Low temperature S(0) biomineralization at a supraglacial spring system in the Canadian High Arctic.
Elemental sulfur (S(0) ) is deposited each summer onto surface ice at Borup Fiord pass on Ellesmere Island, Canada, when high concentrations of aqueous H(2) S are discharged from a supraglacial spring system. 16S rRNA gene clone libraries generated from sulfur deposits were dominated by β-Proteobacteria, particularly Ralstonia sp. Sulfur-cycling micro-organisms such as Thiomicrospira sp., and ε-Proteobacteria such as Sulfuricurvales and Sulfurovumales spp. were also abundant. Concurrent cultivation experiments isolated psychrophilic, sulfide-oxidizing consortia, which produce S(0) in opposing gradients of Na(2) S and oxygen. 16S rRNA gene analyses of sulfur precipitated in gradient tubes show stable sulfur-biomineralizing consortia dominated by Marinobacter sp. in association with Shewanella, Loktanella, Rubrobacter, Flavobacterium, and Sphingomonas spp. Organisms closely related to cultivars appear in environmental 16S rRNA clone libraries; none currently known to oxidize sulfide. Once consortia were simplified to Marinobacter and Flavobacteria spp. through dilution-to-extinction and agar removal, sulfur biomineralization continued. Shewanella, Loktanella, Sphingomonas, and Devosia spp. were also isolated on heterotrophic media, but none produced S(0) alone when reintroduced to Na(2) S gradient tubes. Tubes inoculated with a Marinobacter and Shewanella spp. co-culture did show sulfur biomineralization, suggesting that Marinobacter may be the key sulfide oxidizer in laboratory experiments. Light, florescence and scanning electron microscopy of mineral aggregates produced in Marinobacter experiments revealed abundant cells, with filaments and sheaths variably mineralized with extracellular submicron sulfur grains; similar biomineralization was not observed in abiotic controls. Detailed characterization of mineral products associated with low temperature microbial sulfur-cycling may provide biosignatures relevant to future exploration of Europa and Mars.


The Alberta Heart Failure Etiology and Analysis Research Team (HEART) study.
Nationally, symptomatic heart failure affects 1.5-2% of Canadians, incurs $3 billion in hospital costs annually and the global burden is expected to double in the next 1-2 decades. The current one-year mortality rate after diagnosis of heart failure remains high at >25%. Consequently, new therapeutic strategies need to be developed for this debilitating condition. The objective of the Alberta HEART program (http://albertaheartresearch.ca) is to develop novel diagnostic, therapeutic and prognostic approaches to patients with heart failure with preserved ejection fraction. We hypothesize that novel imaging techniques and biomarkers will aid in describing heart failure with preserved ejection fraction. Furthermore, the development of new diagnostic criteria will allow us to: 1) better define risk factors associated with heart failure with preserved ejection fraction; 2) elucidate clinical, cellular and molecular mechanisms involved with the development and progression of heart failure with preserved ejection fraction; 3) design and test new therapeutic strategies for patients with heart failure with preserved ejection fraction. Additionally, Alberta HEART provides training and education for enhancing translational medicine, knowledge translation and clinical practice in heart failure. This is a prospective observational cohort study of patients with, or at risk for, heart failure. Patients will have sequential testing including quality of life and clinical outcomes over 12 months. After that time, study participants will be passively followed via linkage to external administrative databases. Clinical outcomes of interest include death, hospitalization, emergency department visits, physician resource use and/or heart transplant. Patients will be followed for a total of 5 years. Alberta HEART has the primary objective to define new diagnostic criteria for patients with heart failure with preserved ejection fraction. New criteria will allow for targeted therapies, diagnostic tests and further understanding of the patients, both at-risk for and with heart failure. ClinicalTrials.gov NCT02052804.


IL-6: from arthritis to CAR-T-cell therapy and COVID-19.
Blockade of IL-6 function by an anti-IL-6 receptor (IL-6R) antibody (tocilizumab, trade name Actemra) has been shown to be effective for the treatment of chronic autoimmune inflammatory diseases including rheumatoid arthritis. Interestingly, treatment with tocilizumab has also been found to alleviate the cytokine storm induced by chimeric antigen receptor (CAR)-T-cell therapy. Patients with serious cases of coronavirus disease 2019 (COVID-19) exhibit cytokine release syndrome (CRS), which suggested that tocilizumab might be an effective therapeutic for serious cases of COVID-19. In the first part of this short review, the therapeutic effect of tocilizumab for the disease induced by IL-6 overproduction is described. CRS induced by CAR-T-cell therapy and COVID-19 is then discussed.


Different normalization strategies might cause inconsistent variation in circulating microRNAs in patients with hepatocellular carcinoma.
Circulating microRNA (miRNA) are promising biomarkers for diagnosing and prognosticating numerous diseases. Reports have demonstrated controversial or even contradictory conclusions in studies on circulating microRNA. This study aimed to evaluate the potential bias of using different reference genes for analyzing circulating microRNAs in the same malignant digestive diseases. We measured plasma concentrations of U6-snRNA, let-7a, miRNA-21, miRNA-106a, miRNA-155, miRNA-219, miRNA-221, and miRNA-16 in patients with hepatocellular carcinoma (HCC), gastric carcinoma (GC), hepatic cirrhosis, hepatitis B, and healthy volunteers using quantitative real-time polymerase chain reaction (qPCR). The GeNorm, Normfinder, BestKeeper, and Comparative ΔCq algorithms integrated in RefFinder were used to screen the most suitable reference genes from the candidates. The 4 commonly used statistical evaluation software packages provided different results regarding the stability of the candidate reference genes. RefFinder revealed miRNA-106a and miRNA-21 as the most stably expressed reference genes, with comprehensive stability values of 1.189 and 1.861, respectively. U6-snRNA was the most unstable nucleic acid in our data. When 5 normalization strategies were compared using U6-snRNA, serum volume, miRNA-106a, miRNA-21, or the mean value of miRNA-106a and miRNA-21, obvious expression bias was detected in almost all target microRNAs. Intriguingly, all these normalization strategies indicated that circulating miRNA-155 is greatly upregulated in patients with HCC and GC, but downregulated in benign hepatic disease. Single reference genes used without justification in plasma microRNAs produce significant analysis bias or even erroneous results. Circulating miRNA-155 may be a promising non-invasive biomarker for discriminating malignant digestive tumors from the corresponding benign diseases.


Interaction of flooding and salinity stress on baldcypress (Taxodium distichum).
Coastal wetlands of the southeastern United States are threatened by increases in flooding and salinity as a result of both natural processes and man-induced hydrologic alterations. Furthermore, global climate change scenarios suggest that, as a consequence of rising sea levels, much larger areas of coastal wetlands may be affected by flooding and salinity in the next 50 to 100 years. In this paper, we review studies designed to improve our ability to predict and ameliorate the impacts of increased flooding and salinity stress on baldcypress (Taxodium distichum (L.) Rich.), which is a dominant species of many coastal forested wetlands. Specifically, we review studies on species-level responses to flooding and salinity stress, alone and in combination, we summarize two studies on intraspecific variation in response to flooding and salinity stress, we analyze the physiological mechanisms thought to be responsible for the interaction between flooding and salinity stress, and we discuss the implications for coastal wetland loss and the prospects for developing salt-tolerant lines of baldcypress.


Progress in the palladium-catalyzed cyanation of aryl chlorides.
The development of new palladium catalysts for the cyanation of various aryl and heteroaryl chlorides is described. The combination of amine co-catalysts with chelating phosphine ligands, for example, 1,4-bis(diphenylphosphino)butane (dppb) or 1,5-bis(diphenylphosphino)pentane (dpppe), allows an efficient cyanation of chloroarenes with simple potassium cyanide. General palladium-catalyzed cyanation of nonactivated and deactivated chloroarenes is possible for the first time. Studies of the oxidative addition of aryl halides to palladium triphenylphosphine complexes in the presence and absence of amines suggest that the co-catalyst is capable of preventing catalyst deactivation caused by the presence of excess cyanide ions in solution.


KATNB1 in the human testis and its genetic variants in fertile and oligoasthenoteratozoospermic infertile men.
Oligoasthenoteratozoospermia (OAT) is a phenotype frequently observed in infertile men, and is defined by low spermatozoa number, abnormal spermatozoa morphology and poor motility. We previously showed that a mutation in the Katnb1 gene in mice causes infertility because of OAT. The KATNB1 gene encodes an accessory subunit of the katanin microtubule-severing enzyme complex; this accessory subunit is thought to modulate microtubule-severing location and activity. We hypothesized that KATNB1 may play a role in human spermatogenesis and that genetic variants in KATNB1 could be associated with OAT in humans. Using immunostaining, we defined the localization of the KATNB1 protein in human testes. KATNB1 was present during spermatid development, and in particular localized to the microtubules of the manchette, a structure required for sperm head shaping. To assess a potential association between genetic variants in the KATNB1 gene and infertile men with OAT, we performed direct sequencing of genomic DNA samples from 100 OAT infertile and 100 proven fertile men. Thirty-seven KATNB1 variants were observed, five of which had not previously been described. Ten variants were present only in OAT men, however, statistical analysis did not reveal a significant association with fertility status. Our results suggest that variants in the KATNB1 gene are not commonly associated with OAT infertility in Australian men.


The putative recombination of hepatitis B virus genotype B with pre-C/C region of genotype C.
Among hepatitis B virus (HBV) genotypes the B and C are most prevalent in China. To further study on the inside story of the intertypes, the genotype of 136 sequences from Chinese patients were analyzed either by restriction fragment length polymorphism on fragments or by phylogenetic analysis and bootscanning on full genome. The 22 complete sequences of genotype B clustered with different genotypes depending on gene fragments analyzed, which indicated that recombinant events occurred during HBV evolutionary history. To locate the recombinant regions, the sequences of HBV entire genome were analyzed by SimPlot program. The recombinant regions of B genotype with recombination were mapped in the pre-C/C region with relatively less varied size. Besides, three sequences of genotype C have recombination with genotype B or D in different regions. However, among all of the 136 sequences, none of authentic genotype B was identified. To investigate the possible mechanism responsible for intertype recombination, the selection pressure on the recombinant region was estimated by using CODEML program. All models allow for positively selected sites suggest existence of positive selection pressure. In conclusion, the genotype B with recombination was exclusive subgroup of genotype B in China. The mosaic genotype B might result from immune pressure on the pre-C/C gene.


