Arterial blood flow and resistance in the forearm of arteriosclerotic patients.
Twenty patient with severe atherosclerotic affection of the lower limbs, but without any symptoms of involvement of their upper extremities, and twenty healthy controls were examined. The investigation included measurement of arterial blood flow and resistance in the left forearm at rest and after a three-minute circulatory arrest, using a strain-gauge venous occlusion plethysmograph. Comparison of the results obtained in each group showed statistically significant differences in haemodynamic parameters such as maximal blood flow, resting resistance, and minimal resistance which suggested the presence of vascular changes also in the upper extremities. Arterial resistance proved to be a more sensitive indicator of circulatory disorder than blood flow.


Prophylactic antibiotics in obstetrics-gynecology: a current asset, a future liability?
Currently, prophylactic antibiotics have proven effective in lowering the postoperative and postprocedure infection rate following vaginal hysterectomy, emergency cesarean section for the patient in labor, radical hysterectomy, abdominal hysterectomy, pregnancy termination, hysterosalpingogram and intrauterine device insertion. Guidelines for the most effective and safe use are presented. Concerns are raised regarding the widespread prolonged use of prophylactic antibiotics on women in labor to prevent Group B streptococcal infections in newborn children and women with prolonged preterm membrane rupture. There is also an awareness needed of a growing incidence of infections seen in the hospital from community-acquired methicillin-resistant Staphylococcus aureus and Clostridium difficile. These problems have not been addressed by the current prophylactic antibiotic strategies.


Gas sensing properties and p-type response of ALD TiO2 coated carbon nanotubes.
Amorphous titanium dioxide-coated carbon nanotubes (CNTs) were prepared by atomic layer deposition (ALD) and investigated as sensing layers for resistive NO2 and O2 gas sensors. By varying ALD process conditions and CNT structure, heterostructures with different metal oxide grain size, morphology and coating thickness were synthesized. Higher responses were observed with homogeneous and continuous 5.5 nm thick films onto CNTs at an operating temperature of 150 °C, while CNTs decorated with either discontinuous film or TiO2 nanoparticles showed a weak response close to the one of device made of bare CNTs. An unexpected p-type behavior in presence of the target gas was also noticed, independently of the metal oxide morphology and thickness. Based on previous works, hypotheses were made in order to explain the p-type behavior of TiO2/CNT sensors.


Immobilization of porcupines with tiletamine hydrochloride and zolazepam hydrochloride (Telazol).
Immobilization of North American porcupines (Erethizon dorsatum) with tiletamine hydrochloride (HCl) and zolazepam HCl (Telazol) was evaluated in central Massachusetts (USA) during 1991 and 1992. Doses between 9 and 11 mg/kg resulted in a mean (+/- SD) induction time of 3.2 +/- 1.3 min and a mean (+/- SD) immobilization time of 44.2 +/- 19.5 min. Induction time did not differ by dose, sex, capture method, or porcupine weight. Immobilization time differed by dose and porcupine weight but not by sex or capture method. Tiletamine HCl and zolazepam HCl seems to be an effective combination of drugs for immobilizing porcupines as long as sufficient time is allowed for recovery.


Nonlesional frontal lobe epilepsy (FLE) of childhood: clinical presentation, response to treatment and comorbidity.
Few studies have looked at long-term epileptic and cognitive outcome of frontal lobe epilepsy (FLE) in children. Most are limited by inclusion of lesional and nonlesional patients. To define the epileptic and functional outcome of children with nonlesional FLE. We reviewed medical records and neuropsychological evaluations of patients with nonlesional FLE diagnosed between 1994 and 2004. We included children with either focal or regional frontal EEG and/or functional imaging abnormalities. We reviewed their charts for seizure and neuropsychological outcome. We included 21 children. Twelve (57.1%) presented with daily seizures. Seizures were nocturnal in 8 of 21, secondarily generalized in 6 of 21, adversive in 5 of 21, and focal motor in 6 of 21. Although, initial seizure control was poor in 14 of 21, long-term control was achieved in 10 of 21 after 14.6+/-22.3 months. Early development was normal in 12 of 21 but at later formal neuropsychological evaluation only 3 of 12 still had a normal profile. The majority of children had learning difficulties requiring special education prior to seizure onset (6 of 10). A clearly defined regression after seizure onset was observed in three children. The majority exhibited attention deficit and hyperactivity or impulsivity (14 of 21), behavioral problems (8 of 21), and cognitive impairments (10 of 21). Early seizure control was associated with a better cognitive outcome. Nonlesional FLE is associated with poor seizure and behavioral outcomes. Whether this is secondary to MRI-silent developmental lesions or to the progressive repercussion of seizures on frontal lobe functions remains uncertain. A prospective study with early neuropsychological assessment could help confirm the latter.


Muscle activity in professional classical singing: a study on muscles in the shoulder, neck and trunk.
This study aimed to examine whether changes in the activity of shoulder and neck muscles have consequences for the activation of primary breathing muscles. It further aimed to compare muscle loading levels of professional and student singers. Four professional opera singers participated in the study. Previous unpublished recordings of 4 to 16 student singers and one opera singer were included to allow comparison of EMG loading levels between student and professional singers. Electromyographic (EMG) recordings of trapezius (TR), sternocleidomastoideus (STM), intercostals (INT), rectus abdominis (RC) and the lateral abdominal muscles (OBL) were performed. EMG biofeedback (BF) was performed on TR and STM to lower the activity in these two muscles and the potential change in EMG activity of INT, RC and OBL were examined. Three singing tasks were performed: aria, sustained tones and extreme tones. Each task was performed three times with variation in volume or pitch. Following the first performance of the singing tasks, the BF session was carried out and muscle activity recorded in a repeat performance of the same tasks. The EMG activity levels of all muscles were compared before and after BF. We found no significant effect of reduced TR/STM activity on the activation of INT, RC and OBL. Professional opera singers activated the TR, INT, RC and OBL muscles to higher levels than the student singers did. Another finding was large inter-subject variation in muscle usage, showing an idiosyncratic composition of the muscle contribution to subglottal pressure.


Hormones and Human and Nonhuman Primate Growth.
The aim of this paper was to review information pertaining to the hormonal regulation of nonhuman primate growth, with specific focus on the growth hormone (GH)-insulin-like growth factor (IGF) axis and adrenal androgens. Hormones of the GH-IGF axis are consistently associated with measures of growth - linear, weight, or both - during the growth period; in adulthood, concentrations of IGF-I, IGF-binding protein-3, and GH-binding protein are not associated with any measures of size. Comparing patterns of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS) may be especially relevant for understanding whether the childhood stage of growth and development is unique to humans and perhaps other apes. Genetic, hormonal, and morphological data on adrenarche in other nonhuman primate species suggest that this endocrine transition is delayed in humans, chimpanzees, and possibly gorillas, while present very early in postnatal life in macaques. This suggests that although perhaps permitted by an extension of the pre-adolescent growth period, childhood builds upon existing developmental substrates rather than having been inserted de novo into an ancestral growth trajectory. Hormones can provide insight regarding the evolution of the human growth trajectory.


The mouse Char10 locus regulates severity of pyruvate kinase deficiency and susceptibility to malaria.
Pyruvate kinase (PKLR) deficiency protects mice and humans against blood-stage malaria. Although mouse strain AcB62 carries a malaria-protective PklrI90N genetic mutation, it is phenotypically susceptible to blood stage malaria induced by infection with Plasmodium chabaudi AS, suggesting a genetic modifier of the PklrI90N protective effect. Linkage analysis in a F2 cross between AcB62 (PklrI90N) and another PK deficient strain CBA/Pk (PklrG338D) maps this modifier (designated Char10) to chromosome 9 (LOD = 10.8, 95% Bayesian CI = 50.7-75Mb). To study the mechanistic basis of the Char10 effect, we generated an incipient congenic line (Char10C) that harbors the Char10 chromosome 9 segment from AcB62 fixed on the genetic background of CBA/Pk. The Char10 effect is shown to be highly penetrant as the Char10C line recapitulates the AcB62 phenotype, displaying high parasitemia following P. chabaudi infection, compared to CBA/Pk. Char10C mice also display a reduction in anemia phenotypes associated with the PklrG338D mutation including decreased splenomegaly, decreased circulating reticulocytes, increased density of mature erythrocytes, increased hematocrit, as well as decreased iron overload in kidney and liver and decreased serum iron. Erythroid lineage analyses indicate that the number of total TER119+ cells as well as the numbers of the different CD71+/CD44+ erythroblast sub-populations were all found to be lower in Char10C spleen compared to CBA/Pk. Char10C mice also displayed lower number of CFU-E per spleen compared to CBA/Pk. Taken together, these results indicate that the Char10 locus modulates the severity of pyruvate kinase deficiency by regulating erythroid responses in the presence of PK-deficiency associated haemolytic anemia.


Block of IKs, the slow component of the delayed rectifier K+ current, by the diuretic agent indapamide in guinea pig myocytes.
There is a high incidence of diuretic use among patients who develop exaggerated QT prolongation and polymorphic ventricular tachycardia (torsade de pointes) during treatment with action potential-prolonging agents. Diuretic-induced hypokalemia is thought to be the usual mechanism, but a direct effect of diuretic drugs on repolarizing currents is an additional possibility. Therefore, in this study, we examined the effects of the diuretic agents chlorthalidone and indapamide on the cardiac delayed rectifier current. In guinea pig ventricular myocytes, this current is made up of two components: IKr, a rapidly activating, inwardly rectifying current blocked by most action potential-prolonging antiarrhythmics, and IKs, a slowly activating component. In this preparation, indapamide blocked outward current in a time-, voltage- and concentration-dependent fashion, whereas chlorthalidone (1 mmol/L) was without effect. The following features of the effect of indapamide strongly suggest selective block of IKs: (1) Indapamide block was significantly greater with 5000-millisecond activating pulses (-43 +/- 5% at +50 mV [100 mumol/L indapamide]) than with 225-millisecond ones (-20 +/- 5%; n = 5, P < .01), and the signature of the indapamide-sensitive current was a slowly activating delayed rectifier current. (2) The voltage dependence of indapamide block (EC50, 101 mumol/L at +50 mV and 196 mumol/L at +10 mV) was consistent with preferential block of IKs relative to IKr. (3) In the presence of indapamide, an envelope-of-tails test for IKr was satisfied. The drug-insensitive current had rectifying properties similar to those described for IKr in these cells.(ABSTRACT TRUNCATED AT 250 WORDS)


Surgical or radiosurgical failures on cervical lymph nodes in treatment of head and neck cancer.
From a series of 850 patients with head and neck carcinoma and subjected to lymph node dissection, 80 cases of recurrences in the neck have been collected. Postoperative radiotherapy was performed only in cases with metastatic extranodal spread. Of these recurrences, 56 occurred in the area of lymph node dissection, 7 were marginal and 17 were contralateral. The recurrences occurred prevalently in node-positive (N+) patients (70 of 80). The incidence of recurrences in the dissection area was 41.6% (25 of 60) in cases with metastatic extranodal spread, despite postoperative radiotherapy. The incidence of recurrences in cases with clinically evident metastases at the time of dissection but without extranodal spread and not subjected to postoperative radiotherapy was relatively high (24.1%, or 28 of 116). Since recurrences occurred, despite postoperative radiotherapy, in a relatively high percentage of cases with carcinoma of the oral floor and of the tongue (59.1% and 50%, respectively), it seems justifiable to perform preoperative radiation treatment in cases with clinically evident metastatic lymph nodes. As regards marginal recurrences, which all occurred in patients with carcinoma of the oral floor, it is considered sufficient to extend the surgical treatment to the subhyoid region. The high incidence of contralateral recurrences, which occurred mainly in patients with carcinoma of the larynx (13 of 17), shows the usefulness of radiation treatment of the contralateral region of the neck in these tumors, when dissection is limited to only one side of the neck.


