Leptin secreted by adipocytes promotes EMT transition and endometrial cancer progression via the JAK2/STAT3 signalling pathway.
Endometrial cancer is a malignant tumour with a high incidence and mortality rate, and obesity is one of the most significant risk factors for the disease. However, it remains unclear whether leptin affects cell activity, proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT). Samples of endometrial cancer tissue were obtained from clinical patients and nude mice Enzyme-linked immunosorbent assays (ELISAs) were performed to assess leptin levels. Western blotting, immunohistochemical (IHC) and immunofluorescence (IF) analyses were conducted to detect EMT, JAK2/STAT3 signalling pathway proteins, and cell proliferation biomarkers. Cell Counting Kit-8 (CCK-8) assays, 5-ethynyl-2'-deoxyuridine (EdU) staining, and Transwell assays were used to evaluate cell activity, proliferation, migration, and invasion, respectively. ELISA, western blot and immunohistochemistry (IHC) analyses showed that leptin was highly expressed, and the JAK2/STAT3 signalling pathway was activated in endometrial cancer patients. Cell-based experiments showed that adipocytes secreted leptin, which increased the levels of leptin, and also promoted cell migration and invasion, EMT transition, and cell activity and proliferation. Leptin accelerated cell progression and promoted EMT via the JAK2/STAT3 signalling pathway in a dose-dependent manner. The tumour-promoting effect of leptin on endometrial cancer cells was further verified by in vivo experiments, in which leptin promoted tumour growth and activated the JAK2/STAT3 signalling pathway. Leptin secreted by adipocytes promotes EMT transition and endometrial cancer progression via the JAK2/STAT3 signalling pathway in a dose-dependent manner.Highlights Endometrial cancer patients have high levels of leptinLeptin promotes EMT transition via the JAK2/STAT3 signalling pathwayLeptin promotes endometrial cancer progression via the JAK2/STAT3 signalling pathwayLeptin promotes endometrial cancer in a dose-dependent manner.


Adult onset startle epilepsy.
A 45-year-old gentleman presented for classification of spells precipitated by startle. During these spells, he would briefly lose awareness, develop tonic stiffening of his extremities and fall. He had previously been diagnosed with paroxysmal kinesogenic dyskinesia and treated unsuccessfully with clonazepam, levetiracetam and carbamazepine. The patient was admitted for prolonged video EEG monitoring, during which numerous spells induced by startle were captured. His EEG revealed brief, fast beta activity in the midline central head region during each spell consistent with startle epilepsy. The present case demonstrates that startle epilepsy can rarely be diagnosed in adults; typically seizure onset in this condition is during infancy to childhood. Our patient's ictal EEG further implicates mesial structures in the generation of startle-provoked seizures. Although our patient continued to have startle-provoked seizures at last follow-up, his improvement on lamotrigine supports observations that this anticonvulsant can reduce seizure frequency and resulting morbidity.


Calretinin interneuron density in the caudate nucleus is lower in autism spectrum disorder.
Autism spectrum disorder is a debilitating condition with possible neurodevelopmental origins but unknown neuroanatomical correlates. Whereas investigators have paid much attention to the cerebral cortex, few studies have detailed the basal ganglia in autism. The caudate nucleus may be involved in the repetitive movements and limbic changes of autism. We used immunohistochemistry for calretinin and neuropeptide Y in 24 age- and gender-matched patients with autism spectrum disorder and control subjects ranging in age from 13 to 69 years. Patients with autism had a 35% lower density of calretinin+ interneurons in the caudate that was driven by loss of small calretinin+ neurons. This was not caused by altered size of the caudate, as its cross-sectional surface areas were similar between diagnostic groups. Controls exhibited an age-dependent increase in the density of medium and large calretinin+ neurons, whereas subjects with autism did not. Diagnostic groups did not differ regarding ionized calcium-binding adapter molecule 1+ immunoreactivity for microglia, suggesting chronic inflammation did not cause the decreased calretinin+ density. There was no statistically significant difference in the density of neuropeptide Y+ neurons between subjects with autism and controls. The decreased calretinin+ density may disrupt the excitation/inhibition balance in the caudate leading to dysfunctional corticostriatal circuits. The description of such changes in autism spectrum disorder may clarify pathomechanisms and thereby help identify targets for drug intervention and novel therapeutic strategies.


Prevalence and immune response to Entamoeba histolytica infection in preschool children in Bangladesh.
Entamoeba histolytica infection was present in 5% and E. dispar in 13% of asymptomatic 2-5-year-old children from an urban slum of Dhaka, Bangladesh. Entamoeba dispar-infected children were no more likely than uninfected children to have serum antibodies to lectin. In contrast, all children infected with E. histolytica had serum antibodies to lectin. This anti-lectin response included antibodies against the carbohydrate recognition domain, which have been demonstrated in animal models to confer passive protection from amebiasis. Antibodies to lectin persisted in the sera of 17 children with E. histolytica infection over one year of follow-up, during which time E. histolytica infection cleared without treatment in 15, and with anti-amebic medication in two. We conclude that half of the children in this population have serologic evidence of amebiasis by five years of age, and that an anti-lectin serum antibody response is associated with limitation of E. histolytica infection to the colon.


Generation and subwavelength focusing of longitudinal magnetic fields in a metallized fiber tip.
We demonstrate experimentally and numerically that in fiber tips as they are used in NSOMs azimuthally polarized electrical fields (|E(azi)|2 / |E(tot)|2 ≈55% ± 5% for λ0 = 1550 nm), respectively subwavelength confined (FWHM ≈450 nm ≈λ0/3.5) magnetic fields, are generated for a certain tip aperture diameter (d = 1.4 μm). We attribute the generation of this field distribution in metal-coated fiber tips to symmetry breaking in the bend and subsequent plasmonic mode filtering in the truncated conical taper.


Identification of collagen binding domain residues that govern catalytic activities of matrix metalloproteinase-2 (MMP-2).
An innovative approach to enhance the selectivity of matrix metalloproteinase (MMP) inhibitors comprises targeting these inhibitors to catalytically required substrate binding sites (exosites) that are located outside the catalytic cleft. In MMP-2, positioning of collagen substrate molecules occurs via a unique fibronectin-like domain (CBD) that contains three distinct modular collagen binding sites. To characterize the contributions of these exosites to gelatinolysis by MMP-2, seven MMP-2 variants were generated with single, or concurrent double and triple alanine substitutions in the three fibronectin type II modules of the CBD. Circular dichroism spectroscopy verified that recombinant MMP-2 wild-type (WT) and variants had the same fold. Moreover, the MMP-2 WT and variants had the same activity on a short FRET peptide substrate that is hydrolyzed independently of CBD binding. Among single-point variants, substitution in the module 3 binding site had greatest impact on the affinity of MMP-2 for gelatin. Simultaneous substitutions in two or three CBD modules further reduced gelatin binding. The rates of gelatinolysis of MMP-2 variants were reduced by 20-40% following single-point substitutions, by 60-75% after double-point modifications, and by >90% for triple-point variants. Intriguingly, the three CBD modules contributed differentially to cleavage of dissociated α-1(I) and α-2(I) collagen chains. Importantly, kinetic analyses (k(cat)/K(m)) revealed that catalysis of a triple-helical FRET peptide substrate by MMP-2 relied primarily on the module 3 binding site. Thus, we have identified three collagen binding site residues that are essential for gelatinolysis and constitute promising targets for selective inhibition of MMP-2.


Exacerbated grassland degradation and desertification in Central Asia during 2000-2014.
Grassland degradation and desertification is a complex process, including both state conversion (e.g., grasslands to deserts) and gradual within-state change (e.g., greenness dynamics). Existing studies hardly separated the two components and analyzed it as a whole based on time series vegetation index data, which cannot provide a clear and comprehensive picture for grassland degradation and desertification. Here we propose an integrated assessment strategy, by considering both state conversion and within-state change of grasslands, to investigate grassland degradation and desertification process in Central Asia. First, annual maps of grasslands and sparsely vegetated land were generated to track the state conversions between them. The results showed increasing grasslands were converted to sparsely vegetated lands from 2000 to 2014, with the desertification region concentrating in the latitude range of 43-48° N. A frequency analysis of grassland vs. sparsely vegetated land classification in the last 15 yr allowed a recognition of persistent desert zone (PDZ), persistent grassland zone (PGZ), and transitional zone (TZ). The TZ was identified in southern Kazakhstan as one hotspot that was unstable and vulnerable to desertification. Furthermore, the trend analysis of Enhanced Vegetation Index during thermal growing season (EVITGS ) was investigated in individual zones using linear regression and Mann-Kendall approaches. An overall degradation across the area was found; moreover, the second desertification hotspot was identified in northern Kazakhstan with significant decreasing in EVITGS , which was located in PGZ. Finally, attribution analyses of grassland degradation and desertification were conducted by considering precipitation, temperature, and three different drought indices. We found persistent droughts were the main factor for grassland degradation and desertification in Central Asia. Considering both state conversion and gradual within-state change processes, this study provided reference information for identification of desertification hotspots to support further grassland degradation and desertification treatment, and the method could be useful to be extended to other regions.


Production of FAME biodiesel in E. coli by direct methylation with an insect enzyme.
Most biodiesel currently in use consists of fatty acid methyl esters (FAMEs) produced by transesterification of plant oils with methanol. To reduce competition with food supplies, it would be desirable to directly produce biodiesel in microorganisms. To date, the most effective pathway for the production of biodiesel in bacteria yields fatty acid ethyl esters (FAEEs) at up to ~1.5 g/L. A much simpler route to biodiesel produces FAMEs by direct S-adenosyl-L-methionine (SAM) dependent methylation of free fatty acids, but FAME production by this route has been limited to only ~16 mg/L. Here we employ an alternative, broad spectrum methyltransferase, Drosophila melanogaster Juvenile Hormone Acid O-Methyltransferase (DmJHAMT). By introducing DmJHAMT in E. coli engineered to produce medium chain fatty acids and overproduce SAM, we obtain medium chain FAMEs at titers of 0.56 g/L, a 35-fold increase over titers previously achieved. Although considerable improvements will be needed for viable bacterial production of FAMEs and FAEEs for biofuels, it may be easier to optimize and transport the FAME production pathway to other microorganisms because it involves fewer enzymes.


