Can transvaginal cervical length and cervical strain elastography predict mid-trimester medical induction to abortion intervals?
Mid-trimester pregnancy terminations are becoming an increasingly common practice in obstetrics. Accurate prediction of delay from induction to abortion may help in planning the optimal time for the medical induction process and optimising the use of healthcare services. Therefore, we aimed to assess whether the transvaginal cervical length and cervical elastography can predict the time interval from medical induction to abortion in cases of medically indicated mid-trimester pregnancy termination. We performed a prospective observational pilot study between January 2022 and October 2022 in patients who have undergone medically indicated mid-trimester pregnancy termination with a non-dilated cervix for foetal morphological, chromosomal abnormalities or preterm premature rupture of membranes. Cervical length (CL) and cervical strain ratio (CSR) were measured by transvaginal sonography. The predictive value of CL and CSR on the induction to abortion interval was calculated after medical induction with misoprostol. Fifty-three eligible pregnant women were evaluated. The mean gestational age at abortion was 17.61 ± 2.81 weeks. The mean time interval from induction to abortion was 31.72 ± 16.57 h. In multivariate linear regression analysis, CL and the history of previous vaginal delivery were the significant independent predictors of the induction to abortion interval (all p < 0.01), with no additional significant contribution from CSR. Transvaginal CSR is unlikely to be useful in the prediction of induction to abortion interval in the mid-trimester medically indicated termination of pregnancy.SHORT CONDENSATIONTransvaginal cervical length is the significant independent predictor of the induction to abortion interval in the mid-trimester medically indicated termination of pregnancy with no additional significant contribution from cervical strain ratio.


Three-dimensional alignment of microvasculature and cardiomyocytes in the developing ventricle.
While major coronary artery development and pathologies affecting them have been extensively studied, understanding the development and organization of the coronary microvasculature beyond the earliest developmental stages requires new tools. Without techniques to image the coronary microvasculature over the whole heart, it is likely we are underestimating the microvasculature's impact on normal development and diseases. We present a new imaging and analysis toolset to visualize the coronary microvasculature in intact embryonic hearts and quantify vessel organization. The fluorescent dyes DiI and DAPI were used to stain the coronary vasculature and cardiomyocyte nuclei in quail embryo hearts during rapid growth and morphogenesis of the left ventricular wall. Vessel and cardiomyocytes orientation were automatically extracted and quantified, and vessel density was calculated. The coronary microvasculature was found to follow the known helical organization of cardiomyocytes in the ventricular wall. Vessel density in the left ventricle did not change during and after compaction. This quantitative and automated approach will enable future cohort studies to understand the microvasculature's role in diseases such as hypertrophic cardiomyopathy where misalignment of cardiomyocytes has been observed in utero.


Lymphatic endothelial transcription factor Tbx1 promotes an immunosuppressive microenvironment to facilitate post-myocardial infarction repair.
The heart is an autoimmune-prone organ. It is crucial for the heart to keep injury-induced autoimmunity in check to avoid autoimmune-mediated inflammatory disease. However, little is known about how injury-induced autoimmunity is constrained in hearts. Here, we reveal an unknown intramyocardial immunosuppressive program driven by Tbx1, a DiGeorge syndrome disease gene that encodes a T-box transcription factor (TF). We found induced profound lymphangiogenic and immunomodulatory gene expression changes in lymphatic endothelial cells (LECs) after myocardial infarction (MI). The activated LECs penetrated the infarcted area and functioned as intramyocardial immune hubs to increase the numbers of tolerogenic dendritic cells (tDCs) and regulatory T (Treg) cells through the chemokine Ccl21 and integrin Icam1, thereby inhibiting the expansion of autoreactive CD8+ T cells and promoting reparative macrophage expansion to facilitate post-MI repair. Mimicking its timing and implementation may be an additional approach to treating autoimmunity-mediated cardiac diseases.


Studies on the efficacy of lipoate and dihydrolipoate in the alteration of cadmium2+ toxicity in isolated hepatocytes.
Lipoate (thioctic acid) is presently used in therapy of a variety of diseases such as liver and neurological disorders. However, nothing is known about the efficacy of lipoate and its reduced form dihydrolipoate in acute cadmium (Cd2+) toxicity which involves severe liver disturbances. Therefore, we investigated the effects of these redox compounds on Cd2(+)-induced injuries in isolated rat hepatocytes. The cells were coincubated with 150 microM Cd2+ and either 1.5-6.0 mM lipoate or 17-89 microM dihydrolipoate for up to 90 min and Cd2+ uptake as well as viability criteria were monitored. Both exposure regimens diminished Cd2+ uptake in correspondence to time and concentration. They also ameliorated Cd2(+)-induced cell deterioration as reflected by the decrease in Cd2(+)-induced membrane damage (leakage of aspartate aminotransferase), by the lessening of the Cd2(+)-stimulated lipid peroxidation (TBA-reactants) and by the increase in Cd2(+)-depleted cellular glutathione (GSH + 2 GSSG). Half-maximal protection was achieved at molar ratios of 9.9 to 19 (lipoate vs. Cd2+) and 0.25 to 0.74 (dihydrolipoate vs. Cd2+), indicating a 19.5 to 50.6 lower protective efficacy of lipoate as compared to dihydrolipoate. Lipoate induced an increase in extracellular acid-soluble thiols different from glutathione. It is suggested that dihydrolipoate primarily protects cells by extracellular chelation of Cd2+, whereas intracellular reduction of lipoate to the dihydro-compound followed by complexation of both intra- and extracellular Cd2+ contributes to the amelioration provided by lipoate.


Response of the primate fetus to intra-amniotic saline injection.
The amniotic fluid was replaced with 20 per cent sodium chloride solution during the second half of gestation in 12 pregnant rhesus monkeys. This produced a congealing of the fetal blood in the small umbilical vessels which overlie in the placental chorionic plate. Death of severe asphyxia followed within 20 to 50 minutes in the younger fetuses due to a prompt cessation of umbilical blood flow. During this time, the rise in serum sodium of the fetus was moderate and could not be implicated as the cause of fetal death. In older fetuses, the asphyxia produced by the saline injection was transient and less severe, occasionally permitting survival. The caliber of the affected fetal umbilical blood vessels and their blood flow rates are presented as the principal determinants of the rapidity of development and the severity of the asphyxia produced by saline instillation.


Inhibitory effects of antioxidants on N-bis(2-hydroxypropyl)nitrosamine-induced lung carcinogenesis in rats.
Potential second-stage modifying effects of 8 antioxidants on lung tumorigenesis initiated by N-bis(2-hydroxypropyl)nitrosamine (DHPN) were examined in male F344 rats. After an initial 2-week treatment with DHPN (0.1% in drinking water), rats were administered one of the antioxidants supplemented in the diet for 30 weeks. Although the incidences of lung adenomas were not affected, those of carcinomas were lowered by 2% butylated hydroxyanisole (BHA, 2 rats/20 rats), 1% butylated hydroxytoluene (BHT, 1/20), 0.8% ethoxyquin (EQ, 3/20) and 1% a-tocopherol (a-TP, 2/20) treatments as compared to the control level (9/20), while 5% sodium L-ascorbate (SA), 0.8% catechol (CC), 0.8% resorcinol (RN), and 0.8% hydroquinone (HQ) did not exert any significant effect on incidence. Quantitative analysis of adenomas and carcinomas (numbers and areas of lesions per unit area of lung section) revealed obvious inhibitory effects of SA, CC, and RN as well as BHA, BHT, EQ, and a-TP. Among the antioxidants, BHT exerted the strongest inhibitory activity. In contrast, DHPN-induced thyroid tumorigenesis was significantly enhanced by BHT (14/20) and EQ (20/20) treatments (control = 5/20). Thus the antioxidants showed opposite effects on lung and thyroid carcinogenesis in the rat.


Effective extraction of fluorescent brightener 52 from foods by in situ formation of hydrophobic deep eutectic solvent.
Fluorescent brightener 52 (FWA52) is a coumarin-based compound, and it is difficult to degrade owing to its high chemical stability. Up to now, several methods have been developed to extract and determine FWAs, but toxic, volatile and harmful organic solvents are often used. In this paper, a novel method for the extraction and analysis of FWA52 is proposed for the first time by in situ formation of hydrophobic deep eutectic solvent (DES) with parabens in aqueous solution. The effects of paraben structure, solution pH, system temperature, extractant dosage and initial FWA52 concentration on the extraction recovery were investigated systematically. It is shown that FWA52 can be extracted by 2-ethylhexyl 4-hydroxybenzoate at ultra-trace level (0.05 μg/L FWA52) at room temperature without using harmful organic solvents, and various coexisting inorganic ions and organic compounds have little effect on the extraction efficiency. Based on these results, a novel and simple strategy is developed for the accurate determination of FWA52 in water. It is found that under the optimal experimental conditions, the linear range of this method is 0.20~25 μg/L (R2 = 0.9995), and the detection limit and the quantity limit are 0.045 μg/L and 0.20 μg/L respectively. This method has been successfully applied for the determination of FWA52 in actual food samples and food contact materials, such as noodles, fish balls, mushroom and paper cups, with a recovery from 82 to 113% and a relative standard deviation (RSD) from 4.7 to 9.9%. In addition, the separation mechanism was investigated by FT-IR and 1H NMR, and was discussed from strong hydrogen bonding between FWA52 and 2-ethylhexyl 4-hydroxybenzoate and the formation of corresponding DES.


Estimation of post-mortem interval based on insect species present on a corpse found in a suitcase.
Murderers sometimes dispose of bodies in zipped suitcases in an attempt to conceal their crimes. In these cases, the species of insects found and their succession patterns are typically different from those found on exposed corpses due to hindrances or delays in colonization. Here we report a case in which an unidentified female corpse was found in a soft-shell suitcase in a wetland area among some reeds in Guangdong, China on 13 May 2018. The suitcase was unbroken and zippers were well-sealed. The victim was a young woman, naked, and curled up in the suitcase. The insect evidence we collected include (i) pupae and empty puparia of Chrysomya nigripes (Aubertin) (Diptera: Calliphoridae) and Fannia canicularis (Linnaeus) (Diptera, Muscidae), (ii) larvae, pupae and empty puparia of Megaselia scalaris (Loew) (Diptera: Phoridae) and Hermetia illucens (Linnaeus) (Diptera: Stratiomyidae). According to this insect evidence, we estimated the PMImin as 56 days. Bhadra et al. (2014) show that larvae of Calliphora vomitoria (Linnaeus) (Diptera: Calliphoridae) and Calliphora vicina (Robineau-Desvoidy) (Diptera, Calliphoridae) can colonize carcasses concealed in zipped suitcases. Although the size of the zipper (7mm) in this case is larger than that described in Bhadra et al. (4mm), we did not find Chrysomya megacephala (Fabricius) (Diptera: Calliphoridae), Chrysomya rufifacies (Macquart) (Diptera: Calliphoridae), or Lucilia sericata (Meigen) (Diptera: Calliphoridae) which usually colonize fresh corpses in this area. Therefore, we deduced that the victim may have been killed in winter. After the crime was solved, the murderer confessed that he killed the victim on 5 January.