Design and evaluation of personal audio systems based on speech privacy constraints.
Personal audio refers to the generation of spatially distinct sound zones that allow individuals within a shared space to listen to their own audio material without affecting, or being affected, by others. Recent interest in such systems has focussed on their performance in public spaces where speech privacy is desirable. To achieve this goal, speech is focussed towards the target listener and a masking signal is focussed into the area where the target speech signal could otherwise be overheard. An effective masking signal must substantially reduce the intelligibility in this region without becoming an annoyance to those nearby. To assess these perceptual requirements, listening tests were carried out using two examples of loudspeaker arrays with different spatial aliasing characteristics, to determine the impacts of different masking signal spectra on speech intelligibility and subjective preference. The results of these tests were used, alongside objective and subjective metrics, to form a design specification for private personal audio systems.


Structural mechanism of heavy metal-associated integrated domain engineering of paired nucleotide-binding and leucine-rich repeat proteins in rice.
Plant nucleotide-binding and leucine-rich repeat (NLR) proteins are immune sensors that detect pathogen effectors and initiate a strong immune response. In many cases, single NLR proteins are sufficient for both effector recognition and signaling activation. These proteins possess a conserved architecture, including a C-terminal leucine-rich repeat (LRR) domain, a central nucleotide-binding (NB) domain, and a variable N-terminal domain. Nevertheless, many paired NLRs linked in a head-to-head configuration have now been identified. The ones carrying integrated domains (IDs) can recognize pathogen effector proteins by various modes; these are known as sensor NLR (sNLR) proteins. Structural and biochemical studies have provided insights into the molecular basis of heavy metal-associated IDs (HMA IDs) from paired NLRs in rice and revealed the co-evolution between pathogens and hosts by combining naturally occurring favorable interactions across diverse interfaces. Focusing on structural and molecular models, here we highlight advances in structure-guided engineering to expand and enhance the response profile of paired NLR-HMA IDs in rice to variants of the rice blast pathogen MAX-effectors (Magnaporthe oryzae AVRs and ToxB-like). These results demonstrate that the HMA IDs-based design of rice materials with broad and enhanced resistance profiles possesses great application potential but also face considerable challenges.


In Silico Discovery of Novel Potent Antioxidants on the Basis of Pulvinic Acid and Coumarine Derivatives and Their Experimental Evaluation.
A pigment from the edible mushroom Xerocomus badius norbadione A, which is a natural derivative of pulvinic acid, was found to possess antioxidant properties. Since the pulvinic acid represents a novel antioxidant scaffold, several other derivatives were recently synthetized and evaluated experimentally, along with some structurally related coumarine derivatives. The obtained data formed the basis for the construction of several quantitative structure-activity and pharmacophore models, which were employed in the virtual screening experiments of compound libraries and for the prediction of their antioxidant activity, with the goal of discovering novel compounds possessing antioxidant properties. A final prioritization list of 21 novel compounds alongside 8 established antioxidant compounds was created for their experimental evaluation, consisting of the DPPH assay, 2-deoxyribose assay, β-carotene bleaching assay and the cellular antioxidant activity assay. Ten novel compounds from the tetronic acid and barbituric acid chemical classes displayed promising antioxidant activity in at least one of the used assays, that is comparable to or even better than some standard antioxidants. Compounds 5, 7 and 9 displayed good activity in all the assays, and were furthermore effective preventers of oxidative stress in human peripheral blood mononuclear cells, which are promising features for the potential therapeutic use of such compounds.


IL-32 induces indoleamine 2,3-dioxygenase+CD1c+ dendritic cells and indoleamine 2,3-dioxygenase+CD163+ macrophages: Relevance to mycosis fungoides progression.
Mycosis fungoides (MF) progresses from patch to tumor stage by expansion of malignant T-cells that fail to be controlled by protective immune mechanisms. In this study, we focused on IL-32, a cytokine, highly expressed in MF lesions. Depending on the other cytokines (IL-4, GM-CSF) present during in vitro culture of healthy volunteers' monocytes, IL-32 increased the maturation of CD11c+ myeloid dendritic cells (mDC) and/or CD163+ macrophages, but IL-32 alone showed a clear ability to promote dendritic cell (DC) differentiation from monocytes. DCs matured by IL-32 had the phenotype of skin-resident DCs (CD1c+), but more importantly, also had high expression of indoleamine 2,3-dioxygenase. The presence of DCs with these markers was demonstrated in MF skin lesions. At a molecular level, indoleamine 2,3-dioxygenase messenger RNA (mRNA) levels in MF lesions were higher than those in healthy volunteers, and there was a high correlation between indoleamine 2,3-dioxygenase and IL-32 expression. In contrast, Foxp3 mRNA levels decreased from patch to tumor stage. Increasing expression of IL-10 across MF lesions was highly correlated with IL-32 and indoleamine 2,3-dioxygenase, but not with Foxp3 expression. Thus, IL-32 could contribute to progressive immune dysregulation in MF by directly fostering development of immunosuppressive mDC or macrophages, possibly in association with IL-10.


Paranasal sinus system and upper respiratory tract evolution in Mesozoic pelagic crocodylomorphs.
Thalattosuchians were a predominately marine clade of Mesozoic crocodylomorphs, including semi-aquatic teleosauroid and obligately pelagic metriorhynchid subclades. Recent advances in our understanding of thalattosuchian endocranial anatomy have revealed new details of the evolutionary transition from terrestrial to marine to pelagic taxa. Paranasal sinuses, however, have received little attention. Herein, we investigate the evolution of the paranasal sinus system and part of the upper respiratory system (nasopharyngeal ducts) in Thalattosuchia, by reconstructing the nasal and paranasal anatomy in CT scans of seven thalattosuchian skulls: one teleosauroid, two basal metriorhynchoids and four metriorhynchids. Our outgroups were: three extant crocodylian species (including adult and subadult skulls) and the basal crocodyliform Protosuchus. We found thalattosuchians exhibit exceptionally reduced paranasal sinus systems, solely comprising the antorbital sinus, as has been previously proposed. The semi-aquatic basal thalattosuchians Palgiopthalmosuchus gracilirostris and Pelagosaurus typus both have an antorbital sinus partially located medial to a reduced external antorbital fenestra and broadly communicating with the dorsal alveolar canal. In pelagic metriorhynchids, the antorbital cavity is more extensive than in basal taxa and possibly had an active function associated with a hypothesized accessory suborbital diverticulum, but our reconstructions are insufficient to confirm or reject the presence of such a diverticulum. The nasopharyngeal ducts of metriorhynchids are dorsoventrally enlarged, possibly enabling stronger ventilation. The sequence of acquisition of craniofacial adaptations show a mosaic pattern and appears to predate many skeletal adaptations, suggesting these changes occurred early in the thalattosuchian marine transition.


Turbidity determination of the critical exponent eta in the liquid-liquid mixture methanol and cyclohexane.
The turbidity of the liquid-liquid mixture methanol-cyclohexane has been measured very near its critical point and used to test competing theoretical predictions and to determine the critical correlation-correction exponent eta. By measuring the ratio of the transmitted to incident light intensities over five decades in reduced temperature, we are able to determine that Ferrell's theoretical prediction for the turbidity explains the data with the correlation length amplitude xi0=0.330+/-0.003 nm and critical exponents eta=0.041+/-0.005 and nu=0.632+/-0.002. These values are consistent with the values measured before for xi0 in this system and with the exponents predicted by theory. The data allow five different theoretical expressions to be tested and to select two as being equivalent when very close to the critical point.


[Paracrine regulation of Leydig cell aromatase in the rat: development with age].
The paracrine regulation of rat testicular aromatase activity has been studied at various ages (20, 30, 45, 55, 70, 240 days); seminiferous tubule culture medium (STM) have been prepared at the above ages and added (40%, v/v) to the Percoll purified Leydig cells (150,000) for 5 h at 32 degrees C in presence or absence of oLH (25 ng/ml). In 20 day-old rat, the basal oestradiol-17 beta (E2) output is low (20 pg/10(6) Leydig cells), then gradually increases until day 70 (280 pg) without any change at 240 days (260 pg). In presence of oLH, a 2 fold increase of E2 output is observed whatever the age and the addition of STM further enhances both the basal (21-41%) and the LH-stimulated (14-65%) E2 syntheses. In conclusion, the Leydig cell aromatase activity, is in part regulated by STM factors, mainly after puberty. From 20 days onwards, it is noteworthy, that the Leydig cell testosterone (T) synthesis is highly stimulated by oLH (10 fold) and the addition of STM further increases T outputs (2 fold) which brings about a high intratesticular T level necessary for development of spermatogenesis.