The platelet glycoprotein IIb/IIIa-like protein in human endothelial cells promotes adhesion but not initial attachment to extracellular matrix.
On platelets the membrane glycoprotein IIb/IIIa complex (GPIIb/IIIa) functions in adhesive interactions with fibrinogen, von Willebrand factor, and fibronectin. However, the function of GPIIb/IIIa-like proteins on endothelial cells, as well as the ligand(s) the complex binds, is unknown. Using a highly specific polyclonal antibody we have explored the function of GPIIb/IIIa-like proteins on human umbilical vein endothelial cells (HUVE). Analysis by immunoblotting shows that this antiserum recognizes the endothelial GPIIIa-like protein of the complex. The IgG fraction of the polyclonal antiserum and its Fab' fragments detach confluent and subconfluent HUVE from extracellular substrata. The effect of the anti-GPIIb/IIIa IgG is not toxic as the detached cells maintain their viability after trypsinization and replating. Anti-GPIIb/IIIa IgG does not inhibit HUVE binding to extracellular matrix or purified fibronectin in an attachment assay despite the presence of intact GPIIb/IIIa on HUVE detached from substrate by various methods. Apparently, the GPIIb/IIIa-like protein on HUVE is important in normal HUVE adhesion to the extracellular matrix, but it is not required in the initial attachment of HUVE to extracellular matrix.


Microtubule asymmetry during neutrophil polarization and migration.
The development of cell polarity in response to chemoattractant stimulation in human polymorphonuclear neutrophils (PMNs) is characterized by the rapid conversion from round to polarized morphology with a leading lamellipod at the front and a uropod at the rear. During PMN polarization, the microtubule (MT) array undergoes a dramatic reorientation toward the uropod that is maintained during motility and does not require large-scale MT disassembly or cell adhesion to the substratum. MTs are excluded from the leading lamella during polarization and motility, but treatment with a myosin light chain kinase inhibitor (ML-7) or the actin-disrupting drug cytochalasin D causes an expansion of the MT array and penetration of MTs into the lamellipod. Depolymerization of the MT array before stimulation caused 10% of the cells to lose their polarity by extending two opposing lateral lamellipodia. These multipolar cells showed altered localization of a leading lamella-specific marker, talin, and a uropod-specific marker, CD44. In summary, these results indicate that F-actin- and myosin II-dependent forces lead to the development and maintenance of MT asymmetry that may act to reinforce cell polarity during PMN migration.


Data management in clinical research: An overview.
Clinical Data Management (CDM) is a critical phase in clinical research, which leads to generation of high-quality, reliable, and statistically sound data from clinical trials. This helps to produce a drastic reduction in time from drug development to marketing. Team members of CDM are actively involved in all stages of clinical trial right from inception to completion. They should have adequate process knowledge that helps maintain the quality standards of CDM processes. Various procedures in CDM including Case Report Form (CRF) designing, CRF annotation, database designing, data-entry, data validation, discrepancy management, medical coding, data extraction, and database locking are assessed for quality at regular intervals during a trial. In the present scenario, there is an increased demand to improve the CDM standards to meet the regulatory requirements and stay ahead of the competition by means of faster commercialization of product. With the implementation of regulatory compliant data management tools, CDM team can meet these demands. Additionally, it is becoming mandatory for companies to submit the data electronically. CDM professionals should meet appropriate expectations and set standards for data quality and also have a drive to adapt to the rapidly changing technology. This article highlights the processes involved and provides the reader an overview of the tools and standards adopted as well as the roles and responsibilities in CDM.


Implantation of AMS 700 LGX penile prosthesis preserves penile length without the need for penile lengthening procedures.
Implantation of an inflatable penile prosthesis (IPP) is a well-established definitive solution for erectile dysfunction when conservative treatments fail. Penile implants may shorten the penis. The AMS 700 LGX IPP is in common use but reports on its mechanical reliability, medium-term postsurgical patient satisfaction, and mean penile length preservation are lacking. We investigate the mean penile length, mechanical reliability, and patient satisfaction at 6 and 12 months after implantation of the AMS 700 LGX. This prospective study consecutively enrolled men undergoing first-time IPP implant surgery from February 2009 to April 2012. Stretched flaccid penile length, penile length at 50% and 100% of stiffness (P50 and P100) and International Index of Erectile Function (IIEF) and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) scores, were measured at 6 and 12 months postsurgery. Of 45 patients who underwent AMS 700 LGX implantation (median age 61 years) and completed 6 months' follow-up, 36 (80%) completed the study. A significant difference in stretched flaccid penile length was seen between 6 and 12 months (P = 0.033). P100 was also significantly increased at 6 and 12 months, with a mean 10% increase (1.3 ± 0.4 cm) from baseline to 12 months. Differences in mean IIEF scores at 6 and 12 months were significant for the desired domain (P = 0.0001) and for overall satisfaction (P = 0.002); however, mean EDITS scores at 6 and 12 months were not significantly improved. AMS 700 LGX is a powerful tool for preserving penile length in men undergoing penile prosthesis implantation.


Molecular Mechanisms Preventing Senescence in Response to Prolonged Darkness in a Desiccation-Tolerant Plant.
The desiccation-tolerant plant Haberlea rhodopensis can withstand months of darkness without any visible senescence. Here, we investigated the molecular mechanisms of this adaptation to prolonged (30 d) darkness and subsequent return to light. H. rhodopensis plants remained green and viable throughout the dark treatment. Transcriptomic analysis revealed that darkness regulated several transcription factor (TF) genes. Stress- and autophagy-related TFs such as ERF8, HSFA2b, RD26, TGA1, and WRKY33 were up-regulated, while chloroplast- and flowering-related TFs such as ATH1, COL2, COL4, RL1, and PTAC7 were repressed. PHYTOCHROME INTERACTING FACTOR4, a negative regulator of photomorphogenesis and promoter of senescence, also was down-regulated. In response to darkness, most of the photosynthesis- and photorespiratory-related genes were strongly down-regulated, while genes related to autophagy were up-regulated. This occurred concomitant with the induction of SUCROSE NON-FERMENTING1-RELATED PROTEIN KINASES (SnRK1) signaling pathway genes, which regulate responses to stress-induced starvation and autophagy. Most of the genes associated with chlorophyll catabolism, which are induced by darkness in dark-senescing species, were either unregulated (PHEOPHORBIDE A OXYGENASE, PAO; RED CHLOROPHYLL CATABOLITE REDUCTASE, RCCR) or repressed (STAY GREEN-LIKE, PHEOPHYTINASE, and NON-YELLOW COLORING1). Metabolite profiling revealed increases in the levels of many amino acids in darkness, suggesting increased protein degradation. In darkness, levels of the chloroplastic lipids digalactosyldiacylglycerol, monogalactosyldiacylglycerol, phosphatidylglycerol, and sulfoquinovosyldiacylglycerol decreased, while those of storage triacylglycerols increased, suggesting degradation of chloroplast membrane lipids and their conversion to triacylglycerols for use as energy and carbon sources. Collectively, these data show a coordinated response to darkness, including repression of photosynthetic, photorespiratory, flowering, and chlorophyll catabolic genes, induction of autophagy and SnRK1 pathways, and metabolic reconfigurations that enable survival under prolonged darkness.


Evaluation of glucose homeostasis.
Obesity and dyslipidemia are often found in association with insulin resistance (IR). These components combined with hypertension characterize the most common endocrine disorder in humans, the metabolic syndrome. Thus, in addition to profiling body weight evolution and lipid metabolites, glucose tolerance (a reflection of IR) and insulin sensitivity should also be considered as part of any metabolic phenotyping protocol. The ability to measure IR and glucose tolerance is important not only in the quest to fully understand the pathogenesis of the metabolic syndrome in the mouse, but also to test the effects of potential interventions. This unit presents a variety of tests used for this purpose, including direct blood glucose measurements, insulin measurement by ELISA, the homeostatic model assessment, glucose tolerance and insulin sensitivity tests, and the euglycemic clamp.


Examining which clinicians provide admission hospital care in a high mortality setting and their adherence to guidelines: an observational study in 13 hospitals.
We explored who actually provides most admission care in hospitals offering supervised experiential training to graduating clinicians in a high mortality setting where practices deviate from guideline recommendations. We used a large observational data set from 13 Kenyan county hospitals from November 2015 through November 2018 where patients were linked to admitting clinicians. We explored guideline adherence after creating a cumulative correctness of Paediatric Admission Quality of Care (cPAQC) score on a 5-point scale (0-4) in which points represent correct, sequential progress in providing care perfectly adherent to guidelines comprising admission assessment, diagnosis and treatment. At the point where guideline adherence declined the most we dichotomised the cPAQC score and used multilevel logistic regression models to explore whether clinician and patient-level factors influence adherence. There were 1489 clinicians who could be linked to 53 003 patients over a period of 3 years. Patients were rarely admitted by fully qualified clinicians and predominantly by preregistration medical officer interns (MOI, 46%) and diploma level clinical officer interns (COI, 41%) with a median of 28 MOI (range 11-68) and 52 COI (range 5-160) offering care per study hospital. The cPAQC scores suggest that perfect guideline adherence is found in ≤12% of children with malaria, pneumonia or diarrhoea with dehydration. MOIs were more adherent to guidelines than COI (adjusted OR 1.19 (95% CI 1.07 to 1.34)) but multimorbidity was significantly associated with lower guideline adherence. Over 85% of admissions to hospitals in high mortality settings that offer experiential training in Kenya are conducted by preregistration clinicians. Clinical assessment is good but classifying severity of illness in accordance with guideline recommendations is a challenge. Adherence by MOI with 6 years' training is better than COI with 3 years' training, performance does not seem to improve during their 3 months of paediatric rotations.


BDNF/TrkB signaling mediates the anorectic action of estradiol in the nucleus tractus solitarius.
Although compelling evidence indicates that estradiol (E2) acts in the nucleus tractus solitarius (NTS) to reduce food intake, the underlying mechanisms are largely unknown. We now report that estrogen's anorectic action occurs through enhancing the strength of brain-derived neurotrophic factor (BDNF) and tropomyosin receptor kinase (TrkB) signaling in the NTS. Intra-4th-ventricular administration of a low dose of BDNF reduced food intake to a greater extent in ovariectomized (OVX) rats cyclically treated with E2 than in vehicle-treated OVX rats, implying that cyclic E2 replacement increases BDNF's satiating potency. OVX significantly decreased bdnf gene expression in the NTS, and this was reversed by cyclic replacement of E2. Treatment of cultured primary neuronal cells from embryonic rat brainstem with E2 or PPT (ERα agonist), but not with DPN (ERβ agonist), significantly increased bdnf mRNA levels, indicating that ERα is the primary receptor mediating E2's stimulatory effect on bdnf gene expression. Administration of the selective TrkB antagonist, ANA-12, directly into the NTS significantly attenuated E2-induced reductions of food intake and body weight gain in OVX rats, indicating that TrkB receptor activation is necessary for E2's anorectic effect. Finally, relative to controls, OVX mice with bdnf gene knockdown specifically in the NTS had a blunted feeding response to E2. These data collectively imply that BDNF/TrkB receptor signaling in the NTS is a downstream mediator of E2 in the control of energy intake.