Comprehensive Management of Headache for the Otolaryngologist: A Summary.
Otolaryngologists will frequently encounter patients with head and facial pain. The headache may be a primary disorder or a symptom of a secondary pathology. Understanding diagnostic criteria and the autonomic and otologic manifestations of primary headaches is imperative for accurate diagnosis and treatment. This article summarizes key points in the issue "Comprehensive Management of Headache for the Otolaryngologist" and can be used as a cursory reference.


A modification of the commercial ESR900 cryostat to enable three-dimensional electron-paramagnetic-resonance studies of crystals.
Complete orientation studies of X-band electron-paramagnetic-resonance spectra of crystals largely benefit from the possibility to measure the spectrum for any orientation of the magnetic field with respect to the crystal without the need to remount the crystal. We report on a modification of a commercial cryostat to allow such experiments down to liquid helium temperatures and demonstrate its performance.


Rape Myth Consistency and Gender Differences in Perceiving Rape Victims: A Meta-Analysis.
An overview discusses feminist analyses of oppression, attitudes toward rape victims, and previously studied predictors of individuals' attitudes toward rape victims. To better understand such attitudes, this meta-analysis examines the moderating influences of various rape victim, perpetrator, and crime characteristics' rape myth consistency on gender differences in individuals' perceptions of rape victims (i.e., victim responsibility and blame attributions and rape minimizing attitudes). Consistent with feminist theoretical predictions, results indicated that, overall, men perceived rape victims more negatively than women did. However, this sex difference was moderated by the rape myth consistency within the rape vignettes. Implications for research are discussed.


Antibacterial and antioxidant activities for natural and synthetic dual-active compounds.
Antimicrobial resistance is widely recognized as a grave threat to global health in the 21st century, since the past decades have seen a dramatic increase in human-pathogenic bacteria that are resistant to one or multiple antibiotics. New antimicrobial agents are urgently required, particularly in the treatment of chronic infections such as cystic fibrosis, often associated with persistent colonization by drug-resistant pathogens and epithelial damage by pulmonary oxidative stress. In such events, it would be favourable to find agents that could have antioxidant and antibacterial activities combined in one molecule. The discovery of compounds that can show a dual-target activity considerably increased in the last years, reflecting the growing confidence that this new approach could lead to better therapeutic solutions for complex multigenic diseases. The aim of this review is to report those natural and synthetic compounds displaying significant antioxidant and antibacterial activities. In recent years there has been a growing attention on plant-derived antimicrobials as an alternative to antibiotics, for their efficacy and low tendency in developing bacterial resistance. Moreover, it was found that some natural products could enhance the activity of common antibiotics displaying a synergistic effect. We then report some selected synthetic compounds with an in-built capacity to act on two targets or with the combination in a single structure of two pharmacophores with antioxidant and antibacterial activities. Recent literature instances were screened and the most promising examples of dual-active antibacterial-antioxidant molecules were highlighted.


Immune Checkpoint Blockade for Metastatic Uveal Melanoma: Re-Induction following Resistance or Toxicity.
Re-induction with immune checkpoint blockade (ICB) needs to be considered in many patients with uveal melanoma (UM) due to limited systemic treatment options. Here, we provide hitherto the first analysis of ICB re-induction in UM. A total of 177 patients with metastatic UM treated with ICB were included from German skin cancer centers and the German national skin cancer registry (ADOReg). To investigate the impact of ICB re-induction, two cohorts were compared: patients who received at least one ICB re-induction (cohort A, n = 52) versus those who received only one treatment line of ICB (cohort B, n = 125). In cohort A, a transient benefit of overall survival (OS) was observed at 6 and 12 months after the treatment start of ICB. There was no significant difference in OS between both groups (p = 0.1) with a median OS of 16.2 months (cohort A, 95% CI: 11.1-23.8) versus 9.4 months (cohort B, 95% CI: 6.1-14.9). Patients receiving re-induction of ICB (cohort A) had similar response rates compared to those receiving ICB once. Re-induction of ICB may yield a clinical benefit for a small subgroup of patients even after resistance or development of toxicities.


Optimization of parameter values for complex pulse sequences by simulated annealing: application to 3D MP-RAGE imaging of the brain.
A number of pulse sequence techniques, including magnetization-prepared gradient echo (MP-GRE), segmented GRE, and hybrid RARE, employ a relatively large number of variable pulse sequence parameters and acquire the image data during a transient signal evolution. These sequences have recently been proposed and/or used for clinical applications in the brain, spine, liver, and coronary arteries. Thus, the need for a method of deriving optimal pulse sequence parameter values for this class of sequences now exists. Due to the complexity of these sequences, conventional optimization approaches, such as applying differential calculus to signal difference equations, are inadequate. We have developed a general framework for adapting the simulated annealing algorithm to pulse sequence parameter value optimization, and applied this framework to the specific case of optimizing the white matter-gray matter signal difference for a T1-weighted variable flip angle 3D MP-RAGE sequence. Using our algorithm, the values of 35 sequence parameters, including the magnetization-preparation RF pulse flip angle and delay time, 32 flip angles in the variable flip angle gradient-echo acquisition sequence, and the magnetization recovery time, were derived. Optimized 3D MP-RAGE achieved up to a 130% increase in white matter-gray matter signal difference compared with optimized 3D RF-spoiled FLASH with the same total acquisition time. The simulated annealing approach was effective at deriving optimal parameter values for a specific 3D MP-RAGE imaging objective, and may be useful for other imaging objectives and sequences in this general class.


Trauma exposure and alcohol use disorder among prisoners in Jimma Zone correctional institution, Southwest Ethiopia: a cross-sectional study.
Trauma exposure and alcohol use are closely related, and large proportion of trauma-exposed individuals use alcohol. The data presented in this paper were obtained as part of a study on substance use disorder and associated factors among prisoners in the correctional institution in Jimma, Southwest Ethiopia. Therefore, in this study we examined comorbidity of traumatic life experiences and alcohol use disorder in inmates of correctional institution in Jimma, Southwest Ethiopia. The overall prevalence of lifetime alcohol use disorder was 40.1%, and the prevalence of alcohol use disorder among prisoners with lifetime trauma exposure was 44.0%. Participants with multiple trauma exposures had 2.5-fold higher odds of association for alcohol use disorder than their counterparts (AOR = 2.47 [1.23-4.94]). Living in urban areas (AOR = 4.86 [2.38-9.94]), presence of psychopathy (AOR = 3.33 [1.25-8.86]), khat abuse (AOR = 7.39 [3.99-13.68]), and nicotine dependence (AOR = 2.49 [1.16-5.34]) were also positively associated with alcohol use disorder. The prevalence of alcohol use disorder was higher among prisoners with lifetime trauma exposure. Also, this study indicates that prisoners with multiple trauma exposures had higher odds of association for alcohol use disorder than those with no trauma exposure. A public health intervention targeting survivors of traumatic experiences needs to be designed and implemented.


Clinic-Based Urinary Lipoarabinomannan as a Biomarker of Clinical Disease Severity and Mortality Among Antiretroviral Therapy-Naive Human Immunodeficiency Virus-Infected Adults in South Africa.
Urinary lipoarabinomannan (LAM) has limited sensitivity for diagnosing active human immunodeficiency virus (HIV)-associated tuberculosis (TB) disease, but LAM screening at HIV diagnosis might identify adults with more severe clinical disease or greater risk of mortality. We enrolled antiretroviral therapy-naive HIV-infected adults from 4 clinics in Durban. Nurses performed urine LAM testing using a rapid assay (Determine TB LAM) graded from low (1+) to high (≥3+) intensity. Urine LAM results were not used to guide anti-TB therapy. We assessed TB-related symptoms and obtained sputum for mycobacterial smear and culture. Participants were observed for 12 months, and we used multivariable Cox proportional hazard models to determine hazard ratios for all-cause mortality. Among 726 HIV-infected adults with median CD4 of 205 cells/mm3 (interquartile range, 79-350 cells/mm3), 93 (13%) were LAM positive and 89 (12%) participants died during the follow-up period. In multivariable analyses, urine LAM-positive participants had a mortality hazard ratio (MHR) of 3.58 (95% confidence interval [CI], 2.20-5.81) for all-cause mortality. Among participants with mycobacterial-confirmed TB, urine LAM-positivity had a 2.91 (95% CI, 1.26-6.73) MHR for all participants and a 4.55 (95% CI, 1.71-12.1) MHR for participants with CD4 ≤100 cell/mm3. Participants with LAM-positive TB had significantly more clinical signs and symptoms of disease, compared with participants with LAM-negative TB disease. Among HIV-infected adults, urinary LAM-positive patients had more clinical disease severity and a 3-fold increase in 12-month mortality compared with those who were LAM negative.


Development and external validation of the DOAT and DOATS scores: simple decision support tools to identify disease progression among nonelderly patients with mild/moderate COVID-19.
During the fifth wave of the coronavirus disease 2019 (COVID-19) pandemic in Japan, which took place between June and September 2021, a significant number of COVID-19 cases with deterioration occurred in unvaccinated individuals < 65 years old. However, the risk factors for COVID-19 deterioration in this specific population have not yet been determined. This study developed a prediction method to identify COVID-19 patients < 65 years old who are at a high risk of deterioration. This retrospective study analyzed data from 1,675 patients < 65 years old who were admitted to acute care institutions in Fukushima with mild-to-moderate-1 COVID-19 based on the Japanese disease severity criteria prior to the fifth wave. For validation, 324 similar patients were enrolled from 3 hospitals in Yamagata. Logistic regression analyses using cluster-robust variance estimation were used to determine predictors of disease deterioration, followed by creation of risk prediction scores. Disease deterioration was defined as the initiation of medication for COVID-19, oxygen inhalation, or mechanical ventilation starting one day or later after admission. The patients whose condition deteriorated (8.6%) tended to be older, male, have histories of smoking, and have high body temperatures, low oxygen saturation values, and comorbidities, such as diabetes/obesity and hypertension. Stepwise variable selection using logistic regression to predict COVID-19 deterioration retained comorbidities of diabetes/obesity (DO), age (A), body temperature (T), and oxygen saturation (S). Two predictive scores were created based on the optimism-corrected regression coefficients: the DOATS score, including all of the above risk factors, and the DOAT score, which was the DOATS score without oxygen saturation. In the original cohort, the areas under the receiver operating characteristic curve (AUROCs) of the DOATS and DOAT scores were 0.81 (95% confidence interval [CI] 0.77-0.85) and 0.80 (95% CI 0.76-0.84), respectively. In the validation cohort, the AUROCs for each score were both 0.76 (95% CI 0.69-0.83), and the calibration slopes were both 0.80. A decision curve analysis confirmed the clinical practicability of both scores in the validation cohort. We established two prediction scores that can quickly evaluate the risk of COVID-19 deterioration in mild/moderate patients < 65 years old.


