Mathematical modeling for COVID-19 transmission dynamics: A case study in Ethiopia.
In this paper, we proposed a nonlinear deterministic mathematical model for the transmission dynamics of COVID-19. First, we analyzed the system properties such as boundedness of the solutions, existence of disease-free and endemic equilibria, local and global stability of equilibrium points. Besides, we computed the basic reproduction number R 0 and studied its normalized sensitivity for model parameters to identify the most influencing parameter. The local stability of the disease-free equilibrium point is also verified via the help of the Jacobian matrix and Routh Hurwitz criteria. Moreover, the global stability of the disease-free equilibrium point is proved by using the approach of Castillo-Chavez and Song. We also proved the existence of the forward bifurcation using the center manifold theory. Then the model is fitted with COVID-19 infected cases reported from March 13, 2020, to July 31, 2021, in Ethiopia. The values of model parameters are then estimated from the data reported using the least square method together with the fminsearch function in the MATLAB optimization toolbox. Finally, different simulation cases were performed using PYTHON software to compare with analytical results. The simulation results suggest that the spread of COVID-19 can be managed via minimizing the contact rate of infected and increasing the quarantine of exposed individuals.


Functional gradients of the medial parietal cortex in a healthy cohort with family history of sporadic Alzheimer's disease.
The medial parietal cortex is an early site of pathological protein deposition in Alzheimer's disease (AD). Previous studies have identified different subregions within this area; however, these subregions are often heterogeneous and disregard individual differences or subtle pathological alterations in the underlying functional architecture. To address this limitation, here we measured the continuous connectivity gradients of the medial parietal cortex and assessed their relationship with cerebrospinal fluid (CSF) biomarkers, ApoE ε4 carriership and memory in asymptomatic individuals at risk to develop AD. Two hundred sixty-three cognitively normal participants with a family history of sporadic AD who underwent resting-state and task-based functional MRI using encoding and retrieval tasks were included from the PREVENT-AD cohort. A novel method for characterizing spatially continuous patterns of functional connectivity was applied to estimate functional gradients in the medial parietal cortex during the resting-state and task-based conditions. This resulted in a set of nine parameters that described the appearance of the gradient across different spatial directions. We performed correlation analyses to assess whether these parameters were associated with CSF biomarkers of phosphorylated tau181 (p-tau), total tau (t-tau), and amyloid-ß1-42 (Aß). Then, we compared the spatial parameters between ApoE ε4 carriers and noncarriers, and evaluated the relationship between these parameters and memory. Alterations involving the superior part of the medial parietal cortex, which was connected to regions of the default mode network, were associated with higher p-tau, t-tau levels as well as lower Aß/p-tau levels during the resting-state condition (p < 0.01). Similar alterations were found in ApoE ε4 carriers compared to non-carriers (p < 0.003). In contrast, lower immediate memory scores were associated with changes in the middle part of the medial parietal cortex, which was connected to inferior temporal and posterior parietal regions, during the encoding task (p = 0.001). No results were found when using conventional connectivity measures. Functional alterations in the medial parietal gradients are associated with CSF AD biomarkers, ApoE ε4 carriership, and lower memory in an asymptomatic cohort with a family history of sporadic AD, suggesting that functional gradients are sensitive to subtle changes associated with early AD stages.


Calmodulin functions as an activator of Pur alpha binding to single-stranded purine-rich DNA elements (PUR elements).
Pur alpha is a single stranded DNA-binding protein and binds to a consensus sequence (GGN)n. We have reported that the DNA-binding activity of a single stranded cyclic AMP response element-binding protein (ssCRE-BP) is suppressed in cerebellum treated chronically with morphine, ssCRE-BP is identical to Pur alpha and the DNA binding activity of Pur alpha is markedly enhanced by a heat stable activator in the nuclear extract. In this report, we purified this activator. The amino acid composition and partial amino acid sequence were determined to be identical to those of calmodulin (CaM), which enhanced the binding of GST-Pur alpha to various PUR elements in the 5' non-coding regions of the neuropeptide Y, myelin basic protein and nicotinic Ach receptor beta 4 subunit genes. The data suggest a novel gene expression pathway mediated by Ca/CaM-Pur alpha which may regulate a variety of genes in addition to those regulated through the CREB pathway.


Pathogenesis of secondary hyperparathyroidism.
Secondary hyperparathyroidism is a universal complication in patients with chronic renal failure. Hyperplasia of the parathyroid glands is typically seen in these patients. In early renal failure, alteration in vitamin metabolism, decreased levels of calcitriol and moderate decreases in ionized calcium may allow greater synthesis and secretion of PTH. As the disease progresses, there is a decrease in the number of vitamin D receptors (VDR) and calcium receptors (CaR). The decreased number of VDR and CaR makes the parathyroid glands more resistant to calcitriol and calcium. Phosphorus induces hyperplasia of the parathyroid glands independent of calcium and calcitriol, and by a post-transcriptional mechanism increases PTH synthesis and secretion. Experimental work in uremic rats demonstrated that if the animals are fed a high-phosphorus diet, they not only developed secondary hyperparathyroidism but parathyroid cell hyperplasia. If the diet is then reduced in phosphorus, the levels of PTH return to normal. However, the parathyroid cell hyperplasia persists and no apoptosis is seen. Thus, the control of the three most important factors, calcium, calcitriol and phosphorus, is critical to prevent the development of secondary hyperparathyroidism and hyperplasia of the parathyroid glands.


Dual roles of the bZIP transcription factor PERIANTHIA in the control of floral architecture and homeotic gene expression.
Flowers develop from floral meristems, which harbor stem cells that support the growth of floral organs. The MADS domain transcription factor AGAMOUS (AG) plays a central role in floral patterning and is required not only for the specification of the two reproductive organ types, but also for termination of stem cell fate. Using a highly conserved cis-regulatory motif as bait, we identified the bZIP transcription factor PERIANTHIA (PAN) as a direct regulator of AG in Arabidopsis. PAN and AG expression domains overlap, and mutations in either the PAN-binding site or PAN itself abolish the activity of a reporter devoid of redundant elements. Whereas under long-day conditions pan mutants have merely altered floral organ number, they display in addition typical AG loss-of-function phenotypes when grown under short days. Consistently, we found reduced AG RNA levels in these flowers. Finally, we show that PAN expression persists in ag mutant flowers, suggesting that PAN and AG are engaged in a negative-feedback loop, which might be mediated by the stem-cell-inducing transcription factor WUSCHEL (WUS).


Pineal Parenchymal Tumor of Intermediate Differentiation and DICER1 Syndrome: A Case Report.
DICER1 syndrome is a rare inherited tumor predisposition syndrome associated with an increased risk for several malignant and benign tumors. We present a patient with pineal parenchymal tumor of intermediate differentiation who was found to have a germline pathogenic variant in DICER1 gene. Pineoblastoma is a known DICER1-related tumor; however, the association between pineal parenchymal tumor of intermediate differentiation and DICER1 mutation is rare with only 1 recent large molecular study that has reported this association. This report adds to the evolving tumor spectrum of DICER1 and highlights the importance of molecular evaluation of pediatric brain tumors, for both therapeutic decisions and long-term surveillance.


Consequences of using hyaluronan-coated tympanostomy tubes.
The effects of hyaluronan-coated polyethylene tympanostomy tubes on the tympanic membrane structure were investigated and compared with non-coated polyethylene tubes without the coating. The tubes were inserted into the tympanic membrane (TM) and removed 3 weeks later. After 3 weeks the tubes were reinserted. This tube insertion and removal and reinsertion sequence was repeated 4 times and the tympanic membrane structure was examined histologically at 3 weeks and 12 weeks later. The study did not reveal any differences regarding the thickness and light microscopical appearance when comparing the TMs with the hyaluronan-coated tubes to those with the non-coated polyethylene tubes. However, the present way of evaluating the effects of different tube materials may be too crude. In future experiments aimed at elucidating the effects of different surface coatings of tympanostomy tubes other experimental designs must be employed, e.g. fewer tube insertion sequences and less traumatizing extractions.


Low level laser therapy for sports injuries.
Our hospital has used LLLT in the treatment of athletes since 1990. We had a good result about LLLT for sports injuries. However, few articles have attempted to evaluate the efficacy of LLLT for sports injuries. The aims of this study was to evaluate the efficacy of LLLT for sports injuries. Materials (Subjects) and Methods: Forty one patients underwent LLLT in our hospital. These patients included 22 men and 19 women with an average age of 38.9 years old. Patients were irradiated by diode laser at points of pain and/or acupuncture points. Patients underwent LLLT a maximum treatment of 10 times (mean 4.1 times). We evaluated the efficacy of LLLT using a Pain relief score (PRS). A score of 2 to 5 after treatment was regarded as very good, 6 to 8 as good, and 9 to 10 as poor. A PRS score of less than 5 was regarded as effective. The rate of effectiveness (PRS of 5 or less) after LLLT was 65.9% (27/41 patients). In this study, the resulting rate of effectiveness was 65.9% for all sports injuries. However, we have a high rate of effectiveness for Jumper's knee, tennis elbow and Achilles tendinitis and cases that were irradiated laser by a physician. LLLT is an effective treatment for sports injuries, particularly jumper's knee, tennis elbow and Achilles tendinitis.


An Unusual Suspect Causing Hypoxemic Respiratory Failure.
Introduction: Antisynthetase syndrome (ASS) is characterized by the presence of anti-Jo-1 antibodies in conjunction with clinical findings of fever, polymyositis-dermatomyositis, and interstitial lung disease (ILD). Inflammatory myopathies carry a high risk of malignancy, but this association is less well outlined in ASS. We present the case of a patient with ASS who developed non-Hodgkin's lymphoma with acute hypoxemic respiratory failure. Case Presentation: A 44-year-old female with ASS presented with acute hypoxemic respiratory failure. She was empirically treated with broad-spectrum antibiotics for a health care-associated pneumonia; however, she failed to improve. Chest computed tomography revealed extensive bilateral ground glass opacities as well as extensive mediastinal and axillary lymphadenopathy. Infectious workup was negative. A surgical lung biopsy revealed peripheral T-cell lymphoma (PTCL). The patient was started on chemotherapy with complete resolution of hypoxemic respiratory failure. Conclusions: Malignancy is very rare in the setting of ASS; and our case illustrates the unique presentation of PTCL in ASS. In addition, lung involvement in PTCL is variable (incidence ranging from 8% to 20%); and in this case, bilateral multifocal consolidation was biopsied and proven to be PTCL involving the lungs. This case highlights the rare noninfectious conditions that can present as acute hypoxemic respiratory failure in the setting of ASS.