Albinism-causing mutations in recombinant human tyrosinase alter intrinsic enzymatic activity.
Tyrosinase (TYR) catalyzes the rate-limiting, first step in melanin production and its gene (TYR) is mutated in many cases of oculocutaneous albinism (OCA1), an autosomal recessive cause of childhood blindness. Patients with reduced TYR activity are classified as OCA1B; some OCA1B mutations are temperature-sensitive. Therapeutic research for OCA1 has been hampered, in part, by the absence of purified, active, recombinant wild-type and mutant human enzymes. The intra-melanosomal domain of human tyrosinase (residues 19-469) and two OCA1B related temperature-sensitive mutants, R422Q and R422W were expressed in insect cells and produced in T. ni larvae. The short trans-membrane fragment was deleted to avoid potential protein insolubility, while preserving all other functional features of the enzymes. Purified tyrosinase was obtained with a yield of >1 mg per 10 g of larval biomass. The protein was a monomeric glycoenzyme with maximum enzyme activity at 37°C and neutral pH. The two purified mutants when compared to the wild-type protein were less active and temperature sensitive. These differences are associated with conformational perturbations in secondary structure. The intramelanosomal domains of recombinant wild-type and mutant human tyrosinases are soluble monomeric glycoproteins with activities which mirror their in vivo function. This advance allows for the structure - function analyses of different mutant TYR proteins and correlation with their corresponding human phenotypes; it also provides an important tool to discover drugs that may improve tyrosinase activity and treat OCA1.


Effects of group exercise on cognitive functioning and mood in older women.
A randomised controlled trial was conducted to determine whether a 12-month program of group exercise had beneficial effects on physiological and cognitive functioning and mood in 187 older community-dwelling women. The exercisers (n = 94) and controls (n = 93) were well matched in terms of the test measures and a number of health and life-style assessments. The mean number of classes attended by the 71 exercise subjects who completed the program was 59.0 (range 26 to 82). At the end of the trial, the exercisers showed significant improvements in reaction time, strength, memory span and measures of wellbeing when compared with the controls. There was also an indication that anxiety had been reduced in the exercisers. Within the exercise group, improvements in memory span were associated with concomitant improvements in both reaction time and muscle strength. Also, within this group, initial mood measures were significantly inversely associated with improvements at retest, which suggests that the program may have normalised mood states in subjects who had high initial depression, anxiety and stress levels, rather than inducing improvements in all subjects. These findings suggest that group exercise has beneficial effects on physiological and cognitive functioning and wellbeing in older people.


Brain-derived neurotrophic factor secreted by the cerebral endothelium: A new actor of brain function?
Low cerebral levels of brain-derived neurotrophic factor (BDNF), which plays a critical role in many brain functions, have been implicated in neurodegenerative, neurological and psychiatric diseases. Thus, increasing BDNF levels in the brain is considered an attractive possibility for the prevention/treatment of various brain diseases. To date, BDNF-based therapies have largely focused on neurons. However, given the cross-talk between endothelial cells and neurons and recent evidence that BDNF expressed by the cerebral endothelium largely accounts for BDNF levels present in the brain, it is likely that BDNF-based therapies would be most effective if they also targeted the cerebral endothelium. In this review, we summarize the available knowledge about the biology and actions of BDNF derived from endothelial cells of the cerebral microvasculature and we emphasize the remaining gaps and shortcomings.


Hemidystonia symptomatic of primary antiphospholipid syndrome in childhood.
We report three children with hemidystonia in whom anti-cardiolipin (aCL) antibodies were demonstrated. Systemic lupus erythematosus was excluded on the basis of both clinical and serological criteria, and the diagnosis of primary antiphospholipid syndrome (PAPS) was made. In two cases, aCL antibodies could be causally related to a presumed immune-mediated thrombotic event involving the basal ganglia as shown by magnetic resonance imaging (MRI). In the remaining patient the finding of white matter alteration on NMR might be due to cross-reactivity of anti-phospholipid (aPL) antibodies with cerebral phospholipids, resulting in demyelination. We suggest that PAPS must always be considered when isolated or recurrent focal cerebral ischaemia, and particularly hemidystonia, occur in childhood.


Imipenem/funobactam (formerly XNW4107) in vivo pharmacodynamics against serine carbapenemase-producing Gram-negative bacteria: a novel modelling approach for time-dependent killing.
Imipenem/funobactam (formerly XNW4107) is a novel β-lactam/β-lactamase inhibitor with activity against MDR Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacterales strains. Using a neutropenic murine thigh infection model, we aimed to determine the pharmacokinetic/pharmacodynamic (PK/PD) index, relative to funobactam exposure, that correlated most closely with the in vivo efficacy of imipenem/funobactam combination and the magnitude of index required for efficacy against serine carbapenemase-producing clinical strains. Dose-fractionation was conducted against three strains. Imipenem human-simulated regimen (HSR, 500 mg q6h 1 h infusion) efficacy in combination with escalating funobactam exposures against seven A. baumannii, four P. aeruginosa and four Klebsiella pneumoniae (imipenem/funobactam MICs 0.25-16 mg/L) was assessed as 24 h change in log10cfu/thigh. Increased funobactam fractionation enhanced efficacy, indicating time-dependent killing. Changes in log10cfu/thigh versus %fT > MIC were poorly predictive of efficacy; bactericidal activity was observed at %fT > MIC = 0%. Across different threshold plasma funobactam concentrations (CTs), %fT > CT(1 mg/L) had the highest correlation with efficacy. Normalizing the %fT > CT = 1 mg/L index to the respective isolate imipenem/funobactam MIC ([%fT > CT]/MIC) allowed integration of the isolate's susceptibility, which further enhanced the correlation. Median (%fT > CT[1 mg/L])/MIC values associated with 1-log reductions were 9.82 and 9.90 for A. baumannii and P. aeruginosa, respectively. Median (%fT > CT[1 mg/L])/MIC associated with stasis was 55.73 for K. pneumoniae. Imipenem/funobactam 500/250 mg q6h 1 h infusion HSR produced >1-log kill against 6/7 A. baumannii, 4/4 P. aeruginosa and stasis against 4/4 K. pneumoniae. Imipenem/funobactam showed potent in vivo efficacy against serine carbapenemase-producers. The novel PK/PD index (%fT > CT)/MIC appeared to best describe in vivo activity.


Relations of age with changes in self-efficacy and physical self-concept in preadolescents participating in a physical activity intervention during afterschool care.
An inference from Piaget's theory of cognitive development suggests that preadolescents of different ages who participate in a physical activity intervention may respond differently on measures of their physical self and self-efficacy, so a field investigation was conducted to assess effects. In a sample of 105 children ages 8 to 12 yr. (42% boys, overall M(age) = 10.1 yr., SD = 0.9), participation in a physical activity intervention during afterschool care, based on social cognitive theory and incorporating instruction in self-management and self-regulatory skills, was associated with significant improvements in measures of exercise-related self-efficacy, perceived physical appearance, and physical self-concept over 12 wk. Analyses suggested, however, no difference in changes on these factors was associated with participants' age or children being in either the concrete operations or formal operations stage of cognitive development. After replication, implications for design of physical activity interventions for preadolescents were suggested.


Therapeutic implications of heparin-induced thrombocytopenia complicating acute hemodialysis.
Although patients undergoing acute hemodialysis (HD) constitute a group at risk for heparin-induced thrombocytopenia (HIT), the optimal therapeutic strategy remains undefined. We describe a case of HIT complicated with right subclavian vein thrombosis in a patient with chronic renal insufficiency undergoing acute HD for oligoanuria and pulmonary edema. Circulating anti-heparin-PF4 complex antibodies were detected. Past medical history was relevant for an otherwise unexplained self-limited episode of thrombocytopenia following acute HD one year earlier after an anterior STEMI. All sources of heparin were discontinued and alternative anticoagulation was initiated with argatroban, a direct-thrombin inhibitor with hepatic clearance, followed by transition to warfarin. Prevention of tunneled HD catheter obstruction was accomplished with low-dose alteplase catheter locking solution. No bleeding occurred with argatroban anticoagulation. Platelet count recovered and no further thrombotic complications were observed. The present report illustrates the diagnostic and therapeutic challenges of HIT complicating acute HD.


Effect of acclimated temperature on thermal tolerance, immune response and expression of HSP genes in Labeo rohita, Catla catla and their intergeneric hybrids.
The ability of a species and population to respond to a decrease or an increase in temperature depends on their adaptive potential. Here, the critical thermal tolerance (CTmax and CTmin) of four populations: Labeo rohita, Catla catla, and their reciprocal hybrids L. rohita♀× C. catla♂ (RC) and C. catla♀ × L. rohita♂ (CR) being acclimatized at four acclimation temperatures (22, 26, 30 and 34 °C) were determined. All populations indicated substantial variations (P < 0.05) in CTmax and CTmin values. L. rohita displayed, comparatively the highest CTmax with largest total and intrinsic polygon zones as well as the upper and lower acquired thermal tolerance zones followed by RC and CR hybrids, while C. catla showed significantly the highest CTmin value and the smallest intrinsic and acquired thermal tolerance zones. Both hybrids illustrated low parent heterosis (≤11%). Additionally, the highest expression of Hsp70 and Hsp90 (heat shock proteins) genes, serum lysozyme level, respiratory burst activity and lowest lipid peroxidation level under lower and higher temperature shock further illustrated strong physiological mechanism of L. rohita in contrast to C. catla, to deal with acute temperature, while hybrids, especially F1 RC hybrid appeared as a good option to replace C. catla in relatively higher and lower temperature areas.


De Novo sequencing and transcriptome analysis for Tetramorium bicarinatum: a comprehensive venom gland transcriptome analysis from an ant species.
Arthropod venoms are invaluable sources of bioactive substances with biotechnological application. The limited availability of some venoms, such as those from ants, has restricted the knowledge about the composition and the potential that these biomolecules could represent. In order to provide a global insight on the transcripts expressed in the venom gland of the Brazilian ant species Tetramorium bicarinatum and to unveil the potential of its products, high-throughput approach using Illumina technology has been applied to analyze the genes expressed in active venom glands of this ant species. A total of 212,371,758 pairs of quality-filtered, 100-base-pair Illumina reads were obtained. The de novo assemblies yielded 36,042 contigs for which 27,873 have at least one predicted ORF among which 59.77% produce significant hits in the available databases. The investigation of the reads mapping toxin class revealed a high diversification with the major part consistent with the classical hymenopteran venom protein signature represented by venom allergen (33.3%), followed by a diverse toxin-expression profile including several distinct isoforms of phospholipase A1 and A2, venom serine protease, hyaluronidase, protease inhibitor and secapin. Moreover, our results revealed for the first time the presence of toxin-like peptides that have been previously identified from unrelated venomous animals such as waprin-like (snakes) and agatoxins (spiders and conus).The non-toxin transcripts were mainly represented by contigs involved in protein folding and translation, consistent with the protein-secretory function of the venom gland tissue. Finally, about 40% of the generated contigs have no hits in the databases with 25% of the predicted peptides bearing signal peptide emphasizing the potential of the investigation of these sequences as source of new molecules. Among these contigs, six putative novel peptides that show homologies with previously identified antimicrobial peptides were identified. To the best of our knowledge, this work reports the first large-scale analysis of genes transcribed by the venomous gland of the ant species T. bicarinatum and helps with the identification of Hymenoptera toxin arsenal. In addition, results from this study demonstrate that de novo transcriptome assembly allows useful venom gene expression analysis in a species lacking a genome sequence database.


