Gossypol, a BH3 mimetic, induces apoptosis in chronic lymphocytic leukemia cells.
Gossypol, a cottonseed extract derivative, acts as a BH3-mimetic, binding to the BH3 pocket of antiapoptotic proteins and displacing pro-death partners to induce apoptosis. However, knowledge on the molecular underpinnings of its downstream effects is limited. Since chronic lymphocytic leukemia (CLL) cells express high levels of antiapoptotic proteins that act as a survival mechanism for these replicationally quiescent lymphocytes, we investigated whether gossypol induces apoptosis in these cells and what mechanism underlies gossypol-mediated cytotoxicity. Gossypol induced cell death in a concentration- and time-dependent manner; 24-hour incubation with 30 microM gossypol resulted in 50% cell death (median; range, 10%-80%; n = 47) that was not abrogated by pan-specific caspase inhibitor. Starting at 4 hours, the mitochondrial outer membrane was significantly permeabilized (median, 77%; range, 54%-93%; n = 15). Mitochondrial outer membrane permeabiliztaion (MOMP) was concurrent with increased production of reactive oxygen species (ROS); however, antioxidants did not abrogate gossypol-induced cell death. Mitochondrial membrane permeabilization was also associated with loss of intracellular adenosine triphosphate (ATP), activation of BAX, and release of cytochrome c and apoptosis-inducing factor (AIF), which was translocated to the nucleus. Blocking AIF translocation resulted in a decreased apoptosis, suggesting that AIF contributes to gossypol-mediated cytotoxicity in CLL lymphocytes.


The impact of slice-reduced computed tomography on histogram-based densitometry assessment of lung fibrosis in patients with systemic sclerosis.
To evaluate usability of slice-reduced sequential computed tomography (CT) compared to standard high-resolution CT (HRCT) in patients with systemic sclerosis (SSc) for qualitative and quantitative assessment of interstitial lung disease (ILD) with respect to (I) detection of lung parenchymal abnormalities, (II) qualitative and semiquantitative visual assessment, (III) quantification of ILD by histograms and (IV) accuracy for the 20%-cut off discrimination. From standard chest HRCT of 60 SSc patients sequential 9-slice-computed tomography (reduced HRCT) was retrospectively reconstructed. ILD was assessed by visual scoring and quantitative histogram parameters. Results from standard and reduced HRCT were compared using non-parametric tests and analysed by univariate linear regression analyses. With respect to the detection of parenchymal abnormalities, only the detection of intrapulmonary bronchiectasis was significantly lower in reduced HRCT compared to standard HRCT (P=0.039). No differences were found comparing visual scores for fibrosis severity and extension from standard and reduced HRCT (P=0.051-0.073). All scores correlated significantly (P<0.001) to histogram parameters derived from both, standard and reduced HRCT. Significant higher values of kurtosis and skewness for reduced HRCT were found (both P<0.001). In contrast to standard HRCT histogram parameters from reduced HRCT showed significant discrimination at cut-off 20% fibrosis (sensitivity 88% kurtosis and skewness; specificity 81% kurtosis and 86% skewness; cut-off kurtosis ≤26, cut-off skewness ≤4; both P<0.001). Reduced HRCT is a robust method to assess lung fibrosis in SSc with minimal radiation dose with no difference in scoring assessment of lung fibrosis severity and extension in comparison to standard HRCT. In contrast to standard HRCT histogram parameters derived from the approach of reduced HRCT could discriminate at a threshold of 20% lung fibrosis with high sensitivity and specificity. Hence it might be used to detect early disease progression of lung fibrosis in context of monitoring and treatment of SSc patients.


Comparative genome analysis of Pasteurella multocida strains of porcine origin.
Pasteurella multocida causes acute/chronic pasteurellosis in porcine, resulting in considerable economic losses globally. The draft genomes of two Indian strains NIVEDIPm17 (serogroup D) and NIVEDIPm36 (serogroup A) were sequenced. A total of 2182-2284 coding sequences (CDSs) were predicted along with 5-6 rRNA and 45-46 tRNA genes in the genomes. Multilocus sequence analysis and LPS genotyping showed the presence of ST50: genotype 07 and ST74: genotype 06 in NIVEDIPm17 and NIVEDIPm36, respectively. Pangenome analysis of 61 strains showed the presence of 1653 core genes, 167 soft core genes, 750 shell genes, and 1820 cloud genes. Analysis of virulence-associated genes in 61 genomes indicated the presence of nanB, exbB, exbD, ptfA, ompA, ompH, fur, plpB, fimA, sodA, sodC, tonB, and omp87 in all strains. The 61 genomes contained genes encoding tetracycline (54%), streptomycin (48%), sulphonamide (28%), tigecycline (25%), chloramphenicol (21%), amikacin (7%), cephalosporin (5%), and trimethoprim (5%) resistance. Multilocus sequence type revealed that ST50 was the most common (34%), followed by ST74 (26%), ST13 (24%), ST287 (5%), ST09 (5%), ST122 (3%), and ST07 (2%). Single-nucleotide polymorphism and core genome-based phylogenetic analysis clustered the strains into three major clusters. In conclusion, we described the various virulence factors, mobile genetic elements, and antimicrobial resistance genes in the pangenome of P. multocida of porcine origin, besides the rare presence of LPS genotype 7 in serogroup D.


