Disruption of brain mitochondrial calcium sequestration by methylmercury.
In vitro effects of methylmercury (MeHg) on Ca2+ transport and respiratory control of mitochondria isolated from rat forebrain were examined to determine whether MeHg disrupted sequestration of Ca2+ by neuronal mitochondria. Uptake of 45Ca2+ by mitochondria and release of 45Ca2+ from preloaded mitochondria were measured in the presence and absence of ATP. Release of 45Ca2+ from preloaded mitochondria by MeHg was measured in the presence and absence of ruthenium red (RR), a putative inhibitor of the mitochondrial Ca2+ uptake uniporter. During incubation intervals ranging from 10 sec to 5 min, 10 microM MeHg reduced mitochondrial uptake of 45Ca2+ by about 50% and 100 microM MeHg completely prevented 45Ca2+ uptake. These effects of MeHg occurred in both the presence and absence of ATP. Exposure of mitochondria preloaded with 45Ca2+ to either 10 microM or 100 microM MeHg for 10 sec resulted in increased efflux of 45Ca2+ of 10% and 65%, respectively, in both the absence and presence of ATP. Loading mitochondria with 45Ca2+ in the presence of 20 microM RR reduced total uptake of 45Ca2+ and greatly attenuated MeHg-induced release of 45Ca2+ from mitochondria. RR did not inhibit the effects of MeHg on Ca2+ release by merely preventing the binding of MeHg to mitochondria because RR did not alter mitochondrial binding of methyl[203Hg]. The ratio of state 3 to state 4 respiration (respiratory control ratio) was measured as a means of assessing functional integrity of isolated mitochondria in the absence and presence of MeHg. Control ratios of from 3 to 5 were only marginally reduced by 2 microM MeHg but were greatly reduced by 10 and 20 microM MeHg.(ABSTRACT TRUNCATED AT 250 WORDS)


Bridging Plant and Human Radiation Response and DNA Repair through an In Silico Approach.
The mechanisms of response to radiation exposure are conserved in plants and animals. The DNA damage response (DDR) pathways are the predominant molecular pathways activated upon exposure to radiation, both in plants and animals. The conserved features of DDR in plants and animals might facilitate interdisciplinary studies that cross traditional boundaries between animal and plant biology in order to expand the collection of biomarkers currently used for radiation exposure monitoring (REM) in environmental and biomedical settings. Genes implicated in trans-kingdom conserved DDR networks often triggered by ionizing radiation (IR) and UV light are deposited into biological databases. In this study, we have applied an innovative approach utilizing data pertinent to plant and human genes from publicly available databases towards the design of a 'plant radiation biodosimeter', that is, a plant and DDR gene-based platform that could serve as a REM reliable biomarker for assessing environmental radiation exposure and associated risk. From our analysis, in addition to REM biomarkers, a significant number of genes, both in human and Arabidopsis thaliana, not yet characterized as DDR, are suggested as possible DNA repair players. Last but not least, we provide an example on the applicability of an Arabidopsis thaliana-based plant system monitoring the role of cancer-related DNA repair genes BRCA1, BARD1 and PARP1 in processing DNA lesions.


Doppler flow velocity measurements during coronary angioplasty.
In addition to further studies using Doppler catheters to assess blood flow velocity during coronary angioplasty this study intends to evaluate the functional significance of coronary stenoses and to estimate their hemodynamic relevance prior to and after percutaneous transluminal coronary angioplasty (PTCA). Diameters of coronary artery stenoses were quantified by means of the cardiovascular angiographic analysis system (CAAS) both prior to and following successful PTCA in 37 patients. During coronary artery angioplasty a 12 M:Hz 0.018-in. Doppler-tipped guidewire was used to measure prestenotic and poststenotic parameters of coronary artery flow velocity both prior to and following PTCA. The minimal stenosis diameter was raised from 1.01 +/- 0.58 to 1.76 +/- 0.73 mm (P < 0.0001), the percent diameter stenosis decreased from 63 +/- 11 to 35 +/- 6% (P < 0.0001). Prestenotic average (APV) and maximum peak velocity (MPV), peak velocity integral (PVI), average systolic (ASPV) and diastolic (ADPV) peak velocity, systolic (SPVI) and diastolic (DPVI) peak velocity integral, and diastolic/systolic velocity ratio showed--in contrast to further studies--a considerably significant difference (P < 0.05), whereas poststenotic Doppler data (APV, MPV, PVI, ASPV, DSPV, SPVI, DPVI, DSVR) differed highly significantly (P < 0.0001) prior to and following PTCA. Prestenotic and poststenotic measurements of coronary artery flow velocity differed significantly before and after PTCA and offer the potential for estimating both the hemodynamic relevance of coronary artery stenoses and success of PTCA.


Design, Synthesis, and Biological Evaluation of Novel Quinazolin-4(3H)-One-Based Histone Deacetylase 6 (HDAC6) Inhibitors for Anticancer Activity.
A series of novel quinazoline-4-(3H)-one derivatives were designed and synthesized as histone deacetylase 6 (HDAC6) inhibitors based on novel quinazoline-4-(3H)-one as the cap group and benzhydroxamic acid as the linker and metal-binding group. A total of 19 novel quinazoline-4-(3H)-one analogues (5a-5s) were obtained. The structures of the target compounds were characterized using 1H-NMR, 13C-NMR, LC-MS, and elemental analyses. Characterized compounds were screened for inhibition against HDAC8 class I, HDAC4 class IIa, and HDAC6 class IIb. Among the compounds tested, 5b proved to be the most potent and selective inhibitor of HDAC6 with an IC50 value 150 nM. Some of these compounds showed potent antiproliferative activity in several tumor cell lines (HCT116, MCF7, and B16). Amongst all the compounds tested for their anticancer effect against cancer cell lines, 5c emerged to be most active against the MCF-7 line with an IC50 of 13.7 μM; it exhibited cell-cycle arrest in the G2 phase, as well as promoted apoptosis. Additionally, we noted a significant reduction in the colony-forming capability of cancer cells in the presence of 5c. At the intracellular level, selective inhibition of HDAC6 was enumerated by monitoring the acetylation of α-tubulin with a limited effect on acetyl-H3. Importantly, the obtained results suggested a potent effect of 5c at sub-micromolar concentrations as compared to the other molecules as HDAC6 inhibitors in vitro.


Reliable measurement of the receding contact angle.
Surface wettability is usually evaluated by the contact angle between the perimeter of a water drop and the surface. However, this single measurement is not enough for proper characterization, and the so-called advancing and receding contact angles also need to be measured. Measuring the receding contact angle can be challenging, especially for extremely hydrophobic surfaces. We demonstrate a reliable procedure by using the common needle-in-the-sessile-drop method. Generally, the contact line movement needs to be followed, and true receding movement has to be distinguished from "pseudo-movement" occurring before the receding angle is reached. Depending on the contact angle hysteresis, the initial size of the drop may need to be surprisingly large to achieve a reliable result. Although our motivation for this work was the characterization of superhydrophobic surfaces, we also show that this method works universally ranging from hydrophilic to superhydrophobic surfaces.


Large-scale synthesis and photoluminescence properties of aligned multicore SiC-SiO2 nanocables.
By using a simple and low-cost microwave method, aligned multicore SiC-SiO2 nanocables have been successfully synthesized on a large scale. The composition and structural features of the products were characterized by X-ray diffraction, scanning electron microscopy, and transmission electron microscopy. The results revealed that each of the nanocables was composed of several 3C-SiC nanowires encapsulated in a single amorphous SiO2 shell. The cores were 10-50 nm in diameter and up to hundreds of microns in length. The photoluminescence properties of the nanocables were studied, and strong violet blue light emission was observed at wavelengths of about 339 and 390 nm under 325-nm excitation. The origin of the photoluminescence from the nanocables can be attributed to the central SiC nanowires and defects in silicon oxide or the SiC/SiO2 interface boundary. Based on experimental characterizations, an oxide-assisted vapor-liquid-solid (VLS) growth mechanism was used to elucidate the growth process of the multicore SiC-SiO2 nanocables.


Anxiety and depression in paradoxical insomnia: a case-control study.
To compare anxiety and depression among patients with paradoxical insomnia (Para-I), patients with psychophysiological insomnia (Psy-I), and normal sleepers (NS). A cross-sectional case-control study was conducted in patients with Para-I (n=63), patients with Psy-I (n=63), and NS (n=63) from southwest China. The three groups were matched for age (mean age: 42.0±10.30 years), gender (per group: male =22; female =41), educational level, and nature of occupation. Anxiety and depression were evaluated using the Self-Rating Anxiety Scale and Self-Rating Depression Scale and compared among the groups. Concerning anxiety, patients with Para-I had a significantly higher mean Self-Rating Anxiety Scale score (P<0.05) and significantly higher incidence of anxiety compared to NS (P<0.0167). There were no significant differences between the two insomnia groups on anxiety measures. Concerning depression, patients with Para-I had a significantly higher mean Self-Rating Depression Scale score than patients with Psy-I and NS (both, P<0.05), as well as a significantly higher incidence of moderate to severe depression than in the Psy-I group and NS (both, P<0.0167). Both Psy-I and Para-I patients had significantly higher anxiety and depression than NS. Compared to Psy-I, Para-I patients had slightly (but not significantly) lower anxiety and significantly higher depression.


Exertional-induced bronchoconstriction: comparison between cardiopulmonary exercise test and methacholine challenging test.
Exertional-induced bronchoconstriction is a condition in which the physical activity causes constriction of airways in patients with airway hyper- responsiveness. In this study, we tried to study and evaluate any relationship between the findings of cardiopulmonary exercise testing (CPET) and the response to methacholine challenge test (MCT) in patients with dyspnea after activity. Thirty patients with complaints of dyspnea following activity referred to "Lung Clinic" of Baqiyatallah Hospital but not suffering from asthma were entered into the study. The subjects were excluded from the study if: Suffering from any other pulmonary diseases, smoking more than 1 cigarette a week in the last year, having a history of smoking more than 10 packets of cigarettes/year, having respiratory infection in the past 4 weeks, having abnormal chest X-ray or electrocardiogram, and cannot discontinue the use of medicines interfering with bronchial provocation. Baseline spirometry was performed for all the patients, and the values of forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC), and FEV/FVC were recorded. The MCT and then the CPET were performed on all patients. The mean VO 2 (volume oxygen) in patients with positive methacholine test (20.45 mL/kg/min) was significantly lower than patients with negative MCT (28.69 mL/kg/min) (P = 0.000). Respiratory rates per minute (RR) and minute ventilation in the group with positive MCT (38.85 and 1.636 L) were significantly lower than the group with negative methacholine test (46.78 and 2.114 L) (P < 0.05). Also, the O 2 pulse rate in the group with negative methacholine test (116.27 mL/beat) was significantly higher than the group with positive methacholine test (84.26 mL/beat) (P < 0.001). Pulmonary response to exercise in patients with positive methacholine test is insufficient. The dead space ventilation in these patients has increased. Also, dynamic hyperinflation in patients with positive methacholine test causes the reduced stroke volume and O 2 pulse in these patients.


