Low Geographic and Subspecific Variation in the Loud Call of the Widespread and Phenotypically Cryptic Northern Lesser Galago (Galago senegalensis) Suggests Taxonomic Uniformity.
Like other nocturnal primates, many species of galago (Galagidae) are phenotypically cryptic, making their taxonomic status difficult to resolve. Recent taxonomic work has disentangled some of the confusion. This has resulted in an increase in the number of recognised galago species. The most widespread galago species, and indeed the most widespread nocturnal primate, is the northern lesser galago (Galago senegalensis) whose geographic range stretches >7,000 km across Africa. Based on morphology, 4 subspecies are currently recognised: G. s. senegalensis, G. s. braccatus, G. s. sotikae and G. s. dunni. We explore geographic and subspecific acoustic variation in G. senegalensis, testing three hypotheses: isolation by distance, genetic basis, and isolation by barrier. There is statistical support for isolation by distance for 2 of 4 call parameters (fundamental frequency and unit length). Geographic distance explains a moderate amount of the acoustic variation. Discriminant function analysis provides some degree of separation of geographic regions and subspecies, but the percentage of misdesignation is high. Despite having (putative) parapatric geographic ranges, the most pronounced acoustic differences are between G. s. senegalensis and G. s. dunni. The findings suggest that the Eastern Rift Valley and Niger River are significant barriers for G. senegalensis. The acoustic structures of the loud calls of 121 individuals from 28 widespread sites are not significantly different. Although this makes it unlikely that additional unrecognised species occur within G. senegalensis at the sites sampled, vast areas of the geographic range remain unsampled. We show that wide-ranging species do not necessarily exhibit large amounts of variation in their vocal repertoire. This pattern may also be present in nocturnal primates with smaller geographic ranges.


Efficacy of Enamel Matrix Derivative in Vital Pulp Therapy: A Review of Literature.
Vital pulp therapy (VPT) aims to preserve the health and maintain life of the tooth pulp which has been compromised by caries, trauma or restorative procedures. Recently, enamel matrix derivative (EMD) has been introduced as a material for vital pulp therapy. The aim of this review is to critically analyze and summarize the available literature on EMD for VPT. Online databases (PubMED/MEDLINE, Google Scholar, ISI Web of Science, and Wiley-Online) were searched by using the following keywords in various combinations: Enamel Matrix Derivative, Emdogain, 'Vital Pulp Therapy, 'Apexogenisis', Apexification, Pulp Capping, Endodontics, Dentine and Pulpotomy for studies indexed from January 1949 to April 2016. We used an English-limited search in Google.co.uk for the missing grey literature. All studies fulfilling the selection criteria were carefully reviewed for the focused question: "Does using EMD in VPT, compared with other materials, result in better clinical, radiographic and histological outcomes?". The primary search resulted in 18 articles of which, 14 articles (including 6 animal studies and 6 clinical trials and 2 case reports) met the inclusion criteria for this review and hence were included. The number of teeth tested in the animal studies ranged from 8 to 144 including pigs, rats and dogs teeth. A number of studies used EMD in the experimental group in comparison with calcium hydroxide, propylene glycol alginate (PGA) and MTA as a control. The observation period ranged from 1 to 2 months and 4 out of 6 animal trials reported more favorable outcomes with EMD while two studies reported comparable outcomes. Although EMD has potential for various applications in endodontics, studies conducted to date have failed to demonstrate any significant advantage of EMD over conventional VPT materials. Additionally, the 5-year and 10-year survival rate of EMD-treated teeth is not yet known. Hence, studies with a longer follow-up periods are required to deduce the long-term viability of teeth treated with EMD.


Time-domain analysis of bandgap characteristics of two-dimensional periodic structures by use of a source-model technique.
We introduce a time-domain source-model technique for analysis of two-dimensional, transverse-magnetic, plane-wave scattering by a photonic crystal slab composed of a finite number of identical layers, each comprising a linear periodic array of dielectric cylinders. The proposed technique takes advantage of the periodicity of the slab by solving the problem within a unit cell of the periodic structure. A spectral analysis of the temporal behavior of the fields scattered by the slab shows a clear agreement between frequency bands where the spectral density of the transmitted energy is low and the bandgaps of the corresponding two-dimensionally infinite periodic structure. The effect of the bandwidth of the incident pulse and its center frequency on the manner it is transmitted through and reflected by the slab is studied via numerical examples.


The ethics of state-sponsored and clinical promotion of long-acting reversible contraception.
To review ethical aspects of the promotion and provision of long-acting reversible contraception (LARC). Specifically, to examine (1) the tension between informational exchange and the active promotion of LARC methods to new and existing contraceptive users by healthcare professionals; and (2) the distinct ethical issues arising from the promotion of LARC methods by state-sponsored actors and healthcare professionals. Narrative review and ethical analysis. There is an ethical difference between raising awareness/informational provision and actively promoting or prioritising specific contraceptive methods. It matters whether the policy choice is made, or the promotional activity about contraception is undertaken, by individual healthcare professionals at a local level or by more remote state-sponsored actors, because the relationship between the promoter and the (potential) contraceptive user is of a different kind. Imposing a dual responsibility upon healthcare professionals for raising awareness/informational exchange and the active promotion of LARC creates an unnecessary tension and barrier for the delivery of patient-centred care. This review highlights the need for ethical reflection on the central role of the promoting agent and the distinction between facilitating informational awareness and active promotion of LARC. LARC methods should not be prioritised in isolation and without regard to the wider implications of public promotion. A balanced narrative and information-sharing programme that respects the individual interests of each contraceptive user is called for, especially in direct professional/service user relationships. No assumption should be made that user decision-making will necessarily be determined and influenced solely by the relative effectiveness of the contraceptive method.


Low rate of large polyps (>9 mm) within 10 years after an adequate baseline colonoscopy with no polyps.
Guidelines recommend a 10-year interval between screening colonoscopies with negative results for average-risk individuals. However, many patients are examined at shorter intervals. We investigated outcomes of individuals with no polyps who had repeat colonoscopy in <10 years. Data were collected using the National Endoscopic Database, from 69 gastroenterology centers, on 264,184 asymptomatic subjects who underwent screening colonoscopies from 2000 through 2006, were found to have no polyps, and received another colonoscopy examination within <10 years. No polyps were found in 147,375 patients during a baseline colonoscopy; 17,525 patients (11.9%) had a follow-up colonoscopy within <10 years, including 1806 (10.3%) who received the follow-up colonoscopy within <1 year. The most common reason for repeating the examination within 1 year was that the first was compromised by inadequate bowel preparation or incomplete examination. Of these patients, 6.5% (95% confidence interval: 5.3-7.6) had large polyp(s) >9 mm-a proportion similar to the prevalence in the average-risk screening population. Reasons that examinations were repeated within 1-5 years included average-risk screening (15.7%), family history of colon polyps or cancer (30.1%), bleeding (31.2%), gastrointestinal symptoms (11.8%), or a positive result from a fecal blood test (5.5%). If the baseline examination was adequate, the incidence of large polyps within 1-5 years after baseline colonoscopy was 3.1% (95% confidence interval: 2.7-3.5) and within years 5-10 years was 3.7% (95% confidence interval: 3.3-4.1). Repeat colonoscopies within 10 years are of little benefit to patients who had adequate examinations and were found to have no polyps. Repeat colonoscopies are beneficial to patients when the baseline examination was compromised.


Towards multi-order hard X-ray imaging with multilayer zone plates.
This article describes holographic imaging experiments using a hard X-ray multilayer zone plate (MZP) with an outermost zone width of 10 nm at a photon energy of 18 keV. An order-sorting aperture (OSA) is omitted and emulated during data analysis by a 'software OSA'. Scanning transmission X-ray microscopy usually carried out in the focal plane is generalized to the holographic regime. The MZP focus is characterized by a three-plane phase-retrieval algorithm to an FWHM of 10 nm.


Blood pressure and heart rate responses to centrally administered substance P are increased in spontaneously hypertensive rats.
1. The cardiovascular effects after intracerebroventricular injections of substance P were investigated in normotensive Wistar-Kyoto and in spontaneously hypertensive rats. 2. Substance P increased blood pressor in both rat strains. Wistar-Kyoto rats responded with moderate, dose-dependent blood pressure increases, and heart rate decreased; spontaneously hypertensive rats showed two- to three-fold increased pressor effects and, concomitantly, marked heart rate increases to intracerebroventricular injections of substance P. 3. Sino-aortic baroreceptor denervation rendered Wistar-Kyoto rats supersensitive to intracerebroventricular substance P to a similar degree as unoperated spontaneously hypertensive rats. Sino-aortic denervation had no effect on the blood pressure responses to the peptide in spontaneously hypertensive rats. 4. The central pressure actions of substance P could be markedly attenuated by intracerebroventricular pretreatment with the derivative of gamma-aminobutyric acid, baclofen. 5. We conclude that the baroreceptor reflex is disturbed in spontaneously hypertensive rats. Substance P may contribute to the pathogenesis of hypertension. The effector pathways appear to be different from angiotensin.


Pediatric Primary Care-Based Obesity Prevention for Parents of Preschool Children: A Pilot Study.
The Healthy Homes/Healthy Kids Preschool (HHHK-Preschool) pilot program is an obesity prevention intervention integrating pediatric care provider counseling and a phone-based program to prevent unhealthy weight gain among 2- to 4-year-old children at risk for obesity (BMI percentile between the 50th and 85th percentile and at least one overweight parent) or currently overweight (85th percentile ≤ BMI < 95th percentile). The aim of this randomized, controlled pilot study was to evaluate the feasibility, acceptability, and potential efficacy of the HHHK-Preschool intervention. Sixty parent-child dyads recruited from pediatric primary care clinics were randomized to: (1) the Busy Bodies/Better Bites Obesity Prevention Arm or the (2) Healthy Tots/Safe Spots safety/injury prevention Contact Control Arm. Baseline and 6-month data were collected, including measured height and weight, accelerometry, previous day dietary recalls, and parent surveys. Intervention process data (e.g., call completion) were also collected. High intervention completion and satisfaction rates were observed. Although a statistically significant time by treatment interaction was not observed for BMI percentile or BMI z-score, post-hoc examination of baseline weight status as a moderator of treatment outcome showed that the Busy Bodies/Better Bites obesity prevention intervention appeared to be effective among children who were in the overweight category at baseline relative to those who were categorized as at risk for obesity (p = 0.04). HHHK-Preschool pilot study results support the feasibility, acceptability, and potential efficacy in already overweight children of a pediatric primary care-based obesity prevention intervention integrating brief provider counseling and parent-targeted phone coaching. What's New: Implementing pediatric primary care-based obesity interventions is challenging. Previous interventions have primarily involved in-person sessions, a barrier to sustained parent involvement. HHHK-preschool pilot study results suggest that integrating brief provider counseling and parent-targeted phone coaching is a promising approach.