On the assessment of effects of food on the pharmacokinetics of drugs in early development.
The impact of food on the pharmacokinetics of a drug has important implications in drug development. This commentary is aimed at addressing two key challenges, developability of drugs whose pharmacokinetics are severely influenced by food, and the need for addressing the effects of fruit juice ingredients which modulate metabolic/efflux properties of a compound. Perspectives on the value in predicting food-drug interactions during preclinical development, timing of clinical food-drug interaction studies, and implications of food effects are presented herein.


A novel framework for incorporating patient values and preferences in making guideline recommendations: guideline panel surveys.
Universally acknowledged standards for trustworthy guidelines include the necessity to ground recommendations in patient values and preferences. When information is limited-which is typically the case-guideline panels often find it difficult to explicitly integrate patient values and preferences into their recommendations. Our objective was to develop and evaluate a framework for systematically navigating guideline panels in incorporating patient values and preferences in making recommendations. In the context of developing a guideline for colorectal cancer screening, we generated an initial framework for creating panel surveys to elicit guideline panelists' views of patient values and preferences and to inform panel discussions on recommendations. With further applications in guidelines of diverse topic areas, we dynamically refined the framework through iterative discussions and consensus. The finial framework consists of five steps for creating and implementing panel surveys. The surveys can serve three objectives following from the quantitative information regarding patient values and preferences that guideline panels usually require. An accompanying video provides detailed instructions of the survey. The framework for creating and implementing panel surveys offers explicit guidance for guideline panels considering transparently and systematically incorporating patient values and preferences into guideline recommendations.


Sample Preparation Strategies for the Effective Quantitation of Hydrophilic Metabolites in Serum by Multi-Targeted HILIC-MS/MS.
The effect of endogenous interferences of serum in multi-targeted metabolite profiling HILIC-MS/MS analysis was investigated by studying different sample preparation procedures. A modified QuEChERS dispersive SPE protocol, a HybridSPE protocol, and a combination of liquid extraction with protein precipitation were compared to a simple protein precipitation. Evaluation of extraction efficiency and sample clean-up was performed for all methods. SPE sorbent materials tested were found to retain hydrophilic analytes together with endogenous interferences, thus additional elution steps were needed. Liquid extraction was not shown to minimise matrix effects. In general, it was observed that a balance should be reached in terms of recovery, efficient clean-up, and sample treatment time when a wide range of metabolites are analysed. A quick step for removing phospholipids prior to the determination of hydrophilic endogenous metabolites is required, however, based on the results from the applied methods, further studies are needed to achieve high recoveries for all metabolites.


Perspectives on procedure-based assessments: a thematic analysis of semistructured interviews with 10 UK surgical trainees.
The introduction of competency-based training has necessitated development and implementation of accompanying mechanisms for assessment. Procedure-based assessments (PBAs) are an example of workplace-based assessments that are used to examine focal competencies in the workplace. The primary objective was to understand surgical trainees' perspective on the value of PBA. Semistructured interviews with 10 surgical trainees individually interviewed to explore their views. Interviews were audio-recorded and transcribed; following this, they were open and axial coded. Thematic analysis was then performed. Semistructured interviews yielded several topical and recurring themes. In trainees' experience, the use of PBAs as a summative tool limits their educational value. Trainees reported a lack of support from seniors and variation in the usefulness of the tool based on stage of training. Concerns related to the validity of PBAs for evaluating trainees' performance with reports of 'gaming' the system and trainees completing their own assessments. Trainees did identify the significant value of PBAs when used correctly. Benefits included the identification of additional learning opportunities, standardisation of assessment and their role in providing a measure of progress. The UK surgical trainees interviewed identified both limitations and benefits to PBAs; however, we would argue based on their responses and our experience that their use as a summative tool limits their formative use as an educational opportunity. PBAs should either be used exclusively to support learning or solely as a summative tool; if so, further work is needed to audit, validate and standardise them for this purpose.


A model for standardization of lung function parameters by height.
Lung function parameters are closely associated with the height of the individual and this is the reason why this genetically determined characteristic is present obligatorily in the equations giving their reference values. The present work studies a large group of models by analysing two groups of healthy individuals - 20 healthy boys aged 7 to 14 years (10.6 +/- 2.2; mean +/- SD) with a height of 121 to 170 cm (145.0 +/- 14.2) and 98 healthy men aged 30 to 60 years (44.7 +/- 6.7) with a height of 159 to 192 cm (171.0 +/- 9.1), all of them non-smokers. Statistical analysis shows that standardization of lung function parameters by height of healthy individuals is achieved by using a power function of the height - FEV1/2.7 and VC/H2.6 for boys aged 7 to 14 years and FEV1/H2.5 and VC/H2.4 for men aged 30 to 60 years. The model proposed for children practically neutralizes age completely and can be used as a reference equation. The graphic and correlation analysis of the residuals obtained as a difference between the actual and predicted values of the respective models indicated clearly presence of age peculiarities. In men the correlation coefficients between the residuals and the height were close to zero, and the residuals themselves were relatively evenly distributed around the zero line (a homoscedastic distribution). In children the differences scattering increased with the height, i.e. there is a heteroscedastic distribution.


Improving the cementation of complete cast crowns: a comparison of static and dynamic seating methods.
This study measured the effect of static and dynamic forces, during cementation, on the retention and seating of complete cast crowns made for extracted human teeth prepared with a diamond bur. Under a static load, the castings failed to seat by a mean value of 203 micron. When dynamically loaded, the castings seated an average of 14 micron beyond the point of precementation measurement. No statistically significant differences were found in the retention of the crowns cemented by the two different methods.


Observing stochastic resonance in an underdamped bistable Duffing oscillator by the method of moments.
The method of moments is applied to an underdamped bistable oscillator driven by Gaussian white noise and a weak periodic force for the observations of stochastic resonance and the resulting resonant structures are compared with those from Langevin simulation. The physical mechanisms of the stochastic resonance are explained based on the evolution of the intrawell frequency peak and the above-barrier frequency peak via the noise intensity and the fluctuation-dissipation theorem, and the three possible sources of stochastic resonance in the system are confirmed. Additionally, with the noise intensity fixed, the stochastic resonant structures are also observed by adjusting the nonlinear parameter.


Radiolytic studies of naphthalene in the presence of water.
Naphthalene is an interesting candidate to study in the framework of organic delivery to planetary surfaces as well as in the origin of life. Additionally, naphthalene is of environmental interest, because of its chronic and acute effects on living systems, such as humans and animals (e.g. moths). Naphthalene has been well studied in both fields. In this paper we give an overview of radiolytic studies of naphthalene in the presence of both liquid water and water ice. From our review it appears that OH radicals are formed both in liquid water and in interstellar ices and that these radicals play a considerable role in the degradation of naphthalene. However, it also appears that upon irradiation of naphthalene in liquid water, hydrogen peroxide, a species that accelerates naphthalene degradation, is formed. Based on this review we suggest that the role of hydrogen peroxide in interstellar ices should be further investigated.


Decidual transformation of human extrauterine mesenchymal cells is associated with the appearance of insulin-like growth factor-binding protein-1.
Human extrauterine decidual cells were studied for the presence of insulin-like growth factor-binding protein-1 (IGFBP-1) by using an avidin-biotin complex immunoperoxidase method with a purified monoclonal antibody 6303 against IGFBP-1. It is well established that human decidua expresses mRNA for IGFBP-1 and synthesizes and secretes this protein. We now describe, for the first time, that cells morphologically similar to uterine decidual cells found beneath the peritoneal mesothelium in inguinal hernia and in the cervical mucosa during normal pregnancy and in the mesenchymal tissue of the Fallopian tubes and ovaries at term react with the monoclonal antibody for IGFBP-1 equally to endometrial decidual cells. These results imply that the extrauterine mesenchymal cells, which have undergone decidual transformation, are not only morphologically but also functionally, similar to their counterparts in the uterus. Secondly, the data suggest that IGFBP-1 expression is associated with a special type(s) of cells and a certain stage of differentiation rather than special organs in the body.


Protective action of luminal bile salts in necrotizing acute pancreatitis in mice.
Bile salts in the intestinal lumen act to inhibit the release of cholecystokinin (CCK). Recent studies have shown that CCK may play a permissive role in the development of acute pancreatitis. In this study, the amount of luminal bile salts in female Swiss Webster mice was either decreased by feeding 4% (wt/wt) cholestyramine or increased by feeding 0.5% sodium taurocholate for 1 wk. Plasma levels of CCK were stimulated by cholestyramine and inhibited by taurocholate. Then, acute pancreatitis was induced either by caerulein injections, or by feeding a choline-deficient, ethionine-supplemented (CDE) diet. Feeding of cholestyramine significantly decreased survival from 25% to 0% in the CDE pancreatitis, and increased the magnitude of elevation of serum amylase levels and the extent of pancreatic necrosis in both models of pancreatitis; CCK-receptor blockade with CR-1409 completely abolished the adverse effects of cholestyramine. In contrast, feeding of taurocholate significantly increased survival to 100% and decreased the elevation of serum amylase and pancreatic necrosis; CCK-8 antagonized these actions of taurocholate. Luminal bile salts appear to provide a physiologic protection against necrotizing pancreatitis, at least in part, both by inhibiting the release of CCK and by promoting resistance of the pancreas to CCK excessive stimulation in vivo.


Polymorphism of cellulose I family: reinvestigation of cellulose IVI.
Polymorphs of cellulose I, III(I), and IV(I) have been investigated by X-ray diffraction, FT-IR, and solid-state (13)C NMR spectroscopy. Highly crystalline cellulose III(I) samples were prepared by treating cellulose samples in supercritical ammonia at 140 degrees C for 1 h, and conventional cellulose III(I) samples were prepared by liquid ammonia treatment. The cellulose IV(I) sample of highest crystallinity was that prepared from Cladophora cellulose III(I) in supercritical ammonia, followed by the sample treated in glycerol at 260 degrees C for 0.5 h, whereas the lowest crystallinity was observed in ramie cellulose prepared by conventional liquid ammonia treatment followed by glycerol annealing. In general, the perfection of cellulose IV(I) depends on the crystallinity of the original material: either of the starting cellulose I or of the cellulose III(I) after ammonia treatment. The product thus obtained was analogous to cellulose I(beta), which is what it should be called rather than cellulose IV(I). If the existence of the polymorph cellulose IV(I) is not accepted, the observations on which it has been based may be explained by the fact that the structure termed cellulose IV(I) is cellulose I(beta) which contains lateral disorder.