Computer simulation of macroion layering in a wedge film.
The layering of macroions confined to a wedge slit formed by two uncharged hard walls is studied using a canonical Monte Carlo method combined with a simulation cell that contains both wedge-shaped slit and bath regions. The macroion solution is modeled within a one-component fluid approach that in an effective way incorporates the double layer repulsion due to simple electrolyte ions as well as the discrete nature of an aqueous solvent. The layer formation under a wedge confinement is analyzed by carrying out separate simulation runs for a set of consecutive wedge segments designed to represent a single wedge slit. As the wedge thickness progressively increases, the sequence of regions along the wedge film with distinct features of macroion layering has been established. This sequence comprises (i) a wedge region of the thickness smaller than the macroion diameter that is free of macroions; (ii) a region with a one-dimensional macroion chain along the wedge corner at a wedge thickness of a one macroion diameter; (iii) a region comprising a low-ordered macroion monolayer that extends until the wedge thickness slightly above two macroion diameters; (iv) a region comprising a pair of well-defined two-dimensional configurations of macroions segregated on each of the wedge walls; and (v) a free-of-macroions wedge region between two surface monolayers that now originates from an electrostatic repulsion imposed by the surface macroions, which is followed by (vi) a well-defined macroion monolayer film between two surface monolayers, a less defined bilayer film, a three-layer film, and so on up to the bulk solution. Once formed, the macroion surface monolayers persist for all remaining wedge thicknesses up to the bulk, forming in such a way effective charged wedge boundaries. Such a formation of the macroion surface monolayers on the uncharged confining walls is related to the haloing mechanism for regulating the stability in colloidal suspensions [Tohver et al. Proc. Natl. Acad. Sci. U.S.A. 2001, 98, 8951] and is discussed as well. Finally, the estimated boundary of the free of macroion region between surface monolayers correlates well with the location of the boundary of the so-called "vacuum" phase that has been observed experimentally in an aqueous suspension of charged polystyrene spheres bounded by electrostatically repulsive glass walls [Pieransky et al. Phys. Rev. Lett. 1983, 50, 900].


Factors contributing to carbamazepine-macrolide interactions.
Certain macrolides (e.g. clarithromycin or erythromycin) are known to interact with the carbamazepine antiepileptic drug. Carbamazepine-macrolide interaction leads to an increase in the level of carbamazepine in the blood, so inducing carbamazepine toxicity. The aim of this paper is to compare the extent of the interaction for each macrolide and to study the effects of age, gender, weight, the carbamazepine and macrolide dosages and the use of other antiepileptic drugs on the extent of the carbamazepine-macrolide interaction. Case reports published in the literature were reviewed and analysed to this end. The results show that three macrolides (erythromycin, troleandomycin and, to a lesser extent, clarithromycin) may induce carbamazepine toxicity in clinical practice. Furthermore, it was observed that high dosages of carbamazepine or macrolides and the use of concurrent anticonvulsivant drugs in the case of patients below 60 years of age are associated with the highest carbamazepine levels in carbamazepine-macrolide interactions. This study should help physicians choose a macrolide that does not interact with carbamazepine and evaluate the risk of an interaction between carbamazepine and macrolides.


Author's reply to 'Rickettsia retinitis cases in India: a few comments'.
Diagnosis of rickettsial retinitis remains presumptive when gold standard tests are not available or not done due to financial constrains. History of tick bite followed by fever with skin rash particularly in winter and spring season may point towards Rickettsiosis. The absence of scarring post resolution of rickettsial retinitis suggests inner retinal involvement in contrast to toxoplasmosis. Bilaterality of the disease, 2-4 weeks of latent period, and multifocal nature of retinitis lesions (cotton wool spot-like lesions) especially around the disc and posterior pole may suggest an immune response to recent systemic infection. The use of only antibiotics or only steroids or both together for treatment of rickettsial retinitis is controversial and warrants randomized controlled trials.


Endoscopic ultrasonography-guided portal injection chemotherapy for hepatic metastases.
We hypothesized that endoscopic ultrasonography-guided portal injection chemotherapy (EPIC) using irinotecan-loaded microbeads may achieve increased intrahepatic concentrations, while decreasing systemic exposure. This may achieve enhanced efficacy for the treatment of diffuse liver metastases, while decreasing systemic toxicities. In eight anesthetized 35 kg pigs, EPIC was performed transgastrically using the linear-array echoendoscope and a 22 g fine-needle aspiration. In four animals, irinotecan (100 mg) loaded onto 75-150 micron liquid chromatography (LC) beads was injected. In four animals, saline was injected into the portal vein and unloaded irinotecan (100 mg) was injected into the jugular vein. Plasma (every 15 min), and at 1 h bone marrow, liver and skeletal muscle samples were obtained. Irinotecan and SN-38 (active metabolite) concentrations were assayed by LC/mass spectrometry. The procedure was performed safely in all eight animals. Compared with systemic administration, EPIC resulted in almost twice the hepatic concentration of irinotecan (6242 vs. 3692 ng/g) and half the systemic concentrations in plasma (1092 vs. 2762 ng/mL), bone marrow (815 vs. 1703 ng/mL) and skeletal muscle (521 vs. 1058 ng/g). SN-38 levels were lower with EPIC (liver: 166 vs. 681 ng/g; plasma: 1.8 vs. 2.4 ng/mL; bone marrow: 0.9 vs. 1.4 ng/mL; muscle 4.6 vs. 9.2 ng/g). Liver histology showed the beads within small portal venules. EPIC using irinotecan-loaded microbeads can enhance hepatic exposure to irinotecan, while decreasing systemic concentrations. SN-38 levels were lower with EPIC indicating that a substantial portion of the irinotecan was still loaded onto beads. The microbeads may act as a reservoir resulting in prolonged hepatic drug exposure.


Nucleophilic substitution reactions of the tricyclic triphosphorus cage P3(CBu(t))2: a novel route to polyphosphorus phosphenium complexes.
Substitution of Cl(-) in the tricyclic triphosphorus cage Cl(P(1))-P3(CBu(t))2 by a range of both anionic and neutral nucleophiles has been investigated. With anionic nucleophiles, reaction with fluoride and hydride anion was shown to afford F(P(1))-P3(CBu(t)) and H(P(1))-P3(CBu(t))2 respectively. Subsequent deprotonation of the latter results in the formation of the aromatic anion [1,2,4-P3(CBu(t))2]-. With neutral nucleophiles, addition of either PMe3 or PEt3 to Cl(P(1))-P3(CBu(t))2 in the presence of TlOTf results in the formation of the phosphine-phosphenium complexes [(R3P(P(1))-P3(CBu(t))2][OTf] (R = Me or Et): the structure of the methyl-substituted compound was determined by a single crystal X-ray diffraction study. The phosphine ligand in these complexes is extremely labile and addition of I2 to [(Me3P(P(1))-P3(CBu(t))2]+ results in the formation of I(P(1))-P3(CBu(t))2.


Burden of hypoxia and intraventricular haemorrhage in extremely preterm infants.
Thresholds of cerebral hypoxia through monitoring of near-infrared spectroscopy tissue oxygenation index (TOI) were used to investigate the relationship between intraventricular haemorrhage (IVH) and indices of hypoxia. Prospective observational study. A single-centre neonatal intensive care unit. Infants <28 weeks' gestation with an umbilical artery catheter. Thresholds of hypoxia were determined from mean values of TOI using sequential Χ2 tests and used alongside thresholds from existing literature to calculate percentage of time in hypoxia and burden of hypoxia below each threshold. These indices were then compared between IVH groups. 44 infants were studied for a median of 18.5 (range 6-21) hours in the first 24 hours of life. Sequential Χ2 analysis yielded a TOI threshold of 71% to differentiate between IVH (16 infants) and no IVH (28 infants). Percentage of time in hypoxia was significantly higher in infants with IVH than those without, using thresholds of 60%-67%. Burden of hypoxia was significantly higher in infants with IVH than without, using thresholds of 62%-80%. With the threshold of 71%, percentage of time in hypoxia was lower by 12.2% with a 95% CI of (-25.7 to 1.2) (p=0.073), and the burden of hypoxia was lower by 29.2% hour (%h) (95% CI -55.2 to -3.1)%h (p=0.012) in infants without IVH than those with IVH. Using defined TOI thresholds, infants with IVH spent higher percentage of time in hypoxia with higher burden of cerebral hypoxia than those without, in the first 24 hours of life.


[Strategy for the formation of human resources in biomedical basic sciences].
The author describes the strategy followed in the Higher Institute of Medical Sciences of Havana for manpower training in basic biomedical sciences. This strategy is based on the Government's general policy for scientific development, and has resulted in the establishment of a network of centers of higher education and research institutes employing more than 3,800 professional and technical staff. Four-year specialization courses have been devised for physicians and dentists, and master's programs for which nonmedical professionals may apply. A system for the obtaining of scientific degrees has been structured together with an extensive program of graduate courses and training. The author comments on the excellent results obtained from the planned, efficient use of bilateral agreements with institutions in other countries and of the possibilities for training and qualification of specialists, the experience in which has already been offered to less developed countries.


The C2H2 zinc finger genes of Strongylocentrotus purpuratus and their expression in embryonic development.
The C2H2 zinc finger is one of the most abundant protein domains and is thought to have been extensively replicated in diverse animal clades. Some well-studied proteins that contain this domain are transcriptional regulators. As part of an attempt to delineate all transcription factors encoded in the Strongylocentrotus purpuratus genome, we identified the C2H2 zinc finger genes indicated in the sequence, and examined their involvement in embryonic development. We found 377 zinc finger genes in the sea urchin genome, about half the number found in mice or humans. Their expression was measured by quantitative PCR. Up to the end of gastrulation less than a third of these genes is expressed, and about 75% of the expressed genes are maternal; both parameters distinguish these from all other classes of regulatory genes as measured in other studies. Spatial expression pattern was determined by whole mount in situ hybridization for 43 genes transcribed at a sufficient level, and localized expression was observed in diverse embryonic tissues. These genes may execute important regulatory functions in development. However, the functional meaning of the majority of this large gene family remains undefined.


