI 0.74-0.98]). Studies using multiparametric MRI (conventional+≥2 functional sequences) showed the highest accuracy with sensitivity and specificity of 0.94 (95% CI 0.89-1.00) and 0.95 (95% CI 0.89-0.98), respectively. MRI shows good diagnostic performance for predicting muscle-invasiveness of bladder cancer. Multiparametric 3-T MRI seems to improve both sensitivity and specificity.


Functional analysis of the distal region of the third intracellular loop of PROKR2.
Mutations in the G-protein-coupled receptor PROKR2 have been identified in patients with idiopathic hypogonadotropic hypogonadism (IHH) and Kallmann syndrome (KS) manifesting with delayed puberty and infertility. Recently, the homozygous mutation V274D was identified in a man displaying KS with an apparent reversal of hypogonadism. The affected amino acid, valine 274, is located at the junction region of the third intracellular loop (IL3) and the sixth transmembrane domain (TM6). In this study, we first studied the effect of V274D and related mutations (V274A, V274T, and V274R) on the signaling activity and cell surface expression of PROKR2. Our data indicate that a charged amino acid substitution at residue 274 of PROKR2 results in low cell surface expression and loss-of-function. Furthermore, we studied the effects of two clusters of basic amino acids located at the proximal region of Val274 on the cell surface expression and function of PROKR2. The deletion of RRK (270-272) resulted in undetectable cell surface expression, whereas RKR (264-266)-deleted PROKR2 was expressed normally on the cell surface but showed loss-of-function due to a deficiency in G-protein coupling. Our data indicate that the distal region of the IL3 of PROKR2 may differentially influence receptor trafficking and G-protein coupling.


Chronic kidney disease and carotid atherosclerosis.
Chronic kidney disease is an independent risk factor for cardiovascular disease. The association between carotid intima-media thickness (IMT) and chronic kidney disease is controversial, however. In addition, whether renal dysfunction promotes vascular calcification in patients with chronic kidney disease is not clear. The study subjects were 1003 patients aged ≥50 years who underwent carotid ultrasonography in our hospital. Kidney function was evaluated based on the estimated glomerular filtration rate (eGFR) and the presence of proteinuria. Patients with end-stage renal failure were excluded. We measured the mean max-IMT (which indicates mean maximal wall thickness) at 12 carotid segments, and examined the characteristics of the maximal plaques by carotid ultrasonography. We evaluated the association between mean max-IMT and eGFR, and also evaluated the clinical factors associated with mean max-IMT and calcification of the maximal plaques. We found that eGFR was significantly correlated with mean max-IMT. Reduced eGFR, proteinuria, age, male sex, cardiovascular disease, hypertension, diabetes, and smoking were independently associated with mean max-IMT in multiple regression analysis. Kidney function was not associated with calcified plaque. Kidney dysfunction was associated with carotid atherosclerosis in patients with mild or moderate chronic kidney disease.


Delayed sleep phase syndrome in adolescents.
The delayed sleep phase syndrome is characterized by difficulty in falling asleep at a socially acceptable time of night and an inability to be easily aroused in the morning. Most commonly encountered in adolescents, this condition can produce daytime sleepiness and poor school performance, and it can lead to behavioral problems. The clinical features of the syndrome are described in 22 adolescents. Nine subjects participated in a protocol of polysomnographic recordings to simulate habitual "weekday" and "weekend" sleep patterns. There was a significant increase in total sleep time (p less than 0.005) and REM sleep (p less than 0.001) during the "weekend" sleep period. A multiple sleep latency test was performed between the two nights to assess daytime sleep tendency. Daytime sleepiness was maximal in the morning, with a tendency for greater alertness as the day progressed. The reduced amount of REM sleep during the "weekdays" plus the tendency for sleepiness in the mornings may contribute to the behavioral and educational difficulties seen in these patients. Recognition of this syndrome enables a specific sleep schedule change to be made that effectively treats the problem.


