Dispersion of phyllosilicates in aqueous suspensions: role of the nature and amount of surfactant.
The present work aims at investigating the effect of pH values and additives on the dispersion of two 1:1 dioctahedral phyllosilicates in the presence of water. Two model clays are used for this purpose, BIP kaolin and NZCC halloysite, presenting the same surface chemistry but different morphologies. The effect of sodium hexametaphosphate, sodium silicate and sodium carbonate is discussed. Kaolin and halloysite powders were first characterized using X-ray diffraction, thermogravimetric analysis and scanning electron microscopy. Subsequently, suspensions containing 8 mass% of each clay were prepared with or without additives. Experimental measurements regarding the pH values, the zeta potential and the rheological behavior were performed to determine the most suitable additive. Results show that the conformation of halloysite particles changes regarding pH values of suspensions and is strongly related to the surface charges of these particles. At their natural pH values, halloysite and kaolin suspensions exhibit zeta potentials equal to -50 and -20 mV respectively. This trend indicates that halloysite-based suspensions are well dispersed compared to kaolin-based suspensions. Sodium hexametaphosphate is the most suitable dispersant for both clays. The rheological characterization regarding further applications in casting process indicates a shear-thinning behavior for all studied compositions.


A review of patient self-report tools for chemotherapy-induced nausea and vomiting.
The assessment of chemotherapy-induced nausea, vomiting and retching (CINVR) is important and to date no review has comprehensively assessed available patient self-report tools. The aim was to undertake a review of their utility, content and psychometric properties. One thousand three hundred and forty-seven citations were identified by electronic and hand searches resulting in 24 non-duplicate abstracts, 15 articles for analysis, and six articles, which fitted the inclusion criteria. E-mail investigations discovered a further scale, resulting in seven measures. The review highlighted the strengths and weaknesses of current tools. The multiple domains, phases and aspects of CINVR signify that the assessment tools varied markedly. The diverse requirements of research and clinicians also contribute to the variation. There was a notable disparity in the quality of scales and paucity in terms of their development and psychometric evaluation. We found that several self-assessment scales currently perceived as well-validated tools have problems in terms of their validity, reliability and appropriateness. The constituents of a scale relevant for both clinical and research use were assessed and it was recommended that a modular tool focusing on two domains (nausea and vomiting); two phases (acute and delayed); measuring the aspects of occurrence, frequency, intensity alongside duration and functional interference; and antiemetic use and adverse events should be developed. Based on these recommendations, further research into an appropriate scale would minimise conceptual confusion, increase clinicians' understanding and control of CINVR, decrease patient distress and could have equal utility in both a clinical and a research setting.


Evolution of Cellular Inclusions in Bietti's Crystalline Dystrophy.
Bietti's crystalline dystrophy (BCD) consists of small, yellow-white, glistening intraretinal crystals in the posterior pole, tapetoretinal degeneration with atrophy of the retinal pigment epithelium (RPE) and "sclerosis" of the choroid; in addition, sparking yellow crystals in the superficial marginal cornea are also found in many patients. BCD is inherited as an autosomal-recessive trait (4q35-tel) and usually has its onset in the third decade of life. This review focuses on the ultrastructure of cellular crystals and lipid inclusions of BCD.


Pyronaridine-artesunate or dihydroartemisinin-piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial.
Artemether-lumefantrine and artesunate-amodiaquine are used as first-line artemisinin-based combination therapies (ACTs) in west Africa. Pyronaridine-artesunate and dihydroartemisinin-piperaquine are potentially useful for diversification of ACTs in this region, but further safety and efficacy data are required on malaria retreatment. We did a randomised, multicentre, open-label, longitudinal, controlled phase 3b/4 clinical trial at seven tertiary centres in Burkina Faso, Guinea, and Mali. Eligible participants for first malaria episode and all retreatment episodes were adults and children aged 6 months and older with microscopically confirmed Plasmodium spp malaria (>0 to <200 000 parasites per μL of blood) and fever or history of fever in the previous 24 h. Individuals with severe or complicated malaria, an alanine aminotransferase concentration of more than twice the upper limit of normal, or a QTc greater than 450 ms were excluded. Using a randomisation list for each site, masked using sealed envelopes, participants were assigned to either pyronaridine-artesunate or dihydroartemisinin-piperaquine versus either artesunate-amodiaquine or artemether-lumefantrine. Block sizes were two or four if two treatments were allocated, and three or six if three treatments were allocated. Microscopists doing the parasitological assessments were masked to treatment allocation. All treatments were once-daily or twice-daily tablets or granules given orally and dosed by bodyweight over 3 days at the study centre. Patients were followed up as outpatients up to day 42, receiving clinical assessments on days 0, 1, 2, 3, 7, 14, 21, 28, 35, and 42. Two primary outcomes were compared for non-inferiority: the 2-year incidence rate of all microscopically confirmed, complicated and uncomplicated malaria episodes in patients in the intention-to-treat population (ITT; non-inferiority margin 20%); and adequate clinical and parasitological response (ACPR) in uncomplicated malaria across all episodes (unadjusted and PCR-adjusted for Plasmodium falciparum and unadjusted for other Plasmodium spp) in the per-protocol population on days 28 and 42 (non-inferiority margin 5%). Safety was assessed in all participants who received one dose of study drug. This study is registered at the Pan African Clinical Trials Registry (PACTR201105000286876). Between Oct 24, 2011, and Feb 1, 2016, we assigned 4710 eligible participants to the different treatment strategies: 1342 to pyronaridine-artesunate, 967 to artemether-lumefantrine, 1061 to artesunate-amodiaquine, and 1340 to dihydroartemisinin-piperaquine. The 2-year malaria incidence rate in the ITT population was non-inferior for pyronaridine-artesunate versus artemether-lumefantrine (1·77, 95% CI 1·63-1·93 vs 1·87, 1·72-2·03; rate ratio [RR] 1·05, 95% CI 0·94-1·17); and versus artesunate-amodiaquine (1·39, 95% CI 1·22-1·59 vs 1·35, 1·18-1·54; RR 0·97, 0·87-1·07). Similarly, this endpoint was non-inferior for dihydroartemisinin-piperaquine versus artemether-lumefantrine (1·16, 95% CI 1·01-1·34 vs 1·42 1·25-1·62; RR 1·22, 95% CI 1·06-1·41) and versus artesunate-amodiaquine (1·35, 1·21-1·51 vs 1·68, 1·51-1·88; RR 1·25, 1·02-1·50). For uncomplicated P falciparum malaria, PCR-adjusted ACPR was greater than 99·5% at day 28 and greater than 98·6% at day 42 for all ACTs; unadjusted ACPR was higher for pyronaridine-artesunate versus comparators at day 28 (96·9% vs 82·3% for artemether-lumefantrine and 95·6% vs 89·0% for artesunate-amodiaquine) and for dihydroartemisinin-piperaquine versus comparators (99·5% vs 81·6% for artemether-lumefantrine and 99·0% vs 89·0% for artesunate-amodiaquine). For non-falciparum species, unadjusted ACPR was greater than 98% for all study drugs at day 28 and at day 42 was greater than 83% except for artemether-lumefantrine against Plasmodium ovale (in ten [62·5%] of 16 patients) and against Plasmodium malariae (in nine [75·0%] of 12 patients). Nine deaths occurred during the study, none of which were related to the study treatment. Mostly mild transient elevations in transaminases occurred with pyronaridine-artesunate versus comparators, and mild QTcF prolongation with dihydroartemisinin-piperaquine versus comparators. Pyronaridine-artesunate and dihydroartemisinin-piperaquine treatment and retreatment of malaria were well tolerated with efficacy that was non-inferior to first-line ACTs. Greater access to these efficacious treatments in west Africa is justified. The European and Developing Countries Clinical Trial Partnership, Medicines for Malaria Venture (Geneva, Switzerland), the UK Medical Research Council, the Swedish International Development Cooperation Agency, German Ministry for Education and Research, University Claude Bernard (Lyon, France), University of Science, Techniques and Technologies of Bamako (Bamako, Mali), the Centre National de Recherche et de Formation sur le Paludisme (Burkina Faso), Institut de Recherche en Sciences de la Santé (Bobo-Dioulasso, Burkina Faso), and Centre National de Formation et de Recherche en Santé Rurale (Republic of Guinea).


Characterization of ossification of the posterior rim of acetabulum in the developing hip and its impact on the assessment of femoroacetabular impingement.
Many radiographic indices that are used to assess adolescents for femoroacetabular impingement rely on an ossified posterior acetabular wall. A recent study identified a secondary ossification center in the posterior rim of the acetabulum, the ossification of which may affect perceived acetabular coverage. The purpose of this study was to characterize ossification of the posterior rim of the acetabulum with use of a longitudinal radiographic study and quantify its impact on the radiographic assessment of femoroacetabular impingement. In this study, we utilized a historical collection of annual radiographs made in a population of healthy adolescents. Six hundred and twelve anteroposterior radiographs of the left hip of ninety-eight patients were reviewed to identify the appearance, duration, and fusion of the secondary ossification center in the posterior rim of the acetabulum. The center-edge angle was then measured before appearance and after fusion of the secondary ossification center in a subset of ten patients who had <5° of rotation on all radiographs. The secondary ossification center in the posterior rim was identified in seventy-three of the ninety-eight subjects, with no significant difference between the sexes. The mean patient age at the time of radiographic appearance of this secondary ossification center was fourteen years for males and twelve years for females. The mean duration of radiographic appearance was ten months for both sexes. Serial center-edge angles were measured in a subset of ten patients, and they increased during posterior rim ossification by a mean of 4.1°. The secondary ossification center in the posterior rim of the acetabulum (the posterior rim sign) is a common radiographic finding that reliably appears for ten months around the time of triradiate closure. Posterior rim ossification led to a mean increase of 4° of perceived acetabular coverage through the center-edge angle. Given the narrow margin between normal coverage (33° to 36°) and acetabular overcoverage (>40°), the use of radiographs in adolescents with incompletely ossified hips may lead to misinterpretation of acetabular coverage. In patients with open triradiate cartilage, magnetic resonance imaging may be considered for the assessment of femoroacetabular impingement. The posterior rim ossification sign is a normal finding in adolescent hip development and has important implications for the proper evaluation of femoroacetabular impingement.


Psychiatry in Kenya: yesterday, today and tomorrow.. An overview.
The development of psychiatry in Kenya has passed through three stages with considerable overlap - primitive/non-scientific, humanistic and scientific. These stages are similar to those in the development of psychiatry in the Western societies. The prevalence of psychiatric illness amongst those seeking medical help is no less than 20%. There is a need for a full range of the various psychiatric services, but the problems involved are immense and constitute major differences between the practice of psychiatry in Kenya and in Western countries. There is, however, a clearly evident move to solve these problems.