New formulations of amoxicillin/clavulanic acid: a pharmacokinetic and pharmacodynamic review.
The pharmacokinetic properties of amoxicillin and clavulanic acid when used alone or in combination are extensively reviewed and discussed in this article. The reported data support a nonlinear absorption process for amoxicillin. Saturable transport mechanisms, limited solubility and the existence of an absorption window are possibly involved in the gastrointestinal absorption of this antibacterial, all leading to a decrease in the peak plasma concentration (Cmax)/dose ratio, a prolongation of the time to reach Cmax, and broad variability for high doses of amoxicillin. Data available in the literature also suggest a possible interaction between amoxicillin and clavulanic acid that might decrease the absolute bioavailability of clavulanic acid. In the present review the intrinsic pharmacodynamics of each drug, together with the synergism produced by the amoxicillin/clavulanic acid association, are also reviewed and analysed. Not only beta-lactamase-producing strains, but also Streptococcus pneumoniae strains, seem to be more efficiently eradicated by the association of amoxicillin and clavulanic acid, and a relevant post-antibacterial effect and post-beta-lactamase inhibitor effect are likely to operate when amoxicillin is administered together with clavulanic acid. The principles of pharmacokinetic/pharmacodynamic analysis applied to amoxicillin are reviewed, with special emphasis being placed on the results obtained from in vitro studies and animal models regarding the new pharmacokinetically enhanced formulation. Theoretical considerations concerning the efficacy of this formulation provided by the application of pharmacokinetic/pharmacodynamic analysis to the scarce pharmacokinetic data available are also included. The broad pharmacokinetic variability of both amoxicillin and clavulanic acid, particularly when administered together and at high doses of amoxicillin, is highlighted and the interest in considering this aspect to improve predictions based on pharmacokinetic/pharmacodynamic analyses for the new formulations is indicated. Methodological recommendations such as the Monte Carlo simulation are proposed in order to obtain more realistic predictions in clinical practice.


[The effect of ultraviolet B on interleukin-8 secretion in human keratinocyte cell line].
To investigate the effect of ultraviolet B (UVB) on Interleukin-8 secretion in human keratinocyte cell line. The concentration of IL-8 was detected by ELISA kit 24 h after human keratinocytes (HKC) were irradiated by different doses of UVB, and the level of IL-8 was also determined at different times after the same dose of UVB irradiation. The secretion of IL-8 was increased after the HKC were irradiated by UVB, the effect was dose-dependent when UVB ranged from 10 to 40 mJ/cm2, and there was statistically significant difference between the IL-8 level of UVB groups (20-70 mJ/cm2) and the control (0 mJ/cm2) (P<0.01). The level of IL-8 was increased 1 h after the irradiation of 30 mJ/cm2 UVB, and it reached the peak at 12 h. There was statistically significant difference between the IL-8 levels detected at different times (3 h, 6 h, 12 h, 24 h after irradiation) and that at 0 h (P<0.01). UVB increase the secretion of IL-8, and the effect is dose-dependent to some extent.


[Treatment of ovarian cysts by laparoscopy].
to define limits, risks and results in the long term of laparoscopic treatment of ovarian tumors. retrospective study of adnexal tumors managed initially by laparoscopy from January 1986 to December 1992, among which 9 cancers, 25 borderline tumors, and 769 benign lesions. The ultrasonographic appearance was known for 698 of 803 lesions. 86 patients were postmenopausal (92 lesions). we treated 191 functional cysts, 160 serous cystadenomas, 178 endometriomas, 105 dermoid cysts, 39 mucinous cystadenomas and 96 miscellaneous lesions among which fibrothecomas, paraadnexal cysts, ovarian pregnancies, ovarian abscess. There is a great diversity of ultrasonographic patterns for a same histological type, specially for functional cysts and borderline tumors. Laparoscopic exploration has misdiagnosed two cancers and 10 borderline tumors and considered wrongly as suspects 19 benign lesions. 714 procedures have been led to term by laparoscopy, 89 have been ended by laparotomy, 26 for suspicion of malignancy and 50 for dissection failure. 27 postoperative complications have been counted among which 2 grafts on trocard sites after non protected extraction of one dermoid cyst and one borderline tumor. ultrasonographic appearance could not predict reliably the organic or functional nor benign or malignant character of an adnexal mass. Even careful laparoscopic examination can underestimate early stage ovarian cancer or borderline tumors. When diagnosed during or after laparoscopic procedure an ovarian cancer should always be managed by laparotomy. On the other hand, some borderline tumors can be treated by exclusive laparoscopy. When malignancy is suspected, an adnexectomy can be performed laparoscopically as a biopsy and allows a quick and appropriate treatment after paraffin-embedded sections. Both intraperitoneal and transparietal techniques have a minimal morbidity and allow a feasibility of more than 90%. The management of postmenopausal ovarian tumors differs only by the use of systematic oophorectomy if surgical procedure is indicated.


Novel hybrid composite discharge electrode for electrostatic precipitator.
Over the last few decades, electrostatic precipitators (ESPs) have emerged as effective air pollution control devices for treating coal-fired power plant exhausts. Among the components of the ESP, the discharge electrodes are extremely important in determining the collection efficiency of the ESP. Typically, in wet ESPs, the discharge electrodes used must be made of corrosion-resistant alloys, which makes them extremely expensive and heavy. Hybrid composite discharge electrodes have the potential to be lightweight and corrosion-resistant substitute for traditional metal alloy electrodes used in wet ESPs. In this experimental study, a novel hybrid composite electrode (recently patented at Ohio University) is presented as a substitute for traditional metal electrodes in wet ESPs. The samples of hybrid electrodes were fabricated by using carbon fiber composites, combined with metal mesh, in the shape of a long and thin tape. The electrode's electrical response was evaluated in open atmospheric conditions, while connected to a transformer-rectifier unit to generate a corona current at voltages exceeding 50 kV. Results of these hybrid electrodes were compared with traditional metal electrodes. The hybrid composite discharge electrode produced a uniform corona at comparable power levels to that of metal electrodes, with additional advantages of being compact, lightweight, and highly corrosion resistant. In addition, hybrid composite electrodes exhibited lower corona onset voltage as compared with metal electrodes. The preliminary experimental data are encouraging and show significant potential for this new inexpensive hybrid electrode to replace metal electrodes in wet ESPs, providing comparable (and in some cases exceeding) collection efficiencies with lower ozone generation. The newly invented hybrid composite electrode (HCE) performance was evaluated through experimentation with conventional metal electrodes. The HCE performance was comparable to the metal electrodes. The HCE also exhibited uniform corona fields and steady power while maintaining similar and in some cases superior electrical performance as compared with metal electrodes and thus shows a significant potential to substitute metal electrodes in wet ESP systems.


[Role of Autoantibodies Against 1-Adrenergic Receptor in Cardiovascular Disease].
According to current knowledge, autoantibodies against 1-adrenergic receptors may be involved in pathogenesis of different cardiovascular diseases and are mostly studied in patients with Chagas disease, dilated cardiomyopathy and heart rhythm disorders. They may play an important role in cardiomyocyte apoptosis, alteration of their chrono- and inotropic effects and electrophysiological characteristics. Their effects are transduced via 1-adrenergic receptors and depend on multiple factors as ligand properties, durability of its coupling with the receptor, amount of receptors on the cell surface, their affinity and conformation. Up to the present moment, reasons for autoimmune response and clinical significance of autoantibodies against 1-adrenergic receptors are not thoroughly understood. Autoantibodies against 1-adrenergic receptors can be removed from the bloodstream by immunoadsorption and thus development of validated methods of their identification is relevant.


Effect of longer-term modest salt reduction on blood pressure.
Many randomised trials assessing the effect of salt reduction on blood pressure show reduction in blood pressure in individuals with high blood pressure. However, there is controversy about the magnitude and the clinical significance of the fall in blood pressure in individuals with normal blood pressure. Several meta-analyses of randomised salt reduction trials have been published in the last few years. However, most of these included trials of very short duration (e.g. 5 days) and included trials with salt loading followed by salt deprivation (e.g. from 20 to 1 g/day) over only a few days. These short-term experiments are not appropriate to inform public health policy which is for a modest reduction in salt intake over a prolonged period of time. A meta-analysis by Hooper et al is an important attempt to look at whether advice to achieve a long-term salt reduction (i.e. more than 6 months) in randomised trials causes a fall in blood pressure. However, most trials included in this meta-analysis achieved a small reduction in salt intake; on average, salt intake was reduced by 2 g/day. It is, therefore, not surprising that this analysis showed a small fall in blood pressure, and that a dose-response to salt reduction was not demonstrable. To assess the effect of the currently recommended modest reduction in salt intake (WHO 2003; SACN 2003; Whelton 2002), on blood pressure in individuals with normal and elevated blood pressure. To assess whether the magnitude of the reduction in blood pressure is dependent on the magnitude of the reduction in salt intake. We searched MEDLINE, EMBASE, Cochrane library, CINAHL, and reference list of original and review articles. We included randomised trials with a modest reduction in salt intake and a duration of 4 or more weeks. Data were extracted independently by two persons. Mean effect sizes were calculated using both fixed and random effect models using Review Manager 4.2.1 software. Weighted linear regression was used to examine the relationship between the change in urinary sodium and the change in blood pressure. We used funnel plots to detect publication and other biases in the meta-analysis. Seventeen trials in individuals with elevated blood pressure (n=734) and 11 trials in individuals with normal blood pressure (n=2220) were included. In individuals with elevated blood pressure the median reduction in 24-h urinary sodium excretion was 78 mmol (4.6 g/day of salt), the mean reduction in systolic blood pressure was -4.97 mmHg (95%CI:-5.76 to -4.18), and the mean reduction in diastolic blood pressure was -2.74 mmHg (95% CI:-3.22 to -2.26). In individuals with normal blood pressure the median reduction in 24-h urinary sodium excretion was 74 mmol (4.4 g/day of salt), the mean reduction in systolic blood pressure was -2.03 mmHg (95% CI: -2.56 to -1.50) mmHg, and the mean reduction in diastolic blood pressure was -0.99 mmHg (-1.40 to -0.57). Weighted linear regression analyses showed a correlation between the reduction in urinary sodium and the reduction in blood pressure. Our meta-analysis demonstrates that a modest reduction in salt intake for a duration of 4 or more weeks has a significant and, from a population viewpoint, important effect on blood pressure in both individuals with normal and elevated blood pressure. These results support other evidence suggesting that a modest and long-term reduction in population salt intake could reduce strokes, heart attacks, and heart failure. Furthermore, our meta-analysis demonstrates a correlation between the magnitude of salt reduction and the magnitude of blood pressure reduction. Within the daily intake range of 3 to 12 g/day, the lower the salt intake achieved, the lower the blood pressure.