Comparison of the acute hemodynamic response to intravenous nisoldipine (Bay k 5552) and intravenous nifedipine for left ventricular dysfunction secondary to myocardial infarction.
Dihydropyridine calcium blocking drugs exert potentially dangerous negative inotropic action in selected patients with severe left ventricular dysfunction. In 10 patients peripheral and central hemodynamic effects of nisoldipine were intraindividually compared with nifedipine using a sequential crossover protocol. The drugs were titrated to a similar steady-state reduction of mean arterial pressure by 15 +/- 3% and 15 +/- 2% and systemic vascular resistance by 25 +/- 5% and 17 +/- 2%, respectively. The equi-effective dosage was 0.17 +/- 0.06 microgram/min/kg for nisoldipine and 0.58 +/- 0.1 microgram/min/kg for nifedipine. In contrast to nifedipine, administration of nisoldipine was associated with increases in cardiac index of 0.45 +/- 0.33 liters/min/m2 (p less than 0.05), stroke volume index of 3.91 +/- 3.0 ml/m2 (p less than 0.05) and left ventricular ejection fraction of 4.6 +/- 2.8% (p less than 0.05). Mean pulmonary capillary wedge pressure decreased with nisoldipine from 11.8 +/- 3.4 to 8.0 +/- 3.4 mm Hg (p less than 0.005) and mean pulmonary arterial pressure from 20.4 +/- 4.06 to 16.1 +/- 3.2 mm Hg (p less than 0.005); these variables were unaffected by nifedipine. Thus, intraindividual comparison revealed no cardiodepressive action of nisoldipine, whereas with nifedipine the conceptually beneficial effect of afterload reduction appears to be offset by intrinsic negative inotropic action. Due to higher vasospecificity and more effective unloading, nisoldipine appears to be superior to nifedipine in patients with left ventricular dysfunction secondary to ischemic heart disease.


Assessment of apolipoprotein E genotype for β-amyloid status prediction.
Apolipoprotein E (ApoE) is the major genetic risk factor for sporadic Alzheimer's Disease (AD). Some studies showed a relationship between ApoE4 genotype and the cerebrospinal fluid (CSF) biomarkers (β-amyloid42, p-Tau, t-Tau), as well as with cognitive status. In this sense, it could be interesting to develop an approach to establish amyloid status in a minimally invasive way. The present study assessed the ApoE genotype in different participant groups (mild cognitive impairment due to AD (MCI-AD), mild/moderate dementia due to AD, MCI not due to AD (MCI not AD), other neurological diseases, healthy participants) (n = 342). As expected, the ApoE4 allele was more prevalent in AD patients, characterized by impairment in CSF β-amyloid42 levels (Aβ +), than in the other groups (Aβ -). In this sense, ApoE4-carrier subjects showed lower CSF levels for β-amyloid42 and higher CSF levels for t-Tau and p-Tau. From this, a multivariate model to predict Aβ status was developed by means of partial least square analysis (PLS) and predictive variables (ApoE genotype, cognitive score, sex, age). This model showed suitable AUC-ROC 0.792 (95% CI, 0.744-0.840) and predictive negative value (81.6%). ApoE genotype could be useful in detecting CSF β-amyloid42 impairment associated with early AD development.


The use of multivariate discriminant analysis in the antenatal detection of fetal neural tube defects.
Early second trimester amniotic fluid is classified by stepwise discriminant analysis involving the computer program BMDP77, based upon biochemical analyses for alpha-fetoprotein and eight other easily assayed variables. The outcome of about 800 pregnancies has been predicted on this basis, over 80 of which were associated with fetal neural tube defects. Classification is shown to be more reliable than using alpha-fetoprotein and gestational age alone. Although in practice this approach has now been superceded by the introduction of the analysis of acetylcholine-esterase isoenzyme activity in amniotic fluid, the results demonstrate a successful application of discriminant analysis to medical diagnosis.