Engineering requirements for a haptic simulator for knee arthroscopy training.
This paper describes the initial development of an innovative haptic device that will be integrated into an existing virtual reality training system for knee arthroscopy. The resulting system will be called WISHKATS (Warwick, Imperial, Sheffield Knee Arthroscopy Training System). This haptic device will enable the trainee to feel realistic forces on the probing tool and will work together with software, which will simulate tissue deformation. The proposed haptic system is a compact, multi-degree of freedom, motorised mechanism with force sensors, and will be used to simulate the diagnostic aspects of knee arthroscopy. There are a number of problems associated with the development of a suitable haptic system and this paper explores the engineering requirements of such a device.


Juvenile chronic myelogenous leukemia.
Juvenile chronic myelogenous leukemia (JCML) is an aggressive myeloproliferative disorder of childhood that differs both clinically and pathologically from adult type, Philadelphia chromosome positive chronic myelogenous leukemia, and from the other myeloproliferative disorders that are more common in adulthood. The disease can have widely varying clinical presentations and shares many features with the monosomy 7 syndrome and chronic myelomonocytic leukemia. With no specific marker chromosome, establishing the diagnosis can be difficult, and relies on a constellation of clinical, pathologic, and laboratory findings. This article discusses the differential diagnosis of JCML with an emphasis on the pathologic findings and laboratory data that are particularly important for confirming the diagnosis. The sensitivity, specificity, and clinical utility of cell culture colony assays are reviewed. Finally, current knowledge of the biology of JCML and some of the controversies regarding this disease are discussed.


Isolation and nucleotide sequence of canine glucose-6-phosphatase mRNA: identification of mutation in puppies with glycogen storage disease type Ia.
Two Maltese puppies with massive hepatomegaly and failure to thrive had isolated deficient glucose-6-phosphatase (G-6-Pase) activity in liver and kidney and pathological findings compatible with GSD-Ia. To identify the mutation, we cloned G-6-Pase canine cDNA by RT-PCR with primers from the murine G-6-Pase gene sequence. The canine G-6-Pase cDNA is 2346 bp, with a 5' untranslated region of 87 bp, a coding region of 1071 bp, and a 3' untranslated region of 1185 bp. The difference between the canine and human sequences is in the 3' untranslated region. A greater than 90% amino acid sequence homology was seen with canine, human, murine, and rat G-6-Pase. G-6-Pase cDNA from affected and control puppies revealed complete homology except at nt position 450, which showed a guanine to cytosine (G to C) transversion resulting in substitution of a methionine by isoleucine at codon 121 (M121I) in all five clones studied. The loss of an NcoI restriction site on genomic DNA amplified with primers flanking the mutation allowed us to prove that affected puppies were homozygous for the mutation and parents were heterozygous carriers. The mutant G-6-Pase cDNA had 15 times less enzyme activity than wild-type cDNA following transient transfection. Northern blot analysis of puppies with GSD-Ia revealed increased G-6-Pase mRNA, compared to normal controls. Increased G-6-Pase mRNA was also seen in normal fasted puppies compared to littermates in the fed state, suggesting that the increased G-6-Pase mRNA is a physiologic response to fasting. This is the first report of a molecularly confirmed naturally occurring animal model of GSD-Ia. The establishment of a breeding colony of this dog strain will facilitate studies on the role of G-6-Pase gene in glucose homeostasis, in pathophysiology of disease, and development of novel therapeutic approaches such as gene therapy.


Evaluation of breast cancer incidence: is the increase due entirely to mammographic screening?
To examine the trends in the incidence rates of breast cancer in a population with mammographic screening and in the unscreened women within that population. Data consisted of incident cases of breast cancer notified to the Victorian Cancer Registry in Victoria, Australia, between 1988 and 1996 and cases detected in the population-based BreastScreen Program. These data were grouped by age (25-39, 40-49, 50-59, 60-69 and > or = 70 years of age) and size of tumor (< or =10 mm, > 10-< or =15 mm, and > 15 mm). Poisson regression modeling was used to examine trends by age, tumor size, calendar year and availability of screening. The incidence rate of breast cancer in the total population increased between 1988 and 1996. The greatest increase was seen after 1993 when population-based screening became available. In unscreened women, modeling demonstrated a statistically significant (p < 0.01) 1.5% annual increase in the incidence rate. The annual increase in this rate differed by size of tumor and was approximately 8% (p < 0.01) for small tumors (< or = 10 mm) but not significant for tumors > 10 mm. The greatest increase was in small tumors for women > or = 50 years of age. The incidence of breast cancer has increased since population-based mammographic screening was introduced in 1994. The rate in unscreened women also showed a significant increase. This was greatest in small tumors for women > or = 50 years of age. Whether this will translate into an increase in mortality is uncertain and long-term monitoring is required to determine if cohort and period effects impact on the underlying incidence of breast cancer in Victoria.


Cucurbitacin I inhibits tumorigenic ability and enhances radiochemosensitivity in nonsmall cell lung cancer-derived CD133-positive cells.
Signal transducer and activator of transcription 3 (STAT3) signaling reportedly promotes tumor malignancy and recurrence in nonsmall cell lung cancer (NSCLC). It was demonstrated previously that the STAT3 pathway maintains the tumorigenicity and therapeutic resistance of malignant tumors as well as cancer stem cells (CSCs). The objective of the current study was to investigate the effect of the strong STAT3 inhibitor, cucurbitacin I, in prominin-1 (CD133)-positive lung cancer cells. CD133-positive and CD133-negative NSCLC-derived cells were isolated from 7 patients with NSCLC. CD133-positive NSCLC cells that were treated with or without cucurbitacin I were evaluated for their expression of phosphorylated STAT3 (p-STAT3), tumorigenicity, stemness properties, and resistance to chemotherapeutic drugs and ionizing radiation. Compared with parental or CD133-negative NSCLC cells, CD133-positive NSCLC cells had greater tumorigenicity, greater radioresistance, and higher expression of octamer-binding transcription factor 4 (Oct-4), Nanog homeobox, and sex-determining region Y, box 2 (Sox2) at high p-STAT3 levels. Cucurbitacin I treatment at 100 nM effectively abrogated STAT3 activation, tumorigenic capacity, sphere formation ability, radioresistance, and chemoresistance in CD133-positive NSCLC cells. Microarray data suggested that cucurbitacin I inhibited the stemness gene signature of CD133-positive NSCLC cells and facilitated the differentiation of CD133-positive NSCLC cells into CD133-negative NSCLC cells. It is noteworthy that 150 nM cucurbitacin I effectively blocked STAT3 signaling and downstream survival targets, such as B-cell chronic lymphocytic leukemia/lymphoma 2 (Bcl-2) and Bcl-2-like 1 (Bcl-xL) expression and induced apoptosis in CD133-positive NSCLC cells. Finally, xenotransplantation experiments revealed that cucurbitacin I plus radiotherapy or chemotherapeutic drugs significantly suppressed tumorigenesis and improved survival in NSCLC-CD133-positive-transplanted, immunocompromised mice. Targeting STAT3 signaling in CD133-positive NSCLC cells with cucurbitacin I suppressed CSC-like properties and enhanced chemoradiotherapy response. The potential of cucurbitacin I should be verified further in future anti-CSC therapy.


Interocular velocity difference contributes to stereomotion speed perception.
Two experiments are presented assessing the contributions of the rate of change of disparity (CD) and interocular velocity difference (IOVD) cues to stereomotion speed perception. Using a two-interval forced-choice paradigm, the perceived speed of directly approaching and receding stereomotion and of monocular lateral motion in random dot stereogram (RDS) targets was measured. Prior adaptation using dysjunctively moving random dot stimuli induced a velocity aftereffect (VAE). The degree of interocular correlation in the adapting images was manipulated to assess the effectiveness of each cue. While correlated adaptation involved a conventional RDS stimulus, containing both IOVD and CD cues, uncorrelated adaptation featured an independent dot array in each monocular half-image, and hence lacked a coherent disparity signal. Adaptation produced a larger VAE for stereomotion than for monocular lateral motion, implying effects at neural sites beyond that of binocular combination. For motion passing through the horopter, correlated and uncorrelated adaptation stimuli produced equivalent stereomotion VAEs. The possibility that these results were due to the adaptation of a CD mechanism through random matches in the uncorrelated stimulus was discounted in a control experiment. Here both simultaneous and sequential adaptation of left and right eyes produced similar stereomotion VAEs. Motion at uncrossed disparities was also affected by both correlated and uncorrelated adaptation stimuli, but showed a significantly greater VAE in response to the former. These results show that (1) there are two separate, specialised mechanisms for encoding stereomotion: one through IOVD, the other through CD; (2) the IOVD cue dominates the perception of stereomotion speed for stimuli passing through the horopter; and (3) at a disparity pedestal both the IOVD and the CD cues have a significant influence.


Genetic analysis of transfer and stabilization of Agrobacterium DNA in plant cells.
In an attempt to elucidate the transfer and integration mechanism of Agrobacterium DNA upon crown gall induction, we translocated a borderless T-DNA to different sites of the C58 Ti plasmid. As a result of the physical linkage of the T-DNA onc genes with other Ti plasmid functions, the concerned strain retained tumor-inducing capacity. However, when the borderless T-DNA is separated on an independent replicon while all other pTi functions are provided in trans, the strain can no longer induce tumors on plants. We provide evidence that the right T-DNA border region harbors one or more in cis active functions essential in the transfer and/or stabilization of the T-DNA into plant cells. The strains used in these experiments allowed us to conclude that some function(s) of the Ti plasmid can induce plant cell proliferations independently of the T-DNA transformation event. The results described here indicate that other Ti plasmid sequences than solely the T-region can be transferred to plant cells.