Placing interprofessional learning at the heart of improving practice: the activities and achievements of CLAHRC in Leicestershire, Northamptonshire and Rutland.
The National Institute for Health Research initiative 'collaborations for leadership in applied health research and care' (CLAHRC) in Leicestershire Northamptonshire and Rutland (LNR) is a partnership between the University of Leicester and NHS trusts in LNR that aims to reduce the second gap in translation (the long delay between conducting research and it having an impact on clinical practice). CLAHRC-LNR appointed specialist staff as boundary spanners and knowledge brokers to improve links between academia and the NHS, and to facilitate a range of activities designed to increase the implementation of research evidence. An interprofessional and interdisciplinary approach is used and incorporates a range of activities including: applied research, service evaluation and pilot projects, education and training events, knowledge dissemination activities and developing networks to increase the use of research in the NHS partners. CLAHRC-LNR's close collaboration with partner NHS trusts has aided the development of a programme of applied research that aims to develop interprofessional teamworking to improve healthcare systems and patient outcomes. Co-ordinators (boundary spanners) have been appointed in trusts and have been crucial in facilitating interprofessional working. Activities include a successful programme of training and education courses within the NHS partner trusts using the principles of interprofessional education. CLAHRC-LNR is developing the use of knowledge exchange events and workshops as well as establishing communities of practice to bring together professionals from across LNR NHS trusts and the University of Leicester to share their expertise and build interprofessional relationships. CLAHRC fellows (knowledge brokers) are being appointed to work with co-ordinators to facilitate the use of research evidence in decision making in the trusts and clinical commissioning groups (CCGs). Interprofessional working is integral to the approach adopted by CLAHRC-LNR, running through many of its activities, and is proving vital to addressing and helping to close the second gap in translation.


Comparison of six methods to estimate adherence in an ART-naïve cohort in a resource-poor setting: which best predicts virological and resistance outcomes?
Incomplete adherence to antiretroviral therapy (ART) results in virologic failure and resistance. It remains unclear which adherence measure best predicts these outcomes. We compared six patient-reported and objective adherence measures in one ART-naïve cohort in South Africa. We recruited 230 participants from a community ART clinic and prospectively collected demographic data, CD4 count and HIV-RNA at weeks 0, 16 and 48. We quantified adherence using 3-day self-report (SR), clinic-based pill count (CPC), average adherence by pharmacy refill (PR-average), calculation of medication-free days (PR-gaps), efavirenz therapeutic drug monitoring (TDM) and an electronic adherence monitoring device (EAMD). Associations between adherence measures and virologic and genotypic outcomes were modelled using logistic regression, with the area under the curve (AUC) from the receiver operator characteristic (ROC) analyses derived to assess performance of adherence measures in predicting outcomes. At week 48 median (IQR) adherence was: SR 100% (100-100), CPC 100% (95-107), PR-average 103% (95-105), PR-gaps 100% (95-100) and EAMD 86% (59-94), and efavirenz concentrations were therapeutic (>1 mg/L) in 92%. EAMD, PR-average, PR-gaps and CPC best predicted virological outcome at week 48 with AUC ROC of 0.73 (95% CI 0.61-0.83), 0.73 (95% CI 0.61-0.85), 0.72 (95% CI 0.59-0.84) and 0.64 (95% CI 0.52-0.76) respectively. EAMD, PR-gaps and PR-average were highly predictive of detection of resistance mutations at week 48, with AUC ROC of 0.92 (95% CI 0.87-0.97), 0.86 (0.67-1.0) and 0.83 (95% CI 0.65-1.0) respectively. SR and TDM were poorly predictive of outcomes at week 48. EAMD and both PR measures predicted resistance and virological failure similarly. Pharmacy refill data is a pragmatic adherence measure in resource-limited settings where electronic monitoring is unavailable. Trial registration The trial was retrospectively registered in the Pan African Clinical Trials Registry, number PACTR201311000641402, on the 13 Sep 2013 ( www.pactr.org ). The first participant was enrolled on the 12th July 2012. The last patient last visit (week 48) was 15 April 2014.


Structural Investigations into the retro-Diels-Alder Reaction. Experimental and Theoretical Studies.
The manifestations of the retro-Diels Alder reaction in the ground-state structures of a range of cyclopentadiene and cyclohexadiene cycloadducts 9-15 have been investigated by a combination of techniques. These include low-temperature X-ray crystallography, density functional calculations (B3LYP/6-31G(d,p)) on both the ground states and transition states, and the measurement of (13)C-(13)C coupling constants. We have found that the carbon-carbon bonds (labeled bonds a and b), which break in the rDA, are longer in the cycloadducts 9-15 than in their corresponding saturated analogues 9s-15s, which cannot undergo the rDA reaction. The degree of carbon-carbon bond lengthening appears to be related to the reactivity of the cycloadduct, thus the more reactive benzoquinone cycloadducts 5b and 13 have longer carbon-carbon bonds. Those cycloadducts 14 and 15 which are predicted to undergo asynchronous reactions show differing degrees of carbon-carbon bond lengthening, reflecting the differing degrees of bond breaking at the calculated transition states for the rDA.


Effects of arm weight on C-not-B task performance: implications for the motor inhibitory deficit account of search failures.
Toddlers have been found to fail on a three-location search task involving the invisible displacements of an object, namely the C-not-B task. In this task, a child is shown the experimenter's hand that contains a toy. The toy then successively disappears under the three cloths (A, B, then C). The examiner silently releases the toy under the second cloth (B). The hidden object makes a bump in the B cloth that covers it. Young children emit a strong bias toward the last cloth that the experimenter's hand passes under, and this has been labeled the C-not-B error. One possible explanation for toddlers' failures in the C-not-B task is that children lack the motor inhibitory mechanisms. To test this hypothesis, the robustness of the C-not-B error was tested, in a first experiment, against variations in body parameters. By putting additional weights on the arm, the C-not-B error was reduced substantially and the C-not-B task had a higher rate of success. Indeed, in contrast to control participants, who ignored a visual clue indicating the correct location of the hidden object and reached for the last location of the experimenter's hand, the participants with arm weights initiated their reaching movements by using the visual clue. The findings from the second control group indicate that the dramatic increase in successful performance by children with arm weights is not merely a consequence of the focus on the attention to arm movements. The motion of the experimenter's hand in space appears to have made the task difficult because toddlers had no problems inferring that a lump under a cloth indicates the existence of an object without actually having watched an object be hidden there, as demonstrated in a second experiment. The findings are consistent with the hypothesis that C-not-B task content activates a prepotent motor response that preempts full consideration of a visual clue indicating the correct location of the hidden object. We propose that the success in the C-not-B task of toddlers with additional arm weights could result from a disruption of automatic hand movement that is triggered by sensory signals, namely salient features of the C-not-B task.