Detection of promoter hypermethylation of tumor suppressor genes in urine from kidney cancer patients.
Kidney cancer is curable by surgical resection and therapy, if detected at an early stage. Using sensitive methylation-specific polymerase chain reaction, we screened matched tumor DNA and preoperative urine DNA from 50 kidney cancer patients, for hypermethylation of a panel of six normally unmethylated tumor suppressor genes: VHL, p16/CDKN2a, p14ARF, APC, RASSF1A, and Timp-3. When compared to the tumor DNA, an identical pattern of gene hypermethylation was found in the matched urine DNA from 44 of 50 patients (88% sensitivity) including 27 of 30 cases of stage I disease. By contrast, hypermethylation was not observed in normal and benign disease controls (100% specificity). We conclude that promoter hypermethylation is a common and early event in kidney tumorigenesis and can be detected in the urine DNA from patients with organ-confined renal cancer of all histologic types.


Clinical effectiveness of dolutegravir in the treatment of HIV/AIDS.
Dolutegravir (DTG) is a second-generation integrase strand transfer inhibitor (INSTI), which has now been licensed to be used in different countries including the UK. Earlier studies have demonstrated that DTG when used with nucleoside backbone in treatment-naïve and - experienced patients has been well tolerated and demonstrated virological suppression comparable to other INSTIs and superiority against other first-line agents, including efavirenz and boosted protease inhibitors. Like other INSTIs, DTG uses separate metabolic pathways compared to other antiretrovirals and is a minor substrate for CYP-450. It does not appear to have a significant interaction with drugs, which uses the CYP-450 system. Nonetheless, it uses renal solute transporters that may potentially inhibit the transport of other drugs and can have an effect on the elimination of other drugs. However, the impact of this mechanism appears to be very minimal and insignificant clinically. The side effect profiles of DTG are similar to raltegravir and have been found to be well tolerated. DTG has a long plasma half-life and is suitable for once daily use without the need for a boosting agent. DTG has all the potential to be used as a first-line drug in combination with other nucleoside backbones, especially in the form of a single tablet in combination with abacavir and lamivudine. The purpose of this review article is to present the summary of the available key information about the clinical usefulness of DTG in the treatment of HIV infection.


Behavioural effects of beta,beta'-iminodipropionitrile (IDPN) in the domestic fowl (Gallus domesticus).
The behavioural effects of beta,beta'-iminodipropionitrile (IDPN) were studied in chicks and adult fowls. Repeated administration of IDPN (75 mg/kg) for 5 days induced behavioural changes in chicks and adult fowls characterized by excitation, choreiform head and neck movements and circling (ECC-syndrome). Both acute and chronic administration of IDPN induced EEG desynchronization, EMG activation and enhancement of photic-evoked response (PER) in the hyperstriatum and pontine reticular formation while a decrease in PER was observed in the optic tectum. d-Amphetamine (2.5-5 mg/kg), apomorphine (0.1-0.25 mg/kg), piribedil (2.5-5 mg/kg), atropine (2.5-5 mg/kg), hyoscine (2.5-5 mg/kg) and cyproheptadine (0.5 mg/kg) potentiated the circling and choreiform head and neck movements. These activities were antagonized by pimozide (1 mg/kg), physostigmine (0.5 mg/kg) and quipazine (2.5-5 mg/kg). The results suggest that dopaminergic, serotoninergic and cholinergic mechanisms may be involved in IDPN-induced behavioural effects in chicks.


Small reovirus particle composed solely of sigma NS with specificity for binding different nucleic acids.
We reported previously that polycytidylate [poly(C)]-dependent RNA polymerase activity was a property of small spherical or triangular reovirus-specific particles which sedimented at 13 to 19S and were composed solely of the reovirus protein, sigma NS. Depending on the fraction of cellular extracts from which they were obtained, these particles exhibited marked differences in stability. Most 13 to 19S particles from a particular fraction repeatedly disaggregated into smaller 4 to 5S subunits with no enzymatic activity. Disruption of many particles could be prevented and polymerase activity retained after these particles had bound different single-stranded (ss) RNAs. Our previous results indicated that there was heterogeneity among the 13 to 19S particles in that possession of poly(C)-dependent RNA polymerase activity was a property of only some. Support for this heterogeneity was derived from the demonstration in this report that there were at least three types of binding sites present within particles in any purified preparation: (i) those binding only poly(C); (ii) those binding only reovirus ss RNAs; and (iii) those binding one or the other, but not both at the same time. It is suggested that only those particles able to bind either poly(C) or reovirus ss RNAs had poly(C)-dependent RNA polymerase activity, as reovirus ss RNAs markedly inhibited the polymerase activity. All three size classes of reovirus ss RNAs were equally effective in binding, but once bound, they were not copied. It is possible that heterogeneity in binding capacity of different particles comprised of only one protein, sigma NS, could result from the ability of subunits containing this protein to assemble into slightly different 13 to 19S particles with specificity of binding or polymerase activity conferred by the configuration of the assembled particles. The high capacity of sigma NS to bind many different nucleic acids with some specificity suggests that these particles may act during infection as condensing agents to bring together 10 reovirus ss RNA templates in preparation for double-stranded RNA synthesis.


A Typology of Buyers Grounded in Psychological Risk Factors for Compulsive Buying (Impulsivity, Self-Esteem, and Buying Motives): Latent Class Analysis Approach ina Community Sample.
Our objective was to identify meaningful subgroups of buyers based on psychological risk factors for compulsive buying. A community sample of 242 adult women fulfilled an online survey exploring buying habits and motives, impulsivity, self-esteem, and severity of compulsive buying. A latent class cluster analysis was performed. A nonproblematic cluster (28%) was characterized by low levels of impulsivity and buying motives. An intermediary cluster (51%) was characterized by higher levels of positive and negative reinforcement-related buying motives. Both clusters were characterized by a low frequency of compulsive buying (2 and 8%, respectively), but the severity of compulsive buying was higher for the intermediary cluster. A third cluster (21%) was characterized by a higher frequency of compulsive buying (43%), a higher severity of compulsive buying, a stronger feeling of losing control, and higher levels of negative urgency and coping motive. These results present similarities with the Interaction of Person-Affect-Cognition-Execution (I-PACE) model of addiction and the negative reinforcement model of drug addiction, which both postulate that negative feelings play a central role in motivating and maintaining addiction. These results also echo other typologies performed in problem gamblers and problematic videogame users. These similarities of psychological profiles with other addictive behaviors, and with common symptoms and clinical expressions, are supplementary arguments to consider conceptualizing compulsive buying as an addictive disorder.


Varying importance of soluble and membrane CD14 in endothelial detection of lipopolysaccharide.
The endothelial response to LPS is critical in the recruitment of leukocytes, thereby allowing the host to survive Gram-negative infection. Herein, we investigated the roles of soluble CD14 (sCD14) and membrane CD14 (mCD14) in the endothelial response to low level LPS (0.1 ng/ml), intermediate level LPS (10 ng/ml), and high level LPS (1000 ng/ml). Removal of sCD14 from serum and sCD14-negative serum prevented low level LPS detection and subsequent response. Addition of recombinant sCD14 back into the endothelial system rescued the endothelial response. GPI-linked mCD14 removal from endothelium or endothelial treatment with a CD14 mAb prevented responses to low-level LPS even in the presence of sCD14. This demonstrates essential nonoverlapping roles for both mCD14 and sCD14 in the detection of low-level LPS. At intermediate levels of LPS, sCD14 was not required, but blocking mCD14 still prevented endothelial LPS detection and E-selectin expression, even in the presence of sCD14, suggesting that sCD14 cannot substitute for mCD14. At very high levels of LPS, the absence of mCD14 and sCD14 did not abrogate TLR4-dependent, E-selectin synthesis in response to LPS. The MyD88 independent pathway was detected in endothelium (presence of TRIF-related adaptor molecule TRAM). The MyD88-independent response (IFN-beta) in endothelium required mCD14 even at the highest LPS dose tested. Our results demonstrate an essential role for endothelial mCD14 that cannot be replaced by sCD14. Furthermore, we have provided evidence for a TRAM pathway in endothelium that is dependent on mCD14 even when other responses are no longer mCD14 dependent.


Peripartum cardiomyopathy in the Hospital Albert Schweitzer District of Haiti.
This report details current epidemiologic information on peripartum cardiomyopathy in 1 district of Haiti and represents the initial report of an ongoing investigation that addresses potential etiologic and prognostic factors. Another goal is to alert the medical community of what appears to be a high-incidence area. A detailed peripartum cardiomyopathy registry has been implemented to include a review of case records from 1994 to 2000 and subsequently to identify new cases from February 1, 2000, to July 1, 2001. The Hospital Albert Schweitzer District of Haiti is a 600-square mile area with approximately 258,000 population served by a hospital, an associated clinic, and outlying health centers. There are approximately 7740 live births annually. This report details epidemiologic information on the HAS District peripartum cardiomyopathy patients including incidence, mortality rate, complications, and prognostic factors. There were 47 confirmed patients (retrospective cohort, 20 patients; prospective cohort, 27 patients), which was approximately 1 case per 400 live births (compared with an incidence of 1 case per 3000 to 4000 live births in the United States). There were 4 deaths (14% of 29 patients with follow-up), and 7 complications (pulmonary embolism, 1 case; hemiplegia, 1 case; subsequent deterioration of heart function, 5 cases). The prognosis for subsequent pregnancy was 4 of 5 cases (80%) of recurrent congestive heart failure. Peripartum cardiomyopathy appears to be relatively common in the Hospital Albert Schweitzer District of Haiti. A core group of patients is identified for ongoing epidemiologic and immunohematologic investigation of risk factors and potential etiologic factors.