Disc extrusions and bulges in nonspecific low back pain and sciatica: Exploratory randomised controlled trial comparing yoga therapy and normal medical treatment.
Previous trials of yoga therapy for nonspecific low back pain (nsLBP) (without sciatica) showed beneficial effects. To test effects of yoga therapy on pain and disability associated with lumbar disc extrusions and bulges. Parallel-group, randomised, controlled trial. Sixty-one adults from rural population, aged 20-45, with nsLBP or sciatica, and disc extrusions or bulges. Randomised to yoga (n=30) and control (n=31). Yoga: 3-month yoga course of group classes and home practice, designed to ensure safety for disc extrusions. normal medical care. OUTCOME MEASURES (3-4 months) Primary: Roland Morris Disability Questionnaire (RMDQ); worst pain in past two weeks. Secondary: Aberdeen Low Back Pain Scale; straight leg raise test; structural changes. Disc projections per case ranged from one bulge or one extrusion to three bulges plus two extrusions. Sixty-two percent had sciatica. Intention-to-treat analysis of the RMDQ data, adjusted for age, sex and baseline RMDQ scores, gave a Yoga Group score 3.29 points lower than Control Group (0.98, 5.61; p=0.006) at 3 months. No other significant differences in the endpoints occurred. No adverse effects of yoga were reported. Yoga therapy can be safe and beneficial for patients with nsLBP or sciatica, accompanied by disc extrusions and bulges.


Measuring increase in synchronization to identify muscle endurance limit.
Changes in surface electromyogram (sEMG) spectral content are commonly associated with localized muscle fatigue. However, the significance of the changes is only evident during pair-wise comparison and these can only be used for comparison between the rested and fatigued muscle and cannot be used for identifying the limit of muscle endurance without having the rested data for comparison. This is due to the large variations between sEMG at different levels of strengths of contraction, and between different people. This is further compounded when the contraction is not isometric but is cyclic because there is large variation of sEMG within each cycle. This research has developed a new sEMG based method for studying muscle fatigue and for identifying the limit of muscle endurance. It is based on motor unit synchronization and is called increase in synchronization (IIS) index. IIS index measures the level of independence between two channels of sEMG recorded from the muscle and is the log of the determinant of the global matrix ( log||G||) which is generated by performing independent component analysis on the two channels. The experimental results for biceps brachii demonstrate that when the muscle was rested, the two channels had a high degree of independence and the IIS index was greater than -0.7 (range -0.65 to -0.05). However, the channels became dependent as the muscles progressively fatigued and IIS index became less than -6.2 (range -7.8 to -6.3 ) at the limit of muscle endurance. This was irrespective of the contraction being isometric or cyclic, or of the level of muscle contraction.


Intravital microscopy of capillary hemodynamics in sickle cell disease.
Direct intravital microscopic examinations were made in nailfold capillaries in subjects with homozygous sickle cell disease (HbSS red cells). In the resting state, capillary red cell (rbc) flux exhibited greater intermittence compared with normal subjects, which increased with painful crisis. In crisis-free HbSS subjects, capillary occlusion and red cell sequestration occurred in only 8.2% of all capillaries and diminished to 5.8% during crisis, possibly due to sequestration of less deformable rbcs in other organs. Velocities of rbc's (Vrbc) were measured by video techniques under resting conditions and during postocclusive reactive hyperemia (PORH) induced by a pressure cuff around the finger. Resting Vrbc was normal in crisis-free HbSS subjects, averaging 0.7 mm/s. In contrast, Vrbc was significantly elevated during crisis, to 0.98 mm/s, apparently due to compensatory arteriolar dilation. Crisis subjects exhibited a significantly depressed PORH with the ratio of peak red cell velocity to resting values reduced by 15% due to a loss of vasodilatory reserve, whereas crisis-free subjects exhibited a normal response. A 55% increase in the time to attain peak Vrbc was attributed to resistance increases, possibly resulting from red cell and leukocyte-to-endothelium adhesion during the induced ischemia.


Missed Opportunity? Leveraging Mobile Technology to Reduce Racial Health Disparities.
Blacks and Latinos are less likely than whites to access health insurance and utilize health care. One way to overcome some of these racial barriers to health equity may be through advances in technology that allow people to access and utilize health care in innovative ways. Yet, little research has focused on whether the racial gap that exists for health care utilization also exists for accessing health information online and through mobile technologies. Using data from the Health Information National Trends Survey (HINTS), we examine racial differences in obtaining health information online via mobile devices. We find that blacks and Latinos are more likely to trust online newspapers to get health information than whites. Minorities who have access to a mobile device are more likely to rely on the Internet for health information in a time of strong need. Federally insured individuals who are connected to mobile devices have the highest probability of reliance on the Internet as a go-to source of health information. We conclude by discussing the importance of mobile technologies for health policy, particularly related to developing health literacy, improving health outcomes, and contributing to reducing health disparities by race and health insurance status.


Calcium-dependent fluxes of potassium-42 and chloride-36 during norepinephrine activation of rat aorta.
This study was designed to determine whether alpha-receptor-stimulated monovalent ionic fluxes in rat aorta required calcium, and, if so, whether both extracellular calcium and cellularly stored calcium are active. Calcium removal in the presence of 10 mM magnesium (to maintain membrane stability) inhibited the norepinephrine-stimulated increase in potassium-42 and chloride-36 efflux. However, the norepinephrine-stimulated increase in sodium-24 influx was relatively resistant to calcium depletion. Protocols were designed to measure the time course for the changes in potassium-42 efflux and contraction when calcium was removed or replaced in the presence of norepinephrine. The dose-dependent effect of a calcium antagonist (diltiazem) was also measured. A close correlation (r = 0.94) was found between inhibition of contraction and potassium-42 effluxes which followed the regression: % potassium-42 response = 1.0 X (% contraction) + 1.8%). The slope of 1.0 and intercept near zero suggests the hypothesis that norepinephrine-stimulated potassium-42 efflux and contraction are codependent on cellular calcium concentration. This co-dependence held for short phasic responses (approximately 1 minute), as well as longer tonic responses (greater than or equal to 5 minutes). It appears that calcium-dependent potassium-42 effluxes can be supported by both the influx of extracellular calcium and release of cellular stores. It is concluded that calcium-dependent potassium channels (and possibly chloride channels) are operative in rat aorta and are an important component of the graded membrane response to norepinephrine. The sodium channels, however, do not appear to share this same calcium dependency.


Clinical Core of the Alzheimer's Disease Neuroimaging Initiative: progress and plans.
The Clinical Core of the Alzheimer's Disease Neuroimaging Initiative (ADNI) has provided clinical, operational, and data management support to ADNI since its inception. This article reviews the activities and accomplishments of the core in support of ADNI aims. These include the enrollment and follow-up of more than 800 subjects in the three original cohorts: healthy controls, amnestic mild cognitive impairment (now referred to as late MCI, or LMCI), and mild Alzheimer's disease (AD) in the first phase of ADNI (ADNI 1), with baseline longitudinal, clinical, and cognitive assessments. These data, when combined with genetic, neuroimaging, and cerebrospinal fluid measures, have provided important insights into the neurobiology of the AD spectrum. Furthermore, these data have facilitated the development of novel clinical trial designs. ADNI has recently been extended with funding from an NIH Grand Opportunities (GO) award, and the new ADNI GO phase has been launched; this includes the enrollment of a new cohort, called early MCI, with milder episodic memory impairment than the LMCI group. An application for a further 5 years of ADNI funding (ADNI 2) was recently submitted. This funding would support ongoing follow-up of the original ADNI 1 and ADNI GO cohorts, as well as additional recruitment into all categories. The resulting data would provide valuable data on the earliest stages of AD, and support the development of interventions in these critically important populations.


Systematic misperceptions of 3-D motion explained by Bayesian inference.
People make surprising but reliable perceptual errors. Here, we provide a unified explanation for systematic errors in the perception of three-dimensional (3-D) motion. To do so, we characterized the binocular retinal motion signals produced by objects moving through arbitrary locations in 3-D. Next, we developed a Bayesian model, treating 3-D motion perception as optimal inference given sensory noise in the measurement of retinal motion. The model predicts a set of systematic perceptual errors, which depend on stimulus distance, contrast, and eccentricity. We then used a virtual-reality headset as well as a standard 3-D desktop stereoscopic display to test these predictions in a series of perceptual experiments. As predicted, we found evidence that errors in 3-D motion perception depend on the contrast, viewing distance, and eccentricity of a stimulus. These errors include a lateral bias in perceived motion direction and a surprising tendency to misreport approaching motion as receding and vice versa. In sum, we present a Bayesian model that provides a parsimonious account for a range of systematic misperceptions of motion in naturalistic environments.


Electrophysiological evidence on epileptiform activity enhanced by electrical stimulation of teeth in rats.
The aim of this study was to evaluate the possible effects of electrical stimulation (ES) of tooth on penicillin-induced epileptiform activity in rats. Experiment was realized on 24 adult male Sprague Dawley rats. Rats were assigned three groups [stimulation group (SG), penicillin group (PG), and penicillin+stimulation group (PSG)]. In SG, ES was only applied. Ten pulses of electrical current were delivered to the teeth for a duration of 2 milliseconds at 1-second intervals from a stimulator. Currents were applied in the range of 40-240 μA with 40 μA steps. Electrocorticography (ECoG) recordings were taken before and after ES. In PG, ECoG recordings were taken before and during the injection of penicillin. In PSG, after epileptiform activity was induced, ES was applied and ECoG recordings were taken as in SG. All the data were analyzed with Student's t test. Applied currents did not cause any epileptiform activity in SG. When the PSG was compared with the PG it was seen that the spike frequency of epileptiform activity increased in a statistically significant way after application of 240 μA (P < 0·05). On the other hand current application caused an increase in the spike amplitude of the PSG compared with the amplitude of the PG, but it was not statistically significant. We concluded that ES of tooth with high current can trigger epileptiform activity in rats. For this reason, further research is required to evaluate the effects of ES of tooth for pulp testing on epileptic human subjects and antiepileptic drug users.


Clearance of a dermal Huffmanela sp. in a sandbar shark (Carcharhinus plumbeus) using levamisole.
A wild-caught captive sandbar shark Carcharhinus plumbeus developed a contiguous network of darkly pigmented linear tracks that progressed from the snout to the ventral cervical region. Microscopic examination of a skin scraping revealed nematode eggs of the genus Huffmanela, a group of histozoic nematodes that is known to parasitize requiem sharks and marine and freshwater teleosts. The fresh eggs were darkly pigmented with bipolar plugs, contained a larva, and measured 73.3 to 86.4 by 39.0 to 47.4 microm (n = 10). Formalin-fixed and paraffin-embedded eggs were significantly smaller (Wilcoxon rank sums test, p < 0.005), measuring 70.5 to 78.9 by 33.6 to 41.3 microm (n = 13). These measurements do not correlate with previously reported species of Huffmanela. Serial treatment with levamisole (10 mg kg(-1), intramuscular [i.m.]) cleared the egg tracks within 21 d, with no recurrence or apparent complications.