Transthyretin Cardiac Amyloidosis Disguised as Light Chain Amyloidosis or Multiple Myeloma?
We describe 2 challenging cases of cardiac transthyretin amyloidosis initially treated as cardiac amyloidosis light chain in the setting of active myeloma. Endomyocardial biopsy with mass spectrometry was essential to confirm the appropriate diagnosis to direct the treatment.


Genotoxic activities of drug-nitrite interaction products.
At first 28 orally administered drugs, considered to be potentially nitrosatable on the basis of their chemical structure, have been nitrosated with nitrite under simulated stomach conditions. A maximum daily dose of each drug was incubated with a nitrite concentration that can be found after a normal meal in the stomach at 37 degrees C over 1 h. Reaction was started at pH 6.8-7.0 and stopped at pH 2.0, so we had the same pH change that occurs in the stomach. Secondly the genotoxic activities of drug-nitrite interaction products were tested by the umu-test with Salmonella typhimurium TA 1535/pSK1002 as tester strain in the presence and absence of metabolic activation. By the umu-test, among the nitrosation products of drugs examined 22 products showed genotoxicity at different levels. Other six products showed negative results by the umu-test.


SARS-CoV-2 Vaccines: Status Report.
SARS-CoV-2, the causal agent of COVID-19, first emerged in late 2019 in China. It has since infected more than 870,000 individuals and caused more than 43,000 deaths globally. Here, we discuss therapeutic and prophylactic interventions for SARS-CoV-2 with a focus on vaccine development and its challenges. Vaccines are being rapidly developed but will likely come too late to affect the first wave of a potential pandemic. Nevertheless, critical lessons can be learned for the development of vaccines against rapidly emerging viruses. Importantly, SARS-CoV-2 vaccines will be essential to reducing morbidity and mortality if the virus establishes itself in the population.


A new design and rationale for 3D orthogonally oversampled k-space trajectories.
A novel center-out 3D trajectory for sampling magnetic resonance data is presented. The trajectory set is based on a single Fermat spiral waveform, which is substantially undersampled in the center of k-space. Multiple trajectories are combined in a "stacked cone" configuration to give very uniform sampling throughout a "hub," which is very efficient in terms of gradient performance and uniform trajectory spacing. The fermat looped, orthogonally encoded trajectories (FLORET) design produces less gradient-efficient trajectories near the poles, so multiple orthogonal hub designs are shown. These multihub designs oversample k-space twice with orthogonal trajectories, which gives unique properties but also doubles the minimum scan time for critical sampling of k-space. The trajectory is shown to be much more efficient than the conventional stack of cones trajectory, and has nearly the same signal-to-noise ratio efficiency (but twice the minimum scan time) as a stack of spirals trajectory. As a center-out trajectory, it provides a shorter minimum echo time than stack of spirals, and its spherical k-space coverage can dramatically reduce Gibbs ringing.


Ratio of Klebsiella/Bifidobacterium in early life correlates with later development of paediatric allergy.
Several studies have reported that intestinal microbial colonisation patterns differ between non-allergic and allergic infants. However, the microbial signature underlying the pathogenesis of allergies remains unclear. We aim to gain insight into the development of the intestinal microbiota of healthy infants and infants who develop allergy in early life, and identify potential microbiota biomarkers of later allergic disease. Using a case-control design in a Chinese sub-cohort of a Singaporean birth cohort (GUSTO), we utilised 16S rRNA gene sequencing to assess intestinal microbial composition and diversity of 21 allergic and 18 healthy infants at 3 weeks, 3 months and 6 months of age, and correlated the microbiota with allergy at ages 18 and 36 months. Pronounced differences in intestinal microbiota composition between allergic and healthy infants were observed at 3 months of age. The intestine of healthy infants was colonised with higher abundance of commensal Bifidobacterium. Conversely, Klebsiella, an opportunistic pathogen, was significantly enriched in the allergic infants. Interestingly, infants with a high Klebsiella/Bifidobacterium (K/B) ratio (above the population median K/B ratio) at age 3 months had an odds ratio of developing allergy by 3 years of age of 9.00 (95% confidence interval 1.46-55.50) compared to those with low K/B ratio. This study demonstrated a relationship between the ratio of genera Klebsiella and Bifidobacterium during early infancy and development of paediatric allergy in childhood. Our study postulates that an elevated K/B ratio in early infancy could be a potential indicator of an increased risk of allergy development. This line of research might enable future intervention strategies in early life to prevent or treat allergy. Our study provides new insights into microbial signatures associated with childhood allergy, in particular, suggests that an elevated K/B ratio could be a potential early-life microbiota biomarker of allergic disease.


Applications of amyloid, tau, and neuroinflammation PET imaging to Alzheimer's disease and mild cognitive impairment.
Alzheimer's disease (AD) is a devastating and progressive neurodegenerative disease for which there is no cure. Mild cognitive impairment (MCI) is considered a prodromal stage of the disease. Molecular imaging with positron emission tomography (PET) allows for the in vivo visualisation and tracking of pathophysiological changes in AD and MCI. PET is a very promising methodology for differential diagnosis and novel targets of PET imaging might also serve as biomarkers for disease-modifying therapeutic interventions. This review provides an overview of the current status and applications of in vivo molecular imaging of AD pathology, specifically amyloid, tau, and microglial activation. PET imaging studies were included and evaluated as potential biomarkers and for monitoring disease progression. Although the majority of radiotracers showed the ability to discriminate AD and MCI patients from healthy controls, they had various limitations that prevent the recommendation of a single technique or tracer as an optimal biomarker. Newer research examining amyloid, tau, and microglial PET imaging in combination suggest an alternative approach in studying the disease process.


Lycorine Promotes Autophagy and Apoptosis via TCRP1/Akt/mTOR Axis Inactivation in Human Hepatocellular Carcinoma.
Lycorine is a multifunctional bioactive compound, and it possesses potential anticancer activities. However, little is known about the underlying mechanism. In this research, we have found that lycorine significantly induces the apoptotic and autophagic capacities of hepatocellular carcinoma (HCC) cells in vitro and in vivo Treatment with specific autophagy inhibitor (3-methyladenine/Bafilomycin A1) or knockdown of LC-3B/Atg5 by siRNA drastically enhances the apoptotic cell death effect by facilitating the switch from autophagy to apoptosis. Molecular validation mechanistically demonstrates that lycorine-induced apoptosis and autophagy in HCC cells is associated with decreased protein levels of tongue cancer resistance-associated protein 1 (TCRP1), and we further find that inhibition of TCRP1 decreases phosphorylation level of Akt and represses Akt/mTOR signaling. Finally, lycorine-induced apoptosis and autophagy suppress the growth of xenograft hepatocellular tumors without remarkable toxicity. Our results elucidate a novel molecular mechanism whereby lycorine promotes apoptosis and autophagy through the TCRP1/Akt/mTOR pathway in HCC. Our results reveal that lycorine might be a potential therapeutic agent for the treatment of HCC. Mol Cancer Ther; 16(12); 2711-23. ©2017 AACR.


Efficacy of tigecycline for the treatment of complicated skin and soft-tissue infections in real-life clinical practice from five European observational studies.
Tigecycline is an approved treatment for complicated skin and soft-tissue infections (cSSTIs). The efficacy of tigecycline as monotherapy or in combination with other antibacterials in the treatment of cSSTI in routine practice is described. Individual patient-level data were pooled from five European observational studies (July 2006 to October 2011). A total of 254 cSSTI patients who received tigecycline were included (mean age 63.2 ± 14.9 years). Of these, 34.4% were in intensive care units, 54.5% acquired their infection in hospital and 90.9% had at least one comorbidity. Infection most commonly affected the limbs (62.4%) and 43.8% of infections were classified as necrotizing. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II and Sequential Organ Failure Assessment (SOFA) scores at the beginning of treatment were 15.0 ± 7.9 (n = 205) and 5.8 ± 3.9 (n = 32), respectively, indicating high disease severity. Staphylococcus aureus (52.7%), Escherichia coli (18.0%) and Enterococcus faecium (12.0%) were the most frequently isolated pathogens; 32.9% of infections were polymicrobial and 30.5% were due to resistant pathogens. Overall, 71.8% received tigecycline as monotherapy and 28.2% as combination therapy for a mean duration of 12 days. Clinical response rates at the end of treatment were 79.6% for all patients who received the standard dosage (183/230), 86.7% for patients who received tigecycline as monotherapy (143/165), 75.0% for patients with a nosocomial infection (96/128), 75.3% for patients with an APACHE II score >15 (61/81) and 58.3% for patients with a SOFA score ≥ 7 (7/12). In these real-life studies, tigecycline, alone and in combination, achieved favourable clinical response rates in patients with cSSTI with a high severity of illness.


[Cardiological emergency network in Lombardy].
To achieve a reduction of time to reperfusion through the organization of an interhospital network and the involvement of the Regional Health Authority. Four major endpoints were identified: institutional governance action, clinical management of acute ST-elevation myocardial infarction (STEMI), priority actions for cardiac arrest and early defibrillation, actions to avoid the delay related to decision-making, and logistic factors. Since 2001 in the urban area of Milan a network has been operating among 23 coronary care units, the 118 Dispatch Center (national free number for medical emergencies) and the Health Country Government Agency named Group for Prehospital Cardiac Emergency. In order to monitor the network activity and time to treatment and clinical outcomes a periodic monthly survey, called MOMI (One Month Monitoring Myocardial Infarction), was undertaken and repeated twice yearly. Data were evaluated according to hospital admission modality. Global times are: symptom onset to first medical contact 116 min (interquartile range [IQR] 189), time to first ECG 7 min (IQR 12), door-to-balloon time 77 min (IQR 81.7). Non-parametric test showed that the modality of hospital admittance was the most critical determinant of door-to-balloon time. The shortest one (49.5 min) was that of patients transported by means of advanced rescue units with 12-lead ECG teletransmission and activation of a fast track directly to the cath lab. Our data show how in a complex urban area the organization of an interhospital network and the availability of ECG teletransmission are effective in reducing time to reperfusion, in the treatment of major arrhythmias and in pre-alert of coronary care units and cath labs in case of confirmed STEMI. This experience also stimulated an improvement in technological equipment of rescue units with extension of 12-lead teletransmission to basic life support units. Through the Health Country Government Agency and the Scientific Societies we carry on with our job to create a regional network for cardiac emergency involving all the hospitals.


