Old and new treatments for primary biliary cholangitis.
Primary biliary cholangitis (formerly primary biliary cirrhosis) is a rare progressive cholestatic liver disease, whose hallmark features include a persistently elevated alkaline phosphatase level, presence of anti-mitochondrial antibodies and characteristic histology. Since 1998, ursodeoxycholic acid (UDCA), a bile acid, has been the only available therapeutic agent. Primary biliary cholangitis is associated with the development of end-stage liver disease, increased morbidity and mortality. UDCA has been shown to improve serum biochemistries, histology and delay the need for liver transplantation. The clinical issue is that approximately 25%-40% of patients do not respond to this standard therapy. In recent years, many trials have investigated alternative and adjunctive treatments, leading to the recent approval of obeticholic acid, an analogue of chenodeoxycholic acid, which has shown significant and sustained reductions in alkaline phosphatase levels in combination with UDCA. Obeticholic acid has rapidly been embraced as a new agent to improve the biochemical profile in refractory patients, in addition to being approved for use as monotherapy in patients who cannot tolerate UDCA. There are several other studies and targets which are being investigated. This review is intended to highlight the benefits of UDCA, educate the reader on the newly available obeticholic acid, and to summarize the many ongoing trials and therapeutic targets being investigated in attempts to control and cure primary biliary cholangitis.


Prevalence and severity of pain in cancer patients in an outpatient palliative care setting in Saudi Arabia.
The prevalence and severity of cancer pain in the outpatient palliative care (PC) setting have not been explored previously in Saudi Arabia (SA). Exploration of this basic information may help in evaluating pain severity in patients new to PC as compared to those with previous PC exposure. This paper aims to determine the prevalence and severity of cancer pain among new and follow-up patients attending a PC outpatient clinic. In a PC outpatient setting in a major tertiary hospital in SA, we interviewed adult patients with cancer during their attendance to the clinic. Patients were requested to score the severity of their pain on a 0 to 10 numerical scale. A total of 124 patients were interviewed, of whom 73 (59%) were females. The majority of patients (82.3%) had metastatic disease. The most common cancers were breast (27.4%) and head and neck (15.3%). The majority of patients (85.5%) reported pain, with a median intensity score of 5 and a mean of 4.6. Of those who reported pain, 54 (51%) scored above 4. The mean pain score did not differ between groups of patients according to various characteristics such as age, sex, performance status, type of cancer or encounter type. Pain is a prevalent symptom in new and follow-up cancer patients seen in a PC outpatient setting in SA. Further research on a larger scale is needed to evaluate the magnitude of the problem more comprehensively with emphasis on detailed pain assessment and exploration of the adopted management approaches.


Emergence of Melioidosis in Indonesia and Today's Challenges.
A recent modeling study estimated that there could be as many as 20,000 human melioidosis cases per year in Indonesia, with around 10,000 potential deaths annually. Nonetheless, the true burden of melioidosis in Indonesia is still unknown. The Indonesia Melioidosis Network was formed during the first melioidosis workshop in 2017. Here, we reviewed 101 melioidosis cases (99 human and two animal cases) previously reported and described an additional 45 human melioidosis cases. All 146 culture-confirmed cases were found in Sumatra (n = 15), Java (n = 104), Kalimantan (n = 15), Sulawesi (n = 11) and Nusa Tenggara (n = 1). Misidentification of Burkholderia pseudomallei was not uncommon, and most cases were only recently identified. We also evaluated clinical manifestations and outcome of recent culture-confirmed cases between 2012 and 2017 (n = 42). Overall, 15 (36%) cases were children (age <15 years) and 27 (64%) were adults (age ≥15 years). The overall mortality was 43% (18/42). We conducted a survey and found that 57% (327/548) of healthcare workers had never heard of melioidosis. In conclusion, melioidosis is endemic throughout Indonesia and associated with high mortality. We propose that top priorities are increasing awareness of melioidosis amongst all healthcare workers, increasing the use of bacterial culture, and ensuring accurate identification of B. pseudomalleiand diagnosis of melioidosis.


Nutrition support in clinical practice: review of published data and recommendations for future research directions. Summary of a conference sponsored by the National Institutes of Health, American Society for Parenteral and Enteral Nutrition, and American Society for Clinical Nutrition.
In the last 30 years, marked advances in enteral feeding techniques, venous access, and enteral and parenteral nutrient formulations have made it possible to provide nutrition support to almost all patients. Despite the abundant medical literature and widespread use of nutritional therapy, many areas of nutrition support remain controversial. Therefore, the leadership at the National Institutes of Health, The American Society for Parenteral and Enteral Nutrition, and The American Society for Clinical Nutrition convened an advisory committee to perform a critical review of the current medical literature evaluating the clinical use of nutrition support; the goal was to assess our current body of knowledge and to identify the issues that deserve further investigation. The panel was divided into five groups to evaluate the following areas: nutrition assessment, nutrition support in patients with gastrointestinal diseases, nutrition support in wasting diseases, nutrition support in critically ill patients, and perioperative nutrition support. The findings from each group are summarized in this report. This document is not meant to establish practice guidelines for nutrition support. The use of nutritional therapy requires a careful integration of data from pertinent clinical trials, clinical expertise in the illness or injury being treated, clinical expertise in nutritional therapy, and input from the patient and his/her family. (Journal of Parenteral and Enteral Nutrition 21:133-156, 1997).


Identification of glu-277 as the catalytic nucleophile of Thermoanaerobacterium saccharolyticum beta-xylosidase using electrospray MS.
Thermoanaerobacterium saccharolyticum beta-xylosidase is a member of family 39 of the glycosyl hydrolases. This grouping comprises both retaining beta-d-xylosidases and alpha-l-iduronidases. T. saccharolyticum beta-xylosidase catalyses the hydrolysis of short xylo-oligosaccharides into free xylose via a covalent xylosyl-enzyme intermediate. Incubation of T. saccharolyticum beta-xylosidase with 2,4-dinitrophenyl 2-deoxy-2-fluoro-beta-d-xyloside resulted in time-dependent inactivation of the enzyme (inactivation rate constant ki=0.089 min-1, dissociation constant for the inactivator Ki=65 microM) through the accumulation of a covalent 2-deoxy-2-fluoro-alpha-d-xylosyl-enzyme, as observed by electrospray MS. Removal of excess inactivator and regeneration of the free enzyme through transglycosylation with either xylobiose or thiobenzyl xyloside demonstrated that the covalent intermediate was kinetically competent. Peptic digestion of the 2-deoxy-2-fluoro-alpha-d-xylosyl-enzyme intermediate and subsequent analysis by electrospray ionization triple-quadrupole MS in the neutral-loss mode indicated the presence of a 2-deoxy-2-fluoro-alpha-d-xylosyl peptide. Sequence determination of the labelled peptide by tandem MS in the daughter-ion scan mode permitted the identification of Glu-277 (bold and underlined) as the catalytic nucleophile within the sequence IILNSHFPNLPFHITEY.


The effect of Chlamydia trachomatis infection on the host cell cytoskeleton and membrane compartments.
Human epithelial cells and the McCoy cell line were infected with Chlamydia trachomatis, serotype E. The organization of the cytoplasm was then studied with probes which stained cytoskeletal components and membrane compartments. The major actin-containing stress fibre bundles were not associated with inclusions due to the peri-basal and peri-apical location of these bundles within the host cell. The cytokeratin network was distorted by the presence of inclusions so that a common basket of these intermediate filaments surrounded both nucleus and peri-nuclear inclusions. The microtubule network was similarly distorted, but the nucleus and inclusion were surrounded by separate rather than joint baskets of tubules. After reversible depolymerization by nocadazole the microtubules in amniotic epithelial cells began to reassemble at the peri-nuclear microtubule-organizing centre, so that independent microtubule networks were rapidly regenerated around the nucleus and inclusion. Mitochondria of amniotic epithelial cells were vitally stained with the fluorescent probe DiOC6 (3,3'-dihexyloxacarbocyanine iodide) after 48 h of infection and found to be widely distributed throughout the host cytoplasm. When the morphology of the Golgi complex was examined with C6-NBD-ceramide (N-[7-(4-nitrobenzo-2-oxa-1,3-diazole)] aminocaproyl sphingosine) the main cisternae were retained in a juxta-nuclear position, although scattered stained structures were also present close to the cytoplasmic surface of the inclusion. These results demonstrate that the peri-nuclear position of inclusions is determined by the configuration of the cytoskeleton, and that normal host-cell architecture is maintained during infection, albeit in a distorted form.


Anti-N-methyl-D-aspartate-receptor Encephalitis as a Harbinger of Pediatric HIV Infection.
Anti-N-methyl-D-aspartate-receptor (A-NMDAR) encephalitis is the most common type of autoimmune encephalitis in the pediatric age group. It is known to be triggered by viral infections such as herpes simplex infections. However, A-NMDAR encephalitis with HIV infection is a very rare event, with cases reported mostly in adults. The current report is of a previously healthy child who presented with recurrent vomiting, irritability, visual impairment, and new onset complex partial seizures and right somatosensory seizures with generalization occurring in clusters. Over a period of 3 weeks, he developed rapidly progressive bilateral painless visual loss, visual hallucinations, and behavioral changes. Brain magnetic resonance imaging (MRI) showed predominantly cortical symmetrical T2/FLAIR hyperintense signal change in parieto-occipito-temporal regions. The serum and cerebrospinal fluid were strongly positive for anti-NMDAR antibodies, and he also tested positive for HIV-1 antibodies acquired by vertical transmission. The patient and mother tested positive for HIV antibodies for the first time. Repeat MRI revealed gliosis in the parieto-occipito-temporal regions, and hippocampi showed volume loss and T2/FLAIR hyperintense signal change in the posterior thalami with patchy hyperintensities in the right putamen. The seizures subsided with immunomodulation along with anti-epileptic drugs, but he had residual cortical visual impairment on follow-up. This is the first report of A-NMDAR encephalitis presenting as a harbinger of HIV infection in a child. This calls for testing for A-NMDAR antibodies in children with HIV infection presenting with neurological or neuropsychiatric manifestations.