[Hepatic subcapsular hematoma caused by fascioliasis].
The case of a 22 year old woman from Huaraz is presented herein. She suffered from pain at right hypocondrium, associated to nausea and vomits, which intensified three days prior to admission. Upon examining her, a faded gallbladder murmur was found on the base of the right hemithorax. There is pain in the abdomen when touched at the epigastrium and right hypocondrium. The liver is perceived 3 cm beneath the costal edge: White blood count with severe eosinophilia. Mild cholestasis is observed. Abdominal scan: Heterogeneous hepatic mass, with a 13 cm diameter in the right lobe. CAT scan: Subcapsular 14x8 cm mass. Scintiscan: Liver with a low absorption area showing absence of perfusion to the vascular pool. She undergoes an exploratory laparotomy and an 800 cc subcapsular hematoma is found in segment 6, 7 and 8, which is drained. Evolution evidences the persistence of eosinophilia and positive Arc-2 is obtained for Fasciola. She was administered Triclabendazol and is currently asymptomatic. The invasive stage of human fascioliasis may cause hepatic hematoma as a rare complication. The triad of persisting eosinophilia, painful hepatomegalia and prolonged fever leads to insist in the search of fascioliasis in endemic areas.


Chronic naltrexone treatment and ethanol responsivity in outbred rats.
Acute naltrexone treatment in rats produces significant alterations in ethanol palatability (increase in the aversiveness of the solution) and ethanol consumption during tests of restricted access (decrease in consumption). The effects of chronic naltrexone exposure, accomplished by implantation of osmotic mini-pumps, were examined in the present study. Rats were surgically implanted with intraoral fistulae for taste reactivity testing. The animals were given 2 bottles (distilled water and 10% ethanol, v/v) for 3, 2-week phases: Pre-Drug, Drug, and Post-Drug. After the Pre-Drug phase, rats were assigned to groups (counterbalanced based on ethanol intake) and implanted with a mini-pump containing saline, 7.5 mg/kg/d naltrexone, or 15 mg/kg/d naltrexone. The pumps were removed 2 weeks later. During each 2-week phase, taste reactivity tests with 10% ethanol were conducted at 1, 7, and 14 days (a total of 9 reactivity tests). The 7.5 mg/kg/d dose produced only minor effects on 10% ethanol reactivity and consumption during the Drug phase. The 15 mg/kg/d naltrexone dose generally shifted taste reactivity responding to 10% ethanol in a negative direction and produced a transient decrease in ethanol consumption. The 15 mg/kg/d group significantly increased ethanol consumption beyond the level of consumption by the Saline group when the pumps were removed, although the increase was delayed 48 hours. By the end of the Post-Drug period, this naltrexone group returned to control levels of ethanol consumption. Chronic naltrexone treatment at 15 mg/kg/d significantly decreased the palatability of a 10% ethanol solution, an effect seen even after drug withdrawal. Naltrexone had a minor effect on ethanol consumption during treatment but did decrease overall levels of fluid consumption. The significant increase in ethanol consumption postdrug by the high-dose naltrexone group, presumably due to receptor up-regulation during treatment, is important and understanding this effect and developing means of overcoming it within a clinical practice would be useful goals.


[Renal dysplasia and vesico-ureteral reflux].
We studied two groups of patients in order to evaluate the frequency of association between renal dysplasia and vesicoureteral reflux. The first was composed of 19 patients with dysplastic kidneys, 15 of whom were studied by means of micturition cystourethrography. The second group was made up of 86 patients with 124 kidneys with reflux. In 16 of these we were able to obtain a histopathological diagnosis of the renal lesions (12 nephrectomies, 4 biopsies). In three cases the renal dysplasia was associated with a vesicoureteral reflux, which represents an incidence of reflux in 20% of the patients with renal dysplasia, and an incidence of dysplasia in 19% of the kidneys with reflux examined histopathologically. We contrast these results with the literature, discussing the pathogenic hypotheses that enable us to explain this association as well as the clinical consequences thereof.


Ab initio statistical mechanics of surface adsorption and desorption. II. Nuclear quantum effects.
We show how the path-integral formulation of quantum statistical mechanics can be used to construct practical ab initio techniques for computing the chemical potential of molecules adsorbed on surfaces, with full inclusion of quantum nuclear effects. The techniques we describe are based on the computation of the potential of mean force on a chosen molecule and generalize the techniques developed recently for classical nuclei. We present practical calculations based on density functional theory with a generalized-gradient exchange-correlation functional for the case of H(2)O on the MgO (001) surface at low coverage. We note that the very high vibrational frequencies of the H(2)O molecule would normally require very large numbers of time slices (beads) in path-integral calculations, but we show that this requirement can be dramatically reduced by employing the idea of thermodynamic integration with respect to the number of beads. The validity and correctness of our path-integral calculations on the H(2)O/MgO(001) system are demonstrated by supporting calculations on a set of simple model systems for which quantum contributions to the free energy are known exactly from analytic arguments.