Structure of pyrimidine 5'-nucleotidase type 1. Insight into mechanism of action and inhibition during lead poisoning.
Eukaryotic pyrimidine 5'-nucleotidase type 1 (P5N-1) catalyzes dephosphorylation of pyrimidine 5'-mononucleotides. Deficiency of P5N-1 activity in red blood cells results in nonspherocytic hemolytic anemia. The enzyme deficiency is either familial or can be acquired through lead poisoning. We present the crystal structure of mouse P5N-1 refined to 2.35 A resolution. The mouse P5N-1 has a 92% sequence identity to its human counterpart. The structure revealed that P5N-1 adopts a fold similar to enzymes of the haloacid dehydrogenase superfamily. The active site of this enzyme is structurally highly similar to those of phosphoserine phosphatases. We propose a catalytic mechanism for P5N-1 that is also similar to that of phosphoserine phosphatases and provide experimental evidence for the mechanism in the form of structures of several reaction cycle states, including: 1) P5N-1 with bound Mg(II) at 2.25 A, 2) phosphoenzyme intermediate analog at 2.30 A, 3) product-transition complex analog at 2.35 A, and 4) product complex at 2.1A resolution with phosphate bound in the active site. Furthermore the structure of Pb(II)-inhibited P5N-1 (at 2.35 A) revealed that Pb(II) binds within the active site in a way that compromises function of the cationic cavity, which is required for the recognition and binding of the phosphate group of nucleotides.


A novel, simplified approach to starting nasal CPAP therapy in OSA.
Due to ever increasing referral rates, we have had to move the nasal CPAP induction program for patients with obstructive sleep apnoea (OSA) out of the sleep laboratories and into an outpatient setting. We report the effects this has had on patient outcomes. The last 75 patients with OSA who had an overnight CPAP titration in the sleep laboratory (group 1) were compared with the first 75 coming to an afternoon clinic and set up on CPAP in groups, and who had their CPAP pressure determined from an algorithm (group 2). They were assessed at 1 and 11 months using the Epworth Sleepiness Score, compliance with CPAP (h/night), whether still using CPAP, and the number of clinic appointments required in the first 11 months. The two groups were similar at baseline. There were no differences in any of the outcome measures. ESS values fell from 14.6 to 5.0 and from 14.0 to 5.1 at 11 months in groups 1 and 2, respectively: compliance, 5.2 versus 5.1 h/night; clinic appointments, 1.75 versus 1.96; discontinuation rates at 1 month, 8% and 7%, and at 11 months, 25% and 21%. Using these simple outcome measures, we have shown that using an outpatient-based approach, and CPAP pressure based on an algorithm, have not reduced the efficacy of our CPAP induction program for patients with OSA.


Large-scale comparative sequence analysis of the human and murine Bruton's tyrosine kinase loci reveals conserved regulatory domains.
Large-scale genomic DNA sequencing of orthologous and paralogous loci in different species should contribute to a basic understanding of the evolution of both the protein-coding regions and noncoding regulatory elements. We compared 93 kb of human sequence to 89 kb of mouse sequence in the Bruton's tyrosine kinase (BTK) region. In addition to showing the conservation of both position and orientation of the five functionally unrelated genes in the region (BTK, alpha-D-galactosidase A, L44L, FTP-3, and FCI-12), the comparison revealed conservation of clusters of noncoding sequence flanking the first exon of each gene. Furthermore, in the sequence comparison at the BTK locus, the conservation of clusters of noncoding sequence extends throughout the locus; the noncoding sequence is more highly conserved in the BTK locus in comparison to the flanking loci. This suggests a correlation with the complex developmental regulation of expression of btk. To determine whether a highly conserved 3.5-kb segment flanking the first exon of BTK contains transcriptional regulatory signals, we tested various portions of the segment for promoter and expression activity in several appropriate cell lines. The results demonstrate the contribution of the conserved region flanking the first exon to the cell lineage-specific expression pattern of btk. These data show the usefulness of large scale sequence comparisons to focus investigation on regions of noncoding sequence that play essential roles in complex gene regulation.


Current status of implant-based breast reconstruction in patients receiving postmastectomy radiation therapy.
Increasing numbers of patients with breast cancer are being treated with postmastectomy radiation therapy. The author reviewed the literature to determine the clinical impact of this increasing use of postmastectomy radiation therapy in patients with breast cancer who desire implant-based breast reconstruction. The author searched the MEDLINE database for articles on breast reconstruction and radiation therapy published between January of 2008 and June of 2011 and reviewed the abstracts of those articles to identify articles with information about the impact of irradiation on implant-based breast reconstruction. This subgroup of articles was reviewed in detail. Two hundred eighty-five articles were identified. Nineteen articles were reviewed in detail. Eight articles provided level III evidence; one provided level I or II evidence from high-quality multicenter or single-center randomized controlled trials or prospective cohort studies. Two articles provided level IV evidence from case series and were included in the review because they offered a novel approach or perspective. The most recent studies find a significant need for unplanned or major corrective surgery in irradiated breasts reconstructed with implants. Although breast implant reconstruction in irradiated breasts is associated with high rates of complications, only a minority of patients require conversion to an autologous tissue flap. Although the majority of patients who undergo implant-based reconstruction and irradiation ultimately keep the implant reconstruction, patient surveys show that irradiation has a significantly negative effect on patient satisfaction.


Oregovomab maintenance monoimmunotherapy does not improve outcomes in advanced ovarian cancer.
This phase III study tested the hypothesis that the CA-125-specific murine monoclonal antibody, oregovomab, administered as a monoimmunotherapy after front-line therapy in a selected ovarian cancer population would prolong time to relapse (TTR) and, ultimately, survival. Patients with stage III to IV ovarian cancer with preoperatively elevated CA-125 and objectively defined characteristics were randomly assigned 4 to 12 weeks after front-line carboplatin and paclitaxel chemotherapy to maintenance monoimmunotherapy in a fully blinded protocol. Two mg of oregovomab or placebo was infused over 20 minutes at weeks 0, 4, and 8 and then 12 weeks until recurrence or up to year 5. Patients were evaluated with serial imaging and clinical evaluation for evidence of recurrence at quarterly visits. TTR was the primary end point. Three hundred seventy-three patients were accrued at more than 60 centers; 251 patients were assigned to oregovomab and 120 patients were assigned to placebo. The treatment arms were well balanced. There were no differences in the clinical outcomes between treatment groups. Median TTR measured from randomization after completion of chemotherapy for the integrated study was 10.3 months (95% CI, 9.7 to 13.0 months) for oregovomab and 12.9 months (95% CI, 10.1 to 17.4 months) for placebo (P = .29, log-rank test). The treatment was well tolerated. Grade 3 to 4 toxicity was reported in 24.6% of patients in the placebo group and 20.1% of patients in the oregovomab group, respectively. Although oregovomab has demonstrated bioactivity, the strategy of monoimmunotherapy is not effective as maintenance therapy after front-line treatment of a favorable subset of patients with advanced ovarian cancer. Future studies of this or other tumor-antigen specific immunization strategies should seek ways to further augment induced immunity.


Reliable confidence intervals in quantitative genetics: narrow-sense heritability.
Many quantitative genetic statistics are functions of variance components, for which a large number of replicates is needed for precise estimates and reliable measures of uncertainty, on which sound interpretation depends. Moreover, in large experiments the deaths of some individuals can occur, so methods for analysing such data need to be robust to missing values. We show how confidence intervals for narrow-sense heritability can be calculated in a nested full-sib/half-sib breeding design (males crossed with several females) in the presence of missing values. Simulations indicate that the method provides accurate results, and that estimator uncertainty is lowest for sampling designs with many males relative to the number of females per male, and with more females per male than progenies per female. Missing data generally had little influence on estimator accuracy, thus suggesting that the overall number of observations should be increased even if this results in unbalanced data. We also suggest the use of parametrically simulated data for prior investigation of the accuracy of planned experiments. Together with the proposed confidence intervals an informed decision on the optimal sampling design is possible, which allows efficient allocation of resources.


Inkjet-Deposited Single-Wall Carbon Nanotube Micropatterns on Stretchable PDMS-Ag Substrate-Electrode Structures for Piezoresistive Strain Sensing.
Printed piezoresistive strain sensors based on stretchable roll-to-roll screen-printed silver electrodes on polydimethylsiloxane substrates and inkjet-deposited single-wall carbon nanotube micropatterns are demonstrated in this work. With the optimization of surface wetting and inkjet printing parameters, well-defined microscopic line patterns of the nanotubes with a sheet resistance of <100 Ω/□ could be deposited between stretchable Ag electrodes on the plasma-treated substrate. The developed stretchable devices are highly sensitive to tensile strain with a gauge factor of up to 400 and a pressure sensitivity of ∼0.09 Pa-1, respond to bending down to a radius of 1.5 mm, and are suitable for mounting on the skin to monitor and resolve various movements of the human body such as cardiac cycle, breathing, and finger flexing. This study indicates that inkjet deposition of nanomaterials can complement well other printing technologies to produce flexible and stretchable devices in a versatile manner.


Differential histone H3 Lys-9 and Lys-27 methylation profiles on the X chromosome.
Histone H3 tail modifications are among the earliest chromatin changes in the X-chromosome inactivation process. In this study we investigated the relative profiles of two important repressive marks on the X chromosome: methylation of H3 lysine 9 (K9) and 27 (K27). We found that both H3K9 dimethylation and K27 trimethylation characterize the inactive X in somatic cells and that their relative kinetics of enrichment on the X chromosome as it undergoes inactivation are similar. However, dynamic changes of H3K9 and H3K27 methylation on the inactivating X chromosome compared to the rest of the genome are distinct, suggesting that these two modifications play complementary and perhaps nonredundant roles in the establishment and/or maintenance of X inactivation. Furthermore, we show that a hotspot of H3K9 dimethylation 5' to Xist also displays high levels of H3 tri-meK27. However, analysis of this region in G9a mutant embryonic stem cells shows that these two methyl marks are dependent on different histone methyltransferases.