Forage:Concentrate Ratio Effects on In Vivo Digestibility and In Vitro Degradability of Horse's Diet.
Determination of digestibility represents the first step for the evaluation of the net energy content of feed for livestock animals. The aim of this study was to evaluate the in vivo digestibility and in vitro degradability of five diets characterized by different forage/concentrate ratios (F:C) in horses. The in vitro degradability was determined by the Gas Production Technique (GPT), using as an inoculum source the feces of the same subjects used for the in vivo test. Five diets consisting of poliphyte hay, straw and grains of barley and oats with a different F:C ratio [90/10 (Diet 1); 78/22 (Diet 2); 68/32 (Diet 3); 60/40 (Diet 4); 50/50 (Diet 5) were formulated and administered in succession, starting with Diet 1. In the in vivo results, no significant differences emerged, despite the different F:C content. In in vitro fermentation, four diets out of the five (2, 3, 4, 5) presented a similar trend of the curve of gas production, showing good activity of the fecal micro population during the first hours of incubation. An important correlation between gas and Volatile Fatty Acid (VFA) were found, suggesting that the processes linked to the micro population deriving from the horse's caecum follow metabolic pathways whose products can be modeled in the same way as for the rumen. The GPT could represent the correct method for studying the nutritional characteristics of feed for horses, using feces as the source of inoculum, even if further investigations must be performed to improve the technique.


Red blood cell distribution width as a potential inflammatory marker in pediatric osteomyelitis.
Red cell distribution width (RDW) has been used in the differential diagnosis of anemia and revealed to be a potential marker of inflammation. We conducted a retrospective study of acute-phase reactant changes in correlation with RDW among pediatric patients with osteomyelitis. We identified 82 patients whose mean RDW increased on average by 1% during antibiotic therapy (mean 13.9% on admission, 95% CI 13.4-14.3, and 14.9% at the end of antibiotic therapy, 95% CI 14.5-15.4). Overall, the RDW was weakly correlated with absolute neutrophil count (r = -0.21, P = 0.001), erythrocyte sedimentation rate (r = -0.17, P = 0.007), and C-reactive protein (r = -0.21, P = 0.001). The generalized estimating equation model showed a weak negative correlation between RDW and C-reactive protein during the therapy duration (B= -0.03, P = 0.008). The mild increase in RDW, and its weak negative correlation with other acute-phase reactants during the study course, limits its utility as a therapy response marker in pediatric osteomyelitis.


Squamous cell carcinoma of the rectum arising in an area of squamous metaplasia.
Squamous cell carcinoma of the rectum is a rare tumour. The aetiology of the tumour is disputed, although in the present case there is strong evidence that squamous metaplasia of the rectal mucosa was closely related to the genesis of the carcinoma.


Benign Breast Disease: Periareolar Mastitis, Granulomatous Lobular Mastitis, and Lymphocytic or Diabetic Mastopathy.
Periareolar mastitis, granulomatous lobular mastitis, and lymphocytic or diabetic mastopathy are benign inflammatory breast conditions that require specialized knowledge of the pathophysiology to reduce the morbidity from surgical management.


The evaluation of HLA-DRB1 antigens as susceptibility markers for unilocular cystic echinococcosis in Egyptian patients.
This is the first study dealing with the correlation between HLA antigens and cystic echinococcosis (CE) in Egyptian patients. The potential immunogenetic predisposition for susceptibility and resistance to unilocular echinococcosis was investigated by HLA-DRB1 typing; first by HLA-DRB1 amplification using PCR then using the allele-specific probing technique based on the reverse hybridization principle. The study was carried out on 35 patients with confirmed CE, and 100 apparently healthy individuals. A statistically significant positive association was found between HLA-DR3 and HLA-DR11 and the occurrence of CE. HLA-DR3 antigen was positively associated with the occurrence of isolated pulmonary cysts, multiple cysts, cysts >5 cm in size, non-cured disease and with a common radiological picture of hydatid cyst. A significant positive association of HLA-DR11 with the occurrence of cysts <5 cm in size was detected. This study demonstrates that carriers of DR-3 and DR-11 are at high risk for CE, and that those with DR-3 are more liable to complications.


Genetic association tests based on ranks (GATOR) for quantitative traits with and without censoring.
Linkage disequilibrium mapping of quantitative traits is a powerful method for dissecting the genetic etiology of complex phenotypes. Quantitative traits, however, often exhibit characteristics that make their use problematic. For example, the distribution of the trait may be censored, highly skewed, or contaminated with outlying values. We propose here a rank-based framework for deriving tests of gene and trait association that explicitly take censoring into account and are insensitive to skewness and outlying values. Standard methods for mapping quantitative traits do not take these characteristics into account, which leads to the discarding of valuable information or their improper application. We show how this framework can be applied in nuclear families and discuss its implementation in general pedigrees. The power and efficacy of the approach is illustrated through a series of simulation experiments in which the approach is compared to existing methods.