What is the Healthy Gut Microbiota Composition? A Changing Ecosystem across Age, Environment, Diet, and Diseases.
Each individual is provided with a unique gut microbiota profile that plays many specific functions in host nutrient metabolism, maintenance of structural integrity of the gut mucosal barrier, immunomodulation, and protection against pathogens. Gut microbiota are composed of different bacteria species taxonomically classified by genus, family, order, and phyla. Each human's gut microbiota are shaped in early life as their composition depends on infant transitions (birth gestational date, type of delivery, methods of milk feeding, weaning period) and external factors such as antibiotic use. These personal and healthy core native microbiota remain relatively stable in adulthood but differ between individuals due to enterotypes, body mass index (BMI) level, exercise frequency, lifestyle, and cultural and dietary habits. Accordingly, there is not a unique optimal gut microbiota composition since it is different for each individual. However, a healthy host⁻microorganism balance must be respected in order to optimally perform metabolic and immune functions and prevent disease development. This review will provide an overview of the studies that focus on gut microbiota balances in the same individual and between individuals and highlight the close mutualistic relationship between gut microbiota variations and diseases. Indeed, dysbiosis of gut microbiota is associated not only with intestinal disorders but also with numerous extra-intestinal diseases such as metabolic and neurological disorders. Understanding the cause or consequence of these gut microbiota balances in health and disease and how to maintain or restore a healthy gut microbiota composition should be useful in developing promising therapeutic interventions.


The importance of using routine laboratory tests in the diagnosis and prognosis of patients with coronavirus disease 2019: Shedding light on clinical laboratory data in COVID-19.
Novel coronavirus (COVID-19) pandemic has become a global concern and requires early detection, isolation, and treatment. Our purpose is to find some beneficial information by analyzing the COVID-19 laboratory data to provide guidance for clinical practice. In this study, 174 patients with confirmed COVID-19 infection were admitted. We evaluated the hematological and biochemical parameters in these patients and in 80 healthy individuals. We found that there was significant difference between WBC, LYM, RBC, HB, and HCT parameters of patients and healthy counterparts (p < .001), though there was no remarkable change between NEU, MONO, PLT, and other characteristics of RBC values of patients and the control group (p ≥ .09). Among the evaluated biochemical parameters, the values of CK-MB and LDH in the patient group were significantly different from the control group (p < .01), while other biochemical indicators were in the normal range. Several hematological and biochemistry parameters, in particular WBC, LYM, RBC, HB, HCT, CK-MB, and LDH, could be beneficial supplementary approach for COVID-19 infection evaluation to confirm risk stratification and effective management.


Patients with severe COVID-19 do not have elevated autoantibodies against common diagnostic autoantigens.
Infection by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative pathogen of coronavirus disease 2019 (COVID-19) presents occasionally with an aberrant autoinflammatory response, including the presence of elevated circulating autoantibodies in some individuals. Whether the development of autoantibodies against self-antigens affects COVID-19 outcomes remains unclear. To better understand the prognostic role of autoantibodies in COVID-19, we quantified autoantibodies against 23 markers that are used for diagnosis of autoimmune disease. To this end, we used serum samples from patients with severe [intensive care unit (ICU)] and moderate (ward) COVID-19, across two to six consecutive time points, and compared autoantibody levels to uninfected healthy and ICU controls. Acute and post-acute serum (from 1 to 26 ICU days) was collected from 18 ICU COVID-19-positive patients at three to six time points; 18 ICU COVID-19-negative patients (sampled on ICU day 1 and 3); 21 ward COVID-19-positive patients (sampled on hospital day 1 and 3); and from 59 healthy uninfected controls deriving from two cohorts. Levels of IgG autoantibodies against 23 autoantigens, commonly used for autoimmune disease diagnosis, were measured in serum samples using MSD® U-PLEX electrochemiluminescence technology (MSD division Meso Scale Discovery®), and results were compared between groups. There were no significant elevations of autoantibodies for any of the markers tested in patients with severe COVID-19. Sample collections at longer time points should be considered in future studies, for assessing the possible development of autoantibody responses following infection with SARS-CoV-2.


Adhesion of platelets to surface-bound fibrinogen under flow.
After platelet activation, fibrinogen mediates platelet-platelet interactions leading to platelet aggregation. In addition, fibrinogen can also function as a cell adhesion molecule, providing a substratum for adhesion of platelets and endothelial cells. In this report, we studied the adhesion of platelets to surface-immobilized fibrinogen under flow in different shear rates. Heparinized whole blood containing mepacrine-labeled platelets was perfused for two minutes at various wall shear rates from 250 to 2,000 s-1 in a parallel plate flow chamber. The number of adherent fluorescent platelets was quantitated every 15 seconds with an epifluorescent videomicroscope and digital image processing system. When compared with platelet adhesion and aggregation seen on glass surfaces coated with type I bovine collagen, a significant increase in platelet adhesion was observed on immobilized fibrinogen up to wall shear rates of 800 s-1. The adherent platelets formed a single layer on fibrinogen-coated surfaces. Under identical conditions, no significant adhesion was observed on fibronectin- or vitronectin-coated surfaces. Although platelet adhesion to collagen was substantially inhibited by the platelet inhibitors prostaglandin E1 and theophylline, these inhibitors had no effect on platelet adhesion to fibrinogen. Platelets adhered to recombinant homodimeric wild-type (gamma 400-411) fibrinogen, but not to the recombinant homodimeric gamma' variant of fibrinogen. Platelet adhesion to recombinant fibrinogen with RGD to RGE mutations at positions alpha 95-97 and alpha 572-574 was similar to that with plasma-derived fibrinogen. These results show that platelets adhere to fibrinogen-coated surfaces under moderate wall shear rates, that the interaction is mediated by the fibrinogen 400-411 sequence at the carboxy-terminus of the gamma chain, and that the interaction is independent of platelet activation and the RGD sequences in the alpha chain.