Anti-obesity and anti-hyperglycemic effects of cinnamaldehyde via altered ghrelin secretion and functional impact on food intake and gastric emptying.
Cinnamon extract is associated to different health benefits but the active ingredients or pathways are unknown. Cinnamaldehyde (CIN) imparts the characteristic flavor to cinnamon and is known to be the main agonist of transient receptor potential-ankyrin receptor 1 (TRPA1). Here, expression of TRPA1 in epithelial mouse stomach cells is described. After receiving a single-dose of CIN, mice significantly reduce cumulative food intake and gastric emptying rates. Co-localization of TRPA1 and ghrelin in enteroendocrine cells of the duodenum is observed both in vivo and in the MGN3-1 cell line, a ghrelin secreting cell model, where incubation with CIN up-regulates expression of TRPA1 and Insulin receptor genes. Ghrelin secreted in the culture medium was quantified following CIN stimulation and we observe that octanoyl and total ghrelin are significantly lower than in control conditions. Additionally, obese mice fed for five weeks with CIN-containing diet significantly reduce their cumulative body weight gain and improve glucose tolerance without detectable modification of insulin secretion. Finally, in adipose tissue up-regulation of genes related to fatty acid oxidation was observed. Taken together, the results confirm anti-hyperglycemic and anti-obesity effects of CIN opening a new approach to investigate how certain spice derived compounds regulate endogenous ghrelin release for therapeutic intervention.


Treatment of radioactive liquid waste by sorption on natural zeolite in Turkey.
Liquid radioactive waste has been generated from the use of radioactive materials in industrial applications, research and medicine in Turkey. Natural zeolites (clinoptilolite) have been studied for the removal of several key radionuclides ((137)Cs, (60)Co, (90)Sr and (110m)Ag) from liquid radioactive waste. The aim of the present study is to investigate effectiveness of zeolite treatment on decontamination factor (DF) in a combined process (chemical precipitation and adsorption) at the laboratory tests and scale up to the waste treatment plant. In this study, sorption and precipitation techniques were adapted to decontamination of liquid low level waste (LLW). Effective decontamination was achieved when sorbents are used during the chemical precipitation. Natural zeolite samples were taken from different zeolite formations in Turkey. Comparison of the ion-exchange properties of zeolite minerals from different formations shows that Gordes clinoptilolite was the most suitable natural sorbent for radionuclides under dynamic treatment conditions and as an additive for chemical precipitation process. Clinoptilolite were shown to have a high selectivity for (137)Cs and (110m)Ag as sorbent. In the absence of potassium ions, native clinoptilolite removed (60)Co and (90)Sr very effectively from the liquid waste. In the end of this liquid waste treatment, decontamination factor was provided as 430 by using 0.5 mm clinoptilolite at 30 degrees C.


A grave matter--dental findings of people buried in the 19th and 20th centuries.
The exhumed remains of 181 people, buried during the period 1848-1984 were examined. Because of the carelessness of exhumations, only 125 yielded sufficient information to compare the condition of skulls and jaws with the period in the grave, while 63 yielded information about the teeth. No correlation could be shown between the condition of the skulls and jaws and the period interred, but it was found that the better preserved remains belonged to younger people. Dental findings included the presence of healthy and decayed teeth, gold foil restorations, gold and porcelain inlays, amalgam and silicate fillings, and vulcanite and acrylic dentures. Amalgam restorations were present in people buried from 1875 (114 years ago) and vulcanite dentures from 1882 (107 years ago). The characteristics of the earliest amalgam restorations showed that they could have been placed before 1850. Findings of this study indicate that: (a) one cannot on the appearance of exhumed remains estimate the burial period, (b) dental features were well preserved and can be used for dental identification if antimortem data are available, (c) advanced dentistry could have been practised in South Africa during the last century, and (d) recovery of human skeletal remains from old cemeteries should be undertaken with care to preserve as much information as possible. A plea is made for closer co-operation between developers of old graveyard sites and scientists in order to preserve as much information as possible.


In vitro evaluation of drug release from self micro-emulsifying drug delivery systems using a biodegradable homolipid from Capra hircus.
Self micro-emulsifying drug delivery systems (SMEDDS) are specialized form of delivery systems in which drugs are encapsulated in a lipid base with or without a pharmaceutically acceptable surfactant. In this work, SMEDDS were formulated with a biodegradable homolipid from Capra hircus and Tween 65, and contained lipophilic drug-piroxicam, hydrophilic drug-chlorpheniramine maleate and hydrolipophilic drug-metronidazole. The SMEDDS formulated were evaluated for their drug release and drug content. The drug release studies were conducted in simulated gastric fluid (SGF), simulated intestinal fluid (SIF), and distilled water, representing different pH values. Particle size of the SMEDDS was determined by light microscopy. The results of this study indicated that drug release was affected by the particle size of the SMEDDS. It was found that piroxicam release from the SMEDDS formulated with homolipids from Capra hircus was highest in SIF compared to the other drugs. This method of drug delivery could prove to be a versatile and reliable alternative to conventional drug delivery approaches.


Monolithic-integrated microlaser encoder.
We have developed an extremely small integrated microencoder whose sides are less than 1 mm long. It is 1/100 the size of conventional encoders. This microencoder consists of a laser diode, monolithic photodiodes, and fluorinated polyimide waveguides with total internal reflection mirrors. The instrument can measure the relative displacement between a grating scale and the encoder with a resolution of the order of 0.01 microm; it can also determine the direction in which the scale is moving. By using the two beams that were emitted from the two etched mirrors of the laser diode, by monolithic integration of the waveguide and photodiodes, and by fabrication of a step at the edge of the waveguide, we were able to eliminate conventional bulky optical components such as the beam splitter, the quarter-wavelength plate, bulky mirrors, and bulky photodetectors.


Insights into the demographic history of African Pygmies from complete mitochondrial genomes.
Pygmy populations are among the few hunter-gatherers currently living in sub-Saharan Africa and are mainly represented by two groups, Eastern and Western, according to their current geographical distribution. They are scattered across the Central African belt and surrounded by Bantu-speaking farmers, with whom they have complex social and economic interactions. To investigate the demographic history of Pygmy groups, a population approach was applied to the analysis of 205 complete mitochondrial DNA (mtDNA) sequences from ten central African populations. No sharing of maternal lineages was observed between the two Pygmy groups, with haplogroup L1c being characteristic of the Western group but most of Eastern Pygmy lineages falling into subclades of L0a, L2a, and L5. Demographic inferences based on Bayesian coalescent simulations point to an early split among the maternal ancestors of Pygmies and those of Bantu-speaking farmers (∼ 70,000 years ago [ya]). Evidence for population growth in the ancestors of Bantu-speaking farmers has been observed, starting ∼ 65,000 ya, well before the diffusion of Bantu languages. Subsequently, the effective population size of the ancestors of Pygmies remained constant over time and ∼ 27,000 ya, coincident with the Last Glacial Maximum, Eastern and Western Pygmies diverged, with evidence of subsequent migration only among the Western group and the Bantu-speaking farmers. Western Pygmies show signs of a recent bottleneck 4,000-650 ya, coincident with the diffusion of Bantu languages, whereas Eastern Pygmies seem to have experienced a more ancient decrease in population size (20,000-4,000 ya). In conclusion, the results of this first attempt at analyzing complete mtDNA sequences at the population level in sub-Saharan Africa not only support previous findings but also offer new insights into the demographic history of Pygmy populations, shedding new light on the ancient peopling of the African continent.


Mutations in CHEK2 associated with prostate cancer risk.
The DNA-damage-signaling pathway has been implicated in all human cancers. However, the genetic defects and the mechanisms of this pathway in prostate carcinogenesis remain poorly understood. In this study, we analyzed CHEK2, the upstream regulator of p53 in the DNA-damage-signaling pathway, in several groups of patients with prostate cancer. A total of 28 (4.8%) germline CHEK2 mutations (16 of which were unique) were found among 578 patients. Additional screening for CHEK2 mutations in 149 families with familial prostate cancer revealed 11 mutations (5 unique) in nine families. These mutations included two frameshift and three missense mutations. Importantly, 16 of 18 unique CHEK2 mutations identified in both sporadic and familial cases were not detected among 423 unaffected men, suggesting a pathological effect of CHEK2 mutations in prostate cancer development. Analyses of the two frameshift mutations in Epstein Barr virus-transformed cell lines, using reverse-transcriptase polymerase chain reaction and western blot analysis, revealed abnormal splicing for one mutation and dramatic reduction of CHEK2 protein levels in both cases. Overall, our data suggest that mutations in CHEK2 may contribute to prostate cancer risk and that the DNA-damage-signaling pathway may play an important role in the development of prostate cancer.


Touch communicates distinct emotions.
The study of emotional signaling has focused almost exclusively on the face and voice. In 2 studies, the authors investigated whether people can identify emotions from the experience of being touched by a stranger on the arm (without seeing the touch). In the 3rd study, they investigated whether observers can identify emotions from watching someone being touched on the arm. Two kinds of evidence suggest that humans can communicate numerous emotions with touch. First, participants in the United States (Study 1) and Spain (Study 2) could decode anger, fear, disgust, love, gratitude, and sympathy via touch at much-better-than-chance levels. Second, fine-grained coding documented specific touch behaviors associated with different emotions. In Study 3, the authors provide evidence that participants can accurately decode distinct emotions by merely watching others communicate via touch. The findings are discussed in terms of their contributions to affective science and the evolution of altruism and cooperation.


Pastoral power in the community pharmacy: A Foucauldian analysis of services to promote patient adherence to new medicine use.
Community pharmacists play a growing role in the delivery of primary healthcare. This has led many to consider the changing power of the pharmacy profession in relation to other professions and patient groups. This paper contributes to these debates through developing a Foucauldian analysis of the changing dynamics of power brought about by extended roles in medicines management and patient education. Examining the New Medicine Service, the study considers how both patient and pharmacist subjectivities are transformed as pharmacists seek to survey patient's medicine use, diagnose non-adherence to prescribed medicines, and provide education to promote behaviour change. These extended roles in medicines management and patient education expand the 'pharmacy gaze' to further aspects of patient health and lifestyle, and more significantly, established a form of 'pastoral power' as pharmacists become responsible for shaping patients' self-regulating subjectivities. In concert, pharmacists are themselves enrolled within a new governing regime where their identities are conditioned by corporate and policy rationalities for the modernisation of primary care.