Simultaneous Measurement of ν_{μ} Quasielasticlike Cross Sections on CH, C, H_{2}O, Fe, and Pb as a Function of Muon Kinematics at MINERvA.
This Letter presents the first simultaneous measurement of the quasielasticlike neutrino-nucleus cross sections on C, water, Fe, Pb, and scintillator (hydrocarbon or CH) as a function of longitudinal and transverse muon momentum. The ratio of cross sections per nucleon between Pb and CH is always above unity and has a characteristic shape as a function of transverse muon momentum that evolves slowly as a function of longitudinal muon momentum. The ratio is constant versus longitudinal momentum within uncertainties above a longitudinal momentum of 4.5 GeV/c. The cross section ratios to CH for C, water, and Fe remain roughly constant with increasing longitudinal momentum, and the ratios between water or C to CH do not have any significant deviation from unity. Both the overall cross section level and the shape for Pb and Fe as a function of transverse muon momentum are not reproduced by current neutrino event generators. These measurements provide a direct test of nuclear effects in quasielasticlike interactions, which are major contributors to long-baseline neutrino oscillation data samples.


Further observations on the keratinolytic activity of strains of the genus Epidermophyton.
The ability of 17 strains of Epidermophyton to perforate hair in vitro using the Ajello & Georg's test procedure and a modification of Lu's method has been studied. Following the Ajello & Georg's test procedure only E. stockdaleae perforated hair. Sporadically some strains of E. floccosum perforated horse hair. We noted as well unusual perforations originated from inside to outside of the hair. By the other technique, all strains, excepting E. floccosum var. nigricans in child hair, perforated hair. E. floccosum showed these perforations later than E. stockdaleae.


Conformational control by 'zipping-up' an anion-binding unimolecular capsule.
A flexible capsule has been designed in which the anion-binding preorganisation is enhanced by a urea 'zipper'.


A population study of Dupuytren's contracture.
Nine hundred and nineteen patients attending orthopaedic clinics in the rural areas of the Cotswolds and Chilterns were examined for evidence of Dupuytren's contracture. Five per cent of men and 3.5 per cent of women showed evidence of the disease which was largely bilateral but confined to the palm in forty per cent of men and eighty per cent of women. A positive correlation between repeated stretching of the palmar fascia and the presence of Dupuytren's contracture confined to the palm was established.


[Hydatid liver disease revealed by surgical acute abdominal syndrome].
Hepatic hydatid disease is an uncommon surgical emergency. We report an observation and its diagnosis and treatment. An algerian child consulted in emergency unit for appendicitis syndrome. The surgeon discovered an opened hydatid liver cyst. He performed a cystectomy associated with post-operative chemotherapy. Hepatic hydatid disease is frequent in endemic zone. If not complicated, it is often revealed by hepatomegaly. The diagnosis is radiological and mainly serological. Management is medicosurgical. Prognosis depends on early surgical management. Long-time serological and echographic follow-up is required.


Case of trigger finger related to an intertendinous connection between the flexor tendons.
We report a rare cause of trigger finger related to an anatomical variation of an intertendinous connection between the flexor digitorum superficialis and flexor digitorum profundus tendons in the palmar region.


Omega-3 as well as caloric restriction prevent the age-related modifications of cholesterol metabolism.
Intracellular concentration of cholesterol is regulated by the balance between endogenous synthesis and exogenous uptake; endogenous synthesis is subject to feedback control of hepatic 3-hydroxy-3-methyl-glutaryl-CoA reductase activity, while the exogenous supply is mainly controlled by the modulation of the low-density lipoprotein receptor. During ageing, hepatic lipid modifications occur and caloric restriction are able to prevent these changes. So, the aim of this work was to evaluate the mechanisms underlying the effect exerted both by caloric restrictions and by a diet enriched with Omega-3 fatty acids, on the cholesterol plasma levels during ageing, by studying the regulation of the protein involved in cholesterol homeostasis maintenance. Livers from diet restricted and Omega-3 supplemented diet fed 24-month-old rat were used to analyze, the protein complex of cholesterol homeostasis maintenance and those ones that are able to modulate 3-hydroxy-3-methyl-glutaryl-CoA reductase. The data obtained demonstrate that both caloric restriction and Omega-3 supplemented diets are able to prevent hypercholesterolemia, by regulating HMG-CoAR activation state by controlling ROS production and p38 phosphorylation. Moreover also the age-dependent loss of LDLr membrane exposition is prevented.