Cytotoxic activity of Vitex trifolia purpurea extracts.
Defatted 85% crude hot aqueous methanol extract of Vitex trifolia purpurea (AME) successively extracted with, chloroform and ethyl acetate. Cytotoxicity of (AME), chloroform methanol extract (CE), ethyl acetate methanol extract (EE) and the residue obtained from methanol extract after successive extraction (RME) have been evaluated on brine shrimp (Artemia salina) and Hep-G2 cell lines as well. In brine shrimp lethality bioassay the results revealed that the (RME) is the most potent one with LC50 value 173 microg/ml while LC50 values of (AME), (CE) and (EE) was 180, 199 and 286 microg/ml, respectively. As well as the results of cytotoxic assay against Hep-G2 cell lines are in full agreement with previous results, with IC50 values 6, 10.7, 20.8 and 65.8 microg/ml for (RME), (AME), (CE) and (EE), respectively.


[The therapeutic relationship within the scope of inpatient psychotherapy].
Within psychotherapy-research a kind of paradigm has almost established itself, maintaining that--with high probability--a positive therapeutic relationship early on permits to expect a favourable therapeutic outcome. These conclusions were mainly derived from an outpatient psychotherapy setting of under 30 hours. In our own study we wanted to examine whether an early prognosis of success under such conditions was also possible for psychoanalytically oriented inpatient psychotherapy. We examined a sample--representative by age, sex and diagnosis--of 76 patients with an average duration of treatment of 12 weeks. For the patients' self-rating of therapeutic alliance we translated a questionnaire from Luborsky (1984) into German, whereas for the therapists' rating we conceived our own questionnaire. Contrary to our expectations, we were not able to demonstrate clinically significant correlations between the initial quality of the therapeutic relationship and therapy success later on (patients' rating: r = 0.28, p < 0.01, therapists' rating: r = 0.09, p > 0.10). One hypothesis on this surprising finding seems to be especially plausible: In our opinion a substantial strength of inpatient psychotherapy (regardless of it being shaped more by psychoanalytic or behavioral orientation) is the following: it offers less motivated patients of lower social status and level of education an opportunity to experience essential processes of communicative learning and motivation especially within the first weeks of treatment.


Effect of a non-steroid anti-inflammatory agent on the drug metabolizing activity of the human liver.
Results of animal experiments indicate that indomethacin has a marked inhibitory effect on the activity of the hepatic microsomal mixed function monooxygenase (MFO) enzyme system. In order to verify this effect of indomethacin in humans, the authors studied antipyrine kinetics and D-glucaric acid excretion in 14 patients before and after 7 days treatment with two different doses of the drug. In contrast to the results obtained from animal experiments, there was no change in the activity of MFO in man. This can possibly be explained by species difference.


A wearable textile for respiratory monitoring: Feasibility assessment and analysis of sensors position on system response.
The interest on wearable textiles to monitor vital signs is growing in the research field and clinical scenario related to the increasing demands of long-term monitoring. Despite several smart textile-based solutions have been proposed for assessing the respiratory status, only a limited number of devices allow the respiratory monitoring in a harsh environment or in different positions of the human body. In this paper, we investigated the performances of a smart textile for respiratory rate monitoring characterized by 12 fiber optic sensors (i.e., fiber Bragg grating) placed on specific landmarks for compartmental analysis of the chest wall movements during quiet breathing. We focused on the analysis of the influence of sensor position on both peak-to-peak amplitude of sensors output and accuracy of respiratory rate measurements. This analysis was performed on two participants, who wore the textile in two positions (i.e., standing and supine). Bland-Altman analysis on respiratory rate showed promising results (better than 0.3 breaths per minute). Referring to the peak-to-peak output amplitude, the abdomen compartment showed the highest excursions in both the enrolled participants and positions. Our findings open up new approaches to design and develop smart textile for respiratory rate monitoring.


Experimental Results of Attitude Determination Functional Algorithms Implementation in Strapdown Inertial Navigation System.
Strapdown inertial navigation system (SINS) software developers are usually mainly focused on the attitude determination algorithm design and characteristics. Such an algorithm can be based on different mathematical apparatus. An approach to the derivation of attitude determination algorithm equations in strapdown inertial navigation system is proposed. This algorithm is based on direct heading, pitch, and roll calculation. The qualitative differences between the proposed algorithm and the one using a transformation matrix are noted. The main objective of the paper is direct attitude angles calculation algorithm application possibilities analysis in real SINS operating conditions. The analysis is based on a comparison of the proposed algorithm with another frequently used attitude determination algorithm based on the transformation matrix. Attitude determination algorithms performance investigation results based on car and helicopter experimental tests are presented.


The Cambodian National Oral Health Plan 1992-2000.
The reconstruction of dental services and training in Cambodia following the devastation of the country during the reign of the Khmer Rouge has been limited by minimal help from other countries for political reasons. Following the recent signing of a peace treaty, a National Conference on Oral Health has been held, and a National Oral Health Plan formulated, outlining goals for the year 2000, and strategies to improve the oral health status in the country.


CD34(+)/CD38(-) stem cells in chronic myeloid leukemia express Siglec-3 (CD33) and are responsive to the CD33-targeting drug gemtuzumab/ozogamicin.
CD33 is a well-known stem cell target in acute myeloid leukemia. So far, however, little is known about expression of CD33 on leukemic stem cells in chronic leukemias. We analyzed expression of CD33 in leukemic progenitors in chronic myeloid leukemia by multi-color flow cytometry and quantitative polymerase chain reaction. In addition, the effects of a CD33-targeting drug, gemtuzumab/ozogamicin, were examined. As assessed by flow cytometry, stem cell-enriched CD34(+)/CD38(-)/CD123(+) leukemic cells expressed significantly higher levels of CD33 compared to normal CD34(+)/CD38(-) stem cells. Moreover, highly enriched leukemic CD34(+)/CD38(-) cells (>98% purity) displayed higher levels of CD33 mRNA. In chronic phase patients, CD33 was found to be expressed invariably on most or all stem cells, whereas in accelerated or blast phase of the disease, the levels of CD33 on stem cells varied from donor to donor. The MDR1 antigen, supposedly involved in resistance against ozogamicin, was not detectable on leukemic CD34(+)/CD38(-) cells. Correspondingly, gemtuzumab/ozogamicin produced growth inhibition in leukemic progenitor cells in all patients tested. The effects of gemtuzumab/ozogamicin were dose-dependent, occurred at low concentrations, and were accompanied by apoptosis in suspension culture. Moreover, the drug was found to inhibit growth of leukemic cells in a colony assay and long-term culture-initiating cell assay. Finally, gemtuzumab/ozogamicin was found to synergize with nilotinib and bosutinib in inducing growth inhibition in leukemic cells. CD33 is expressed abundantly on immature CD34(+)/CD38(-) stem cells and may serve as a stem cell target in chronic myeloid leukemia.


Fabrication of Ag nanoparticles embedded in TiO2 nanotubes: using electrospun nanofibers for controlling plasmonic effects.
Composites of electrospun poly(ethylene oxide) (PEO) fibers and silver nanoparticles (Ag NPs) were used as a soft template for coating with TiO2 by atomic layer deposition (ALD). Whereas the as-deposited TiO2 layers on PEO fibers and Ag NPs were completely amorphous, the TiO2 layers were transformed into polycrystalline TiO2 nanotubes (NTs) with embedded Ag NPs after calcination. Their plasmonic effect can be controlled by varying the thickness of the dielectric Al2 O3 spacer between Ag NPs and dye molecules by means of the ALD process. Electronic and spectroscopic analyses demonstrated enhanced photocurrent generation and solar-cell performance due to the intense electromagnetic field of the dye resulting from the surface plasmon effect of the Ag NPs.


Physicochemical, antimicrobial, and biological properties of White-MTAFlow.
To evaluate a new material containing tantalum oxide as an alternative radiopacifier, and a water-based gel for hydration, in comparison with two calcium silicate-based cement: ProRoot MTA and Biodentine. ProRoot MTA (Dentsply), Biodentine (Septodont), and a new hydraulic calcium silicate cement White-MTAFlow (Ultradent) (in 'thin' consistency) were characterized using X-ray diffraction (XRD), scanning electron microscopy (SEM), and energy-dispersive spectroscopy (EDS). The interaction with dentin was also assessed using SEM and EDS. Physical and chemical properties radiopacity, setting time, linear flow, volumetric central filling, and lateral flow, pH, and volume change were investigated together with the color luminosity (L) and color change (ΔE). The agar diffusion and direct contact antimicrobial activity, and methylthiazolyldiphenyl-tetrazolium-bromide (MTT) cytotoxicity using human fibroblast cells were also evaluated. Data were statistically analyzed at a 5% significance level. All materials were composed of tricalcium and dicalcium silicate but had different radiopacifiers, and calcium hydroxide (portlandite) deposition was detected in XRD analysis. White-MTAFlow exhibited radiopacity values in accordance with ISO standard, and the longest setting time. The water-based gel provided the highest linear flow, a comparable cavity central filling, and the highest groove-lateral flow in the volumetric flow analysis. White-MTAFlow exhibited an alkalinity reduction, and Biodentine, a progressive increase of pH values after 28 days. However, similar volume loss for White-MTAFlow was assessed in comparison to Biodentine after the 28-day immersion. White-MTAFlow showed the highest L value (91.5), and ProRoot MTA the lowest (78.1) due to dentin staining caused by bismuth migration. None of the materials exhibited inhibition halos against the tested bacteria, and similar turbidity values were obtained after 48 h in direct contact with E. faecalis, indicating an upregulation to bacterial growth. White-MTAFlow showed MTT cytocompatibility similarly to the control group. White-MTAFlow in 'thin' consistency presents comparable physicochemical, biological, and antimicrobial properties to ProRoot MTA and Biodentine, and does not cause color alteration in dentin. White-MTAFlow is a suitable material for use as reparative endodontic cement. Further studies considering its biocompatibility are necessary.


Loss-of-function variants of the human melanocortin-1 receptor gene in melanoma cells define structural determinants of receptor function.
The alpha-melanocyte-stimulating hormone (alphaMSH) receptor (MC1R) is a major determinant of mammalian skin and hair pigmentation. Binding of alphaMSH to MC1R in human melanocytes stimulates cell proliferation and synthesis of photoprotective eumelanin pigments. Certain MC1R alleles have been associated with increased risk of melanoma. This can be theoretically considered on two grounds. First, gain-of-function mutations may stimulate proliferation, thus promoting dysplastic lesions. Second, and opposite, loss-of-function mutations may decrease eumelanin contents, and impair protection against the carcinogenic effects of UV light, thus predisposing to skin cancers. To test these possibilities, we sequenced the MC1R gene from seven human melanoma cell (HMC) lines and three giant congenital nevus cell (GCNC) cultures. Four HMC lines and two GCNC cultures contained MC1R allelic variants. These were the known loss-of-function Arg142His and Arg151Cys alleles and a new variant, Leu93Arg. Moreover, impaired response to a superpotent alphaMSH analog was demonstrated for the cell line carrying the Leu93Arg allele and for a HMC line homozygous for wild-type MC1R. Functional analysis in heterologous cells stably or transiently expressing this variant demonstrated that Leu93Arg is a loss-of-function mutation abolishing agonist binding. These results, together with site-directed mutagenesis of the vicinal Glu94, demonstrate that the MC1R second transmembrane fragment is critical for agonist binding and maintenance of a resting conformation, whereas the second intracellular loop is essential for coupling to the cAMP system. Therefore, loss-of-function, but not activating MC1R mutations are common in HMC. Their study provides important clues to understand MC1R structure-function relationships.