WMS-R and MAS correlations in a neuropsychological population.
The present study was an attempt to examine the relationship between the Wechsler Memory Scale-Revised (WMS-R; Wechsler, 1987) and the Memory Assessment Scale (MAS; Williams, 1991). The sample consisted of 51 patients referred for neuropsychological examination. Average age was 55.29 (SD = 20.94). Average education was 11.94 years (SD = 3.18). Average Full Scale IQ was 94.75 (SD = 15.44). The results showed that no MAS index correlated higher than.60 with any of the WMS-R indices. There was minimal specific prediction between instruments across each memory domain. Agreement between the tests clinically was low as well. Corrections for such factors as age, education, intelligence or diagnosis lowered the relationships between the tests although not significantly. Corrections to the correlations for the inherent reliability of each test increased correlations between the tests but still resulted in a maximum common variance of 56% (for the visual measures) down to 40% (for General Memory). These results are consistent with the argument that "general memory" is not as useful a construct as that of "general intelligence" and that these tests of general memory measure different underlying constructs. This has important impact on how we conceive and report memory test results.


Implications of technology in music therapy practice and research for music therapy education: a review of literature.
This article reviews the use of technology in music therapy practice and research for the purpose of providing music therapy educators and clinicians with specific and accurate accounts of the types and benefits of technology being used in various settings. Additionally, this knowledge will help universities comply with National Association of Schools of Music requirements and help to standardize the education and training of music therapists in this rapidly changing area. Information was gathered through a literature review of music therapy and related professional journals and a wide variety of books and personal communications. More data were gathered in a survey requesting information on current use of technology in education and practice. This solicitation was sent to all American Music Therapy Association approved universities and clinical training directors. Technology applications in music therapy are organized according to the following categories: (a) adapted musical instruments, (b) recording technology, (c) electric/electronic musical instruments, (d) computer applications, (e) medical technology, (f) assistive technology for the disabled, and (g) technology-based music/sound healing practices. The literature reviewed covers 177 books and articles from a span of almost 40 years. Recommendations are made for incorporating technology into music therapy course work and for review and revision of AMTA competencies. The need for an all-encompassing clinical survey of the use of technology in current music therapy practice is also identified.


Multilocus outbreak of foodborne botulism linked to contaminated sausage in Hebei province, China.
In 2007, an outbreak of foodborne botulism occurred in Hebei province, China. An epidemiological investigation and laboratory detection studies showed that sausage contaminated by type A Clostridium botulinum caused this outbreak of food poisoning. Its clinical and epidemiological features were different from previous reports of food poisoning.


Molecularly Imprinted Polymers: Novel Discovery for Drug Delivery.
Molecularly imprinted polymers (MIP) are novel carriers synthesized by imprinting of a template over a polymer. This paper presents the recent application of MIP for diagnostic and therapeutic drug delivery. MIP owing to their 3D polymeric structures and due to bond formation with the template serves as a reservoir of active causing stimuli sensitive, enantioselective, targetted and/or controlled release. The review elaborates about key factors for optimization of MIP, controlled release by MIP for various administration routes various forms like patches, contact lenses, nanowires along with illustrations. To overcome the limitation of organic solvent usage causing increased cost, water compatible MIP and use of supercritical fluid technology for molecular imprinting were developed. Novel methods for developing water compatible MIP like pickering emulsion polymerization, co-precipitation method, cyclodextrin imprinting, surface grafting, controlled/living radical chain polymerization methods are described with illustration in this review. Various protein imprinting methods like bulk, epitope and surface imprinting are described along with illustrations. Further, application of MIP in microdevices as biomimetic sensing element for personalized therapy is elaborated. Although development and application of MIP in drug delivery is still at its infancy, constant efforts of researchers will lead to a novel intelligent drug delivery with commercial value. Efforts should be directed in developing solid oral dosage forms consisting of MIP for therapeutic protein and peptide delivery and targeted release of potent drugs addressing life threatening disease like cancer. Amalgamation of bio-engineering and pharmaceutical techniques can make these future prospects into reality.


Dissociation between the effects of somatostatin (SS) and octapeptide SS-analogs on hormone release in a small subgroup of pituitary- and islet cell tumors.
The effects of somatostatin (SS-14 and/or SS-28) and of the three octapeptide SS-analogs that are available for clinical use (octreotide, BIM-23014 and RC-160) on hormone release by primary cultures of 15 clinically nonfunctioning pituitary adenomas (NFA), 7 prolactinomas, and 2 insulinomas were investigated. In the pituitary adenoma cultures, a comparison was made with the effects of the dopamine (DA) agonists bromocriptine and/or quinagolide. In 5 NFAs, 2 prolactinomas and 1 insulinoma somatostatin receptor (subtype) expression was determined by ligand binding studies and by in situ hybridization to detect sst1, sst2, and sst3 messenger RNAs (mRNAs). Four NFA cultures did not secrete detectable amounts of alpha-subunit, FSH, and/or LH. In the other cultures, hormone and/or subunit release was inhibited by DA-agonists (10 nM) in 9 of 11, by SS (10 nM) in 7 of 11, and by octapeptide SS-analogs (10 nM) in 3 of 10 cultures. In three NFA cultures, hormone release was sensitive to SS but not to SS-analogs. In all cultures, except for one, DA-agonists were the most effective in inhibiting hormone release. In the prolactinoma cultures, PRL release was inhibited by DA-agonists (10 nM) in 7 of 7, by SS in 4 of 4, and by octapeptide SS-analogs in 3 of 7 cultures. A dissociation between the effects of SS and SS-analogs was found in 3 cases. In the cultures sensitive to both bromocriptine and SS-28, bromocriptine was the most potent compound in 2 out of 4 cultures. In the 2 other cultures, both compounds were equally effective. In 2 insulinoma cultures, insulin release was inhibited by SS, and by octapeptide SS-analogs in only one. The presence or absence of an inhibitory effect by octreotide was in all cases in parallel with the presence or absence of the inhibitory effect by BIM-23014 and RC-160. Autoradiographic studies using [125I-Tyr0]SS28 showed specific binding in 4 of 5 NFAs, 1 of 2 prolactinomas, and 1 of 1 insulinoma. Specific [125I-Tyr3]octreotide binding was found in 2 of 5 NFAs, in 1 of 2 prolactinomas, and in the insulinoma. Two NFAs showed binding of SS28, but not of the sst2.5 specific ligand octreotide. The tumors showed variable sst1 and/or sst3 mRNA expression, whereas no sst2 expression was found. In conclusion, a dissociation between the inhibitory effects of SS on the one hand and of the octapeptide SS-analogs octreotide, BIM-23014 and RC-160 on the other hand, is observed in a small subgroup of NFAs, prolactinomas, and insulinomas, suggesting that novel sst subtype specific SS-analogs might be of benefit in the treatment of selected patients with somatostatin receptor positive secreting tumors not responding to octapeptide SS-analogs. However, in the majority of NFAs and prolactinomas, DA-agonists were equally or more effective than SS in the suppression of tumoral secretion products.