The use of multiple novel tumor biomarkers for the detection of ovarian carcinoma in patients with a pelvic mass.
The CA125 tumor marker is used to help predict the presence of ovarian cancer in patients with an adnexal mass. Because elevated CA125 levels occur in many benign gynecologic conditions, we set out to identify other novel biomarkers that would increase the sensitivity and specificity of CA125. Serum and urine samples were obtained preoperatively from women undergoing surgery for an adnexal mass. The samples were analyzed for levels of CA125, SMRP, HE4, CA72-4, activin, inhibin, osteopontin, epidermal growth factor (EGFR), and ERBB2 (Her2) and were compared to final pathology results. Logistic regression models were estimated for all markers and combinations, with cross-validation analysis performed to obtain the sensitivities at set specificities of 90%, 95%, and 98%. Two hundred and fifty-nine patients with adnexal masses were enrolled. Of these, 233 patients were eligible for analysis with 67 invasive epithelial ovarian cancers and 166 benign ovarian neoplasms. Mean values for all marker levels except Her2 differed significantly between patients with benign masses and cancer. As a single marker, HE4 had the highest sensitivity at 72.9% (specificity 95%). Comparatively, combined CA125 and HE4 yielded the highest sensitivity at 76.4% (specificity 95%), with additional markers adding minimally to the sensitivity of this combination. HE4 was the best single marker for Stage I disease, with no increase in sensitivity when combined with CA125 or any other marker. As a single tumor marker, HE4 had the highest sensitivity for detecting ovarian cancer, especially Stage I disease. Combined CA125 and HE4 is a more accurate predictor of malignancy than either alone.


Coronary angiography in worsening heart failure: determinants, findings and prognostic implications.
Coronary angiography is regularly performed in patients with worsening signs and/or symptoms of heart failure (HF). However, little is known on the determinants, findings and associated clinical outcomes of coronary angiography performed in patients with worsening HF. The BIOSTAT-CHF (a systems BIOlogy Study to TAilored Treatment in Chronic Heart Failure) programme enrolled 2516 patients with worsening symptoms and/or signs of HF, either hospitalised or in the outpatient setting. All patients were included in the present analysis. Of the 2516 patients included, 315 (12.5%) underwent coronary angiography within the 30 days after the onset of worsening symptoms and/or signs of HF. Subjects who underwent angiography were more often observed as inpatients, had more often an overt acute coronary syndrome, had higher troponin I levels, were younger and had better renal function (all p≤0.01). Patients who underwent coronary angiography had a lower risk of the primary outcome of death and/or HF hospitalisation (adjusted HR=0.71, 95% CI 0.57 to 0.89, p=0.003) and death (adjusted HR=0.59, 95% CI 0.43 to 0.80, p=0.001). Among the patients who underwent coronary angiography, those with a coronary stenosis (39%) had a worse prognosis than those without stenosis (adjusted HR for the primary outcome=1.71, 95% CI 1.10 to 2.64, p=0.016). Coronary angiography was performed in <13% of patients with symptoms and/or signs of worsening HF. These patients were remarkably different from those who did not undergo coronary angiography and had a lower risk of subsequent events. The presence of coronary stenosis on coronary angiography was associated with a worse prognosis.


Functional response of healthy and diseased glomeruli to a large, protein-rich meal.
Differential solute clearances and hormone assays were used to characterize the effect of a large, protein-rich meal (1.5 g/kg) on glomerular function in 12 healthy volunteers (group I) and 12 patients with chronic glomerular disease (group II). Changes from baseline during 3 h after the meal included an elevation of plasma osmolality, progressive urinary concentration, and increasingly positive fluid balance. Plasma renin activity and arginine vasopressin levels (measured in group II only) increased significantly. Nevertheless, the rate of peak postmeal renal plasma flow became elevated by 13 and 33% in groups I and II, respectively. Corresponding peak increases in postmeal glomerular filtration rate exceeded baseline by 10 and 16%. In the proteinuric subjects of group II the fractional clearances of albumin, IgG and uncharged dextrans in the radius interval 36-54 A, declined significantly after the meal. A similar depression of the fractional dextran-clearance profile was observed also in group I. Applying the fractional clearances of relatively permeant dextrans (radii less than or equal to 44 A) to a model of hindered solute transport through an isoporous membrane, we estimate that transmembrane hydraulic pressure difference increased by 12% in group I and by between 0 to 12% in group II after protein ingestion. We conclude (i) that oral protein ingestion increases glomerular ultrafiltration pressure and rate in both normal and diseased glomeruli, (ii) that this hemodynamic response may be mediated in part by the glomerulopressor hormones angiotensin II and arginine vasopressin, and (iii) that the foregoing hemodynamic changes exert no acute adverse effect on glomerular barrier size-selectivity.


Molecular Diagnostics and Genetic Counseling in Primary Congenital Glaucoma.
Primary congenital glaucoma (PCG) is a childhood irreversible blinding disorder with onset at birth or in the first year of life. It is characterized by the classical traid of symptoms viz. epiphora (excessive tearing), photophobia (hypersensitivity to light) and blepharospasm (inflammation of eyelids). The only anatomical defect seen in PCG is trabecular meshwork dysgenesis. PCG shows autosomal recessive mode of inheritance with considerable number of sporadic cases. The etiology of this disease has not been fully understood but some genes like CYP1B1, MYOC, FOXC1, LTBP2 have been implicated. Various chromosomal aberrations and mutations in mitochondrial genome have also been reported. Molecular biology has developed novel techniques in order to do genetic and biochemical characterization of many genetic disorders including PCG. Techniques like polymerase chain reaction, single strand conformational polymorphism and sequencing are already in use for diagnosis of PCG and other techniques like protein truncation testing and functional genomics are beginning to find their way into molecular workout of this disorder. In the light of its genetic etiology, it is important to develop methods for genetic counseling for the patients and their families so as to bring down its incidence. In this review, we ought to develop a genetic insight into PCG with possible use of molecular biology and functional genomics in understanding the disease etiology, pathogenesis, pathology and mechanism of inheritance. We will also discuss the possibilities and use of genetic counseling in this disease. How to cite this article: Faiq M, Mohanty K, Dada R, Dada T. Molecular Diagnostics and Genetic Counseling in Primary Congenital Glaucoma. J Current Glau Prac 2013;7(1):25-35.


Molecular analysis of dispersal in giant pandas.
Although dispersal in the giant panda (Ailuropoda melanoleuca) is a demographic mechanism which can potentially counteract the negative effect of habitat fragmentation, little is known about dispersal in this species because of difficulties in observing individuals. Using data from faecal microsatellite genotyping, we compared the spatial distribution of giant pandas in two populations and the proximity of relatives in one key population to infer their dispersal pattern. We conclude that giant pandas exhibit female-biased dispersal because: (i) vAIc (variance of assignment index) for females was significantly larger than for males, suggesting that females comprise both 'local' and 'foreign' genotypes; (ii) the average spatial distance of related female dyads was significantly larger than that of males; (iii) larger r (relatedness), F(ST) (genetic variance among populations) and mAIc (mean of assignment index) values were found in males using the software FSTAT, although the differences were not significant; (iv) males set up territories neighbouring to their birth place; (v) significant population structure using microsatellites with a concomitant lack of mitochondrial structure was found in a previous study, possibly indicating more extensive female dispersal; and (vi) female-biased dispersal was strongly supported by evidence from concomitant ecological studies. Considering previous ecological data and life-history characteristics of the giant panda, female-biased dispersal is most likely to be due to competition for birth dens among females, inbreeding avoidance and enhancing inclusive fitness among related males.


Protective effect of brown Brazilian propolis against acute vaginal lesions caused by herpes simplex virus type 2 in mice: involvement of antioxidant and anti-inflammatory mechanisms.
Propolis has been highlighted for its antioxidant, anti-inflammatory and antiviral properties. The purpose of this study was to investigate if brown Brazilian hydroalcoholic propolis extract (HPE) protects against vaginal lesions caused by herpes simplex virus type 2 (HSV-2) in female BALB/c mice. The treatment was divided in 5 days of pre-treatment with HPE [50 mg · kg(-1), once a day, intragastric (i.g.)], HSV-2 infection [10 µl of a solution 1 × 10(2) plaque-forming unit (PFU · ml(-1) HSV-2), intravaginal inoculation at day 6] and post-treatment with HPE (50 mg · kg(-1)) for 5 days more. At day 11, the animals were killed, and the in vivo analysis (score of lesions) and ex vivo analysis [haematological and histological evaluation; superoxide dismutase (SOD), catalase (CAT) and myeloperoxidase (MPO) activities; reactive species (RS), tyrosine nitration levels, non-protein thiols (NPSH) and ascorbic acid (AA) levels] were carried out. HPE treatment reduced extravaginal lesions and the histological damage caused by HSV-2 infection in vaginal tissues of animals. HPE was able to decrease RS, tyrosine nitration, AA levels and MPO activity. Also, it protected against the inhibition of CAT activity in vaginal tissues of mice. HPE promoted protective effect on HSV-2 infected animals by acting on inflammatory and oxidative processes, and this effect probably is caused by its antioxidant and anti-inflammatory properties.


MicroRNAs in adipose tissue: their role in adipogenesis and obesity.
MicroRNAs (miRNAs) are endogenous small RNAs that posttranscriptionally regulate gene expression and that have been shown to have important roles in numerous disease processes. There is growing evidence for an important role of miRNAs in regulating the pathways in adipose tissue that control a range of processes including adipogenesis, insulin resistance and inflammation. Several high-throughput studies have identified differentially expressed miRNAs in adipose tissue pathology and during adipogenesis and a number of these have now been characterised functionally in terms of their actions and targets. This review will summarise the current literature on miRNAs in adipose tissue, as well as discussing the methodologies used in this area of research and the potential application of miRNAs as biomarkers and as therapeutic targets.