Effect of Moxibustion on Behavioral Changes and Expression of APP and BACE1 in Hippocampus of SAMP8 Mice.
To observe the effect of moxibustion on cognitive function of aging mice, to observe the effect of moxibustion on protein and gene expression of APP metabolism pathway, and to explore the mechanism of action in moxibustion. 24 SAMP8 were randomly divided into 2 groups (12 in each group): moxibustion group and model group. 12 SAMR1 mice were used as blank controls. Mice in the moxibustion group were treated with moxibustion for 8 weeks, 10 minutes each time, 5 times a week, and for a total of 8 weeks. The model group and the blank group were treated with sham-moxibustion. Behavior tests were used to detect the learning and memory ability of each group of mice. Immunohistochemical, western blot, and RT-PCR were used to detect the protein and mRNA expression of APP and BACE1. Furthermore, the expressions of miR-29 and miR-101 were observed by RT-PCR method to explore the mechanism of moxibustion at the genetic level. In this study, relative to normal mice, we found that aging mice showed behavioral changes consistent with the onset of AD. However, moxibustion interventions were able to mitigate these effects to some degree in aging mice. In addition, moxibustion was proved to regulate APP metabolism pathway at protein and gene level through molecular biology tests. The data suggest that the effect of moxibustion intervention on cognitive function in aging mice is related to the regulation of genes and proteins involved in APP metabolism pathway; this may be a potential target for treating Alzheimer's disease.


A novel synthetic analog of Militarin, MA-1 induces mitochondrial dependent apoptosis by ROS generation in human lung cancer cells.
A synthetic Militarin analog-1[(2R,3R,4R,5R)-1,6-bis(4-(2,4,4-trimethylpentan-2-yl)phenoxy) hexane-2,3,4,5-tetraol] is a novel derivative of constituents from Cordyceps militaris, which has been used to treat a variety of chronic diseases including inflammation, diabetes, hyperglycemia and cancers. Here, we report for the first time the synthesis of Militarin analog-1 (MA-1) and the apoptotic mechanism of MA-1 against human lung cancer cell lines. Treatment with MA-1 significantly inhibited the viability of 3 human lung cancer cell lines. The inhibition of viability and growth in MA-1-treated A549 cells with an IC50 of 5μM were mediated through apoptosis induction, as demonstrated by an increase in DNA fragmentation, sub-G0/G1-DNA fraction, nuclear condensation, and phosphatidylserine exposure. The apoptotic cell death caused mitochondrial membrane permeabilization through regulation of expression of the Bcl-2 family proteins, leading to cytochrome c release in a time-dependent manner. Subsequently, the final stage of apoptosis, activation of caspase-9/-3 and cleavage of poly (ADP ribose) polymerase, was induced. Furthermore, A549 lung cancer cells were more responsive to MA-1 than a bronchial epithelial cell line (BEAS-2B), involving the rapid generation of reactive oxygen species (ROS), c-Jun N-terminal kinase (JNK) and p38 mitogen-activated protein kinase (MAPK) activation. The pharmacological inhibition of ROS generation and JNK/p38 MAPK exhibited attenuated DNA fragmentation in MA-1-induced apoptosis. Oral administration of MA-1 also retarded growth of A549 orthotopic xenografts. In conclusion, the present study indicates that the new synthetic derivative MA-1 triggers mitochondrial apoptosis through ROS generation and regulation of MAPKs and may be a potent therapeutic agent against human lung cancer.


The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors.
BCR-ABL1-specific tyrosine kinase inhibitors prolong the life of patients with chronic myeloid leukemia (CML) but cannot completely eradicate CML progenitors. The BH3 mimetic, ABT-263, targets prosurvival BCL2 family members, and has activity against CML progenitors. However, the inhibitory effect of ABT-263 on BCL-XL, which mediates platelet survival, produces dose-limiting thrombocytopenia. A second-generation BH3 mimetic, ABT-199, has been developed to specifically bind BCL2 but not BCL-XL. We determined the activity of ABT-199 against CML cell lines, as well as primary CML and normal cord blood (NCB) progenitors. We find that BCL2 expression levels predict sensitivity to ABT-199 in CML and NCB progenitors, and that high NCB BCL2 levels may explain the reported hematologic toxicities in ABT-199-treated patients. Also, while single agent ABT-199 has modest activity against CML progenitors, when combined with imatinib, ABT-199 significantly enhances imatinib activity against CML progenitors at concentrations predicted to avoid hematologic toxicities.


[An autoradiographic study of alpha 1-adrenoceptors in hepatic tissues in cirrhotic patients with portal hypertension].
We studied hepatic alpha 1-adrenoceptors of 8 hepatitis virus B-related cirrhotic patients with portal hypertension and 8 control surgical patients without liver disease by light radioautography. The density of alpha 1-adrenoceptors in various hepatic structures ("healthy" control vs. patients, per 10,000 microns 2) was as follows: on hypatocytes 1255.07 +/- 151.44/583.37 +/- 47.64 (P < 0.01); on intrahepatic artery walls 705.06 +/- 188.68/183.54 +/- 46.77 (P < 0.01); on intrahepatic portal walls 409.98 +/- 88.73/154.02 +/- 20.65 (P < 0.01); on hepatic venule walls 339.29 +/- 94.85/.... The decrease of density of alpha 1-adrenoceptors in cirrhotic liver tissues may be a result of the destruction of nomal hepatic structure by hepatitis virus B and the down-regulation of alpha 1-adrenoceptors.


Origin of laser-induced near-subwavelength ripples: interference between surface plasmons and incident laser.
We show that short-pulse laser-induced classical ripples on dielectrics, semiconductors, and conductors exhibit a prominent "non-classical" characteristic-in normal incidence the periods are definitely smaller than laser wavelengths, which indicates that the simplified scattering model should be revised. Taking into account the surface plasmons (SPs), we consider that the ripples result from the initial direct SP-laser interference and the subsequent grating-assisted SP-laser coupling. With the model, the period-decreasing phenomenon originates in the admixture of the field-distribution effect and the grating-coupling effect. Further, we propose an approach for obtaining the dielectric constant, electron density, and electron collision time of the high-excited surface. With the derived parameters, the numerical simulations are in good agreement with the experimental results. On the other hand, our results confirm that the surface irradiated by short-pulse laser with damage-threshold fluence should behave metallic, no matter for metal, semiconductor, or dielectric, and the short-pulse laser-induced subwavelength structures should be ascribed to a phenomenon of nano-optics.


An alternative portal for scapulothoracic arthroscopy.
Access to the superior angle of the scapula during scapulothoracic arthroscopy with current standard portals can be difficult. A safe, effective alternative portal for scapulothoracic arthroscopy, located superior to the scapula, is described, which enables easier resection of the superomedial angle for treatment of the snapping scapula.


Protection and regrowth of the auditory nerve after deafness: neurotrophins, antioxidants and depolarization are effective in vivo.
Deafness, with loss of sensory (hair) cells, results in progressive pathophysiological changes ending in the degeneration of most auditory nerve neurons. It is now possible to consider these events in the broader context of anti-apoptotic survival factors in the peripheral and central nervous system. One consequence of deafferentation of a neuron is the loss of neurotrophins that can lead to a change in oxidative state (formation of free radicals), changes in intracellular Ca(2+), and an up-regulation of apoptotic genes. Interventions that can modify availability of neurotrophins, [Ca(2+)](I), and/or free radical formation or their destructive effects, may preserve the auditory nerve. Some interventions (neurotrophins) may also lead to a regrowth of neurites. Studies in this area are of basic value and also of immediate clinical interest for the application of the cochlear prosthesis to the severe and profoundly deaf, since the benefits of this prosthesis are directly dependent on auditory nerve survival and the proximity of stimulating electrode to neuron. We, and others, have found that auditory nerve degeneration can be prevented by chronic electrical stimulation. We have demonstrated in vivo that this effect can be blocked by tetrodotoxin, thus indicating that propagated action potentials are a necessary condition, and by verapamil (Ca(2+) channel blocker), supporting in vitro studies by others, indicating that L-type Ca(2+) channels are necessary for stimulation-induced rescue of the deafferented auditory nerve. The intensities of electrical stimulation required for rescue are at levels sufficient to express the intermediate-early gene c-fos which can initiate transcription of anti-apoptotic genes and pathways, and up-regulate expression of neurotrophins that may act in an autocrine manner to protect the nerve from death. We, and others, have found that chronic local delivery (osmotic pump and microcannulation of the inner ear fluid spaces) of individual neurotrophins and cocktails of factors can also enhance survival of the deafferented nerve, and some can also initiate a regrowth of degenerated peripheral processes of the nerve into the region of the destroyed sensory epitheliae. Recently, we have shown that this rescue can occur with delayed intervention, after degeneration of some neurons has begun, more closely mimicking the human clinical situation. Finally, we have shown that interventions with antioxidants may also be effective in preventing pathophysiological changes of the auditory nerve following deafness. These studies in the auditory periphery support the 'neurotrophic factor hypothesis' as proposed as a general mechanism underlying neurodegenerative and age-related pathology of the central nervous system. Additional animal studies can yield a rational scientific basis to justify human trials, with a goal to maintain auditory cell survival and initiate and direct fiber growth to the next generation of prosthesis. Intimate contact between electrode and a dense population of auditory neurons should greatly enhance the benefits of these devices for the profoundly deaf.


Pitfalls and successes of peer review in neurosurgery.
As the first editor of the Journal of Neurosurgery, Louise Eisenhardt, acting with the advice of the editorial board, was responsible for making decisions on the acceptance or rejection of submitted manuscripts. Her log, covering the first 14 years of editorial decisions, is a record of neurosurgical progress and of the forces--scientific, technical and other--that shaped the field of neurosurgery. Any peer-review process is subject to pitfalls that become evident in retrospect, but an effective peer-review process is one of the basic ingredients of scientific progress. The decisions to accept or reject manuscripts submitted to the Journal of Neurosurgery during Eisenhardt's tenure are highlighted in this historical vignette.