Structural features of aluminium(III) complexes with bioligands in glutamate dehydrogenase reaction system--a review.
Aluminium(III) complexes are essential for understanding the toxicity, bioavailability and transport mechanisms of aluminium in environmental and biological systems. Since elucidation of the exact structures of these weakly coordinated systems is very difficult, the structures of Al(III) complexes in glutamate dehydrogenase reactions system were investigated recently from the following four aspects: (1) Constitutional studies: The keto-enol tautomerism of the complexes between aluminium(III) ion and alpha-ketoglutarate ligands in acidic aqueous solutions was studied. It is clearly demonstrated that Al(III) can promote the keto-enol tautomerization of alpha-ketoglutarate. (2) Configurational studies: Compared with L-Glu, the complex stability of D-Glu-Al is stronger, especially for the tridentate species. The result was further supported by computational results in the molecular mechanics model with the UFF forcefield. It is implied that Al(III) complexation may favor the racemization from L- to D-amino acids. (3) Conformational studies: At biologically relevant pH and concentrations of Al(III) and NADH, Al(III) was found to increase the percentage of folded forms of NADH, which results in reducing the activity of the coenzyme NADH in the hollow-dehydrogenase reactions system. However, the conformations of NAD(+) and Al-NAD(+) are dependent upon the solvents and other ligands in the complexes. (4) Biological effects: The effects of Al(III) on the activity of the glutamate dehydrogenase-catalyzed reactions were studied by monitoring the differential-pulse polarography reduction current of NAD(+). At the physiologically relevant pH values (pH 6.5 and 7.5), the activity of the GDH enzyme was strongly dependent on the concentration of the Al(III) in the assayed mixture solutions.


Translational research in neurology and neuroscience 2010: multiple sclerosis.
Over the past 2 decades, enormous progress has been made with regard to pharmacotherapies for patients with multiple sclerosis. There is perhaps no other subspecialty in neurology in which more agents have been approved that substantially alter the clinical course of a disabling disorder. Many of the pharmaceuticals that are currently approved, in clinical trials, or in preclinical development were initially evaluated in an animal model of multiple sclerosis, experimental autoimmune encephalomyelitis. Two Food and Drug Administration-approved agents (glatiramer acetate and natalizumab) were developed using the experimental autoimmune encephalomyelitis model. This model has served clinician-scientists for many decades to enable understanding the inflammatory cascade that underlies clinical disease activity and disease surrogate markers detected in patients.


Differential gender effects of a reduced-calorie diet on systemic inflammatory and immune parameters in nonhuman primates.
Dietary manipulation, including caloric restriction, has been shown to impact host response capabilities significantly, particularly in association with aging. This investigation compared systemic inflammatory and immune-response molecules in rhesus monkeys (Macaca mulatta). Monkeys on continuous long-term calorie-restricted diets and a matched group of animals on a control ad libitum diet, were examined for systemic response profiles including the effects of both gender and aging. The results demonstrated that haptoglobin and alpha1-antiglycoprotein levels were elevated in the serum of male monkeys. Serum IgG responses to Campylobacter rectus, Actinobacillus actinomycetemcomitans and Porphyromonas gingivalis were significantly elevated in female monkeys. While only the antibody to Fusobacterium nucleatum was significantly affected by the calorie-restricted diet in female monkeys, antibody levels to Prevotella intermedia, C. rectus and Treponema denticola demonstrated a similar trend. In this investigation, only certain serum antibody levels were influenced by the age of male animals, which was seemingly related to increasing clinical disease in this gender. More generally, analytes were modulated by gender and/or diet in this oral model system of mucosal microbial challenge.


Growth, encystment and survival of Acanthamoeba castellanii grazing on different bacteria.
Free-living amoebae of the genus Acanthamoeba are widely distributed in soil and water collections, where trophozoites (vegetative, multiplicative stages) feed mainly by phagocytosis and thus control bacterial populations in the environment. Here, we examined the growth, encystment and survival of Acanthamoeba castellanii receiving different bacteria (Escherichia coli, Pseudomonas aeruginosa, Enterobacter cloacae, Bacillus subtilis, Bacillus megaterium, Micrococcus luteus, and Staphylococcus aureus) in nonnutrient saline. All bacteria assayed induced a dose-dependent proliferative response, in most cases maximized with a bacterial dose of 1 x 10(9) mL(-1); except for M. luteus, trophozoites grew better with viable than with heat-killed bacteria. In addition, Acanthamoeba growth was improved by adding bacteria on alternate days. Single-dose experiments indicated a temporal association between the growth of trophozoite and bacterial consumption, and higher consumption of M. luteus, E. coli and P. aeruginosa, bacterial species that allowed the highest trophozoite yields. Long-term Acanthamoeba-bacteria incubation revealed that encystment was significantly delayed by almost all the bacteria assayed (including S. aureus, which elicited a poor growth response) and that the presence of bacteria markedly increased cyst yield; final cyst recovery clearly depended on both the dose and the type of the bacterium given, being much higher with E. coli, M. luteus and P. aeruginosa.


Craniovertebral junction anomalies seen at Kenyatta National Hospital, Nairobi.
To study the frequency, mode of presentation and outcome following surgery of anomalies of the craniovertebral junction at the Kenyatta National Hospital. A retrospective study. Kenyatta National Hospital, Nairobi. Thirty eight patients with craniovertebral junction anomaly who were treated at the Kenyatta National Hospital. Thirty eight patients were diagnosed to have craniovertebral junction anomaly at the Kenyatta National Hospital between January 1988 and December 1994. Thirty of those patients underwent surgery. The ages ranged between 10 years and 49 years with a peak in the third decade. The male to female ratio was 2:1. The common mode of presentation was weakness of the extremities (90%) followed by sensory disturbances such as numbness of the extremities (30%), headache (30%) and neck pain (20%). The common clinical findings were ataxia, muscle wasting, sensory loss and brisk deep tendon reflexes. Most of the patients had computerised tomography (CT) scanning (80%) done. Other radiological investigations which were done were plain x-rays of the skull and cervical spine (50%), myelographic studies (36%) and tomographic studies (12%). Forty percent of the patients improved following surgery while further neurological deterioration was prevented in 48%. There was an immediate post-operative mortality of 8%. Craniovertebral junction anomaly is an important clinicopathological, condition common amongst certain ethnic groups found in high altitude areas of the Kenya. Surgery may cause clinical improvement in 40% of the patients, mainly those who have been symptomatic for less than three years.


Induced degradation of protein kinases by bifunctional small molecules: a next-generation strategy.
Introduction: Protein kinases are a major target for small-molecule drug development. However, relatively few compounds are free of off-target toxicity and reach the clinic. Because the 500-plus kinases share conserved ATP-binding clefts, the site targeted by competitive inhibitors, generation of specific therapeutics remains a nearly intractable challenge. Areas covered: Inducing degradation, instead of inhibition by occupancy-driven drugs, is an emerging strategy that offers the long-sought specificity, as well as mechanistic benefits. Currently approved inhibitors require steady-state binding and leave proteins intact for interactions in multi-protein complexes. After a general background about induced protein degradation, perspectives on protein kinases are provided. Expert opinion: Induced degradation by state-of-the-art compounds (proteolysis-targeting chimeras, PROTACs) has been shown for protein kinases, albeit in early pre-clinical stages. Further work is required to expand the number of enzymes that could be exploited to direct proteins for degradation by ubiquitylation. In addition, despite the simple modularity of the chimeras, generation of hits will require empirical approaches due to the role of protein-protein interactions and distribution of tagging sites. However, given the advantages of degradation, drug discovery efforts targeting protein kinases should increasingly shift toward generation and screening of inducers of degradation and away from occupancy-based inhibitors of old.


Changing aspects of radiation enteropathy.
Fifty-two patients with radiation enteropathy secondary to radiation for abdominal or pelvic malignant neoplasms are described. This series (1977 to 1984) is compared with a series of 50 patients from the same institution over an earlier period (1961 to 1977). Intestinal obstruction was the principal complication in both series; 96% of the patients underwent either intestinal resection or anastomotic bypass of the affected segment. Changes that have occurred since the last report are as follows: changes in source of radiation energy (linear accelerator); less evidence of mucosal damage; increased serosal reaction ("serosal peel"); and increased use of elemental diets, parenteral nutrition, and long intestinal tubes in surgical management. Since postoperative radiation injury occurs most frequently in the pelvis, new developments for the exclusion of small bowel from the pelvis during radiation are reviewed. Changes in fractionation of radiation dosage should also be considered in patients with enteric symptoms during radiation therapy.


Comparative assessment of ELISAs using recombinant saposin-like protein 2 and recombinant cathepsin L-1 from Fasciola hepatica for the serodiagnosis of human Fasciolosis.
Two recombinant Fasciola hepatica antigens, saposin-like protein-2 (recSAP2) and cathepsin L-1 (recCL1), were assessed individually and in combination in enzyme-linked immunosorbent assays (ELISA) for the specific serodiagnosis of human fasciolosis in areas of low endemicity as encountered in Central Europe. Antibody detection was conducted using ProteinA/ProteinG (PAG) conjugated to alkaline phosphatase. Test characteristics as well as agreement with results from an ELISA using excretory-secretory products (FhES) from adult stage liver flukes was assessed by receiver operator characteristic (ROC) analysis, specificity, sensitivity, Youdens J and overall accuracy. Cross-reactivity was assessed using three different groups of serum samples from healthy individuals (n=20), patients with other parasitic infections (n=87) and patients with malignancies (n=121). The best combined diagnostic results for recombinant antigens were obtained using the recSAP2-ELISA (87% sensitivity, 99% specificity and 97% overall accuracy) employing the threshold (cut-off) to discriminate between positive and negative reactions that maximized Youdens J. The findings showed that recSAP2-ELISA can be used for the routine serodiagnosis of chronic fasciolosis in clinical laboratories; the use of the PAG-conjugate offers the opportunity to employ, for example, rabbit hyperimmune serum for the standardization of positive controls.


Low-temperature switching by photoinduced protonation in photochromic fluorescent proteins.
We have studied the photoswitching behaviour of a number of photochromic fluorescent proteins at cryo-temperature. Spectroscopic investigations at the ensemble level showed that EYFP, Dronpa and IrisFP all exhibit reversible photoswitching at 100 K, albeit with a low quantum yield. The photophysics of the process were studied in more details in the case of EYFP. The data suggest that photoinduced protonation of the chromophore is responsible for off-switching at cryo-temperature, and thus is possible in the absence of significant conformational freedom. This finding is consistent with the hypothesis that chromophore protonation may precede large amplitude conformational changes such as cis-trans isomerisation during off-photoswitching at room temperature. However, our data suggest that low-barrier photoinduced protonation pathways may in fact compete with room-temperature off-switching reactions in photochromic fluorescent proteins. The occurrence of reversible photoswitching at low-temperature is of interest to envisage cryo-nanoscopy experiments using genetically encoded fluorophores.