First international conference on infections in children in Arab countries.
This conference was the first of its kind but the need for similar meetings in the future was recognized by the participants. Considering the vast importance of infectious diseases in children in Arab countries, research in this area should receive a high priority in pediatrics. Improvements of diagnosis, management and prevention would appear particularly rewarding and could lead to significant results in a relatively short period of time.


Influence of imperatorin on the anticonvulsant activity and acute adverse-effect profile of lamotrigine in maximal electroshock-induced seizures and chimney test in mice.
The influence of imperatorin (IMP) on the anticonvulsant activity and acute adverse-effect potential of lamotrigine (LTG, a second generation antiepileptic drug) was studied in the maximal electroshock-induced seizure (MES) model and chimney test in mice. In order to assess the nature of interaction between IMP and LTG in the MES test, total brain LTG concentrations were evaluated with high-pressure liquid chromatography (HPLC). Results indicate that IMP administered ip, 30 min before the test, at a dose of 50 mg/kg significantly enhanced the anticonvulsant action of LTG in the MES test by reducing the median effective dose (ED(50)) of LTG from 6.11 to 2.47 mg/kg (p < 0.05). In contrast, IMP administered ip at doses of 30 and 40 mg/kg did not significantly potentiate the anticonvulsant activity of LTG against MES induced seizures, although a reduction of the ED(50) values for LTG from 6.11 to 5.77, and 4.28 mg/kg, respectively, was observed. On the other hand, IMP administered ip, at doses of 30, 40 and 50 mg/kg had no impact on the acute adverse effects of LTG, and the median toxic doses for LTG (TD(50)) were almost unchanged, ranging from 22.13 to 30.04 mg/kg in the chimney test. The protective index (TD(50) to ED(50) ratio) for LTG administered alone was 4.90 and increased to 5.21, 6.77, and 8.96 for LTG in combination with IMPat doses of 30, 40 and 50 mg/kg, respectively. Pharmacokinetic evaluation of total brain LTG concentration with HPLC revealed that IMP at the dose of 50 mg/kg did not affect total brain LTG concentration in experimental animals and thus, the observed interaction between IMP and LTG in the MES test was pharmacodynamic in nature. The present study demonstrates that IMP ameliorates the pharmacological profile of LTG, when considering both, the antiseizure and acute adverse effects of the drug in preclinical study on animals. The combination of LTG with IMPcan be of pivotal importance for epileptic patients as a potentially advantageous combination if it is proven that the results of this study can be extrapolated to clinical settings.


Perioperative and Delayed Major Complications Following Surgical Treatment of Adolescent Idiopathic Scoliosis.
Reporting accurate surgical complication rates to patients and their families is important in the management of adolescent idiopathic scoliosis (AIS). In this study, we report the rate of major complications following the surgical treatment of AIS both in the perioperative period and among patients with a minimum of 2 years of follow-up. We reviewed the prospectively collected data of a multicenter registry of patients who underwent surgical treatment of AIS during the period of 1995 to 2014 in order to identify all complications. A complication was defined as "major" if it resulted in reoperation or in spinal cord or nerve root injury, or was life-threatening. A total of 3,582 patients with preoperative and early postoperative data (4 to 6 weeks of follow-up) were included. A subset of 2,220 patients with a minimum of 2 years of follow-up comprised the cohort for delayed complications. Overall complication rates were calculated, as was the percentage of complications according to the year of the index surgery and type of surgical approach. The mean age of the 3,582 patients at the time of surgery was 14.8 ± 2.2 years. The average major curve magnitude was 56° ± 13° for thoracic curves and 51° ± 11° for lumbar. In 365 patients, anterior spinal fusion (ASF) with instrumentation was performed, and in 3,217 patients, posterior spinal fusion (PSF) with instrumentation was performed; 142 patients in the PSF group underwent concomitant anterior release. There were 192 major complications, with 93 (2.6%) occurring perioperatively. Perioperative complications included wound-related (1.0% of the patients), neurologic (0.5%), pulmonary (0.4%), instrumentation-related (0.4%), and gastrointestinal (0.2%) complications. One patient died. The mean annual perioperative major complication rate based on the year of surgery ranged from 0% to 10.5%. The complication rate by surgical approach was 3.0% for ASF and 2.6% for PSF (2.4% for PSF only and 5.6% for PSF with anterior release). The major complication rate for the 2,220 patients with at least 2 years of follow-up was 4.1%; all but 1 had a reoperation (4.1%). The majority of these major complications were wound and instrumentation-related (1.9% and 0.8%, respectively). After surgery for AIS, a 2.6% rate of perioperative major complications and a 4.1% rate of major complications at 2 or more years after surgery can be anticipated. The complication rate decreased over the period of study. Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.


Natural male hybrid common shrews with a very long chromosomal multivalent at meiosis appear not to be completely sterile.
Among 36 known chromosomal hybrid zones of the common shrew Sorex araneus, the Moscow-Seliger hybrid zone is of special interest because inter-racial complex heterozygotes (F1 hybrids) produce the longest meiotic configuration, consisting of 11 chromosomes with monobrachial homology (undecavalent or chain-of-eleven: CXI). Different studies suggest that such a multivalent may negatively affect meiotic progression and in general should significantly reduce fertility of hybrids. In this work, by immunocytochemical and electron microscopy methods, we investigated for the first time chromosome synapsis, recombination and meiotic silencing in pachytene spermatocytes of natural inter-racial heterozygous shrew males carrying CXI configurations. Despite some abnormalities detected in spermatocytes, such as associations of chromosomes, stretched centromeres, and the absence of recombination nodules in some arms of the multivalent, a large number of morphologically normal spermatozoa were observed. Possible low stringency of pachytene checkpoints may mean that even very long meiotic configurations do not cause complete sterility of such complex inter-racial heterozygotes.


Altered expression of retinal occludin and glial fibrillary acidic protein in experimental diabetes. The Penn State Retina Research Group.
To investigate how diabetes alters vascular endothelial cell tight junction protein and glial cell morphology at the blood-retinal barrier (BRB). The distribution of the glial marker, glial fibrillary acidic protein (GFAP), and the endothelial cell tight junction protein occludin were explored by immunofluorescence histochemistry in flatmounted retinas of streptozotocin (STZ)-diabetic and age-matched control rats, and in BB/Wor diabetes-prone and age-matched diabetes-resistant rats. GFAP immunoreactivity was limited to astrocytes in control retinas. Two months of STZ-diabetes reduced GFAP immunoreactivity in astrocytes and increased GFAP immunoreactivity in small groups of Müller cells. After 4 months of STZ-induced diabetes, all Müller cells had intense GFAP immunoreactivity, whereas there was virtually none in the astrocytes. BB/Wor diabetic rats had similar changes in GFAP immunoreactivity. Occludin immunoreactivity in normal rats was greatest in the capillary bed of the outer plexiform layer and arterioles of the inner retina but much less intense in the postcapillary venules. Diabetes reduced occludin immunoreactivity in the capillaries and induced redistribution from continuous cell border to interrupted, punctate immunoreactivity in the arterioles. Forty-eight hours of insulin treatment reversed the pattern of GFAP and occludin immunoreactivity in the STZ-diabetic rats. Diabetes alters GFAP expression in retinal glial cells, accompanied by reduction and redistribution of occludin in endothelial cells. These changes are consistent with the concept that altered glial-endothelial cell interactions at the BRB contribute to diabetic retinopathy.


Elevated V-ATPase Activity Following PTEN Loss Is Required for Enhanced Oncogenic Signaling in Breast Cancer.
PTEN loss-of-function contributes to hyperactivation of the PI3K pathway and to drug resistance in breast cancer. Unchecked PI3K pathway signaling increases activation of the mechanistic target of rapamycin complex 1 (mTORC1), which promotes tumorigenicity. Several studies have suggested that vacuolar (H+)-ATPase (V-ATPase) complex activity is regulated by PI3K signaling. In this study, we showed that loss of PTEN elevated V-ATPase activity. Enhanced V-ATPase activity was mediated by increased expression of the ATPase H+ transporting accessory protein 2 (ATP6AP2), also known as the prorenin receptor (PRR). PRR is cleaved into a secreted extracellular fragment (sPRR) and an intracellular fragment (M8.9) that remains associated with the V-ATPase complex. Reduced PTEN expression increased V-ATPase complex activity in a PRR-dependent manner. Breast cancer cell lines with reduced PTEN expression demonstrated increased PRR expression. Similarly, PRR expression became elevated upon PTEN deletion in a mouse model of breast cancer. Interestingly, concentration of sPRR was elevated in the plasma of patients with breast cancer and correlated with tumor burden in HER2-enriched cancers. Moreover, PRR was essential for proper HER2 receptor expression, localization, and signaling. PRR knockdown attenuated HER2 signaling and resulted in reduced Akt and ERK 1/2 phosphorylation, and in lower mTORC1 activity. Overall, our study demonstrates a mechanism by which PTEN loss in breast cancer can potentiate multiple signaling pathways through upregulation of the V-ATPase complex. IMPLICATIONS: Our study contributed to the understanding of the role of the V-ATPase complex in breast cancer cell tumorigenesis and provided a potential biomarker in breast cancer.


Caloric restriction recovers impaired β-cell-β-cell gap junction coupling, calcium oscillation coordination, and insulin secretion in prediabetic mice.
Caloric restriction can decrease the incidence of metabolic diseases, such as obesity and Type 2 diabetes mellitus. The mechanisms underlying the benefits of caloric restriction involved in insulin secretion and glucose homeostasis are not fully understood. Intercellular communication within the islets of Langerhans, mediated by Connexin36 (Cx36) gap junctions, regulates insulin secretion dynamics and glucose homeostasis. The goal of this study was to determine whether caloric restriction can protect against decreases in Cx36 gap junction coupling and altered islet function induced in models of obesity and prediabetes. C57BL6 mice were fed with a high-fat diet (HFD), showing indications of prediabetes after 2 mo, including weight gain, insulin resistance, and elevated fasting glucose and insulin levels. Subsequently, mice were submitted to 1 mo of 40% caloric restriction (2 g/day of HFD). Mice under 40% caloric restriction showed reversal in weight gain and recovered insulin sensitivity, fasting glucose, and insulin levels. In islets of mice fed the HFD, caloric restriction protected against obesity-induced decreases in gap junction coupling and preserved glucose-stimulated calcium signaling, including Ca2+ oscillation coordination and oscillation amplitude. Caloric restriction also promoted a slight increase in glucose metabolism, as measured by increased NAD(P)H autofluorescence, as well as recovering glucose-stimulated insulin secretion. We conclude that declines in Cx36 gap junction coupling that occur in obesity can be completely recovered by caloric restriction and obesity reversal, improving Ca2+ dynamics and insulin secretion regulation. This suggests a critical role for caloric restriction in the context of obesity to prevent islet dysfunction.