The impact of COVID-19 on hospitalization outcomes of patients with acute myocardial infarction in the USA.
The effect of the COVID-19 pandemic affected health care delivery, as it led to variable outcomes in different disease states including cardiovascular diseases. In this study, we evaluated the impact of coexisting COVID-19 on Acute Myocardial Infarction (AMI). We analyzed discharge records of AMI patients from the National Inpatient Sample (NIS) in the year 2020. Using propensity score matching, we assessed the impact of COVID-19 infection on the in-hospital outcomes of patients presenting with AMI. There were 1154 patients with concomitant COVID-19 infection and AMI who were matched with 109,990 patients with AMI and without COVID-19. We found that patients with COVID-19 who had AMI were less likely to have dyslipidemia (64.6 % vs. 70.4 %, p < 0.001), peripheral vascular disease (2.4 % vs. 3.8 % p = 0.0017), smoking history (23.5 % vs. 28.2 % p < 0.0001) and hypertension (37.1 % vs. 40.1 % p = 0.004).COVID-19 was associated with higher hospital mortality rates (Adjusted odds ratio aOR: 2.72, CI: 2.23-3.30, p < 0.001), cardiac arrest (aOR: 1.65, 95 % CI: 1.26-2.15, p < 0.001), cardiogenic shock (aOR:1.36,95 % CI: 1.10-1.68, p = 0.004) and respiratory failure (aOR:1.81, 95 % CI: 1.55-2.11 p < 0.001) compared to AMI patients without COVID-19. There was also a significant association between coexisting COVID-19 and longer duration of hospital stay (Adjusted mean differences:1.40, 95 % CI: 1.31-1.59 p < 0.0001) in AMI patients. COVID-19 infection is associated with worse in-hospital mortality and cardiorespiratory complications in patients with AMI.


[Acute myocardial infarct in a 14-year-old girl treated with contraceptives. Coronary arteriography and immediate thrombolytic therapy].
A 14 year old girl on oral contraceptive treatment for menstrual disorders, was admitted with an acute anterior myocardial infarction and underwent immediate coronary arteriography and intracoronary thrombolysis (urokinase 350,000 units) within 4 hours of the onset of symptoms. A segmental occlusion of the left anterior descending artery with no evidence of coronary atherosclerosis elsewhere was shown. A successful re-canalization was documented after fibrinolytic therapy. The present is the first reported case, in a patient of this age, with an angiographic demonstration during the acute phase of the thromboembolic pathogenesis of myocardial infarction in contraceptive users. The potential benefit of early thrombolytic treatment in this rare clinical setting is thus suggested.


IQ decline following early unilateral brain injury: a longitudinal study.
We examine whether children with early unilateral brain injury show an IQ decline over the course of development. Fifteen brain injured children were administered an IQ test once before age 7 and again several years later. Post-7 IQ scores were significantly lower than pre-7 IQ scores. In addition, pre-7 IQ scores were lower for children with larger lesions, but children with smaller lesions and higher pre-7 IQ scores showed a greater IQ decline over time. These findings suggest that the cognitive outcomes of children with early lesions, particularly those with relatively small lesions, change over the course of development.


Regulation of urea permeability in frog urinary bladder by prostaglandin E(2).
The present study was performed to investigate the role of prostaglandin E(2) (PGE(2)) in the regulation of urea transport in the frog urinary bladder, which is known to occur via a specialized arginine-vasotocin- (AVT-) regulated urea transporter. The bladders isolated from Rana temporaria L. were filled with amphibian Ringer solution containing 370 Bq/ml (0.01 microCi/ml) of [14C]urea, and urea permeability ( P(urea)) was determined by sampling the serosal and mucosal bathing medium at 30-min intervals for measurement of radioactivity. It was found that, from the serosal side, PGE(2) (10 nM to 1 microM) caused a dose-dependent increase in P(urea) [(7.2+/-1.8)x10(-6) cm/s in the presence of 0.5 microM PGE(2)versus (1.0+/-0.2)x10(-6) cm/s in control, n=9, P<0.001]. As in response to AVT, the PGE(2)-induced P(urea)reached a maximum in 1-1.5 h after the agonist was added. The stimulatory effects of PGE(2) and AVT applied together were not additive. PGE(2)-induced urea transport was strongly inhibited by nearly 75% in the presence of mucosal or serosal phloretin (10(-4) M). P(urea) was enhanced up to (4.7+/-0.8)x10(-6) cm/s (n=12, P<0.001) by butaprost (5 x 10(-6) M), a selective EP(2) receptor agonist, while sulprostone (EP(1)/EP(3) agonist, 10(-6) M) caused no changes in P(urea). PGE(2)dose-dependently increased the content of cAMP in mucosal epithelial cells (control: 18.0+/-1.8; 10(-6) M PGE(2): 74.2+/-9.3 pmol cAMP/mg protein per 30 min, n=7, P<0.001). Phorbol esters did not alter PGE(2)-induced P(urea), whereas H-89 (20 microM), a protein kinase A inhibitor, reduced it by 45.1+/-9.9% ( n=5, P<0.05). PGE(2)did not change the AVT-stimulated P(urea) measured in isoosmotic conditions, but inhibited the last one in the presence of a serosa-to-mucosa osmotic gradient. The data obtained show that, in the frog urinary bladder, PGE(2)is a stimulator of phloretin-inhibitable urea transport. Its effect seems to be mediated by EP(2) receptor-coupled generation of intracellular cAMP.


[Indication for conservative therapy of reflux esophagitis (author's transl)].
Conservative treatment is sufficient for the majority of patients with pathologic gastroesophageal reflux and reflux esophagitis proved by endoscopic and histologic examination. The indications for operation are failure of conservative therapy with progressive reflux esophagitis, or the occurrence of rare complications such as stenosis or massive hemorrhage. Even in these complicated cases the decision to operate will depend on the clinical status and risk factors for individual patients.


Understanding and tuning blue-to-near-infrared photon cutting by the Tm3+/Yb3+ couple.
Lanthanide-based photon-cutting phosphors absorb high-energy photons and 'cut' them into multiple smaller excitation quanta. These quanta are subsequently emitted, resulting in photon-conversion efficiencies exceeding unity. The photon-cutting process relies on energy transfer between optically active lanthanide ions doped in the phosphor. However, it is not always easy to determine, let alone predict, which energy-transfer mechanisms are operative in a particular phosphor. This makes the identification and design of new promising photon-cutting phosphors difficult. Here we unravel the possibility of using the Tm3+/Yb3+ lanthanide couple for photon cutting. We compare the performance of this couple in four different host materials. Cooperative energy transfer from Tm3+ to Yb3+ would enable blue-to-near-infrared conversion with 200% efficiency. However, we identify phonon-assisted cross-relaxation as the dominant Tm3+-to-Yb3+ energy-transfer mechanism in YBO3, YAG, and Y2O3. In NaYF4, in contrast, the low maximum phonon energy renders phonon-assisted cross-relaxation impossible, making the desired cooperative mechanism the dominant energy-transfer pathway. Our work demonstrates that previous claims of high photon-cutting efficiencies obtained with the Tm3+/Yb3+ couple must be interpreted with care. Nevertheless, the Tm3+/Yb3+ couple is potentially promising, but the host material-more specifically, its maximum phonon energy-has a critical effect on the energy-transfer mechanisms and thereby on the photon-cutting performance.


Systems and integrative biology as alternative guises for pharmacology: prime time for an iPharm concept?
Understanding the molecular basis of human disease pathophysiology is critical to accurate disease diagnosis, defining disease progression and to identifying new drugs that more specifically address target diseases. Advances in the understanding of tissue function (including draft maps of the human genome) coupled with industrial-scale, 'enabling' technologies like high throughput screening, combinatorial chemistry, proteomics, etc., have generated data on a scale never before possible. Despite this, there continues to be a dearth of new drug approvals ascribed to: (i) the challenges of working with novel, often non-validated disease targets; (ii) targeting diseases (stroke, Alzheimer's) with limited (if any) treatment and ill-defined clinical trial endpoints; (iii) enhanced regulatory hurdles for drug approval; (iv) insufficient time for the new knowledge and enabling technologies to have reached a productive level. An alternate viewpoint is that unfettered access to such technologies, where exclusion rather than integration has been the hallmark, has markedly reduced the intellectual competent of the biomedical research endeavor, with perceived technological 'quick fixes' displacing the integrative, hierarchical approach of pharmacology, that with medicinal chemistry, represents the core of the drug discovery process. After two decades of profound neglect, pharmacology has re-emerged as the key discipline in providing context to the drug discovery process, facilitating more timely, context-relevant and data-driven outcomes in the search for new drugs. Rather than viewing the future of drug discovery in terms of the 'new' biologies, systems and integrative, a rubric along the lines of iPharm, integrating both established and new technologies, is required.


Combining the AKT inhibitor capivasertib and SERD fulvestrant is effective in palbociclib-resistant ER+ breast cancer preclinical models.
Combining the selective AKT inhibitor, capivasertib, and SERD, fulvestrant improved PFS in a Phase III clinical trial (CAPItello-291), treating HR+ breast cancer patients following aromatase inhibitors, with or without CDK4/6 inhibitors. However, clinical data suggests CDK4/6 treatment may reduce response to subsequent monotherapy endocrine treatment. To support understanding of trials such as CAPItello-291 and gain insight into this emerging population of patients, we explored how CDK4/6 inhibitor treatment influences ER+ breast tumour cell function and response to fulvestrant and capivasertib after CDK4/6 inhibitor treatment. In RB+, RB- T47D and MCF7 palbociclib-resistant cells ER pathway ER and Greb-1 expression were reduced versus naïve cells. PI3K-AKT pathway activation was also modified in RB+ cells, with capivasertib less effective at reducing pS6 in RB+ cells compared to parental cells. Expression profiling of parental versus palbociclib-resistant cells confirmed capivasertib, fulvestrant and the combination differentially impacted gene expression modulation in resistant cells, with different responses seen in T47D and MCF7 cells. Fulvestrant inhibition of ER-dependent genes was reduced. In resistant cells, the combination was less effective at reducing cell cycle genes, but a consistent reduction in cell fraction in S-phase was observed in naïve and resistant cells. Despite modified signalling responses, both RB+ and RB- resistant cells responded to combination treatment despite some reduction in relative efficacy and was effective in vivo in palbociclib-resistant PDX models. Collectively these findings demonstrate that simultaneous inhibition of AKT and ER signalling can be effective in models representing palbociclib resistance despite changes in pathway dependency.


Human macrophage metabolism of low density lipoprotein oxidized by stimulated neutrophils and ferritin.
The metabolism of low density lipoprotein (LDL) oxidized with phorbol myristate acetate (PMA) stimulated neutrophils plus ferritin (LDLox) by human monocyte-derived macrophage (HMDM) was studied. Binding of 125I-labeled LDLox to HMDM and further uptake and degradation were higher than for native 125I-labeled LDL. LDLox seems to be taken up by HMDM through the scavenger receptor as indicated by competition studies with unlabeled native and autoxidized LDL. An increased concentration of cellular cholesteryl esters was observed in HMDM exposed to LDLox. Oxidative modification of LDL increased its electrophoretic migration on agarose gel and also the fragmentation of apolipoprotein B. Data suggest that LDLox is incorporated by human macrophages and can potentially induce foam-cell formation.