[Percentage of tonsil hypertrophy in orthodontic patients with different sagittal skeletal relationship].
Objective: To investigate the prevalence of tonsil hypertrophy in patients with different sagittal skeletal craniofacial patterns, as well as the correlation between tonsil hypertrophy and the type of skeletal pattern. Methods: Lateral cephalograms of patients who visited the Department of Orthodontics Division 1, School of Stomatology, Wuhan University during January to August, 2019 were retrospectively collected. Patients (children: age≥6 and ≤12 year; adults: age≥18 year) were divided into three groups according to the ANB (subspinale-nasion-supramental) angle: the skeletal class Ⅰ group (0°≤ANB≤4°), skeletal class Ⅱ group (ANB>4°) and skeletal class Ⅲ group (ANB<0°). Tonsil hypertrophy was diagnosed with lateral cephalogram by two specifically trained orthodontists independently, according to the Baroni's method. The between-group differences in tonsil hypertrophy prevalence were analyzed using chi-square tests with Bonferroni correction (α=0.017). Results: A total of 1 776 patients (593 children and 1 183 adults) were included, among which 672 (37.8%) were with class Ⅰ, 849 (47.8%) with class Ⅱ, and 255 (14.4%) with class Ⅲ skeletal pattern. The prevalence of tonsil hypertrophy in children was 66.3% (393/593). The proportion of children with tonsil hypertrophy in class Ⅲ group [87.0% (60/69)] were significantly higher than that in class Ⅰ [65.6% (145/221), χ²=11.56, P<0.017] and class Ⅱ [62.0% (188/303), χ²=15.69, P<0.017] groups. The prevalence of tonsil hypertrophy in adults was 23.2% (275/1 183). The proportion of adults with tonsil hypertrophy in class Ⅲ group [42.5% (79/186)] was significantly higher than that in class Ⅰ [19.1% (86/451), χ²=36.50, P<0.017] and class Ⅱ [20.2% (110/546), χ²=35.00, P<0.017] groups. However, there was no significant difference in the prevalence of tonsil hypertrophy between class Ⅰ and class Ⅱ groups for both children (χ²=0.70, P>0.017) and adults (χ²=0.18, P>0.017). Conclusions: The prevalence of tonsil hypertrophy in skeletal class Ⅲ patients was significantly higher than that in patients with skeletal class Ⅰ and Ⅱmalocclusion. Tonsil hypertrophy could be an important risk factor for skeletal class Ⅲ patients.


Probing (1)J(C-F) and (n)J(F-F) spin-spin coupling constants for fluoroazines: an ab initio theoretical investigation.
Ab initio equation-of-motion coupled cluster singles and doubles calculations have been carried out to evaluate one-bond C-F coupling constants (1)J(C-F) and three-, four-, and five-bond F-F coupling constants (n)J(F-F) for a series of mono-, di-, and trifluoroazines. The computed (1)J(C-F) and (n)J(F-F) values for these are in good agreement with available experimental coupling constants. The values of (1)J(C-F) vary as the number and positions of N atoms and the number and relative positions of C-F bonds change, but it is difficult to discern general patterns for these changes due to opposing effects of the Fermi contact and paramagnetic spin-orbit terms. The majority of (1)J(C-F) values lie in a range that includes the three monosubstituted pyridines. For trifluoroazines, (1)J(C-F) for a C-F bond that is ortho to two other C-F bonds is greater than (1)J(C-F) for the other two bonds. F-F coupling constants arise in these molecules when the two C-F bonds are ortho, meta, or para. Values of (3)J(F-F) are relatively large and negative, whereas values of (5)J(F-F) are relatively large and positive. (4)J(F-F) may be positive or negative and large or small. The value of this coupling constant depends on the nature of the atom that links the two C-F bonds and the number and positions of N atoms in the ring. The calculations carried out in this study at a reliable level of theory give values for one-bond C-F and n-bond F-F spin-spin coupling constants for the fluoroazines that are not available experimentally. In addition, the patterns that describe the changes that occur in these molecules provide a basis for predicting their values in larger, related systems in the absence of experimental data and direct calculations.


Wnt5a is expressed in spondyloarthritis and exerts opposite effects on enthesis and bone in murine organ and cell cultures.
Spondyloarthritis (SpA) is a chronic inflammatory joint disorder that initiates at the enthesis, where tendons attach to bone through a fibrocartilage zone. At late stages, excessive bone apposition appears within the diseased enthesis. Because Wnt5a participates to normal bone formation and appears related to inflammatory processes, we investigated the role of this Wnt growth factor in inflammation-associated ossification in SpA. The concentration of Wnt5a assessed by enzyme-linked immunosorbent assay in synovial fluids of patients with SpA (2.58 ± 0.98 ng/mL) was higher than in osteoarthritic patients (1.33 ± 0.71 ng/mL). In murine primary cultures of tendon cells, chondrocytes, and osteoblasts and in an organotypic model of mouse ankle, we showed that tumor necrosis factor α reversibly diminished Wnt5a expression and secretion, respectively. Wnt5a decreased gene expression of differentiation markers and mineralization in cultured chondrocytes and reduced alkaline phosphatase activity in Achilles tendon enthesis (-14%) and osteocalcin protein levels released by ankle explants (-36%). On the contrary, Wnt5a stimulated ossification markers' expression in cultured osteoblasts and increased the bone volume of the tibial plateau of the cultured explants (+19%). In conclusion, our results suggest that Wnt5a is expressed locally in the joints of patients with SpA. Wnt5a appears more associated with ossification than with inflammation and tends to inhibit mineralization in chondrocytes and enthesis, whereas it seems to favor the ossification process in osteoblasts and bone. Further studies are needed to decipher the opposing effects observed locally in enthesis and systemically in bone in SpA.


Associations between chromosomal anomalies and congenital heart defects: a database search.
Recent technical advances in molecular biology and cytogenetics, as well as a more developmental approach to congenital heart disorders (CHDs), have led to considerable progress in our understanding of their pathogenesis, especially of the important causative role of genetic factors. The complex embryology of the heart suggests the involvement of numerous genes, and hence, numerous chromosomal loci, such as the recently identified 22q11, in normal cardiomorphogenesis. In order to identify other loci, the Human Cytogenetics DataBase was searched for all chromosome anomalies associated with CHD. Through the application of several (arbitrary) criteria we have selected associations occurring so frequently that they may not be forfuituous, suggesting assignment of a gene or genes responsible for specific CHDs to certain chromosome regions. The results of this study may be a first step in the detection of specific chromosome defects responsible for CHD, which will be useful in daily patient care and may provide clues for further cytogenetic and molecular studies.


Overexpressed HER2 in NSCLC is a possible therapeutic target of EGFR inhibitors.
"Oncogene addiction" is a concept in which tumor cells exhibit dependence on certain oncogene(s) for their sustained proliferation and survival, thus providing the rationale for molecular targeted therapies. Cancer cells addicted to epidermal growth factor receptor (EGFR) bear activated mutations in the EGFR gene, and these mutations are used as the markers for predicting carcinomas susceptible to EGFR inhibitors such as gefitinib and erlotinib. However, other unknown mechanisms underlying susceptibility to EGFR inhibitors have also been suggested. The susceptibility of non-small-cell lung cancer (NSCLC) cell lines to EGFR inhibitors and the pattern of their oncogene addiction was examined. The effect of EGFR inhibitors on the activation of the oncogene was analyzed. The possible use of the oncogene protein expression as a biomarker was assessed. HER2 addicted, non-EGFR expressing NSCLC cell line NCI-H2170 was susceptible to EGFR inhibitors. EGFR inhibitor treatment led to markedly decreased phosphorylation levels of activated HER2 and its downstream effector AKT. Furthermore, the soluble form of HER2 was secreted by NCI-H2170 cells and was positively detected in the blood of xenografted mice. HER2 seems to be a valid therapeutic target of EGFR inhibitors in HER2-addicted lung carcinomas, and soluble HER2 may be an effective biomarker to guide the appropriate treatment of such cancer cells.


[Topical inhibition of angiogenesis at the cornea. Safety and efficacy].
The efficacy and safety of novel topical inhibitors of corneal neovascularisation will be discussed. A literature review after a PUBMED search and own clinical and experimental results are presented. The off-label use of Avastin eye drops and GS101 eye drops against insulin receptor substrate (IRS)-1, which have been tested in phase II trial, both seem to be relatively efficient and safe ways to inhibit progressive corneal neovascularisation. Other VEGF antagonists, such as ranibizumab and pegaptanib eye drops also inhibit corneal neovascularisation. Avastin and GS101 eye drops are the first specific angiogenesis inhibitors for topical inhibition of corneal angiogenesis available for clinical use.


Inactivation and reactivation of intracellular S-adenosylhomocysteinase in the presence of nucleoside analogues in rat hepatocytes.
Several nucleoside analogues, some of which are potent inactivators of isolated S-adenosylhomocysteinase (AdoHcyase), were tested with respect to their effect on intracellular AdoHcyase and S-adenosylhomocysteine (AdoHcy) catabolism in intact rat hepatocytes. Among the analogues tested, 9-beta-D-arabinofuranosyladenine and 9-beta-D-arabinofuranosyl-3-deazaadenine were the most potent inactivators of intracellular AdoHcyase. Compounds like 2-chloroadenosine and carbocyclic adenosine are extremely efficient inactivators of the isolated enzyme, but these nucleosides exerted only a limited effect on the enzyme in intact hepatocytes. Only a moderate effect was observed with 2-chloro-3-deazaadenosine and 2'-deoxyadenosine, and a high concentration of 5'-deoxy-5'-methylthioadenosine was required to inactivate the enzyme. There was a correlation between inactivation and accumulation of AdoHcy. Carbocyclic-3-deazaadenosine caused no inactivation of AdoHcyase in liver cells but caused a massive accumulation of AdoHcy, suggesting that this analogue functions as a reversible inhibitor of the enzyme. Residual enzyme activity was observed with all the nucleoside analogues tested. The intracellular enzyme inactivated in the presence of 2'-deoxyadenosine and 9-beta-D-arabinofuranosyladenine was readily recovered when the cells were transferred to fresh medium containing adenosine deaminase, but reactivation of the enzyme activity after treatment of the cells with 2-chloroadenosine and 5'-deoxy-5'-methylthioadenosine was also observed. The inactivation of intracellular enzyme induced by 2-chloro-3-deazaadenosine, 9-beta-D-arabinofuranosyl-3-deazaadenine, and carbocyclic adenosine was essentially irreversible under the conditions of the experiments. Factors determining the effect of nucleoside analogues on intracellular AdoHcyase are discussed.


The prosurvival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB that blocks TNFalpha-induced apoptosis.
Bcl-2-family proteins are key regulators of the apoptotic response. Here, we demonstrate that the pro-survival Bcl-2 homolog Bfl-1/A1 is a direct transcriptional target of NF-kappaB. We show that bfl-1 gene expression is dependent on NF-kappaB activity and that it can substitute for NF-kappaB to suppress TNFalpha-induced apoptosis. bfl-1 promoter analysis identified an NF-kappaB site responsible for its Rel/NF-kappaB-dependent induction. The expression of bfl-1 in immune tissues supports the protective role of NF-kappaB in the immune system. The activation of Bfl-1 may be the means by which NF-kappaB functions in oncogenesis and promotes cell resistance to anti-cancer therapy.