Injectable Multifunctional Composite Hydrogel as a Combination Therapy for Preventing Postsurgical Adhesion.
Postsurgical adhesion (PA) is a common and serious postoperative complication that affects millions of patients worldwide. However, current commercial barrier materials are insufficient to inhibit diverse pathological factors during PA formation, and thus, highly bioactive materials are needed. Here, this work designs an injectable multifunctional composite hydrogel that can serve as a combination therapy for preventing PA. In brief, this work reveals that multiple pathological events, such as chronic inflammatory and fibrotic processes, contribute to adhesion formation in vivo, and such processes can not be attenuated by barrier material (e.g., hydrogel) alone treatments. To solve this limitation, this work designs a composite hydrogel made of the cationic self-assembling peptide KLD2R and TGF-β receptor inhibitor (TGF-βRi)-loaded mesenchymal stem cell-derived nanovesicles (MSC-NVs). The resulting composite hydrogel displays multiple functions, including physical separation of the injured tissue areas, antibacterial effects, and local delivery and sustained release of anti-inflammatory MSC-NVs and antifibrotic TGF-βRi. As a result, this composite hydrogel effectively inhibited local inflammation, fibrosis and adhesion formation in vivo. Moreover, the hydrogel also exhibits good biocompatibility and biodegradability in vivo. Together, the results highlight that this "all-in-one" composite hydrogel strategy may provide insights into designing advanced therapies for many types of tissue injury.


TRPV1 mediates histamine-induced itching via the activation of phospholipase A2 and 12-lipoxygenase.
Histamine provokes itching and is a major skin disease complaint. Histamine is known to excite a subset of sensory neurons, predominantly C-fibers. Although histamine is pruritogenic, its signaling pathways that excite sensory neurons have not been identified. Because the metabolic products of lipoxygenases (LOs) activate transient receptor potential vanilloid receptor-1 (TRPV1) in sensory neurons, we hypothesized that histamine excites sensory neurons by activating TRPV1 via phospholipase A2 (PLA2) and LO stimulation. In cultured sensory neurons, histamine evoked inward currents that were reduced by capsazepine, a TRPV1 blocker. Moreover, histamine provoked inward currents when histamine receptor subtype 1 (H1R) and TRPV1 were expressed heterologously, but not when H1R or TRPV1 was expressed alone. In addition, histamine caused Ca2+ influxes in sensory neurons in wild-type mice but not in TRPV1-/- mice. Furthermore, histamine caused a 2.5-fold increase in the production of 12-hydroxyeicosatetraenoic acid, a metabolite of LO, in cultured sensory neurons. When injected subcutaneously into the necks of mice, histamine caused bouts of scratching, which were greatly reduced by pretreatment with capsazepine, a TRPV1 blocker, and by inhibitors of PLA2, LO, and H1R. Furthermore, mice lacking TRPV1 markedly reduced histamine-induced scratching compared with wild type. Together, these results indicate that TRPV1 plays a key role in mediating the pruritogenic action of histamine via the PLA2/LO pathway.


Conserved simple sequence repeats for the Limnanthaceae (Brassicales).
The Limnanthaceae (Order Brassicales) is a family of 18 taxa of Limnanthes (meadowfoam) native to California, Oregon, and British Columbia. Cultivated meadowfoam ( L. alba Benth.), a recently domesticated plant, has been the focus of research and development as an industrial oilseed for three decades. The goal of the present research was to develop several hundred simple sequence repeat (SSR) markers for genetic mapping, molecular breeding, and genomics research in wild and cultivated meadowfoam taxa. We developed 389 SSR markers for cultivated meadowfoam by isolating and sequencing 1,596 clones from L. alba genomic DNA libraries enriched for AG(n) or AC(n) repeats, identifying one or more unique SSRs in 696 clone sequences, and designing and testing primers for 624 unique SSRs. The SSR markers were screened for cross- taxa utility and polymorphisms among ten of 17 taxa in the Limnanthaceae; 373 of these markers were polymorphic and 106 amplified loci from every taxon. Cross-taxa amplification percentages ranged from 37.3% in L. douglasii ssp. rosea (145/389) to 85.6% in L. montana (333/389). The SSR markers amplified 4,160 unique bands from 14 genotypes sampled from ten taxa (10.7 unique bands per SSR marker), of which 972 were genotype-specific. Mean and maximum haplotype heterozygosities were 0.71 and 0.90, respectively, among six L. alba genotypes and 0.63 and 0.93, respectively, among 14 genotypes (ten taxa). The SSR markers supply a critical mass of high-throughput DNA markers for biological and agricultural research across the Limnanthaceae and open the way to the development of a genetic linkage map for meadowfoam ( x = 5).


Induction of spontaneous recurrent epileptiform discharges causes long-term changes in intracellular calcium homeostatic mechanisms.
Calcium and calcium-dependent systems have been long implicated in the induction of epilepsy. We have previously observed that intracellular calcium ([Ca2+]i) levels remain elevated in cells undergoing epileptogenesis in the hippocampal neuronal culture (HNC) model. In this study, we employed the hippocampal neuronal culture (HNC) model of in vitro 'epilepsy' which produces spontaneous recurrent epileptiform discharges (SREDs) for the life of the neurons in culture to investigate alterations in [Ca2+]i homeostatic mechanisms that may be associated with the 'epileptic' phenotype. [Ca2+]i imaging fluorescence microscopy was performed on control and 'epileptic' neurons with two different fluorescent dyes ranging from high to low affinities for [Ca2+]i. We measured baseline [Ca2+]i levels and the ability to restore resting [Ca2+]i levels after a brief 2-min exposure to the excitatory amino acid glutamate in control neurons and neurons with SREDs. Neurons manifesting SREDs had statistically significantly higher baseline [Ca2+]i levels that persisted for the life of the culture. In addition, the 'epileptic' phenotype was associated with an inability to rapidly restore [Ca2+]i levels to baseline following a glutamate induced [Ca2+]i load. The use of the low affinity dye Fura-FF demonstrated that the difference in restoring baseline [Ca2+]i levels was not due to saturation of the high affinity dye Indo-1, which was utilized for evaluating the [Ca2+]i kinetics at lower [Ca2+]i levels. Peak [Ca2+]i levels in response to glutamate were the same in both 'epileptic' and control neurons. While [Ca2+]i levels recovered in approximately 30 min in control cells, it took more than 90 min to reach baseline levels in cells manifesting SREDs. Alterations of [Ca2+]i homeostatic mechanisms observed with the 'epileptic' phenotype were shown to be independent of the presence of continuous SREDs and persisted for the life of the neurons in culture. Epileptogenesis was shown not to affect the degree or duration of glutamate induced neuronal depolarization in comparing control and 'epileptic' neurons. The results indicate that epileptogenesis in this in vitro model produced long-lasting alterations in [Ca2+]i regulation that may underlie the 'epileptic' phenotype and contribute to the persistent neuroplasticity changes associated with epilepsy.


Outcomes in Women and Minorities Compared With White Men 1 Year After Everolimus-Eluting Stent Implantation: Insights and Results From the PLATINUM Diversity and PROMUS Element Plus Post-Approval Study Pooled Analysis.
There exist limited outcomes data for women and minorities after contemporary percutaneous coronary intervention (PCI). To examine 1-year outcomes in women and minorities vs white men after PCI with everolimus-eluting stents. The PLATINUM Diversity study was a single-arm study enrolling women and minorities. Patient-level pooling with the PROMUS Element Plus Post-Approval Study was prespecified. Data on social determinants of health and language were collected in the PLATINUM Diversity cohort, which included 1501 patients at 52 US sites. The PROMUS Element Plus Post-Approval study enrolled 2681 patients at 52 US sites with some site overlap and included an "all-comers" population. All patients were enrolled beginning in October 2014 and were followed for 12 months. Analyses began in August 2016. Patients received 1 or more everolimus-eluting stent implantation. The primary end point was 1-year major adverse cardiac events (MACE), which included death/myocardial infarction (MI)/target vessel revascularization. Secondary ischemic end points were also evaluated. The pooled study consisted of 4182 patients: 1635 white men (39.1%), 1863 women (white and minority) (44.5%), and 1059 minority patients (women and men) (25.3%). Women and minorities had a higher prevalence of diabetes, prior stroke, hypertension, renal disease, and congestive heart failure than white men but lower rates of multivessel disease, prior coronary artery bypass graft surgery, prior MI, and smoking. Unadjusted 1-year MACE rates (white men, 7.6%; women, 8.6%; minorities, 9.6%) were similar between groups with no significant differences after risk adjustment. The adjusted risk of death/MI was higher among women (odds ratio, 1.6; 95% CI, 1.1-2.4) and minorities (odds ratio, 1.9; 95% CI, 1.2-2.8) compared with white men and the adjusted risk of MI was higher in minorities (odds ratio, 2.6; 95% CI, 1.4-4.8). These differences were driven primarily by nonstent-related MIs. Within the PLATINUM Diversity cohort, the independent predictors of MACE were cardiogenic shock, renal disease, history of peripheral vascular disease, multivessel disease, widowhood, and lack of private insurance. After contemporary everolimus-eluting stent implantation, women and minorities experience a similar risk of 1-year MACE but a higher adjusted risk of recurrent ischemic events primarily because of nonstent-related MIs. Both clinical and angiographic factors and social determinants of health, including widowhood and insurance status, contribute to 1-year MACE among women and minorities.


Inhibition of T7 RNA polymerase: transcription initiation and transition from initiation to elongation are inhibited by T7 lysozyme via a ternary complex with RNA polymerase and promoter DNA.
The mechanism of transcription repression of T7 RNA polymerase by T7 lysozyme was investigated using a combination of kinetic and equilibrium methods. HPLC gel-filtration experiments demonstrated complex formation between T7 lysozyme, T7 RNA polymerase, and promoter DNA. The interactions between the two proteins were quantitated by measuring in real time the changes in protein fluorescence upon binary complex formation using stopped-flow kinetics. Complex formation between T7 lysozyme and the RNA polymerase was found to occur by a one-step process, with a bimolecular association rate constant of 38 microM-1 S-1 and a dissociation rate constant of 3.5 S-1. These constants provided an equilibrium dissociation constant, Kd, of 92 nM for the polymerase lysozyme complex. The interactions of the polymerase with the DNA were studied by stopped-flow kinetics and nitrocellulose equilibrium DNA binding experiments in the absence and in the presence of T7 lysozyme. The results showed that T7 lysozyme did not prevent or change the kinetic or thermodynamic interactions of the RNA polymerase with the DNA. T7 lysozyme by itself did not bind to the DNA, but since it bound to the RNA polymerase as well as to the polymerase DNA complex, transcription repression must involve the formation of the ternary complex between T7 lysozyme, T7 RNA polymerase and the promoter DNA. The effect of T7 lysozyme was most striking on runoff product synthesis which was greatly inhibited whereas the steady-state synthesis of abortive products, limited by polymerase cycling or RNA dissociation, was relatively unaffected by the presence of T7 lysozyme. Investigation of the pre-steady-state kinetics of transcription in the presence and absence of T7 lysozyme indicated that the inhibition of runoff product synthesis was largely due to inhibition of transcription initiation and transition from initiation to elongation.