Hybrid CRISPR/Cas protein for one-pot detection of DNA and RNA.
Clustered regularly interspaced short palindromic repeats (CRISPR)-based diagnostics have emerged as next-generation molecular diagnostics. In CRISPR-based diagnostics, Cas12 and Cas13 proteins have been widely employed to detect DNA and RNA, respectively. Herein, we developed a novel hybrid Cas protein capable of detecting universal nucleic acids (DNA and RNA). The CRISPR/hybrid Cas system simultaneously recognizes both DNA and RNA, enabling the dual detection of pathogenic viruses in a single tube. Using wild-type (WT) and N501Y mutant severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) as detection models, we successfully detected both virus strains with a detection limit of 10 viral copies per reaction without cross-reactivity. Furthermore, it is demonstrated the detection of WT SARS-CoV-2 and N501Y mutant variants in clinical samples by using the CRISPR/hybrid Cas system. The hybrid Cas protein is expected to be utilized in a molecular diagnostic method for infectious diseases, tissue and liquid biopsies, and other nucleic acid biomarkers.


List length and overlap effects in forced-choice associative recognition.
Two experiments examined forced-choice associative recognition for OLAP and NOLAP test conditions. OLAP test trials consist of pairs with overlapping items (e.g., AB vs. AD), whereas NOLAP test trials contain no overlapping items (e.g., AB vs. CF). Previous results show better performance for NOLAP than for OLAP tests, contrary to the predictions of global memory models. The present experiments varied list length to examine the hypothesis that the NOLAP advantage is produced by recall-like retrieval processes. The use of longer lists either eliminated (Experiment 1) or greatly reduced (Experiment 2) the NOLAP advantage. However, a reliable OLAP advantage was not obtained. Implications for models are discussed.


Differential reactivity of brain microvascular endothelial cells to TNF reflects the genetic susceptibility to cerebral malaria.
Upon infection with Plasmodium berghei ANKA (PbA), various inbred strains of mice exhibit different susceptibility to the development of cerebral malaria (CM). Tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN-gamma) have been shown to be crucial mediators in the pathogenesis of this neurovascular complication. Brain microvascular endothelial cells (MVEC) represent an important target of both cytokines. In the present study, we show that brain MVEC purified from CM-susceptible (CM-S) CBA/J mice and CM-resistant (CM-R) BALB/c mice exhibit a different sensitivity to TNF. CBA/J brain MVEC displayed a higher capacity to produce IL-6 and to up-regulate intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in response to TNF than BALB/c brain MVEC. In contrast, no difference was found in the induction of E-selectin after TNF challenge. CM-S brain MVEC were also significantly more sensitive to TNF-induced lysis. This differential reactivity to TNF was further substantiated by comparing TNF receptor expression on CM-S and CM-R brain MVEC. Although the constitutive expression of TNF receptors was comparable on cells from the two origins, TNF induced an up-regulation of both p55 and p75 TNF receptors in CM-S, but not in CM-R brain MVEC. A similar regulation was found at the level of TNF receptor mRNA, but not for receptor shedding. Although a protein kinase C inhibitor blocked the response to TNF in both the brain MVEC, an inhibitor of protein kinase A selectively abolished the response to TNF in CM-R, but not CM-S brain MVEC, suggesting a differential protein kinase involvement in TNF-induced activation of CM-S and CM-R brain MVEC. These results indicate that brain MVEC purified from CM-S and CM-R mice exhibit distinctive sensitivity to TNF This difference may be partly due to a differential regulation of TNF receptors and via distinct protein kinase pathways.


Telomerase reverse transcriptase regulates the expression of a key cell cycle regulator, cyclin D1.
Cells require a mechanism to maintain telomere stability in order to overcome replicative senescence and telomerase catalyzes the synthesis and extension of telomeric DNA, therefore, be a rate-limiting step in cellular immortality and oncogenesis. However, some studies have raised questions about whether the stabilization of chromosome ends entirely explains the ability of telomerase to promote tumorigenesis. To elucidate non-canonical functions of human telomerase reverse transcriptase (hTERT), we used loss-of-function and gain-of-function studies. We demonstrated that hTERT shRNA down-regulated and hTERT overexpression up-regulated the expression and transcriptional activity of a key cell cycle regulator, cyclin D1, in human prostate epithelial cell lines, DU-145 and BPH-1. Based on these observations, we propose that in addition to its well-defined function in telomere length regulation, hTERT has a novel role in the modulation of cyclin D1 expression.


Water Is Needed to Exist: Habitat Preferences of Tiger Beetles (Coleoptera: Cicindelidae) in a Desert Country.
Tiger beetles are a group of predatory insects occurring mainly in diverse sandy areas, with particular species often characterised by narrow habitat preferences, which makes them both very important bioindicators for determining patterns of biodiversity and a flagship group for nature conservation. However, the precise roles of particular habitat parameters in the distribution of these beetles in desert areas are almost unknown. Habitat preferences for four tiger beetles species were analysed in Tunisia. Fifty samples from a major part of the country were collected, for which climate data, macrohabitat types. and soil parameters (soil humidity, salinity, pH, and structure) were studied. Here we show that most studied Cicindelidae were characterised by unique habitat preferences and did not co-occur with other ones, including two taxa found as habitat specialists, occurring in only one type of macrohabitat. Two other species were noted as more eurythopic and occupied 2-3 macrohabitat types, with Lophyra flexuosa as the most ubiquitous species not related to the measured parameters. The presence of a source of water (understood as a part of the habitat type, such as river banks and oases, or high soil humidity) was found as the most important factor in the distribution of the studied tiger beetle species. The present study is the first one focused on habitat preferences and habitat specialization of Cicindelidae fauna of Maghreb, and one of only a few in Africa.


A highly selective potentiometric sensor of molybdate based on a mu-oxo-bridged manganeseporphyrin dimer.
A novel high-selective potentiometric sensor for molybdate was prepared with a PVC membrane combining mu-oxo-bis[5,10,15,20-tetra(p-methylphenyl)porphinatomanganese(III)] [[Mn(p-Me)TPP](2)O] as an electroactive material and 2-nitrophenyl octyl ether (o-NPOE) as a plasticizer in the percentage ratio of 3:65:32, [Mn(p-Me)TPP](2)O:o-NPOE:PVC (w:w). The sensor exhibited a linear response with a Nernstian slope of 30.5 mV per decade within a concentration range of 2.1 x 10(-6) to 1.0 x 10(-1) M MoO4(2-), with a working pH range from 5.0 to 12.5, and a fast response time of less than 15 s. The electrode showed improved selectivity toward molybdate with respect to common coexisting anions compared to monometalloporphyrin counterparts. Several electroactive materials and solvent mediators were compared and the experimental conditions were optimized. The sensor is preliminary applied to the assay of MoO4(2-) in corrosion inhibitor samples with satisfactory results.


A retrospective study of patients with Robin sequence: Patient characteristics and their impact on clinical outcomes.
Robin sequence (RS) is a congenital set of abnormalities of the head and neck, consisting of a hypoplastic mandible (micrognathia), a tongue that is displaced posteriorly (glossoptosis), and obstruction of the airway. A clear set of diagnostic criteria for this complex condition has recently been established, but there is still no consensus in the literature with respect to managing the associated airway, feeding, and hearing difficulties. The objectives of the study are: 1) to describe the management of airway and feeding issues in children with RS; and 2) to evaluate the impact of airway and feeding strategies on important clinical outcomes. A retrospective chart review was conducted of all pediatric patients diagnosed with RS at London Health Sciences Centre from January 1995 until September 2017. The frequencies of all airway and feeding interventions were collected. Data were collected on several clinical outcomes including initial admission length, enteral feeding duration, tympanostomy tube insertion frequency, and hearing thresholds. Statistical analyses to evaluate the impact of airway and feeding strategies on clinical outcomes were carried out using independent samples t-tests and Chi-square tests, where appropriate. Twenty-four patients were identified. Five patients (20.8%) required airway surgery and 18 patients (75.0%) required enteral feeding. Airway surgery was significantly associated with a longer ICU admission (15.8 vs. 4.3 days, p < 0.05), a longer overall hospital admission (73.0 vs. 25.2 days, p < 0.05), a delay in introducing oral feeds (222.8 vs. 11.5 days, p < 0.05), and a higher frequency of tympanostomy tube insertions (80% vs. 23.5% requiring ≥2 insertions, p < 0.05). Enteral feeding was significantly associated with a longer ICU admission (8.8 vs. 0 days, p < 0.05) and a longer overall hospital admission (43.9 vs. 5.6 days, p < 0.05). This study demonstrates the substantial impact that airway and feeding difficulties have on RS patient morbidity, particularly with respect to length of hospital and ICU admission. This information has prognostic value and may be helpful in generating a management algorithm for this complex patient population.


Analysis on the complete genome of a novel caprine parainfluenza virus 3.
Parainfluenza virus type 3 (PIV3) is one of the most important viral respiratory pathogens for humans and for many animals. One unique caprine PIV3 (CPIV3) strain named JS2013 was isolated in Chinese goat flocks with respiratory diseases in 2013. Now, the complete genome sequence of the strain JS2013 had been determined. A total of 15 overlapping DNA clones, covering the entire genome of the virus, were obtained by primer walking RT-PCR. The sequences of the 3' and 5' termini of the viral genome were amplified by 3' and 5' RACE. The viral genome was 15,618 nucleotides (nt) in length, which was consisted of six genes in the order 5'-leader-N-P/C/V-M-F-HN-L-tailer-3'. The junction sequences between two genes were highly conserved gene start and stop signal sequences, and trinucleotide intergenic regions (IGR) similar to those of other reported PIV3 strains. Phylogenetic analysis based on the complete genomes of JS2013 with other strains of genus Respirovirus demonstrated that the JS2013 obviously differed from HPIV1, Sendai virus, HPIV3 and other reported BPIV3 genotypes. Further analysis of HN genes of JS2013 along with two more CPIV3 strains isolated later indicated that CPIV3 strains formed a separate cluster. The results presented here suggested that CPIV3 is a new member of the genus Respirovirus.