[Annual report of perioperative mortality and morbidity for the year 2000 at certified training hospitals of Japanese Society of Anesthesiologists: with a special reference to anesthetic methods--report of the Japanese Society of Anesthesiologists Committee on Operating Room Safety].
The Committee on Operating Room Safety of Japan Society of Anesthesiologists (JSA) sends annually confidential questionnaires of perioperative mortality and morbidity (cardiac arrest, severe hypotension, severe hypoxia) to Certified Training Hospitals of JSA. This report is a special reference to anesthetic methods in perioperative mortality and morbidity in 2000. Five hundreds and twenty hospitals reported perioperative mortality and morbidity referred to anesthetic methods and total numbers of reported cases were 910,007. The percentage of cases reported by each anesthetic method was as follows; inhalation anesthesia 45.47%, total intravenous anesthesia (TIVA) 6.15%, inhalation anesthesia + epidural or spinal or conduction block 24.48%, TIVA + epidural or spinal or conduction block 6.33%, spinal with continuous epidural block (CSEA) 3.67%, epidural anesthesia 1.92%, spinal anesthesia 10%, conduction block 0.47% and others 1.49%. The incidence of cardiac arrest per 10,000 cases due to all etiology (anesthetic management, preoperative complications, intraoperative complications, surgery, others) is estimated to be 6.55 cases in average; 5.36 cases in inhalation anesthesia, 30.72 cases in total intravenous anesthesia (TIVA), 4.62 cases in inhalation anesthesia + epidural or spinal or conduction block, 2.6 cases in TIVA + epidural or spinal or conduction block, 1.2 cases in spinal with continuous epidural block (CSEA), 0.57 cases in epidural anesthesia, 1.65 cases in spinal anesthesia, 2.36 cases in conduction block and 46.38 cases in other methods. However, the incidence of cardiac arrest per 10,000 cases totally attributable to anesthetic management is estimated to be 0.54 cases in average; 0.34 cases in inhalation anesthesia, 1.07 cases in TIVA, 0.58 cases in inhalation anesthesia + epidural or spinal or conduction block, 0.17 cases in TIVA + epidural or spinal or conduction block, 0.9 cases in CSEA, 0.57 cases in epidural anesthesia, 0.99 cases in spinal anesthesia, zero case in conduction block and 1.47 cases in other methods. The incidence of severe hypotension per 10,000 cases due to all etiology is estimated to be 11.14 cases in average; 11.31 cases in inhalation anesthesia, 36.61 cases in TIVA, 9.29 cases in inhalation anesthesia + epidural or spinal or conduction block, 6.59 cases in TIVA + epidural or spinal or conduction block, 3.59 cases in CSEA, 6.3 cases in epidural anesthesia, 4.39 cases in spinal anesthesia, 2.36 cases in conduction block and 23.56 cases in other methods. On the other hand, the incidence of severe hypotension per 10,000 cases totally attributable to anesthetic management is estimated to be 1.25 cases in average; 0.97 cases in inhalation anesthesia, 0.89 cases in TIVA, 1.39 cases in inhalation anesthesia + epidural or spinal or conduction block, 1.39 cases in TIVA + epidural or spinal or conduction block, 2.09 cases in CSEA, 3.44 cases in epidural anesthesia, 1.87 cases in spinal anesthesia, zero case in conduction block and zero case in other methods. The incidence of severe hypoxia per 10,000 cases due to all etiology is estimated to be 4.8 cases in average; 6.35 cases in inhalation anesthesia, 9.64 cases in TIVA, 3.82 cases in inhalation anesthesia + epidural or spinal or conduction block, 2.26 cases in TIVA + epidural or spinal or conduction block, 0.3 cases in CSEA, 1.15 case in epidural anesthesia, 1.21 cases in spinal anesthesia, zero case in conduction block and 5.89 cases in other methods. On the other hands, the incidence of severe hypoxia per 10,000 cases totally attributable to anesthetic management is estimated to be 1.98 cases in average; 3.09 cases in inhalation anesthesia, 2.32 cases in TIVA, 1.3 cases in inhalation anesthesia + epidural or spinal or conduction block, 0.87 cases in TIVA + epidural or spinal or conduction block, zero case in CSEA, zero case in epidural anesthesia, 0.55 cases in spinal anesthesia, zero case in conduction block and zero case in other methods. The mortality rate of cardiac arrest within 7 postoperative days per 10,000 cases due to all etiology is estimated to be 3.55 (54.2%) cases in average; 3.12 (58.1%) cases in inhalation anesthesia, 19.29 (62.8%) cases in TIVA, 1.17 (25.2%) cases in inhalation anesthesia + epidural or spinal or conduction block, 0.52 (20%) cases in TIVA + epidural or spinal or conduction block, zero cases in CSEA, zero case in epidural anesthesia, 0.33 (20%) cases in spinal anesthesia, zero case in conduction block and 39.76 (85.7%) cases in other methods. On the other hands, the mortality rate of cardiac arrest per 10,000 cases totally attributable to anesthesia is estimated to be 0.07 (12.2%) case in average, 0.07 (21.4%) case in inhalation anesthesia, 0.18 (16.8%) case in TIVA, zero case in inhalation anesthesia + epidural or spinal or conduction block, zero case in TIVA + epidural or spinal or conduction block, zero case in CSEA, zero case in epidural anesthesia, 0.11 (11.1%) case in spinal anesthesia, zero case in conduction block and 0.74 (50%) case in other methods. Five major combinations of listed critical incidents, causes and anesthetic methods were as follows: 18.93 cases in TIVA, preoperative complications and severe hypotension; 18.75 cases in TIVA, preoperative complications and cardiac arrest; 11.07 cases in TIVA, surgery and severe hypotension; 6.79 cases in TIVA, surgery and cardiac arrest; 5.24 cases in inhalation anesthesia, preoperative complications and severe hypotension. In summary: 1. There was no significant difference with regard to perioperative mortality and morbidity due to anesthetic management among anesthetic methods. 2. The percentage of each anesthetic method in 2000 was not different significantly from that in 1999 in spite of increased cases reported. 3. Incidence of severe hypotension due to all etiology of TIVA in 2000 decreased significantly compared with that in 1999 (P < 0.05). This may be attributed to the decreased incidence in preoperative complication (shock) and massive bleeding due to surgery.


Shoulder instability in athletes. The Asian perspective.
Recently, there has been an upsurge of interest among the orthopaedic sports medicine community in Asia on this subject of athletic shoulder instability. This is particularly prominent in countries such as Japan, Korea, Taiwan, and Hong Kong, where sports requiring throwing and overhead use of the upper limb are popular. In this review, the classification of the condition is analyzed with a specific account of the rotator interval injury. A systematic plan of clinical assessment is presented highlighting the specific regional considerations in clinical practice and cost-effectiveness of the health care systems in Asia. The management of athletic shoulder instability depends on patient attitude and cultural background. In Asia, the popular choice of Bankart repair with capsular shift procedure is presented with special reference to the unique experience of multidirectional and habitual posterior instability. Arthroscopic surgery is becoming popular in Asia, and the indications and limitations of the technique in the management of shoulder instability are discussed.


Enamel growth rate variation of inner, mid, and outer enamel regions between select permanent tooth types across five temporally distinct British samples.
This study explored differences in the regional daily growth rates of human enamel between tooth types across a temporal transect in Britain. Upper permanent central incisors (n = 81), upper permanent canines (n = 69), and upper and lower permanent first molars (n = 115) from Roman, Pre-Medieval, Medieval, and Modern day populations were analysed using histological methods. Daily secretion rates (DSRs) were collected for inner, mid, and outer regions of cuspal and lateral enamel for each tooth type and temporal sample. Variation in DSRs between the tooth types, within each population, was sought using Welch's tests. Numerous significant differences were observed in DSRs between equivalent enamel regions of different tooth types. The majority of differences were observed between molars and the anterior teeth, but there were no obvious trends as to which typically grew faster/slower, nor was there any consistency across the temporal samples. In contrast, comparisons between incisors and canines yielded minimal differences and variation, when significant, was found to be enamel area- and sample-specific. This study presents evidence for a high level of variation in DSRs between anterior teeth and first molars of the permanent dentition. This variation appears sporadic with no clear trend outside of anterior tooth comparisons, where analyses of the Late Pre-Medieval and Modern-day populations highlight how DSRs within cuspal and lateral enamel can vary independently.


Effect of bicarbonate and other anions on the oxidized and reduced forms of F1-ATPase.
The effect of activating anions on the hydrolysis of ATP catalyzed by mitochondrial ATPase was higher on the oxidized than on the reduced form of the enzyme. On the contrary the effect of inhibitory anions on this reaction was more manifest on the reduced form of the enzyme. Kinetic data show that both activating and inhibitory anions compete for the same sites of the ATPase. A unifying mechanism of action is suggested according to which the anions could establish coordination bonds with the suggested iron atoms of the catalytic site. The preferential displacement of electrons of such bonds towards the ligand, or towards the metal atom, would lead respectively to an inhibition or to an activation of the enzyme.


Community service for the mentally ill: what is the community?
In his study of the successive efforts of a DHA to plan for community services for the mentally ill, Dylan Tomlinson argues that there is a basic question which is necessary, but difficult, to answer: "In which neighbourhood is the pattern of ordinary social interaction such as to foster good relationships between 'ex patient' and other residents in a community?"


Active and passive recovery and acid-base kinetics following multiple bouts of intense exercise to exhaustion.
The purpose of this study was to profile the effect of active versus passive recovery on acid-base kinetics during multiple bouts of intense exercise. Ten males completed two exercise trials. The trials consisted of three exercise bouts to exhaustion with either a 12 min active (20% workload max) or passive recovery between bouts. Blood pH was lower in the passive (p) recovery compared to active (a) throughout the second and third recovery periods [second recovery: 7.18 +/- 0.08 to 7.24 +/- 0.09 (p), 7.23 +/- 0.07 to 7.32 +/- 0.07 (a), P < 0.05; third recovery: 7.17 +/- 0.08 to 7.22 +/- 0.09 (p), 7.23 +/- 0.08 to 7.32 +/- 0.08 (a), P < 0.05]. Exercise performance times did not differ between recovery conditions (P = 0.28). No difference was found between conditions for recovery kinetics (slope and half-time to recovery). Subsequent performance during multiple bouts of intense exercise to exhaustion may not be influenced by blood acidosis or mode of recovery.