Spontaneous complete remission of type 1 diabetes mellitus in an adult - review and case report.
Type 1 diabetes mellitus (T1DM) is an autoimmune condition that results in low plasma insulin levels by destruction of beta cells of the pancreas. As part of the natural progression of this disease, some patients regain beta cell activity transiently. This period is often referred to as the 'honeymoon period' or remission of T1DM. During this period, patients manifest improved glycemic control with reduced or no use of insulin or anti-diabetic medications. The incidence rates of remission and duration of remission is extremely variable. Various factors seem to influence the remission rates and duration. These include but are not limited to C-peptide level, serum bicarbonate level at the time of diagnosis, duration of T1DM symptoms, haemoglobin A1C (HbA1C) levels at the time of diagnosis, sex, and age of the patient. Mechanism of remission is not clearly understood. Extensive research is ongoing in regard to the possible prevention and reversal of T1DM. However, most of the studies that showed positive results were small and uncontrolled. We present a 32-year-old newly diagnosed T1DM patient who presented with diabetic ketoacidosis (DKA) and HbA1C of 12.7%. She was on basal bolus insulin regimen for the first 4 months after diagnosis. Later, she stopped taking insulin and other anti-diabetic medications due to compliance and logistical issues. Eleven months after diagnosis, her HbA1C spontaneously improved to 5.6%. Currently (14 months after T1DM diagnosis), she is still in complete remission, not requiring insulin therapy.


Doctors' views about their first postgraduate year in UK medical practice: House officers in 2003.
To report house officers' views in 2003 of their first postgraduate year, and to compare their responses with those of house officers 2 and 3 years previously. Postal questionnaires to all house officers in 2003 who graduated from UK medical schools in 2002. The response rate was 65.3% (2778/4257). The house officers of 2003 enjoyed the year more than those of 2000-1. A total of 78% of respondents in 2003 scored 7-10 in reply to the question 'How much have you enjoyed the house officer year overall?', scored from 0 (no enjoyment) to 10 (enjoyed it greatly), compared with 70% of 2000-1 house officers. They were more satisfied with leisure time available to them (51% scoring 6-10 in 2003; 35% in 2000-1). There were significant improvements in almost every aspect of doctors' experience. Hospital medical posts were rated more highly than surgical posts, and general practice posts higher still. Overall, 38% of respondents regarded their training as having been of a high standard, and 37% felt that they received constructive feedback on their performance. Differences between men and women in their views about their jobs were small. The house officers of 2003 reported more positively on their experiences than did those of 2000-1. Although a substantial percentage were negative about specific aspects of clinical support and training, particularly in surgical posts, almost all the responses covering training and clinical support moved in a favourable direction over time.


Proton Environments in Biomimetic Calcium Phosphates Formed from Mesoporous Bioactive CaO-SiO2-P2O5 Glasses in Vitro: Insights from Solid-State NMR.
When exposed to body fluids, mesoporous bioactive glasses (MBGs) of the CaO-SiO2-P2O5 system develop a bone-bonding surface layer that initially consists of amorphous calcium phosphate (ACP), which transforms into hydroxy-carbonate apatite (HCA) with a very similar composition as bone/dentin mineral. Information from various 1H-based solid-state nuclear magnetic resonance (NMR) experiments was combined to elucidate the evolution of the proton speciations both at the MBG surface and within each ACP/HCA constituent of the biomimetic phosphate layer formed when each of three MBGs with distinct Ca, Si, and P contents was immersed in a simulated body fluid (SBF) for variable periods between 15 min and 30 days. Directly excited magic-angle-spinning (MAS) 1H NMR spectra mainly reflect the MBG component, whose surface is rich in water and silanol (SiOH) moieties. Double-quantum-single-quantum correlation 1H NMR experimentation at fast MAS revealed their interatomic proximities. The comparatively minor H species of each ACP and HCA component were probed selectively by heteronuclear 1H-31P NMR experimentation. The initially prevailing ACP phase comprises H2O and "nonapatitic" HPO42-/PO43- groups, whereas for prolonged MBG soaking over days, a well-progressed ACP → HCA transformation was evidenced by a dominating O1H resonance from HCA. We show that 1H-detected 1H → 31P cross-polarization NMR is markedly more sensitive than utilizing powder X-ray diffraction or 31P NMR for detecting the onset of HCA formation, notably so for P-bearing (M)BGs. In relation to the long-standing controversy as to whether bone mineral comprises ACP and/or forms via an ACP precursor, we discuss a recently accepted structural core-shell picture of both synthetic and biological HCA, highlighting the close relationship between the disordered surface layer and ACP.


Drinking water fluoridation: bone mineral density and hip fracture incidence.
The role of drinking water fluoride content for prevention of osteoporosis remains controversial. Therefore, we analyzed the influence of drinking water fluoridation on the incidence of osteoporotic hip fractures and bone mineral density (BMD) in two different communities in eastern Germany: in Chemnitz, drinking water was fluoridated (1 mg/L) over a period of 30 years; in Halle, the water was not fluoridated. BMD was measured in healthy hospital employees aged 20-60 years (Halle: 214 women, 98 men; Chemnitz: 201 women, 43 men, respectively) using dual-energy X-ray absorptiometry. Hip fractures in patients > or = 35 years admitted to the local hospitals in the years 1987-1989 were collected from the clinic registers. There was no difference in age, anthropometric, hormonal, or lifestyle variables between the two groups. Mean fluoride exposure in Chemnitz was 25.2 +/- 7.3 years. No correlation was found between fluoride exposure and age-adjusted BMD. We found no significant difference in spinal or femoral BMD between subjects living in Halle and Chemnitz [lumbar spine: 0.997 +/- 0.129 (g/cm2) vs. 1.045 + 0.171 (g/cm2), p = 0.08, for men; 1.055 +/- 0.112 (g/cm2) vs. 1.046 +/- 0.117 (g/cm2), p = 0.47, for women]. The fracture incidence showed an exponential increase with aging in men and women with an incidence about 3.5 times higher for women. In Chemnitz, we calculated an age-adjusted annual incidence of 142.2 per 100,000 for women and 72.5 per 100,000 for men, respectively. In Halle, the incidences were 178.5 per 100,000 for women and 89.2 per 100,000 for men. There was a lower hip fracture incidence after the age of 85 in women in Chemnitz (1391 per 100,000 in Chemnitz vs. 1957 per 100,000) in Halle, p = 0.006). Using the age-adjusted incidences, significantly fewer hip fractures occurred in Chemnitz in both men and women. In conclusion, our study suggests that optimal drinking water fluoridation (1 mg/L), which is advocated for prevention of dental caries, does not influence peak bone density but may reduce the incidence of osteoporotic hip fractures in the very old.


Advances in biotechnological synthetic applications of carbon nanostructured systems.
In the last few years carbon nanostructures have been applied for the immobilization of enzymes and biomimetic organo-metallic species useful for biotechnological applications. The nature of the support and the method of immobilization are responsible for the stability, reactivity and selectivity of the system. In this review, we focus on the recent advances in the use of carbon nanostructures, carbon nanotubes, carbon nanorods, fullerene and graphene for the preparation of biocatalytic and biomimetic systems and for their application in the development of green chemical processes.


Enhancement of the Replication of Hepatitis C Virus Replicons of Genotypes 1 to 4 by Manipulation of CpG and UpA Dinucleotide Frequencies and Use of Cell Lines Expressing SECL14L2 for Antiviral Resistance Testing.
Treatment for hepatitis C virus (HCV) has improved greatly through the use of direct-acting antivirals (DAAs). However, their effectiveness and potential for drug resistance development in non-genotype 1 variants of HCV remain relatively unexplored, as in vitro assays to assess drug susceptibility are poorly developed and unsuited for a transient-transfection format. In the current study, we have evaluated the effects of dinucleotide frequency changes in the replicon and the use of a SEC14L2-expressing cell line on the replication of HCVs of different genotypes and evaluated the resulting assay formats for measurements of susceptibility to the DAA sofosbuvir. Removal of CpG and UpA dinucleotides from the luciferase gene used in HCV replicons of genotype 1b (Con1) and genotype 2a (JFH-1) achieved between 10- and 100-fold enhancement of replication over that of the wild type posttransfection. Removal of CpG and UpA dinucleotides in the neomycin gene or deletion of the whole gene in replicons of genotype 3a (S52) and genotype 4a (ED43) enhanced replication, but phenotypic effects on altering luciferase gene composition were minimal. A further 10-fold replication enhancement of replicons from all four genotypes was achieved by using a transgenic Huh7.5 cell line expressing SECL14L2, whose expression showed a dose-dependent effect on HCV replication that was reversible by small interfering RNA (siRNA) knockdown of gene expression. By combining these strategies, the 100- to 1,000-fold enhancement of replication allowed the susceptibility of all four genotypes to the RNA polymerase inhibitor sofosbuvir to be robustly determined in a transient-transfection assay format. These methods of replication enhancement provide new tools for monitoring the susceptibility and resistance of a wide range of HCV genotypes to DAAs.


Regulation of VanB-type vancomycin resistance gene expression by the VanS(B)-VanR (B) two-component regulatory system in Enterococcus faecalis V583.
Acquired VanA- and VanB-type glycopeptide resistance in enterococci is due to synthesis of modified peptidoglycan precursors terminating in D-lactate. As opposed to VanA-type strains which are resistant to both vancomycin and teicoplanin, VanB-type strains remain teicoplanin susceptible. We have determined the sequence of a 7,160-bp DNA fragment associated with VanB-type resistance in Enterococcus faecalis V583 that contains seven open reading frames. The distal part encoded the VanH (B), VanB, and VanX (B) proteins that are highly similar to the putative VanH, VanA, and VanX proteins responsible for VanA-type resistance. Upstream from the structural genes for these proteins were the vanY(B) gene encoding a D,D-carboxypeptidase and an open reading frame vanW with an unknown function. The proximal part of the gene cluster coded for the apparent VanS(B)-VanR (B) two-component regulatory system. VanR (B) was related to response regulators of the OmpR subclass, and VanS (B) was related to membrane-associated histidine protein kinases. Analysis of transcriptional fusions with a reporter gene and promoter mapping indicated that the VanR B-VanS B two-component regulatory system activates a promoter located immediately downstream from the vanS B gene. Vancomycin, but not teicoplanin, was an inducer, which explains teicoplanin susceptibility of VanB-type enterococci.