The effect of community-based support services on clinical efficacy and health-related quality of life in HIV/AIDS patients in resource-limited settings in sub-Saharan Africa.
Antiretroviral therapy (ART) for HIV/AIDS in developing countries has been rapidly scaled up through directed public and private resources. Data on the efficacy of ART in developing countries are limited, as are operational research studies to determine the effect of selected nonmedical supportive care services on health outcomes in patients receiving ART. We report here on an investigation of the delivery of medical care combined with community-based supportive services for patients with HIV/AIDS in four resource-limited settings in sub-Saharan Africa, carried out between 2005 and 2007. The clinical and health-related quality of life (HRQOL) efficacy of ART combined with community support services was studied in a cohort of 377 HIV-infected patients followed for 18 months, in community-based clinics through patient interviews, clinical evaluations, and questionnaires. Patients exposed to community-based supportive services experienced a more rapid and greater overall increase in CD4 cell counts than unexposed patients. They also had higher levels of adherence, attributed primarily to exposure to home-based care services. In addition, patients receiving home-based care and/or food support services showed greater improvements in selected health-related QOL indicators. This report discusses the feasibility of effective ART in a large number of patients in resource-limited settings and the added value of concomitant community-based supportive care services.


Temperature effect on the bioluminescence spectra of firefly luciferases: potential applicability for ratiometric biosensing of temperature and pH.
Bioluminescence spectra of firefly luciferases are affected by pH, heavy metals and high temperatures. Previously, we compared the effect of pH and heavy metals on the bioluminescence spectra of different firefly luciferases and showed that such spectral sensitivity can be harnessed to ratiometrically estimate the pH inside cells and metal concentration. Here, we compared the effect of temperature on the spectral sensitivity of four firefly luciferases (Amydetes vivianii: 539 nm; Cratomorphus distinctus: 548 nm; Photinus pyralis: 558 nm and Macrolampis sp2: 594 nm) and investigated whether a ratiometric curve could be used to estimate temperature. The ratio of intensities of bioluminescence at two wavelengths (green and red) at different temperatures (5-35 °C) was determined. The results confirm that, in the case of pH-sensitive luciferases, the more blue-shifted the bioluminescence spectrum, the more thermostable the enzyme and the less sensitive the emission spectrum to temperature. An almost linear relationship between temperature and the ratio of bioluminescence intensities in the green and red region of the spectrum was found for the four luciferases: the more blue-shifted and less sensitive luciferases exhibit a smaller slope and the more red-shifted luciferases exhibit a steeper slope in the following order: Amy < Crt < Ppy < Mac. This relationship offers the possibility of using firefly luciferases as ratiometric indicators of temperature and may allow the compensation of the effect of temperature in the ratiometric analysis of intracellular pH and heavy metal concentration for each enzyme.


Evaluation of polycaprolactone scaffold with basic fibroblast growth factor and fibroblasts in an athymic rat model for anterior cruciate ligament reconstruction.
Anterior cruciate ligament (ACL) rupture is a common ligamentous injury often necessitating surgery. Current surgical treatment options include ligament reconstruction with autograft or allograft, which have their inherent limitations. Thus, there is interest in a tissue-engineered substitute for use in ACL regeneration. However, there have been relatively few in vivo studies to date. In this study, an athymic rat model of ACL reconstruction was used to evaluate electrospun polycaprolactone (PCL) grafts, with and without the addition of basic fibroblast growth factor (bFGF) and human foreskin fibroblasts. We examined the regenerative potential of tissue-engineered ACL grafts using histology, immunohistochemistry, and mechanical testing up to 16 weeks postoperatively. Histology showed infiltration of the grafts with cells, and immunohistochemistry demonstrated aligned collagen deposition with minimal inflammatory reaction. Mechanical testing of the grafts demonstrated significantly higher mechanical properties than immediately postimplantation. Acellular grafts loaded with bFGF achieved 58.8% of the stiffness and 40.7% of the peak load of healthy native ACL. Grafts without bFGF achieved 31.3% of the stiffness and 28.2% of the peak load of healthy native ACL. In this in vivo rodent model study for ACL reconstruction, the histological and mechanical evaluation demonstrated excellent healing and regenerative potential of our electrospun PCL ligament graft.