Dual fluorescence of graphene oxide: a time-resolved study.
The fluorescence properties of graphene oxide (GO) was studied by recording the fluorescence lifetime, fluorescence emission, and excitation spectra, as well as UV-visible and near-IR absorption spectra. For the first time, we showed that a blue band (ca. 440 nm) and a long wavelength (LW) band (ca. 700 nm) are coexistent, which can be recorded simultaneously by controlling concentration, excitation wavelength, and pH values. Two bands are closely related by the protonation or deprotonation of GO. The blue band is favored by low GO concentration, short excitation wavelength, and high pH value, while the LW band is favored by low pH and long excitation wavelength. To reveal the nature of the dual emission of GO, the fluorescence lifetimes under various conditions were also measured. The blue band contains three emitting components; one of them has a lifetime as long as 10 ns, and its emitting intensity is fairly sensitive to pH, showing the potential for applications in sensing H(+) and fluorescence lifetime imaging. Combining the results under various conditions, we conclude that the electronic transition for this component is very likely due to n-π* transition. The LW band contains two main emitting components (0.2 and 2.1 ns) that also appear in the blue band as minor contributors; the related emission is assigned to π-π* transition. In summary, GO emission is of broadband (300-1250 nm), long-lived, pH sensitive, and excitation wavelength dependent. This makes it easily tailored for versatile applications.


Primary Peritoneal High-grade Serous Carcinoma Misinterpreted as Metastatic Breast Carcinoma: A Rare Encounter in Peritoneal Fluid Cytology.
Peritoneal fluid (PF) cytology is critical for distinguishing high-grade serous carcinoma (HGSC) from metastatic disease in patients with breast carcinoma who present with peritoneal carcinomatosis (PC). A 50-year-old woman underwent surgery and adjuvant therapy for pT1N0 grade 2/2 luminal A breast carcinoma. Sixteen months postoperatively, palliative chemotherapy was administered following a pleural biopsy and diagnosis of metastatic carcinoma. The patient developed PC despite chemotherapy. PF cytology specimens suggested metastatic carcinoma. However, we observed a papillary cellular arrangement during the review of cytology slides. HGSC was confirmed by immunocytochemistry showing positive paired box 8 (PAX8) and Wilms' tumor 1 (WT1) expression and negative GATA-binding protein 3 expression. In patients with breast carcinoma history, an awareness of characteristic cytomorphology of HGSC, including a papillary pattern with positive PAX8 and WT1 immunoreactivity, is essential to prevent the misdiagnosis of such cases and in ensuring accurate treatment and management.


Retinal vascular alterations in reticular pseudodrusen with and without outer retinal atrophy assessed by optical coherence tomography angiography.
To investigate the intraretinal structural and vascular alterations in patients featuring reticular pseudodrusen (RPD), RPD with outer retinal atrophy (ORA), and drusen. Observational cross-sectional study. Clinical practice study including 68 eyes of 57 patients (22 eyes of 17 patients with RPD; 24 eyes of 21 patients with RPD+ORA; 22 eyes of 19 patients with drusen). Each patient underwent spectral-domain optical coherence tomography (OCT) and OCT angiography (OCT-A). Measurement of retinal layers' thickness was obtained by the automated segmentation protocol of the Spectralis OCT (Heidelberg Eye Explorer V.18.104.22.168). The superficial capillary plexus (SCP) and the deep capillary plexus (DCP) vessel density, as well as the size of the foveal avascular zone were calculated on 3×3 OCT-A. Main outcome was to compare vessel density at the SCP and DCP among the groups and controls. At the SCP, the vessel density was lower in RPD and RPD+ORA patients with respect to controls (P=0.02 and P=0.003, respectively). At the DCP, meaningful disparity was found between the study groups and the healthy subjects in the vessel density (P<0.001, P=0.04 and P=0.001 for RPD, RDP+ORA and drusen, respectively). The ganglion cell layer (GCL) was thinner in all patients affected either by RPD, RPD+ORA or drusen compared with healthy subjects (P=0.02, P=0.03 and P=0.004, respectively). Significant retinal vascular loss is a common feature of patients with non-exudative age-related macular degeneration, more pronounced in those featuring RPD and RPD+ORA. It is associated with retinal thinning, localised particularly at the GCL, compared with controls.


[Clinical trial of coenzyme A in hepatopathies].
Coenzyme A (900 L.U. i.v.) was administered for 20 days in 18 cases of viral hepatitis, 2 of chronic ethylic hepatosis, and 5 of ascitic portal cirrhosis. Blood lactic acid, pyruvic acid, serum transaminase and beta/alpha lipoprotein ratio were determined. BSF and colloidal serolability tests were also carried out. The benefits of coenzyme A treatment were particularly indicated by the significant changes noted in lactic and pyruvic acid values.


Systemic Treatment-Decision Algorithms in Muscle-Invasive Bladder Cancer: Clinical Complexities and Navigating for Improved Outcomes.
Muscle-invasive bladder cancer has poor prognosis. If organ confined, it is potentially curable; however, across all prognostic groups, approximately half of patients will relapse. For patients with advanced disease, the median overall survival remains under two years. Systemic treatment options are centered on the use of platinum-based combination chemotherapy, with the choice of cisplatin- or carboplatin-based regimens determined on the basis of criteria including performance status and renal function. PD-1/PD-L1 checkpoint-directed immunotherapy has been established for use in advanced disease with modest overall improvements in survival outcomes. Based on current data, optimal utilization appears to be a switch maintenance strategy on completion of chemotherapy. In the curative setting, cisplatin-based chemotherapy provides modest improvements in cure rates in those fit to receive it. Data on the use of adjuvant immunotherapy are currently contradictory, with disease-free survival demonstrated for adjuvant nivolumab, but not atezolizumab, and no overall survival benefit has yet been confirmed. The Nectin-4 directed antibody drug conjugate enfortumab vedotin is an established treatment option for patients previously treated with both chemotherapy and immunotherapy. The emerging therapeutic targets under evaluation include Trop-2 with sacituzumab govitecan, fibroblast growth factor receptors, HER2, and DNA repair deficiency in biomarker-selected patients. The development of properly validated predictive biomarkers has proven challenging for this disease and should be a central priority in the future development of treatment options. This review summarizes the available systemic treatment options in both palliative and curative disease settings, and highlights the available evidence and current limitations for making treatment recommendations.


The effect of wheat bran fiber and calcium supplementation on rectal mucosal proliferation rates in patients with resected adenomatous colorectal polyps.
Colorectal cancers continue as the second most common cause of death from cancer in the United States. Only a few prospective, randomized clinical trials have been performed to evaluate the potential preventive effects of dietary fiber or calcium in patients with an increased risk for the development or recurrence of colorectal cancer. We designed and conducted a double-blinded, placebo-controlled randomized trial involving supplementation of fiber and calcium intake and measurements of [3H]thymidine labeling index (LI) percentages in rectal mucosal biopsies obtained from patients with resected colorectal adenomas to examine the potential mechanisms by which dietary interventions might reduce colorectal cancer risk. We performed a randomized, double-blinded, Phase II study, using a factorial design to measure the effects of supplemental dietary wheat bran fiber (2.0 or 13.5 g/day) and calcium carbonate (250 or 1500 mg/day elemental calcium) supplementation on [3H]thymidine LI percentages in rectal mucosal crypts and 24-h in vitro outgrowth cultures. Measurements were made at baseline randomization (i.e., after a 3-month placebo run-in period using 2.0 g of wheat bran fiber plus 250 mg of calcium carbonate) and after 3 and 9 months on treatment in 100 randomized participants who had a history of colon adenoma resection. Neither the wheat bran fiber nor the calcium carbonate supplements significantly reduced [3H]thymidine LI percentages in rectal mucosal crypts (total or compartmental analysis) or 24-h in vitro outgrowth cultures at either 3 or 9 months of daily supplementation in the 93 evaluable participants. We conclude that 9 months of high-dose wheat bran fiber and calcium carbonate supplementation in study participants with a history of recently resected colorectal adenomas does not have a significant effect on cellular proliferation rates in rectal mucosal biopsies, comparing 3- and 9-month results to baseline results. Ultimately, there is great need for the evaluation of these two different nutrient interventions in the setting of Phase III studies wherein adenomatous polyp recurrence, rather than a rectal mucosal biomarker, serves as the primary end point.


Manipulation of oil synthesis in Nannochloropsis strain NIES-2145 with a phosphorus starvation-inducible promoter from Chlamydomonas reinhardtii.
Microalgae accumulate triacylglycerols (TAGs) under conditions of nutrient stress. Phosphorus (P) starvation induces the accumulation of TAGs, and the cells under P starvation maintain growth through photosynthesis. We recently reported that P starvation-dependent overexpression of type-2 diacylglycerol acyl-CoA acyltransferase (CrDGTT4) from Chlamydomonas reinhardtii using a sulfoquinovosyldiacylglycerol synthase 2 (SQD2) promoter, which has increased activity during P starvation, enhances TAG accumulation in C. reinhardtii cells. As a result, the content of C18:1 fatty acid, a preferred substrate of CrDGTT4, is increased in TAGs. Here we isolated genes encoding SQD2 from strain NIES-2145 of the eustigmatophyte Nannochloropsis and showed that their expression, like that in C. reinhardtii, was up-regulated during P starvation. To enhance oil accumulation under P starvation, we transformed pCrSQD2-CrDGTT4 into Nannochloropsis strain NIES-2145. The transformants had a fatty acid composition that was more similar to that of C. reinhardtii, which resulted in enhanced TAG accumulation and higher 18:1(9) content. The results indicated that the P starvation-inducible promoter of C. reinhardtii was able to drive expression of the CrDGTT4 gene in Nannochloropsis strain NIES-2145 under P starvation. We conclude that the heterologous CrSQD2 promoter is effective in manipulating TAG synthesis in Nannochloropsis during P starvation.