Photoelectrochemical alcohol oxidation by mixed-linker metal-organic frameworks.
Metal-organic frameworks (MOFs) provide a suitable platform for stable and efficient heterogeneous photoelectrochemical oxidation catalysis due to their highly ordered structure, large surface area, and synthetic tunability. Herein, a mixed-linker MOF comprising of a photosensitizer [Ru(dcbpy)(bpy)2]2+ (bpy = 2,2'-bipyridine, dcbpy = 5,5'-dicarboxy-2,2'-bipyridine) and catalyst [Ru(tpy)(dcbpy)Cl]+ (tpy = 2,2':6',2''-terpyridine) that were incorporated into the UiO-67 framework and grown as thin films on a TiO2-coated, fluorine-doped tin oxide (FTO) electrode (RuB-RuTB-UiO-67/TiO2/FTO). When used as an electrode for the photoelectrochemical oxidation of benzyl alcohol, the mixed-linker MOF film showed a faradaic efficiency of 34%, corresponding to a 3-fold increase in efficiency relative to the RuB-UiO-67/TiO2/FTO control. This increase in catalytic efficiency is ascribed to the activation of RuTB moieties via oxidation by photogenerated RuIIIB. Transient absorption spectroscopy revealed the delayed appearance of RuIIITB* or RuIIITB formation, occurring with a lifetime of 21 ns, due to energy and/or electron transfer. The recovery kinetics of the charge separated state was increased (283 μs) in comparison to single-component control experiments (105 μs for RuB-UiO-67/TiO2/FTO and 7 μs for RuTB-UiO-67/TiO2/FTO) indicating a cooperative effect that could be exploited in chromophore/catalyst MOF motifs.


Solid and papillary epithelial neoplasm of the pancreas: CT and MR findings.
Solid and papillary epithelial neoplasm of the pancreas is a very rare low-grade malignant neoplasm with only 126 cases reported in the literature and seen mostly in young female patients. Surgical excision means cure in cases before malignant degeneration developed. Its characteristic findings are typical location in the tail of the pancreas, peripheral capsule formation, hypodensity on CT images, and hyperintense internal signal characteristics on T1-weighted MR images secondary to hemorrhage and accumulation of methemoglobine molecule. These findings are enough for the preoperative diagnosis that may lead to early surgery and cure. We present the CT and MR findings of this very rare neoplasm in a case report.


[Study of the amplification and expression of c-erbB2 oncogene in epithelial ovarian tumors].
Protooncogene c-erbB2 amplification and expression were studied in 62 cases of epithelial ovarian tumor by using immunohistochemical method and in situ hybridization. c-erbB2 gene amplification was observed in 30 of 47 ovarian cancers (63.8%) and in none of 15 benign tumors. The gene expression was found in 38 of the former and in 9 of the latter tumors. The gene amplification showed significant difference between malignant and benign tumors (P < 0.01). But for gene expression, only the strongly positive staining demonstrated significant difference (P < 0.01). There was correlation between c-erbB2 gene amplification and expression in epithelial ovarian carcionoma. The status of c-erbB2 gene amplification and expression had no relationship with histopathological types of ovarian carcinoma. The results indicate that there is extensive expression of c-erbB2 in epithelial ovarian tumors and it is over-expressed in ovarian carcinoma. Gene amplification is perhaps only one way by which c-erb2 gene is activated, and its overexpression might be one of the factors that promotes epithelial ovarian cancer development.


Modification of the theory of dual radiation action for attenuated fields. II. Application to the analysis of soft X-ray results.
A formalism developed in the first paper in this series, based on the generalized Theory of Dual Radiation Action, is applied to survival data for cells exposed to soft X rays. It is shown that, in contrast to previous published analyses, this formalism--modified to account for the attenuation of dose across the sensitive matrix of the cell--is fully consistent with the experimental results. The reasons for previous disagreements are discussed.


The chromosomal protein SMCHD1 regulates DNA methylation and the 2c-like state of embryonic stem cells by antagonizing TET proteins.
5-Methylcytosine (5mC) oxidases, the ten-eleven translocation (TET) proteins, initiate DNA demethylation, but it is unclear how 5mC oxidation is regulated. We show that the protein SMCHD1 (structural maintenance of chromosomes flexible hinge domain containing 1) is found in complexes with TET proteins and negatively regulates TET activities. Removal of SMCHD1 from mouse embryonic stem (ES) cells induces DNA hypomethylation, preferentially at SMCHD1 target sites and accumulation of 5-hydroxymethylcytosine (5hmC), along with promoter demethylation and activation of the Dux double-homeobox gene. In the absence of SMCHD1, ES cells acquire a two-cell (2c) embryo-like state characterized by activation of an early embryonic transcriptome that is substantially imposed by Dux Using Smchd1/Tet1/Tet2/Tet3 quadruple-knockout cells, we show that DNA demethylation, activation of Dux, and other genes upon SMCHD1 loss depend on TET proteins. These data identify SMCHD1 as an antagonist of the 2c-like state of ES cells and of TET-mediated DNA demethylation.


Inhibition of miR-92b suppresses nonsmall cell lung cancer cells growth and motility by targeting RECK.
microRNAs play critical roles in the progression and metastasis of nonsmall cell lung cancer (NSCLC). miR-92b acts as an oncogene in some malignancies; however, its role in NSCLC remains poorly understood. Here, we found that miR-92b was significantly increased in human NSCLC tissues and cell lines. Inhibition of miR-92b remarkably suppressed cell proliferation, migration, and invasion of NSCLC cells. Reversion-inducing-cysteine-rich protein with kazal motifs (RECK) was identified to be a target of miR-92b. Expression of miR-92b was negatively correlated with RECK in NSCLC tissues. Collectively, miR-92b might promote NSCLC cell growth and motility partially by inhibiting RECK.


Influence of infection with Brachyspira hyodysenteriae on clinical expression, growth performance, and digestibility in growing pigs fed diets varying in type and level of fiber.
Research on the effects of different fiber types and levels on infection with Brachyspira hyodysenteriae on growth performance and nutrients digestibility in pigs is scarce. The objective of the current study was to investigate the effects of infection with B. hyodysenteriae when feeding diets varying in soluble and insoluble dietary fiber (DF) on the expression of swine dysentery, growth performance, and digestibility of organic matter (OM) nutrients. A total of 96 growing pigs (26.9 ± 2.5 kg) were used for the experiment and divided into six blocks. The growing pigs were fed one of four diets for 12 wk: low fiber (LF), high fiber (HF), high soluble fiber (HS), and high insoluble fiber (HI). After 2 wk, half of the pigs were inoculated with B. hyodysenteriae. Half of the pigs in each group were euthanized at week 6 for the measurement of the apparent digestibility at the ileum, cecum, colon, and total tract. The remaining pigs were maintained to observe and analyze the clinical expression of fecal score and excretion of B. hyodysenteriae, growth performance, and total tract digestibility up to 12 wk. In the current study, the experimental diets did not influence the expression of infection in the pigs. The body weight and average daily gain (ADG) were in line with the results of clinical expression from week 4 to 6. However, the ADG of the infected pigs started to recover from week 6 (P < 0.05) and then recovered from week 8 to 12 (P < 0.05). The infection with B. hyodysenteriae did not impair apparent ileal digestibility (AID; P > 0.05), whereas the apparent digestibility of OM, total non-starch polysaccharide, non-cellulosic polysaccharide, and cellulose in the cecum of the infected pigs was higher than non-infected pigs (P < 0.05). The apparent colonic digestibility of ash and nitrogen was higher in non-infected pigs than in infected pigs (P < 0.05). The pigs fed the LF diet had a higher digestibility in all segments of the intestinal tract, whereas the HS diet had the lowest AID but higher or similar to the LF diet in the cecum, colon, and the total tract (P < 0.05). The pigs fed the HF and HI diets, with a high proportion of insoluble fiber, had a lower digestibility in the hindgut than the other two diets (P < 0.05). In conclusion, the infection with B. hyodysenteriae negatively influenced clinical signs of swine dysentery and growth performance but did not impair AID, and neither soluble nor insoluble DF influenced the expression of the infection.


Metabolic syndrome and short-term heart rate variability in young adults. The cardiovascular risk in young Finns study.
Heart rate variability (HRV) can be used to estimate autonomic nervous control of the cardiovascular system. In middle-aged subjects, the metabolic syndrome (MetS) is associated with lower HRV. We hypothesized that alterations in autonomic balance are already present in young adults with the MetS, and analysed the association of short-term HRV with the MetS (using the National Cholesterol Education Program definition), in 1889 subjects aged 24-39 years. Short-term (3 min) HRV analysis included high-frequency (HF), low-frequency (LF) and total (TP) spectral components of HRV and LF/HF ratio. The presence of the MetS was associated with lower HF, LF and TP in men and women, and with higher LF/HF ratio in women. In men, waist circumference was the strongest individual MetS component that associated with HRV. After adjustments for age and heart rate, MetS was associated with lower HF and higher LF/HF ratio in women, but only with a lower TP in men (all P < 0.05). MetS is associated with lower HRV in young adults. The individual components of MetS are differentially associated with HRV in men and in women. Our results are consistent with lower vagal activity and a possible increase in sympathetic predominance in women with the MetS. This sex difference in vagal activity and sympathovagal balance may partly explain the greater increase in cardiovascular risk associated with MetS in women than in men.


Development and Characterization of Semi-Refined Iota Carrageenan/SiO2-ZnO Bionanocomposite Film with the Addition of Cassava Starch for Application on Minced Chicken Meat Packaging.
In the current study, film based on semi-refined ι-carrageenan/cassava starch (SRiC/CS) incorporated with SiO2-ZnO nanoparticles was fabricated and characterized to deal with serious environmental problems resulting from plastic packaging materials. This study aimed to evaluate film properties with the variation of SRiC/CS proportions of bionanocomposite films for application to minced chicken meat packaging. Increasing CS portion contributed to increased transparency, reduced surface roughness, and decreased mechanical properties of films. The variable significantly (p < 0.05) increased the water vapor permeability (WVP) and reduced the water solubility of films. The incorporation of the nanoparticles significantly (p < 0.05) increased UV screening, decreased WVP, and enhanced the antimicrobial activity of films. Furthermore, the substitution of 0.5 wt% (weight percentage) CS provided the best film characteristics. Based on the color and the total volatile base nitrogen (TVBN) results, SRiC film incorporated with the nanoparticles preserved minced chicken quality up to six days. Thus, the developed films are desirable for biodegradable food packaging.


Simultaneous two-hydrogen transfer as a mechanism for efficient CO(2) reduction.
Two-hydrogen transfer (simultaneous protic and hydridic hydrogen transfer) is examined as a potentially efficient mechanism for the selective reduction of CO(2) to methanol. High-level ab initio CCSD(T) coupled-cluster theory simulations of ammonia-borane (AB), which contains both protic and hydridic hydrogen, show the effectiveness of this mechanism. AB demonstrates how simultaneous two-hydrogen transfer is kinetically efficient because (1) two-hydrogen transfer avoids high-energy single-electron-reduced intermediates, (2) the CO(2)'s HOMO is protonated while the LUMO is concurrently reduced by a hydride, and (3) complementary charge polarities around the six-membered-ring transition-state structures stabilize the transition states. This study suggests that an effective mechanism for the reduction of CO(2) to methanol proceeds through three two-hydrogen-transfer steps and that suitable catalysts should be developed that exploit two-hydrogen transfer without the use of AB.