Emotional decision-making in autism spectrum disorder: the roles of interoception and alexithymia.
The way choices are framed influences decision-making. These "framing effects" emerge through the integration of emotional responses into decision-making under uncertainty. It was previously reported that susceptibility to the framing effect was reduced in individuals with autism spectrum disorder (ASD) due to a reduced tendency to incorporate emotional information into the decision-making process. However, recent research indicates that, where observed, emotional processing impairments in ASD may be due to co-occurring alexithymia. Alexithymia is thought to arise due to impaired interoception (the ability to perceive the internal state of one's body), raising the possibility that emotional signals are not perceived and thus not integrated into decision-making in those with alexithymia and that therefore reduced framing effects in ASD are a product of co-occurring alexithymia rather than ASD per se. Accordingly, the present study compared framing effects in autistic individuals with neurotypical controls matched for alexithymia. Results showed a marked deviation between groups. The framing effect was, in line with previous data, significantly smaller in autistic individuals, and there was no relationship between alexithymia or interoception and decision-making in the ASD group. In the neurotypical group, however, the size of the framing effect was associated with alexithymia and interoception, even after controlling for autistic traits. These results demonstrate that although framing effects are associated with interoception and alexithymia in the neurotypical population, emotional and interoceptive signals have less impact upon the decision-making process in ASD.


A taxometric analysis of type-D personality.
To test the dimensionality of Type-D personality, using taxometric procedures, to assess if Type-D personality is taxonic or dimensional. Type-D personality is treated as a categorical variable and caseness has been shown to be a risk factor for poor prognosis in coronary heart disease. However, at present, there is no direct evidence to support the assumption that Type D is categorical and able to differentiate true cases from noncases. In total, 1012 healthy young adults from across the United Kingdom and Ireland completed the DS14, the standard index of Type D, and scores were submitted to two taxometric procedures MAMBAC and MAXCOV. Graphical representations (comparing actual with simulated data) and fit indices indicated that Type D is more accurately represented as a dimensional rather than categorical construct. Type D is better represented as a dimensional construct. Implications for theory development and clinical practice with respect to Type D are examined as well as the wider use of taxometrics within psychosomatic medicine (e.g., to investigate if there are medically unexplained syndrome taxons, such as a Gulf War Syndrome taxon).


Evaluation of arthroscopy and macroscopic scoring.
Arthroscopy is a minimally invasive technique for retrieving synovial biopsies in rheumatology during the past 20 years. Vital for its use is continual evaluation of its safety and efficacy. Important for sampling is the fact of intraarticular variation for synovial markers. For microscopic measurements scoring systems have been developed and validated, but for macroscopic evaluations there is a need for further comprehensive description and validation of equivalent scoring systems. We studied the complication rate and yield of arthroscopies performed at our clinic between 1998 and 2005. We also created and evaluated a macroscopic score set of instructions for synovitis. Of 408 procedures, we had two major and one minor complication; two haemarthrosis and one wound infection, respectively. Pain was most often not a problem, but 12 procedures had to be prematurely ended due to pain. Yield of biopsies adequate for histology were 83% over all, 94% for knee joints and 34% for smaller joints. Video printer photographs of synovium taken during arthroscopy were jointly and individually reviewed by seven raters in several settings, and intra and inter rater variation was calculated. A macroscopic synovial scoring system for arthroscopy was created (Macro-score), based upon hypertrophy, vascularity and global synovitis. These written instructions were evaluated by five control-raters, and when evaluated individual parameters were without greater intra or inter rater variability, indicating that the score is reliable and easy to use. In our hands rheumatologic arthroscopy is a safe method with very few complications. For knee joints it is a reliable method to retrieve representative tissue in clinical longitudinal studies. We also created an easy to use macroscopic score, that needs to be validated against other methodologies. We hope it will be of value in further developing international standards in this area.


Primary care organisational interventions for secondary prevention of ischaemic heart disease: a systematic review and meta-analysis.
Ischaemic heart disease (IHD) is the most common cause of death worldwide. To determine the long-term impact of organisational interventions for secondary prevention of IHD. Systematic review and meta-analysis of studies from CENTRAL, MEDLINE(®), Embase, and CINAHL published January 2007 to January 2013. Searches were conducted for randomised controlled trials of patients with established IHD, with long-term follow-up, of cardiac secondary prevention programmes targeting organisational change in primary care or community settings. A random-effects model was used and risk ratios were calculated. Five studies were included with 4005 participants. Meta-analysis of four studies with mortality data at 4.7-6 years showed that organisational interventions were associated with approximately 20% reduced mortality, with a risk ratio (RR) for all-cause mortality of 0.79 (95% confidence interval [CI] = 0.66 to 0.93), and a RR for cardiac-related mortality of 0.74 (95% CI = 0.58 to 0.94). Two studies reported mortality data at 10 years. Analysis of these data showed no significant differences between groups. There were insufficient data to conduct a meta-analysis on the effect of interventions on hospital admissions. Additional analyses showed no significant association between organisational interventions and risk factor management or appropriate prescribing at 4.7-6 years. Cardiac secondary prevention programmes targeting organisational change are associated with a reduced risk of death for at least 4-6 years. There is insufficient evidence to conclude whether this beneficial effect is maintained indefinitely.


The impact of inadequate terminal disinfection on an outbreak of imipenem-resistant Acinetobacter baumannii in an intensive care unit.
This study was conducted to investigate an outbreak caused by imipenem-resistant Acinetobacter baumannii (IRAB) in a medical intensive care unit (ICU) in a regional hospital. In response to an IRAB outbreak from October 2012 to February 2013, we developed several infection control measures, including an extensive review process of environmental cleaning and disinfection, and used molecular methods to identify each clinical and environmental IRAB isolate. During this five-month period, 22 patients were colonized with IRAB and 18 patients had IRAB infections. The in-hospital mortality rate was significantly higher among patients with infections rather than colonizations (44.4% vs 9.1%, p = 0.028). Additionally, nine environmental specimens, including five specimens collected after terminal disinfection, were positive for IRAB. 12 environmental isolates and 28 of 36 available clinical isolates belonged to one unique pulsotype A, which was confirmed by molecular methods. We found the concentration of disinfectant, 0.08% sodium hypochlorite, was inadequate. After correcting the environmental cleansing methods, the surveillance study showed no further IRAB isolates on the control panel surfaces of the medical equipment or in patients in the ICU. Additionally, an in vitro study of IRAB immersed in different concentrations of sodium hypochlorite showed that 0.5% sodium hypochlorite eradicates IRAB after 30 seconds of inoculation, but 0.08% sodium hypochlorite only reduces the bacterial load. This study highlights the importance of the preparation of disinfectants to adequately achieve environmental disinfection in the control of IRAB outbreaks in the ICU.


A critical look at descriptive epidemiology of sexual dysfunction in Asia compared to the rest of the world - a call for evidence-based data.
Recently evidence-based medicine has been applied to comparative epidemiological papers regarding sexual dysfunction that have appeared in the literature. This review is intended to focus the readers on a validated and standardized methodological evidence-based process for preparing such articles. It reviews four key articles that have been published in the English language that have obtained a high evidence-based score for reliability that have included descriptive epidemiology of sexual dysfunctions in men and women in Asia compared to the rest of the world. These four papers are analyzed in detail in order to provide stress of what constitutes evidence-based studies in descriptive epidemiology for sexual function. As can be seen there has not yet been a perfect article that compares the prevalence of sexual function in Asia compared to the rest of the world since there are key methodological problems in the collection of the data. In addition, there is a paucity of incidence studies for sexual dysfunction in Asian populations. The readers are encouraged to use this data in preparation of future descriptive epidemiological studies that involve Asian countries.


Comparing and evaluating process-based ecosystem model predictions of carbon and water fluxes in major European forest biomes.
Process-based models can be classified into: (a) terrestrial biogeochemical models (TBMs), which simulate fluxes of carbon, water and nitrogen coupled within terrestrial ecosystems, and (b) dynamic global vegetation models (DGVMs), which further couple these processes interactively with changes in slow ecosystem processes depending on resource competition, establishment, growth and mortality of different vegetation types. In this study, four models - RHESSys, GOTILWA+, LPJ-GUESS and ORCHIDEE - representing both modelling approaches were compared and evaluated against benchmarks provided by eddy-covariance measurements of carbon and water fluxes at 15 forest sites within the EUROFLUX project. Overall, model-measurement agreement varied greatly among sites. Both modelling approaches have somewhat different strengths, but there was no model among those tested that universally performed well on the two variables evaluated. Small biases and errors suggest that ORCHIDEE and GOTILWA+ performed better in simulating carbon fluxes while LPJ-GUESS and RHESSys did a better job in simulating water fluxes. In general, the models can be considered as useful tools for studies of climate change impacts on carbon and water cycling in forests. However, the various sources of variation among models simulations and between models simulations and observed data described in this study place some constraints on the results and to some extent reduce their reliability. For example, at most sites in the Mediterranean region all models generally performed poorly most likely because of problems in the representation of water stress effects on both carbon uptake by photosynthesis and carbon release by heterotrophic respiration (Rh ). The use of flux data as a means of assessing key processes in models of this type is an important approach to improving model performance. Our results show that the models have value but that further model development is necessary with regard to the representation of the some of the key ecosystem processes.


NMR approaches for structural analysis of multidomain proteins and complexes in solution.
NMR spectroscopy is a key method for studying the structure and dynamics of (large) multidomain proteins and complexes in solution. It plays a unique role in integrated structural biology approaches as especially information about conformational dynamics can be readily obtained at residue resolution. Here, we review NMR techniques for such studies focusing on state-of-the-art tools and practical aspects. An efficient approach for determining the quaternary structure of multidomain complexes starts from the structures of individual domains or subunits. The arrangement of the domains/subunits within the complex is then defined based on NMR measurements that provide information about the domain interfaces combined with (long-range) distance and orientational restraints. Aspects discussed include sample preparation, specific isotope labeling and spin labeling; determination of binding interfaces and domain/subunit arrangements from chemical shift perturbations (CSP), nuclear Overhauser effects (NOEs), isotope editing/filtering, cross-saturation, and differential line broadening; and based on paramagnetic relaxation enhancements (PRE) using covalent and soluble spin labels. Finally, the utility of complementary methods such as small-angle X-ray or neutron scattering (SAXS, SANS), electron paramagnetic resonance (EPR) or fluorescence spectroscopy techniques is discussed. The applications of NMR techniques are illustrated with studies of challenging (high molecular weight) protein complexes.