Human gene (c-fes) related to the onc sequences of Snyder-Theilen feline sarcoma virus.
The onc gene (v-fes) of the acutely transforming feline sarcoma virus (Snyder-Theilen strain) has homologous cellular sequences (c-fes) in all vertebrate species, including humans. We isolated from a human DNA library recombinant phages containing overlapping c-fes sequences. The human c-fes locus spans a region of 3.4 kilobases and contains 1.4 kilobases of DNA homologous to the viral onc sequence interspersed with three intervening sequences.


Ordered mesoporous carbon-covered carbonized silk fabrics for flexible electrochemical dopamine detection.
Flexible dopamine (DA) sensors were fabricated with ordered mesoporous carbon-covered carbonized silk fabrics (OMC/CSFs) as the working electrodes. These free-standing OMC/CSF electrodes were derived from the co-assembly of resol and block polymers with CSFs as substrates and subsequent carbonization of the resulting composites. As a result, a homogeneous OMC layer with vertically aligned ordered mesopore arrays grew on the surface of the CSFs, which effectively influenced the electrochemical detection behavior of OMC/CSFs towards DA. Using the flexible OMC/CSF electrodes, the electrochemical DA sensors exhibited high sensitivity, good selectivity, a large linear detection range of 0.2-80 μM, and a low limit detection of 0.11 μM, which were better than those of recently reported flexible DA sensors based on precious-metal-free electrodes.


Stroke due to typical thrombotic thrombocytopenic purpura treated successfully with intravenous thrombolysis and therapeutic plasma exchange.
We report a case of a 39-year-old man with expressive aphasia due to occlusion of the temporal stem of the left middle cerebral artery. Laboratory tests showed microangiopathic haemolytic anaemia and thrombocytopenia. A thrombotic thrombocytopenic purpura (TTP) was diagnosed, and thrombolytic therapy (TT) with alteplase followed by therapeutic plasma exchange (TPE) were performed with complete resolution of symptoms. The gold standard TTP treatment is TPE, and its delay can be lethal. The use of TT in TTP is controversial and has potential risks. This case shows a successful TT in a patient with typical TTP presenting as a stroke due to a large cerebral artery occlusion.


Intended versus inferred management after PET for cancer restaging: analysis of Medicare claims linked to a coverage with evidence development registry.
The National Oncologic PET Registry (NOPR) ascertained changes in the intended management of cancer patients using questionnaire data obtained before and after positron emission tomography (PET) under Medicare's coverage with evidence development policy. To assess the concordance between intended care plans and care received as ascertained through administrative claims data. Analysis of linked data of NOPR participants from 2006 to 2008 and their corresponding Medicare claims. Consenting patients aged older than 65 years having their first PET for restaging of bladder, kidney, ovarian, pancreas, prostate, small cell lung, or stomach cancer. : Agreement (positive predictive values and κ) between NOPR post-PET intended management plans for treatment (systemic therapy, radiotherapy, surgery, or combinations), biopsy, or watching as compared to claims-inferred care 30 days after PET. A total of 8460 patients with linked data were assessed. A total of 43.5% had metastatic disease and 45.3% had treatment planned (predominantly systemic therapy only), 11.1% biopsy and 43.5% watching. Claims-confirmed intended plans (positive predictive value) for single-mode systemic therapy in 62.0%, radiation in 66.0%, surgery in 45.6%, and biopsy in 55.7%. A total of 25.7% of patients with a plan of watching had treatment claims. By cancer type, κ ranged for systemic therapy only from 0.17 to 0.40 and for watching from 0.21 to 0.41. Agreement rates varied by cancer types but were minimally associated with patient age, performance status, comorbidity, or stage. Among elderly cancer patients undergoing PET for restaging, there was moderate concordance between their physicians' planned management and claims-inferred actions within a narrow time window. When higher accuracy levels are required in future coverage with evidence development studies, alternative designs will be needed.


Arterial stiffness and bone demineralization: the Baltimore longitudinal study of aging.
Arterial stiffening is one of the hallmarks of vascular aging, and is an important risk factor for cardiovascular morbidity and mortality. Aging is also associated with bone demineralization. Accumulating evidence indicate that arterial stiffness and bone demineralization might share common pathways. The aims of this study were to evaluate whether the association between arterial stiffness and bone demineralization is independent of age, and to explore putative mechanisms that may mediate their relationship. A cross-sectional analysis was performed using data from 321 men (68 ± 12 years) and 312 women (65 ± 13 years) of the Baltimore Longitudinal Study of Aging. Arterial stiffness was assessed by carotid-femoral pulse wave velocity (PWV) and cross-sectional cortical bone area (cCSA) was assessed at the level of the mid-tibia with computed tomography (CT) imaging. Age was significantly correlated with PWV in men (r = 0.38, P < 0.0001) and women (r = 0.35, P < 0.0001). Age was associated with cCSA in women (r = -0.14, P = 0.0008), but not in men. Age-adjusted linear regression analysis showed a significant inverse association between PWV and cCSA, in women but not in men. The association between PWV and cCSA remained significant in women after adjusting for age, mean arterial pressure (MAP), obesity, menopause, drugs, alcohol intake, physical activity, renal function, serum calcium, and total estradiol concentration. Independent of age and other shared risk factors, arterial stiffness is inversely related to cortical bone area in women. The sex-specific signaling and molecular pathways that putatively underlie the cross-talk between central arteries and bone are not completely understood.


Selection for surgery and survival of synchronous colorectal liver metastases; a nationwide study.
Resection of colorectal liver metastases (CRLM) is associated with improved survival but we currently have limited population-based data on selection for surgery. Patients in the Swedish Colorectal Cancer Register reported with liver metastases at diagnosis in 2007-2011 were identified. Clinical characteristics including American Society of Anesthesiologists classification, type of hospital and health care region were retrieved. Linkage to the National Patient Register and Statistics Sweden provided information on liver resection and socioeconomic variables. Synchronous CRLM was found in 4243/27,990 (15.2%) patients, of whom 1094 (25.8%) also had concurrent lung metastases. Of 3149 patients with liver-only metastases, 556 (17.8%) were subjected to liver resection. The resection rate varied by subsite; right-sided 11.7%, left-sided 19.7% and rectal cancer 22.7% (p = 0.001). It varied by type of hospital 14.1-23.6%, by region 11.5-22.7%, and was 19.8% in men and 14.9% in women (all p < 0.001). The adjusted odds were 0.74 (0.59-0.93) for females, 0.58 (0.46-0.74) for general district and 0.50 (0.37-0.68) for district hospital patients, and there were large regional differences. Patients >75 years were very unlikely to receive liver surgery 0.22 (0.15-0.32). In patients subjected to liver surgery, median survival was 57 months, 5-year survival rate was 45.4%, and those with left-sided colon cancer had the best outcome (48.8%; p = 0.02). Five-year hazard ratio for patients not subjected to liver surgery was 4.3 (3.7-5.0). Nationwide outcome after resection of synchronous CRLM was impressing but ambiguous selection mechanisms and inaccessibility need to be resolved. The implications of subsite deserve further attention.


COVID-19 Pandemic Impact on Academic Global Health Programs: Results of a Large International Survey.
The COVID-19 pandemic caused significant disruptions in international communications and travel for academic global health programs (AGHPs) in both high-income countries (HICs) and low- and middle-income countries (LMICs). Given the importance of international travel and communication to AGHPs, the pandemic has likely had considerable impact on the education, research, and administrative components of these programs. To date, no substantive study has determined the impacts of the COVID-19 pandemic on AGHPs in HICs and LMICs. This study assessed the impacts and resultant adaptations of AGHPs to pandemic realities with the goal of sharing strategies and approaches. This study applied a mixed methods sequential explanatory design to survey AGHPs in HICs and LMICs about the impacts of the COVID-19 pandemic on three program domains: education, research, and administration. First, we surveyed a range of AGHP stakeholders to capture quantitative data on the pandemic's impact. Subsequently we conducted semi-structured interviews with select survey participants to gather qualitative data expanding on specific survey responses. Data from both phases were then compared and interpreted together to develop conclusions and suggest adaptive/innovative approaches for AGHPs. AGHPs in both HICs and LMICs were significantly impacted by the pandemic in all three domains, though in different ways. While education initiatives managed to adapt by pivoting towards virtual learning, research programs were impacted more negatively by the disruptions in communication and international travel. The impact of the pandemic on scholarly output as well as on funding for education and research was quite variable, although LMIC programs were more negatively impacted. Administratively, AGHPs implemented a range of safety and risk mitigation strategies and showed a low risk tolerance for international travel. The pandemic posed many challenges but also revealed opportunities for AGHPs. The COVID-19 pandemic disrupted AGHPs in HICs and LMICs in expected and unexpected ways. Programs noted some unanticipated reductions in education program funding, negative impacts on research programs, and reduced scholarly output. Many programs reported well-coordinated adaptive responses to the pandemic including, for instance, virtual (in place of in-person) collaboration in research. The pandemic will likely have lasting impacts with regard to education, research collaborations, and administration of programs.