Anti-allodynic effects of obtusifolin and gluco-obtusifolin against inflammatory and neuropathic pain.
Inflammatory pain and neuropathic pain are major health issues that represent considerable social and economic burden worldwide. In this study we investigated the potential of obtusifolin and gluco-obtusifolin, two anthraquinones found in the seeds of the widely used traditional Chinese medical botanical Cassia obtusifolia, to reduce neuropathic and inflammatory pain. The potential analgesic effects of obtusifolin and gluco-obtusifolin were evaluated by mice formalin test and complete Freund's adjuvant (CFA)-induced nociceptive behaviors in rats. Chronic constriction injury (CCI), L5 spinal nerve ligation (L5 SNL), diabetes, and chemotherapeutics inducing allodynia were used to test whether repeated treatment with obtusifolin and gluco-obtusifolin ameliorated neuropathic pain. Finally, we explored whether obtusifolin and gluco-obtusifolin altered the degree of neuroinflammation in rat spinal cord after CFA administration and CCI induction. Obtusifolin and gluco-obtusifolin (0.25, 0.5, 1, and 2 mg/kg) reduced licking/biting time in dose-dependent manner in phase 2 of formalin-induced behavior in mice. Furthermore, repeated administration of obtusifolin and gluco-obtusifolin (0.25, 0.5, 1, and 2 mg/kg) reversed mechanical allodynia induced by CFA, CCI, L5 SNL, diabetes, and oxaliplatin in a dose-dependent manner in rats. Levels of activated nuclear factor-kappa B (NF-κB) and proinflammatory cytokines (interleukin (IL)-1β, IL-6, tumor necrosis factor α (TNF-α)) in lumbar spinal cord were elevated in rats following CFA treatment and CCI induction, and obtusifolin and gluco-obtusifolin significantly inhibited these effects. Our results demonstrate that obtusifolin and gluco-obtusifolin produce significant antinociceptive action in rodent behavioral models of inflammatory/neuropathic pain, and that this activity is associated with modulation of neuroinflammation in spinal cord.


From process to product: writing engagement and performance of EFL learners under computer-generated feedback instruction.
Artificial intelligence (AI) technology is gradually penetrating the domain of education, opening up many possibilities for teaching and learning. Many educators, faced with the burden of commenting on substantial student essays, have introduced automated writing evaluation (AWE) into second language (L2) writing considering its affordance of immediate scores and diagnostic information. However, students' processing strategies and perceptions of such computer-generated feedback and its impact on student writing quality, particularly as mediated by language proficiency, remain under-explored. This study examines the impact of Pigai, a Chinese AWE system, on revision processes and writing products of 42 English as a foreign language (EFL) learners with varying language levels by analyzing feedback points, feedback uptake, text quality in complexity, accuracy, and fluency (CAF), and perceptions. The findings are as follows. When confronted with AWE instruction, the majority of student work focuses on correcting errors, but higher-level students exhibit an emphasis on language improvement beyond the surface level compared to lower-level students. According to CAF measures, automated feedback exerts greater effects on accuracy for unskilled learners and lexical complexity for skilled learners in the development of interlanguage. Learner profiles and perceptions of students at different levels are explored along four dimensions: writing quality, cognitive engagement, behavioral engagement, and affective engagement. Finally, the potential issues of such technology-based writing instruction are pointed out.


Diagnostic Performance of PET Versus SPECT Myocardial Perfusion Imaging in Patients with Smaller Left Ventricles: A Substudy of the 18F-Flurpiridaz Phase III Clinical Trial.
The performance of SPECT myocardial perfusion imaging (MPI) may deteriorate in smaller hearts, primarily because of the lower resolution of conventional Anger cameras. 18F-flurpiridaz is a novel PET MPI agent with superior image and defect resolution. We sought to determine the diagnostic performance of 99mTc-labeled SPECT MPI compared with 18F-flurpiridaz PET MPI according to left ventricle (LV) size. Methods: We conducted a substudy of the phase III clinical trial of flurpiridaz (n = 750) and stratified diagnostic performance according to the median PET LV end-diastolic volume (LVEDV), with smaller LVs defined as having an LVEDV of less than 113 mL (n = 369) and larger LVs defined as having an LVEDV of at least 113 mL (n = 381). Images were interpreted by the majority rule of 3 independent masked readers. The reference standard was quantitative invasive angiography, with at least 50% stenosis in at least 1 coronary artery considered significant. Results: SPECT performance decreased significantly from an area under the curve (AUC) of 0.75 in larger LVs to 0.67 in smaller LVs (P = 0.03), whereas PET performance was similar in larger and smaller LVs (AUC, 0.79 vs. 0.77, P = 0.49). Accordingly, in smaller LVs, PET had a higher AUC (0.77) than the SPECT AUC (0.67) (P < 0.0001), a phenomenon driven by female patients (P < 0.0001). In smaller LVs, there was a degradation of SPECT sensitivity that was highly significant (P < 0.001), whereas there was no significant change in PET sensitivity according to LV size (P = 0.07). Overall, PET had significantly higher sensitivity than SPECT in both smaller LVs (67% vs. 43%, P < 0.001) and larger LVs (76% vs. 61%, P < 0.001). The specificities of PET and SPECT were similar in larger LVs (76% vs. 83%, P = 0.11). Although SPECT specificity improved in smaller compared with larger LVs (90% vs. 83%, P = 0.03), the PET specificity did not change with LV size (76% vs. 76%, P = 0.9). Conclusion: The diagnostic performance of 18F-flurpiridaz PET MPI is not affected by LV size and is superior to SPECT MPI in patients with smaller LVs, highlighting the importance of appropriate test selection in these patients.


Altered relation between lipopolysaccharide-induced inflammatory response and excitotoxicity in rat organotypic hippocampal slice cultures during ethanol withdrawal.
Ethanol (EtOH) causes neurotoxicity by several mechanisms including excitotoxicity and neuroinflammation, but little is known about the interaction between these mechanisms. Because neuroinflammation is known to enhance excitotoxicity, we hypothesized that neuroinflammation contributes to the enhanced excitotoxicity, which is associated with EtOH withdrawal (EWD). The aim of this study was to evaluate the lipopolysaccharide (LPS)-induced inflammatory response of cultured hippocampal tissue during EWD and its effects on the enhanced N-methyl-d-aspartate (NMDA) receptor-mediated excitotoxicity, which occurs at this time. Using a neonatal organotypic hippocampal slice culture (OHSC) model, we assessed the effects of NMDA and LPS (separately or combined) during EWD after 10 days of EtOH exposure. Neurotoxicity was assessed using propidium iodide uptake, and the inflammatory response was evaluated by measuring the release of tumor necrosis factor (TNF)-alpha (quantified by enzyme-linked immunosorbent assay) and nitric oxide (NO; quantified by the Griess reaction) into culture media. Furthermore, we explored the potential role of the microglial cell type using immortalized BV2 microglia treated with EtOH for 10 days and challenged with LPS during EWD. As predicted, NMDA-induced toxicity was potentiated by LPS under control conditions. However, during EWD, the reverse was observed and LPS inhibited peak NMDA-induced toxicity. Additionally, LPS-induced release of TNF-alpha and NO during EWD was reduced compared to control conditions. In BV2 microglia, following EtOH exposure, LPS-induced release of NO was reduced, whereas TNF-alpha release was potentiated. During EWD following chronic EtOH exposure, OHSC exhibited a desensitized inflammatory response to LPS and the effects of LPS on NMDA toxicity were reversed. This might be explained by a change in microglia to an anti-inflammatory and neuroprotective phenotype. In support, studies on BV2 microglia indicate that EtOH exposure and EWD do alter the response of these cells to LPS, but this cannot fully explain the changes observed in the OHSC. The data suggest that neuroinflammation and excitotoxicity do interact during EWD. However, the interaction is not as simple as we originally proposed. This in turn illustrates the need to assess the extent, importance, and relation of these mechanisms in models of EtOH exposure producing neurotoxicity.


Process Principles for Large-Scale Nanomanufacturing.
Nanomanufacturing-the fabrication of macroscopic products from well-defined nanoscale building blocks-in a truly scalable and versatile manner is still far from our current reality. Here, we describe the barriers to large-scale nanomanufacturing and identify routes to overcome them. We argue for nanomanufacturing systems consisting of an iterative sequence of synthesis/assembly and separation/sorting unit operations, analogous to those used in chemicals manufacturing. In addition to performance and economic considerations, phenomena unique to the nanoscale must guide the design of each unit operation and the overall process flow. We identify and discuss four key nanomanufacturing process design needs: (a) appropriately selected process break points, (b) synthesis techniques appropriate for large-scale manufacturing,


Extended Experience with High Submuscular Placement of Urological Prosthetic Balloons and Reservoirs: Refined Technique for Optimal Outcomes.
Since 2012, we have routinely placed urological prosthetic balloons and reservoirs in a high submuscular location between the transversalis fascia and rectus abdominis muscle during inflatable penile prosthesis and artificial urinary sphincter surgery. We review our experience of more than 600 high submuscular cases, describe refinements in our technique through time and compare outcomes to prior consecutive space of Retzius prosthetic cases. We retrospectively reviewed patients who underwent inflatable penile prosthesis and/or artificial urinary sphincter placement between January 2009 and April 2016. Complications and need for surgical revision were recorded and compared between the 2 placement locations. During the study period 872 prosthetic cases were performed, including 619 high submuscular cases from 2012 to 2016 (inflatable penile prosthesis in 344, artificial urinary sphincter in 275). Of 399 first-time high submuscular implants 54 (14%) required revision, of which 8 (2%) were attributable to the urological balloon or reservoir due to "pain/bother" (4) or herniation (4). Of the 161 space of Retzius urological balloons and reservoirs placed from 2009 to 2011 a similar rate of herniation (3 cases, 1.9%) was noted, although higher rates of deep pelvic complications (3, 1.9%) were noted compared to high submuscular cases (2, 0.5%; p=0.14). Since implementing our refined high submuscular technique, no deep pelvic complications have occurred. Experience with high submuscular placement of urological balloons and reservoirs confirms that it is safe and well tolerated. With refinements in technique the complication rates are similar in frequency to those with space of Retzius but appear to be minor in nature with negligible risk of visceral or vascular injury.