A prevalence study of chronic rhinitis among residents in Telok Blangah Town, Singapore.
A community-based questionnaire survey on a random sample of 562 persons aged seven to 81 years residing in the flatted housing estate of Telok Blangah, Singapore, was studied to determine the prevalence of chronic rhinitis, its associated risk factors and severity of the symptomatology. Chronic rhinitis was defined as the presence of nasal obstruction or clear, watery discharge together with any or both of the following: tearing eyes or sneezing, for a period of more than one month. The overall prevalence was 32.5% with Chinese having the highest ethnic specific rate of 33.9% followed by Indians (27.1%) and Malays (25.4%). The age-specific prevalence rates showed a clear downward trend with increasing age (P < 0.0001). Among the risk factors studied, family history of atopy ranked the highest followed by personal history of atopy and age group (< 30 years and 30 years or more). Most of the chronic rhinitis' symptoms (79%) were graded as not severe.


Targeting ions-induced autophagy in cancer.
Autophagy is an important cellular homeostasis pathway, but its role in cancer remains to be fully elucidated. In this issue of Cancer Cell, Hall and colleagues describe a TRPM3-dependent autophagy pathway that is selectively important for clear cell renal cell carcinoma and can be effectively inhibited.


Drug-induced Nephrotoxicity and Medicinal Plants.
Drug-induced nephrotoxicity is one of the most common causes of acute kidney injury. There are various agents that exert nephrotoxic effects through different pathogenic mechanisms. Aminoglycoside antibiotics, chemotherapeutic agents, radiocontrast media, and nonsteroidal anti-inflammatory drugs are among common nephrotoxic agents. In recent years, natural compounds are being increasingly used in the treatment of kidney diseases. Given many reports available on the curative effects of a variety of medicinal plants against drug-associated nephrotoxicity, we aimed to review the protective effects of medicinal plants on certain nephrotoxic drugs.


Chromosomes and speciation in Mus musculus domesticus.
Thirty years after its identification, the model of chromosomal speciation in Mus musculus domesticus is reevaluated using the methods of population biology, molecular cytogenetics and functional genomics. Three main points are considered: (1) the structural predisposition of M. m. domesticus chromosomes to Robertsonian fusion; (2) the impediment of structural heterozygosity to gene flow between populations of mice with karyotypes rearranged by Robertsonian fusion and between them and populations with the standard all-acrocentric 40-chromosome karyotype; (3) the selective advantage of chromosomal novelty, essential for the attainment of homozygosis and the rapid fixation of the new karyotype in the population.


Is the decreased longevity among left-handers related to an increase in heart disease?
Many studies report that left-handers have a shorter longevity than right-handers, and the present study may provide a possible explanation for that finding. In a Cardiac Rehabilitation Unit for the elderly with a mean age of 75.2 years the prevalence of left-handers was 16.7%. This latter value was significantly different (p = 0.0028) from the 6.7% in controls of similar age. These data suggest that heart disease may be one reason for a reduced longevity among left-handers. Left-handers use the right hemisphere for movement, and unilateral activation of that hemisphere in the form of EEG desynchronization and deactivation in the form of EEG slow waves are both related to cardiac abnormalities.


Probabilistic assessment of contamination using the two-phase flow model.
A physically motivated model is indispensable for a successful analysis of the impact of leaching from nuclear waste storage sites on the environment and public health. While most analyses use the single-phase flow model for modelling unsaturated flow and solute transport, the two-phase flow model considering the resistance of gas to water flow is a more realistic one. The effect of the two-phase flow model on the water content is theoretically investigated first in this study. Then, by combining a geostatistical generator using the turning bands method and a multi-phase transport code TOUGH2, an automatic process is used for Monte Carlo simulation of the solute transport. This stochastic approach is applied to a potentially polluted site by low-level nuclear waste in Taiwan. In the simulation, the saturated hydraulic conductivity is treated as the random variable. The stochastic approach provides a probabilistic assessment of contamination. The results show that even though water content from the two-phase flow model is only 1.5% less than the one from the single-phase flow model, the two-phase flow causes a slower movement but a wider lateral spreading of the plume in the unsaturated zone. The stochastic approach provides useful probability information which is not available from the deterministic approach. The probability assessment of groundwater contamination provides the basis for more informed waste management, better environmental assessment and improved evaluation of impact on public health.


Identification of two Bacillus thuringiensis Cry3Aa toxin-binding aminopeptidase N from Rhynchophorus ferrugineus (Coleoptera: Curculionidae).
Rhynchophorus ferrugineus is a quarantine pest that mainly damages plants in tropical regions, which are essential economic resources. Cry3Aa has been used to control coleopteran pests and is known to be toxic to R. ferrugineus. The binding of the Cry toxin to specific receptors on the target insect plays a crucial role in the toxicological mechanism of Cry toxins. However, in the case of R. ferrugineus, the nature and identity of the receptor proteins involved remain unknown. In the present study, pull-down assays and mass spectrometry were used to identify two proteins of aminopeptidase N proteins (RfAPN2a and RfAPN2b) in the larval midguts of R. ferrugineus. Cry3Aa was able to bind to RfAPN2a (Kd = 108.5 nM) and RfAPN2b (Kd = 68.2 nM), as well as midgut brush border membrane vesicles (Kd = 482.5 nM). In silico analysis of both RfAPN proteins included the signal peptide and anchored sites for glycosyl phosphatidyl inositol. In addition, RfAPN2a and RfAPN2b were expressed in the human embryonic kidney 293T cell line, and cytotoxicity assays showed that the transgenic cells were not susceptible to activated Cry3Aa. Our results show that RfAPN2a and RfAPN2b are Cry3Aa-binding proteins involved in the Cry3Aa toxicity of R. ferrugineus. This study deepens our understanding of the action mechanism of Cry3Aa in R. ferrugineus larvae.


Ezetimibe-Simvastatin Therapy Reduce Recurrent Ischemic Stroke Risks in Type 2 Diabetic Patients.
Statin is the main lipid-lowering therapy for type 2 diabetes mellitus patients. Recent evidence suggested the cardiovascular protective effects of ezetimibe-simvastatin in acute coronary syndrome patients. To investigate the effect of ezetimibe-simvastatin combination therapy on stroke prevention among diabetic stroke patients. Design, Setting, Participants, and Outcome Measures: This is a retrospective cohort study. Between March 1, 2009 and December 31, 2011, all patients with type 2 diabetes mellitus in Taiwan's National Health Insurance Research Database were screened. Those admitted for ischemic stroke (IS) were recruited and divided into 10-mg ezetimibe-20-mg simvastatin (EZ-SIM), 40-mg atorvastatin (ATOR), and 20-mg simvastatin (SIM) groups for further analyses. The primary outcomes were IS, myocardial infarction, and death from any cause. Patients were followed from index hospitalization to the date of death, loss of follow-up, or study termination. During the 34-month follow-up period, the risk of recurrent IS in the SIM group was higher than that of the ATOR (hazard ratio [HR], 2.03; 95% confidence interval [CI], 1.46-2.82) and EZ-SIM (HR, 1.69; 95% CI, 1.14-2.50) groups. The risk of recurrent IS was not significantly lower in the EZ-SIM compared with the ATOR group (HR, 1.20; 95% CI, 0.85-1.69). The incidence of composite endpoint was highest in the SIM group (28.2%), followed by the ATOR (16.1%) and EZ-SIM (15.4%) groups. The multivariate adjusted survival curve showed lower trends of recurrent IS in the EZ-SIM and ATOR groups compared with the SIM group. High-potency lipid-lowering therapy effectively reduces the risk of recurrent IS in diabetic patients regardless of ATOR or EZ-SIM combination therapy.


Unusual Undergraduate Training in Medicinal Chemistry in Collaboration between Academia and Industry.
Globalization has driven new paradigms for drug discovery and development. Activities previously carried out predominantly in the United States, Europe, and Japan are now carried out globally. This has caused considerable change in large pharma including how medicinal chemists are trained. Described here is the training of chemistry undergraduates in medicinal chemistry (as practiced in industry) in two modules developed in collaboration between the University of Nottingham (UoN) and GlaxoSmithKline (GSK). The students complete several design-synthesize-test iterations on medicinal chemistry projects where they carry out the design and synthesis, and GSK tests the compounds. Considerable emphasis is placed on standard design properties used within industry. The modules are popular with the students and usually oversubscribed. An unexpected benefit has been the opportunities that have emerged with research and commercial potential. Graduate and postgraduate training of medicinal chemists at GSK is also briefly described.


Strategies to meet the need for long-term data.
Chronic diseases afflict patients for many years, often to the end of life, and there is increasing need for estimating lifelong risk and for evaluating the effects of treatment in the long term. Yet recommendations for lifelong treatment are most frequently based on findings from randomized clinical trials lasting only a few years. There is therefore a clear need for much longer term data, and here we present the advantages and disadvantages of many strategies, including the use of long-term posttrial follow-up, of long-term prospective cohort studies, registry databases, and of administrative databases. We also emphasize the need for long-term cost-effectiveness studies. One of the most promising strategies comes from linkage of data gathered through the ever-expanding pool of administrative databases worldwide with data from other sources, including randomized trials and the many forms of observational study.


Effects of exon-deleted estrogen receptor beta transcript variants on growth, apoptosis and gene expression of human breast cancer cell lines.
Estrogen receptor beta gene codes for a variety of transcript isoforms resulting from alternative splicing, which are expressed both in mammary gland and in breast cancer cells. We studied the function of two exon-deleted ERbeta isoforms recently identified by our group in comparison to ERbeta1 in regulation of growth, apoptosis and gene expression of two breast cancer cell lines with different ERalpha status. Overexpression of ERbeta1, but not of the exon-deleted variants exerted strong antitumoral effects both on ERalpha-positive MCF-7 and ERalpha-negative SK-BR-3 cells. ERbeta1 overexpression slowed growth of MCF-7 and SK-BR-3 cells in the absence of E2 and also inhibited E2-triggered growth stimulation of MCF-7 cells, but overexpression of the exon-skipped variants did not affect cell growth. Whereas overexpression of ERbeta1 triggered an increased basal and tamoxifen-induced apoptosis of MCF-7 and SK-BR-3 cells, the isoforms ERbetadelta125 or ERbetadelta1256 did not affect cellular tamoxifen response. The observed lack of function of the exon-deleted variants in terms of regulation of proliferation was accompanied both by their inability to affect expression of cyclins D1 and A2, p21 (WAF1) and PR and their disability to modulate estrogen response element (ERE) activation. In contrast, our results demonstrating antitumoral effects of ERbeta1 on breast cancer cells with different ERalpha-status support the hypothesis that ERbeta is able to exert antitumoral actions both on ERalpha-positive and -negative breast cancer cells.