Psychophysical analysis of contrast processing segregated into magnocellular and parvocellular systems in asymptomatic carriers of 11778 Leber's hereditary optic neuropathy.
We examined achromatic contrast discrimination in asymptomatic carriers of 11778 Leber's hereditary optic neuropathy (LHON 18 controls) and 18 age-match were also tested. To evaluate magnocellular (MC) and Parvocellular (PC) contrast discrimination, we used a version of Pokorny and Smith's (1997) pulsed/steady-pedestal paradigms (PPP/SPP) thought to be detected via PC and MC pathways, respectively. A luminance pedestal (four 1 degree x 1 degree squares) was presented on a 12 cd/m2 surround. The luminance of one of the squares (trial square, TS) was randomly incremented for either 17 or 133 ms. Observers had to detect the TS, in a forced-choice task, at each duration, for three pedestal levels: 7, 12, 19 cd/m2. In the SPP, the pedestal was fixed, and the TS was modulated. For the PPP, all four pedestal squares pulsed for 17 or 133 ms, and the TS was simultaneously incremented or decremented. We found that contrast discrimination thresholds of LHON carriers were significantly higher than controls' in the condition with the highest luminance of both paradigms, implying impaired contrast processing with no evidence of differential sensitivity losses between the two systems. Carriers' thresholds manifested significantly longer temporal integration than controls in the SPP, consistent with slowed MC responses. The SPP and PPP paradigms can identify contrast and temporal processing deficits in asymptomatic LHON carriers, and thus provide an additional tool for early detection and characterization of the disease.


The English Channel: Contamination status of its transitional and coastal waters.
The chemical contamination (organic compounds, metals, radionuclides, microplastics, nutrients) of English Channel waters has been reviewed, focussing on the sources, concentrations and impacts. River loads were only reliable for Pb, whereas atmospheric loads appeared robust for Cd, Pb, Hg, PCB-153 and γ-HCH. Temporal trends in atmospheric inputs were decreasing. Contaminant concentrations in biota were relatively constant or decreasing, but not for Cd, Hg and HBCDD, and deleterious impacts on fish and copepods were reported. However, data on ecotoxicological effects were generally sparse for legacy and emerging contaminants. Intercomparison of activity concentrations of artificial radionuclides in sediments and biota on both Channel coasts was hindered by differences in methodological approaches. Riverine phosphate loads decreased with time, while nitrate loads remained uniform. Increased biomass of algae, attributable to terrestrial inputs of nutrients, has affected benthic production and shellfisheries. A strategic approach to the identification of contaminant impacts on marine biota is recommended.


Photorefractive keratectomy in patients with mild to moderate stable keratoconus: a five-year prospective follow-up study.
The purpose of this study was to evaluate the visual outcome of photorefractive keratectomy (PRK) in patients with mild to moderate stable keratoconus and to assess the risk of progression of the disease after the excimer laser procedure. In this prospective study, carried out at the Clemenceau Medical Center, an affiliate of Johns Hopkins International, in Beirut, Lebanon, 119 eyes from 72 patients with grade 1-2 keratoconus (Amsler-Krumeich classification) underwent PRK. Forty-seven patients had both eyes treated and 25 patients had one eye treated. The procedure was done using the Wavelight Eye Q Excimer laser. Uncorrected and best-corrected visual acuity, corneal topography, and pachymetry were assessed before the procedure and 3, 6, 12, 36, and 60 months after the procedure. Mean uncorrected visual acuity showed a statistically significant improvement (P < 0.05) at one, 3, and 5 years follow-up. One hundred and seventeen eyes (98.3%) showed no progression while two eyes (1.7%) showed progression of the disease at 5 years follow-up, as documented by corneal topography and pachymetry. These two eyes were treated with corneal collagen crosslinking. PRK in mild to moderate keratoconus is a safe and effective procedure for improving uncorrected vision in patients with mild refractive errors. However, close follow-up of patients is needed to detect any progression of the disease. Longer follow-up is needed to assess the overall effect of this procedure on progression of the disease.


New insights into histidine triad proteins: solution structure of a Streptococcus pneumoniae PhtD domain and zinc transfer to AdcAII.
Zinc (Zn(2+)) homeostasis is critical for pathogen host colonization and invasion. Polyhistidine triad (Pht) proteins, located at the surface of various streptococci, have been proposed to be involved in Zn(2+) homeostasis. The phtD gene, coding for a Zn(2+)-binding protein, is organized in an operon with adcAII coding for the extracellular part of a Zn(2+) transporter. In the present work, we investigate the relationship between PhtD and AdcAII using biochemical and structural biology approaches. Immuno-precipitation experiments on purified membranes of Streptococcus pneumoniae (S. pneumoniae) demonstrate that native PhtD and AdcAII interact in vivo confirming our previous in vitro observations. NMR was used to demonstrate Zn(2+) transfer from the Zn(2+)-bound form of a 137 amino acid N-terminal domain of PhtD (t-PhtD) to AdcAII. The high resolution NMR structure of t-PhtD shows that Zn(2+) is bound in a tetrahedral site by histidines 83, 86, and 88 as well as by glutamate 63. Comparison of the NMR parameters measured for apo- and Zn(2+)-t-PhtD shows that the loss of Zn(2+) leads to a diminished helical propensity at the C-terminus and increases the local dynamics and overall molecular volume. Structural comparison with the crystal structure of a 55-long fragment of PhtA suggests that Pht proteins are built from short repetitive units formed by three β-strands containing the conserved HxxHxH motif. Taken together, these results support a role for S. pneumoniae PhtD as a Zn(2+) scavenger for later release to the surface transporter AdcAII, leading to Zn(2+) uptake.


Establishing positional information through gradient dynamics: a lesson from the Hedgehog signaling pathway.
A long standing question in developmental biology is how morphogen gradients establish positional information during development. Although the existence of gradients and their role in developmental patterning is no longer in doubt, the ability of cells to respond to different morphogen concentrations has been controversial. In the Drosophila wing disc, Hedgehog (Hh) forms a concentration gradient along the anterior-posterior axis and establishes at least three different gene expression patterns. In a recent study, we challenged the prevailing idea that Hh establishes positional information in a dose-dependent manner and proposed a model in which dynamics of the gradient, resulting from the Hh gene network architecture, determines pattern formation in the wing disc. In this Extra View, we discuss further the methodology used in this study, highlight differences between this and other models of developmental patterning, and also present some questions that remain to be answered in this system.


Patients' Reactions to Local Anaesthetic Application Devices in Paediatric Dentistry.
Local anaesthesia is the most common medium for pain control in most dental treatments. Physical appearance of syringe itself can be considered as a provoking factor for the emergence of dental fear and anxiety (DFA). In this research the patient reactions to local anaesthesia application devices, as one of the main causes for DFA emergence, were inquired. The sample comprised of 120 patients, divided in three age groups, formed of 40 patients aged 8, 12 and 15 years. DFA prevalence was quantified by Children Fear Survey Schedule-Dental Subscale (CFSS-DS). Three different syringes were offered to the patients. Reasons for choosing one of the syringes were detected. Patients assigned statistically highest rank to plastic syringe. Boys chose metal and intraligamental syringe statistically more often than girls. Patients with higher CFSS-DS scores chose metal syringe as last option. None of the reasons for selection was dominant, except pain that could be caused by usage of any of the three syringes. A large number of patients did not mention any of the reasons for choosing particular syringes. Plastic syringe represented the most acceptable device for local anaesthetic application to our patients. Patients often linked pain with dental syringes.


Amplification of the murine leukemia virus Mr 70,000 glycoprotein gene product by human xenografts in athymic mice.
Passage of human tumors in athymic mice is accompanied by an increase in serum levels of the Mr 70,000 murine leukemia virus envelope protein, gp70. Elevated levels of gp70 can be detected in tissues of the hematopoietic systems of mice bearing human xenografts, but there is no evidence of synthesis of gp70 in these tissues. By far, the highest concentration of gp70 is in the human xenografts themselves. When assayed for gp70, 8 human xenografts and 12 cell lines established from human xenografts were all positive. In the plasma membrane of the human astrocytoma xenograft, T24, the gp70 was found to be approximately 10% of the total membrane protein. In contrast, the concentration of the Mr 30,000 viral core protein, p30, was 17-fold less. Only trace amounts of complete infectious virus could be detected. A human prostate carcinoma line that had not been grown in the athymic mice was found to have no gp70, but was shown to be able to synthesize gp70 after a single passage in the athymic mice.


[Migration and transformation of anthropogenic platinum group elements in environment: a review].
Anthropogenic platinum group elements (PGEs) are widely applied in vehicle exhaust catalytic converters (VECs), industrial catalysts, and pharmaceutics, making the PGEs, especially Pt, Pd, and Rh, become the newly environmental pollutants in some fields. Given the positive correlations between the Pt/Pd and Pt/Rh ratios in various environmental samples and the active components of VECs, the VECs containing PGEs as catalysts are regarded as the primary source of PGEs pollution. Sufficient reports indicated that in the past three decades, there was a significant increase of PGEs concentrations in diverse environmental matrices like airborne particulate matters, aquatic ecosystem components (e.g., river water, rain water, groundwater, seawater, and sediments), soils, road dusts, and organisms. It was generally assumed that anthropogenic PGEs behave in inert manner, and the health risks associated with the environmental exposures to PGEs are minimal. However, the recent studies on PGEs toxicity and environmental bioavailability indicated that once entering environment, anthropogenic PGEs might easily be mobilized and transformed into more toxic forms under the actions of various biogeochemical processes, and thereby, enhanced their bioavailability and posed potential health risks to human beings through food chain. This paper summarized the research results about the sources, distribution, and biogeochemical behaviors of PGEs in various environmental media, and it was considered that to establish the standards of PGEs for human health risks, to develop standard substances of PGEs for environmental measurements, to study the PGEs in the sediments of marginal seas, and to assess the toxicity of PGEs to marine mollusks, the present contamination status of PGEs in foods, and the risks of PGEs to human health would be the hot research topics in the future.


Folic acid deficiency in leukemia and lymphomas.
Serum folic acid levels and the urinary excretion of Figlu have been studied in patients with leukaemia or lymphomas. The results indicate that folic acid deficiency is a common complication of these diseases. Bone marrow examinations of those with evidence of such a deficiency frequently show megaloblastic erythropoiesis. The Figlu test appears to be a useful screening test for folic acid deficiency in patients with leukaemia or lymphomas.


Tissue-nonspecific alkaline phosphatase and plasma cell membrane glycoprotein-1 are central antagonistic regulators of bone mineralization.
Osteoblasts mineralize bone matrix by promoting hydroxyapatite crystal formation and growth in the interior of membrane-limited matrix vesicles (MVs) and by propagating the crystals onto the collagenous extracellular matrix. Two osteoblast proteins, tissue-nonspecific alkaline phosphatase (TNAP) and plasma cell membrane glycoprotein-1 (PC-1) are involved in this process. Mutations in the TNAP gene result in the inborn error of metabolism known as hypophosphatasia, characterized by poorly mineralized bones, spontaneous fractures, and elevated extracellular concentrations of inorganic pyrophosphate (PP(i)). PP(i) suppresses the formation and growth of hydroxyapatite crystals. PP(i) is produced by the nucleoside triphosphate pyrophosphohydrolase activity of a family of isozymes, with PC-1 being the only member present in MVs. Mice with spontaneous mutations in the PC-1 gene have hypermineralization abnormalities that include osteoarthritis and ossification of the posterior longitudinal ligament of the spine. Here, we show the respective correction of bone mineralization abnormalities in knockout mice null for both the TNAP (Akp2) and PC-1 (Enpp1) genes. Each allele of Akp2 and Enpp1 has a measurable influence on mineralization status in vivo. Ex vivo experiments using cultured double-knockout osteoblasts and their MVs demonstrate normalization of PP(i) content and mineral deposition. Our data provide evidence that TNAP and PC-1 are key regulators of the extracellular PP(i) concentrations required for controlled bone mineralization. Our results suggest that inhibiting PC-1 function may be a viable therapeutic strategy for hypophosphatasia. Conversely, interfering with TNAP activity may correct pathological hyperossification because of PP(i) insufficiency.