The Hospital Anxiety and Depression Scale: a diagnostic meta-analysis of case-finding ability.
To quantify the accuracy of the Hospital Anxiety and Depression Scale (HADS) as a case-finding instrument for anxiety and depressive disorders. MEDLINE, PSYCHINFO, EMBASE, CINAHL, BNI, and AMED were searched from January 1983 to June 2006. Studies were included that administered the HADS, used a standardized psychiatric interview to establish a diagnosis of anxiety or depression, and provided sufficient data on sensitivity and specificity (N=41). Summary sensitivity, specificity, likelihood ratios, and diagnostic odds ratios were calculated for each study. Random effects meta-analytic pooling across studies at the recommended clinical (7/8) and research (10/11) cutoff points was undertaken and summary receiver operating characteristic curves constructed. For major depressive disorders, a cut point of ≥8 gave a sensitivity of 0.82 (95% CI, 0.73-0.89) and a specificity of 0.74 (95% CI, 0.60-0.84) and a cut point ≥11 gave a sensitivity of 0.56 (95% CI, 0.40-0.71) and a specificity of 0.92 (95% CI, 0.79-0.97). Many studies have shown that the HADS is a useful screening tool to identify emotional distress in nonpsychiatric patients. However, it does not appear to be superior to other screening instruments in terms of identifying specific mental disorders in physical health settings.


Characterization of weak alleles at the DIA1 locus (Mustapha 1, Mustapha 2, and Mustapha 3) in the Algerian population.
One percent of the Algerian population carries a weak allele at the DIA1 locus, responsible for a 50% decrease of red cell soluble cytochrome b5 reductase activity. Quantitative abnormalities of the soluble and the membrane-bound enzyme have been investigated in the red cells and in the leukocytes of seven subjects considered to be heterozygous at the DIA1 locus. Conventional electrophoretic or isoelectrophoretic studies did not show any qualitative abnormality. However, continuous titration obtained by combined IEF-electrophoresis displayed in five out of seven subjects a discrete abnormal line on the titration curve compatible with an Arg leads to His substitution. In fact, at least three types of weak alleles could be defined by combining the qualitative and quantitative results obtained with the erythrocyte (soluble and membrane-bound) and leukocyte enzyme. We call these subgroups DIA Mustapha1, DIA Mustapha2, and DIA Mustapha3.


[Secretion of cortisol and growth hormone in patients with peptic ulcers of the stomach and the duodenal bulb].
A total of 42 patients with gastric ulcer and ulcer of the duodenal bulb were investigated. A decrease in the blood concentration of STH and cortisol, high indices of gastric acidifying function in the 2nd hour after insulin administration were noted in the patients with gastric ulcer indicating a decrease in the trophic influence of the hormones of the hypophysis-adrenal system on the GI tract, on the one hand, and raised sensitivity of parietal cells to the effects of this system, on the other hand. In the patients with duodenal ulcer the blood levels of STH and cortisol did not change, indices of gastric acidifying function within the 1st hour after insulin administration were higher than during the 2nd hour indicating an important role of the vagus nerve hypertonicity in the pathogenesis of this disease.


Cysteinesulfonate and beta-sulfopyruvate metabolism. Partitioning between decarboxylation, transamination, and reduction pathways.
L-Cysteinesulfonate (L-cysteate) is present in plasma, urine, and tissues in concentrations comparable to that of L-cysteinesulfinate, the primary oxidative metabolite of L-cysteine. Although cysteinesulfonate is known to be decarboxylated to taurine by cysteinesulfinate decarboxylase, the occurrence and importance of other metabolisms has not been examined. The present studies indicate that cysteinesulfonate partitions in vivo between decarboxylation and transamination; the latter reaction is catalyzed by aspartate aminotransferase and yields beta-sulfopyruvate. Whereas beta-sulfinylpyruvate, the product of cysteinesulfinate transamination, decomposes spontaneously, beta-sulfopyruvate is stable and is reduced by malate dehydrogenase to beta-sulfolactate. When L-[1-14C]cysteinesulfonate is given to mice, 60-75% is decarboxylated to taurine and about 25% is excreted in the urine as beta-sulfolactate. beta-Sulfo[1-14C] pyruvate is found to partition about equally between beta-sulfolactate and cysteinesulfonate formation; greater than 90% of the latter is decarboxylated. Parenterally administered beta-sulfo[1-14C]lactate is mostly excreted in the urine, but 12% is metabolized via beta-sulfopyruvate and cysteinesulfonate to 14CO2 and taurine. beta-Sulfopyruvate is not excreted, and only traces of sulfoacetate, perhaps formed by oxidative decarboxylation, are detected. These studies establish that cysteinesulfonate, beta-sulfopyruvate, and beta-sulfolactate are reversibly interconverted in vivo. Since only cysteinesulfonate is directly metabolized to CO2, the rate of 14CO2 formation from L-[1-14C]cysteinesulfonate is a valid measure of total cysteinesulfinate decarboxylase activity in vivo; use of this assay permits inhibitor effects to be accurately determined in intact mice. Thus, whereas in vitro assays indicate that beta-methyleneaspartate inhibits brain, liver, and kidney cysteinesulfinate decarboxylase by 0, greater than 60, and 90%, respectively, in vivo studies with L-[1-14C]cysteinesulfonate show net metabolic inhibition is about 40%.


Noradrenergic systems in human cerebellum.
Thin, beaded axons, immunostained with antisera to human dopamine beta-hydroxylase (DBH), were present in all layers of the anterior vermis of human cerebellum. This plexus appears similar to that described in rodents and provides information complementary to receptor autoradiographic studies that show significant noradrenergic innervation of mammalian cerebellum. Moreover, in two aged controls, we demonstrated abnormal, swollen, tortuous axons not visualized in young controls.


Retrotrapezoid nucleus in the rat.
The retrotrapezoid nucleus (RTN), recently described in the cat, is an anatomically identified cell group of the ventral medulla. It is of interest because of its possible role in the generation or control of breathing. The present investigation confirms the existence in the rat of an analogous cell group, as identified by retrograde transport of rhodamine microbeads from an injection site in the ventral respiratory group of the ventral medulla. Electrophysiological recordings from the region of RTN reveal individual units with respiratory related activity. These results support a possible role for the RTN in the control of breathing.


Ecophysiology of omega Fatty acids: a lid for every jar.
Omega fatty acids affect various physiological functions, such as locomotion, cardiac function, and thermogenesis. We highlight evidence from animal models that points to pathways by which specific omega fatty acids exert differential effects. We suggest that optimizing the omega fatty acid composition of tissues involves trade-offs between costs and benefits of specific fatty acids.


Evidence for separate mechanisms of antiproliferative action of indomethacin and prostaglandin on MCF-7 breast cancer cells.
Indomethacin is reported to decrease the growth of many tumour cell lines. It is also known to be an anti-inflammatory agent acting by the inhibition of prostaglandin (PG) synthesis. To evaluate a clinical application as antitumoral agent, we have studied whether antiproliferative effect of indomethacin in breast cancer is related to its action on the prostaglandin production. We have observed that indomethacin as well as PGE1, PGE2, PGD2, and PGI2 inhibited the proliferation of MCF-7 breast cancer cells. As breast carcinomas were described to secrete mainly PGE2, we studied the effect of PGE2 on MCF-7 cells. These cells contain two types of binding sites for PGE2: high-affinity (Kd = 0.2 nM) and low-affinity (Kd = 20 nM) receptors. In this cell line, indomethacin and PGE2 inhibitory effects were additive. In addition, we showed that PGE2 increased the cAMP level in MCF-7 cells 30-fold (p < 0.001) while indomethacin did not change basal cAMP accumulation. Like for combination PGE2/indomethacin, the inhibitory effects of a cAMP analog (8-Br-cAMP) and indomethacin were additive. In conclusion, indomethacin inhibits the MCF-7 growth in specific manner independently of PG synthesis, PG action and cAMP accumulation.


The barriers and facilitators to managing diabetes with insulin in adults with intellectual disabilities: A systemised review of the literature.
People with intellectual disabilities are more likely to have diabetes and develop complications from it. Diabetes management is complex and insulin treatment in particular, people with intellectual disabilities may require additional support that is not always available. This review aimed to identify barriers and facilitators to managing diabetes with insulin in adults with intellectual disabilities. Patient and public involvement (PPI) was integral to the development of the research question. A systemised review was conducted across CINAHL, the British Nursing Index and MEDLINE. PRISMA guidelines were followed. Narrative synthesis of the evidence was undertaken. Barriers and facilitators to managing diabetes with insulin in people with intellectual disabilities were identified related to the individual, other people participating in their care, and broader environmental and social factors. People with intellectual disabilities who use insulin, require reasonable adjustments to education, support, and a person-centred approach to facilitate supported self-management. More training for their supporters is needed and further inclusive research with PPI is recommended.


[Injection of resorbable materials].
Resorbable filling materials are currently the safest products available. The side effects with this type of material are few compared to the number of patients treated. We can therefore suggest materials that have maximum safety to our patients, particularly in cosmetic indications.


Delivering elsewhere between the first and second deliveries is a risk marker for obstetric complications in the second delivery.
We speculate that parturients who deliver elsewhere between the first and second deliveries compose a unique clinical group, characterized by higher rates of cesarean section (CS) both in the first and second deliveries, compared with parturients who deliver both deliveries at the same hospital. A retrospective study conducted at Shaare Zedek Medical Center in a tertiary university-affiliated hospital. The cohort included all women in the second delivery, aged ≤24 years with a singleton pregnancy who delivered their second child in our medical center during 2010-2012. Parturients who delivered both the first and second children in our medical center ("stayers") were compared with parturients who delivered their first child in a different hospital ("switchers"). Groups were compared in regard to history of CS in the first delivery and obstetric complications in the second delivery, including CS, instrumental vaginal delivery (IVD), preterm delivery (PTD), and postpartum hemorrhage (PPH). Logistic regressions were constructed to study if delivering elsewhere between the first and second deliveries was a risk for adverse pregnancy outcome, followed by multivariate analysis controlling for confounders. In all, 4166 parturients were included: "stayers" = 3163 and "switchers" = 1003. History of CS in the first delivery was approximately twice as prevalent in "switchers" (12 versus 6.3 %, p < 0.000). "Switchers" experienced higher rates of CS: OR = 1.8 (95 % CI 1.2-2.3); IVD: OR = 1.3 (95 % CI 0.8-2.1); and PTD (<37w): OR = 1.4 (95 % CI 1.0-1.9). Parturients who deliver elsewhere between the first and second childbirth are at increased risk for CS and PTD in the second delivery; hence, the decision to deliver elsewhere after the first delivery should be considered as a risk marker for obstetric complication.


Estimation of metabolic heat production and methane emission in Sahiwal and Karan Fries heifers under different feeding regimes.
The objective of this study was designed to estimate the metabolic heat production and methane emission in Sahiwal and Karan Fries (Holstein-Friesian X Tharparkar) heifers under two different feeding regimes, i.e., feeding regime-1 as per the National Research Council (NRC) (2001) and feeding regime-2 having 15% higher energy (supplementation of molasses) than NRC (2001). Six (n = 6) healthy heifers of Sahiwal and Karan Fries with 18-24 months of age were selected from Indian Council of Agricultural Research-National Dairy Research Institute, Karnal. An initial 15 days was maintained under feeding regime-1 and feeding regime-2 as adaptation period; actual experiment was conducted from 16(th) day onward for next 15 days. At the end of feeding regimes (on day 15(th) and 16(th)), expired air and volume were collected in Douglas bag for two consecutive days (morning [6:00 am] and evening [4:00 pm]). The fraction of methane and expired air volume were measured by methane analyzer and wet test meter, respectively. The oxygen consumption and carbon dioxide production were measured by iWorx LabScribe2. The heat production (kcal/day) was significantly (p<0.05) higher in feeding regime-2 as compared to feeding regimen-1 in both breeds. The heat production per unit metabolic body weight was numerically higher in feeding regime-1 than feeding regime-2; however, the values were found statistically non-significant (p>0.05). The energy loss as methane (%) from total heat production was significantly (p<0.05) higher in feeding regime-1. The body weight (kg), metabolic body weight (W(0.75)), and basal metabolic rate (kcal/kg(0.75)) were significantly (p<0.05) higher in feeding regime-2 in both breeds. This study indicates that higher energy diet by supplementing molasses may reduce energy loss as methane and enhance the growth of Sahiwal and Karan Fries heifers.