IL-2 as adjuvant for vaccination with cells malignantly converted by HPV 16 or 3-MC.
Experiments were designed to investigate the effects of murine recombinant IL-2 used as adjuvant for tumour vaccines in two model systems. The first system employed the Syrian hamster K3/II cell line transformed malignantly in vitro with DNA from E6-E7 oncogenes from HPV 16 and transplanted in Syrian hamsters. The second system made use of murine sarcoma Mc 12 induced with MC and transplanted in histocompatible mice. Both tumours were previously shown to express TRA capable of inducing transplantation resistance. It has been demonstrated here that the effect of the immunization in both tumour model systems could be substantially increased by IL-2 injected repeatedly at the site of vaccination. Some of the experimental mice were sacrificed after immunization and their spleen as well as regional lymph node cells were used for phenotypic analysis. IL-2 administration was found to be accompanied with an increase of TCR alpha beta(+), CD4(+) T cells in the spleen. Also in regional lymph nodes the T cell subsets showed a characteristic kinetics due to IL-2 administration. Following the IL-2 treatment, the percentage of lymph node TCR alpha beta(+), CD4(+) and CD8(+) cells dropped to less than half of the pretreatment values and then again gradually increased. No such kinetics was observed in vaccinated mice that did not receive IL-2. These results suggest that local administration of IL-2 at the site of vaccination elicits, in addition to the reaction in regional lymph nodes, a systemic reaction detectable in the spleen; they also suggest that the increase of CD4(+), TCR alpha beta(+) T splenocytes may play an important role in the mechanism of the observed adjuvant effect of IL-2. The adjuvant IL-2 effect augmenting the function of cell vaccines expressing HPV 16 E6-E7 oncoproteins deserves further studies, particularly with regard to its prospective utilization for treatment of human cervical carcinoma.


The EORTC QLQ-C30 Summary Score as Prognostic Factor for Survival of Patients with Cancer in the "Real-World": Results from the Population-Based PROFILES Registry.
Health-related quality of life (HRQoL) has been shown to be a prognostic factor for cancer survival in randomized clinical trials and observational "real-world" cohort studies; however, it remains unclear which HRQoL domains are the best prognosticators. The primary aims of this population-based, observational study were to (a) investigate the association between the novel European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-Core30 (QLQ-C30) summary score and all-cause mortality, adjusting for the more traditional sociodemographic and clinical prognostic factors; and (b) compare the prognostic value of the QLQ-C30 summary score with the global quality of life (QoL) and physical functioning scales of the QLQ-C30. Between 2008 and 2015, patients with cancer (12 tumor types) were invited to participate in PROFILES disease-specific registry studies (response rate, 69%). In this secondary analysis of 6,895 patients, multivariate Cox proportional hazard regression models were used to investigate the association between the QLQ-C30 scores and all-cause mortality. In the overall Cox regression model including sociodemographic and clinical variables, the QLQ-C30 summary score was associated significantly with all-cause mortality (hazard ratio [HR], 0.77; 99% confidence interval [CI], 0.71-0.82). In stratified analyses, significant associations between the summary score and all-cause mortality were observed for colon, rectal, and prostate cancer, non-Hodgkin lymphoma, chronic lymphocytic leukemia, and multiple myeloma. The QLQ-C30 summary score had a stronger association with all-cause mortality than the global QoL scale (HR, 0.82; 99% CI, 0.77-0.86) or the physical functioning scale (HR, 0.81; 95% CI, 0.77-0.85). In a real-world setting, the QLQ-C30 summary score has a strong prognostic value for overall survival for a number of populations of patients with cancer above and beyond that provided by clinical and sociodemographic variables. The QLQ-C30 summary score appears to have more prognostic value than the global QoL, physical functioning, or any other scale within the QLQ-C30. The finding that health-related quality of life provides distinct prognostic information beyond known sociodemographic and clinical measures, not only around cancer diagnosis (baseline) but also at follow-up, has implications for clinical practice. Implementation of cancer survivorship monitoring systems for ongoing surveillance may improve post-treatment rehabilitation that leads to better outcomes.


Axonal self-destruction and neurodegeneration.
Neurons seem to have at least two self-destruct programs. Like other cell types, they have an intracellular death program for undergoing apoptosis when they are injured, infected, or not needed. In addition, they apparently have a second, molecularly distinct self-destruct program in their axon. This program is activated when the axon is severed and leads to the rapid degeneration of the isolated part of the cut axon. Do neurons also use this second program to prune their axonal tree during development and to conserve resources in response to chronic insults?


[A rapid method for determining the viability of Escherichia coli cells subjected to the action of low temperatures].
When Escherichia coli cells are frozen at a low temperature, various damages appear in them, in particular, in the membranous apparatus. Only stable disorders in the barrier properties of the cytoplasmic membranes are of a critical importance for the cell viability. These disorders should be taken into account when express methods are developed for assaying the viability of bacterial cells. Critical structures (properties) are to be revealed by their analysis after varying the intensity (dose) of the main damaging factors. Provided that the critical feature of each cell has two states (damaged and intact) after the action of extreme factors, its quantitative change correlates in a linear mode with the number of viable cells in the population.


Hydrodynamic lubrication in colloidal gels.
Colloidal gels are elasto-plastic materials composed of an out-of-equilibrium, self-assembled network of micron-sized (solid) particles suspended in a fluid. Recent work has shown that far-field hydrodynamic interactions do not change gel structure, only the rate at which the network forms and ages. However, during gel formation, the interplay between short-ranged attractions leading to gelation and equally short-ranged hydrodynamic lubrication interactions remains poorly understood. Here, we therefore study gelation using a range of hydrodynamic descriptions: from single-body (Brownian Dynamics), to pairwise (Rotne-Prager-Yamakawa), to (non-)lubrication-corrected many-body (Stokesian Dynamics). We confirm the current understanding informed by simulations accurate in the far-field. Yet, we find that accounting for lubrication can strongly impact structure at low colloid volume fraction. Counterintuitively, strongly dissipative lubrication interactions also accelerate the aging of a gel, irrespective of colloid volume fraction. Both elements can be explained by lubrication forces facilitating collective dynamics and therefore phase-separation. Our findings indicate that despite the computational cost, lubricated hydrodynamic modeling with many-body far-field interactions is needed to accurately capture the evolution of the gel structure.