Direct Observation of Gas Meniscus Formation on a Superhydrophobic Surface.
The formation of a bridging gas meniscus via cavitation or nanobubbles is considered the most likely origin of the submicrometer long-range attractive forces measured between hydrophobic surfaces in aqueous solution. However, the dynamics of the formation and evolution of the gas meniscus is still under debate, in particular, in the presence of a thin air layer on a superhydrophobic surface. On superhydrophobic surfaces the range can even exceed 10 μm. Here, we report microscopic images of the formation and growth of a gas meniscus during force measurements between a superhydrophobic surface and a hydrophobic microsphere immersed in water. This is achieved by combining laser scanning confocal microscopy and colloidal probe atomic force microscopy. The configuration allows determination of the volume and shape of the meniscus, together with direct calculation of the Young-Laplace capillary pressure. The long-range attractive interactions acting on separation are due to meniscus formation and volume growth as air is transported from the surface layer.


Open-access microcavities for chemical sensing.
The recent development of open-access optical microcavities opens up a number of intriguing possibilities in the realm of chemical sensing. We provide an overview of the different possible sensing modalities, with examples of refractive index sensing, optical absorption measurements, and optical tracking and trapping of nanoparticles. The extremely small mode volumes within an optical microcavity allow very small numbers of molecules to be probed: our current best detection limits for refractive index and absorption sensing are around 10(5) and 10(2) molecules, respectively, with scope for further improvements in the future.


B0 shimming for in vivo magnetic resonance spectroscopy: Experts' consensus recommendations.
Magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) allow the chemical analysis of physiological processes in vivo and provide powerful tools in the life sciences and for clinical diagnostics. Excellent homogeneity of the static B0 magnetic field over the object of interest is essential for achieving high-quality spectral results and quantitative metabolic measurements. The experimental minimization of B0 variation is performed in a process called B0 shimming. In this article, we summarize the concepts of B0 field shimming using spherical harmonic shimming techniques, specific strategies for B0 homogenization and crucial factors to consider for implementation and use in both brain and body. In addition, experts' recommendations are provided for minimum requirements for B0 shim hardware and evaluation criteria for the primary outcome of adequate B0 shimming for MRS and MRSI, such as the water spectroscopic linewidth.


Synthesis and in Vitro Evaluation of Monodisperse Amino-Functional Polyester Dendrimers with Rapid Degradability and Antibacterial Properties.
Amine functional polymers, especially cationically charged, are interesting biomacromolecules for several reasons, including easy cell membrane entrance, their ability to escape endosomes through the proton sponge effect, spontaneous complexation and delivery of drugs and siRNA, and simple functionalization in aqueous solutions. Dendrimers, a subclass of precision polymers, are monodisperse and exhibit a large and exact number of peripheral end groups in relation to their size and have shown promise in drug delivery, biomedical imaging and as antiviral agents. In this work, hydroxyl functional dendrimers of generation 1 to 5 based on 2,2-bis(methylol)propionic acid (bis-MPA) were modified to bear 6 to 96 peripheral amino groups through esterification reactions with beta-alanine. All dendrimers were isolated in high yields and with remarkable monodispersity. This was successfully accomplished utilizing the present advantages of fluoride-promoted esterification (FPE) with imidazole-activated monomers. Straightforward postfunctionalization was conducted on a second generation amino-functional dendrimer with tetraethylene glycol through NHS-amidation and carbonyl diimidazole (CDI) activation to full conversion with short reaction times. Fast biodegradation of the dendrimers through loss of peripheral beta-alanine groups was observed and generational- and dose-dependent cytotoxicity was evaluated with a set of cell lines. An increase in neurotoxicity compared to hydroxyl-functional dendrimers was shown in neuronal cells, however, the dendrimers were slightly less neurotoxic than commercially available poly(amidoamine) dendrimers (PAMAMs). Additionally, their effect on bacteria was evaluated and the second generation dendrimer was found unique inhibiting the growth of Escherichia coli at physiological conditions while being nontoxic toward human cells. Finally, these results cement a robust and sustainable synthetic route to amino-functional polyester dendrimers with interesting chemical and biological properties.


Prognostic value of TP53, KRAS and EGFR mutations in nonsmall cell lung cancer: the EUELC cohort.
Nonsmall cell lung cancer samples from the European Early Lung Cancer biobank were analysed to assess the prognostic significance of mutations in the TP53, KRAS and EGFR genes. The series included 11 never-smokers, 86 former smokers, 152 current smokers and one patient without informed smoking status. There were 110 squamous cell carcinomas (SCCs), 133 adenocarcinomas (ADCs) and seven large cell carcinomas or mixed histologies. Expression of p53 was analysed by immunohistochemistry. DNA was extracted from frozen tumour tissues. TP53 mutations were detected in 48.8% of cases and were more frequent among SCCs than ADCs (p<0.0001). TP53 mutation status was not associated with prognosis. G to T transversions, known to be associated with smoking, were marginally more common among patients who developed a second primary lung cancer or recurrence/metastasis (progressive disease). EGFR mutations were almost exclusively found in never-smoking females (p=0.0067). KRAS mutations were detected in 18.5% of cases, mainly ADC (p<0.0001), and showed a tendency toward association with progressive disease status. These results suggest that mutations are good markers of different aetiologies and histopathological forms of lung cancers but have little prognostic value, with the exception of KRAS mutation, which may have a prognostic value in ADC.


Clinical course of severe and critical coronavirus disease 2019 in hospitalized pregnancies: a United States cohort study.
The coronavirus disease 2019 pandemic has had an impact on healthcare systems around the world with 3 million people contracting the disease and 208,000 cases resulting in death as of this writing. Information regarding coronavirus infection in pregnancy is still limited. This study aimed to describe the clinical course of severe and critical coronavirus disease 2019 in hospitalized pregnant women with positive laboratory testing for severe acute respiratory syndrome coronavirus 2. This is a cohort study of pregnant women with severe or critical coronavirus disease 2019 hospitalized at 12 US institutions between March 5, 2020, and April 20, 2020. Severe disease was defined according to published criteria as patient-reported dyspnea, respiratory rate >30 per minute, blood oxygen saturation ≤93% on room air, ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen <300 mm Hg, or lung infiltrates >50% within 24-48 hours on chest imaging. Critical disease was defined as respiratory failure, septic shock, or multiple organ dysfunction or failure. Women were excluded from the study if they had presumed coronavirus disease 2019, but laboratory testing was negative. The primary outcome was median duration from hospital admission to discharge. Secondary outcomes included need for supplemental oxygen, intubation, cardiomyopathy, cardiac arrest, death, and timing of delivery. The clinical courses are described by the median disease day on which these outcomes occurred after the onset of symptoms. Treatment and neonatal outcomes are also reported. Of 64 hospitalized pregnant women with coronavirus disease 2019, 44 (69%) had severe disease, and 20 (31%) had critical disease. The following preexisting comorbidities were observed: 25% had a pulmonary condition, 17% had cardiac disease, and the mean body mass index was 34 kg/m2. Gestational age was at a mean of 29±6 weeks at symptom onset and a mean of 30±6 weeks at hospital admission, with a median disease day 7 since first symptoms. Most women (81%) were treated with hydroxychloroquine; 7% of women with severe disease and 65% of women with critical disease received remdesivir. All women with critical disease received either prophylactic or therapeutic anticoagulation during their admission. The median duration of hospital stay was 6 days (6 days [severe group] and 10.5 days [critical group]; P=.01). Intubation was usually performed around day 9 on patients who required it, and peak respiratory support for women with severe disease was performed on day 8. In women with critical disease, prone positioning was required in 20% of cases, the rate of acute respiratory distress syndrome was 70%, and reintubation was necessary in 20%. There was 1 case of maternal cardiac arrest, but there were no cases of cardiomyopathy or maternal death. Thirty-two of 64 (50%) women with coronavirus disease 2019 in this cohort delivered during their hospitalization (34% [severe group] and 85% [critical group]). Furthermore, 15 of 17 (88%) pregnant women with critical coronavirus disease 2019 delivered preterm during their disease course, with 16 of 17 (94%) pregnant women giving birth through cesarean delivery; overall, 15 of 20 (75%) women with critical disease delivered preterm. There were no stillbirths or neonatal deaths or cases of vertical transmission. In pregnant women with severe or critical coronavirus disease 2019, admission into the hospital typically occurred about 7 days after symptom onset, and the duration of hospitalization was 6 days (6 [severe group] vs 12 [critical group]). Women with critical disease had a high rate of acute respiratory distress syndrome, and there was 1 case of cardiac arrest, but there were no cases of cardiomyopathy or maternal mortality. Hospitalization of pregnant women with severe or critical coronavirus disease 2019 resulted in delivery during the clinical course of the disease in 50% of this cohort, usually in the third trimester. There were no perinatal deaths in this cohort.


Physiological correlates of skating performance in women's and men's ice hockey.
The purpose of the current investigation was to identify relationships between physiological off-ice tests and on-ice performance in female and male ice hockey players on a comparable competitive level. Eleven women, 24 ± 3.0 years, and 10 male ice hockey players, 23 ± 2.4 years, were tested for background variables: height, body weight (BW), ice hockey history, and lean body mass (LBM) and peak torque (PT) of the thigh muscles, VO2peak and aerobic performance (Onset of Blood Lactate Accumulation [OBLA], respiratory exchange ratio [RER1]) during an incremental bicycle ergometer test. Four different on-ice tests were used to measure ice skating performance. For women, skating time was positively correlated (p < 0.05) to BW and negatively correlated to LBM%, PT/BW, OBLA, RER 1, and VO2peak (ml O2·kg(-1) BW(-1)·min(-1)) in the Speed test. Acceleration test was positively correlated to BW and negatively correlated to OBLA and RER 1. For men, correlation analysis revealed only 1 significant correlation where skating time was positively correlated to VO2peak (L O2·min(-1)) in the Acceleration test. The male group had significantly higher physiological test values in all variables (absolute and relative to BW) but not in relation to LBM. Selected off-ice tests predict skating performance for women but not for men. The group of women was significantly smaller and had a lower physiological performance than the group of men and were slower in the on-ice performance tests. However, gender differences in off-ice variables were reduced or disappeared when values were related to LBM, indicating a similar capacity of producing strength and aerobic power in female and male hockey players. Skating performance in female hockey players may be improved by increasing thigh muscle strength, oxygen uptake, and relative muscle mass.