Retroperitoneal ganglioneuroma with nodal involvement in an adult patient with human immunodeficiency virus: a case report and review of the literature.
Ganglioneuromas are a benign tumor originating from neural crest cells. As one of the neuroblastic tumors, ganglioneuromas are most common in children, with a mean age at presentation of 7 years. Ganglioneuromas are typically singular in nature, but rarely can present with lymph node involvement and distant metastasis. We present a rare case of a retroperitoneal ganglioneuroma found in a human immunodeficiency virus positive adult, which was complicated by lymph node involvement. This case is notable not only in regard to the age of the patient, but also because of his human immunodeficiency virus positive status and the extension of tumor to lymph nodes. A 27-year-old Latino male with history of human immunodeficiency virus presented with a 6-month history of left upper quadrant and epigastric abdominal pain with associated nausea and vomiting. The patient had a computed tomography scan showing a retroperitoneal mass encasing the aorta, celiac axis, and superior mesenteric artery. Core needle biopsy revealed ganglioneuroma. Owing to obstructive symptoms, resection of the mass along with partial gastric resection, partial pancreatic resection, and splenectomy was performed by a multidisciplinary group of surgeons. Pathology results revealed metastatic spread of ganglioneuroma to surrounding lymph nodes. Ganglioneuromas are most common in children and very rarely occur in adults. However, it is still important to consider this entity in the differential for patients presenting with suspicious symptoms. While rare, it is essential to consider metastasis in this generally benign disease.


High solids loading pretreatment: The core of lignocellulose biorefinery as an industrial technology - An overview.
Pretreatment is the first and most determinative, yet the least mature step of lignocellulose biorefinery chain. The current stagnation of biorefinery commercialization indicates the barriers of the existing pretreatment technologies are needed to be unlocked. This review focused on one of the core factors, the high lignocellulose solids loading in pretreatment. The high solids loading of pretreatment significantly reduces water input, energy requirement, toxic compound discharge, solid/liquid separation costs, and carbon dioxide emissions, improves the titers of sugars and biproducts to meet the industrial requirements. Meanwhile, lignocellulose feedstock after high solids loading pretreatment is compatible with the existing logistics system for densification, packaging, storage, and transportation. Both the technical-economic analysis and the cellulosic ethanol conversion performance suggest that the solids loading in the pretreatment step need to be further elevated towards an industrial technology and the effective solutions should be proposed to the technical barriers in high solids loading pretreatment operations.


In utero exposure to triphenyltin disrupts rat fetal testis development.
Triphenyltin is an organotin that is widely used as an anti-fouling agent and may have endocrine-disrupting effects. The objective of the current study was to investigate effects of triphenyltin on the development of rat fetal testis. Female pregnant Sprague Dawley dams were gavaged daily with triphenyltin (0, 0.5, 1, and 2 mg/kg body weight/day) from gestational day 12 to day 21. Triphenyltin dose-dependently decreased serum testosterone levels (0.971 ± 0.072 and 0.972 ± 0.231 ng/ml at 1 and 2 mg/kg, respectively) from control level (2.099 ± 0.351 ng/ml). Triphenyltin at 1 and 2 mg/kg doses also induced fetal Leydig cell aggregation, decreased fetal Leydig cell size and cytoplasmic size. Triphenyltin decreased the expression levels of Lhcgr, Scarb1, Star, Cyp11a1, Cyp17a1, Insl3, Fshr, Pdgfa, and Sox9 by 0.5 mg/kg dose and above. However, triphenyltin did not affect Leydig and Sertoli cell numbers. In conclusion, the current study indicated that in utero exposure of triphenyltin disrupted fetal Leydig and Sertoli cell development.


Inverse correlation of CD3 & vascular endothelial growth factor in incisional oral squamous cell carcinoma biopsies predicts nodal metastasis & poor survival of patients.
Oral squamous cell carcinoma (OSCC) is widely prevalent in the Indian subcontinent mainly due to habit-associated aetiologies. Immune regulation and angiogenesis are the part of tumourigenesis that play a crucial role in metastasis and survival. However, the concurrent expression of vascular endothelial growth factor (VEGF) and CD3 (immune regulator receptor on T-lymphocyte) in the same OSCC tissue samples has not been reported in the Indian population. The present study evaluated the expression of CD3+ T-cells and VEGF in OSCC tissue samples and studied the clinicopathological correlation and survival analysis in an Indian population. This was a retrospective study conducted on 30 formalin-fixed and paraffin embedded sections which were histologically diagnosed as OSCC cases comprising of 15 metastatic OSCC and 15 non-metastatic OSCC with available clinical data and survival status. Reduced expression of CD3+ T-cells and increased VEGF expression were observed in metastatic OSCC samples. The correlation of expression of CD3+ T-cells and VEGF with clinicopathological parameters showed a significant association between these markers with age, nodal status, site of the lesion and survival. Reduced expression of CD3+ T-cells in OSCC was found to be associated with a significantly poor survival. VEGF was found to be over expressed in metastatic OSCC as compared to that in non-metastatic OSCC. The study findings suggest that the evaluation of CD3 and VEGF in incisional OSCC biopsies can be considered for predicting the survival outcome and metastasis.


An in vivo active 1,2,5-oxadiazole Pt(II) complex: A promising anticancer agent endowed with STAT3 inhibitory properties.
New Pt(II) complexes (Pt-1-3) bearing 1,2,5-oxadiazole ligands (1-3) were synthesized, characterized and evaluated for their ability to disrupt STAT3 dimerization. Ligand 3·HCl showed cytotoxic effects on HCT-116 cells (IC50 = 95.2 μM) and a selective ability to interact with STAT3 (IC50 = 8.2 μM) versus STAT1 (IC50 > 30 μM). Its corresponding platinum complex Pt-3 exhibited an increased cytotoxicity (IC50 = 18.4 μM) and a stronger interaction with STAT3 (IC50 = 1.4 μM), leading to inhibition of its signaling pathway. Pt-3 was also evaluated in cell-based assays for its action on p53 expression and on STAT3 phosphorylation. In syngeneic murine Lewis lung carcinoma (LLC) implanted in C57BL/6 mice, Pt-3 showed a higher antitumor activity with fewer side effects than cisplatin.


Therapeutic and pharmacokinetic characterizations of an anti-amyloidogenic bis-styrylbenzene derivative for Alzheimer's disease treatment.
Alzheimer's disease drug discovery regarding exploration into the molecules and processes has focused on the intrinsic causes of the brain disorder correlated with the accumulation of amyloid-β. An anti-amyloidogenic bis-styrylbenzene derivative, KMS80013, showed excellent oral bioavailability (F=46.2%), facilitated brain penetration (26%, iv) in mouse and target specific in vivo efficacy in acute AD mouse model attenuating the cognitive deficiency in Y-maze test. Acute toxicity (LD50 >2000 mg/kg) and hERG channel inhibition (14% at 10 μM) results indicated safety of KMS80013.


Tetrodotoxin slightly shortens action potential duration in ventricular but not in atrial heart muscle.
Tetrodotoxin (TTX), at concentrations significantly decreasing maximal upstroke velocity (dV/dtmax) of the action potential, exerted variable effects on action potential duration (APD) in different myocardial preparations. APD was virtually unchanged by tetrodotoxin in the guinea pig atrium, but slightly shortened in the guinea pig ventricle at maximally effective concentrations. In the human ventricle, both dV/dtmax and APD were reduced in the same concentration range of TTX. These results suggest that a TTX-sensitive sodium current significantly contributes to the repolarization phase of the action potential in ventricular but not in atrial heart muscle.


Immobilization results in sustained calcium transport in Nostoc calcicola Bréb.
The uptake pattern of Ca2+ by the cyanobacterium Nostoc calcicola Bréb in its freely suspended and immobilized form is comprised of two distinct phages; (a) rapid uptake for 1st 10 min followed by (b) slower transport at least up to 60 min. Entrapment of cyanobacterial cells in polyvinyl foam always maintained a higher Ca2+ profile over freely suspended cells. Also, the intracellular Ca2+ concentration was three times more in the former under similar experimental conditions. Whereas, illumination supported maximum Ca2+ transport in all the sets, darkness resulted in drastic reduction (90%) of Ca2+ uptake in freely suspended cells and least (15%) in polyvinyl entrapped cyanobacterial cells. Exogenously added ATP (10 microM) on the other hand, enhanced Ca2+ uptake in dark incubated freely suspended cells; ATP at the same concentration failed to bring out any significant enhancement in cation uptake in immobilized cells facing dark exposure. It was observed that these cells were still able to sustain sufficient ATP preserves to drive active transport of Ca2+ even in the dark. Furthermore, the immobilized cells exhibited remarkable Ca2+ transport rate even at the age of 20 and 50 days at which its free living counterpart took up insignificant Ca2+. These findings suggest the improved metabolic efficiency of polyvinyl foam entrapped cells over freely suspended cells in terms of Ca2+ accumulation and its possible use as a bioreactor for metal accumulation/removal in repetitive cycles without any measurable loss in cell biomass.


Carticaine versus lidocaine for peribulbar anesthesia in cataract surgery.
To compare carticaine 4% and lidocaine 2% for peribulbar anesthesia in cataract surgery. Ain Shams and Cairo University Hospitals, Cairo, Egypt. This prospective double-blind randomized study comprised 200 cataract patients assigned to 1 of 2 groups of 100 each based on type of anesthesia: carticaine 4% or lidocaine 2%. The efficacy, safety, and duration of the motor and the analgesic block produced by carticaine 4% adrenaline hyaluronidase mixture and lidocaine 2% adrenaline hyaluronidase mixture used as peribulbar anesthesia were compared. The mean time for satisfactory block, need for supplementary injections, incidence of intraoperative and postoperative pain, and postoperative complications were evaluated. The data were analyzed using the Student t test and Mann-Whitney U test for intergroup differences. The chi-square or Fisher exact test was used to assess eye movement scores, the need for supplementary injections, the onset of postoperative pain, and the incidence of postoperative complications. The mean time for satisfactory anesthesia was 7.5 minutes +/- 1.68 (SD) for lidocaine 2% and 2.5 +/- 1.53 minutes for carticaine 4% (P <.001). The need for supplementary injections was 28% in the lidocaine group and 4% in the carticaine group (P <.001). The mean onset of postoperative pain was 2.00 +/- 0.86 hours in the lidocaine group and 5.52 +/- 1.80 hours in the carticaine group (P <.05). There were no cases of postoperative neurotoxicity or extraocular muscle dysfunction in either group. Carticaine 4% adrenaline hyaluronidase mixture was an effective and safe agent for peribulbar anesthesia. It was more efficient than lidocaine 2% adrenaline hyaluronidase mixture in the onset and quality of anesthesia as well as postoperative analgesia.