Remineralising Dentine Caries Using Sodium Fluoride with Silver Nanoparticles: An In Vitro Study.
To investigate the remineralizing and staining effects of sodium fluoride (NaF) solution with polyethylene glycol-coated silver nanoparticles (PEG-AgNPs) on artificial dentine caries. Demineralized human dentine blocks were allocated to three groups. The blocks in group 1 underwent a topical application of a 12% silver diamine fluoride (SDF, 14,150 ppm fluoride) solution. The blocks in group 2 received a topical application of a 2.5% NaF (11,310 ppm fluoride) with PEG-AgNPs (400 ppm silver). The blocks in group 3 received deionized water. All blocks were subjected to pH cycling for 8 days. The surface morphology and cross-sectional features were investigated using scanning electron microscopy (SEM). The color parameters, crystal characteristics, lesion depth, and collagen degradation of the blocks were assessed using digital spectrophotometry, X-ray diffraction (XRD), micro-computed tomography, and spectrophotometry with a hydroxyproline assay, respectively. The SEM showed that dentine collagen was exposed in group 3 but not in groups 1 and 2. The mean lesion depths in groups 1 to 3 were 118±7 µm, 121±14 µm, and 339±20 µm, respectively (groups1,2<3; p<0.001). The data indicated that fluoridated PEG-AgNPs introduced no significant color effect on dentine, but SDF caused distinct discoloration. The XRD indicated that silver chloride was formed in group 1, and fluorapatite was detected in groups 1 and 2. The concentration of hydroxyproline liberated from collagen was significantly less in groups 1 and 2 than in group 3. The use of NaF solution with PEG-AgNPs can remineralize artificial dentine caries and inhibit collagen degradation without causing significant tooth staining.


[Semen cryopreservation applied to intrauterine insemination cycles for oligospermia and asthenospermia in infertile men].
To explore the application value of semen cryopreservation in intrauterine insemination cycles for the treatment of oligospermia and asthenospermia in infertile males. A total of 152 cycles of intrauterine insemination were performed for 103 couples with constitutional infertility, which were divided into Groups 1 (normal semen, n=53), 2 (oligospermia and asthenospermia, n=52) and 3 (fresh combined with cryopreserved semen, n=47). Semen parameters and forward motile sperm count after processing were recorded by Makler chamber, and all were followed up for the outcome of clinical pregnancy. Compared with Group 2, Group 3 showed obviously lower semen volume, sperm motility and grade a sperm count before semen processing, with extremely significant differences (P < 0.01), but a higher rate of grade a sperm after semen processing, though with no significant differences (P > 0.05). There were no statistically significant differences in the pregnancy rate between Groups 2 and 3 (9.6% versus 14.9%, P > 0.05). Semen cryopreservation can improve the forward motile sperm count and pregnancy rate in oligospermia and asthenospermia patients after intrauterine insemination. Semen cryopreservation combined with intrauterine insemination seems an ideal treatment for oligospermia and asthenospermia in infertile men.


Assessment of the effect of chemical agents used in dentistry on the removal of Porphyromonas gingivalis and Escherichia coli from sandblasted acid-etched titanium dental implants: an in vitro study.
The aim of this study was to evaluate the capability of chemicals to decontaminate Escherichia coli (E coli) or Porphyromonas gingivalis (P gingivalis) from sandblasted acid-etched (SAE) titanium dental implants. SAE titanium dental implants were contaminated with E coli or P gingivalis and incubated in a sterile bacterial culture media under aerobic and anaerobic conditions, respectively. The implants were treated with 10 different conditions: calcium hydroxide [Ca(OH)₂] paste for 1 minute and saline irrigation for 1 minute; Ca(OH)2 paste for 1 minute and 0.2% chlorhexidine digluconate (CHXD) irrigation for 1 minute; 0.2% CHXD for 1 minute; Dakin's solution for 1 minute; tetracycline hydrochloride (T-HCl) as a 1 g per 20 mL solution for 1, 2, and 3 minutes; and T-HCl paste for 1, 2, and 3 minutes. All implants were irrigated with 1 mL of saline solution and incubated under aerobic and anaerobic conditions for 24 hours or 48 hours for E coli- and P gingivalis-contaminated implants, respectively. The control group was submitted to all procedures except for the chemical treatments. Aliquots were removed, and turbidity was measured by spectrophotometry. The level of bacterial growth in control cultures was considered to have a decontamination percentage (DC%) of 0. Spectrophotometric analysis showed that all chemical treatments resulted in significantly higher DC% compared to controls for SAE implants contaminated with E coli (P < .05) or P gingivalis (P < .05). For the P gingivalis experiments, SAE implants treated with Ca(OH)₂ paste and saline solution had a lower DC% (39.3%) than those in the other treatment groups. In the E coli experiments, DC% was significantly lower for SAE implants treated with Ca(OH)₂ paste and saline solution (48.7%), Dakin's solution (92.7%), or T-HCl paste for 1 minute (96.6%) than those in the other groups. The DC% of SAE implants contaminated with E coli or P gingivalis by means of chemicals commonly used in dentistry is high, with the exception of Ca(OH)₂ paste burnished for 1 minute and then irrigated with saline solution for 1 minute.


Juxtaposition of the HPFH2 enhancer is not sufficient to reactivate the gamma-globin gene in adult erythropoiesis.
Previous studies have suggested that juxtaposition of a downstream enhancer to the fetal gamma-globin gene results in reactivation of the gamma-gene in adult erythrocytes of individuals with hereditary persistence of fetal hemoglobin (HPFH). To test the hypothesis in a much stricter basis, we produced beta locus YAC transgenic mice carrying an exact beta locus replicate of a deletional HPFH mutation, HPFH 2. Although the gamma-globin gene was expressed in the HPFH 2/beta locus YAC (HPFH2/YAC) transgenic mice in the early stage of development, it was completely silenced in the adult mice. The failure of gamma-gene reactivation by the juxtaposed HPFH2 enhancer contradicts the results of previous studies. We speculate that the discrepant results reflect differences in the distance between the locus of region (LCR) and the gamma-globin gene characteristic of the plasmid, cosmid or YAC constructs used for production of transgenic mice. The difference in the phenotype of the HPFH2/YAC transgenic mice and the humans with HPFH2 mutation suggests that in addition to juxtaposition of HPFH enhancers, the upstream region that is absent in the beta-YAC construct might be involved in gamma-gene reactivation in HPFH individuals. The DNase I hypersensitive sites of the LCR were well formed and the chromatin histones were acetylated. A moderate level of pol II binding was detected in the LCR, despite the fact that no transcription occurred in the globin-genes of the adult HPFH2/YAC transgenic mice. The results suggest that formation of the LCR chromatin structure in erythroid cells is independent of globin-gene transcription in the locus.


Cholinergic sprouting in the hippocampus: a proposed role for IL-1.
Damage to the entorhinal afferents (i.e., perforant path) to the hippocampal dentate gyrus leads to sprouting of the remaining intact septal cholinergic afferents within the denervated outer molecular layer. To investigate the cellular and molecular events which may contribute to this sprouting response, we describe the temporal sequence of cellular changes in the denervated zone prior to the observed neural reorganization. Rats were given perforant path (PP) transections and sacrificed at various time points following the lesion, on Days (D) 1, 2, 3, 4, 5, 6, and 30. Coronal sections at the level of the dorsal hippocampus were immunostained to localize microglia (OX-42), interleukin-1 (IL-1), and astroctytes (GFAP). We observed a rapid increase in the number of immunoreactive microglia in the denervated molecular layer within the first day following PP transection. Parallel sections show a concomitant increase in the number of IL-1-positive cells. Maximal reactive changes (i.e., hypertrophy and increase in number) in GFAP-positive astrocytes are not observed until D5. This time course of events suggests a role of microglia in astrocyte activation in vivo via production of IL-1 and offers support for a proposed hypothesis postulating a cascade of glial events which may lead to cholinergic sprouting following PP transection.


Current Practice and Utility of Chromosome Microarray Analysis in Infants Undergoing Cardiac Surgery.
Traditionally, karyotype and fluorescence in situ hybridization (FISH) were used for cytogenetic testing of infants with congenital heart disease (CHD) who underwent cardiac surgery at our institution. Recently, chromosome microarray analysis (CMA) has been performed in lieu of the traditional tests. A standardized approach to cytogenetic testing does not exist in this population. The purpose of this study was to assess the utility of CMA based on our current ordering practice. We reviewed the records of all infants (<1 year old) who underwent cardiac surgery at our institution from January 2010 to June 2013. Data included results of all cytogenetic testing performed. Diagnostic yield was calculated as the percentage of significant abnormal results obtained by each test modality. Patients were grouped by classification of CHD. Two hundred seventy-five (51%) of 535 infants who underwent cardiac surgery had cytogenetic testing. Of those tested, 154 (56%) had multiple tests performed and at least 18% were redundant or overlapping. The utilization of CMA has increased each year since its implementation. The diagnostic yield for karyotype, FISH and CMA was 10%, 12%, and 14%, respectively. CMA yield was significantly higher in patients with septal defects (33%, P = .01) compared with all other CHD classes. CMA detected abnormalities of unknown clinical significance in 13% of infants tested. In our center, redundant cytogenetic testing is frequently performed in infants undergoing cardiac surgery. The utilization of CMA has increased over time and abnormalities of unknown clinical significance are detected in an important subset of patients. A screening algorithm that risk-stratifies based on classification of CHD and clinical suspicion may provide a practical, data-driven approach to genetic testing in this population and limit unnecessary resource utilization.


[Communication, knowledge and medicine].
Knowledge developed by humanity has had profound transcendence concerning its communication and preservation. An example of this are the advances in explanations regarding health and disease, whose mainly printed circulation is rapidly losing its place to digital publications. That is the way it happens with the Revista Médica del Instituto Mexicano del Seguro Social, whose aim is the same: to disseminate new knowledge.


Rapidly progressive heart failure requiring transplantation in muscular dystrophy: a need for frequent screening.
Fukuyama congenital muscular dystrophy weakens both skeletal and cardiac muscles, but the rate of cardiomyopathic progression can accelerate faster than that of skeletal muscles. A 14-year-old boy with Fukuyama congenital muscular dystrophy presented with mild skeletal myopathy but severe cardiomyopathy requiring heart transplantation within 1 year of declining heart function. These patients need frequent screening regardless of musculoskeletal symptoms.