Inactivation of the tumor suppressor WTX in a subset of pediatric tumors.
WTX is a tumor suppressor gene expressed during embryonic development and inactivated in 20-30% of cases of Wilms tumor, the most common pediatric kidney cancer. WTX has been implicated in several cellular processes including Wnt signaling, WT1 transcription, NRF2 degradation, and p53 function. Given that WTX is widely expressed during embryonic development and has been recently shown to regulate mesenchymal precursor cells in several organs, we tested for the potential involvement of WTX in a panel of pediatric tumors and adult sarcomas. A total of 353 tumors were screened for WTX deletions by fluorescence in situ hybridization (FISH). Discrete somatic WTX deletions were identified in two cases, one hepatoblastoma and one embryonal rhabdomyosarcoma, and confirmed by array comparative genomic hybridization. Direct sequencing of the full WTX open reading frame in 24 hepatoblastomas and 21 embryonal rhabdomyosarcomas did not identify additional mutations in these tumor types. The presence of WTX mRNA was confirmed in hepatoblastomas and embryonal rhabdomyosarcomas without WTX deletions by RNA-in situ hybridization. Notably, tumors with evidence of WTX inactivation, Wilms tumor, hepatoblastoma and rhabdomyosarcoma, are primitive tumors that resemble undifferentiated precursor cells and are linked to overgrowth syndromes. These results indicate that WTX inactivation occurs in a wider variety of tumor types than previously appreciated and point to shared pathogenic mechanisms between a subset of pediatric malignancies.


[Direct percutaneous transluminal coronary angioplasty].
Early reperfusion in acute myocardial infarction (AMI) effectively reduces mortality. Direct. percutaneous. transluminal coronary angioplasty (PTCA) is a recognized alternative to intravenous thrombolytic therapy in early AMI. Of 289 PTCAs performed during a year, 29 (10%) were direct PTCAs. Indications for direct PTCA in 21 patients (72%) were large infarcts, and in 8 (28%) cardiogenic shock. The left anterior descending artery was involved in 15 patients (52%), the right coronary artery in 10 (34%), the left circumflex in 3 (10%), and the left main artery in 1 (3%). Satisfactory opening of the occlusion was achieved in 26 (90%); there was partial success in 2 (7%) and failure in 1 (3%). 4 patients required stent deployment for treatment of dissection. There was no major complication. A patient in whom success was only partial, and the one in whom PTCA failed, were sent for operation. These data do not differ from our success rate in elective PTCA. It is concluded that direct PTCA is a safe procedure with a high rate of successful reperfusion in AMI.


Characteristics of the Flank Magnetopause: THEMIS Observations.
The terrestrial magnetopause is the boundary that shields the Earth's magnetosphere on one side from the shocked solar wind and its embedded interplanetary magnetic field on the other side. In this paper, we show observations from two of the Time History of Events and Macroscales Interactions during Substorms (THEMIS) satellites, comparing dayside magnetopause crossings with flank crossings near the terminator. Macroscopic properties such as current sheet thickness, motion, and current density are examined for a large number of magnetopause crossings. The results show that the flank magnetopause is typically thicker than the dayside magnetopause and has a lower current density. Consistent with earlier results from Cluster observations, we also find a persistent dawn-dusk asymmetry with a thicker and more dynamic magnetopause at dawn than at dusk.


Versatility of V-Y Flap in Gluteal Area.
Lesions in perineal area are common. The usual treatment is coverage by skin graft and flaps which may be local, pedicled or free types. In this paper V-Y flaps were used to cover the defects. V-Y flaps were used in the gluteal area in 15 patients. Lesions were due to different causes. Of 15 patients, 11 were males and 4 were females. Their ages ranged from 3 weeks to 52 years old. Two cases were due to myelomeningocele, necrotizing fasciitis (2 cases) and the rest were due to bed sores (11 cases). The flaps were located over the trochanter (3 cases), ischial (6 cases) and sacral (6 cases). Good healing and durable coverage were obtained in all cases except one case. V-Y flap as a working horse flap is recommended in the gluteal area.


The "ABCs of AD": A pilot test of an online educational module to increase use of the autonomic dysreflexia clinical practice guidelines among paramedic and nurse trainees.
Despite availability of clinical practice guidelines (CPGs), gaps in autonomic dysreflexia (AD) knowledge and practice persist. A free, online educational module, the "ABCs of AD", was developed to improve knowledge of the AD-CPGs among emergency healthcare personnel. We examine short-term changes in paramedic and nurse trainees' knowledge of, and social cognitions towards using, the AD-CPGs following module completion. Pre-post. Thirty-four paramedic and nurse trainees from two training programs in Canada completed measures immediately before and after viewing the online "ABCs of AD" module. AD knowledge test; Theory of Planned Behavior social cognition questionnaire; module feedback survey. Paired samples t-tests revealed significant increases in participants' AD knowledge test scores (M ± SDpre = 9.00 ± 2.46, M ± SDpost = 12.03 ± 4.07, P < 0.001; d = 0.84). Prior to viewing the module, participants reported positive social cognitions for using the AD-CPGs (all Ms ≥ 4.84 out of 7). From pre- to post-module, no significant changes were seen in participants' social cognitions for using the AD-CPGs. Participants' average module viewing time was 36.73 ± 24.17 minutes (range 8-90 minutes). There was a decline in viewing from the first to the last module sections, with only half of participants viewing all six sections. Knowledge alone is insufficient for clinical behavior change; as such, social cognitive determinants of behavior should be explicitly targeted in future iterations of the module to increase the likelihood of increased use of the AD-CPGs. To engage viewers across all module sections, the "ABCs of AD" module should include supplementary learning strategies, such as interactive quizzes and peer-to-peer interaction.


3D Comparison of Mandibular Response to Functional Appliances: Balters Bionator versus Sander Bite Jumping.
To assess the three-dimensional (3D) maxillomandibular and dental response to Balters Bionator (BB) and the Sander Bite Jumping Appliance (SBJA) in growing patients. Twenty-seven Class II division 1 patients (13 males, 14 females), consecutively treated with either the BB (9 females, 7 males; 10.1 ± 1.6 years) or SBJA (5 females, 6 males; 11 ± 1.9 years), were collected from a single orthodontic practice. All patients presented overjet ≥5 mm, full Class II or end-to-end molar relationship, mandibular retrusion. CBCT scans were available at T1 and after removal of the functional appliances (T2) with a mean interval of 18 months. The 3D location and direction of skeletal and dental changes with growth and treatment were quantitatively assessed. Statistical analysis was performed by means of Mann-Whitney U test (p < 0.05). Patients treated with the SBJA and BB orthopedic appliances presented, respectively, 4.7 mm and 4.5 mm of 3D displacement of the chin, with marked ramus growth of, respectively, 3.7 mm and 2.3 mm. While the mandible and maxilla grew downward and forward, no opening of the mandible plane was observed. Both appliances adequately controlled labial inclination of lower incisors (1.3° and 0.3°, for the SBJA and BB groups, resp.). No significant between-group differences were found for the T2-T1 changes for any of the variables, with the exception of molar displacements (significantly greater in the SBJA group than in the BB group, 1.2 mm and 0.9 mm, resp.). The maxillomandibular and dental growth responses to BB and SBJA therapies are characterized by vertical ramus growth and elongation of mandible that improve the maxillomandibular relationship with adequate control of lower incisor position.


Role of Dusp6 Phosphatase as a Tumor Suppressor in Non-Small Cell Lung Cancer.
DUSP6/MKP3 is a dual-specific phosphatase that regulates extracellular regulated kinase ERK1/2 and ERK5 activity, with an increasingly recognized role as tumor suppressor. In silico studies from Gene expression Omnibus (GEO) and Cancer Genome atlas (TCGA) databases reveal poor prognosis in those Non-small cell lung cancer (NSCLC) patients with low expression levels of DUSP6. In agreement with these data, here we show that DUSP6 plays a major role in the regulation of cell migration, motility and tumor growth. We have found upregulation in the expression of several genes involved in epithelial to mesenchymal transition (EMT) in NSCLC-DUSP6 depleted cells. Data obtained in RNA-seq studies carried out in DUSP6 depleted cells identified EGFR, TGF-β and WNT signaling pathways and several genes such as VAV3, RUNXR2, LEF1, FGFR2 whose expression is upregulated in these cells and therefore affecting cellular functions such as integrin mediated cell adhesion, focal adhesion and motility. Furthermore, EGF signaling pathway is activated via ERK5 and not ERK1/2 and TGF-β via SMAD2/3 in DUSP6 depleted cells. In summary DUSP6 is a tumor suppressor in NSCLC and re-establishment of its expression may be a potential strategy to revert poor outcome in NSCLC patients.


Breast Cancer-Related Lymphedema Risk is Related to Multidisciplinary Treatment and Not Surgery Alone: Results from a Large Cohort Study.
Breast cancer-related lymphedema (BCRL) is a significant complication for women undergoing treatment. We assessed BCRL incidence and risk factors in a large population-based cohort. We utilized the Olmsted County Rochester Epidemiology Project Breast Cancer Cohort from 1990-2010 and ascertained BCRL and risk factors. The cumulative incidence estimator was used to estimate the rate of BCRL; competing risks regression was used for multivariable analysis. A total of 1794 patients with stage 0-3 breast cancer with a median of 10 years follow-up were included. The cumulative incidence of BCRL diagnosis within 5 years was 9.1% [95% confidence interval (CI) 7.8-10.5%]. No BCRL events occurred among patients without axillary surgery. In the axillary surgery subset (n = 1512), the 5-year incidence of BCRL was 5.3% in sentinel lymph node (SLN) surgery and 15.9% in axillary dissection (ALND) patients (p < 0.001). In patients treated with surgery only, BCRL rates were not different between ALND versus SLN (3.5 and 4.1% at 5 years, p = 0.36). Addition of breast or chest wall radiation more than doubled the BCRL rate in ALND patients (3.5 vs. 9.5% at 5 years, p = 0.01). The groups with highest risk (>25% at 5 years) all involved ALND with nodal RT and/or anthracycline/cytoxan + taxane chemotherapy. In multivariable analysis of patients with any axillary surgery factors significantly associated with BCRL were ALND, chemotherapy, radiation, and obesity. BCRL is a sequelae of multimodal breast cancer treatment and risk is multifactorial. BCRL rates are higher in patients receiving chemotherapy, radiation, ALND, more advanced disease stage, and higher body mass index.