Continuing Education Workshops in Bioinformatics Positively Impact Research and Careers.
Bioinformatics.ca has been hosting continuing education programs in introductory and advanced bioinformatics topics in Canada since 1999 and has trained more than 2,000 participants to date. These workshops have been adapted over the years to keep pace with advances in both science and technology as well as the changing landscape in available learning modalities and the bioinformatics training needs of our audience. Post-workshop surveys have been a mandatory component of each workshop and are used to ensure appropriate adjustments are made to workshops to maximize learning. However, neither bioinformatics.ca nor others offering similar training programs have explored the long-term impact of bioinformatics continuing education training. Bioinformatics.ca recently initiated a look back on the impact its workshops have had on the career trajectories, research outcomes, publications, and collaborations of its participants. Using an anonymous online survey, bioinformatics.ca analyzed responses from those surveyed and discovered its workshops have had a positive impact on collaborations, research, publications, and career progression.


Tailoring vocabularies for NLP in sub-domains: a method to detect unused word sense.
We developed a method to help tailor a comprehensive vocabulary system (e.g. the UMLS) for a sub-domain (e.g. clinical reports) in support of natural language processing (NLP). The method detects unused sense in a sub-domain by comparing the relational neighborhood of a word/term in the vocabulary with the semantic neighborhood of the word/term in the sub-domain. The semantic neighborhood of the word/term in the sub-domain is determined using latent semantic analysis (LSA). We trained and tested the unused sense detection on two clinical text corpora: one contains discharge summaries and the other outpatient visit notes. We were able to detect unused senses with precision from 79% to 87%, recall from 48% to 74%, and an area under receiver operation curve (AUC) of 72% to 87%.


Observation of optical anisotropy and a linear dichroism transition in layered silicon phosphide.
The investigation of in-plane two-dimensional (2D) anisotropic materials has garnered significant attention due to their exceptional electronic, optical, and mechanical characteristics. The anisotropic optical properties and angle-dependent photodetectors based on 2D anisotropic materials have been extensively studied. However, novel in-plane anisotropic materials still need to be explored to satisfy for distinct environments and devices. Here, we report the remarkable anisotropic behavior of excitons and demonstrate a unique linear-dichroism transition of absorption between ultraviolet and visible light in layered silicon phosphide (SiP) through the analysis of polarization photoluminescence (PL) and absorbance spectra. Its high absorption linear dichroism ratio of 1.16 at 388 nm, 1.15 at 532 nm, and 1.19 at 733 nm is revealed, suggesting the brilliant non-isotropic responses. The robust periodic variation of the A1 and A2 Raman modes in 2D SiP materials allows for the determination of their crystal orientation. Furthermore, the presence of indirect excitons with phonon sidebands in the temperature-dependent PL spectra exhibits non-monotonic energy shifts with increasing temperature, which is attributed to an enhanced electron-phonon interaction and thermal expansion. Our findings provide valuable insights into the fundamental physical properties of layered SiP and offer guidelines for designing polarization-sensitive photodetectors and angle-dependent devices based on 2D anisotropic materials.


Effect of coronary vasodilation produced by hypopnea upon regional myocardial oxygen balance.
An attempt was made to differentiate between autoregulatory coronary vasodilation and changes in vasomotor tone produced by factors extrinsic to the heart. this was done by investigating the relation between local cardiac force and local coronary blood supply. Intracellular NADH redox levels were also measured in order to further elucidate the oxygen balance under various experimental conditions. In anaesthetized open-chest dogs, local blood supply was estimated with the aid of a thermistor probe, and the oxidation-reduction state of mitochondrial pyridine nucleotide was measured by a surface fluorometric technique. Local myocardial contractile force, as well as blood pressure and ECG were recorded simultaneously with the above parameters. The heart was paced at frequencies from 60/min to 300/min with an electronic stimulator, under both normoxic and hypopneic conditions. It was found that elevation of heart rate caused a progressive increase in local blood flow during both normal and hypopneic ventilation. The absolute flow values during hypopnea were approximately double those during normoxia. Heart rates above 120/min or 150/min resulted in a progressive increase in NADH fluorescence. This response to elevated heart rate was less prominent or absent during hypopnea. Contractile force during hypopnea was greater at elevated heart rates than during normal breathing. Data are brought which suggest that whereas vasodilation following increased heart rate is probably due to an autoregulatory mechanism, the marked vasodilatatory effect of hypopnea is related to elevated arterial CO2 levels. It is suggested that hypercapnia markedly stimulates extrinsic coronary vasodilation thereby supplying enough oxygen to maintain contractility even at very high heart rates. Moreover, intracellular O2 concentration (mitochondrial NADH level) is maintained at a normal level despite the greatly increased demand.


Epstein-Barr virus infections in males with the X-linked lymphoproliferative syndrome.
A registry of persons with the X-linked lymphoproliferative syndrome, which is characterized by marked susceptibility to diseases induced by the Epstein-Barr virus, has enrolled 161 patients within 44 kindreds. Fifty-seven percent of the males died of infectious mononucleosis, 29% developed acquired hypogammaglobulinemia, and 24% had malignant lymphoma. The mortality rate was 80%; 70% died by 10 years of age and 100% by 40 years. Thirty-two boys survive, most with malignant lymphoma, acquired hypogammaglobulinemia, or both. We hypothesized that the defective lymphoproliferative control locus on the X chromosome results in unregulated cytotoxic lymphocytic responses to the Epstein-Barr virus; hence, severe hepatitis and virus-associated hemophagocytic syndrome occur with the infectious mononucleosis phenotype. T-cell suppression of immunoglobulin secretion by B cells is responsible for acquired hypogammaglobulinemia. A sustained polyclonal B-cell proliferation probably converts to a monoclonal B-cell malignancy as a result of molecular alterations.


Epidermal modifications in a hill stream catfish, Hara hara in relation to its natural habitat: A scanning electron microscope and histochemical investigation.
In the present study, the epidermis of the hill stream fish Hara hara has been investigated employing scanning electron microscope, histology, histochemistry and immunofluorescence techniques. The epidermis is characteristically differentiated into plaques separated from each other by deep furrows. In plaques, the epidermis is keratinized. In contrast, in furrows, it is mucogenic. Surface epithelial cells in plaques get modified into characteristic spine-like unculi. At the distal ends of these unculi, we find tree-like branched dendritic structures. The keratinized epithelial cells in plaques together with unculi frequently exfoliate at the surface. The epidermis in furrows is equipped with secretory glandular cells, that is, mucous goblet cells, sacciform cells and club cells; and sensory structures, that is, the taste buds. These glandular cells are involved in the elaboration of different types of carbohydrate and protein moieties. Further, in the epidermis of both, plaques and furrows, melanophores are frequently interspersed between the epithelial cells. In the plaque epidermis, in addition to melanophores, melanin granules are observed in epithelial cells undergoing keratinization as well as in those sloughing at the surface. Sloughing of keratinized epithelial cells together with spine-like unculi at the surface of the plaques; the secretions of the glandular cells, the distribution of melanophore and the taste buds interspersed between the epithelial cells and the presence of melanin granules in the keratinized epithelial cells have been associated with different functional roles. These include hydrodynamic advantage, protection from mechanical stress, pathogens, UV radiation, localization of food accurately and so on in relation to the natural habitat of the fish.


Costs of implementing integrated community case management (iCCM) in six African countries: implications for sustainability.
Sub-Saharan Africa still reports the highest rates of under-five mortality. Low cost, high impact interventions exist, however poor access remains a challenge. Integrated community case management (iCCM) was introduced to improve access to essential services for children 2-59 months through diagnosis, treatment and referral services by community health workers for malaria, pneumonia and diarrhea. This paper presents the results of an economic analysis of iCCM implementation in regions supported by UNICEF in six countries and assesses country-level scale-up implications. The paper focuses on costs to provider (health system and donors) to inform planning and budgeting, and does not cover cost-effectiveness. The analysis combines annualised set-up costs and 1 year implementation costs to calculate incremental economic and financial costs per treatment from a provider perspective. Affordability is assessed by calculating the per capita financial cost of the program as a percentage of the public health expenditure per capita. Time and financial implications of a 30% increase in utilization were modeled. Country scale-up is modeled for all children under 5 in rural areas. Utilization of iCCM services varied from 0.05 treatment/y/under-five in Ethiopia to over 1 in Niger. There were between 10 and 603 treatments/community health worker (CHW)/y. Consultation cost represented between 93% and 22% of economic costs per treatment influenced by the level of utilization. Weighted economic cost per treatment ranged from US$ 13 (2015 USD) in Ghana to US$ 2 in Malawi. CHWs spent from 1 to 9 hours a week on iCCM. A 30% increase in utilization would add up to 2 hours a week, but reduce cost per treatment (by 20% in countries with low utilization). Country scale up would amount to under US$ 0.8 per capita total population (US$ 0.06-US$0.74), between 0.5% and 2% of public health expenditure per capita but 8% in Niger. iCCM addresses unmet needs and impacts on under 5 mortality. An economic cost of under US$ 1/capita/y represents a sound investment. Utilization remains low however, and strategies must be developed as a priority to improve demand. Continued donor support is required to sustain iCCM services and strengthen its integration within national health systems.