Vibrational mode-specific dynamics of the F- + CH3CH2Cl multi-channel reaction.
We investigate the mode-specific dynamics of the ground-state, C-Cl stretching (v10), CH2 wagging (v7), sym-CH2 stretching (v1), and sym-CH3 stretching (v3) excited F- + CH3CH2Cl(vk = 0, 1) [k = 10, 7, 1, 3] → Cl- + CH3CH2F (SN2), HF + CH3CHCl-, FH⋯Cl- + C2H4, and Cl- + HF + C2H4 (E2) reactions using a full-dimensional high-level analytical global potential energy surface and the quasi-classical trajectory method. Excitation of the C-Cl stretching, CH2 stretching, and CH2/CH3 stretching modes enhances the SN2, proton abstraction, and FH⋯Cl- and E2 channels, respectively. Anti-E2 dominates over syn-E2 (kinetic anti-E2 preference) and the thermodynamically-favored SN2 (wider reactive anti-E2 attack angle range). The direct (a) SN2, (b) proton abstraction, (c) FH⋯Cl- + C2H4, (d) syn-E2, and (e) anti-E2 channels proceed with (a) back-side/backward, (b) isotropic/forward, (c) side-on/forward, (d) front-side/forward, and (e) back-side/forward attack/scattering, respectively. The HF products are vibrationally cold, especially for proton abstraction, and their rotational excitation increases for proton abstraction, anti-E2, and syn-E2, in order. Product internal-energy and mode-specific vibrational distributions show that CH3CH2F is internally hot with significant C-F stretching and CH2 wagging excitations, whereas C2H4 is colder. One-dimensional Gaussian binning technique is proved to solve the normal mode analysis failure caused by methyl internal rotation.


Estimation of genetic parameters for individual udder quarter milk content traits in Brown Swiss cattle.
The aim of this study was to estimate genetic parameters and accuracies of breeding values for milk content traits of individual udder quarters in Brown Swiss cattle. Data of 1,799 phenotyped cows from 40 Swiss dairy herds were analyzed, taking the complete pedigree into account. Fat, protein, lactose, and urea contents, somatic cell score (SCS), and information about hyperkeratosis were available for each udder quarter. The milk of rear udder quarters was found to have significantly higher lactose content and significantly lower fat content than milk of the front udder quarters. The same trend found for fat content was observed for protein content, whereas no differences between the udder quarters were observed for urea content, SCS, or hyperkeratosis. Heritabilities for each udder quarter were in the following ranges: fat content 0.09±0.06 to 0.14±0.06, protein content 0.20±0.09 to 0.33±0.07, lactose content 0.04±0.03 to 0.16±0.07, urea content 0.13±0.07 to 0.22±0.08, SCS 0.18±0.06 to 0.32±0.07, and hyperkeratosis 0.12±0.04 to 0.26±0.05. In our study, hyperkeratosis, protein content, and SCS showed higher heritabilities in the front udder quarters, fat content had higher heritabilities in the rear udder quarters, and no systematic pattern in heritability was observed for lactose content or urea content. Additive genetic correlations between all udder quarters were >0.90 for protein and urea contents, whereas they were remarkably low (<0.60) for SCS. For fat and lactose contents, the genetic correlations between the 2 front or between the 2 rear quarters, respectively, were notably higher than correlations between 1 front and 1 rear quarter, suggesting that the front and the rear udders could be considered as partly genetically different organs. The variability within the udder as such was found to be of low heritability (<0.10) in general, but repeatability was moderate to high for some traits (lactose content: 0.33±0.05, protein content: 0.53±0.05). Some of these findings can be explained by differences in the physiological background of the traits.


Association between androgen deprivation therapy and anxiety among 78 000 patients with localized prostate cancer.
To examine whether any androgen deprivation therapy use or longer duration is associated with an increased risk of anxiety in patients with prostate cancer. We identified 78 552 men aged ≥66 years with stage I-III prostate cancer using the Surveillance, Epidemiology, and End Results-Medicare linked database from 1992 to 2006, excluding patients with psychiatric diagnoses within the year prior or 6 months after prostate cancer diagnosis. Multivariable Cox regression was used to examine the association between pharmacological androgen deprivation therapy and diagnosis of anxiety. The 43.1% (33 882) of patients who received androgen deprivation therapy experienced a higher 3-year cumulative incidence of anxiety compared with men who did not (4.1% vs 3.5%, P < 0.001). Any androgen deprivation therapy use was associated with a nearly significant increased risk of anxiety (adjusted hazard ratio 1.08, 95% confidence interval 1.00-1.17, P = 0.054). There was a significant trend between a longer duration of therapy and increased risk of anxiety (P-trend = 0.012), with a 16% higher risk for ≥12 months (adjusted hazard ratio 1.16, 95% confidence interval 1.04-1.29, P = 0.010). Androgen deprivation therapy was associated with an elevated risk of anxiety in this cohort of elderly men with localized prostate cancer, with the risk higher with a longer duration of treatment. Anxiety should be considered among the possible psychiatric effects of androgen deprivation therapy and discussed before initiating treatment, particularly if a long course is anticipated.


Community trauma exposure and post-traumatic stress disorder in Chinese children and adolescents.
An increasing number of studies have shown the association between traumatic events occurring in childhood and adolescence and post-traumatic stress disorder (PTSD). A gap remains in the literature on the epidemiology and influencing factors of traumatic events and post-traumatic stress disorder in communities in northern China. This study aimed to determine the prevalence of traumatic events and PTSD in communities in northern China, to explore the types of stressful traumatic events and the impact of these traumatic events on children and adolescents, and to investigate the effect of sociodemographic factors on PTSD. A cross-sectional survey study was conducted among 6,027 students (7-17 years old) from 6 cities in Liaoning Province, China. The sample consisted of 2,853 males (47.34%) and 3,174 females (52.66%). The Essen Trauma-Inventory for Children and Adolescents (ETI-CA) Scale was used. The ETI-CA has 5 sections, which include type of traumatic events, worst traumatic event, post-traumatic symptoms, onset, duration, burden of PTSD, and present difficulties in different areas of life. PTSD symptoms were assessed with 23 items in Part 3 of the ETI-CA. We found that 2,068 (34.3%) of 6,027 participants experienced trauma events and 686 (33.2%) of 2,068 reported PTSD. Among trauma-exposed youth (2,068), the sudden death of close relatives (33.9%), serious accidents (20.9%), and parental divorce (15.5%) were reported as the worst traumatic events. Studies have shown that after exposure to stressful life events, more than 30% of people feel nervous or upset (39.8%), scared (33.4%), helpless (32.6%), and about 10% have headaches (15.5%), rapid heartbeat (13.3%), and dizziness (11.8%). Multivariable logistic regression analyses showed that students in middle school [OR = 1.29 (1.016, 1.637)], not a student leader [OR = 0.738 (0.618, 0.881)], and their parents in single marital status significantly predicted higher PTSD prevalence the remarried [OR = 0.474 (0.252, 0.893)], married [OR = 0.42 (0.227, 0.778)]. The present study suggests the government to train psychological counselors in schools and communities to provide emotional and psychological support, as well as the school leaders and parents to elevate adolescents' psychological suzhi. Particularly, counseling and professional support should be given to those students whose parents are single.


The variability of AOAC methods of analysis as used in analytical pharmaceutical chemistry.
Pharmaceutical analytical chemistry, which ordinarily deals with the analysis of formulations containing from 0.1 to 100% of active ingredient, uses methods with a reproducibility (between-laboratory variability) of about 2.5% and a repeatability (within-laboratory variability) of about half that amount. The best between-laboratory precision attainable appears to be about 1.0% and within-laboratory precision, about 0.5%. On the basis of the results available, automated methods do not appear to be any more precise than manual methods, although the studies show fewer outlying data points. Replicates (preferably blind ones) should always be conducted in a collaborative interlaboratory study in order to obtain the important information as to whether efforts should be concentrated on improving the method itself or on the performance of laboratories and analysis in applying it.


Optoelectronic materials as emerging photocatalysts: opportunities in sustainable organic synthesis.
To overcome the energy and environmental crisis, the development of efficient, sustainable photocatalysts to convert inexhaustible solar energy into chemical energy is of great significance. Due to their unique optoelectronic properties, organic electronic materials have been translated into the photocatalytic field. These emerging photocatalysts are attractive because of their metal-free nature, chemical stability, and structural diversity. However, as many small molecules fail to absorb visible light solely, incorporating them into crosslinked frameworks is found to be an effective strategy to extend the conjugation and enhance visible-light absorption. In addition, the photophysical properties of these heterogeneous materials can be adjusted through structural modification and linkage engineering. Finally, these insoluble photocatalysts exhibit good recyclability and reusability. As a representative illustration, this feature article describes recent examples of the use of two types of organic electronic materials including phenothiazine and truxene in heterogeneous photocatalytic organic transformations. The synthesis and key photophysical properties of both organic electronic material-based photocatalysts are discussed combined with specific synthetic applications. We anticipate this feature article will stimulate the implementation of more diverse organic electronic materials in the field of photocatalysis, which may lead to unprecedented synthetic applications.


A Dissolution/Precipitation Equilibrium on the Surface of Iridium-Based Perovskites Controls Their Activity as Oxygen Evolution Reaction Catalysts in Acidic Media.
Recently, IrV -based perovskite-like materials were proposed as oxygen evolution reaction (OER) catalysts in acidic media with promising performance. However, iridium dissolution and surface reconstruction were observed, questioning the real active sites on the surface of these catalysts. In this work, Sr2 MIr(V) O6 (M=Fe, Co) and Sr2 Fe0.5 Ir0.5 (V) O4 were explored as OER catalysts in acidic media. Their activities were observed to be roughly equal to those previously reported for La2 LiIrO6 or Ba2 PrIrO6 . Coupling electrochemical measurements with iridium dissolution studies under chemical or electrochemical conditions, we show that the deposition of an IrOx layer on the surface of these perovskites is responsible for their OER activity. Furthermore, we experimentally reconstruct the iridium Pourbaix diagram, which will help guide future research in controlling the dissolution/precipitation equilibrium of iridium species for the design of better Ir-based OER catalysts.


Application of Localization and Needle Placement Guided by Mammographic, Ultrasound and Fiberoptic Ductoscopy for Resection of Non-palpable Breast Lesions.
To evaluate the usefulness of localization needles under mammographic, ultrasound or fiberoptic ductoscopy guidance for non-palpable breast lesions. Eighty-three patients undergoing needle localization and biopsy of non-palpable breast lesions under mammographic, ultrasound or fiberoptic ductoscopy guidance from June 2013 to December 2014 in Beijing Friendship Hospital were included in the study. The preoperative imaging assessment, application of localization needles, surgical operation and pathological examination were recorded and analyzed retrospectively. A total of 83 localization and biopsies were carried out, of which 27 were performed under mammographic guidance, 32 under ultrasound guidance and 24 under fiberoptic ductoscopy guidance. Twenty-seven cases of breast microcalcifications were localized under mammographic guidance and surgically removed, of which eight cases were pathologically diagnosed as malignant. Thirty-two cases of non-palpable breast lesions were localized under ultrasound guidance and 30 pathologically diagnosed, of these, four cases were pathologically diagnosed as malignant. Twenty-four cases of intraductal space-occupying lesions were localized under ductoscopy guidance and surgically removed, of which five cases were pathologically diagnosed as malignant. Utilization of localization needles under mammographic, ultrasound or fiberoptic ductoscopy guidance for non-palpable breast lesions is a safe and effective procedure, and is helpful in the diagnosis of breast cancer. With the help of this procedure, more malignant lesions can be localized and surgically removed.