Vasodilator effects of dopaminomimetics in the perfused rat kidney.
The renal vascular effects of dopaminomimetics were studied in the isolated perfused rat kidney after pretreatment with 10(-5) M phenoxybenzamine and 10(-5) M sotalol and after contraction of the vascular bed with prostaglandin F2 alpha (10(-7) to 3 x 10(-6) M). Under these conditions, our criterion for vascular dopaminomimetic activity was renal vasodilation, competitively inhibited by d-butaclamol (10(-8) M) but not by 1-butaclamol (3 x 10(-8) M). Dopamine is active at micromolar concentrations (ED50 = 2.53 +/- 0.34 x 10(-6) M). The N-alkylated analogues of dopamine preserve this activity if the alkyl group is a methyl group (epinine) or two n-propyl groups (di-n-propyl-dopamine). The catechol nucleus appears essential for renal vascular dopaminomimetic activity (SK&F 38393, active; p-tyramine, di-n-propyl-m-tyramine and RU 24926, inactive). Bromocriptine reproduces renal dopaminergic vasodilation with an ED50 of 1.3 +/- 0.14 x 10(-6) M. The study of structure-activity relationships of dopaminomimetics relates the vascular dopamine receptor, associated with renal vasodilation, to the dopamine receptor, associated with stimulation of dopamine-sensitive adenylate cyclase.


Animal production predominantly contributes to antibiotic profiles in the Yangtze River.
Human-induced antibiotic pollution in the world's large rivers poses significant risk to riverine ecosystems, water quality, and human health. This study identified geophysical and socioeconomic factors driving antibiotic pollution in the Yangtze River by quantifying 83 target antibiotics in water and sediment samples collected in its 6300-km-long reach, followed by source apportionment and statistical modeling. Total antibiotic concentrations ranged between 2.05-111 ng/L in water samples and 0.57-57.9 ng/g in sediment samples, contributed predominantly by veterinary antibiotics, sulfonamides and tetracyclines, respectively. Antibiotic compositions were clustered according to three landform regions (plateau, mountain-basin-foothill, and plains), resulting from varying animal production practices (cattle, sheep, pig, poultry, and aquaculture) in the sub-basins. Population density, animal production, total nitrogen concentration, and river water temperature are directly associated with antibiotic concentrations in the water samples. This study revealed that the species and production of food animals are key determinants of the geographic distribution pattern of antibiotics in the Yangtze River. Therefore, effective strategies to mitigate antibiotic pollution in the Yangtze River should include proper management of antibiotic use and waste treatment in animal production.


Effect of endogenous nitric oxide on energy metabolism of rat heart mitochondria during ischemia and reperfusion.
The effects of ischemia and postischemic reperfusion on the functions of the heart and its mitochondria were studied with special attention to the effect of nitric oxide (NO) by treatment of rat hearts with the nitric oxide synthase (NOS) inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME) or its noninhibitory isomer N(G)-nitro-D-arginine methyl ester (D-NAME). NO generated during reperfusion caused increase in coronary flow (CF), but had no effect on the left ventricular pressure (LVP) or heart rate (HR). The ATP level of the heart decreased during ischemia and was not completely restored by introduction of oxygen during reperfusion due to damage of complexes I and II of the respiratory chain of mitochondria by NO. Inhibition of the respiratory chain resulted in generation of hydrogen peroxide, and NO and NO-derived species generated after production of NO caused further damage of various proteins in mitochondria, such as complexes I and II of the respiratory chain and pyruvate dehydrogenase (PDH). These results suggested that NO generated on reperfusion was the primary cause of mitochondrial dysfunction by damage of complexes I and II of the respiratory chain, with consequent increase of CF in the heart.


Characterization of household food insecurity in Québec: food and feelings.
This study was undertaken to understand food insecurity from the perspective of households who experienced it. The results of group interviews and personal interviews with 98 low-income households from urban and rural areas in and around Québec City, Canada, elicited the meaning of "enough food" for the households and the range of manifestations of food insecurity. Two classes of manifestations characterized the experience of food insecurity: (1) its core characteristics: a lack of food encompassing the shortage of food, the unsuitability of both food and diet and a preoccupation with continuity in access to enough food; and a lack of control of households over their food situation; and (2) a related set of potential reactions: socio-familial perturbations, hunger and physical impairment, and psychological suffering. The results substantiate the existence of food insecurity among Québecers and confirm that the nature of this experience is consistent with many of the core components identified in upstate New York. This study underlines the monotony of the diet, describes the feeling of alienation, differentiates between a lack of food and the reactions that it engenders, and emphasizes the dynamic nature of the experience.


Histology of the transverse carpal ligament and flexor tenosynovium in idiopathic carpal tunnel syndrome.
Histology of the transverse carpal ligament and flexor tenosynovium was investigated in 166 wrists from 130 patients with idiopathic carpal tunnel syndrome. Nine wrists from 9 controls were used for comparison. In the patients, 73.5% of the ligament and 56.0% of the tenosynovium showed normal histology. In the remaining specimens, the ligament showed mucoid change (17.5%), amyloid deposits (7.8%), inflammation (3.0%), and chondrometaplasia (2.4%), and the tenosynovium showed fibrosis (25.3%), edema (7.2%), inflammation (10.2%), amyloid deposits (8.4%), and vascular hypertrophy (4.8%). The majority of these changes were mild in degree and the pathophysiology did not appear to be meaningful. We conclude that in idiopathic carpal tunnel syndrome, the ligament and tenosynovium often show normal histology and there are no typical or consistent changes with which idiopathic carpal tunnel syndrome can be associated.


Targeting immunosuppression after standard sorafenib treatment to facilitate immune checkpoint blockade in hepatocellular carcinoma - an auto-commentary on clinical potential and future development.
Immunotherapy has shown great promise to transform solid cancer treatment. The challenge is to optimally incorporate novel immunotherapeutics, such as immune checkpoint blockers, with standard therapies. This is well exemplified by multimodal therapies recently developed for liver cancer in which immunomodulation using CXCR4 inhibition prevented immunosuppression and enhanced sorafenib and anti-PD-1 therapeutic outcome.


Homogamous assortative mating among Puerto Rican families: intergenerational processes and the migration experience.
Homogamous assortative mating is examined in the context of intergenerational processes and the migration experience in two generations of Puerto Rican families in New York City: mothers and fathers in a parent generation (100 pairs) and their married child and the child's spouse in the child generation (100 pairs). The variables used to examine intergenerational processes and to assess homogamy are age, education, and the degree of acceptance of two Puerto Rican cultural values--familism and fatalism. The findings indicate clear and pervasive intergenerational differences and discontinuities but homogamous marital patterns in each generation. The sociocultural dislocations resulting from the migration experience from Puerto Rico to New York City do not impede the restitution of marital homogamy in the host society with respect to either general or culture specific variables.


Circular HER2 RNA positive triple negative breast cancer is sensitive to Pertuzumab.
Triple negative breast cancer (TNBC) remains the most challenging breast cancer subtype so far. Specific therapeutic approaches have rarely achieved clinical improvements in treatment of TNBC patients and effective molecular biomarkers are largely unknown. We used paired TNBC samples and high throughput RNA sequencing to identify differentially expressed circRNAs. Sucrose gradient polysome fractionation assay, antibody and Mass spectra were used to validate active circRNA translation. The novel protein function was validated in vitro and in vivo by gain or loss of function assays. Mechanistic results were concluded by immunoprecipitation analyses and kinase activity assay. Circular HER2 RNA (circ-HER2) encoded a novel protein, HER2-103. Unexpectedly, while HER2 mRNA and protein were barely detected, circ-HER2/HER2-103 was expressed in ~ 30% TNBC clinical samples. Circ-HER2/HER2-103 positive TNBC patients harbored worse overall prognosis than circ-HER2/HER2-103 negative patients. Knockdown circ-HER2 inhibited TNBC cells proliferation, invasion and tumorigenesis in vitro and in vivo, suggesting the critical role of circ-HER2/HER2-103 in TNBC tumorigenicity. Mechanistically, HER2-103 promoted homo/hetero dimerization of epidermal growth factor receptor (EGFR)/HER3, sustained AKT phosphorylation and downstream malignant phenotypes. Furthermore, HER2-103 shared most of the same amino acid sequences as HER2 CR1 domain which could be antagonized by Pertuzumab, a clinical used HER2 antibody. Pertuzumab markedly attenuated in vivo tumorigenicity of circ-HER2/HER2-103 expressing TNBC cells but showed no effects in circ-HER2/HER2-103 negative TNBC cells. Our results not only demonstrated that certain TNBCs were not truly 'HER2 negative' but also highlighted the clinical implications of Pertuzumab in circ-HER2/HER2-103 expressing TNBC patients.


[The structure of the morbidity with temporary loss of work capacity among female workers in the cotton industry].
A comparative study of the levels of temporary loss of working capacity among females working in the cotton production industry in different working and social conditions allowed to reveal higher incidence of morbidity in this category of workers as compared with the control group and to work out a complex of measures aimed at reducing this morbidity and ensuring stable recovery.


Chikungunya virus: evolution and genetic determinants of emergence.
Chikungunya virus (CHIKV) causes a severe and often persistent arthralgic disease that is occasionally fatal. A mosquito-borne virus, CHIKV exists in enzootic, non-human primate cycles in Africa, but occasionally emerges into urban, human cycles to cause major epidemics. Between 1920 and 1950, and again in 2005, CHIKV emerged into India and Southeast Asia, where major urban epidemics ensued. Unlike the early introduction, the 2005 emergence was accompanied by an adaptive mutation that allowed CHIKV to exploit a new epidemic vector, Aedes albopictus, via an A226V substitution in the E1 envelope glycoprotein. However, recent reverse genetic studies indicate that lineage-specific epistatic restrictions can prevent this from exerting its phenotype on mosquito infectivity. Thus, the A. albopictus-adaptive A226V substitution that is facilitating the dramatic geographic spread CHIKV epidemics, was prevented for decades or longer from being selected in most African enzootic strains as well as in the older endemic Asian lineage.