Molecular follow-up of disease progression and interferon therapy in chronic myelocytic leukemia.
We previously reported that the abl promoter (Pa) undergoes de novo DNA methylation in the course of chronic myelocytic leukemia (CML). The clinical implications of this finding are the subject of the present study in which samples of CML patients, including a group treated with interferon alpha (IFNalpha) were surveyed. The methylation status of the abl promoter was monitored by polymerase chain reaction (PCR) amplification of the Pa region after digestion with several site-methylation sensitive restriction enzymes. Some 74% of the DNA samples from blood and marrow drawn in the chronic phase were nonmethylated, similar to control samples from non-CML patients. The remaining 26% were partially methylated in the abl Pa region. The latter samples were derived from patients who were indistinguishable from the others on the basis of clinical presentation. Methylated samples were mostly derived from patients known to have a disease of longer duration (26 months v 7.5 months, P = .01). Samples of 30 IFNalpha-treated patients were sequentially analyzed in the course of treatment. Fifteen patients with no evidence of Pa methylation before treatment remained methylation-free. The remainder, who displayed Pa methylation before treatment, reverted to the methylation-free status. The outcome is attributed to IFNalpha therapy, as the Pa methylation status was not reversed in any of the patients treated with hydroxyurea. Methylation of the abl promoter indicates a disease of long-standing, most likely associated with a higher probability of imminent blastic transformation. It appears to predict the outcome of IFNalpha therapy far better than the cytogenetic response.


Long-term outcomes of a Web-based diabetes prevention program: 2-year results of a single-arm longitudinal study.
Digital therapeutics are evidence-based behavioral treatments delivered online that can increase accessibility and effectiveness of health care. However, few studies have examined long-term clinical outcomes of digital therapeutics. The objective of this study was to conduct a 2-year follow-up on participants in the Internet-based Prevent diabetes prevention program pilot study, specifically examining the effects on body weight and A1c, which are risk factors for diabetes development. A quasi-experimental research design was used, including a single-arm pre- and post-intervention assessment of outcomes. Participants underwent a 16-week weight loss intervention and an ongoing weight maintenance intervention. As part of the program, participants received a wireless scale, which was used to collect body weight data on an ongoing basis. Participants also received A1c test kits at baseline, 0.5 year, 1 year, and 2-year time points. Participants previously diagnosed with prediabetes (n=220) were originally enrolled in the pilot study. A subset of participants (n=187) met Centers for Disease Control and Prevention (CDC) criteria for starting the program (starters), and a further subset (n=155) met CDC criteria for completing the program (completers) and were both included in analyses. Program starters lost an average of 4.7% (SD 0.4) of baseline body weight after 1 year and 4.2% (SD 0.8) after 2 years, and reduced A1c by mean 0.38% (SD 0.07) after 1 year and 0.43% (SD 0.08) after 2 years. Program completers lost mean 4.9% (SD 0.5) of baseline body weight after 1 year and 4.3% (SD 0.8) after 2 years, and reduced A1c by 0.40% (SD 0.07) after 1 year and 0.46% (SD 0.08) after 2 years. For both groups, neither 2-year weight loss nor A1c results were significantly different from 1-year results. Users of the Prevent program experienced significant reductions in body weight and A1c that are maintained after 2 years. Contrary to the expected progression from prediabetes to diabetes over time, average A1c levels continued to show an average regression from within the prediabetic range (5.7%-6.4%) initially to the normal range (<5.7%) after 2 years. Further investigation is warranted to test digital therapeutics as a scalable solution to address national diabetes and cardiovascular disease prevention efforts.


The impact of biological sex on diseases of the urinary tract.
Biological sex, being female or male, broadly influences diverse immune phenotypes, including immune responses to diseases at mucosal surfaces. Sex hormones, sex chromosomes, sexual dimorphism, and gender differences all contribute to how an organism will respond to diseases of the urinary tract, such as bladder infection or cancer. Although the incidence of urinary tract infection is strongly sex biased, rates of infection change over a lifetime in women and men, suggesting that accompanying changes in the levels of sex hormones may play a role in the response to infection. Bladder cancer is also sex biased in that 75% of newly diagnosed patients are men. Bladder cancer development is shaped by contributions from both sex hormones and sex chromosomes, demonstrating that the influence of sex on disease can be complex. With a better understanding of how sex influences disease and immunity, we can envision sex-specific therapies to better treat diseases of the urinary tract and potentially diseases of other mucosal tissues.


Comparison of dairy desserts produced with a potentially probiotic mixed culture and dispersions obtained from Gracilaria birdiae and Gracilaria domingensis seaweeds used as thickening agents.
Dairy desserts have emerged as interesting options for the incorporation of probiotics, bioactive ingredients and alternative sources of thickeners. This shows an opportunity to investigate the use of Gracilaria seaweeds in the formulation of potentially probiotic dairy desserts. This study aimed to compare the effects of dispersions obtained from Gracilaria domingensis and Gracilaria birdiae used as thickening agents on texture properties of dairy desserts fermented with SAB 440-A, composed of the starter Streptococcus thermophilus and the potential probiotics Bifidobacterium animalis and Lactobacillus acidophilus, and also to study their physicochemical characteristics, microbial viability and sensory acceptability. No significant differences between desserts with G. birdiae or G. domingensis dispersions regarding total solids, ash and fat content, as well as pH, titratable acidity, the viability of the microorganisms of the mixed culture and sensory acceptability were verified (P > 0.05). Nonetheless, the dessert with G. domingensis dispersion showed higher dietary fibre content and significantly increased firmness than the one produced with G. birdiae (P < 0.05). Moreover, B. animalis was able to maintain higher populations, above 7 log cfu g-1 during 21 days of storage of desserts, in the presence of either G. birdiae or G. domingensis dispersions, despite the fact that L. acidophilus has shown low viability in the final products. Therefore, the G. domingensis dispersion is suitable to be used as a thickening agent to produce dairy desserts with enhanced firmness and good sensory acceptability, it being also advisable to use only B. animalis as a probiotic for this product.


Automated protein-DNA interaction screening of Drosophila regulatory elements.
Drosophila melanogaster has one of the best characterized metazoan genomes in terms of functionally annotated regulatory elements. To explore how these elements contribute to gene regulation, we need convenient tools to identify the proteins that bind to them. Here we describe the development and validation of a high-throughput yeast one-hybrid platform, which enables screening of DNA elements versus an array of full-length, sequence-verified clones containing over 85% of predicted Drosophila transcription factors. Using six well-characterized regulatory elements, we identified 33 transcription factor-DNA interactions of which 27 were previously unidentified. To simultaneously validate these interactions and locate the binding sites of involved transcription factors, we implemented a powerful microfluidics-based approach that enabled us to retrieve DNA-occupancy data for each transcription factor throughout the respective target DNA elements. Finally, we biologically validated several interactions and identified two new regulators of sine oculis gene expression and hence eye development.


The essentials of chemotherapy-induced infusion reactions.
Almost all systemic agents used in cancer therapy can cause infusion-related reactions. Hypersensitivity or infusion reactions to platinum compounds are acquired, whereas reactions to taxanes and monoclonal antibodies usually occur during the first few minutes of the first infusion. By understanding the symptoms and treatment of infusion reactions, healthcare team members can provide timely and appropriate treatment and positively impact patient care.


Surgical treatment of cervical kyphosis.
Cervical kyphosis is an uncommon but potentially debilitating and challenging condition. We reviewed the etiology, presentation, clinical and radiological evaluation, and treatment of cervical kyphosis. Based on the current controversy as to the ideal mode of surgical management, we paid particular attention to the available surgical strategies. There are three approaches for cervical kyphosis: the anterior, posterior or combined procedures. The principal indication for the posterior strategy is a flexible kyphosis or kyphosis caused by ankylosing spondylitis. The main point of debate is between the choice of the anterior or the combined strategy. The two strategies were compared with regard to clinical outcome, correction of deformity, rate of fusion, complications, revision surgery, and mortality. The combined strategy appears to result in a greater degree of correction than the anterior-alone strategy, and it is more likely to improve the cervical alignment to achieve a lordosis. However, the procedure carries a higher rate of postoperative neurological deterioration, complications, revision surgery, and mortality. Although the anterior-alone strategy achieves a smaller reduction of cervical kyphosis, it has a lower rate of postoperative neurological deterioration, complications, revision surgery, and mortality. We recommend that the surgical treatment of cervical kyphosis should be planned on an individual basis. A multicenter, prospective, randomized controlled study would be necessary to determine the ideal mode of treatment for complex cervical kyphosis.


Inhibition of PI3K signaling spurs new therapeutic opportunities in inflammatory/autoimmune diseases and hematological malignancies.
The phosphoinositide 3-kinase/mammalian target of rapamycin/protein kinase B (PI3K/mTOR/Akt) signaling pathway is central to a plethora of cellular mechanisms in a wide variety of cells including leukocytes. Perturbation of this signaling cascade is implicated in inflammatory and autoimmune disorders as well as hematological malignancies. Proteins within the PI3K/mTOR/Akt pathway therefore represent attractive targets for therapeutic intervention. There has been a remarkable evolution of PI3K inhibitors in the past 20 years from the early chemical tool compounds to drugs that are showing promise as anticancer agents in clinical trials. The use of animal models and pharmacological tools has expanded our knowledge about the contribution of individual class I PI3K isoforms to immune cell function. In addition, class II and III PI3K isoforms are emerging as nonredundant regulators of immune cell signaling revealing potentially novel targets for disease treatment. Further complexity is added to the PI3K/mTOR/Akt pathway by a number of novel signaling inputs and feedback mechanisms. These can present either caveats or opportunities for novel drug targets. Here, we consider recent advances in 1) our understanding of the contribution of individual PI3K isoforms to immune cell function and their relevance to inflammatory/autoimmune diseases as well as lymphoma and 2) development of small molecules with which to inhibit the PI3K pathway. We also consider whether manipulating other proximal elements of the PI3K signaling cascade (such as class II and III PI3Ks or lipid phosphatases) are likely to be successful in fighting off different immune diseases.