Obstetric outcomes of Human Immunodeficiency Virus positive mothers in tertiary care hospital.
To evaluate the pregnancy outcome of human immunodeficiency syndrome-positive mothers. The prospective observational study was conducted at the Department of Gynaecology and Obstetrics, Aziz Bhatti Shaheed Teaching Hospital, Gujrat, Pakistan, from June 2011 to March 2018, and comprised pregnant women screened positive for human immunodeficiency syndrome. Risk factors and perinatal outcomes were noted on a predesigned proforma. Data was analysed using SPSS 20. Of the 74 subjects with a mean age of 29±5.27 years, 63(85.1%) were multiparous and 11(14.9%) were nulliparous. Major risk factors included unsterilized nasal or ear piercing in 70(94.6%) subjects, history of blood transfusion 57(77%) and history of dental procedure in unsterilized settings 23(31.1%). Spouses of 43(58.1%) subjects were positive for human immunodeficiency syndrome, 22(29.7%) were negative and 9(12.2%) had unknown status in this regard. In terms of outcome, 12(16.3%) subjects had spontaneous abortion, 11(12.2%) had intrauterine death of foetus, 6(8.1%) had preterm delivery and 45(60.8%) reached full term and were delivered. There were 2(2.6%) patients with stage 4 disease who died during pregnancy. Human immunodeficiency syndrome infection in pregnant women was found to be associated with poor pregnancy outcome.


[Micronucleus formation in the bone marrow cells of chronically irradiated mice with subsequent acute gamma irradiation].
With the use of the micronuclear test method it has been shown that mice preirradiated with gamma rays at a low dose rate exhibit a decreased frequency of chromosome aberrations induced in bone marrow cells by subsequent acute exposure to gamma radiation as compared to mice not subjected to preliminary irradiation. Such animals have a higher radioresistance with respect to the survival rate. The results obtained suggest the possibility of induction by ionizing radiation, at a low dose rate, of adaptive repair response at the organism level.


Acupuncture therapy in acute abdomen.
Acupuncture as a therapeutic measure for abdominal pain was early recorded in Huangdi Neijing ("Yellow Emperor's Canon of Medicine"). Fruitful experiences have been accumulated in the practice of the long historical years. Nowadays acupuncture therapy has become one of the main therapeutic methods in surgical acute abdomen and is widely used clinically.


The neuropsychology of autobiographical memory.
This special issue of Cortex focuses on the relative contribution of different neural networks to memory and the interaction of 'core' memory processes with other cognitive processes. In this article, we examine both. Specifically, we identify cognitive processes other than encoding and retrieval that are thought to be involved in memory; we then examine the consequences of damage to brain regions that support these processes. This approach forces a consideration of the roles of brain regions outside of the frontal, medial-temporal, and diencephalic regions that form a central part of neurobiological theories of memory. Certain kinds of damage to visual cortex or lateral temporal cortex produced impairments of visual imagery or semantic memory; these patterns of impairment are associated with a unique pattern of amnesia that was distinctly different from the pattern associated with medial-temporal trauma. On the other hand, damage to language regions, auditory cortex, or parietal cortex produced impairments of language, auditory imagery, or spatial imagery; however, these impairments were not associated with amnesia. Therefore, a full model of autobiographical memory must consider cognitive processes that are not generally considered 'core processes,' as well as the brain regions upon which these processes depend.


The prevalence and significance of oestrogen receptor (ER) positivity in breast cancer at the University Hospital of the West Indies, Jamaica.
To identify the prevalence of oestrogen receptor (ER) positivity, and determine the relationship of ER status with patient and tumour characteristics, in patients with breast cancer A retrospective review was conducted regarding the prevalence and clinical significance of ER in patients with breast cancer at the University Hospital of the West Indies (UHWI). Oestrogen receptor status results of 243 patients treated at UHWI were collected for the period January 1, 2002 to December 31, 2009. One hundred and ninety-nine were available for review. Oestrogen receptor status was positive in 125 (63%) and negative in 74 (37%) patients. Mean age at diagnosis was 52.6 +/- 13.0 years for the ER positive group and 58.5 +/- 14.23 years for the ER negative group. Postmenopausal women accounted for 55.2% and 64.9% of the ER positive and negative groups, respectively. Mean BMI was 28.0 kg/m2 and 29.6 kg/m2 for the ER positive and negative groups, respectively. Menarche occurred mainly between ages 12 and 13 years for both groups. Mean age at 1st parity was 23.4 years for the ER positive and 21.4 years for the ER negative group with median parity of two for both groups. The most prevalent risk factors were oral contraceptive pill (OCP) use (24.3% for the ER positive group, 17.1% for the ER negative group), family history of breast cancer (12.0%; 13.4%) and previous smoking (8.4%; 6.9%). Tumour node metastasis (TNM) stage was Stage II in most cases (46%; 49%). Infiltrating ductal histology was most common (81.5%; 87.7%). Her 2/ neu status was negative for most patients (91.3%; 91.5%). Most patients were disease free (77.6%; 70.0%) after an average follow-up period of 3.5 years. More persons in the ER negative group had locoregional recurrence (8%) and metastases (22%). Oestrogen receptor positive cohort was more prevalent. The ER negative group was older (p = 0.003).


The prevalence of distraction among passenger vehicle drivers: a roadside observational approach.
Distracted driving contributes to a large proportion of motor vehicle crashes, yet little is known about the prevalence of distracted driving and the specific types of distracting behaviors. The objective of this study was to estimate the prevalence of driver distraction using a roadside observational study design. A cross-sectional survey involving direct roadside observation was conducted at 11 selected intersections. Trained investigators observed a sample of passenger vehicles and recorded distraction-related behaviors, driver characteristics, and contextual factors such as vehicle speed and traffic flow. Of the 3,265 drivers observed, the prevalence of distracted driving was 32.7%. Among those involved in a distracting activity, the most frequently observed distractions included interacting with another passenger (53.2%, where passengers were present), talking on the phone (31.4%), external-vehicle distractions (20.4%), and texting/dialing a phone (16.6%). The prevalence of talking on the phone was higher among females than males (38.6% vs. 24.3%), whereas external vehicle distractions were higher among males than females (25.8% vs. 24.3%). Drivers <30 years were observed being engaged in any distracting activity, interacting with other passengers, and texting/dialing more frequently than drivers aged 30-50 and >50 years. Drivers were engaged in distracting behaviors more frequently when the car was stopped. When using similar methodology, roadside observational studies generate comparable prevalence estimates of driver distraction as naturalistic driving studies. Driver distraction is a common problem among passenger vehicle drivers. Despite the increased awareness on the dangers of texting and cell phone use while driving, these specific activities were 2 of the most frequently observed distractions. There is a continued need for road safety education about the dangers of distracted driving, especially for younger drivers.


Interference in initial adhesion of uropathogenic bacteria and yeasts to silicone rubber by a Lactobacillus acidophilus biosurfactant.
The ability of the Lactobacillus acidophilus RC14 biosurfactant 'surlactin' to inhibit the initial adhesion of various uropathogenic bacteria and two yeast strains to silicone rubber was investigated in a parallel-plate flow chamber in filter-sterilised pooled human urine. A parallel-plate flow chamber with a silicone rubber bottom plate was filled with a 1.0 mg/ml biosurfactant solution for adsorption overnight (18 h). Subsequently, the adhesion of the bacterial or yeast cells from a urine suspension under low flow (shear rate 15 s(-1)) was followed in situ by automated image analysis. Control tests were with untreated silicone rubber. Initial deposition rates and numbers of adhering cells after 4 h of flow were determined. Surlactin layers caused a marked inhibition of the initial deposition rates and adhesion numbers after 4 h for the majority of the bacteria (11 of 15 strains tested) and this inhibition was particularly effective against Enterococcus faecalis, Escherichia coli and Staphylococcus epidermidis. Although the initial deposition rates of the two Candida albicans strains were reduced by c. 50% in comparison with the controls, the numbers of yeast cells adhering after 4 h were similar.


Thanks for inviting me to the party: Virtual poster sessions as a way to connect in a time of disconnection.
COVID-19 presented the world with trauma and isolation, but many people, including educators, have offered bright spots of creativity and engagement. As we confronted these issues in our own ecology classroom, we sought solutions to carry-forward the learning objectives we set for our students in January 2020, yet encourage interaction with the sensitivity that a pandemic requires. In the rapid transition to online course delivery, we opted to retain the original end-of-semester poster project in our introductory ecology course. However, we experimented with a new virtual platform where students could disseminate their work and communicate with the community. In this paper, we discuss the Mozilla Hubs virtual reality platform that we used for our event. We also collected qualitative data to share the benefits and challenges of this experience felt by the students, the instructors, and external observers.


Arginase Signalling as a Key Player in Chronic Wound Pathophysiology and Healing.
Arginase (ARG) represents an important evolutionarily conserved enzyme that is expressed by multiple cell types in the skin. Arg acts as the mediator of the last step of the urea cycle, thus providing protection against excessive ammonia under homeostatic conditions through the production of L-ornithine and urea. L-ornithine represents the intersection point between the ARG-dependent pathways and the urea cycle, therefore contributing to cell detoxification, proliferation and collagen production. The ARG pathways help balance pro- and anti-inflammatory responses in the context of wound healing. However, local and systemic dysfunctionalities of the ARG pathways have been shown to contribute to the hindrance of the healing process and the occurrence of chronic wounds. This review discusses the functions of ARG in macrophages and fibroblasts while detailing the deleterious implications of a malfunctioning ARG enzyme in chronic skin conditions such as leg ulcers. The review also highlights how ARG links with the microbiota and how this impacts on infected chronic wounds. Lastly, the review depicts chronic wound treatments targeting the ARG pathway, alongside future diagnosis and treatment perspectives.


Role of autologous rabbit adipose-derived stem cells in the early phases of the repairing process of critical bone defects.
Adipose-derived stem cells (ASCs) may represent a novel and efficient tool to promote bone regeneration. In this study, rabbit ASCs were expanded in culture and used for the regeneration of full-thickness bone defects in the proximal epiphysis of tibia of 12 New Zealand rabbits. Defects were implanted with graft material as follows: untreated (control), empty hydroxyapatite (HA) disk, ASCs alone, and HA disk seeded with ASCs. Each isolated ASCs population was tested in vitro: they all showed a high proliferation rate, a marked clonogenic ability, and osteogenic differentiation potential. Eight weeks after implantation, macroscopic analyses of all the samples showed satisfactory filling of the lesions without any significant differences in term of stiffness between groups treated with or without cells (p > 0.05). In both the scaffold-treated groups, a good osteointegration was radiographically observed. Even if HA was not completely reabsorbed, ASCs-loaded HA displayed a higher scaffold resorption than the unloaded ones. Histological analyses showed that the osteogenic abilities of the scaffold-treated defects was greater than those of scaffold-free samples, and in particular new formed bone was more mature and more similar to native bone in presence of ASCs. These results demonstrated that autologous ASCs-HA constructs is a potential treatment for the regeneration of bone defects.