Hand washing behavior and associated factors in Vietnam based on the Multiple Indicator Cluster Survey, 2010-2011.
Handwashing is a cost-effective way of preventing communicable diseases such as respiratory and food-borne illnesses. However, handwashing rates are low in developing countries. Target 7C of the seventh Millennium Development Goals was to increase by half the proportion of people with sustainable access to safe drinking water and basic sanitation by 2015. Studies have found that better access to improved water sources and sanitation is associated with higher rates of handwashing. Our goal was to describe handwashing behaviour and identify the associated factors in Vietnamese households. Data from 12,000 households participating in the Vietnam Multiple Indicator Cluster Survey 2011 were used. The survey used a multistage sampling method to randomly select 100 clusters and 20 households per cluster. Self-administered questionnaires were used to collect data from a household representative. Demographic variables, the presence of a specific place for handwashing, soap and water, access to improved sanitation, and access to improved water sources were tested for association with handwashing behaviour in logistic regression. Almost 98% of households had a specific place for handwashing, and 85% had cleansing materials and water at such a place. The prevalence of handwashing in the sample was almost 85%. Educational level, ethnicity of the household head, and household wealth were factors associated with handwashing practice (p<0.05). Those having access to an improved sanitation facility were more likely to practise handwashing [odds ratio (OR)=1.69, 95% confidence interval (CI): 1.37-2.09, p<0.001], as were those with access to improved water sources (OR=1.74, 95% CI: 1.37-2.21, p<0.001). Households with low education, low wealth, belonging to ethnic minorities, and with low access to improved sanitation facilities and water sources should be targeted for interventions implementing handwashing practice. In addition, the availability of soap and water at handwashing sites should be increased and practical teaching programs should be deployed in order to increase handwashing rates.


Direct inhibition of platelet function by organic nitrates via nitric oxide formation.
This study investigates the mechanisms of platelet inhibition by the nitrate esters isosorbide dinitrate, isoidide dinitrate, isomannide dinitrate, isosorbide 2-mononitrate and isosorbide 5-mononitrate as compared to the spontaneous nitric oxide (NO)-donor linsidomine, the active metabolite of molsidomine. Nitrates and linsidomine dose-dependently inhibited aggregation, ATP secretion and thromboxane formation of washed human platelets at a rank order of potency, identical with that for stimulation of cyclic GMP in cultured rat lung fibroblasts. While linsidomine (0.1 mM) caused a 3-fold platelet cGMP elevation, there was a weak (< or = 30%) but significant cGMP stimulation by organic nitroesters, which was tightly correlated with inhibition of platelet aggregation (r = 0.926, P = 0.008). Zaprinast (2 microM) potentiated, while methylene blue (1 microM) and oxyhemoglobin (10 microM) reversed the antiaggregatory effects. Linsidomine (0.5 microM-0.1 mM) dose-dependently released NO in a cell-free system. No spontaneous NO release was detected with organic nitroesters (0.1 mM). These data suggest that, to some extent, bioactivation of organic nitroesters occurs in platelets, resulting in platelet inhibition via the NO/cGMP system.


Barrett's esophagus: current views of etiology and treatment.
Barrett's esophagus is now thought to be an acquired condition rather than a congenital condition. It has a dangerous potential for malignancy; yet, aggressive medical management, antireflux procedures, and diligent follow-up may reduce the incidence of malignancy in this condition.


Plasma cells and their precursors. I. Preexistent antibody-forming cell precursors dominate the anti-sheep red blood cell and anti-human gamma globulin IgG antibody response.
Rabbits were immunized by a single i.v. injection of SRBC or HGG and were bled serially. Sera were analyzed by IEF using the gel overlay technique to investigate clonal patterns of circulating IgG antibodies. Clonal patterns of primary-response IgG antibodies were quite stable over a period of months, showing that this response is dominated by plasma-cell precursors already present at the time of antigenic stimulation. In the late phase of the primary IgG response, new bands were occasionally observed in the antibody spectra, suggesting the presence and triggering of newly formed plasma-cell precursors. Primary-response antisera had individually unique clonal patterns. In secondary-response antisera elicited by a second single i.v. injection, the IEF spectra were found to be more complex and could be individually distinguished only with difficulty.


Interaction between the Kansas City Cardiomyopathy Questionnaire and the Pocock's clinical score in predicting heart failure outcomes.
Heart failure (HF) is a complex syndrome. Its appropriate management should combine several health measurements. We assessed the relationship between the Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Pocock's clinical score. We conducted a prospective registry of HF outpatients. The main outcome was occurrence of death or hospitalization during a 6-month follow-up. A multivariate logistic regression was performed, including the KCCQ overall summary score, the Pocock's clinical score and their interaction in the model. From January 2008 to December 2010, 143 patients were involved. Mean age of patients was 68 years, and 74% were men. KCCQ's overall summary score and Pocock's clinical score were inversely correlated (r = -0.24, p = 0.026). A total of 61 (42.7%) events occurred. There was a high proportion of events (77.8%) in patients with a Pocock's clinical score > 50%, whatever the KCCQ score value. When the KCCQ score was ≤ 50 %, there was a low increase in risk as the Pocock's clinical score increased (OR 2.0 [0.6; 6.6]). However, when the KCCQ score was between 50 and 75 or ≥ 75 %, there was a high increase in risk as the Pocock's clinical score increased (OR 6.9 [1.2; 38.9] and OR 7.4 [0.8; 69.7], respectively). Patients with a high Pocock's clinical score are at a high risk of death or hospitalization. For patients with a low Pocock's clinical score, the KCCQ score can identify those at risk of these events.


Prehospital cardiac rhythm deterioration in a system providing only basic life support.
Access to an ambulance service trained to provide only basic cardiac life support (BCLS) and adjunctive ventilation with oxygen provided the opportunity to study cardiac rhythms during BCLS in patients with circulatory arrest. Holter monitoring was attempted in 43 patients. Technically adequate traces throughout transport to hospital were obtained in 21. The average monitored time was 11.9 minutes. A tachydysrhythmia (mainly VF/VT) was initially found in 10, heart block or bradycardia in 9, and asystole in 2 persons. During BCLS, six patients with bradycardic rhythms converted temporarily to VF. The first ECG tracing obtained in the hospital revealed, however, that only five were still in a tachydysrhythmia and 15 were asystolic. These data demonstrate that important rhythm changes occur when BCLS is continued for several minutes during circulatory arrest. Although some bradycardic rhythms convert to VF, the VF is not sustained. After an average of 12 minutes, 90% of those initially in bradycardic rhythm and 50% of those initially in VF/VT were asystolic. This study provides further evidence that BCLS does not prevent cardiac deterioration.


Implications of risk stratification for diabetes prevention: the case of hemoglobin A1c.
Although glycated hemoglobin (HbA1c) has been widely recommended for the diagnosis of diabetes, considerable ambiguity remains about how HbA1c should be used to identify people with prediabetes or other high-risk states for preventive interventions. The current paper provides a synthesis of the epidemiologic basis and the health and economic implications of using various HbA1c-based risk-stratification approaches for diabetes prevention. HbA1c predicts diabetes and related outcomes across a wide range of HbA1c values. However, the authors estimate that, among U.S. adults, the top 15% of the nondiabetic HBA1c distribution (HbA1c of 5.7%-6.4%) accounts for 47% of diabetes cases over 5 years, and the top 30% (5.5%-6.4%) accounts for about 70% of cases. Although this clustering of eventual cases at the high end of the HbA1c risk distribution means that intervention resources will be more efficient when applied to the upper end of the distribution, no obvious threshold exists to prioritize people for preventive interventions. Thus, the choice of optimal thresholds is a tradeoff, wherein selecting a lower HbA1c cut-point will lead to a higher rate of eligibility and health benefits for more people, and a higher HbA1c cut-point will lead to fewer cases of diabetes prevented but greater "economic efficiency" in terms of diabetes cases prevented per intervention participant. Selection of optimal HbA1c thresholds also may change with the evolving science, as better evidence on the biologic effectiveness of lower-intensity interventions and effects of lifestyle interventions on additional outcomes could pave the way for a more comprehensive, tiered approach to risk stratification.


Skeletal secretion of FGF-23 regulates phosphate and vitamin D metabolism.
The discovery of fibroblast growth factor 23 (FGF-23) has expanded our understanding of phosphate and vitamin D homeostasis and provided new insights into the pathogenesis of hereditary hypophosphatemic and hyperphosphatemic disorders, as well as acquired disorders of phosphate metabolism, such as chronic kidney disease. FGF-23 is secreted by osteoblasts and osteocytes in bone and principally targets the kidney to regulate the reabsorption of phosphate, the production and catabolism of 1,25-dihydroxyvitamin D and the expression of α-Klotho, an anti-ageing hormone. Secreted FGF-23 plays a central role in complex endocrine networks involving local bone-derived factors that regulate mineralization of extracellular matrix and systemic hormones involved in mineral metabolism. Inactivating mutations of PHEX, DMP1 and ENPP1, which cause hereditary hypophosphatemic disorders and primary defects in bone mineralization, stimulate FGF23 gene transcription in osteoblasts and osteocytes, at least in part, through canonical and intracrine FGF receptor pathways. These FGF-23 regulatory pathways may enable systemic phosphate and vitamin D homeostasis to be coordinated with bone mineralization. FGF-23 also functions as a counter-regulatory hormone for 1,25-dihydroxyvitamin D in a bone-kidney endocrine loop. FGF-23, through regulation of additional genes in the kidney and extrarenal tissues, probably has broader physiological functions beyond regulation of mineral metabolism that account for the association between FGF-23 and increased mortality and morbidity in chronic kidney disease.


Diagnosis of thoracic outlet syndrome with the lower trunk compression of brachial plexus by high-frequency ultrasonography.
Thoracic outlet syndrome (TOS) with the lower trunk compression of brachial plexus (BP) is difficult to diagnosis. This study aimed to summarize the features of thoracic outlet syndrome (TOS) with the lower trunk compression of brachial plexus observed on high-frequency ultrasonography (HFUS). The ultrasound data of 27 patients who had TOS with the lower trunk compression of brachial plexus were collected and eventually confirmed by surgery. The imaging data were compared, and the pathogenesis of TOS was analyzed on the basis of surgical data. TOS occurred predominantly in females (70.4%). Most cases had unilateral involvement (92.6%), mainly on the right side (66.7%). The HFUS features of TOS can be summarized as follows: (1) Lower trunk compression. HFUS revealed focal thinning that reflected compression at the level of the lower trunk; furthermore, the distal part of the nerve was thickened for edema (Affected side: 0.49 ± 0.12 cm vs. Healthy side: 0.38 ± 0.06, P = 0.009), and the cross-sectional area of brachial plexus cords was markedly greater on the injured side than on the healthy side (0.95 ± 0.08 cm² vs. 0.65 ± 0.11 cm², P = 0.004). (2) Hyperechoic fibromuscular bands behind the compressed nerve (mostly the scalenus minimus muscle). (3) Abnormal bony structures: cervical ribs or elongated transverse processes of the 7th cervical vertebra (C7). Surgical results showed that the etiological factors contributing to TOS were (1) muscle hypertrophy and/or fibrosis (100%) and (2) cervical ribs/elongated C7 transverse processes (20.7%). TOS with the lower trunk compression of brachial plexus can be diagnosed accurately and reliably by high-frequency ultrasound.