Microtransplantation of Synaptic Membranes to Reactivate Human Synaptic Receptors for Functional Studies.
Excitatory and inhibitory ionotropic receptors are the major gates of ion fluxes that determine the activity of synapses during physiological neuronal communication. Therefore, alterations in their abundance, function, and relationships with other synaptic elements have been observed as a major correlate of alterations in brain function and cognitive impairment in neurodegenerative diseases and mental disorders. Understanding how the function of excitatory and inhibitory synaptic receptors is altered by disease is of critical importance for the development of effective therapies. To gain disease-relevant information, it is important to record the electrical activity of neurotransmitter receptors that remain functional in the diseased human brain. So far this is the closest approach to assess pathological alterations in receptors' function. In this work, a methodology is presented to perform microtransplantation of synaptic membranes, which consists of reactivating synaptic membranes from snap frozen human brain tissue containing human receptors, by its injection and posterior fusion into the membrane of Xenopus laevis oocytes. The protocol also provides the methodological strategy to obtain consistent and reliable responses of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and γ-aminobutyric acid (GABA) receptors, as well as novel detailed methods that are used for normalization and rigorous data analysis.


Tuning the structure, dimensionality and luminescent properties of lanthanide metal-organic frameworks under ancillary ligand influence.
This manuscript addresses the synthesis, structural characterization and optical properties of a 1D coordination polymer (CPs) and 2D and 3D Metal-Organic Frameworks (MOFs) obtained from lanthanide metals, 3-hydroxinaftalene-2,7-disulfonic acid (3-OHNDS) and two different phenanthroline derivates as ancillary ligands. The first is a family of 2D compounds with formula [Ln(3-OHNDS)(H2O)2], where Ln = La(), Pr(), Nd() and Sm(). The addition of 1,10-phenanthroline (phen) in the reaction produces 1D compounds with general formula [Ln(3-OHNDS)(phen)(H2O)]·3H2O, where Ln = La(), Pr(), Nd() and Sm(). Finally, the synthesis with 3,4,7,8-tetramethyl-1,10-phenanthroline (3,4,7,8-TMPhen) as an ancillary ligand results in the formation of the 3D [La(3-OHNDS)(3,4,7,8-TMphen)(H2O)] () compound. The photoluminescence (PL) properties of 1D and 2D compounds were fully investigated in comparison with the 3-OHNDS ligand. One of the most important results was the obtaining of a white-light single-emitter without adding dopant atoms in the structure. With all these results in mind it was possible to establish structure-property relationships.


Receptors for C3b and C3bi promote phagocytosis but not the release of toxic oxygen from human phagocytes.
We have measured the release of H2O2 from granulocytes, monocytes, and macrophages during spreading on ligand-coated culture surfaces. While IgG-coated surfaces stimulate vigorous release of H2O2, neither C3b- nor C3bi-coated surfaces promoted appreciable release of H2O2 despite full ligation of C3b and C3bi receptors. We also measured release of H2O2 from cultured monocytes spreading on surfaces coated with both fibronectin and C3. Under such circumstances, the C3 receptors elicit a strong phagocytic response, but no H2O2 release was recorded. We conclude that the C3b and C3bi receptors of monocytes and granulocytes do not signal the generation of toxic oxygen intermediates from these cells.


Added sugar and sugar-sweetened foods and beverages and the risk of pancreatic cancer in the National Institutes of Health-AARP Diet and Health Study.
Although it has been hypothesized that hyperglycemia, hyperinsulinemia, and insulin resistance are involved in the development of pancreatic cancer, results from epidemiologic studies of added sugar intake are inconclusive. Our objective was to investigate whether the consumption of total added sugar and sugar-sweetened foods and beverages is associated with pancreatic cancer risk. In 1995 and 1996, we prospectively examined 487 922 men and women aged 50-71 y and free of cancer and diabetes. Total added dietary sugar intake (in tsp/d; based on the US Department of Agriculture's Pyramid Servings Database) was assessed with a food-frequency questionnaire. Relative risks (RRs) and 95% CIs were calculated with adjustment for total energy and potential confounding factors. During an average 7.2 y of follow-up, 1258 incident pancreatic cancer cases were ascertained. The median intakes for the lowest and highest quintiles of total added sugar intake were 12.6 (3 tsp/d) and 96.2 (22.9 tsp/d) g/d, respectively. No overall greater risk of pancreatic cancer was observed in men or women with high intake of total added sugar or sugar-sweetened foods and beverages. For men and women combined, the multivariate RRs of the highest versus lowest intake categories were 0.85 (95% CI: 0.68, 1.06; P for trend = 0.07) for total added sugar, 1.01 (0.82,1.23; P for trend = 0.58) for sweets, 0.98 (0.82,1.18; P for trend = 0.49) for dairy desserts, 1.12 (0.91,1.39; P for trend = 0.35) for sugar added to coffee and tea, and 1.01 (0.77,1.31; P for trend = 0.76) for regular soft drinks. Our results do not support the hypothesis that consumption of added sugar or of sugar-sweetened foods and beverages is associated with overall risk of pancreatic cancer.


LARP6 proteins in plants.
RNA binding proteins, through control of mRNA fate and expression, are key players of organism development. The LARP family of RBPs sharing the La motif, are largely present in eukaryotes. They classify into five subfamilies which members acquired specific additional domains, including the RRM1 moiety which teams up with the La motif to form a versatile RNA binding unit. The LARP6 subfamily has had a peculiar history during plant evolution. While containing a single LARP6 in algae and non-vascular plants, they expanded and neofunctionalized into three subclusters in vascular plants. Studies from Arabidopsis thaliana, support that they acquired specific RNA binding properties and physiological roles. In particular LARP6C participates, through spatiotemporal control of translation, to male fertilization, a role seemingly conserved in maize. Interestingly, human LARP6 also acts in translation control and mRNA transport and similarly to LARP6C which is required for pollen tube guided elongation, is necessary to cell migration, through protrusion extension. This opens the possibility that some cellular and molecular functions of LARP6 were retained across eukaryote evolution. With their peculiar evolutionary history, plants provide a unique opportunity to uncover how La-module RNA binding properties evolved and identify species specific and basal roles of the LARP6 function. Deciphering of how LARP6, in particular LARP6C, acts at the molecular level, will foster novel knowledge on translation regulation and dynamics in changing cellular contexts. Considering the seemingly conserved function of LARP6C in male reproduction, it should fuel studies aimed at deriving crop species with improved seed yields.


Clinical outcomes of patients with estimated low or intermediate surgical risk undergoing transcatheter aortic valve implantation.
Transcatheter aortic valve implantation (TAVI) is an established treatment alternative to surgical aortic valve replacement in high-risk and inoperable patients and outcomes among patients with estimated low or intermediate risk remain to be determined. The aim of this study was to assess clinical outcomes among patients with estimated low or intermediate surgical risk undergoing TAVI. Between August 2007 and October 2011, 389 consecutive patients underwent TAVI and were categorized according to the Society of Thoracic Surgeons (STS) score into low (STS < 3%; n = 41, 10.5%), intermediate (STS ≥3% and ≤8%, n = 254, 65.3%), and high-risk (STS > 8%; n = 94, 24.2%) groups for the purpose of this study. Significant differences were found between the groups (low risk vs. intermediate risk vs. high risk) for age (78.2 ± 6.7 vs. 82.7 ± 5.7 vs. 83.7 ± 4.9, P < 0.001), body mass index (28.1 ± 6.1 vs. 26.5 ± 4.9 vs. 24.4 ± 4.6, P < 0.001), chronic renal failure (34 vs. 67 vs. 90%, P < 0.001), all-cause mortality at 30 days (2.4 vs. 3.9 vs. 14.9%, P = 0.001), and all-cause mortality at 1 year (10.1 vs. 16.1 vs. 34.5%, P = 0.0003). No differences were observed with regards to cerebrovascular accidents and myocardial infarction during 1-year follow-up. In contemporary practice, TAVI is not limited to inoperable or STS-defined high-risk patients and should be guided by the decision of an interdisciplinary Heart Team. Compared with patients at calculated high risk, well-selected patients with STS-defined intermediate or low risk appear to have favourable clinical outcomes.


Effect of mutations in the second extracellular loop of CXCR4 on its utilization by human and feline immunodeficiency viruses.
CCR5 and CXCR4 are the principal CD4-associated coreceptors used by human immunodeficiency virus type 1 (HIV-1). CXCR4 is also a receptor for the feline immunodeficiency virus (FIV). The rat CXCR4 cannot mediate infection by HIV-1NDK or by FIVPET (both cell line-adapted strains) because of sequence differences with human CXCR4 in the second extracellular loop (ECL2). Here we made similar observations for HIV-189.6 (a strain also using CCR5) and for a primary HIV-1 isolate. It showed the role of ECL2 in the coreceptor activity of CXCR4 for different types of HIV-1 strains. By exchanging ECL2 residues between human and rat CXCR4, we found that several amino acid differences contributed to the inactivity of the rat CXCR4 toward HIV-189.6. In contrast, its inactivity toward HIV-1NDK seemed principally due to a serine at position 193 instead of to an aspartic acid (Asp193) in human CXCR4. Likewise, a mutation of Asp187 prevented usage of CXCR4 by FIVPET. Different mutations of Asp193, including its replacement by a glutamic acid, markedly reduced or suppressed the activity of CXCR4 for HIV-1NDK infection, indicating that the negative charge was not the only requirement. Mutations of Asp193 and of arginine residues (Arg183 and Arg188) of CXCR4 reduced the efficiency of HIV-1 infection for all HIV-1 strains tested. Other ECL2 mutations tested had strain-specific effects or no apparent effect on HIV-1 infection. The ECL2 mutants allowed us to identify residues contributing to the epitope of the 12G5 monoclonal antibody. Overall, residues with different charges and interspersed in ECL2 seem to participate in the coreceptor activity of CXCR4. This suggests that a conformational rather than linear epitope of ECL2 contributes to the HIV-1 binding site. However, certain HIV-1 and FIV strains seem to require the presence of a particular ECL2 residue.