White-rot basidiomycete-mediated decomposition of C60 fullerol.
Industrially produced carbon-based nanomaterials (CNM), including fullerenes and nanotubes, will be introduced into the environment in increasing amounts in the next decades. One likely environmental chemical transformation of C60 is oxidation to C60 fullerol through both abiotic- and biotic-mediated means. Unfortunately, knowledge of the environmental fate of oxidized CNM is lacking. This study used bulk and compound-specific 13C stable isotope ratio mass spectrometry techniques and spectroradiometry analysis to examine the ability of two white rot basidiomycete fungi (Phlebia tremellosa and Trametes versicolor) to metabolize and degrade an oxygenated CNM, C60 fullerol. After 32 weeks of decay, both fungi were able to bleach and oxidize fullerol to CO2. Additionally, the fungi incorporated minor amounts of the fullerol carbon into lipid biomass. These findings are significant in that they represent the first report of direct biodegradation and utilization of any fullerene derivative and provide valuable information about the possible environmental fates of other CNM.


Utilization and Outcomes of Nephroureterectomy for Upper Tract Urothelial Carcinoma by Surgical Approach.
To compare outcomes and survival of open-, robotic-, and laparoscopic nephroureterectomy (ONU, RNU, LNU) using population-based data. Using the National Cancer Database, we identified patients who underwent nephroureterectomy for localized upper tract urothelial carcinoma between 2010 and 2013. Demographic and clinicopathologic characteristics were compared among the three operative approaches. Multivariate regression analyses were used to determine the impact of approach on performance of lymphadenectomy (LND), positive surgical margins (PSM), and overall survival (OS). In total, there were 9401 cases identified for analysis, including 3199 ONU (34%), 2098 RNU (22%), and 4104 LNU (44%). From 2010 to 2013, utilization of RNU increased from 14% to 30%. On multivariate analysis, LND was more likely in RNU (odds ratio [OR] 1.52; p < 0.01) and less likely in LNU (OR 0.77; p < 0.01) compared with ONU. RNU was associated with decreased PSM compared with ONU (OR = 0.73; p = 0.04). After adjusting for other factors, OS was not significantly associated with surgical approach. RNU utilization doubled over the study period. While RNU was associated with greater likelihood of LND performance as well as lower PSM rates when compared with ONU and LNU, surgical approach did not independently affect OS.


Obstetric use of continuous epidural block in a private community hospital: review of 500 cases.
Five hundred consecutive births in which continuous lumbar epidural block was used for analgesia were reviewed retrospectively. We wished to evaluate the safety and practicality of this anesthetic technic as done by practicing obstetricians in a predominantly private practice. Although many of the results confirmed those of previous studies, the most important findings were than the cesarean section rate was no higher than in the total obstetric population during the study period and that there was a high incidence of forceps usage in patients who had epidural analgesia. There was no maternal mortality, low maternal morbidity, and complications were not serious. Perinatal morbidity was not increased despite the high incidence of forceps deliveries. Continuous lumbar epidural analgesia was shown to be an effective and safe anesthetic technic for use by practicing obstetricians.


[Molecular basis of phenotype heterogeneity in cystic fibrosis].
The cystic fibrosis transmembrane conductance regulator (CFTR) gene, responsible for the cystic fibrosis phenotype, was cloned and sequenced in 1989. Since then, more than 650 mutations have been reported. The analysis of the entire coding sequence of the CFTR gene (27 exons) has been able to characterize more than 90% of the mutations in different populations. Moreover, screening of the entire coding and flanking sequences of the CFTR gene in males with congenital bilateral absence of the vas deferens revealed that 80% of these subjects are at least heterozygous for a CF mutation. These results help to improve genetic counselling and prenatal diagnosis of cystic fibrosis. Different studies examining the relation between phenotype and genotype in CF with respect to AF508 or non delta F508 mutations have demonstrated that some "severe" mutations are strongly associated with pancreatic insufficiency or complications. It has been also showed a relationship between the presumed severity of the mutations and the observed phenotype, not only for pancreatic status, but also for the severity of the respiratory involvement. However, some studies found that some individuals do not fit the outcome of their general group of genotype. These findings reinforce the conviction that other factors besides the CFTR mutation are involved in the severity and outcome of the disease.


Unusual presentation of an insulinoma in an elderly male patient.
Insulinoma is a rare neuroendocrine tumor originating from hypersecreting beta-cells of islets of Langerhans in the pancreas. We report a case of 72-year-old male, with chronic alcohol abuse, presenting with atypical features like refractory recurrent secondary generalized seizures and behavioral disturbances with increased irritability, initially mistreated as alcohol withdrawal. Detailed history, particularly the relationship of the symptoms with food intake, made us think of other causes of seizures. Fasting biochemical investigations and localizing studies helped clinch the diagnosis. The tumor was localized with the help of endoscopic ultrasonography and whole-body Ga68-DOTANOC PET-CT. The patient was treated conservatively with diazoxide and is doing well on follow-up. The present case report emphasizes the importance of detailed clinical history, more so in atypically presenting cases of refractory seizures. Insulinoma can be medically managed despite surgery being the gold standard curative treatment.


Determinants of perceived severity of hypertension and drug-compliance in hypertensive patients.
Severity of illness is not an important determinant of drug-compliance. In this paper we hypothesize that the perceived severity of illness rather than the true severity of illness is a determinant of drug-compliance. If this is true, then it will be worthwhile for physicians to look for factors determining this perceived severity of illness. (I) To test in a prospective survey whether this hypothesis can be confirmed in mildly hypertensive patients, and (II) to identify factors determining their perceived severity of illness. 450 patients were invited to participate in a prospective survey if their systolic blood pressure had been between 140 and 170 mm Hg and their diastolic blood pressure between 90 and 100 mm Hg despite treatment, for at least three clinic visits. Based on previously published data three factors possibly contributing to the perceived severity of hypertension were identified: (1) objective medical information, (2) expected physical symptoms, and (3) a positive social identification with fellow-patients. These factors were used as independent determinants in a multiple linear regression model with perceived severity of hypertension as outcome variable. Subsequently, this outcome variable together with patient characteristics was used as an independent variable in a multiple logistic regression model with drug-compliance as outcome variable. 176 patients, mean age 62 years, 52% females, completed the study. In the multiple linear regression analysis all of the three identified factors were statistically significant predictors of the perceived severity of hypertension with beta-values from 0.22 to 0.26, and p-values between 0.031 and 0.004. The multiple logistic regression analysis demonstrated that, after adjustment for gender, age, school, and general health status, the perceived severity of hypertension was a significant determinant of drug-compliance at p = 0.040. The present study shows what information patients use to conclude on the level of their blood pressure being too high or not. This information can be used to better understand the patients' ideas about health and possibly to influence these ideas. Patients' conclusion about the level of their blood pressure predicted their drug-compliance. Our study increased insight into the psychology of the patient and the results may be helpful to physicians in order to further understand and influence patient behaviors, particularly, adherence to antihypertensive medication.


Plasma-derived proteomic biomarkers in human leukocyte antigen-haploidentical or human leukocyte antigen-matched bone marrow transplantation using post-transplantation cyclophosphamide.
Recent studies have suggested that plasma-derived proteins may be potential biomarkers relevant for graft-versus-host disease and/or non-relapse mortality occurring after allogeneic blood or marrow transplantation. However, none of these putative biomarkers have been assessed in patients treated either with human leukocyte antigen-haploidentical blood or marrow transplantation or with post-transplantation cyclophosphamide, which has been repeatedly associated with low rates of severe acute graft-versus-host disease, chronic graft-versus-host disease, and non-relapse mortality. We explored whether seven of these plasma-derived proteins, as measured by enzyme-linked immunosorbent assays, were predictive of clinical outcomes in post-transplantation cyclophosphamide-treated patients using plasma samples collected at serial predetermined timepoints from patients treated on prospective clinical studies of human leukocyte antigen-haploidentical (n=58; clinicaltrials.gov Identifier: 00796562) or human leukocyte antigen-matched-related or -unrelated (n=100; clinicaltrials.gov Identifiers: 00134017 and 00809276) T-cell-replete bone marrow transplantation. Day 30 levels of interleukin-2 receptor α, tumor necrosis factor receptor 1, serum STimulation-2 (IL1RL1 gene product), and regenerating islet-derived 3-α all had high areas under the curve of 0.74-0.97 for predicting non-relapse mortality occurrence by 3 months post-transplant in both the human leukocyte antigen-matched and human leukocyte antigen-haploidentical cohorts. In both cohorts, all four of these proteins were also predictive of subsequent non-relapse mortality occurring by 6, 9, or 12 months post-transplant and were significantly associated with non-relapse mortality in univariable analyses. Furthermore, day 30 elevations of interleukin-2 receptor α were associated with grade II-IV and III-IV acute graft-versus-host disease occurring after day 30 in both cohorts. These data confirm that plasma-derived proteins previously assessed in other transplantation platforms appear to retain prognostic and predictive utility in patients treated with post-transplantation cyclophosphamide.


Silencing of a BYPASS1 homolog results in root-independent pleiotrophic developmental defects in Nicotiana benthamiana.
The Arabidopsis bypass1 mutant (bps1) exhibits defective shoot and root growth that is associated with constitutive production of a root-derived carotenoid-related signal (Van Norman et al., Curr Biol 14:1739-1746, 2004). Since the identity of the signal and the function of BPS1 are still unknown, we investigated effects of BPS1 depletion in Nicotiana benthamiana to elucidate BPS1 function in plant growth and development. The predicted protein of NbBPS1, a BPS1 homolog of N. benthamiana, contains a central transmembrane domain, and a NbBPS1:GFP fusion protein was mainly associated with the endoplasmic reticulum. Virus-induced gene silencing (VIGS) of NbBPS1 resulted in pleiotrophic phenotypes, including growth retardation and abnormal leaf development. At the cellular level, the plants exhibited hyperproliferation of the cambial cells and defective xylem differentiation during stem vascular development. Hyperactivity of the cambium was associated with an elevated auxin and cytokinin response. In contrast, the leaves had reduced numbers of cells with increased cell size and elevated endoreduplication. Cell death in NbBPS1 VIGS leaves started with vacuole collapse, followed by degeneration of the organelles. Interestingly, these phenotypes were mainly caused by silencing of NbBPS1 in the aerial parts of the plants, different from the case of the Arabidopsis bps1 mutant. These results suggest that NbBPS1 plays a role in the control of cell division and differentiation in the cambium of N. benthamiana, and BPS homologs may have a diverse function in different tissues and in different species.