Human skeletal muscle releases leptin in vivo.
Leptin is considered an adipokine, however, cultured myocytes have also been found to release leptin. Therefore, as proof-of-concept we investigated if human skeletal muscle synthesized leptin by measuring leptin in skeletal muscle biopsies. Following this, we quantified human skeletal muscle and adipose tissue leptin release in vivo. We recruited 16 healthy male human participants. Catheters were inserted into the femoral artery and vein draining skeletal muscle, as well as an epigastric vein draining the abdominal subcutaneous adipose tissue. By combining the veno-arterial differences in plasma leptin with measurements of blood flow, leptin release from both tissues was quantified. To induce changes in leptin, the participants were infused with either saline or adrenaline in normo-physiological concentrations. The presence of leptin in skeletal muscle was confirmed by western blotting. Leptin was released from leg skeletal muscle (50.6 ± 12 ng min(-1)) and the pattern of release was different from subcutaneous adipose tissue. Moreover, during adrenaline infusion the leptin release from leg skeletal muscle was strongly suppressed (20.5 ± 7.9 ng min(-1), p<0.017), whereas the release from fat was unaltered. During saline infusion the adipose tissue release averaged 0.8 ± 0.3 ng min(-1) 100g tissue(-1) whereas skeletal muscle release was 0.5 ± 0.1 ng min(-1) 100g tissue(-1). In young healthy humans, skeletal muscle contribution to whole body leptin production could be substantial given the greater mass of muscle compared to fat. An understanding of the role that leptin plays in skeletal muscle metabolism may prove important in light of several late-phase trials with recombinant leptin as an anti-obesity drug.


Tandem Probe Analysis Mode for Synchrotron XFM: Doubling Throughput Capacity.
Synchrotron-based X-ray fluorescence microscopy (XFM) analysis is a powerful technique that can be used to visualize elemental distributions across a broad range of sample types. Compared to conventional mapping techniques such as laser ablation inductively coupled plasma mass spectrometry or benchtop XFM, synchrotron-based XFM provides faster and more sensitive analyses. However, access to synchrotron XFM beamlines is highly competitive, and as a result, these beamlines are often oversubscribed. Therefore, XFM experiments that require many large samples to be scanned can penalize beamline throughput. Our study was largely driven by the need to scan large gels (170 cm2) using XFM without decreasing beamline throughput. We describe a novel approach for acquiring two sets of XFM data using two fluorescence detectors in tandem; essentially performing two separate experiments simultaneously. We measured the effects of tandem scanning on beam quality by analyzing a range of contrasting samples downstream while simultaneously scanning different gel materials upstream. The upstream gels were thin (<200 μm) diffusive gradients in thin-film (DGT) binding gels. DGTs are passive samplers that are deployed in water, soil, and sediment to measure the concentration and distribution of potentially bioavailable nutrients and contaminants. When deployed on soil, DGTs are typically small (2.5 cm2), so we developed large DGTs (170 cm2), which can be used to provide extensive maps to visualize the diffusion of fertilizers in soil. Of the DGT gel materials tested (bis-acrylamide, polyacrylamide, and polyurethane), polyurethane gels were most suitable for XFM analysis, having favorable handling, drying, and analytical properties. This gel type enabled quantitative (>99%) transmittance with minimal (<3%) flux variation during raster scanning, whereas the other gels had a substantial effect on the beam focus. For the first time, we have (1) used XFM for mapping analytes in large DGTs and (2) developed a tandem probe analysis mode for synchrotron-based XFM, effectively doubling throughput. The novel tandem probe analysis mode described here is of broad applicability across many XFM beamlines as it could be used for future experiments where any uniform, highly transmissive sample could be analyzed upstream in the "background" of downstream samples.


Influence of N-terminal residue composition on the structure of proline-containing b2+ ions.
To probe the structural implications of the proline residue on its characteristic peptide fragmentation patterns, in particular its unusual cleavage at its C-terminus in formation of a b(2) ion in XxxProZzz sequences, the structures of a series of proline-containing b(2)(+) ions were studied by using action infrared multiphoton dissociation (IRMPD) spectroscopy and fragment ion hydrogen-deuterium exchange (HDX). Five different Xxx-Pro b(2)(+) ions were studied, with glycine, alanine, isoleucine, valine, or histidine in the N-terminal position. The residues selected feature different sizes, chain lengths, and gas phase basicities to explore whether the structure of the N-terminal residue influences the Xxx-Pro b(2)(+) ion structure. In proteins, the proline side chain-to-backbone attachment causes its peptide bonds to be in the cis conformation more than any other amino acid, although trans is still favored over cis. However, HP is the only b(2)(+) ion studied here that forms the diketopiperazine exclusively. The GP, AP, IP, and VP b(2)(+) ions formed from protonated tripeptide precursors predominantly featured oxazolone structures with small diketopiperazine contributions. In contrast to the b(2)(+) ions generated from tripeptides, synthetic cyclic dipeptides VP and HP were confirmed to have exclusive diketopiperazine structures.


Smaller and larger deletions of the Williams Beuren syndrome region implicate genes involved in mild facial phenotype, epilepsy and autistic traits.
Williams Beuren syndrome (WBS) is a multisystemic disorder caused by a hemizygous deletion of 1.5 Mb on chromosome 7q11.23 spanning 28 genes. A few patients with larger and smaller WBS deletion have been reported. They show clinical features that vary between isolated SVAS to the full spectrum of WBS phenotype, associated with epilepsy or autism spectrum behavior. Here we describe four patients with atypical WBS 7q11.23 deletions. Two carry ~3.5 Mb larger deletion towards the telomere that includes Huntingtin-interacting protein 1 (HIP1) and tyrosine 3-monooxygenase/tryptophan 5-monooxigenase activation protein gamma (YWHAG) genes. Other two carry a shorter deletion of ~1.2 Mb at centromeric side that excludes the distal WBS genes BAZ1B and FZD9. Along with previously reported cases, genotype-phenotype correlation in the patients described here further suggests that haploinsufficiency of HIP1 and YWHAG might cause the severe neurological and neuropsychological deficits including epilepsy and autistic traits, and that the preservation of BAZ1B and FZD9 genes may be related to mild facial features and moderate neuropsychological deficits. This report highlights the importance to characterize additional patients with 7q11.23 atypical deletions comparing neuropsychological and clinical features between these individuals to shed light on the pathogenic role of genes within and flanking the WBS region.


Beaming light from a subwavelength aperture.
Light usually diffracts in all directions when it emerges from a subwavelength aperture, which puts a lower limit on the size of features that can be used in photonics. This limitation can be overcome by creating a periodic texture on the exit side of a single aperture in a metal film. The transmitted light emerges from the aperture as a beam with a small angular divergence (approximately +/-3 degrees ) whose directionality can be controlled. This finding is especially surprising, considering that the radiating region is mainly confined to an area with lateral dimensions comparable to the wavelength of the light. The device occupies no more than one cubic micrometer and, when combined with enhanced transmission, suggests that a wide range of photonic applications is possible.


Individual cognitive stimulation therapy for dementia: a clinical effectiveness and cost-effectiveness pragmatic, multicentre, randomised controlled trial.
Group cognitive stimulation therapy programmes can benefit cognition and quality of life for people with dementia. Evidence for home-based, carer-led cognitive stimulation interventions is limited. To evaluate the clinical effectiveness and cost-effectiveness of carer-delivered individual cognitive stimulation therapy (iCST) for people with dementia and their family carers, compared with treatment as usual (TAU). A multicentre, single-blind, randomised controlled trial assessing clinical effectiveness and cost-effectiveness. Assessments were at baseline, 13 weeks and 26 weeks (primary end point). Participants were recruited through Memory Clinics and Community Mental Health Teams for older people. A total of 356 caregiving dyads were recruited and 273 completed the trial. iCST consisted of structured cognitive stimulation sessions for people with dementia, completed up to three times weekly over 25 weeks. Family carers were supported to deliver the sessions at home. Primary outcomes for the person with dementia were cognition and quality of life. Secondary outcomes included behavioural and psychological symptoms, activities of daily living, depressive symptoms and relationship quality. The primary outcome for the family carers was mental/physical health (Short Form questionnaire-12 items). Health-related quality of life (European Quality of Life-5 Dimensions), mood symptoms, resilience and relationship quality comprised the secondary outcomes. Costs were estimated from health and social care and societal perspectives. There were no differences in any of the primary outcomes for people with dementia between intervention and TAU [cognition: mean difference -0.55, 95% confidence interval (CI) -2.00 to 0.90; p-value = 0.45; self-reported quality of life: mean difference -0.02, 95% CI -1.22 to 0.82; p-value = 0.97 at the 6-month follow-up]. iCST did not improve mental/physical health for carers. People with dementia in the iCST group experienced better relationship quality with their carer, but there was no evidence that iCST improved their activities of daily living, depression or behavioural and psychological symptoms. iCST seemed to improve health-related quality of life for carers but did not benefit carers' resilience or their relationship quality with their relative. Carers conducting more sessions had fewer depressive symptoms. Qualitative data suggested that people with dementia and their carers experienced better communication owing to iCST. Adjusted mean costs were not significantly different between the groups. From the societal perspective, both health gains and cost savings were observed. iCST did not improve cognition or quality of life for people with dementia, or carers' physical and mental health. Costs of the intervention were offset by some reductions in social care and other services. Although there was some evidence of improvement in terms of the caregiving relationship and carers' health-related quality of life, iCST does not appear to deliver clinical benefits for cognition and quality of life for people with dementia. Most people received fewer than the recommended number of iCST sessions. Further research is needed to ascertain the clinical effectiveness of carer-led cognitive stimulation interventions for people with dementia. Current Controlled Trials ISRCTN65945963. This project was funded by the National Institute of Health Research (NIHR) Health Technology Assessment (HTA) programme and will be published in full in Health Technology Assessment; Vol. 19, No. 64. See the NIHR Journals Library website for further information.