Social participation of diabetes and ex-leprosy patients in the Netherlands and patient preference for combined self-care groups.
Earlier, we showed that neuropathic complications limit social participation of ex-leprosy patients, even in a non-endemic leprosy setting like the Netherlands. Self-care groups for ex-leprosy patients can strengthen self-worth of participants, prevent further handicap, and enable the exchange of coping strategies. For non-endemic leprosy settings with a very low rate of leprosy patients, a self-care group exclusively for (ex)leprosy patients is not likely to be feasible. A combined group with patients facing comparable morbidity would be more efficient than disease-specific self-care groups. Here, we studied the comparability in social constraints of diabetic patients and ex-leprosy patients. Moreover, we investigated if combined self-care groups for ex-leprosy patients and diabetic patients would be desirable and acceptable for possible participants. Social participation was studied based on in-depth interviews and Participation Scale information collected from 41 diabetic patients and compared with the data of 31 ex-leprosy patients from a prior study. Moreover, we made an inventory of potential strengths and limitations and attitudes toward combined self-care groups for diabetic patients with neuropathy. The following themes emerged among diabetic patients: disease confrontation, dependency, conflict with partner or relatives, feelings of inferiority, stigma, abandoning social activities, fear of the future, lack of information, and hiding the disease. These themes were very similar to those voiced by the previously interviewed ex-leprosy patients. The latter more often mentioned stigma and disease ignorance among Dutch health care workers. Whereas ex-leprosy patients perceived stigma on multiple fronts, diabetic patients only mentioned feeling inferior. Diabetic patients experienced some form of participation restriction in 39% of the cases as opposed to 71% of the ex-leprosy patients. Diabetic patients did acknowledge the comparability with leprosy as far as their neuropathic complaints concerned. Yet only 17% showed interest in combined self-care groups. The majority preferred disease-specific self-care groups only focused on diabetic patients. This might have been caused partly by the perception that a self-care group is yet another disease-related demand on their time, rather than an opportunity to become less dependent on health care services. The physical complications and social problems in ex-leprosy and diabetic patients with neuropathy are similar. Both groups show social participation limitations, yet in contrast to diabetic patients, ex-leprosy patients perceive stigma in more domains in life. Despite the fact that diabetic patients preferred disease-specific, homogeneous self-care groups, we believe that the option of combined groups with ex-leprosy patients and possibly even other people needing chronic wound care is a promising strategy. Therefore, further research is warranted into the acceptance and impact of self-care groups as a strategy to reduce social constraints by diseases causing neuropathy.


Protective effect of Ocimum sanctum L after high-dose 131iodine exposure in mice: an in vivo study.
Radioprotective effect of aqueous extract of Ocimum sanctum (40 mg/kg body weight, for 15 days) in mice exposed to high-doses (3.7 MBq) of oral 131iodine was investigated by studying the organ weights, lipid peroxidation and antioxidant defense enzymes in various target organs like liver, kidneys, salivary glands and stomach at 24 hr after exposure in adult Swiss mice. The mean weight of the salivary glands showed significant increase after 131iodine administration. 131iodine exposure significantly increased lipid peroxidation in kidneys and salivary glands in comparison to control animals. Pretreatment with O. sanctum in radioiodine exposed group showed significant reduction in lipid peroxidation in both kidneys and salivary glands. In liver, reduced glutathione (GSH) levels showed significant reduction after radioiodine exposure while pretreatment with O. sanctum exhibited less depletion in GSH level even after 131iodine exposure. However, no such changes were observed in stomach. The results indicate the possibility of using aqueous extract of O. sanctum for ameliorating 131Iodine induced damage to the salivary glands.


Payment Reform Pilot In Beijing Hospitals Reduced Expenditures And Out-Of-Pocket Payments Per Admission.
In 2009 China announced plans to reform provider payment methods at public hospitals by moving from fee-for-service (FFS) to prospective and aggregated payment methods that included the use of diagnosis-related groups (DRGs) to control health expenditures. In October 2011 health policy makers selected six Beijing hospitals to pioneer the first DRG payment system in China. We used hospital discharge data from the six pilot hospitals and eight other hospitals, which continued to use FFS and served as controls, from the period 2010-12 to evaluate the pilot's impact on cost containment through a difference-in-differences methods design. Our study found that DRG payment led to reductions of 6.2 percent and 10.5 percent, respectively, in health expenditures and out-of-pocket payments by patients per hospital admission. We did not find evidence of any increase in hospital readmission rates or cost shifting from cases eligible for DRG payment to ineligible cases. However, hospitals continued to use FFS payments for patients who were older and had more complications than other patients, which reduced the effectiveness of payment reform. Continuous evidence-based monitoring and evaluation linked with adequate management systems are necessary to enable China and other low- and middle-income countries to broadly implement DRGs and refine payment systems.


Towards an ecological understanding of readiness to engage with interventions for children exposed to domestic violence and abuse: Systematic review and qualitative synthesis of perspectives of children, parents and practitioners.
Children who grow up in homes affected by domestic violence and abuse (DVA) are at risk of poor outcomes across the lifespan, yet there is limited evidence on the acceptability and effectiveness of interventions for them. A recent review of child-focused interventions highlighted a gap in understanding the factors influencing the willingness of parents and children to engage with these programmes. We conducted a systematic review of qualitative evidence on the experiences of receiving and delivering interventions with the aim of identifying factors at different levels of the social-ecological context that may influence parent and child readiness to take up interventions. We searched literature till April 2016 and found 12 reports of eight programmes. Two authors independently screened papers for inclusion, extracted data and identified the first- and second-order constructs. The third-order constructs were derived and fitted to the ecological framework to inform a picture of readiness to engage with interventions. Three key findings emerged from this review: (a) parent and child readiness is influenced by a complex interplay of individual, relationship and organisational factors, highlighting that individual readiness to take up child-focussed interventions must be viewed in an ecological context; (b) the specific process through which women become ready to engage in or facilitate child-focussed interventions may differ from that related to uptake of safety-promoting behaviours and requires parents to be aware of the impact of DVA on children and to focus on children's needs; (c) there are distinct but interlinked processes through which parents and children reach a point of readiness to engage in an interventions aimed at improving child outcomes. We discuss the implications of these findings for both practice and research.


Recognizing uncommon presentations of psychogenic (functional) movement disorders.
Psychogenic or functional movement disorders (PMDs) pose a challenge in clinical diagnosis. There are several clues, including sudden onset, incongruous symptoms, distractibility, suggestibility, entrainment of symptoms, and lack of response to otherwise effective pharmacological therapies, that help identify the most common psychogenic movements such as tremor, dystonia, and myoclonus. In this manuscript, we review the frequency, distinct clinical features, functional imaging, and neurophysiological tests that can help in the diagnosis of uncommon presentations of PMDs, such as psychogenic parkinsonism, tics, and chorea; facial, palatal, and ocular movements are also reviewed. In addition, we discuss PMDs at the extremes of age and mass psychogenic illness. Psychogenic parkinsonism (PP) is observed in less than 10% of the case series about PMDs, with a female-male ratio of roughly 1:1. Lack of amplitude decrement in repetitive movements and of cogwheel rigidity help to differentiate PP from true parkinsonism. Dopamine transporter imaging with photon emission tomography can also help in the diagnostic process. Psychogenic movements resembling tics are reported in about 5% of PMD patients. Lack of transient suppressibility of abnormal movements helps to differentiate them from organic tics. Psychogenic facial movements can present with hemifacial spasm, blepharospasm, and other movements. Some patients with essential palatal tremor have been shown to be psychogenic. Convergence ocular spasm has demonstrated a high specificity for psychogenic movements. PMDs can also present in the context of mass psychogenic illness or at the extremes of age. Clinical features and ancillary studies are helpful in the diagnosis of patients with uncommon presentations of psychogenic movement disorders.


Artificial Intelligence for Hospital Health Care: Application Cases and Answers to Challenges in European Hospitals.
The development and implementation of artificial intelligence (AI) applications in health care contexts is a concurrent research and management question. Especially for hospitals, the expectations regarding improved efficiency and effectiveness by the introduction of novel AI applications are huge. However, experiences with real-life AI use cases are still scarce. As a first step towards structuring and comparing such experiences, this paper is presenting a comparative approach from nine European hospitals and eleven different use cases with possible application areas and benefits of hospital AI technologies. This is structured as a current review and opinion article from a diverse range of researchers and health care professionals. This contributes to important improvement options also for pandemic crises challenges, e.g., the current COVID-19 situation. The expected advantages as well as challenges regarding data protection, privacy, or human acceptance are reported. Altogether, the diversity of application cases is a core characteristic of AI applications in hospitals, and this requires a specific approach for successful implementation in the health care sector. This can include specialized solutions for hospitals regarding human-computer interaction, data management, and communication in AI implementation projects.


Mechanism and energy landscape of domain swapping in the B1 domain of protein G.
Three-dimensional domain swapping has emerged as a ubiquitous process for homo-oligomer formation in many unrelated proteins, but the molecular mechanism of this process is still poorly understood. Here we present a mechanism for the swapping reaction in the B1 domain of the immunoglobulin G binding protein from group G of Streptococcus (GB1). This is a particularly attractive system for investigating the swapping process, as the swapped dimer formed by the quadruple mutant (L5V/F30V/Y33F/A34F) of GB1 was recently shown to exist in equilibrium with a monomer-like conformation over time scales of minutes. According to our mechanism, swapping in GB1 starts from the C-terminus of the polypeptide chain and progresses by exchanging an increasing portion of the chains until a stable conformational state is reached. This exchange process does not involve unfolding. Rather, the conformational changes of individual monomers and their association are tightly coupled to minimize solvent exposure and maximize the total number of native contacts at all times, thereby closely approximating the minimum energy path of the reaction. Using detailed atomic descriptions, we compute the complete free-energy profiles of the exchange reaction for the GB1 quadruple mutant that forms swapped dimers and for the wild-type protein, which is monomeric. In both GB1 forms, intermediates sample a surprisingly wide range of nearly isoenergetic association modes and hinge conformations, indicating that the exchange reaction is a non-specific process akin to encounter complex formation where the amino acid sequence plays a marginal role. The main role of the mutations in the swapping process is to destabilize the GB1 monomer state, while stabilizing the swapped dimer conformation, with non-native intersubunit interactions, fostered by mutant side chains, contributing significantly to this stabilization. Our findings are rationalized in terms of a generic swapping mechanism that involves the association of activated molecular species, and it is argued that a similar mechanism may apply to swapping in other protein systems.


Functional abilities at age 4 years of children born before 29 weeks of gestation.
To assess the rate of impairment and disability among babies born very preterm and to investigate the association between such impairment and gestational age at birth. Cohort study of a geographically defined population of babies. Oxford Regional Health Authority. All babies born alive before 29 weeks of gestation to mothers resident in the region during 1984-6. Survival rates and rates of impairment and disability among survivors at the age of 4 years. Of the 342 babies, half (170) survived to be discharged home. Of the 164 survivors to age 4 years, 153 (93%) were assessed. A total of 35 (23%; 95% confidence interval 16% to 30%) were severely disabled and only 54 (35%; 28% to 43%) were unimpaired. The risk of impairment and disability increased with decreasing gestational age at birth (p < 0.003). With the increasing survival rate among babies born before 29 weeks of gestation, we need urgently to establish reliable ways of monitoring the proportion of survivors who have a disability.