Determination of azathioprine/6-mercaptopurine metabolites in dried blood spots: Correlation with RBC concentrations.
The analysis of 6-thioguanine (6-TG) and 6-methylmercaptopurine (6-mMP) in biological samples is not straight forward and requires pre-treatment of samples. There are no validated published methods for the analysis of azathioprine/6-mercaptopurine (AZA/6-MP) metabolites in dried blood spot (DBS) samples that study the correlation with red blood cells (RBC) concentrations. DBS was prepared by applying fifteen microliters of blood [spiked with analytes or samples obtained from patients] to a Guthrie card which was then dried at room temperature overnight. The sample treatment procedure used protein precipitation followed by a hydrolysis step in which, 6-mMP was converted into 4-amino-5-(methylthio)carbonyl imidazole (AMTCI) then analytes were transferred to a solid phase extraction cartridge. The extracted sample was chromatographed using a reversed phase system (C18) column preceded by a guard column of matching chemistry. The method gave a linear calibration over the range 0.5-15 μmol/L and 3.75-175 μmol/L for 6-TG and 6-mMP, respectively. The method has been applied successfully to the determination of 6-TG and 6-mMP concentrations in DBS finger-prick samples from 27 paediatric patients with IBD who were receiving (AZA/6-MP). Patient 6-TG and 6-mMP RBC concentrations, calculated from whole blood finger prick DBS samples and those measured in RBCs derived from matched venous samples (analyzed using conventional HPLC-UV technique) showed good agreement using the Bland-Altman test. This is the first published method for determining 6-TG and 6-mMP in DBS that studies their correlation with RBCs concentrations. It is applicable to a range of clinical studies such as adherence and pharmacokinetic studies involving AZA/6-MP.


Low serum testosterone is associated with impaired graft function early after heart transplantation.
We sought to investigate a correlation between serum testosterone levels and graft function early after heart transplantation. In a cross-sectional study, we measured serum testosterone levels 4 weeks after heart transplantation in 49 consecutive male recipients. Echocardiography was carried out to evaluate graft function. Low serum testosterone was defined as <11 nmol/L. Low serum testosterone was present in 21 (43%) recipients (Group A), and 28 (57%) had normal testosterone levels (Group B). The two groups did not differ in age and presence of renal dysfunction, arterial hypertension, diabetes, or hyperlipidemia. Donor age and allograft ischemic time were not different between the two groups. Both groups had comparable tacrolimus through levels, dose of mycophenolate mophetil, and methylprednisolone. Patients in Group A had significantly lower LVEF (58±5% vs 65±6% vs Group B, P=.001) and TAPSE (1.3±0.3 cm vs 1.6±0.3 cm in Group B, P=.01). In comparison with Group B, more patients in Group A were found to have low grade (1R) rejection (25% vs 3%; P=.02). Low serum testosterone levels appear to be associated with impaired graft function and an increased incidence of low-grade rejection episodes early after heart transplantation.


Assay and characteristics of the iron binding moiety of reticulocyte endocytic vesicles.
A 59Fe assay was designed to detect an Fe(III) binding capacity in NP-40 solubilized proteins from rabbit reticulocyte endocytic vesicles. The iron binding capacity had an apparent molecular weight as determined by gel exclusion chromatography of 450,000 daltons. The iron binding moiety coincided with the major nontransferrin iron-containing material of endocytic vesicles labeled in vivo by incubation of cells with 59Fe, 125I-labeled transferrin. The material solubilized from vesicles with NP-40 exhibited two classes of saturable binding sites, one with an association constant for 59Fe-citrate of 3.63 x 10(9) M-1 and with 6.6 x 10(-12) moles of iron bound per mg protein and the other with a constant of 3.96 x 10(8) M-1 and 1.0 x 10(-12) moles of iron bound per mg protein. These affinities are sufficient to satisfy the solubility characteristics of Fe(III) at pH 5.0. Most of the 59Fe bound both in vivo and in vitro to the iron binding moiety could be displaced with 56Fe and an equivalent amount of 59Fe could subsequently be rebound in vitro. The iron binding assay was adopted to vesicle proteins separated by SDS-polyacrylamide gel electrophoresis with subsequent transfer to nitrocellulose and revealed an iron binding activity of molecular weight approximately 95,000 daltons.