Semi-empirical quantum optics for mid-infrared molecular nanophotonics.
Nanoscale infrared (IR) resonators with sub-diffraction limited mode volumes and open geometries have emerged as new platforms for implementing cavity quantum electrodynamics at room temperature. The use of IR nanoantennas and tip nanoprobes to study strong light-matter coupling of molecular vibrations with the vacuum field can be exploited for IR quantum control with nanometer spatial and femtosecond temporal resolution. In order to advance the development of molecule-based quantum nanophotonics in the mid-IR, we propose a generally applicable semi-empirical methodology based on quantum optics to describe light-matter interaction in systems driven by mid-IR femtosecond laser pulses. The theory is shown to reproduce recent experiments on the acceleration of the vibrational relaxation rate in infrared nanostructures. It also provides physical insights on the implementation of coherent phase rotations of the near-field using broadband nanotips. We then apply the quantum framework to develop general tip-design rules for the experimental manipulation of vibrational strong coupling and Fano interference effects in open infrared resonators. We finally propose the possibility of transferring the natural anharmonicity of molecular vibrational levels to the resonator near-field in the weak coupling regime to implement intensity-dependent phase shifts of the coupled system response with strong pulses and develop a vibrational chirping model to understand the effect. The semi-empirical quantum theory is equivalent to first-principles techniques based on Maxwell's equations, but its lower computational cost suggests its use as a rapid design tool for the development of strongly coupled infrared nanophotonic hardware for applications ranging from quantum control of materials to quantum information processing.


A Powerful Chiral Phosphoric Acid Catalyst for Enantioselective Mukaiyama-Mannich Reactions.
A new BINOL-derived chiral phosphoric acid bearing 2,4,6-trimethyl-3,5-dinitrophenyl substituents at the 3,3'-positions was developed. The utility of this chiral phosphoric acid is demonstrated by a highly enantioselective (ee up to >99 %) and diastereoselective (syn/anti up to >99:1) asymmetric Mukaiyama-Mannich reaction of imines with a wide range of ketene silyl acetals. Moreover, this method was successfully applied to the construction of vicinal tertiary and quaternary stereogenic centers with excellent diastereo- and enantioselectivity. Significantly, BINOL-derived N-triflyl phosphoramide constitutes a complementary catalyst system that allows the title reaction to be applied to more challenging imines without an N-(2-hydroxyphenyl) moiety.


Immunohistochemical identification of galanin and growth hormone-releasing factor-containing neurons projecting to the median eminence of the rat.
Through the combined demonstration of the retrograde transport of True blue and the immunohistochemical staining of galanin (GAL), the GAL neurons that project to the median eminence were identified. Moreover, the distribution of GAL and growth hormone-releasing factor (GRF) was analyzed in the arcuate nucleus (ARC) with an elution-restaining procedure. Following the injection of True blue into the median eminence, GAL-positive cells labeled with True blue were found mainly in the ARC. In addition, a few GAL neurons in the periventricular, the paraventricular and the supraoptic nuclei were labeled with True blue. The elution-restaining results revealed that many retrogradely labeled GAL neurons in the ARC contained GRF. These findings suggest that a subpopulation of GAL neurons in the ARC sending axons to the median eminence produces, stores and releases a GRF-like peptide.


In vitro production of steroidal saponin, total phenols and antioxidant activity in callus suspension culture of Paris polyphylla Smith: an important Himalayan medicinal plant.
Paris polyphylla Smith (Melanthiaceae) family, which is native to the Himalayan region, has received a lot of attention recently due to its extensive history of usage in traditional medicine. The production of steroidal saponin from callus suspension cultures of P. polyphylla was observed in the current study. The current study attempted to develop a P. polyphylla plant callus suspension culture through optimization of cultivation technique for callus suspension, quantification of total phenolic components and estimation of the extract's antioxidant activity. A light-yellow callus was formed within six weeks of cultivating rhizomes on Murashige and Skoog (MS) media supplemented with Thidiazuron (TDZ). Furthermore, the effect of TDZ, Methyl Jasmonate (MeJA), and Yeast Extract (YE) on callus growth, steroidal saponin (dioscin and diosgenin), total phenolic content, total flavonoids, total tannin, and total antioxidant activity was also measured. The medium containing 0.5 μM TDZ depicted the maximum callus biomass (2.98 g fresh weight). Significantly high phenolic and tannin content was observed in the MS medium containing 50 μM MeJA, whereas, no significant increase was observed in total tannin production in any treatment. Three in vitro assays, DPPH (2,2-diphenyl-1-picrylhydrazyl), ABTS (2,2'-azino-bis (3-ethylbenzothiazoline- 6-sulfonic acid)) and FRAP (ferric ion reducing antioxidant potential) and FC (Folin-Ciocalteu), were used to assess antioxidant potential of callus. Maximum antioxidant analysis reported in 1.0 μM TDZ (6.89 mM AAE/100 g) containing medium followed by 50 μM MeJA (6.44 mM AAE/100 g). The HPLC analysis showed a high presence of dioscin and diosgenin (5.43% and 21.09%, respectively) compared to the wild sample (2.56% and 15.05%, respectively). According to the results, callus produced on media supplemented with 50 μM MeJA have significant phenolic contents and elevated antioxidant activity; nevertheless, callus growth was greater in the presence of 0.5 μM TDZ. The findings of the current study have commercial implications since greater biomass production will result in active phytochemicals that the pharmaceutical and nutraceutical sectors are in need desperately.


Voriconazole-Based Salts Are Active against Multidrug-Resistant Human Pathogenic Yeasts.
Voriconazole (VOR) hydrochloride is unequivocally converted into VOR lactates and valinates upon reaction with silver salts of organic acids. This study found that the anticandidal in vitro activity of these compounds was comparable or slightly better than that of VOR. The Candida albicans clinical isolate overexpressing CaCDR1/CaCDR2 genes, highly resistant to VOR, was apparently more susceptible to VOR salts. On the other hand, the susceptibility of another C. albicans clinical isolate (demonstrating multidrug resistance due to the overexpression of CaMDR1) to VOR salts was comparable to that to VOR. Comparative studies on the influence of VOR and its salts on Rhodamine 6G efflux from susceptible and multidrug-resistant C. albicans cells revealed that VOR salts are poorer substrates for the CaCdr1p drug efflux pump than VOR.


Urban vegetation and particle air pollution: Experimental campaigns in a traffic hotspot.
This work presents the main results of two experimental campaigns carried out in summer and winter seasons in a complex pollution hotspot near a large park, El Retiro, in Madrid (Spain). These campaigns were aimed at understanding the microscale spatio-temporal variation of ambient concentration levels in areas with high pollution values to obtain data to validate models on the effect of urban trees on particulate matter concentrations. Two different measuring approaches have been used. The first one was static, with instruments continuously characterizing the meteorological variables and the particulate matter concentration outside and inside the park. During the summer campaign, the particulate matter concentration was clearly influenced by a Saharan dust outbreak during the period 23 June to 10 July 2016, when most of the particulate matter was in the fraction PM2.5-10. During the winter campaign, the mass concentrations were related to the meteorological conditions and the high atmospheric stability. The second approach was a dynamic case with mobile measurements by portable instruments. During the summer campaign, a DustTrak instrument was used to measure PM10 and PM2.5 in different transects close to and inside the park at different distances from the traffic lane. It was observed a decrease in the concentrations up to 25% at 20 m and 50% at 200 m. High PM10 values were linked to dust resuspension caused by recreational activities and to a Saharan dust outbreak. The highest PM values were measured at the Independencia square, an area with many bus stops and high traffic density. During the winter campaign, three microaethalometers were used for Black Carbon measurement. Both pollutants also showed a reduction in their concentrations when moving towards inside the park. For PM10 and PM2.5, reductions up to 50% were observed, while for BC this reduction was smaller, about 20%.


THE SIGNIFICANCE OF GENETIC EROSION IN THE PROCESS OF EXTINCTION. IV. INBREEDING LOAD AND HETEROSIS IN RELATION TO POPULATION SIZE IN THE MINT SALVIA PRATENSIS.
If, because of genetic erosion, the level of homozygosity in small populations is high, additional selfing will result in small reductions of fitness. In addition, in small populations with a long inbreeding history selection may have purged the population of its genetic load. Therefore, a positive relationship between population size (or level of genetic variation) and level of additional inbreeding depression, here referred to as inbreeding load, may be expected. In a previous study on the rare and threatened perennial Salvia pratensis, a positive correlation between population size and level of allozyme variation has been demonstrated. In the present study, the inbreeding load in six populations of varying size and allozyme variation was investigated. In the greenhouse, significant inbreeding load in mean seed weight, proportion of germination, plant size, regenerative capacity, and survival was demonstrated. In a field experiment with the two largest and the two smallest populations, survival of selfed progeny was 16% to 63% lower than survival of outcrossed progeny. In addition, survival of outcrossed progeny was, with the exception of the largest population, lower (16% to 37%) than of hybrid progeny, resulting from crosses between populations. Effects on plant size were qualitatively similar to the effects on survival, but these effects were variable in time because of differential survival of larger individuals. In all populations the total inbreeding load, that is, the effects on size and survival multiplicated, increased in time. It was demonstrated that inbreeding load in different characters may be independent. At no time and for no character was inbreeding load or the heterosis effect correlated to the mean number of alleles per locus, indicating that allozyme variation is not representative for variation at fitness loci in these populations. Combined with results of previous investigations, these results suggest that the small populations are in an early phase of the genetic erosion process. In this phase, allozyme variation, which is supposed to be (nearly) neutral, has been affected by genetic erosion but the selectively nonneutral variation is only slightly affected. These results stress the need for detailed information about the inbreeding history of small populations. The relative performance of selfed progeny was lowest in all populations, in the greenhouse as well as in the field, and inbreeding depression could still influence the extinction probabilities of the small populations.