Asterionellopsis tropicalis (Bacillariophyceae): a new tropical species found in diatom accumulations.
The diatom Asterionellopsis glacialis sensu lato forms high-density patches in the surf zone of some sandy beaches worldwide and was until recently considered a cosmopolitan species. With the recent description of four cryptic species, the identity of specimens found in these accumulations remains uncertain. In this study, diatom patches were sampled from two sandy beaches of the Brazilian coast: one tropical (Futuro Beach, 3° S; 38° W) and one subtropical (Cassino Beach, 32° S; 52° W). Fine structure of frustules and the sequencing of three phylogenetic markers revealed the subtropical strains to be A. guyunusae and the tropical strains to be a new species, here described as Asterionellopsis tropicalis sp. nov. A. tropicalis was differentiated morphologically by the number of striae in 10 μm at the foot pole and head (39-44; 38-45, respectively), from A. lenisilicea (46-55; 46-64), A. maritima (46-51; 46-60), and A. thurstonii (42-58; 55-70). The number of striae at the head region of the valvocopula (10 μm) helped to distinguish A. tropicalis (56-62) from A. guyunusae (61-64), but A. tropicalis was morphologically undistinguishable from A. glacialis. The sequence divergence from other identified Asterionellopsis species was 13%-16% (Cox1), 11%-12% (5.8S + ITS2) and 2%-6% (RbcL), and A. tropicalis formed a distinct monophyletic clade with high support in all analyzed phylogenetic trees (single or multi-locus). This work will aid in the understanding of the ecological and physiological diversity of diatom patches that are key to the trophic webs of sandy beaches.


The novel GATA1-interacting protein HES6 is an essential transcriptional cofactor for human erythropoiesis.
Normal erythropoiesis requires the precise regulation of gene expression patterns, and transcription cofactors play a vital role in this process. Deregulation of cofactors has emerged as a key mechanism contributing to erythroid disorders. Through gene expression profiling, we found HES6 as an abundant cofactor expressed at gene level during human erythropoiesis. HES6 physically interacted with GATA1 and influenced the interaction of GATA1 with FOG1. Knockdown of HES6 impaired human erythropoiesis by decreasing GATA1 expression. Chromatin immunoprecipitation and RNA sequencing revealed a rich set of HES6- and GATA1-co-regulated genes involved in erythroid-related pathways. We also discovered a positive feedback loop composed of HES6, GATA1 and STAT1 in the regulation of erythropoiesis. Notably, erythropoietin (EPO) stimulation led to up-regulation of these loop components. Increased expression levels of loop components were observed in CD34+ cells of polycythemia vera patients. Interference by either HES6 knockdown or inhibition of STAT1 activity suppressed proliferation of erythroid cells with the JAK2V617F mutation. We further explored the impact of HES6 on polycythemia vera phenotypes in mice. The identification of the HES6-GATA1 regulatory loop and its regulation by EPO provides novel insights into human erythropoiesis regulated by EPO/EPOR and a potential therapeutic target for the management of polycythemia vera.


Electrochemical studies and square-wave voltammetric determination of fenofibrate in pharmaceutical formulations.
The electrochemical reduction of fenofibrate at a hanging mercury drop electrode (HMDE) was investigated by cyclic voltammetry, square-wave voltammetry, and chronoamperometry. Different buffer solutions were used over a wide pH range (3.0-10.0). The best definition of the analytical signals was found in borate buffer (pH 9.0)-tetrabutylammonium iodide mixture containing 12.5% (v/v) methanol at -1.2 V (versus Ag/AgCl). According to cyclic voltammetric studies, the reduction was irreversible and diffusion controlled. The diffusion coefficient was 2.38x10(-6) cm2 s(-1) as determined by chronoamperometry. Under optimized conditions of square-wave voltammetry, a linear relationship was obtained between 0.146-4.96 microg mL(-1) of fenofibrate with a limit of detection of 0.025 microg mL(-1). Validation parameters such as sensitivity, accuracy, precision, and recovery were evaluated. The proposed method was applied to the determination of fenofibrate in pharmaceutical formulations. The results were compared with those obtained by a published high-performance liquid chromatography method. No difference was found statistically.


A practical guide about biosimilar data for health care providers treating inflammatory diseases.
To make informed decisions about the safety, efficacy, and clinical utility of a biosimilar, health care providers should understand the types and be able to analyze data generated from a biosimilar development program. This article reviews the biosimilar guidelines, the biosimilar development process to provide education and context about biosimilarity, and uses examples from infliximab biosimilars to review the terminology and potential types of analyses that may be used to compare potential biosimilars to the originator biologic. A biosimilar is a biologic product that is highly similar to an approved (originator) biologic, notwithstanding minor differences in clinically inactive components, and with no clinically meaningful differences in terms of the safety, purity, and potency of the product. Due to their complex nature and production in living systems, it is not possible to exactly duplicate the approved originator biologic. To ensure biosimilars provide consistent, safe, and effective treatment comparable to the originator biologic, extensive analyses of the potential biosimilar are conducted, including side-by-side analytical, nonclinical, and clinical comparisons. A key goal is to determine whether there are sufficient relevant similarities in chemical composition, biologic activity, and pharmacokinetic aspects between the potential biosimilar and the originator. Regulatory approvals and marketing authorizations for biosimilars are made on a case-by-case and agency-by-agency basis after evaluating the totality of the evidence generated from the entire development program. Understanding how regulatory agencies review data for approval can help health care providers make appropriate decisions when biosimilars become available for use in the treatment of inflammatory diseases, and therefore they should review the literature to gain further information about specific biosimilars.


Immunohistochemical studies of the endocrine cells within the gastro-entero-pancreatic system of Osteoglossomorpha, an ancient teleostean group.
The identification and distribution of endocrine cells within the gastro-entero-pancreatic (GEP) system of five species of the Osteoglossomorpha (Osteoglossum bicirrhosum, Scleropages jardini, Pantodon buchholzi, Notopterus chitala and Gnathonemus petersii) were analyzed by immunohistochemistry. Four immunoreactive cell types were identified within the pancreatic islets (A, B, D, and F cells), using antisera directed against mammalian insulin (m-INS), somatostatins (SST-14, SST-25), and members of the pancreatic polypeptide (aPY, NPY, PYY) and glucagon (GLU, GLP) families. The B cells were located throughout the center of the islets in the five species and, in general, D cells had a similar distribution. However, immunoreactivity to anti-somatostatins varied between four of the species and G. petersii, which showed less intensely stained D cells in the islets, but greater SST immunoreactivity in both the intestinal and the stomach epithelia than in comparable epithelia of other species. For peptides of both the pancreatic polypeptide and the glucagon families, the immunoreactivity was detected at the periphery of the islets, and there was a suggestion of an interfamily colocalization of peptides in some cells. In addition, glucagon family peptides showed a scattered immunoreactivity throughout the central portion of the islets. A moderately abundant number of cells in the intestine were immunoreactive to the PP family antisera in all five species. However, immunoreactivities to GLU, GLP, SST, and m-INS antisera were variable in intestinal cells of the species. Immunoreactivity with sera raised against m-INS and PYY was also observed in the stomach of P. buchholzi. The significance of these findings is discussed in both ontogenetic and phylogenetic contexts with respect to the GEP system in actinopterygian fishes and with respect to the possibility of variable processing of prohormones in the different organs of these osteoglossomorphs.


A Pixel-Array Detector for Time-Resolved X-ray Diffraction.
An integrating pixel-array detector for recording time-resolved X-ray diffraction measurements on microsecond timescales has been designed and tested as a 4 x 4 pixel prototype. Operational characteristics and radiation tolerance are discussed. A 100 x 92 array with 151.2 micro m square pixels is currently under construction.


Interaction of Mycoplasma hominis PG21 with Human Dendritic Cells: Interleukin-23-Inducing Mycoplasmal Lipoproteins and Inflammasome Activation of the Cell.
Mycoplasma hominis lacks a cell wall, and lipoproteins anchored to the extracellular side of the plasma membrane are in direct contact with the host components. A Triton X-114 extract of M. hominis enriched with lipoproteins was shown to stimulate the production of interleukin-23 (IL-23) by human dendritic cells (hDCs). The inflammasome activation of the host cell has never been reported upon M. hominis infection. We studied here the interaction between M. hominis PG21 and hDCs by analyzing both the inflammation-inducing mycoplasmal lipoproteins and the inflammasome activation of the host cell. IL-23-inducing lipoproteins were determined using a sequential extraction strategy with two nondenaturing detergents, Sarkosyl and Triton X-114, followed by SDS-PAGE separation and mass spectrometry identification. The activation of the hDC inflammasome was assessed using PCR array and enzyme-linked immunosorbent assay (ELISA). We defined a list of 24 lipoproteins that could induce the secretion of IL-23 by hDCs, 5 with a molecular mass between 20 and 35 kDa and 19 with a molecular mass between 40 and 100 kDa. Among them, lipoprotein MHO_4720 was identified as potentially bioactive, and a synthetic lipopeptide corresponding to the N-terminal part of the lipoprotein was subsequently shown to induce IL-23 release by hDCs. Regarding the hDC innate immune response, inflammasome activation with caspase-dependent production of IL-1β was observed. After 24 h of coincubation of hDCs with M. hominis, downregulation of the NLRP3-encoding gene and of the adaptor PYCARD-encoding gene was noticed. Overall, this study provides insight into both protagonists of the interaction of M. hominis and hDCs.IMPORTANCEMycoplasma hominis is a human urogenital pathogen involved in gynecologic and opportunistic infections. M. hominis lacks a cell wall, and its membrane contains many lipoproteins that are anchored to the extracellular side of the plasma membrane. In the present study, we focused on the interaction between M. hominis and human dendritic cells and examined both sides of the interaction, the mycoplasmal lipoproteins involved in the activation of the host cell and the immune response of the cell. On the mycoplasmal side, we showed for the first time that M. hominis lipoproteins with high molecular mass were potentially bioactive. On the cell side, we reported an activation of the inflammasome, which is involved in the innate immune response.