Heart failure development in obesity: underlying risk factors and mechanistic pathways.
People with obesity are at risk for developing heart failure (HF), but little is known about the mechanistic pathways that link obesity with cardiac dysfunction. We included 2030 participants from the Swedish Obese Subjects study who received conventional obesity treatment. First-time detection of HF was obtained by cross-checking the study population with the Swedish National Patient Register and the Swedish Cause of Death Register. We also examined if atrial fibrillation and myocardial infarction as time-dependent variables could predict incident HF The mean age of the study cohort was 48.7 years, and 28% were men. The mean body mass index at baseline was 40.1 kg/m2 and remained stable during a median follow-up of 20.1 years. First-time diagnosis of HF occurred in 266 of patients and was related to male sex, increasing age, greater waist-hip ratio, hypertension, higher cholesterol, diabetes mellitus, and elevated free thyroxine in univariable analysis. Estimated glomerular filtration rate was negatively related to HF risk. In multivariable analysis, atrial fibrillation, which is related to HF with preserved ejection fraction (HFpEF), and myocardial infarction, which is linked to HF with reduced ejection fraction (HFrEF), were strongly associated with incident HF with sub-hazard ratios 3.75 (95% confidence interval: 2.72-5.18, P < 0.001) and 3.68 (95% confidence interval: 2.55-5.30, P < 0.001), respectively. Both atrial fibrillation and myocardial infarction as time-dependent variables were independently and strongly related to incident HF in people with excess body fat, suggesting two main obesity-related mechanistic pathways leading to either HFpEF or HFrEF.


Differentiation of phenotypic activity and its genetic analysis in native populations of the Caucasus.
This study introduces a novel approach to the dissection of polygenic variation. First, multidimensional analysis was used to define groups within the normal population. Next, these groups were compared on behavioral and physiological measures to establish underlying mechanisms. Finally, groups were compared on a range of polymorphic markers to determine the extent of single-gene effects. As this approach was conducted using three ethnic populations, the implications of between-, as well as within-, population variation can be assessed.


Column preconcentration of lead in aqueous solution with macroporous epoxy resin-based polymer monolithic matrix.
The objective of this article was to investigate the feasibility of epoxy resin-based monoliths prepared by stepwise polymerization and column preconcentration of metal ions using large-scale monolithic matrix. A novel macroporous polymer monolith matrix was prepared from epoxy resin (EP) and ethylenediamine (EDA) and pore-forming reagent (polyethylene glycol, PEG-1000) by in situ step-addition polymerization. The morphology of the resulting polymer monolith was characterized by scanning electron microscopy (SEM). A solid-phase extraction (SPE) cartridge prepared from a simple glass-tube was used for the preconcentration and determination of Pb(II) combined with flame atomic absorption spectroscopy (FAAS). The characteristics of the monoliths for the extraction of Pb(II) in aqueous solution were investigated. The experimental results showed that trace Pb(II) ions could be quantitatively preconcentrated in the pH range of 4.0-9.0 with recoveries of >95%. The maximum static adsorption capacity of the monolith adsorbent was 106.8 mg g(-1). The column was eluted by 1.0 mol L(-1) HNO3 and recovery of Pb(II) was more than 97%. Moreover, the polymer monolith adsorbent shows superior reusability and stability. The precision and the accuracy of the proposed procedure were satisfactory by analyzing a standard reference material and three natural water samples. It was shown that the EP-EDA monolith was suitable for the preconcentration of environmental Pb(II) as an ion-selective SPE adsorbent.