Pancreatic polypeptide secretion in patients with chronic pancreatitis and after pancreatic surgery.
We investigated polypeptide (PP) secretion under basal conditions, in response to bombesin infusion and to meal ingestion in patients with chronic pancreatitis (CP) and patients after different types of pancreatic surgery. Included were patients with CP without (n = 20) and with (n = 30) exocrine pancreatic insufficiency, patients after duodenum preserving resection of the head of the pancreas (DPRHP; n = 20), after Whipple's procedure (n = 19), following distal pancreatectomy (DP; n = 12), and healthy controls (n = 36). In CP patients basal and bombesin stimulated PP levels were significantly (p<0.01) reduced compared to controls only when exocrine insufficiency was present. Meal-stimulated PP secretion was significantly (p<0.01-0.05) reduced in CP patients both with and without exocrine insufficiency. Plasma PP peak increments after bombesin and meal ingestion correlated significantly with exocrine function. Basal PP, meal, and bombesin-stimulated PP secretion had low sensitivities of 22%, 42%, and 60% respectively, in detecting chronic pancreatitis. In patients after pancreatic surgery that included pancreatic head resection (DPRHP or Whipple operation) basal and stimulated PP secretion were significantly (p<0.01-0.05) reduced. Basal and meal or bombesin-stimulated PP levels are significantly reduced in patients with CP only when exocrine insufficiency is present. Determination of plasma PP levels has low sensitivity and is not useful in detecting chronic pancreatitis without exocrine insufficiency. In patients after pancreatic surgery, PP secretion is dependent on the type of operation (head vs tail resection).


Symptoms and development of anxiety in children with or without intellectual disability.
The purpose of this study was to examine group differences in presentation and trajectory of anxiety symptoms and disorders in children with moderate to borderline intellectual disability (ID) and children with typical cognitive development (TD). Examined anxiety disorders and symptoms in children with ID (n=74) or TD (n=116) annually from ages 5 through 9 using a parent structured interview and questionnaire. Logistic regression was used to examine odds of meeting anxiety criteria and hierarchical linear modeling was used to examine anxiety trajectory. Children with ID had significantly higher rates of clinical levels of anxiety on the Child Behavior Checklist at ages 8 and 9 and higher rates of separation anxiety disorder at age 5 compared to those with TD. Children with ID were also more likely to have externalizing problems co-occurring with anxiety. The rate of increase of anxiety symptoms over time was positive and similar in the two groups, and neither group showed sex differences in anxiety rates. Results suggest that children with ID have both higher rates of anxiety across time and are delayed in showing typical decreases in separation anxiety in early childhood. Implications for intervention are discussed in terms of the importance of screening for and treating anxiety in children with ID.


Ligand activation of ELK receptor tyrosine kinase promotes its association with Grb10 and Grb2 in vascular endothelial cells.
ELK is a member of the Eph-related tyrosine kinase family that includes receptors signaling axonal guidance, neuronal bundling, and angiogenesis. We recently identified ELK expression in human renal microvascular endothelial cells and sought to identify intracellular proteins through which it signals responses. The cytoplasmic domain of ELK was used as "bait" in a yeast two-hybrid screen to identify interactive proteins expressed from a randomly primed embryonic murine library (E9.5-10.5). Among interactive products of 76 cDNAs characterized, 10 nonidentical, overlapping clones encoded the SH2 domain of the recently reported Grb10 adapter protein, and an additional 3 encoded Grb2. A self-phosphorylated recombinant, baculovirus-expressed GST-ELKcy fusion protein bound Grb10 and Grb2 from human renal microvascular endothelial cell extracts, while the unphosphorylated fusion form did not. Site-directed mutation identified Tyr-929 as a putative phosphorylation site required for Grb10, but not Grb2, interaction in yeast and recombinant protein assays. The ELK ligand, LERK-2/Fc, stimulated tyrosine phosphorylation of ELK, and recruitment of Grb10 and Grb2 to endothelial ELK receptors recovered by wheat germ agglutinin lectin and immunoprecipitation. These findings define ligand-activated interaction between ELK and the SH2 domains of Grb2 and the newly identified Grb10 protein that shares homology with a Caenorhabditis elegans gene product implicated in neural cell migration.


Cholesterol synthesis is associated with hepatic lipid content and dependent on fructose/glucose intake in healthy humans.
Visceral obesity and fatty liver have been related to high synthesis and low absorption of cholesterol. This study aimed to investigate the associations of cholesterol metabolism with liver and visceral fat content in healthy humans. Another objective was to explore the effects of very-high-fructose and very-high-glucose diets on cholesterol homeostasis. We report on a cohort of 20 people (12 males, 8 females; age 30.5 ± 2.0 years; body mass index 25.9 ± 0.5 kg/m(2)) who completed a four-week dietary intervention study. Between the baseline and the followup examination the study participants in addition to a balanced weight-maintaining diet received 150 g of either fructose or glucose per day. Visceral and liver fat were measured with magnetic resonance (MR) imaging and (1)H-MR spectroscopy, respectively. Cholesterol absorption and synthesis were estimated from the serum noncholesterol sterol concentrations. Performing cross-sectional analyses the lanosterol and desmosterol to cholesterol ratios were positively correlated with visceral and liver fat content (all P < .03). The lathosterol to cholesterol ratio decreased in response to high-fructose diet (P = .006) but not in response to high-glucose diet. To conclude, visceral and liver fat content are associated with cholesterol synthesis in healthy humans. Furthermore, cholesterol synthesis appears to be dependent on fructose/glucose intake.


The relationship between cognitive function and life space: the potential role of personal control beliefs.
We examined the relationship of cognitive and functional measures with life space (a measure of spatial mobility examining extent of movement within a person's environment) in older adults, and investigated the potential moderating role of personal control beliefs. Internal control beliefs reflect feelings of competence and personal agency, while attributions of external control imply a more dependent or passive point of view. Participants were 2,737 adults from the ACTIVE study, with a mean age of 74 years. Females comprised 76% of the sample, with good minority representation (27% African American). In multiple regression models controlling for demographic factors, cognitive domains of memory, reasoning, and processing speed were significantly associated with life space (p < .001 for each), and reasoning ability appeared most predictive (B = .117). Measures of everyday function also showed significant associations with life space, independent from the traditional cognitive measures. Interactions between cognitive function and control beliefs were tested, and external control beliefs moderated the relationship between memory and life space, with the combination of high objective memory and low external control beliefs yielding the highest life space (t = -2.07; p = .039). In conclusion, older adults with better cognitive function have a larger overall life space. Performance-based measures of everyday function may also be useful in assessing the functional outcome of life space. Additionally, subjective external control beliefs may moderate the relationship between objective cognitive function and life space. Future studies examining the relationships between these factors longitudinally appear worthwhile to further elucidate the interrelationships of cognitive function, control beliefs, and life space.


Evaluation of a real-time PCR assay for the detection and quantification of Bacillus cereus group spores in food.
A procedure based on quantitative real-time PCR was evaluated for the detection and quantification of Bacillus cereus spores. Several methods for DNA isolation, such as various heat treatments and germination solutions, were evaluated on spore suspensions of representative strains of the B. cereus group. Overall, the commercially available DNeasy tissue kit yielded the maximum amount of DNA. The procedure also was used to construct calibration curves for different food matrices, with a wide spore quantification range of 5 log units using serial dilutions of spore suspensions of B. cereus CECT 148T. The detection limit for B. cereus in artificially contaminated liquid egg and reconstituted infant formula was about 4 spores per reaction or 60 spores per ml. The newly developed methodology based on the DNeasy tissue kit and an SYBR Green quantitative real-time PCR assay is very suitable for the rapid and accurate detection and quantification of B. cereus group strains and their spores in food samples.


Educating a Diverse Nursing Staff: One Hospital's Tips for Success.
Identifying process breaks that increase risks to patient safety in hospitals results in the need for educational interventions. These interventions must be effective to meet the needs of a diverse nursing staff. Finding ways to best reach nursing staff and overcome challenges requires creative solutions to keep a large, diverse nursing staff up-to-date on current and best practices. Strategies include blended learning, electronic distribution, and educational flyers to provide a variety of formats to meet the educational needs within the organization. [J Contin Educ Nurs. 2020;51(11):498-500.].


The roles of eicosanoids in experimental glomerulonephritis.
There is accumulating evidence showing alterations of renal eicosanoid synthesis in glomerular disease. Despite the complexity of their role in glomerulonephritis, these compounds appear to play a major part in the inflammatory response and in control of renal hemodynamics. The role of eicosanoids in the filtration of macromolecules has not been established, but there is indirect evidence of their involvement in mediating proteinuria. Dietary manipulation, either by high EPA, high linoleic acid, or EFA-deficient diet, in experimental glomerulonephritis have shown promising results as summarized in Table 1. The therapeutic potential of alterations in dietary fatty acid to modulate the inflammatory response appears to be of great value. Table 2 summarizes the effects of different dietary fatty acid alterations on eicosanoid synthesis. Nonetheless, we should point out that most of the studies of alterations in dietary fatty acids did not document changes in glomerular synthesis of prostaglandin, thromboxane, or HETES. Further studies examining the effects of different fatty acid regimens on glomerular eicosanoid synthesis and the role of these eicosanoids in the development of glomerulonephritis will provide valuable information. These findings could determine the specific type of dietary manipulation to inhibit or stimulate the production of selected eicosanoids.


Demethylation of the NRF2 Promoter Protects Against Carcinogenesis Induced by Nano-SiO2.
Nano silicon dioxide (Nano-SiO2) has been widely used in industries such as the field of biomedical engineering. Despite the existing evidence that Nano-SiO2 exposure could induce oxidative stress and inflammatory responses in multiple organ systems, the carcinogenicity of Nano-SiO2 exposure has rarely been investigated. Thus in this study, two types of human bronchial epithelial cell lines (16HBE and BEAS-2B) were selected as in vitro models to investigate the carcinogenicity of Nano-SiO2. Our results revealed that Nano-SiO2 induces a malignant cellular transformation in human bronchial epithelial cells according to the soft agar colony formation assay. The carcinogenesis induced by Nano-SiO2 was also confirmed in nude mice. By using immunofluorescence assay and high-performance capillary electrophoresis (HPCE), we observed a genome-wide DNA hypomethylation induced by Nano-SiO2. Besides the reduced enzyme activity of total DNMTs upon Nano-SiO2 treatment, altered expression of DNMTs and methyl-CpG binding proteins were observed. Besides, we found that the expression of NRF2 was activated by demethylation of CpG islands within the NRF2 promoter region and the overexpression of NRF2 could alleviate the carcinogenesis induced by Nano-SiO2. Taken together, our results suggested that Nano-SiO2 induces malignant cellular transformation with a global DNA hypomethylation, and the demethylation of NRF2 promoter activates the expression of NRF2, which plays an important role in protecting against the carcinogenesis induced by Nano-SiO2.