Three-Dimensional Bioprinting of Cartilage by the Use of Stem Cells: A Strategy to Improve Regeneration.
Cartilage lesions fail to heal spontaneously, leading to the development of chronic conditions which worsen the life quality of patients. Three-dimensional scaffold-based bioprinting holds the potential of tissue regeneration through the creation of organized, living constructs via a "layer-by-layer" deposition of small units of biomaterials and cells. This technique displays important advantages to mimic natural cartilage over traditional methods by allowing a fine control of cell distribution, and the modulation of mechanical and chemical properties. This opens up a number of new perspectives including personalized medicine through the development of complex structures (the osteochondral compartment), different types of cartilage (hyaline, fibrous), and constructs according to a specific patient's needs. However, the choice of the ideal combination of biomaterials and cells for cartilage bioprinting is still a challenge. Stem cells may improve material mimicry ability thanks to their unique properties: the immune-privileged status and the paracrine activity. Here, we review the recent advances in cartilage three-dimensional, scaffold-based bioprinting using stem cells and identify future developments for clinical translation. Database search terms used to write this review were: "articular cartilage", "menisci", "3D bioprinting", "bioinks", "stem cells", and "cartilage tissue engineering".


Amiodarone-induced bone marrow granulomas: an unusual cause of reversible pancytopenia.
Bone marrow infiltration by granulomas rarely presents with cytopenias and is usually a result of atypical infections, lymphomas, or sarcoidosis. Drugs are also an important but often overlooked causal agent of bone marrow granulomas. Although rare, amiodarone has been associated with bone marrow granuloma formation. This case report describes a 73-year-old male who presented with pancytopenia during a preoperative evaluation. Amiodarone therapy was suspected to be the causal agent after diagnostic evaluation and exclusion of other causes. After cessation of amiodarone, the patient's pancytopenia gradually resolved over a period of several months. Our report illustrates an often overlooked yet important cause of reversible pancytopenia owing to suspected amiodarone-induced bone marrow granuloma formation, and guides clinicians in an expected timeline for blood count improvement after cessation of this drug.


Magneto-Mechanical Actuation Induces Endothelial Permeability.
Cancer treatment is one of the major health problems that burden our society. According to the American Cancer Society, over 1.9 million new cancer cases and ∼0.6 million deaths from cancer are expected in the US in 2023. Therapeutic targeting is considered to be the gold standard in cancer treatment. However, when a tumor grows beyond a critical size, its vascular system differentiates abnormally and erratically, creating a heterogeneous endothelial barrier that further restricts drug delivery into tumors. While several methods exist, these prompt tumor migration and the appearance of new metastatic sites. Herein, we propose an innovative method based on magneto-mechanical actuation (MMA) to induce endothelial permeability. This method employs FDA-approved PEGylated superparamagnetic iron oxide nanoparticles (PEG-SPIONs) and alternating nonheating magnetic fields. MMA lies in the translation of magnetic forces into mechanical agitation. As a proof of concept, we developed a 2D cell culture model based on human umbilical vein endothelial cells (HUVEC), which were incubated with PEG-SPIONs and then exposed to different magnetic doses. After adjusting the particle concentration, incubation times, and parameters (amplitude, frequency, and exposure time) of the magnetic field generator, we induced actin filament remodeling and subsequent vascular endothelial-cadherin junction disruption. This led to transient gaps in cell monolayers, through which fluorescein isothiocyanate-dextran was translocated. We observed no cell viability reduction for 3 h of particle incubation up to a concentration of 100 μg/mL in the presence and absence of magnetic fields. For optimal permeability studies, the magnetic field parameters were adjusted to 100 mT, 65 Hz, and 30 min in a pulse mode with 5 min OFF intervals. We found that the endothelial permeability reached the highest value (33%) when 2 h postmagnetic field treatment was used. To explain these findings, a magneto-mechanical transduced stress mechanism mediated by intracellular forces was proposed. This method can open new avenues for targeted drug delivery into anatomic regions within the body for a broad range of disease interventions.


Regulation of Drosophila wing vein patterning: net encodes a bHLH protein repressing rhomboid and is repressed by rhomboid-dependent Egfr signalling.
The stereotyped pattern of veins in the Drosophila wing is generated in response to local EGF signalling. Mutations in the rhomboid (rho) gene, which encodes a sevenpass membrane protein required to enhance signalling transmitted by the EGF receptor (Egfr), inhibit vein development and disrupt the vein pattern. By contrast, net mutations produce ectopic veins in intervein regions. We have cloned the net gene and show that it encodes a basic HLH protein that probably acts as a transcriptional repressor. net and rho are expressed in mutually exclusive patterns during the development of the wing imaginal disc. Lack of net activity causes rho expression to expand, and vice versa. Furthermore, ectopic expression of net or rho results in their mutual repression and thus suppresses vein formation or generates tube-like wings composed of vein-like tissue. Egfr signalling and net exert mutually antagonising activities during the specification of vein versus intervein fate. While Egfr signalling represses net transcription, net exhibits a two-tiered control by repressing rho transcription and interfering with Egfr signalling downstream of Rho. Our results further suggest that net is required to maintain intervein development by restricting Egfr signalling, which promotes vein development, to the Net-free vein regions of the wing disc.


Pharmacokinetics of coumarin upon i.v. administration in man.
The disposition pharmacokinetics of coumarin has been studied after i.v. administration in man, and might be described best by an open two-compartment model. Three dose sizes have been studied, 0.125, 0.2 and 0.25 mg/kg. The mean biological half-life was found to be 1.81, 1.45 and 1.49 h, respectively, for the three dose sizes. Coumarin is extensively distributed. The volume of the central compartment apparently comprises the extracellular and intracellular fluid. The study indicates dose-dependent (non-linear) pharmacokinetics with respect to distribution.


Origins, Admixture Dynamics, and Homogenization of the African Gene Pool in the Americas.
The Transatlantic Slave Trade transported more than 9 million Africans to the Americas between the early 16th and the mid-19th centuries. We performed a genome-wide analysis using 6,267 individuals from 25 populations to infer how different African groups contributed to North-, South-American, and Caribbean populations, in the context of geographic and geopolitical factors, and compared genetic data with demographic history records of the Transatlantic Slave Trade. We observed that West-Central Africa and Western Africa-associated ancestry clusters are more prevalent in northern latitudes of the Americas, whereas the South/East Africa-associated ancestry cluster is more prevalent in southern latitudes of the Americas. This pattern results from geographic and geopolitical factors leading to population differentiation. However, there is a substantial decrease in the between-population differentiation of the African gene pool within the Americas, when compared with the regions of origin from Africa, underscoring the importance of historical factors favoring admixture between individuals with different African origins in the New World. This between-population homogenization in the Americas is consistent with the excess of West-Central Africa ancestry (the most prevalent in the Americas) in the United States and Southeast-Brazil, with respect to historical-demography expectations. We also inferred that in most of the Americas, intercontinental admixture intensification occurred between 1750 and 1850, which correlates strongly with the peak of arrivals from Africa. This study contributes with a population genetics perspective to the ongoing social, cultural, and political debate regarding ancestry, admixture, and the mestizaje process in the Americas.


Glutathione S-transferases and cancer (Review).
Cytosolic glutathione S-transferases are a family of enzymes involved in the metabolism of drugs, toxins, carcinogens and also of anticancer drugs. Recent studies have indicated that glutathione S-transferases (GSTs) may play an important role in the resistance of cells to toxins and carcinogens but also to anticancer drugs. This report reviews the current literature concerning the role of glutathione S-transferases in anticancer drug resistance. Moreover, the significance of GST pi in carcinogenesis and its role as prognostic factor is discussed.


Real world evidence (RWE) - a disruptive innovation or the quiet evolution of medical evidence generation?
Stakeholders in healthcare are increasingly turning to real world evidence (RWE) to inform their decisions, alongside evidence from randomized controlled trials. RWE is generated by analysing data gathered from routine clinical practice, and can be used across the product lifecycle, providing insights into areas including disease epidemiology, treatment effectiveness and safety, and health economic value and impact. Recently, the US Food and Drug Administration and the European Medicines Agency have stated their ambition for greater use of RWE to support applications for new indications, and are now consulting with their stakeholders to formalize standards and expected methods for generating RWE. Pharmaceutical companies are responding to the increasing demands for RWE by developing standards and processes for each stage of the evidence generation pathway. Some conventions are already in place for assuring quality, whereas other processes are specific to the research question and data sources available. As evidence generation increasingly becomes a core role of medical affairs divisions in large pharmaceutical companies, standards of rigour will continue to evolve and improve. Senior pharmaceutical leaders can drive this change by making RWE a core element of their corporate strategy, providing top-level direction on how their respective companies should approach RWE for maximum quality. Here, we describe the current and future areas of RWE application within the pharmaceutical industry, necessary access to data to generate RWE, and the challenges in communicating RWE. Supporting and building on viewpoints from industry and publicly funded research, our perspective is that at each stage of RWE generation, quality will be critical to the impact that RWE has on healthcare decision-makers; not only where RWE is an established and evolving tool, but also in new areas that have the potential to disrupt and to improve drug development pathways.


Long term follow-up of titanium implants installed in block-grafted areas: A systematic review.
An enduring clinical question concerns the outcome (ie, success) of implants placed in areas grafted with block-grafts. To undertake a systematic review of the literature on the long term results (≥5 years) of implants placed in maxillofacial areas grafted with any type of osseous block-grafts in two-stage surgeries. Further, the review addresses how available success criteria were used within the studies. The MEDLINE (PubMed) and EMBASE bibliographic databases were searched up to March 2017 for studies evaluating the long term results of implants placed in grafted areas. The search strategy was restricted to English language publications using combined terms which referred to the treatment method (implants placed in areas grafted with bone blocks), and follow-up characteristics (≥5 years and assessment of at least one parameter related to implant success criteria). To qualify for inclusion, studies should present outcome measurements indicating the success (or at least the survival) of the implants. The search strategy yielded 17 studies, which were included in this systematic review. These studies presented survival rates ranging from 88.7% (after 15 years follow-up) to 98.7% (after 5 years follow-up). Five studies presented data based on predefined success criteria with success rates ranging from 86.8% to 100%. In these studies, the term "success" was often not properly defined. The long term survival (≥5 years) of implants placed into block-grafted areas in two-stage surgeries was not lower than 75%, while success rates ranged from 86.8% to 100%. Although it was possible to identify published success criteria for implant follow-up, there is no broad consensus on how to report implant success in a consistent manner.