[Survey of alcohol and psychoactive drug consumption in a sample of high school students of the 9th and 19th local health units in the Marche Region].
A random sample of high school students of the Health Districts N. 9 and N. 19 of Marche Region, Central Italy, was interviewed about their alcohol and psychoactive medicine consumption. The questionnaire, previously used in other surveys in Italy, was anonymous and collected information on demographic and socio-economic status, smoking and drinking habits, psychoactive medicine consumption attitudes and knowledges on the health hazards of alcohol and psychoactive medicine abuse. A total of 237 males and 352 females in the 9th grade (mean age: 14.7 yrs) and of 131 males and 207 females in the 13th grade (mean age: 18.4 yrs) were enrolled in the survey. We observed higher alcohol consumption in males than in females and in grade-13 than in grade-9 for each beverage. Wine was the most used alcohol beverage: 30.4% of males in grade-9 and 39.7% in grade-13 were used to drink it daily, 13.7% of females in grade-9 and 17.4% in grade-13 were daily drinkers. In the youngest group, 6.8% of males and 0.3% of females drank 4 or more glasses of wine a day, while in grade-13 the percentages of heavy wine drinkers were 7.6% of males and 0.5% of females. On the contrary, beer consumption seemed to be more occasional: 55.7% of males and 33.6% of females in grade-9, and 67.2% of males and 49.4% of males and 36.8% of females in grade-13 were occasionally drinkers. However, the percentages of heavy drinkers of beer were not far from those observed in wine drinkers: 2.9% of males and 0.3% of females in grade-9 and 6.9% of males and 0.5% of females in grade-13 daily drank 4 glasses of beer or more. Spirit consumption reached a particularly high level in grade-13th males. And 22.9% of them were used to have 11 or more drinks per month. Among spirit drinkers, about 35-40% of males drank brandy, whisky, cognac and other strong spirits, while females showed to prefer less alcoholic liquors. According to the amount of pure alcohol consumed, 10.1% of males in grade-9 and 16.9% of males in grade-13 drank 200 or more g/week, while only 1.5% of females admitted such a high consumption. A large part of students in the youngest group drank more than one alcoholic beverage, particularly wine and beer. Among grade-13 students, 47.3% of males and 15.9% of females daily or occasionally drank wine, beer and spirits.(ABSTRACT TRUNCATED AT 400 WORDS)


A comparison of single-channel linear amplification and two-channel wide-dynamic-range-compression amplification by means of an independent-group design.
The present study used an independent-group design to compare the benefits provided by binaural, single-channel, linear, full-shell in-the-ear hearing aids and binaural, 2-channel, wide-dynamic-range-compression in-the-canal hearing aids in groups of older hearing aid wearers. Hearing aid outcome measures were obtained at both 1-month (n = 53) and 6-month (n = 34) postfit intervals with each device. Outcome measures included multiple measures of speech-recognition performance and self-report measures of hearing aid benefit, satisfaction, and usage. Aided sound-quality measurements were also obtained. Although both devices provided significant benefits to the wearers, there were no significant differences in the benefits provided by either device at the 1-month or 6-month postfit intervals.


Process Evaluation of a Workers' Health Surveillance Program for Meat Processing Workers.
Objective To evaluate the implementation process of a workers' health surveillance (WHS) program in a Dutch meat processing company. Methods Workers from five plants were eligible to participate in the WHS program. The program consisted of four evaluative components and an intervention component. Qualitative and quantitative methods were used to evaluate seven process aspects. Data were gathered by interviews with stakeholders, participant questionnaires, and from registries of the company and occupational health service. Results Two recruitment strategies were used: open invitation or automatic participation. Of the 986 eligible workers, 305 participated in the program. Average reach was 53 %. Two out of five program components could not be assessed on dose delivered, dose received and fidelity. If components were assessable, 85-100 % of the components was delivered, 66-100 % of the components was received by participants, and fidelity was 100 %. Participants were satisfied with the WHS program (mean score 7.6). Contextual factors that facilitated implementation were among others societal developments and management support. Factors that formed barriers were program novelty and delayed follow-up. Conclusion The WHS program was well received by participants. Not all participants were offered the same number of program components, and not all components were performed according to protocol. Deviation from protocol is an indication of program failure and may affect program effectiveness.


Variolin B from sea sponge against lung cancer: a multitargeted molecular docking with fingerprinting and molecular dynamics simulation study.
Lung Cancer is the one that causes more fatalities in the world compared to other cancers, and its uniqueness is that it can be found in both males and females. However, recent data has shown that males are more affected due to lifestyle habits like smoking, tobacco consumption and inhaling polluted air. The World Health Organization has kept lung cancer on its priority list as it causes 1.8 million deaths worldwide each year, and the predictions show that the cases are going to increase year by year, and by 2050, there can be 3.8 million new cases and 3.2 million deaths, and the global health system is not prepared for it. Also, finding drug candidates that can help shrink cancerous cells and lead to their death is essential to reduce global mortality. The system needs drug compounds that can inhibit multiple paths together not to enter drug resistance quickly and to reduce costs. Our study identified a compound named Variolin B (DB08694) that belongs to the organic compounds class of pyrrolopyridines. The identified compound can inhibit multiple proteins, drastically reducing the global burden. Variolin B was identified as a potential candidate against lung cancer using the multisampling algorithm such as HTVS, SP, and XP, followed by MM\GBSA calculations showing the docking score of -9.245 Kcal/mol to -5.92 Kcal/mol. Also, we have validated it with ADMET predictions and molecular fingerprinting to analyse the interaction patterns. Further, the study was extended to molecular dynamics simulations for 100 ns to understand the complex stability and simulative interactions. The complex's overall molecular dynamics simulation helped us understand that the identified candidate is stable with the lowest deviation and fluctuations.Communicated by Ramaswamy H. Sarma.


Geometric unfolding of synchronization dynamics on networks.
We study the synchronized state in a population of network-coupled, heterogeneous oscillators. In particular, we show that the steady-state solution of the linearized dynamics may be written as a geometric series whose subsequent terms represent different spatial scales of the network. Specifically, each additional term incorporates contributions from wider network neighborhoods. We prove that this geometric expansion converges for arbitrary frequency distributions and for both undirected and directed networks provided that the adjacency matrix is primitive. We also show that the error in the truncated series grows geometrically with the second largest eigenvalue of the normalized adjacency matrix, analogously to the rate of convergence to the stationary distribution of a random walk. Last, we derive a local approximation for the synchronized state by truncating the spatial series, at the first neighborhood term, to illustrate the practical advantages of our approach.


Attenuation of heat shock-induced cardioprotection by treatment with the opiate receptor antagonist naloxone.
Whole body hyperthermia induces heat shock proteins (HSPs), which confer cardioprotection. Several opioid receptor subtypes are expressed in the heart and are linked to cardioprotection; however, no one has attempted to link the protection elicited by heat stress (HS) to opioids. Therefore, we investigated the effect of an opiate receptor antagonist, naloxone, on HS-induced cardioprotection. Anesthetized Sprague-Dawley rats were subjected to HS (42 degrees C for 20 min) with and without naloxone pretreatment and were allowed to recover for 48 h. They then underwent 30 min of ischemia followed by 2 h of reperfusion. An acute HS group was given an intravenous bolus of naloxone (3 mg/kg) 10 min before index ischemia. Infarct size (IS), expressed as a percentage of the area at risk (IS/AAR), was determined. The right heart was excised for analysis of HSP content by Western blot. Heat-shocked rats showed significant reductions in IS/AAR versus control (16 +/- 3 vs. 58 +/- 4%, P < 0.001). Pretreatment with naloxone before HS attenuated the protective effects in a dose-dependent fashion, with significant attenuation of protection occurring at 15 mg/kg naloxone versus heat shock (42 +/- 6 vs. 16 +/- 3%, P < 0.001). Acute treatment with naloxone (3 mg/kg) 48 h after recovery from HS also significantly attenuated the delayed protective effect (47 +/- 4 vs. 16 +/- 3%, P < 0.001). No difference was seen in the level of HSP70 induced in the different groups. We conclude that heat shock-induced cardioprotection can be attenuated by naloxone, an opiate receptor antagonist, without reducing the levels of certain HSPs. These results suggest there may be a link between the endogenous release of opioids and HS that mediates cardioprotection.


Alternating lumbar lateral shift: a case report.
A lumbar lateral shift (LLS) is a common clinical observation in patients with low back pain (LBP), and a shift contralateral to the side of pain is the most common presentation. An LLS that can rapidly alternate sides presents several treatment difficulties and has rarely been described. The purpose of the current case report was to describe the presentation and management of a patient with an alternating LLS. A 39-year-old male with a 7-week history of LBP and previous lower extremity radicular pain was referred to physical therapy. An alternating LLS was present. The patient was treated for six visits over 37 days. Treatment included modified self-correction of the LLS, motor control and trunk muscle endurance training, and development of an activity management program. The patient's LLS resolved, his worst pain improved from 3/10 to 0/10, and the Oswestry Disability Index improved from 26% to 4% disability. The patient reported maintenance of improvement at 6-month follow-up. The current approach produced a positive outcome in a patient with an alternating LLS. The current understanding of mechanisms and optimal treatment of an alternating LLS is limited. 4.


Force fabric and macroscopic friction in two-dimensional granular materials.
We study the relationship between the local grain-grain friction and the force texture in a granular pile to its macroscopic emergent frictional values. We account for the force geometrical properties by a model that assumes the existence of slide planes that define macroscopic friction angles. The model depends on the measured angular distribution of contact forces and a single parameter, to be fitted, that is a function of the roughness of the slide plane. The model is tested by a state-of-the-art model of a two-dimensional granular pile built by depositing grains under gravity and submitted to an external uniaxial stress.


Drug prescribing in hospitals: an international comparison.
This paper presents a comparison of prescribing habits for patients hospitalized in medical wards of university hospitals in America and Scotland. American patients received almost twice as many drugs both during and prior to hospitalization than did comparable Scots. The differences between the countries were consistent for symptomatic and for more specific therapies. As compared to Scotland, drug therapy in America costs patients more in terms of financial outlay and adverse drug effects. The data do not permit evaluation of the relative benefits to the patients of the different quantities or types of drug used for similar circumstances in these countries.


Updating Normal Organ Weights Using a Large Current Sample Database.
Organ weights are an essential part of autopsy analysis. Deviations from normal organ weights provide important clues to disease processes. The assessment of normal organ weights depends on reliable reference tables, but most widely available reference tables are based on data that are either decades old or derived from relatively small sample sizes. To provide an updated reference table of organ weights based on contemporary sources and a large sample size. Organ weights from 4197 carefully screened autopsies performed on adults at the Palm Beach County Medical Examiner's Office in West Palm Beach, Florida, and the Mayo Clinic Hospital in Rochester, Minnesota. Height and body weight data in this study reflect the well-recognized increases in both variables, but most particularly in body weight, seen during the last decades. The study data show a strong positive association between organ weight and body weight for the heart, liver, and spleen. There is a similar but weaker association between body weight and the weight of the lungs and kidneys. Brain weight is independent of body weight but shows a strong negative association with age. Even when controlling for body weight, men's organs are heavier, except for the weight of the liver, which is comparable in men and women. These associations are in agreement with the findings of previous studies. The current study suggests that, for some of the commonly weighed organs, there has been an increase in median organ weight when compared with existing references. The tables presented here provide an updated reference that should prove useful to autopsy pathologists in the forensic and hospital settings.