Dynamics of Mammalian Cell Infection by Trypanosoma cruzi trypomastigotes.
In a recent work we demonstrated that Trypanosoma cruzi trypomastigotes change their motility patterns in the presence of mammalian cells, that the extent of the changes depends on the cell line, and that this extent is positively correlated with the efficiency with which parasites invade the different cell lines. These results open the question of what cellular characteristics are relevant for parasite identification and invasion. In the present work, we tackled such question. We performed infection-kinetics experiments on various cell lines, and developed a mathematical model to simulate the experimental outcomes. An analysis of the cell-parasite mechanisms included in the model, together with the parameter values that allowed it to replicate the experimental results, suggests that a process related to the cell replication rate may strongly influence the parasite invasion efficiency, and the infection dynamics in general.


An evaluation of the periapical status of teeth with necrotic pulps using periapical radiography and cone-beam computed tomography.
To evaluate the presence or absence of periapical (PA) radiolucencies on individual roots of teeth with necrotic pulps, as assessed with digital PA radiographs and cone-beam computed tomography (CBCT). Digital PA radiographs and CBCT scans were taken from 161 endodontically untreated teeth (from 155 patients) diagnosed with non-vital pulps (pulp necrosis with normal PA tissue, symptomatic apical periodontitis, asymptomatic apical periodontitis, acute apical abscess and chronic apical abscess). Images were assessed by two calibrated endodontists to analyse the radiographic PA status of the teeth. A consensus was reached in the event of any disagreement. The data were analysed using a McNemar's test, and significance was set at P ≤ 0.05. Three hundred and forty paired images of roots were assessed with both digital PA radiographs and CBCT images. Fifteen additional roots were identified with CBCT. PA radiolucencies were present in 132 (38.8%) roots when assessed with PA radiographs, and in 196 (57.6%) roots when assessed with CBCT. This difference was statistically significant (P < 0.05). In teeth diagnosed with pulp necrosis, symptomatic apical periodontitis or acute apical abscess, CBCT images revealed a statistically larger number of PA radiolucencies than did PA radiographs (P < 0.05). No statistical differences were observed between PA radiographs and CBCT in teeth classified with asymptomatic apical periodontitis (P = 0.31) or chronic apical abscess (P = 1). Unlike PA radiographs, CBCT revealed a higher prevalence of PA radiolucencies when endodontically untreated teeth with non-vital pulps were examined.


[Evaluation of drug-drug interactions between yimitasvir phosphate capsules with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets].
Objective: To evaluate the drug-drug interactions and the tolerability of combined medication between yimitasvir phosphate capsules with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets in healthy volunteers. Methods: A randomized, open, and continuous administration design was used in trial 1 (yimitasvir phosphate capsules with sofosbuvir tablets). 28 subjects were randomly divided into two groups. A non-randomized, open design was used in trial 2 (yimitasvir phosphate capsules with omeprazole magnesium enteric-coated tablets), and included 42 subjects divided into three groups. The open design method was used in trial 3 (yimitasvir phosphate capsules with rosuvastatin calcium tablets), and included 14 subjects. The plasma concentrations of yimitasvir phosphate, sofosbuvir and their main metabolites GS-331007, omeprazole and rosuvastatin were validated by a liquid chromatography/tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated by Phoenix winNonlin software. Results: (1) in trial 1, after single and co-administration, the 90% CI of sofosbuvir C(max) and AUC(0-tau) geometric mean ratio (GMR) were 152.0% (118.0% ~ 197.0%) and 230.0% (184.0% ~ 287.0%), with an increase of 52.0% and 130.0% compared to single dose of sofosbuvir, respectively. The 90% CI of GS-331007 C(max) GMR was 74.0% (67.5% ~ 81.2%) and reduced by 26% compared to single dose of sofosbuvir. (2) in trial 2, the 90% CI of C(max) GMR after yimitasvir single or co-administration at the same time, with a 4-hours interval, or with a 12- hours interval were 68.9% (44.5% ~ 106.7%) , 64.0% (43.8% ~ 93.6%) and 56.4%(38.9% ~ 81.9%), and the 90% CI of AUC(0-t) GMR were 68.6% (46.5% ~ 101.2%), 68.3% (47.6% ~ 98.0%) and 60.5% (41.8% ~ 87.5%), respectively. Compared with single dose of yimitasvir, the C(max) and AUC(0-t) were decreased by 31.1% and 31.4%, 36.0% and 31.7%, 43.6% and 39.5%, respectively. (3) In trial 3, after single and co-administration, the 90% CI of rosuvastatin C(max) and AUC(0-72) GMR were 172.4% (153.6% ~ 193.5%) and 158.0% (144.3% ~ 172.9%), respectively, with an increase of 74.9% and 60.5% compared to single dose of rosuvastatin. There were no serious adverse events and adverse events leading to withdrawal from the trial. Conclusion: Yimitasvir phosphate capsules have drug-drug interactions with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets.


INTerface Builder: A Fast Protein-Protein Interface Reconstruction Tool.
INTerface Builder (INTBuilder) is a fast, easy-to-use program to compute protein-protein interfaces. It is designed to retrieve interfaces from molecular docking software outputs in an empirically determined linear complexity. INTBuilder directly reads the output formats of popular docking programs like ATTRACT, HEX, MAXDo, and ZDOCK, as well as a more generic format and Protein Data Bank (PDB) files. It identifies interacting surfaces at both residue and atom resolutions. INTerface Builder is an open source software written in C and freely available for noncommercial use (CeCILL license) at https://www.lcqb.upmc.fr/INTBuilder .


Analysis of TCRβ and TCRγ genes in Chinese alligator provides insights into the evolution of TCR genes in jawed vertebrates.
All jawed vertebrates have four T cell receptor (TCR) chains that are expressed by thymus-derived lymphocytes and play a major role in animal immune defence. However, few studies have investigated the TCR chains of crocodilians compared with those of birds and mammals, despite their key evolutionary position linking amphibians, reptiles, birds and mammals. Here, employing an Alligator sinensis genomic bacterial artificial chromosome (BAC) library and available genome data, we characterized the genomic organization, evolution and expression of TRB and TRG loci in Alligator sinensis. According to the sequencing data, the Alligator sinensis TRB locus spans approximately 500 Kb of genomic DNA containing two D-J-C clusters and 43 V gene segments and is organized as Vβ(39)-pJβ1-pCβ1-pDβ1-Dβ2- Jβ2(12)-Cβ2-Vβ(4), whereas the TRG locus spans 115 Kb of DNA genomic sequence consisting of 18 V gene segments, nine J gene segments and one C gene segment and is organized in a classical translocon pattern as Vγ(18)-Jγ(9)-Cγ. Moreover, syntenic analysis of TRB and TRG chain loci suggested a high degree of conserved synteny in the genomic regions across mammals, birds and Alligator sinensis. By analysing the cloned TRB/TRG cDNA, we identified the usage pattern of V families in the expressed TRB and TRG. An analysis of the junctions of the recombined VJ revealed the presence of N and P nucleotides in both expressed TRB and TRG sequences. Phylogenetic analysis revealed that TRB and TRG loci possess distinct evolutionary patterns. Most Alligator sinensis V subgroups have closely related orthologues in chicken and duck, and a small number of Alligator sinensis V subgroups have orthologues in mammals, which supports the hypothesis that crocodiles are the closest relatives of birds and mammals. Collectively, these data provide insights into TCR gene evolution in vertebrates and improve our understanding of the Alligator sinensis immune system.


[Mode of antiretroviral treatment based on the medical needs of people living with HIV/AIDS].
To explore and evaluate the model of antiretroviral treatment that oriented to the medical needs of people living with HIV/AIDS (HIV/AIDS), based on the local prevalence of HIV/AIDS. A total of 268 HIV/AIDS were selected the CDC of 13 administrative district in Wuhan from 2012 to 2013 and 275 HIV/AIDS were selected in the hospitals of 13 administrative district in Wuhan from 2013 to 2014. The antiretroviral effect of the two groups was compared and the related factors were analyzed. An antiretroviral treatment network that oriented to the medical needs of HIV/AIDS was developed. Data showed that the adherence of patients was better than that when the treatment was carried out at the CDC offices and the status of immuno-recovery on HIV/AIDS was more effective than the hospital-based treatment (P<0.05). Data from multivariable logistic regression analysis showed that different patterns did play different roles on the effects of treatment. The mode of antiretroviral treatment that oriented to the medical needs of HIV/AIDS could effectively improve the adherence and outcomes of treatment. We believe this model could also be adopted elsewhere.


Ecological contingency in the effects of climatic warming on forest herb communities.
Downscaling from the predictions of general climate models is critical to current strategies for mitigating species loss caused by climate change. A key impediment to this downscaling is that we lack a fully developed understanding of how variation in physical, biological, or land-use characteristics mediates the effects of climate change on ecological communities within regions. We analyzed change in understory herb communities over a 60-y period (1949/1951-2007/2009) in a complex montane landscape (the Siskiyou Mountains, Oregon) where mean temperatures have increased 2 °C since 1948, similar to projections for other terrestrial communities. Our 185 sites included primary and secondary-growth lower montane forests (500-1.200 m above sea level) and primary upper montane to subalpine forests (1,500-2,100 m above sea level). In lower montane forests, regardless of land-use history, we found multiple herb-community changes consistent with an effectively drier climate, including lower mean specific leaf area, lower relative cover by species of northern biogeographic affinity, and greater compositional resemblance to communities in southerly topographic positions. At higher elevations we found qualitatively different and more modest changes, including increases in herbs of northern biogeographic affinity and in forest canopy cover. Our results provide community-level validation of predicted nonlinearities in climate change effects.


An update on the management of latent tuberculosis infection and active disease in patients with chronic kidney disease.
In 2010, the British Thoracic Society published guidelines on the management of tuberculosis (TB) infection and disease in patients with chronic kidney disease (CKD), in response to physicians' concerns about the challenges encountered in treating this complex patient group. Later, in 2010, we summarized the main messages from these guidelines for readers of this journal. The purpose of this review is an update on the current management of latent and active Mycobacterium tuberculosis infection in patients with CKD. Patients with CKD have an increased risk of both infection and disease with Mycobacterium tuberculosis, and practice varies between renal units. Since 2010, the majority of published data have focused on screening for TB infection in immunosuppressed patients, including those with CKD and transplant recipients. While there is currently no perfect screening test, the evidence suggests that we should be using the available interferon‑γ release assays, with or without the tuberculin skin test, to try and reduce the undoubted risk of active TB in these patients. While we are not aware of any new evidence to change the recommended treatment regimens, we have reiterated some of the important recommendations outlined in the original guidelines.