Noninvasive observation of embryonic behavior in chicks using holographic interference.
Laser holographic techniques offer a sensitive means of detecting small displacements. This paper describes the use of holographic interference to study the movements of an embryo in an intact incubating egg. The method is noninvasive and enables one to monitor the development of behavior in the chick embryo. Movements are displayed in the form of fringes on a TV screen and recorded on videocassettes as a function of time. This is the first report of the use of an optical interference phenomenon to detect movements of an embryo. Besides being useful in the study of the prenatal motility cycle, the method allows one to discriminate diverse types of movement, their onset, duration, and frequency of repetition. Examples are provided to illustrate some movements. The spectacular holographic aided visioning of the pipping behavior of the chick embryo is then briefly described.


Arbuscular mycorrhizal symbiosis is accompanied by local and systemic alterations in gene expression and an increase in disease resistance in the shoots.
In natural ecosystems, the roots of many plants exist in association with arbuscular mycorrhizal (AM) fungi, and the resulting symbiosis has profound effects on the plant. The most frequently documented response is an increase in phosphorus nutrition; however, other effects have been noted, including increased resistance to abiotic and biotic stresses. Here we used a 16,000-feature oligonucleotide array and real-time quantitative RT-PCR to explore transcriptional changes triggered in Medicago truncatula roots and shoots as a result of AM symbiosis. By controlling the experimental conditions, phosphorus-related effects were minimized, and both local and systemic transcriptional responses to the AM fungus were revealed. The transcriptional response of the roots and shoots differed in both the magnitude of gene induction and the predicted functional categories of the mycorrhiza-regulated genes. In the roots, genes regulated in response to three different AM fungi were identified, and, through split-root experiments, an additional layer of regulation, in the colonized or non-colonized sections of the mycorrhizal root system, was uncovered. Transcript profiles of the shoots of mycorrhizal plants indicated the systemic induction of many genes predicted to be involved in stress or defense responses, and suggested that mycorrhizal plants might display enhanced disease resistance. Experimental evidence supports this prediction, and mycorrhizal M. truncatula plants showed increased resistance to a virulent bacterial pathogen, Xanthomonas campestris. Thus, the symbiosis is accompanied by a complex pattern of local and systemic changes in gene expression, including the induction of a functional defense response.


How life history influences population dynamics in fluctuating environments.
A major question in ecology is how age-specific variation in demographic parameters influences population dynamics. Based on long-term studies of growing populations of birds and mammals, we analyze population dynamics by using fluctuations in the total reproductive value of the population. This enables us to account for random fluctuations in age distribution. The influence of demographic and environmental stochasticity on the population dynamics of a species decreased with generation time. Variation in age-specific contributions to total reproductive value and to stochastic components of population dynamics was correlated with the position of the species along the slow-fast continuum of life-history variation. Younger age classes relative to the generation time accounted for larger contributions to the total reproductive value and to demographic stochasticity in "slow" than in "fast" species, in which many age classes contributed more equally. In contrast, fluctuations in population growth rate attributable to stochastic environmental variation involved a larger proportion of all age classes independent of life history. Thus, changes in population growth rates can be surprisingly well explained by basic species-specific life-history characteristics.


Use of fluorine-18 fluorodeoxyglucose positron emission tomography in the detection of silent metastases from malignant melanoma.
Correct staging is crucial for the management and prognosis of patients with malignant melanoma. The aim of this prospective study was to compare staging by whole-body positron emission tomography using fluorine-18 fluorodeoxyglucose (18F-FDG) with staging by conventional methods. Thirty-eight patients with malignant melanoma of clinical stage II (local recurrence, in-transit and regional lymph node metastases) or III (metastases to other sites than in stage II) were included in the study. The results of the PET scans were compared with those obtained by clinical examination, computed tomography, ultrasound, radiography, and liver function tests and histology or clinical follow-up. With 18F-FDG PET we found for all foci a sensitivity of 97% and a specificity of 56%, compared with 62% and 22%, respectively, when using routine methods. For intra-abdominal foci, the sensitivity and specificity were 100% for both 18F-FDG PET and routine methods. Corresponding figures for pulmonary/intrathoracic foci were 100% and 33%, respectively. Of the patients included in this study, 34% would not have been staged correctly by conventional methods alone. We conclude from this study that 18F-FDG PET is a sensitive method superior to conventional methods for detecting widespread metastases from malignant melanoma. Mutilating surgery of no benefit can thereby be avoided. 18F-FDG PET is useful as a supplement to clinical examination in melanoma staging.


Analysis of spatial mobility in subjects from a Dengue endemic urban locality in Morelos State, Mexico.
Mathematical models and field data suggest that human mobility is an important driver for Dengue virus transmission. Nonetheless little is known on this matter due the lack of instruments for precise mobility quantification and study design difficulties. We carried out a cohort-nested, case-control study with 126 individuals (42 cases, 42 intradomestic controls and 42 population controls) with the goal of describing human mobility patterns of recently Dengue virus-infected subjects, and comparing them with those of non-infected subjects living in an urban endemic locality. Mobility was quantified using a GPS-data logger registering waypoints at 60-second intervals for a minimum of 15 natural days. Although absolute displacement was highly biased towards the intradomestic and peridomestic areas, occasional displacements exceeding a 100-Km radius from the center of the studied locality were recorded for all three study groups and individual displacements were recorded traveling across six states from central Mexico. Additionally, cases had a larger number of visits out of the municipality´s administrative limits when compared to intradomestic controls (cases: 10.4 versus intradomestic controls: 2.9, p = 0.0282). We were able to identify extradomestic places within and out of the locality that were independently visited by apparently non-related infected subjects, consistent with houses, working and leisure places. Results of this study show that human mobility in a small urban setting exceeded that considered by local health authority's administrative limits, and was different between recently infected and non-infected subjects living in the same household. These observations provide important insights about the role that human mobility may have in Dengue virus transmission and persistence across endemic geographic areas that need to be taken into account when planning preventive and control measures. Finally, these results are a valuable reference when setting the parameters for future mathematical modeling studies.


Survival of elderly patients with acute myeloid leukemia.
The prognosis of elderly patients with acute myelogenous leukemia (AML) is usually dismal, while the true survival of older patients not included in clinical trials is not known. We retrospectively evaluated the impact on survival of an aggressive versus a non-aggressive approach in 1005 patients aged >60 years registered in the database of the GIMEMA cooperative group. Group A patients (n=621) received aggressive treatment, while group B patients (n=384) underwent non-aggressive therapy. The groups were different for risk factor distribution: the patients in group B had a higher median age, worse performance status (PS) and a higher proportion of previous myelodysplastic disease. The overall median survival was 7 and 5 months in groups A and B, respectively (p min of 0.0001). At multivariate analysis the following factors were associated with a significantly shorter survival: age >71 years (RR=1.27; 95% CI=1.07-1.50), PS=2-4 (RR=1.44; 95% CI=1.24-1.68), white cell count > 10,000 mL (RR=1.37; 95% CI=1.06-1.75), and heart dysfunction requiring treatment (RR=1.26; 95% CI=1.05-1.50). No difference in survival was associated with aggressive or non-aggressive treatment (RR=1.1; 95% CI=0.94-1.32). Patients aged min of 70 years, with no heart disease, but a white cell count > 10,000/mL showed a significantly better survival when treated aggressively (median survival 7 vs 3 months, p = 0.011). Despite an obvious selection of patients with a worse prognosis in group B, the difference in survival between the two groups was marginal. Multivariate analysis failed to demonstrate a significant survival benefit in aggressively treated patients. All these considerations indicate that elderly patients with AML are overall unlikely to benefit from aggressive treatment, so that this should be offered only to selected patients.


Occupational asthma.
Occupational asthma is a common disorder that may be caused by several hundred agents and has a variety of pathogenetic mechanisms. Level of exposure is an important risk factor, and reduction of exposure is the only certain method of prevention. Atopy and smoking are further risk factors for IgE-mediated asthma but have not been found to increase risk in forms of the disorder that have other mechanisms. The key to diagnosis is a low threshold of suspicion; several investigative procedures can be used to confirm the diagnosis. Many patients suffer from continued asthma despite cessation of exposure; early diagnosis and early removal from exposure are the most important factors for improving the long-term outcome.


A rapid assessment scorecard to identify informal settlements at higher maternal and child health risk in Mumbai.
The communities who live in urban informal settlements are diverse, as are their environmental conditions. Characteristics include inadequate access to safe water and sanitation, poor quality of housing, overcrowding, and insecure residential status. Interventions to improve health should be equity-driven and target those at higher risk, but it is not clear how to prioritise informal settlements for health action. In implementing a maternal and child health programme in Mumbai, India, we had conducted a detailed vulnerability assessment which, though important, was time-consuming and may have included collection of redundant information. Subsequent data collection allowed us to examine three issues: whether community environmental characteristics were associated with maternal and newborn healthcare and outcomes; whether it was possible to develop a triage scorecard to rank the health vulnerability of informal settlements based on a few rapidly observable characteristics; and whether the scorecard might be useful for future prioritisation. The City Initiative for Newborn Health documented births in 48 urban slum areas over 2 years. Information was collected on maternal and newborn care and mortality, and also on household and community environment. We selected three outcomes-less than three antenatal care visits, home delivery, and neonatal mortality-and used logistic regression and classification and regression tree analysis to test their association with rapidly observable environmental characteristics. We developed a simple triage scorecard and tested its utility as a means of assessing maternal and newborn health risk. In analyses on a sample of 10,754 births, we found associations of health vulnerability with inadequate access to water, toilets, and electricity; non-durable housing; hazardous location; and rental tenancy. A simple scorecard based on these had limited sensitivity and positive predictive value, but relatively high specificity and negative predictive value. The scorecard needs further testing in a range of urban contexts, but we intend to use it to identify informal settlements in particular need of family health interventions in a subsequent program.