Incidence and outcomes of symptomatic neonatal arterial ischemic stroke.
Neonatal arterial ischemic stroke (NAIS) is associated with considerable lifetime burdens such as cerebral palsy, epilepsy, and cognitive impairment. Prospective epidemiologic studies that include outcome assessments are scarce. This study aimed to provide information on the epidemiology, clinical manifestations, infarct characteristics, associated clinical variables, treatment strategies, and outcomes of NAIS in a prospective, population-based cohort of Swiss children. This prospective study evaluated the epidemiology, clinical manifestations, vascular territories, associated clinical variables, and treatment of all full-term neonates diagnosed with NAIS and born in Switzerland between 2000 and 2010. Follow-up was performed 2 years (mean 23.3 months, SD 4.3 months) after birth. One hundred neonates (67 boys) had a diagnosis of NAIS. The NAIS incidence in Switzerland during this time was 13 (95% confidence interval [CI], 11-17) per 100,000 live births. Seizures were the most common symptom (95%). Eighty-one percent had unilateral (80% left-sided) and 19% had bilateral lesions. Risk factors included maternal risk conditions (32%), birth complications (68%), and neonatal comorbidities (54%). Antithrombotic and antiplatelet therapy use was low (17%). No serious side effects were reported. Two years after birth, 39% were diagnosed with cerebral palsy and 31% had delayed mental performance. NAIS in Switzerland shows a similar incidence as other population-based studies. About one-third of patients developed cerebral palsy or showed delayed mental performance 2 years after birth, and children with normal mental performance may still develop deficits later in life.


Comparisons of 7- to 78-joint ultrasonography scores: all different joint combinations show equal response to adalimumab treatment in patients with rheumatoid arthritis.
The primary objectives were to explore the associations between a comprehensive ultrasonographic (US) assessment of joints, tendons and bursae and previously described reduced joint counts (7-, 12-, 28- and 44-joint score) as well as to assess the sensitivity to change of these different US joint combinations during biological treatment. Twenty patients with rheumatoid arthritis (RA) were examined by US (B-mode (BM) and power Doppler (PD)) with use of a semi-quantitative (0 to 3) score of 78 joints, 36 tendons/tendon groups and two bursae (hereafter described as the 78-joint score) at baseline and 1, 3, 6 and 12 months after initiating treatment with adalimumab. BM and PD scores for the different joint combinations were generated. The reduced joint scores had high correlation coefficients with the 78-joint score at all examinations (range 0.79 to 0.99 for BM and 0.77 to 0.99 for PD, each P < 0.001) and sum BM and PD scores of all the different joint combinations improved significantly during follow-up (P ≤ 0.05 to 0.001). The reduced joint combinations were highly associated to the 78-joint score. Furthermore, all the joint combinations presently explored responded well to biological treatment. This indicates that an approach focusing on few joints and tendons gives equivalent information about the inflammatory activity in RA patients as a comprehensive US examination. The optimal combination of joints and tendons for a valid, reliable and feasible US measurement should be further explored to define a US score for follow-up of RA patients on biological treatment.


What we know and what we don't know about cancer risks associated with radiation doses from radiological imaging.
Quantifying radiation-induced cancer risks associated with radiological examinations is not easy, which has resulted in much controversy. We can clarify the situation by distinguishing between higher dose examinations, such as CT, positron emission tomography-CT or fluoroscopically guided interventions, and lower dose "conventional" X-ray examinations. For higher dose examinations, the epidemiological data, from atomic bomb survivors exposed to low doses and from direct epidemiological studies of paediatric CT, are reasonably consistent, suggesting that we do have a reasonable quantitative understanding of the individual risks: in summary, very small but unlikely to be zero. For lower dose examinations, we have very little data, and the situation is much less certain, however, the collective dose from these lower dose examinations is comparatively unimportant from a public health perspective.


Hierarchical Order Parameters for Macromolecular Assembly Simulations I: Construction and Dynamical Properties of Order Parameters.
Macromolecular assemblies often display a hierarchical organization of macromolecules or their sub-assemblies. To model this, we have formulated a space warping method that enables capturing overall macromolecular structure and dynamics via a set of coarse-grained order parameters (OPs). This article is the first of two describing the construction and computational implementation of an additional class of OPs that has built into them the hierarchical architecture of macromolecular assemblies. To accomplish this, first, the system is divided into subsystems, each of which is described via a representative set of OPs. Then, a global set of variables is constructed from these subsystem-centered OPs to capture overall system organization. Dynamical properties of the resulting OPs are compared to those of our previous nonhierarchical ones, and implied conceptual and computational advantages are discussed for a 100ns, 2 million atom solvated Human Papillomavirus-like particle simulation. In the second article, the hierarchical OPs are shown to enable a multiscale analysis that starts with the N-atom Liouville equation and yields rigorous Langevin equations of stochastic OP dynamics. The latter is demonstrated via a force-field based simulation algorithm that probes key structural transition pathways, simultaneously accounting for all-atom details and overall structure.


Conflict of interest in the debate over calcium-channel antagonists.
Physicians' financial relationships with the pharmaceutical industry are controversial because such relationships may pose a conflict of interest. It is unknown to what extent industry support of medical education and research influences the opinions and behavior of clinicians and researchers. The recent debate over the safety of calcium-channel antagonists provided an opportunity to examine the effect of financial conflicts of interest. We searched the English-language medical literature published from March 1995 through September 1996 for articles examining the controversy about the safety of calcium-channel antagonists. Articles were reviewed and classified as being supportive, neutral, or critical with respect to the use of calcium-channel antagonists. The authors of the articles were asked about their financial relationships with both manufacturers of calcium-channel antagonists and manufacturers of competing products (i.e., beta-blockers, angiotensin-converting-enzyme inhibitors, diuretics, and nitrates). We examined the authors' published positions on the safety of calcium-channel antagonists according to their financial relationships with pharmaceutical companies. Authors who supported the use of calcium-channel antagonists were significantly more likely than neutral or critical authors to have financial relationships with manufacturers of calcium-channel antagonists (96 percent, vs. 60 percent and 37 percent, respectively; P<0.001). Supportive authors were also more likely than neutral or critical authors to have financial relationships with any pharmaceutical manufacturer, irrespective of the product (100 percent, vs. 67 percent and 43 percent, respectively; P< 0.001). Our results demonstrate a strong association between authors' published positions on the safety of calcium-channel antagonists and their financial relationships with pharmaceutical manufacturers. The medical profession needs to develop a more effective policy on conflict of interest. We support complete disclosure of relationships with pharmaceutical manufacturers for clinicians and researchers who write articles examining pharmaceutical products.


Auxetic oesophageal stents: structure and mechanical properties.
Oesophageal cancer is the ninth leading cause of malignant cancer death and its prognosis remains poor, ranking as the sixth most frequent cause of death in the world. This research work aims to adopt an Auxetic (rotating-squares) geometry device, that had previously been examined theoretically and analysed by Grima and Evans (J Mater Sci Lett 19(17):1563-1565, 2000), to produce a novel Auxetic oesophageal stent and stent-grafts relevant to the palliative treatment of oesophageal cancer and also for the prevention of dysphagia. This paper discusses the manufacture of a small diameter Auxetic oesophageal stent and stent-graft. The oral deployment of such an Auxetic stent would be simplest if a commercial balloon dilatational catheter was used as this obviates the need for an expensive dedicated delivery system. A novel manufacturing route was employed in this research to develop both Auxetic films and Auxetic oesophageal stents, which ranged from conventional subtractive techniques to a new additive manufacturing method. Polyurethane was selected as a material for the fabrication of Auxetic films and Auxetic oesophageal stents because of its good biocompatibility and non-toxicological properties. The Auxetic films were later used for the fabrication of seamed Auxetic oesophageal stents. The flexible polyurethane tubular grafts were also attached to the inner luminal side of the seamless Auxetic oesophageal stents, in order to prevent tumour in-growth. Scanning electron microscopy was used to conduct surface morphology study by using different Auxetic specimens developed from different conventional and new additive manufacturing techniques. Tensile testing of the Auxetic films was performed to characterise their mechanical properties. The stent expansion tests of the Auxetic stents were done to analyse the longitudinal extension and radial expansion of the Auxetic stent at a range of radial pressures applied by the balloon catheter, and to also identify the pressure values where the Auxetic stent fails. Finite element models of both Auxetic film and Auxetic stent were developed, and the results were compared with experimental results with a good agreement. The tensile testing of the Auxetic polyurethane films revealed that the Poisson's ratio of the sample ranged between -0.87 and -0.963 at different uniaxial tensile load values. From the stent expansion test, it was found that the Auxetic oesophageal stent radially expanded from 0.5 to 5.73 mm and longitudinally extended from 0.15 to 1.83 mm at a range of applied pressure increments (0.5-2.7 bar) from the balloon catheter.


Sports Hernia/Athletic Pubalgia Among Women.
"Athletic pubalgia," a term that has gained acceptance over "sports hernia," is more common in men than women; however, it represents a significant source of morbidity for patients of both sexes. Inconsistent terminology surrounding this entity poses a diagnostic challenge and makes studying the populations at risk difficult. To review a case series of women with athletic pubalgia by analyzing their presentations, concomitant pathologies, and surgical outcomes. Case series; Level of evidence, 4. Between 2013 and 2016, 197 patients were seen and evaluated for the diagnosis of athletic pubalgia. Eighteen patients seen during this time were women. All patients received "pubalgia protocol" magnetic resonance imaging and subsequent surgical intervention for their pathologies. Outcomes among 17 women were assessed with a patient questionnaire >1 year after surgery. Of the 17 women, 9 had rectus aponeurotic plate injury only, or pure athletic pubalgia; the remaining 8 had athletic pubalgia in combination with ≥1 inguinal, obturator, and femoral hernias. Regarding female patients in both groups, 88.2% reported that the surgery was a success at follow-up. Surgical repair of athletic pubalgia among women is successful in dramatically reducing pain levels in this important subset of patients.