Estimation of a monotone percentile residual life function under random censorship.
In this paper, we introduce a new estimator of a percentile residual life function with censored data under a monotonicity constraint. Specifically, it is assumed that the percentile residual life is a decreasing function. This assumption is useful when estimating the percentile residual life of units, which degenerate with age. We establish a law of the iterated logarithm for the proposed estimator, and its n-equivalence to the unrestricted estimator. The asymptotic normal distribution of the estimator and its strong approximation to a Gaussian process are also established. We investigate the finite sample performance of the monotone estimator in an extensive simulation study. Finally, data from a clinical trial in primary biliary cirrhosis of the liver are analyzed with the proposed methods. One of the conclusions of our work is that the restricted estimator may be much more efficient than the unrestricted one.


Comparison Between a Job-Exposure Matrix (JEM) Score and Self-Reported Exposures for Carrying Heavy Loads Over the Working Lifetime in the CONSTANCES Cohort.
Job-exposure matrices (JEMs) were developed to allow assessment of past work exposure for large population-based studies where better exposures data are unavailable. Few studies have directly compared biomechanical JEMs to self-administered questionnaires. We compared assessments of cumulative exposure to carrying heavy loads based on 'JEM Constances' to individually self-reported (SR) exposures. In the French CONSTANCES cohort at inception, past SR exposure to carrying heavy loads (ever/never and durations) and a detailed job history were available for 26 929 subjects. JEM Constances, an existing biomechanical JEM based on SR current exposures from 26 821 asymptomatic workers, was combined with job history to build a cumulative biomechanical exposure score. Using individual SR exposure as the reference, Area Under the Curve (AUC) of Receiver Operating Characteristic (ROC) curves, sensitivity, and specificity were calculated. For both methods, associations with low back pain and knee pain were computed using multinomial logistic models. Additional analyses compared older (>10 years) to more recent (≤10 years) exposures. AUCs ranged from 0.795 (0.789-0.800) when all periods were considered, to 0.826 (0.820-0.833) for more recent biomechanical exposure (≤10 years). Associations between carrying heavy loads and low back pain or knee pain were less strong using JEM assessment than individually SR exposure: for low back pain ORSR = 3.02 (2.79-3.26) versus ORJEM = 1.70 (1.59-1.82) and for knee pain ORSR = 2.27 (2.10-2.46) versus ORJEM = 1.64 (1.53-1.77). JEM Constances' assessment of cumulative exposure of carrying heavy loads seems to be a useful method compared to a self-administrated questionnaire for large population-based studies where other methods are not available.


Now we are 30: 10 more years of MASCC.
This paper chronicles the third decade of MASCC from 2010. There was a generational change in this decade, building on the solid foundation of the founders. It included the first female President, and a new Executive Director with a background in strategy and business development and operations as applied to healthcare. The headquarters moved from Copenhagen to Toronto. The first meeting to be held outside of Europe or North America was held in Adelaide, Australia, and the membership in the Asia Pacific region expanded. A program of international affiliates saw national supportive care organisations formally link with MASCC. In cancer supportive care, there was a raft of new toxicities to manage as immunotherapies were added to conventional cytotoxic treatment. There was also a greater emphasis on the psychosocial needs of patients and families. New MASCC groups were formed to respond to this evolution in cancer management. The MASCC journal, Supportive Care in Cancer, continued to grow in impact, and MASCC published two editions of a textbook of supportive care and survivorship. The decade ended with the challenge of the COVID-19 pandemic, but that served to highlight the importance of good supportive care to patients with cancer.


The effect of hypocapnia on the autoregulation of cerebral blood flow during administration of isoflurane.
Isoflurane impairs autoregulation of cerebral blood flow in a dose-related manner. Previous investigations in several other conditions have demonstrated that impaired autoregulation can be restored by hyperventilation. We hypothesized that hypocapnia may restore cerebral autoregulation impaired by isoflurane anesthesia. We administered isoflurane in 100% oxygen to 12 healthy patients aged 21-59 yr scheduled for elective nonneurological surgery. Isoflurane end-tidal concentration was individualized at 0.1% to 0.2% less than that required to induce short periods of isoelectric electroencephalogram. This resulted in an end-tidal isoflurane concentration of 1.6% +/- 0.2% (mean +/- sd) corresponding to an age-adjusted minimum alveolar anesthetic concentration multiple of 1.4. Mean arterial blood pressure was reduced to <80 mm Hg, by infusion of remifentanil if required. Cerebral autoregulation was assessed by infusing phenylephrine to increase mean arterial blood pressure to 100 mm Hg while monitoring middle cerebral artery blood flow velocity with transcranial Doppler ultrasonography. The change in flow velocity was used to calculate the autoregulation index (ARI). The ARI ranges between 0 and 1 and an ARI < or =0.4 indicates significantly impaired autoregulation. Autoregulation was tested twice in randomized order: once during normocapnia (Paco(2) 38-43 mm Hg) and once during hypocapnia (Paco(2) 27-34 mm Hg). The median (interquartile range) ARI was 0.29 (0.23-0.64) during normocapnia and 0.77 (0.70-0.78) during hypocapnia (P < 0.005). Of the 12 subjects, autoregulation was significantly impaired in 8 subjects during normocapnia and none during hypocapnia (P = 0.001). Hypocapnia restored cerebral autoregulation in normal subjects during isoflurane-induced impairment of autoregulation.


Transition of allele-specific DNA hydroxymethylation at regulatory loci is associated with phenotypic variation in monozygotic twins discordant for psychiatric disorders.
Major psychiatric disorders such as schizophrenia (SCZ) and bipolar disorder (BPD) are complex genetic mental illnesses. Their non-Mendelian features, such as those observed in monozygotic twins discordant for SCZ or BPD, are likely complicated by environmental modifiers of genetic effects. 5-Hydroxymethylcytosine (5hmC) is an important epigenetic mark in gene regulation, and whether it is linked to genetic variants that contribute to non-Mendelian features remains largely unexplored. We combined the 5hmC-selective chemical labeling method (5hmC-seq) and whole-genome sequencing (WGS) analysis of peripheral blood DNA obtained from monozygotic (MZ) twins discordant for SCZ or BPD to identify allelic imbalances in hydroxymethylome maps, and examined association of allele-specific hydroxymethylation (AShM) transition with disease susceptibility based on Bayes factors (BF) derived from the Bayesian generalized additive linear mixed model. We then performed multi-omics integrative analysis to determine the molecular pathogenic basis of those AShM sites. We finally employed luciferase reporter, CRISPR/Cas9 technology, electrophoretic mobility shift assay (EMSA), chromatin immunoprecipitation (ChIP), PCR, FM4-64 imaging analysis, and RNA sequencing to validate the function of interested AShM sites in the human neuroblastoma SK-N-SH cells and human embryonic kidney 293T (HEK293T) cells. We identified thousands of genetic variants associated with AShM imbalances that exhibited phenotypic variation-associated AShM changes at regulatory loci. These AShM marks showed plausible associations with SCZ or BPD based on their effects on interactions among transcription factors (TFs), DNA methylation levels, or other epigenomic marks and thus contributed to dysregulated gene expression, which ultimately increased disease susceptibility. We then validated that competitive binding of POU3F2 on the alternative allele at the AShM site rs4558409 (G/T) in PLLP-enhanced PLLP expression, while the hydroxymethylated alternative allele, which alleviated the POU3F2 binding activity at the rs4558409 site, might be associated with the downregulated PLLP expression observed in BPD or SCZ. Moreover, disruption of rs4558409 promoted neural development and vesicle trafficking. Our study provides a powerful strategy for prioritizing regulatory risk variants and contributes to our understanding of the interplay between genetic and epigenetic factors in mediating SCZ or BPD susceptibility.


Hypoxia-regulated lncRNA CRPAT4 promotes cell migration via regulating AVL9 in clear cell renal cell carcinomas.
Long noncoding RNAs (lncRNAs) are proven to be key regulators in cancer biology. Our screening effort for clear cell renal cell carcinoma (ccRCC) prognosis-associated lncRNAs identified a novel lncRNA, ccRCC prognosis-associated transcript 4 (CRPAT4), as one of the top candidates that was previously uncharacterized. The aim of this study was to verify the clinical significance of CRPAT4 in ccRCC patients and to explore its biological role as well as the underlying mechanisms, in ccRCC cell lines. Quantitative real-time polymerase chain reaction (PCR) was performed to demonstrate that CRPAT4 was differentially expressed between ccRCC and the normal controls and that high CRPAT4 expression significantly associated with advanced Fuhrman nuclear grades. Kaplan-Meier survival analysis with The Cancer Genome Atlas KIRC RNA sequencing data indicated that high CRPAT4 expression was significantly associated with poor overall survival and progression-free survival. Functional studies indicated that CRPAT4 was an HIF-1α regulated gene, and CRPAT4 knockdown significantly inhibited cell migration and proliferation in the absence of HIF-1α. In addition, a mechanistic study revealed that CRPAT4 could regulate the expression of the migration-associated protein AVL9. Collectively, our study first identified CRPAT4 as a hypoxia-regulated lncRNA, acting as an oncogene in ccRCC progression via regulating AVL9 protein, thus expanding our knowledge on the hypoxia pathway in ccRCC biology from a noncoding perspective. Moreover, CRPAT4 has the potential to be a prognostic marker in ccRCC patients.


Lung surfactant microbubbles increase lipophilic drug payload for ultrasound-targeted delivery.
The cavitation response of circulating microbubbles to targeted ultrasound can be used for noninvasive, site-specific delivery of shell-loaded materials. One challenge for microbubble-mediated delivery of lipophilic compounds is the limitation of drug loading into the microbubble shell, which is commonly a single phospholipid monolayer. In this study, we investigated the use of natural lung surfactant extract (Survanta(®), Abbott Nutrition) as a microbubble shell material in order to improve drug payload and delivery. Pulmonary surfactant extracts such as Survanta contain hydrophobic surfactant proteins (SP-B and SP-C) that facilitate lipid folding and retention on lipid monolayers. Here, we show that Survanta-based microbubbles exhibit wrinkles in bright-field microscopy and increased lipid retention on the microbubble surface in the form of surface-associated aggregates observed with fluorescence microscopy. The payload of a model lipophilic drug (DiO), measured by flow cytometry, increased by over 2-fold compared to lipid-coated microbubbles lacking SP-B and SP-C. Lung surfactant microbubbles were highly echogenic to contrast enhanced ultrasound imaging at low acoustic intensities. At higher ultrasound intensity, excess lipid was observed to be acoustically cleaved for localized release. To demonstrate targeting, a biotinylated lipopolymer was incorporated into the shell, and the microbubbles were subjected to a sequence of radiation force and fragmentation pulses as they passed through an avidinated hollow fiber. Lung surfactant microbubbles showed a 3-fold increase in targeted deposition of the model fluorescent drug compared to lipid-only microbubbles. Our results demonstrate that lung surfactant microbubbles maintain the acoustic responsiveness of lipid-coated microbubbles with the added benefit of increased lipophilic drug payload.