The glue ear 'epidemic': a historical perspective.
This paper explores the historical context of the dramatic rise in surgery for glue ear in the mid-20th century, and questions the published assertion that this represented a manufactured 'epidemic'. In examining historical sources, the reader's theoretical viewpoint greatly influences their conclusions: the sustained rise in treatment for glue ear may be seen as the advance of science in a golden age or the resistance of insular professionals to reason in the light of new scientific study methods. Current views on the practice of medicine, consumerism, science and standardisation, rationing and the nature of 'truth' all affect the way that we see this period. Technological advances clearly allowed better diagnosis and more effective treatment, but these did not appear to drive an 'epidemic', rather they were developed to meet the pre-existing challenges of otological practice. The proposition that an 'epidemic' was created does not appear to have any solid grounding. Society's perception of what constitutes disease and what needs treatment may have evolved, but the prevalence of other important diseases changed dramatically over this time period, and a real change in the epidemiology of glue ear cannot be dismissed. In defining the case for and against surgical treatment, a solely positivist, quantitative worldview cannot give us a complete picture of benefit and risk to individuals, families and society at large.


Hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC): molecular mechanisms and novel paradigms.
Chronic hepatitis B (HBV) infection is a major risk factor for hepatocellular carcinoma (HCC). Most HCCs complicate the evolution of an active or inactive cirrhosis. However, some tumors occur on livers with minimal histological changes; the prevalence of such cases varies from one geographical region to the other, being much higher in the Southern half of Africa (around 40% of HCCs) than in Asia, America and Europe, where at least 90% of HCCs are associated in the cirrhosis. This heterogeneity is probably a reflection of different environmental and genetic factors. This review will summarise the current knowledge on the mechanisms involved in HBV-related liver carcinogenesis. It will show in particular how viruses can be viewed as tools to discover and dissect new cellular pathways involved in cancer development and emphasize the potential synergistic effects between HBV and hepatitis C virus (HCV), as well as between viral infections and other environmental factors, such as alcohol.


Development and Characterization of Lecithin-based Self-assembling Mixed Polymeric Micellar (saMPMs) Drug Delivery Systems for Curcumin.
Self-assembling mixed polymeric micelles (saMPMs) were developed for overcoming major obstacles of poor bioavailability (BA) associated with curcumin delivery. Lecithin added was functioned to enlarge the hydrophobic core of MPMs providing greater solubilization capacity. Amphiphilic polymers (sodium deoxycholate [NaDOC], TPGS, CREMOPHOR, or a PLURONIC series) were examined for potentially self-assembling to form MPMs (saMPMs) with the addition of lecithin. Particle size, size distribution, encapsulation efficacy (E.E.), and drug loading (D.L.) of the mixed micelles were optimally studied for their influences on the physical stability and release of encapsulated drugs. Overall, curcumin:lecithin:NaDOC and curcumin:lecithin:PLURONIC P123 in ratios of 2:1:5 and 5:2:20, respectively, were optimally obtained with a particle size of < 200 nm, an E.E. of >80%, and a D.L. of >10%. The formulated system efficiently stabilized curcumin in phosphate-buffered saline (PBS) at room temperature or 4 °C and in fetal bovine serum or PBS at 37 °C and delayed the in vitro curcumin release. In vivo results further demonstrated that the slow release of curcumin from micelles and prolonged duration increased the curcumin BA followed oral and intravenous administrations in rats. Thus, lecithin-based saMPMs represent an effective curcumin delivery system, and enhancing BA of curcumin can enable its wide applications for treating human disorders.


Dissociations between motor timing, motor coordination, and time perception after the administration of alcohol or caffeine.
The impacts of psychoactive drugs on timing have usefully informed theories of timing and its substrates. The objectives of the study are to test the effects of alcohol and caffeine on the explicit timing involved in tapping with the implicit timing observed in the coordinated picking up of an object, and with the temporal discrimination. Participants in the "alcohol" experiment (N = 16) received placebo, "low" (0.12 g/kg or 0.14 g/kg for women/men, respectively) or "high" (0.37 g/kg or 0.42 g/kg, respectively) doses of alcohol, and those in the "caffeine" experiment (N = 16) received placebo, 200 or 400 mg caffeine. Time production variability was measured by repetitive tapping of specified intervals, and sources of variance attributable to central timer processes and peripheral motor implementation were dissociated. The explicit timing in tapping was compared with the implicit timing in the coordinated picking up of an object. Time perception was measured as discrimination thresholds for intervals of similar duration. Drug effects on reaction time were also measured. For tapping, alcohol significantly increased timer variability, but not motor variability; it did not affect coordination timing in the grip-lift task. Conversely, for time perception, the low dose of alcohol improved temporal discrimination. Caffeine produced no effects on any of the timing tasks, despite significantly reducing reaction times. The effects of alcohol argue against a common clock process underlying time interval perception and production in the range below 1 s. In contrast to reaction time measures, time perception and time production appear relatively insensitive to caffeine.


Aceruloplasminemia: an inherited neurodegenerative disease with impairment of iron homeostasis.
In 1987, Miyajima et al. first characterized an autosomal recessive, adult-onset neurodegenerative disorder resembling Parkinson's disease associated with near-absent circulating serum ceruloplasmin levels. Coined "familial apoceruloplasmin deficiency", they described a patient with a presenting triad of diabetes mellitus, retinal degeneration, and neurodegeneration with blepharospasm. Neuropathological evaluation revealed abundant iron deposition in selected neurons of the basal ganglia and substantia nigra with associated neuronal dropout and spongioform degeneration without evidence of reactive gliosis. Subsequently, mutations in the ceruloplasmin gene have been determined to result in the excessive iron accumulation seen in the pancreas, retina, and brain. Elevated serum ferritin suggests a systemic iron overload syndrome, yet affected patients had low transferrin saturation and a mild anemia. This new disease, "aceruloplasminemia", reveals a role for ceruloplasmin as an essential ferroxidase critical for iron homeostasis. This multicopper oxidase promotes efficient iron efflux such that individuals lacking ceruloplasmin develop a presumed oxidative injury secondary to iron accumulation and significant neuronal damage. Aceruloplasminemic mice provide a valuable model to further study the mechanisms by which ceruloplasmin regulates iron trafficking and the role of iron in oxidative injury. Despite the dependence of ceruloplasmin on copper for its function, aceruloplasminemia represents an iron storage disease and not a defect in copper metabolism. However, recent evidence in Saccharomyces cerevisiae indicates that Fet3, the yeast homologue of ceruloplasmin, functions as an essential cuprous oxidase. Further investigation into the mechanisms by which ceruloplasmin regulates iron and copper homeostasis will provide valuable insight into the pathogenesis of metallo-mediated diseases and elucidate mechanisms for transition metal (copper, iron) neuropathology.


Respiratory responses to hypercapnia and hypoxia in mice with genetic ablation of Kir5.1 (Kcnj16).
Inward rectifier (Kir) potassium channels contribute to the control of electrical activity in excitable tissues and their activity is modulated by many biochemical factors, including protons. Heteromeric Kir4.1-Kir5.1 channels are highly pH sensitive within the physiological range of pH changes and are strongly expressed by the peripheral chemosensors as well as in the brainstem pH-sensitive areas which mediate respiratory responses to changes in blood and brain levels of P(CO(2))/[H(+)]. In the present study, Kir5.1 knockout mice (Kir5.1(-/-)) were used to determine the role of these channels in the chemosensory control of breathing. We found that Kir5.1(-/-) mice presented with persistent metabolic acidosis and a clear respiratory phenotype. Despite metabolic acidosis, ventilation at rest and in hyperoxic hypercapnia were similar in wild-type and Kir5.1(-/-) mice. Ventilatory responses to hypoxia and normoxic hypercapnia were significantly reduced in Kir5.1(-/-) mice; however, carotid body chemoafferent responses to hypoxia and CO(2) were not affected. In the in situ brainstem-spinal cord preparations with denervated peripheral chemoreceptors, resting phrenic nerve activity and phrenic nerve responses to respiratory acidosis or isohydric hypercapnia were also similar in Kir5.1(-/-) and wild-type mice. In in situ preparations of Kir5.1(-/-) mice with intact peripheral chemoreceptors, application of CN(-) resulted in a significantly reduced phrenic nerve response, suggesting that the relay of peripheral chemosensory information to the CNS is compromised. We suggest that this compensatory modulation of the peripheral chemosensory inputs develops in Kir5.1(-/-) mice in order to counteract the effect of continuing metabolic acidosis on the activity of the peripheral chemoreceptors. These results therefore suggest that despite their intrinsic pH sensitivity, Kir4.1-Kir5.1 channels are dispensable for functional central and peripheral respiratory chemosensitivity.


Structure-function relationship in a winter flounder antifreeze polypeptide. II. Alteration of the component growth rates of ice by synthetic antifreeze polypeptides.
Using synthetic analogs of an alpha-helical winter flounder antifreeze polypeptide (AFP) we investigated some important molecular details of the mechanism of action of this AFP. Of the seven peptides synthesized, all but one were amino-terminal deletions of the native AFP. Three of the seven synthetic analogs possessed the same antifreeze activity as the native polypeptide; the other analogs were devoid of antifreeze activity. The growth rates along the a and c axes of ice in solutions of varying concentrations of the three active AFP analogs were examined. The a axis growth rates of ice were inversely proportional to the concentration of the active peptides. The c-axis growth rates of ice were also dependent on peptide concentration. The active peptides enhanced c-axis growth at lower concentrations, while at higher concentrations they inhibited c axis growth. The ability of the peptides to develop antifreeze activity and to alter the a and c axis growth rates of ice depended on the presence of appropriately positioned amino acid residues with hydrogen bonding side chains. From these observations we propose that at low concentrations the AFP, through dipolar interactions and hydrogen bonding, interact with the prism faces of ice retarding a axis growth. At these concentrations, the electrical field of the AFP helix-dipole, like an externally applied field (Bartlett, J.T., van der Heuval, A.P., and Mason, B.J. (1963) Z. Angew. Math. Phys. 14, 599-610), can enhance ice c axis growth. At higher concentrations, the AFP interact with all ice crystal planes and retard both a and c axis growth.