Antitumor activity of MGI 114 (6-hydroxymethylacylfulvene, HMAF), a semisynthetic derivative of illudin S, against adult and pediatric human tumor colony-forming units.
MGI 114 (6-hydroxymethylacylfulvene, HMAF) is a novel semisynthetic antitumor compound derived from the sesquiterpene mushroom toxin illudin S. Although illudins did not demonstrate significant activity as antiproliferative agents in tumor-bearing animals, several properties including its potent inhibition of DNA synthesis and a unique interaction with DNA led to a structure-activity-based synthetic effort to obtain analogs with improved therapeutic potential. MGI 114 was selected for further development based on its antitumor activity in numerous preclinical tests. MGI 114 was evaluated against adult and pediatric human tumors taken directly from cancer patients and cultured in a human tumor colony-forming assay (HTCFA) to assess the antitumor spectra, concentration-response relationship, schedule dependence and activity of this agent against tumors considered resistant to conventional anticancer drugs. Human tumor colony-forming units were treated with HMAF at concentrations of 0.001, 0.01, 0.1 and 1 microg/ml, both as a 1 h exposure and as a continuous 14 day exposure. A response was scored if there was 50% or less colony survival. In vitro response rates in the range of 50-80% were observed against tumor colony-forming units originating from carcinomas of the colon, kidney, breast, lung cancer, ovary and melanoma. MGI 114 also demonstrated antitumor activity against neuroblastoma colony-forming units. Antitumor activity was not influenced by exposure time as demonstrated by the similar responses rates obtained with the 1 h and continuous exposure at all concentrations tested. However, there was a significant positive concentration-response relationship to both exposure duration with responses increasing from below 10% at the lowest concentration to over 70% at the highest concentration, except for the pediatric tumors on the 1 h exposure for which this relationship was less apparent. At the higher concentration tested, MGI 114 displayed substantial antiproliferative effects in the range of 70% against tumor specimens resistant to classic cytotoxic agents including irinotecan, paclitaxel, 5-fluorouracil, cisplatin, doxorubicin and cyclophosphamide. These results demonstrate that MGI 114 exhibits a broad spectrum of antitumor activity against both adult and pediatric primary tumor colony-forming units in a concentration-dependent manner both at short and prolonged exposure duration. The substantial in vitro activity of MGI 114 at concentrations achievable in clinical trials, together with its activity against tumors resistant to classic standard cytotoxic drugs, justifies the further clinical evaluation of this unique agent.


Conservation planning with uncertain climate change projections.
Climate change is affecting biodiversity worldwide, but conservation responses are constrained by considerable uncertainty regarding the magnitude, rate and ecological consequences of expected climate change. Here we propose a framework to account for several sources of uncertainty in conservation prioritization. Within this framework we account for uncertainties arising from (i) species distributions that shift following climate change, (ii) basic connectivity requirements of species, (iii) alternative climate change scenarios and their impacts, (iv) in the modelling of species distributions, and (v) different levels of confidence about present and future. When future impacts of climate change are uncertain, robustness of decision-making can be improved by quantifying the risks and trade-offs associated with climate scenarios. Sensible prioritization that accounts simultaneously for the present and potential future distributions of species is achievable without overly jeopardising present-day conservation values. Doing so requires systematic treatment of uncertainties and testing of the sensitivity of results to assumptions about climate. We illustrate the proposed framework by identifying priority areas for amphibians and reptiles in Europe.


Using GPS and activity tracking to reveal the influence of adolescents' food environment exposure on junk food purchasing.
This study examines the influence of adolescents' exposure to unhealthy food outlets on junk food purchasing during trips between home and school, with particular attention to how exposure and purchasing differ according to child's biological sex, mode of transportation, and direction to or from school. Between 2010 and 2013, students (n = 654) aged 9-13 years from 25 schools in London and Middlesex County, ON, completed a socio-demographic survey and an activity diary (to identify food purchases), and were observed via a global positioning system for 2 weeks (to track routes for trips to/from school). Spatial data on routes and purchase data were integrated with a validated food outlet database in a geographic information system, and exposure was measured as the minutes a child spent within 50 m of an unhealthy food outlet (i.e., fast food restaurants, variety stores). For trips involving junk food exposure (n = 4588), multilevel logistic regression was used to assess the relationship between exposure and purchasing. Multilevel analyses indicated that adolescents' duration of exposure to unhealthy food outlets between home and school had a significant effect on the likelihood of junk food purchasing. This relationship remained significant when the data were stratified by sex (female/male), trip direction (to/from school) and travel mode (active/car), with the exception of adolescents who travelled by bus. Policies and programs that mitigate the concentration of unhealthy food outlets close to schools are critical for encouraging healthy eating behaviours among children and reducing diet-related health issues such as obesity.


The pathogenic role of intestinal flora in IBD and colon cancer.
The intestine is populated by a large variety of microorganisms that colonize the host soon after birth. The gut microflora contributes to several intestinal functions, including the development of the mucosal immune system, the absorption of complex macromolecules, the synthesis of amino acids and vitamins and the protection against pathogenic microorganisms. Its composition varies along the different segments of the gut, with a gradient from the stomach to the colon where it is more abundant. Given the vital relationship between the microflora and the intestinal function, it is important that the microflora is kept continuously under control so to preserve gut homeostasis. When this is not achieved or perturbed, several immune disorders can arise, like allergies or inflammation. Protracted immune deregulations can also lead to severe disorders including diabetes, cancer and inflammatory bowel disease (IBD). It is therefore crucial that the immune system learns both to tolerate and to control the growth of beneficial microorganisms so to preserve the intestinal homeostasis. The mechanisms that are in place to achieve this control are not yet understood but recent work has started to unravel the complex relationship between several players including the microflora, intestinal barriers and immune cells. In this review we will analyze how the microflora interacts with the host and how deregulation of this interaction can lead to inflammatory disorders and eventually also to cancer.


Divergent molecular mechanisms underlying the pleiotropic functions of macrophage inhibitory cytokine-1 in cancer.
Multifunctional macrophage inhibitory cytokine-1, MIC-1, is a member of the transforming growth factor-beta (TGF-beta) superfamily that plays key roles in the prenatal development and regulation of the cellular responses to stress signals and inflammation and tissue repair after acute injuries in adult life. The stringent control of the MIC-1 expression, secretion, and functions involves complex regulatory mechanisms and the interplay of other growth factor signaling networks that control the cell behavior. The deregulation of MIC-1 expression and signaling pathways has been associated with diverse human diseases and cancer progression. The MIC-1 expression levels substantially increase in cancer cells, serum, and/or cerebrospinal fluid during the progression of diverse human aggressive cancers, such as intracranial brain tumors, melanoma, and lung, gastrointestinal, pancreatic, colorectal, prostate, and breast epithelial cancers. Of clinical interest, an enhanced MIC-1 expression has been positively correlated with poor prognosis and patient survival. Secreted MIC-1 cytokine, like the TGF-beta prototypic member of the superfamily, may provide pleiotropic roles in the early and late stages of carcinogenesis. In particular, MIC-1 may contribute to the proliferation, migration, invasion, metastases, and treatment resistance of cancer cells as well as tumor-induced anorexia and weight loss in the late stages of cancer. Thus, secreted MIC-1 cytokine constitutes a new potential biomarker and therapeutic target of great clinical interest for the development of novel diagnostic and prognostic methods and/or cancer treatment against numerous metastatic, recurrent, and lethal cancers.


Changes in technique throughout a 1500-m speed skating time-trial in junior elite athletes: Differences between sexes, performance levels and competitive seasons.
Speed skating is a technical endurance sport. Still, little is known about technical changes in junior speed skaters. Therefore, changes in technique throughout a 1500-m time-trial of elite junior speed skaters is investigated to explore differences between sexes, performance levels and competitive seasons. At (inter)national 1500-m competitions, knee and push-off angles were obtained for 120 elite junior speed skaters (56 female, 64 male, age 17.6±1.1 years) per lap at 250m (lap 1), 650m (lap 2), 1050m (lap 3) and 1450m (lap 4). Additionally, 1500m end-times and lap-times were obtained to divide skaters in faster and slower performance groups and to analyze pacing behavior. Fifteen skaters (8 female, 7 male, age 17.3±1.5 years) were measured again after 1.6±0.6 years. (Repeated measures) ANOVAs were used for statistical analyses (p<0.05). ICC, determined in a pilot study, was 0.55 for knee and 0.76 for push-off angles. Elite junior speed skaters increased their knee angles throughout the race (p<0.005), regardless of sex (p = 0.110) or performance level (p = 0.714). Push-off angles increased from lap 1-3 (p<0.001), in which men showed a larger decay than female skaters (p<0.05), this holds for both performance groups (p = 0.103). Faster skaters had smaller knee and push-off angles than slower skaters (p<0.05). Males showed smaller body angles than females (p<0.001). Faster male and female skaters showed a relative slower start and faster lap 3 compared to slower skaters (p<0.05). Development over competitive seasons showed a shift towards smaller push-off angles (p = 0.038) and less decay in knee angles from lap 2-3 (p = 0.026). The present study shows that technique throughout the 1500m deteriorates. Deterioration in technique is regardless of performance level, even with different pacing behaviors. Differences between sexes were found for push-off angles. The longitudinal development suggests changes in technique towards senior level and highlights the importance of studying juniors separate from seniors.


An occupation-centered discussion of development and implications for practice.
Children's learning to do everyday activities seems so obvious that the mechanisms bringing about the development of occupations remain essentially unstudied. Therefore, occupational therapy uses developmental models from other disciplines as foundation for practice. We specialists in childhood occupations need a theory-based and empirically tested body of knowledge about the processes leading to change to inform practice and guide interventions during efficacy studies. One body of knowledge about developmental mechanisms views change as originating from within the child and informs practice centered on changing the child. Given the inseparable nature of children and their social environments and daily activities, we introduce the philosophy of contextualism and outline a potential body of knowledge about a change process that is occupation centered. An intervention arising from a contextual perspective illustrates how this way of thinking leads to occupation-centered practice that uses multiple strategies and supports a child's occupation with social participation with peers.