Intensity-dependent activation of the primary auditory cortex in functional magnetic resonance imaging.
The purpose of this study was to investigate the activation patterns of the primary auditory cortex in response to varying intensities of pure tone stimuli. A 1,000-Hz pure tone stimulus was delivered monaurally to the right ear of 12 normal-hearing right-handed volunteers in 20-second on-off cycles. Stimuli were applied at 20 and 50 dB hearing level (HL) above threshold in 12 subjects and at 0, 20, 40, and 50 dB HL above threshold in 6 subjects. Functional magnetic resonance imaging (fMRI) data were obtained using a 1.5-T scanner and echoplanar imaging. Activated pixels were identified in the transverse temporal gyrus (TTG) of both hemispheres in response to pure tone stimuli at each intensity level using cross-correlation analysis (0.6; P < 0.0001). Of the 24 right and left TTGs imaged (n = 12), activation to pure tone stimuli at 20 and 50 dB HL above threshold was seen in 46% and 79% of TTGs, respectively, with bilateral hemispheric activation in 27% and 64% of subjects, respectively. The mean numbers of activated voxels were 4.0 and 13.0, respectively. Of the 12 right and left TTGs imaged at 0, 20, 40, and 50 dB HL above threshold, activation was seen in 33%, 42%, 58%, and 75% of TTGs, respectively. The mean numbers of activated voxels were 5.8, 3.2, 9.8, and 15.3, respectively. There was a nonsignificant trend toward contralateral (left) dominant TTG activation with increased tone intensity. Our results show an increased likelihood of TTG activation, increased TTG activation volume, and increased bilateral hemisphere TTG activation with increasing pure tone intensity. Our results suggest that the primary auditory cortex reflects or is directly involved in the central processing of sound intensity and that varying the intensity of even simple stimuli can alter the patterns of fMRI activation in auditory cortex.


Marijuana Use in Adults Living with Sickle Cell Disease.
Introduction: Legal access to marijuana, most frequently as "medical marijuana," is becoming more common in the United States, but most states do not specify sickle cell disease as a qualifying condition. We were aware that some of our patients living with sickle cell disease used illicit marijuana, and we sought more information about this. Materials and Methods: We practice at an urban, academic medical center and provide primary, secondary, and tertiary care for ∼130 adults living with sickle cell disease. We surveyed our patients with a brief, anonymous, paper-and-pen instrument. We reviewed institutional records for clinically driven urine drug testing. We tracked patient requests for certification for medical marijuana. Results: Among 58 patients surveyed, 42% reported marijuana use within the past 2 years. Among users, most endorsed five medicinal indications; a minority reported recreational use. Among 57 patients who had at least one urine drug test, 18% tested positive for cannabinoids only, 12% tested positive for cocaine and/or phencyclidine only, and 5% tested positive for both cannabinoids and cocaine/phencyclidine. Subsequent to these studies, sickle cell disease became a qualifying condition for medical marijuana in our state. In the interval ∼1.5 years, 44 patients have requested certification. Conclusion: Our findings and those of others create a rationale for research into the possible therapeutic effects of marijuana or cannabinoids, the presumed active constituents of marijuana, in sickle cell disease. Explicit inclusion of sickle cell disease as a qualifying condition for medical marijuana might reduce illicit marijuana use and related risks and costs to both persons living with sickle cell disease and society.


Prevalence of overweight and obesity and their association with hypertension and diabetes mellitus in an Indo-Asian population.
The associations of body mass index (BMI) and chronic disease may differ between Indo-Asian and Western populations. We used Indo-Asian-specific definitions of overweight and obesity to determine the prevalence of these problems in Pakistan and studied the sensitivity and specificity of BMI cutoff values for an association with hypertension and diabetes mellitus. We analyzed data for 8972 people aged 15 years or more from the National Health Survey of Pakistan (1990-1994). People considered overweight or obese were those with a BMI of 23 kg/m2 or greater, and those considered obese as having a BMI of 27 kg/m2 or greater. We built multivariable models and performed logistic regression analysis. The prevalence of overweight and obesity, weighted to the general Pakistani population, was 25.0% (95% confidence interval [CI] 21.8%-28.2%). The prevalence of obesity was 10.3% (95% CI 7.0%-13.2%). The factors independently and significantly associated with overweight and obesity included greater age, being female, urban residence, being literate, and having a high (v. low) economic status and a high (v. low) intake of meat. With receiver operating characteristic curves, we found that the use of even lower BMI cutoff values (21.2 and 22.1 kg/m2 for men and 21.2 and 22.9 kg/m2 for women) than those recommended for an Indo-Asian population yielded the optimal areas under the curve for an association with hypertension and diabetes, respectively. A quarter of the population of Pakistan would be classified as overweight or obese with the use of Indo-Asian-specific BMI cutoff values. Optimal identification of those at risk of hypertension and diabetes and healthy targets may require the use of even lower BMI cutoff values than those already proposed for an Indo-Asian population.


Plasmonic detection of a model analyte in serum by a gold nanorod sensor.
We describe the fabrication of a label-free, chip-based biosensor based on the localized surface plasmon resonance (LSPR) of gold nanorods. Gold nanorods were chemisorbed onto a mercaptosilane-modified glass substrate, followed by conjugation of biotin to the nanorods. Streptavidin binding to biotin was monitored by the wavelength shift of the LSPR peak in the UV-vis extinction spectrum of the immobilized gold nanorods due to the change in local refractive index at the gold nanorod surface induced by streptavidin binding. The limit of detection of the sensor is 0.005 microg/mL (94 pM) in PBS and 1 microg/mL (19 nM) in serum, and the dynamic range spans 94 pM to 0.19 microM. The advantages of the nanorod-based sensor over an LSPR sensor that we had previously fabricated from gold nanospheres (Nath, N.; Chilkoti, A. Anal. Chem. 2002, 74, 504-509; J. Fluoresc. 2004, 14, 377-389; Anal. Chem. 2004, 76, 5370-5378) are the significantly lower detection limit and the internal self-reference that the signal of the nanorod sensor provides based on the measurement of peak wavelength shift.


Like a rolling stone: Colonization and migration dynamics of the gray reef shark (Carcharhinus amblyrhynchos).
Designing appropriate management plans requires knowledge of both the dispersal ability and what has shaped the current distribution of the species under consideration. Here, we investigated the evolutionary history of the endangered gray reef shark (Carcharhinus amblyrhynchos) across its range by sequencing thousands of RADseq loci in 173 individuals in the Indo-Pacific (IP). We first bring evidence of the occurrence of a range expansion (RE) originating close to the Indo-Australian Archipelago (IAA) where two stepping-stone waves (east and westward) colonized almost the entire IP. Coalescent modeling additionally highlighted a homogenous connectivity (Nm ~ 10 per generation) throughout the range, and isolation by distance model suggested the absence of barriers to dispersal despite the affinity of C. amblyrhynchos to coral reefs. This coincides with long-distance swims previously recorded, suggesting that the strong genetic structure at the IP scale (F ST ~ 0.56 between its ends) is the consequence of its broad current distribution and organization in a large number of demes. Our results strongly suggest that management plans for the gray reef shark should be designed on a range-wide rather than a local scale due to its continuous genetic structure. We further contrasted these results with those obtained previously for the sympatric but strictly lagoon-associated Carcharhinus melanopterus, known for its restricted dispersal ability. Carcharhinus melanopterus exhibits a similar RE dynamic but is characterized by a stronger genetic structure and a nonhomogeneous connectivity largely dependent on local coral reefs availability. This sheds new light on shark evolution, emphasizing the roles of IAA as source of biodiversity and of life-history traits in shaping the extent of genetic structure and diversity.


Change in viral bronchiolitis management in primary care in the UK after the publication of NICE guideline.
The aim of this study was to investigate changes in general practitioner (GP) management before and after the publication of the National Institute for Health and Care Excellence bronchiolitis guideline. In March 2015 and May 2016, an electronic questionnaire was sent to GPs. It was completed by 1001 GPs in 2015 and 1009 in 2016. There were small but significant improvements in proportions of GPs using a guideline, measuring oxygen saturations and providing written guidance, and appropriate reductions in those prescribing medications. Thirty-five per cent had read the guideline and 25% changed their practice since guideline publication. There were modest but significant improvements in reported management by GPs after guideline publication.


Impaired homocysteine metabolism in patients with alcoholic liver disease in Taiwan.
Impaired homocysteine metabolism plays an important role in alcoholic liver disease (ALD); however, there are limited data about its relationship with the risk and severity of patients with ALD in Taiwan. To understand plasma homocysteine and related vitamin concentrations in patients with ALD in Taiwan, we recruited 50 male patients with ALD from Cathay General Hospital, with 49 age-and gender-matched healthy adults as the control group. The Institutional Review Board for Human Studies approved the study, and informed consent was obtained from all patients prior to blood collection. Significantly higher plasma homocysteine concentrations but lower folate concentrations were obtained from patients with ALD. In addition, patients with ALD showed a significant lower erythrocyte reduced glutathione (GSH)/oxidized glutathione (GSSG) ratio but higher plasma thiobarbituric acid-reactive substance (TBARS) concentration, which indicated that oxidative stress was occurring in patients with ALD. A negative correlation between plasma folate and homocysteine was observed in all subjects. There was also a negative correlation between plasma homocysteine and the erythrocyte GSH/GSSG ratio which indicated impaired homocysteine metabolism may have disrupted the antioxidative status. In addition, patients in Child-Pugh Class B and C showed higher plasma vitamin B12 concentrations than did patients without cirrhosis and patients in Child-Pugh Class A. These findings show that impaired homocysteine metabolism was observed in patients with ALD in Taiwan. In addition, the plasma vitamin B12 concentration may reflect the degree of liver injury.


MTG16 is a tumor suppressor in colitis-associated carcinoma.
MTG16 is a member of the myeloid translocation gene (MTG) family of transcriptional corepressors. While MTGs were originally identified in chromosomal translocations in acute myeloid leukemia, recent studies have uncovered a role in intestinal biology. For example, Mtg16-/- mice have increased intestinal proliferation and are more sensitive to intestinal injury in colitis models. MTG16 is also underexpressed in patients with moderate/severe ulcerative colitis. Based on these findings, we postulated that MTG16 might protect against colitis-associated carcinogenesis. MTG16 was downregulated at the protein and RNA levels in patients with inflammatory bowel disease and in those with colitis-associated carcinoma. Mtg16-/- mice subjected to inflammatory carcinogenesis modeling exhibited worse colitis and increased tumor multiplicity and size. Loss of MTG16 also increased severity of dysplasia, apoptosis, proliferation, DNA damage, and WNT signaling. Moreover, transplantation of WT marrow into Mtg16-/- mice failed to rescue the Mtg16-/- protumorigenic phenotypes, indicating an epithelium-specific role for MTG16. While MTG dysfunction is widely appreciated in hematopoietic malignancies, the role of this gene family in epithelial homeostasis, and in colon cancer, was unrealized. This report identifies MTG16 as an important modulator of colitis and tumor development in inflammatory carcinogenesis.