Coenzyme Q10 benefits symptoms in Gulf War veterans: results of a randomized double-blind study.
We sought to assess whether coenzyme Q10 (CoQ10) benefits the chronic multisymptom problems that affect one-quarter to one-third of 1990-1 Gulf War veterans, using a randomized, double-blind, placebo-controlled study. Participants were 46 veterans meeting Kansas and Centers for Disease Control criteria for Gulf War illness. Intervention was PharmaNord (Denmark) CoQ10 100 mg per day (Q100), 300 mg per day (Q300), or an identical-appearing placebo for 3.5 ± 0.5 months. General self-rated health (GSRH), the primary outcome, differed across randomization arms at baseline, and sex significantly predicted GSRH change, compelling adjustment for baseline GSRH and prompting sex-stratified analysis. GSRH showed no significant benefit in the combined-sex sample. Among males (85% of participants), Q100 significantly benefited GSRH versus placebo and versus Q300, providing emphasis on Q100. Physical function (summary performance score, SPS) improved on Q100 versus placebo. A rise in CoQ10 approached significance as a predictor of improvement in GSRH and significantly predicted SPS improvement. Among 20 symptoms each present in half or more of the enrolled veterans, direction-of-difference on Q100 versus placebo was favorable for all except sleep problems; sign test 19:1, p=0.00004) with several symptoms individually significant. Significance for these symptoms despite the small sample underscores large effect sizes, and an apparent relation of key outcomes to CoQ10 change increases prospects for causality. In conclusion, Q100 conferred benefit to physical function and symptoms in veterans with Gulf War illness. Examination in a larger sample is warranted, and findings from this study can inform the conduct of a larger trial.


Effects of growth stimulatory factors on mitogenicity and c-myc expression in poorly differentiated and well differentiated human colon carcinoma cells.
We demonstrate the differential sensitivity of poorly differentiated and well differentiated human colon carcinoma cells to nutrients alone or to nutrients and polypeptide growth factors under completely serum-free conditions. 3H-Thymidine incorporation into trichloroacetic acid precipitable material and autoradiographic analysis indicated that nutrient replenishment alone was sufficient to initiate DNA synthesis in quiescent poorly differentiated cells, whereas defined polypeptide growth factors produced no additional effect. In contrast, well differentiated cells were mitogenically stimulated to a much greater extent by growth factors (epidermal growth factor + insulin + transferrin), than by nutrient replenishment alone. Expression of the c-myc protooncogene was increased approximately 5-fold after growth factor addition to the well differentiated cells. Maximal expression of c-myc occurred at 4 h post stimulation. In contrast, nutrients resulted in only a slight up-regulation of c-myc (1.8-fold) at approximately 90 min after addition. Addition of nutrients and/or growth factors to the poorly differentiated colon carcinoma cells resulted in an initial decline in c-myc expression (90 min), presumably due to removal of endogenous growth stimulators. Expression of c-myc returned to baseline levels by 24 h after additions. The results indicate that differential sensitivity to polypeptide growth factors is related to differentiation status in this model system and suggest that the insensitivity of poorly differentiated cells to exogenous growth factors may be due to a greater production of autocrine growth stimulators.


Diets derived from maize monoculture cause maternal infanticides in the endangered European hamster due to a vitamin B3 deficiency.
From 1735 to 1940, maize-based diets led to the death of hundreds of thousands of people from pellagra, a complex disease caused by tryptophan and vitamin B3 deficiencies. The current cereal monoculture trend restricts farmland animals to similarly monotonous diets. However, few studies have distinguished the effects of crop nutritional properties on the reproduction of these species from those of other detrimental factors such as pesticide toxicity or agricultural ploughing. This study shows that maize-based diets cause high rates of maternal infanticides in the European hamster, a farmland species on the verge of extinction in Western Europe. Vitamin B3 supplementation is shown to effectively restore reproductive success in maize-fed females. This study pinpoints how nutritional deficiencies caused by maize monoculture could affect farmland animal reproduction and hence their fitness.


Associations between perceived parental physical activity and aerobic fitness in schoolchildren.
Parental behavior is an important correlate of child health. The aim of this study was to investigate the association between perceived parental physical activity (PA) and schoolchildren's aerobic fitness. English schoolchildren's (n = 4029, 54% boys, 10.0-15.9 yrs) fitness was assessed by 20 m shuttle run test and categorized using criterion-referenced standards. Parental PA was reported by the child. Boys and girls were more likely to be fit (OR 1.4, 95% CI 1.1-1.8; OR 1.5, 95% CI 1.1-2.0; respectively) if at least 1 parent was perceived as active compared with when neither parents were. Girls were even more likely to be fit (OR 1.8, 95% CI 1.2-2.8) if both parents were active. Associations between parental PA and child fitness were generally stronger when parent and child were of the same gender, although girls with active fathers were more likely (OR 2.5, 95% CI 1.7-3.7) to be fit compared with inactive fathers. Schoolchildren perceiving at least 1 parent as active are more likely to meet health-related fitness standards. Underlying mechanisms remain elusive, but same-gender associations suggest that social rather than genetic factors are of greater importance. Targeting parental PA or at least perceptions of parental PA should be given consideration in interventions aiming to improve child health.


First Evaluation of P Dispersion and Tp-e Parameters in Electrocardiograms of Children with Diabetic Ketoacidosis
Diabetic ketoacidosis (DKA) is an important complication of type 1 diabetes mellitus. We aimed to evaluate the effect of metabolic disorders of DKA on electrocardiography (ECG) parameters in children. This study was performed between December 2018 and March 2020 and included 39 children with DKA and 40 healthy children. Three ECGs (one before and two after treatment) were obtained from the patient group. P-wave dispersion (Pd), QT dispersion (QTd), QTc dispersion (QTcd), Tp-e intervals, and the ratios of Tp-e/QT and Tp-e/QTc were measured electrocardiographically. ECG parameters from children with DKA and healthy controls were compared statistically. The mean age of the patient group was 10.50±4.12 years. There was no significant difference in terms of age, gender, weight, height and body mass index between patients and controls. In the patient group, a statistically significant increase was found in Pd, QTd and QTcd in the initial ECG compared to the second and third ECGs. Also, when the first and third ECGs were compared, a significant increase in Tp-e and Tp-e/QT was evident in the first ECG. There was a significant difference in the values of Pd, QTd, QTcd, Tp-e and Tp-e/QT in the first ECGs, obtained before DKA treatment, and those values obtained from the control group. This is the first article evaluating Pd and Tp-e parameters in children with DKA. Cardiac arrhythmia risk markers were increased in children with DKA compared to controls. Therefore, clinicians should be aware of the possibility of developing new arrhythmias during DKA treatment.


A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry.
According to guidelines, a nationwide non-medical switch from originator (INX, Remicade) to biosimilar infliximab (Remsima, CT-P13) was conducted in Danish patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA). We investigated disease activity before/after switching and retention rates in the DANBIO registry. Disease activities 3 months before and after switch and changes over time were calculated. Flare was defined as change in 28 Joint Disease Activity Score (∆DAS28) ≥1.2 (RA/PsA) or Ankylosing Spondylitis Disease Activity Score (∆ASDAS) ≥1.3 (AxSpA). Crude and adjusted retention rates were compared with a historic cohort of INX-treated patients. Eight hundred and two patients switched (403 RA/120 PsA/279 AxSpA; 51% women, age (median (IQR): 55 (44-66)) years). Follow-up was 413 (339-442) days. Prior INX treatment duration was 6.8 (4.3-9.5) years. Disease activities were similar 3 months before/after switch. Crude 1-year CT-P13 retention rate (84.1 (95% CI 81.3 to 86.5)) was similar to the historic IFX cohort (86.2 (95% CI 84.0 to 88.0), p=0.22). The adjusted absolute retention rates were 83.4 (95% CI 80.8 to 86.2) and 86.8% (95% CI 84.8 to 88.8), respectively (p=0.03). In total 132 patients withdrew (lack of effect: 71/132=54%, adverse events: 37/132=28%). Patients with previous INX treatment duration >5 years had longer CT-P13 retention. In 802 arthritis patients treated with INX for median >6 years, a nationwide non-medical switch to CT-P13 had no negative impact on disease activity. Adjusted 1-year CT-P13 retention rate was slightly lower than for INX in a historic cohort.


Avocado fruit (Persea americana Mill) exhibits chemo-protective potentiality against cyclophosphamide induced genotoxicity in human lymphocyte culture.
Diets rich in fruits and vegetables have been associated with reduced risks for many types of cancers. Avocado (Persea americana Mill.) is a widely consumed fruit containing many cancer preventing nutrients, vitamins and phytochemicals. Studies have shown that phytochemicals extracted from the avocado fruit selectively induce cell cycle arrest, inhibit growth, and induce apoptosis in precancerous and cancer cell lines. Our recent studies indicate that phytochemicals extracted with 50% Methanol from avocado fruits help in proliferation of human lymphocyte cells and decrease chromosomal aberrations induced by cyclophosphamide. Among three concentrations (100 mg, 150 mg and 200 mg per Kg Body Weight), the most effective conc. of extract was 200 mg/Kg Body Wt. It decreased significant level of numerical and structural aberrations (breaks, premature centromeric division etc. up to 88%, p < 0.0001)), and accrocentric associtation within D & G group (up to 78%, p = 0.0008). These studies suggest that phytochemicals from the avocado fruit can be utilized for making active chemoprotective ingredient for lowering the side effect of chemotherapy like cyclophosphamide in cancer therapy.


Lower copay and oral administration: predictors of first-fill adherence to new asthma prescriptions.
Nonadherence to asthma medications is associated with increased emergency department visits and hospitalizations. If adherence is to be improved, first-fill adherence is the first goal to meet after the physician and patient have decided to begin treatment. Little is known about first-fill adherence with asthma medications and the factors for no-fill. The goal of the study was to examine the proportion of patients who fill a new prescription for an asthma medication and analyze characteristics associated with this first-fill. This retrospective cohort study linked electronic health records with pharmacy claims. The cohort was comprised of 2023 patients aged 18 years or older who sought care from the Geisinger Clinic, had Geisinger Health Plan pharmacy benefits, and were prescribed an asthma medication for the first time between 2002 and 2006. The primary outcome of interest was first-time prescription filled by the patient within 30 days of the prescription order date. Covariates examined included factors related to the patient (ie, age, sex, and ethnicity), comorbidities and utilization (ie, Charlson comorbidity index, number of office visits, number of additional medications), asthma treatment (ie, delivery route, pharmacologic class), and pharmacy copay amount. A logistic-regression model was used to determine covariates associated with first-fill. The overall first-fill rate for new asthma medications was 78%. First-fill rate was lower for patients with a copay above the mean of $12 (odds ratio = 0.76; 95% confidence interval, 0.58-0.99) and higher for patients prescribed oral plus inhaled medications (versus inhaled only, odds ratio = 3.91; 95% confidence interval, 2.15-7.11). SEVERAL FACTORS ASSOCIATED WITH FAILING TO FILL AN INITIAL PRESCRIPTION FOR ASTHMA CAN BE ADDRESSED THROUGH SIMPLE INTERVENTIONS: screening for difficulties a patient may have in filling prescriptions, avoiding nonformulary medications, and recognizing the barrier that high copays present. In addition, for employers and policymakers, decreasing copay may improve adherence and, therefore, asthma control.