Three initial diets for management of mild acute pancreatitis: a meta-analysis.
To compare non-liquid and clear-liquid diets, and to assess whether the latter is the optimal treatment for mild acute pancreatitis. The Cochrane Library, PUBMED, EMBASE, EBM review databases, Science Citation Index Expanded, and several Chinese databases were searched up to March 2011. Randomized controlled trials (RCTs) that compared non-liquid with clear-liquid diets in patients with mild acute pancreatitis were included. A meta-analysis was performed using available evidence from RCTs. Three RCTs of adequate quality involving a total of 362 participants were included in the final analysis. Compared to liquid diet, non-liquid diet significantly decreased the length of hospitalization [mean difference (MD): 1.18, 95% CI: 0.82-1.55; P﹤0.00001] and total length of hospitalization (MD: 1.31, 95% CI: 0.45-2.17; P = 0.003). The subgroup analysis showed solid diet was more favorable than clear liquid diet in the length of hospitalization, with a pooled MD being -1.05 (95% CI: -1.43 to -0.66; P﹤0.00001). However, compared with clear liquid diet, both soft and solid diets did not show any significant differences for recurrence of pain after re-feeding, either alone [relative risk (RR): 0.95; 95% CI: 0.51-1.87; P = 0.88] and (RR: 1.22; 95% CI: 0.69-2.16; P = 0.49), respectively, or analyzed together as non-liquid diet (RR: 0.80; 95% CI: 0.47-1.36; P = 0.41). The non-liquid soft or solid diet did not increase pain recurrence after re-feeding, compared with the clear-liquid diet. The non-liquid diet reduced hospitalization.


Differential ubiquitination and proteasome regulation of Ca(V)2.2 N-type channel splice isoforms.
Ca(V)2.2 (N-type) calcium channels control the entry of calcium into neurons to regulate essential functions but most notably presynaptic transmitter release. Ca(V)2.2 channel expression levels are precisely controlled, but we know little of the cellular mechanisms involved. The ubiquitin proteasome system (UPS) is known to regulate expression of many synaptic proteins, including presynaptic elements, to optimize synaptic efficiency. However, we have limited information about ubiquitination of Ca(V)2 channels. Here we show that Ca(V)2.2 proteins are ubiquitinated, and that elements in the proximal C terminus of Ca(V)2.2 encoded by exon 37b of the mouse Cacna1b gene predispose cloned and native channels to downregulation by the UPS. Ca(V)2.2 channels containing e37b are expressed throughout the mammalian nervous system, but in some cells, notably nociceptors, sometimes e37a--not e37b--is selected during alternative splicing of Ca(V)2.2 pre-mRNA. By a combination of biochemical and functional analyses we show e37b promotes a form of ubiquitination that is coupled to reduced Ca(V)2.2 current density and increased sensitivity to the UPS. Cell-specific alternative splicing of e37a in nociceptors reduces Ca(V)2.2 channel ubiquitination and sensitivity to the UPS, suggesting a role in pain processing.


Insulin sensitivity and β-cell function in adults with lifetime, untreated isolated growth hormone deficiency.
GH reduces insulin sensitivity (IS), whereas IGF-I increases it. IGF-I seems to be critical for the development of the β-cells, and impaired IS has been reported in GH deficiency (GHD). The aim of the study was to assess IS and β-cell function in adult patients with untreated isolated GHD (IGHD) due to a homozygous mutation in the GHRH receptor gene. We conducted a cross-sectional study in 24 GH-naive adult IGHD subjects and 25 controls. We performed an oral glucose tolerance test with glucose and insulin measurements at 0, 30, 60, 90, 120, and 180 min. IS was assessed by homeostasis model assessment index of insulin resistance (IR), quantitative IS check index, oral glucose IS in 2 h (OGIS2) and 3 h (OGIS3). β-Cell function was assayed by homeostasis model assessment index-β, insulinogenic index, and area under the curve of insulin-glucose ratio. During the oral glucose tolerance test, glucose levels were higher in IGHD subjects (P<0.0001), whereas insulin response presented a trend toward reduction (P=0.08). The number of individuals with impaired glucose tolerance was higher in the IGHD group (P=0.001), whereas the frequency of diabetes was similar in the two groups. Homeostasis model assessment index of IR was lower (P=0.04), and quantitative IS check index and OGIS2 showed a nonsignificant trend toward elevation (P=0.066 and P=0.09, respectively) in IGHD. OGIS3 showed no difference between the groups. Homeostasis model assessment index-β, insulinogenic index, and ratio of the areas of the insulin and glucose curves were reduced in the IGDH group (P=0.015, P<0.0001, and P=0.02, respectively). Adult subjects with lifetime congenital untreated IGHD present reduced β-cell function, no evidence of IR, and higher frequency of impaired glucose tolerance.


The relation of the natriuretic hormone to essential hypertension.
Following the demonstration of a circulating inhibitor of Na+-K+-ATPase in the rat, dog and man, there is now accumulating evidence that the concentration of this inhibitor is increased in patients with essential hypertension:--1. the defect in white cell sodium transport is inversely related to levels of plasma renin activity on a low sodium diet; 2. incubation of leucocytes from normotensive subjects in serum obtained from patients with essential hypertension impairs their ouabain sensitive sodium leucocyte efflux rate constant to the same extent as that found in the leucocytes of hypertensive patients; 3. using a cytochemical technique to measure G6PD activity as a marker of the plasma's ability to inhibit Na+-K+-ATPase it has been found that patients with essential hypertension appear to have an increased concentration of a circulating inhibitor of Na+-K+-ATPase.


High risk of cerebral-vein thrombosis in carriers of a prothrombin-gene mutation and in users of oral contraceptives.
Idiopathic cerebral-vein thrombosis can cause serious neurologic disability. We evaluated risk factors for this disorder, including genetic risk factors (mutations in the genes encoding factor V and prothrombin) and nongenetic risk factors (such as the use of oral contraceptive agents). We compared the prevalence of these risk factors in 40 patients with cerebral-vein thrombosis, 80 patients with deep-vein thrombosis of the lower extremities, and 120 healthy controls. The G1691A mutation in the factor V gene and the G20210A prothrombin-gene mutation, which are established genetic risk factors for venous thrombosis, were studied. We also assessed the use of oral contraceptives and other risk factors for thrombosis. The prevalence of the prothrombin-gene mutation was higher in patients with cerebral-vein thrombosis (20 percent) than in healthy controls (3 percent; odds ratio, 10.2; 95 percent confidence interval, 2.3 to 31.0) and was similar to that in patients with deep-vein thrombosis (18 percent). Similar results were obtained for the mutation in the factor V gene. The use of oral contraceptives was more frequent among women with cerebral-vein thrombosis (96 percent) than among controls (32 percent; odds ratio, 22.1; 95 percent confidence interval, 5.9 to 84.2) and among those with deep-vein thrombosis (61 percent; odds ratio, 4.4; 95 percent confidence interval, 1.1 to 17.8). For women who were taking oral contraceptives and who also had the prothrombin-gene mutation (seven patients with cerebral-vein thrombosis but only one control), the odds ratio for cerebral-vein thrombosis rose to 149.3 (95 percent confidence interval, 31.0 to 711.0). Mutations in the prothrombin gene and the factor V gene are associated with cerebral-vein thrombosis. The use of oral contraceptives is also strongly and independently associated with the disorder. The presence of both the prothrombin-gene mutation and oral-contraceptive use raises the risk of cerebral-vein thrombosis further.


Visualization of Surfactants on Nanostructured Palladium Clusters by a Combination of STM and High-Resolution TEM.
Scanning tunneling microscopy (STM) and high-resolution transmission electron microscopy (TEM) have been used to determine the dimensions of a series of palladium clusters stabilized by tetraalkylammonium salts. Electrochemically prepared colloids were used in which the average diameter of the inner metal core was varied between 2 and 4 nanometers, and the size of the ammonium ions was adjusted in the series (+)N(n-C(4)H(9))(4) < (+)N(n-C(8)H(17))(4) < (+)N(n-C(18)H(37))(4). The difference between the mean diameter determined by STM and that measured by TEM allows the determination of the thickness of the protective surfactant layer. On the basis of these studies, a model of the geometric properties of ammonium-stabilized palladium clusters has been proposed. Suggestions for the mechanism of the STM imaging process are also made.


Visual perception and its impairment in schizophrenia.
Much work in the cognitive neuroscience of schizophrenia has focused on attention, memory, and executive functioning. To date, less work has focused on perceptual processing. However, perceptual functions are frequently disrupted in schizophrenia, and thus this domain has been included in the CNTRICS (Cognitive Neuroscience Treatment Research to Improve Cognition in Schizophrenia) project. In this article, we describe the basic science presentation and the breakout group discussion on the topic of perception from the first CNTRICS meeting, held in Bethesda, Maryland on February 26 and 27, 2007. The importance of perceptual dysfunction in schizophrenia, the nature of perceptual abnormalities in this disorder, and the critical need to develop perceptual tests appropriate for future clinical trials were discussed. Although deficits are also seen in auditory, olfactory, and somatosensory processing in schizophrenia, the first CNTRICS meeting focused on visual processing deficits. Key concepts of gain control and integration in visual perception were introduced. Definitions and examples of these concepts are provided in this article. Use of visual gain control and integration fit a number of the criteria suggested by the CNTRICS committee, provide fundamental constructs for understanding the visual system in schizophrenia, and are inclusive of both lower-level and higher-level perceptual deficits.


5'-Deoxyribose phosphate lyase activity of human DNA polymerase iota in vitro.
DNA polymerase iota (pol iota) is one of several recently discovered DNA polymerases in mammalian cells whose function is unknown. We report here that human pol iota has an intrinsic 5'-deoxyribose phosphate (dRP) lyase activity. In reactions reconstituted with uracil-DNA glycosylase (UDG), apurinic/apyrimidinic (AP) endonuclease and DNA ligase I, pol iota can use its dRP lyase and polymerase activities to repair G*U and A*U pairs in DNA. These data and three distinct catalytic properties of pol iota implicate it in specialized forms of base excision repair (BER).