Elevated circulating TGFβ1 during acute liver failure activates TGFβR2 on cortical neurons and exacerbates neuroinflammation and hepatic encephalopathy in mice.
Acute liver failure resulting from drug-induced liver injury can lead to the development of neurological complications called hepatic encephalopathy (HE). Hepatic transforming growth factor beta 1 (TGFβ1) is upregulated due to liver failure in mice and inhibiting circulating TGFβ reduced HE progression. However, the specific contributions of TGFβ1 on brain cell populations and neuroinflammation during HE are not known. Therefore, the aim of this study was to characterize hepatic and brain TGFβ1 signaling during acute liver failure and its contribution to HE progression using a combination of pharmacological and genetic approaches. C57Bl/6 or neuron-specific transforming growth factor beta receptor 2 (TGFβR2) null mice (TGFβR2ΔNeu) were treated with azoxymethane (AOM) to induce acute liver failure and HE. The activity of circulating TGFβ1 was inhibited in C57Bl/6 mice via injection of a neutralizing antibody against TGFβ1 (anti-TGFβ1) prior to AOM injection. In all mouse treatment groups, liver damage, neuroinflammation, and neurological deficits were assessed. Inflammatory signaling between neurons and microglia were investigated in in vitro studies through the use of pharmacological inhibitors of TGFβ1 signaling in HT-22 and EOC-20 cells. TGFβ1 was expressed and upregulated in the liver following AOM injection. Pharmacological inhibition of TGFβ1 after AOM injection attenuated neurological decline, microglia activation, and neuroinflammation with no significant changes in liver damage. TGFβR2ΔNeu mice administered AOM showed no effect on liver pathology but significantly reduced neurological decline compared to control mice. Microglia activation and neuroinflammation were attenuated in mice with pharmacological inhibition of TGFβ1 or in TGFβR2ΔNeu mice. TGFβ1 increased chemokine ligand 2 (CCL2) and decreased C-X3-C motif ligand 1 (CX3CL1) expression in HT-22 cells and reduced interleukin-1 beta (IL-1ß) expression, tumor necrosis factor alpha (TNFα) expression, and phagocytosis activity in EOC-20 cells. Increased circulating TGFβ1 following acute liver failure results in activation of neuronal TGFβR2 signaling, driving neuroinflammation and neurological decline during AOM-induced HE.


Height and prostate cancer risk: a large nested case-control study (ProtecT) and meta-analysis.
Height, a marker of childhood environmental exposures, is positively associated with prostate cancer risk, perhaps through the insulin-like growth factor system. We investigated the relationship of prostate cancer with height and its components (leg and trunk length) in a nested case-control study and with height in a dose-response meta-analysis. We nested a case-control study within a population-based randomized controlled trial evaluating treatments for localized prostate cancer in British men ages 50 to 69 years, including 1,357 cases detected through prostate-specific antigen testing and 7,990 controls (matched on age, general practice, assessment date). Nine bibliographic databases were searched systematically for studies on the height-prostate cancer association that were pooled in a meta-analysis. Based on the nested case-control, the odds ratio (OR) of prostate-specific antigen-detected prostate cancer per 10 cm increase in height was 1.06 [95% confidence interval (95% CI): 0.97-1.16; p(trend) = 0.2]. There was stronger evidence of an association of height with high-grade prostate cancer (OR: 1.23; 95% CI: 1.06-1.43), mainly due to the leg component, but not with low-grade disease (OR: 0.99; 95% CI: 0.90-1.10). In general, associations with leg or trunk length were similar. A meta-analysis of 58 studies found evidence that height is positively associated with prostate cancer (random-effects OR per 10 cm: 1.06; 95% CI: 1.03-1.09), with a stronger effect for prospective studies of more advanced/aggressive cancers (random-effects OR: 1.12; 95% CI: 1.05-1.19). These data indicate a limited role for childhood environmental exposures-as indexed by adult height-on prostate cancer incidence, while suggesting a greater role for progression, through mechanisms requiring further investigation.


Differential Response of Glioma Stem Cells to Arsenic Trioxide Therapy Is Regulated by MNK1 and mRNA Translation.
Mesenchymal (MES) and proneural (PN) are two distinct glioma stem cell (GSC) populations that drive therapeutic resistance in glioblastoma (GBM). We screened a panel of 650 small molecules against patient-derived GBM cells to discover compounds targeting specific GBM subtypes. Arsenic trioxide (ATO), an FDA-approved drug that crosses the blood-brain barrier, was identified as a potent PN-specific compound in the initial screen and follow-up validation studies. Furthermore, MES and PN GSCs exhibited differential sensitivity to ATO. As ATO has been shown to activate the MAPK-interacting kinase 1 (MNK1)-eukaryotic translation initiation factor 4E (eIF4E) pathway and subsequent mRNA translation in a negative regulatory feedback manner, the mechanistic role of ATO resistance in MES GBM was explored. In GBM cells, ATO-activated translation initiation cellular events via the MNK1-eIF4E signaling axis. Furthermore, resistance to ATO in intracranial PDX tumors correlated with high eIF4E phosphorylation. Polysomal fractionation and microarray analysis of GBM cells were performed to identify ATO's effect on mRNA translation and enrichment of anti-apoptotic mRNAs in the ATO-induced translatome was found. Additionally, it was determined that MNK inhibition sensitized MES GSCs to ATO in neurosphere and apoptosis assays. Finally, examination of the effect of ATO on patients from a phase I/II clinical trial of ATO revealed that PN GBM patients responded better to ATO than other subtypes as demonstrated by longer overall and progression-free survival.Implications: These findings raise the possibility of a unique therapeutic approach for GBM, involving MNK1 targeting to sensitize MES GSCs to drugs like arsenic trioxide. Mol Cancer Res; 16(1); 32-46. ©2017 AACR.


[How effective is spa treatment? A systematic review of randomized studies].
In the context of general financial constraints within many national health services spa treatment is being looked at ever more critically in various European countries. An important argument against spa treatment has been the supposed lack of evidence for its efficacy. This analysis was undertaken to gather firm data bearing on this problem. Several data bases were searched systematically for randomized studies of spa treatment. Only those were included in which one patient cohort had received spa treatment, while the control cohort had been treated for the same ailment on an ambulant basis at home. Nonrandomized studies were excluded. Only three randomized studies were found in which two patient cohorts, one with and one without spa treatment, were compared (postsalpingitis, back pain and osteoarthritis, respectively). In all three the evidence indicated some additional benefit from spa treatment. The data are not sufficient to prove the benefit of spa treatment, nor are they adequate to disprove it. More evidence-based studies are necessary to arrive at rationally based decisions relating to the efficacy of spa treatment.


Selective reflection of Airy beam at an interface between dielectric and homogeneous atomic medium.
We examine selective reflection (SR) spectrum of an Airy beam at an interface between a dielectric and a homogeneous atomic medium. It is shown that both the general reflection (GR) and the SR of Airy beams exhibit accelerating dynamics with a parabolic trajectory, however, the accelerating rate for the SR is slightly greater than that for the GR. Due to interaction of atoms and the Airy beams at the interface between dielectric and resonant atoms, the SR beams can create far-field interference patterns. We also show that the amplitude of the SR can be dramatically modified by the detuning of the incident fields, the reduced x-coordinate and the distance from the interface. The SR at the resonant medium interface of Airy beams can probably be a powerful tool in the use of optical power delivering, resonant particle manipulation and spatial spectrum detection of a resonant medium at an interface.


A multicentre validation study of the diagnostic value of plasma neurofilament light.
Increased cerebrospinal fluid neurofilament light (NfL) is a recognized biomarker for neurodegeneration that can also be assessed in blood. Here, we investigate plasma NfL as a marker of neurodegeneration in 13 neurodegenerative disorders, Down syndrome, depression and cognitively unimpaired controls from two multicenter cohorts: King's College London (n = 805) and the Swedish BioFINDER study (n = 1,464). Plasma NfL was significantly increased in all cortical neurodegenerative disorders, amyotrophic lateral sclerosis and atypical parkinsonian disorders. We demonstrate that plasma NfL is clinically useful in identifying atypical parkinsonian disorders in patients with parkinsonism, dementia in individuals with Down syndrome, dementia among psychiatric disorders, and frontotemporal dementia in patients with cognitive impairment. Data-driven cut-offs highlighted the fundamental importance of age-related clinical cut-offs for disorders with a younger age of onset. Finally, plasma NfL performs best when applied to indicate no underlying neurodegeneration, with low false positives, in all age-related cut-offs.


Comparison of chondrogensis in static and perfused bioreactor culture.
As a result of the low yield of cartilage from primary patient harvests and a high demand for autologous cartilage for reconstructive surgery and structural repair, primary explant cartilage must be augmented by tissue engineering techniques. In this study, chondrocytes seeded on PLLA/PGA scaffolds in static culture and a direct perfusion bioreactor were biochemically and histologically analyzed to determine the effects of fluid flow and media pH on matrix assembly. A gradual media pH change was maintained in the bioreactor within 7.4-6.96 over 2 weeks compared to a more rapid decrease from 7.4 to 6.58 in static culture over 3 days. Seeded scaffolds subjected to 1 microm/s flow demonstrated a 118% increase (p < 0.05) in DNA content, a 184% increase (p < 0.05) in GAG content, and a 155% (p < 0.05) increase in hydroxyproline content compared to static culture. Distinct differences were noted in tissue morphology, including more intense staining for proteoglycans by safranin-O and alignment of cells in the direction of media flow. Culture of chondrocyte seeded matrices thus offers the possibility of rapid in vitro expansion of donor cartilage for the repair of structural defects, tracheal injury, and vascularized tissue damage.


Why do policies change? Institutions, interests, ideas and networks in three cases of policy reform.
Policy researchers have used various categories of variables to explain why policies change, including those related to institutions, interests and ideas. Recent research has paid growing attention to the role of policy networks-the actors involved in policy-making, their relationships with each other, and the structure formed by those relationships-in policy reform across settings and issues; however, this literature has largely ignored the theoretical integration of networks with other policy theories, including the '3Is' of institutions, interests and ideas. This article proposes a conceptual framework integrating these variables and tests it on three cases of policy change in Burkina Faso, addressing the need for theoretical integration with networks as well as the broader aim of theory-driven health policy analysis research in low- and middle-income countries. We use historical process tracing, a type of comparative case study, to interpret and compare documents and in-depth interview data within and between cases. We found that while network changes were indeed associated with policy reform, this relationship was mediated by one or more of institutions, interests and ideas. In a context of high donor dependency, new donor rules affected the composition and structure of actors in the networks, which enabled the entry and dissemination of new ideas and shifts in the overall balance of interest power ultimately leading to policy change. The case of strategic networking occurred in only one case, by civil society actors, suggesting that network change is rarely the spark that initiates the process towards policy change. This analysis highlights the important role of changes in institutions and ideas to drive policymaking, but hints that network change is a necessary intermediate step in these processes.