Microalgae in the postgenomic era: a blooming reservoir for new natural products.
Bacteria, fungi, algae and higher plants are the most prolific producers of natural products (secondary metabolites). Compared to macroalgae, considerably fewer natural products have been isolated from microalgae, which offer the possibility of obtaining sufficient and well-defined biological material from laboratory cultures. Interest in microalgae is reinforced by large-scale data sets from genome sequencing projects and the development of genetic tools such as transformation protocols. This review highlights what is currently known about the biosynthesis and biological role of natural products in microalgae, with examples from isoprenoids, complex polyketides, nonribosomal peptides, polyunsaturated fatty acids and oxylipins, alkaloids, and aromatic secondary metabolites. In addition, we introduce a bioinformatic analysis of available genome sequences from totally 16 microalgae, belonging to the green and red algae, heterokonts and haptophytes. The results suggest that the biosynthetic potential of microalgae is underestimated and many microalgal natural products remain to be discovered.


Saltatory Conduction along Myelinated Axons Involves a Periaxonal Nanocircuit.
The propagation of electrical impulses along axons is highly accelerated by the myelin sheath and produces saltating or "jumping" action potentials across internodes, from one node of Ranvier to the next. The underlying electrical circuit, as well as the existence and role of submyelin conduction in saltatory conduction remain, however, elusive. Here, we made patch-clamp and high-speed voltage-calibrated optical recordings of potentials across the nodal and internodal axolemma of myelinated neocortical pyramidal axons combined with electron microscopy and experimentally constrained cable modeling. Our results reveal a nanoscale yet conductive periaxonal space, incompletely sealed at the paranodes, which separates the potentials across the low-capacitance myelin sheath and internodal axolemma. The emerging double-cable model reproduces the recorded evolution of voltage waveforms across nodes and internodes, including rapid nodal potentials traveling in advance of attenuated waves in the internodal axolemma, revealing a mechanism for saltation across time and space.


Targeting tyrosine kinases in cancer: the second wave.
One of the most exciting developments in cancer research in recent years has been the clinical validation of molecularly targeted drugs that inhibit the action of pathogenic tyrosine kinases. Treatment of appropriately selected patients with these drugs can alter the natural history of their disease and improve survival. The clinical validation of these "first-generation" tyrosine kinase inhibitors has been the prelude to a second wave of advances in molecular targeting that is expected to further change the way we classify and treat cancer. Efforts are now being directed at identifying the tumor subtypes and patients who will benefit the most from these drugs. In addition, new compounds that circumvent acquired resistance to the first-generation tyrosine kinase inhibitors are being tested in patients with refractory disease. Agents directed against new molecular targets are also being explored.


VEGF Polymorphism rs3025039 and Human T-Cell Leukemia Virus 1 (HTLV-1) Infection among Older Japanese Individuals: A Cross-Sectional Study.
Previous studies have reported a close correlation between vascular endothelial growth factor (VEGF), which plays an important role in angiogenesis, and human T-cell leukemia virus 1 (HTLV-1). However, an association between genetic characteristics related to VEGF and HTLV-1 infection has not yet been reported. Because the VEGF polymorphism rs3025039 is inversely associated with serum concentrations of VEGF, we focus on rs3025039 in the present study. To clarify the association between the VEGF polymorphism rs3025039 and HTLV-1 infection, a cross-sectional study of 1924 Japanese individuals aged 60-79 years who participated in general health check-ups was conducted. Using logistic regression, odds ratios (ORs) and 95% confidence intervals (CIs) for HTLV-1 infection in relation to rs3025039 genotype were calculated with adjustment for known confounders. Compared with rs3025039 CC-homozygotes, (T) allele carriers had a significantly lower OR for HTLV-1 infection. The adjusted OR and 95% CI for HTLV-1 infection was 0.70 (0.54-0.91) (p = 0.009). Genetic characteristics related to lower angiogenesis activity might be associated with a lower chance of establishing HTLV-1 infection. Although further investigation is necessary, angiogenesis might play a crucial role in the establishment of HTLV-1 infection.


Triggering the succinate receptor GPR91 enhances pressure overload-induced right ventricular hypertrophy.
Pulmonary arterial hypertension (PAH) leads to pressure overload in the right ventricle (RV) and induces right ventricular hypertrophy (RVH). GPR91 is an orphan G-protein-coupled receptor (GPCR) that has been characterized as a receptor for succinate, which increases in RVH; however, its role remains unknown. We studied succinate-GPR91 signaling in a pulmonary arterial banding (PAB) model of RVH in the SD rats due to pressure overload. We report that GPR91 was located in cardiomyocytes. We found that the expressions of GPR91 and p-Akt in the RV significantly increased in the PAB model compared with the sham. In the PAB rats, the treatment of succinate further increased the p-Akt levels and aggravated RVH in vivo. In in vitro studies, succinate stimulated the up-regulation of the hypertrophic gene marker anp. All these effects were inhibited by the antagonist of PI3K, wortmannin, both in vivo and in vitro. Finally, we found that the GPR91-PI3K/Akt axis was also up-regulated compared with the sham in human RVH. Our results suggest that succinate-GPR91 is involved in RVH via PI3K/Akt signaling in vivo and in vitro. GPR91 may be a novel therapeutic target for RVH induced by pressure overload.


Phenotype-based clustering of glycosylation-related genes by RNAi-mediated gene silencing.
Glycan structures are synthesized by a series of reactions conducted by glycosylation-related (GR) proteins such as glycosyltransferases, glycan-modifying enzymes, and nucleotide-sugar transporters. For example, the common core region of glycosaminoglycans (GAGs) is sequentially synthesized by peptide-O-xylosyltransferase, β1,4-galactosyltransferase I, β1,3-galactosyltransferase II, and β1,3-glucuronyltransferase. This raises the possibility that functional impairment of GR proteins involved in synthesis of the same glycan might result in the same phenotypic abnormality. To examine this possibility, comprehensive silencing of genes encoding GR and proteoglycan core proteins was conducted in Drosophila. Drosophila GR candidate genes (125) were classified into five functional groups for synthesis of GAGs, N-linked, O-linked, Notch-related, and unknown glycans. Spatiotemporally regulated silencing caused a range of malformed phenotypes that fell into three types: extra veins, thick veins, and depigmentation. The clustered phenotypes reflected the biosynthetic pathways of GAGs, Fringe-dependent glycan on Notch, and glycans placed at or near nonreducing ends (herein termed terminal domains of glycans). Based on the phenotypic clustering, CG33145 was predicted to be involved in formation of terminal domains. Our further analysis showed that CG33145 exhibited galactosyltransferase activity in synthesis of terminal N-linked glycans. Phenotypic clustering, therefore, has potential for the functional prediction of novel GR genes.


[The effect of the essential oil from Aloysia triphylla britton (lemon verbena) on Trypanosoma cruzi in mice].
To determine the in-vivo anti-Trypanosoma cruzi activity of the essential oil from Aloysia triphylla in mice. The mice (n = 15) in the study were randomly assigned to the following groups: infected and untreated (G1), infected and treated with benznidazole 100 mg/kg (G2), infected and treated with of Aloysia triphylla essential oil 100 mg/kg (G3), infected and treated with of Aloysia triphylla essential oil 250 mg/kg (G4), uninfected and untreated (G5), and uninfected and treated with 250 mg/kg of Aloysia triphyla (G6). The infection was conducted using 104 blood T. cruzi trypomastigotes and the treatment began on the 8th day post-infection (dpi) through 28 dpi. The parasitemia was determined through optical microscopy every 2 days using 5 μL of blood sampled from the tail. In dpi 14, 21 and 28, the blood sample was obtained from the queue for testing creatine kinase-MB, alanine aminotransferase and creatinine, then animals were euthanized and the heart was removed for histopathological study. The essential oil of lemon verbena produced a significant reduction of the parasitemia, 85.4% with the peak at a the dose of 250 mg/ kg. It was also observed a reduction in the number of amastigotes and inflammatory infiltrates in the heart. The creatine kinase-MB plasma levels also decreased at dpi 28 as a result of such treatment. Under experimental conditions, the essential oil of Aloysia triphylla (lemon verbena) has in vivo anti-Trypanosoma cruzi effect in mice.


Current Issues Affecting the Practice of Pediatric Orthopaedic Surgeons: Results of the 2014 Workforce Survey of American Academy of Pediatrics Section on Orthopaedics.
The opinions of the pediatric orthopaedic workforce are shaped by market forces, regulatory processes, and local experience. The purpose of this report is to summarize the findings of the recent Workforce Survey of the American Academy of Pediatrics (AAP) Section on Orthopaedics (SOOr). This submission has been reviewed and approved by the Board of Directors of the Pediatric Orthopaedic Society of North America (POSNA). In 2014, the AAP generated a survey to assess perceptions of pediatric orthopaedic surgeons about current issues that affect practice. The survey was sent to 856 POSNA and 141 AAP-SOOr members. Responses were topically organized to report current workforce composition, practice patterns, and perceptions about electronic medical records (EMRs). Responses were collected from August to December, 2014, from 496 (50%) survey recipients including 83 of 141 (59%) AAP-SOOr members and 413 of 856 (48%) POSNA members. Analyses were restricted to the 397 respondents who reported that they are currently practicing pediatric orthopaedics. Nearly all of these (390/391, 100%) indicated that they provide direct patient care and work an average of 60 hours per week. Many (105/378, 28%) indicated that they would soon limit their practice or retire. A majority (299/394, 76%) indicated that they face competition in their geographic area, predominantly due to pediatric orthopaedic subspecialists (269/299, 90%). Major business changes had recently occurred or were anticipated by 21% of participants. Respondents reported that use of EMR makes them less efficient (252/397, 63%) and interferes with the patient-physician relationship (172/397, 43%). This workforce survey suggests that pediatric orthopaedic surgeons are concerned with challenges of competition despite concurrent increasing volume and complexity of referrals. External processes such as EMR changes are perceived to negatively impact practice efficiency and satisfaction.