Geomapping of pediatric dermatologists: A tool to promote diversity and equity in dermatology.
There is a lack of racial and ethnic diversity across the field of dermatology, including the subspecialty of pediatric dermatology. Residency programs are improving recruitment and mentorship of medical students who identify with racial or ethnic minority communities (underrepresented in medicine [URiM]) to dermatology overall, a goal similarly held by our subspecialty. The objectives of this study were to create an online mapping tool to visually centralize the list of 142 dermatology residency programs, 105 with practicing pediatric dermatologists on faculty and 51 that offer financial scholarships for URiM visiting medical students completing away rotations. With this tool, we hope that prospective students may not only identify potential pediatric dermatology mentors for virtual and in-person activities, but that they may also build connections with and increase their chance of matching at prospective residency programs with demonstrable commitment to diversity, equity, and inclusion.


Recent advances and opportunities in research on lupus: environmental influences and mechanisms of disease.
In this review we summarize research on mechanisms through which environmental agents may affect the pathogenesis of lupus, discuss three exposures that have been the focus of research in this area, and propose recommendations for new research initiatives. We examined studies pertaining to key mechanistic events and specific exposures. Apoptosis leading to increased production or decreased clearance of immunogenic intracellular self-antigens and defective apoptosis of autoreactive immune cells both have been implicated in the loss of self-tolerance. The adjuvant or bystander effect is also needed to produce a sustained autoimmune response. Activation of toll-like receptors is one mechanism through which these effects may occur. Abnormal DNA methylation may also contribute to the pathogenesis of lupus. Each of the specific exposures we examined--Epstein-Barr virus, silica, and trichloroethylene--has been shown, in humans or in mice, to act upon one or more of these pathogenic steps. Specific recommendations for the continued advancement of our understanding of environmental influences on lupus and other autoimmune diseases include the development and use of mouse models with varying degrees of penetrance and manifestations of disease, identification of molecular or physiologic targets of specific exposures, development and use of improved exposure assessment methodologies, and multisite collaborations designed to examine understudied environmental exposures in humans. The advances made in the past decade concerning our understanding of mechanisms involved in the development of lupus and the influence of environmental agents on this process provide a strong foundation for further developments in this field.


[Conservative treatment of dislocated proximal humeral fractures].
Between 11/1989 and 6/1998 52 patients (10 m., 42 f., age median 72 years, 31-88) with proximal humeral fractures have been treated by conservative means (angulation of humeral head > 45 degrees and/or shaft displacement > 1 cm and displacement of greater tuberosity > 0.5 cm). In 37 patients (71%, 31 f., 6 m., age median 75 years, 36-88) a clinical and radiological follow-up could be obtained after median 20 months (3-93). According to the Neer-classification, subcapital 2-part fractures were found in 19 cases and 3-part fractures in 12 cases. 4-part fractures were diagnosed in 6 cases. By using the Constant-Score, the final result was scored "excellent" in 10 patients and "good" in 13 patients. In 7 patients each the results achieved were "moderate" or "poor". The underlying cause for the poor results was primarily due to persisting painful impairment in range of motion and loss of strength. Radiologically, persisting axial deviation was present in 23 cases, arthrosis in 14 patients and humeral head necrosis in 8 patients. Most commonly, poor functional and radiological results occurred in 4-part fractures. However, conservative therapy of displaced 2-part and 3-part fractures is a considerable therapeutical option since the final results are predominantly good. In contrast, due to the poor results after conservative therapy 4-part fractures should be treated surgically.


Developmental dyslexia in Chinese and English populations: dissociating the effect of dyslexia from language differences.
Previous neuroimaging studies have suggested that developmental dyslexia has a different neural basis in Chinese and English populations because of known differences in the processing demands of the Chinese and English writing systems. Here, using functional magnetic resonance imaging, we provide the first direct statistically based investigation into how the effect of dyslexia on brain activation is influenced by the Chinese and English writing systems. Brain activation for semantic decisions on written words was compared in English dyslexics, Chinese dyslexics, English normal readers and Chinese normal readers, while controlling for all other experimental parameters. By investigating the effects of dyslexia and language in one study, we show common activation in Chinese and English dyslexics despite different activation in Chinese versus English normal readers. The effect of dyslexia in both languages was observed as less than normal activation in the left angular gyrus and in left middle frontal, posterior temporal and occipitotemporal regions. Differences in Chinese and English normal reading were observed as increased activation for Chinese relative to English in the left inferior frontal sulcus; and increased activation for English relative to Chinese in the left posterior superior temporal sulcus. These cultural differences were not observed in dyslexics who activated both left inferior frontal sulcus and left posterior superior temporal sulcus, consistent with the use of culturally independent strategies when reading is less efficient. By dissociating the effect of dyslexia from differences in Chinese and English normal reading, our results reconcile brain activation results with a substantial body of behavioural studies showing commonalities in the cognitive manifestation of dyslexia in Chinese and English populations. They also demonstrate the influence of cognitive ability and learning environment on a common neural system for reading.


BH3-only protein BIM mediates heat shock-induced apoptosis.
Acute heat shock can induce apoptosis through a canonical pathway involving the upstream activation of caspase-2, followed by BID cleavage and stimulation of the intrinsic pathway. Herein, we report that the BH3-only protein BIM, rather than BID, is essential to heat shock-induced cell death. We observed that BIM-deficient cells were highly resistant to heat shock, exhibiting short and long-term survival equivalent to Bax(-/-)Bak(-/-) cells and better than either Bid(-/-) or dominant-negative caspase-9-expressing cells. Only Bim(-/-) and Bax(-/-)Bak(-/-) cells exhibited resistance to mitochondrial outer membrane permeabilization and loss of mitochondrial inner membrane potential. Moreover, while dimerized caspase-2 failed to induce apoptosis in Bid(-/-) cells, it readily did so in Bim(-/-) cells, implying that caspase-2 kills exclusively through BID, not BIM. Finally, BIM reportedly associates with MCL-1 following heat shock, and Mcl-1(-/-) cells were indeed sensitized to heat shock-induced apoptosis. However, pharmacological inhibition of BCL-2 and BCL-X(L) with ABT-737 also sensitized cells to heat shock, most likely through liberation of BIM. Thus, BIM mediates heat shock-induced apoptosis through a BAX/BAK-dependent pathway that is antagonized by antiapoptotic BCL-2 family members.


Effect of total-body prehabilitation on postoperative outcomes: a systematic review and meta-analysis.
To systematically review the evidence of pre-operative exercise, known as 'prehabilitation', on peri- and postoperative outcomes in adult surgical populations. Systematic review and meta-analysis. CENTRAL, Medline, EMBASE, CINAHL, PsycINFO and PEDro were searched from 1950 to 2011. Two reviewers independently examined relevant, English-language articles that examined the effects of pre-operative total-body exercise with peri- and postoperative outcome analysis. Given the nascence of this field, controlled and uncontrolled trials were included. Risk of bias was assessed using the Cochrane Risk of Bias Assessment tool. Only data on length of stay were considered eligible for meta-analysis due to the heterogeneity of measures and methodologies for assessing other outcomes. In total, 4597 citations were identified by the search strategy, of which 21 studies were included. Trials were generally small (median=54 participants) and of moderate to poor methodological quality. Compared with standard care, the majority of studies found that total-body prehabilitation improved postoperative pain, length of stay and physical function, but it was not consistently effective in improving health-related quality of life or aerobic fitness in the studies that examined these outcomes. The meta-analysis indicated that prehabilitation reduced postoperative length of stay with a small to moderate effect size (Hedges' g=-0.39, P=0.033). Intervention-related adverse events were reported in two of 669 exercising participants. The literature provides early evidence that prehabilitation may reduce length of stay and possibly provide postoperative physical benefits. Cautious interpretation of these findings is warranted given modest methodological quality and significant risk of bias.


Declining fecundity and ovarian ageing in natural fertility populations.
Worldwide, human fertility declines with increasing maternal age, after contraceptive-use patterns and behavioral factors are taken into consideration. Here, we summarize some of our theoretical and empirical work examining the biological factors contributing to this age pattern of fertility. We undertook an 11 month prospective endocrinological study in a natural fertility (non-contracepting) population (rural Bangladesh) to estimate the contributions of fetal loss and fecundability (the probability of conception) to declining fecundity with age. Prospective interviews and urine samples for pregnancy tests were collected twice weekly from up to 700 women. These data were used to test mathematical models of the underlying biological processes contributing to changing fecundability and fetal loss risk with maternal age. The results indicate that much of the decline in fecundity can be attributed to an increasing risk of fetal loss with maternal age. Much of this fetal loss is due to chromosomal abnormalities--a result of ageing oocytes. Fecundability, on the other hand, does not begin to decline until the early 40s. We hypothesize that this is also a result of ageing at the ovarian level, namely follicular atresia, in the years just prior to menopause. The irregularity of menstrual cycles--longer cycles and increasingly variable hormonal patterns--at these ages may be a direct result of the small and rapidly dwindling remaining pool of follicles. We present a simple mathematical model of this process, and some preliminary laboratory results that support the model.


Ketamine alters oscillatory coupling in the hippocampus.
Recent studies show that higher order oscillatory interactions such as cross-frequency coupling are important for brain functions that are impaired in schizophrenia, including perception, attention and memory. Here we investigated the dynamics of oscillatory coupling in the hippocampus of awake rats upon NMDA receptor blockade by ketamine, a pharmacological model of schizophrenia. Ketamine (25, 50 and 75 mg/kg i.p.) increased gamma and high-frequency oscillations (HFO) in all depths of the CA1-dentate axis, while theta power changes depended on anatomical location and were independent of a transient increase of delta oscillations. Phase coherence of gamma and HFO increased across hippocampal layers. Phase-amplitude coupling between theta and fast oscillations was markedly altered in a dose-dependent manner: ketamine increased hippocampal theta-HFO coupling at all doses, while theta-gamma coupling increased at the lowest dose and was disrupted at the highest dose. Our results demonstrate that ketamine alters network interactions that underlie cognitively relevant theta-gamma coupling.