Nursing children and adolescents with bipolar disorder: assessment, diagnosis, treatment, and management.
The role of the mental health nurse in the assessment, diagnosis, treatment, and management of children and adolescents with bipolar disorder in community and hospital settings. In many areas of clinical practice, mental health nurses have more contact with service users than any other professional group. They are therefore well placed to support children and adolescents with bipolar disorder during first contact with primary care services, through engagement with specialist mental health services, and in accessing early intervention and crisis services. This paper summarizes the contribution that child and adolescent mental health nurses make to the care of children and adolescents with bipolar disorder. This paper is based on evidence from systematic reviews; meta-analyses and best practice evidence from CINAHL; EMBASE; MEDLINE, PsychINFO; Cochrane Collaboration; National Institute for Health and Clinical Excellence; National Collaborating Centre for Mental Health; NHS Centre for Reviews and Dissemination; Oxford Centre for Evidence Based Medicine; United States Agency for Healthcare Research and Quality. Child and adolescent mental health nurses work with children and adolescents who have bipolar disorder in a range of settings. These include community mental health services, hospitals, and schools. Due to the multidisciplinary nature of the treatment and management of bipolar disorder during childhood and adolescence, nurses have a major role to play in providing frontline assessment services, monitoring treatment, and delivering psychosocial interventions.


Nonredundant roles for CD1d-restricted natural killer T cells and conventional CD4+ T cells in the induction of immunoglobulin E antibodies in response to interleukin 18 treatment of mice.
Interleukin (IL)-18 synergizes with IL-12 to promote T helper cell (Th)1 responses. Somewhat paradoxically, IL-18 administration alone strongly induces immunoglobulin (Ig)E production and allergic inflammation, indicating a role for IL-18 in the generation of Th2 responses. The ability of IL-18 to induce IgE is dependent on CD4+ T cells, IL-4, and signal transducer and activator of transcription (stat)6. Here, we show that IL-18 fails to induce IgE both in CD1d-/- mice that lack natural killer T (NKT) cells and in class II-/- mice that lack conventional CD4+ T cells. However, class II-/- mice reconstituted with conventional CD4+ T cells show the capacity to produce IgE in response to IL-18. NKT cells express high levels of IL-18 receptor (R)alpha chain and produce significant amounts of IL-4, IL-9, and IL-13, and induce CD40 ligand expression in response to IL-2 and IL-18 stimulation in vitro. In contrast, conventional CD4+ T cells express low levels of IL-18Ralpha and poorly respond to IL-2 and IL-18. Nevertheless, conventional CD4+ T cells are essential for B cell IgE responses after the administration of IL-18. These findings indicate that NKT cells might be the major source of IL-4 in response to IL-18 administration and that conventional CD4+ T cells demonstrate their helper function in the presence of NKT cells.


Bell's Palsy.
Bell's palsy is a common outpatient problem, and while the diagnosis is usually straightforward, a number of diagnostic pitfalls can occur, and a lengthy differential diagnosis exists. Recognition and management of Bell's palsy relies on knowledge of the anatomy and function of the various motor and nonmotor components of the facial nerve. Avoiding diagnostic pitfalls relies on recognizing red flags or features atypical for Bell's palsy, suggesting an alternative cause of peripheral facial palsy. The first American Academy of Neurology (AAN) evidence-based review on the treatment of Bell's palsy in 2001 concluded that corticosteroids were probably effective and that the antiviral acyclovir was possibly effective in increasing the likelihood of a complete recovery from Bell's palsy. Subsequent studies led to a revision of these recommendations in the 2012 evidence-based review, concluding that corticosteroids, when used shortly after the onset of Bell's palsy, were "highly likely" to increase the probability of recovery of facial weakness and should be offered; the addition of an antiviral to steroids may increase the likelihood of recovery but, if so, only by a very modest effect. Bell's palsy is characterized by the spontaneous acute onset of unilateral peripheral facial paresis or palsy in isolation, meaning that no features from the history, neurologic examination, or head and neck examination suggest a specific or alternative cause. In this setting, no further testing is necessary. Even without treatment, the outcome of Bell's palsy is favorable, but treatment with corticosteroids significantly increases the likelihood of improvement.


Hepatic organic anion transporting polypeptide transporter and thyroid hormone receptor interplay determines cholesterol and glucose homeostasis.
The role of organic anion transporting polypeptides (OATPs), particularly the members of OATP1B subfamily, in hepatocellular handling of endogenous and exogenous compounds is an important and emerging area of research. Using a mouse model lacking Slco1b2, the murine ortholog of the OATP1B subfamily, we have demonstrated previously that genetic ablation causes reduced hepatic clearance capacity for substrates. In this study, we focused on the physiological function of the hepatic OATP1B transporters. First, we studied the influence of the Oatp1b2 deletion on bile acid (BA) metabolism, showing that lack of the transporter results in a significantly reduced expression of Cyp7a1, the key enzyme of BA synthesis, resulting in elevated cholesterol levels after high dietary fat challenge. Furthermore, Slco1b2-/- mice exhibited delayed clearance after oral glucose challenge resulting from reduced hepatic glucose uptake. In addition to increased hepatic glycogen content, Slco1b2-/- mice exhibited reduced glucose output after pyruvate challenge. This is in accordance with reduced hepatic expression of phosphoenolpyruvate carboxykinase (PEPCK) in knockout mice. We show that this phenotype is due to the loss of liver-specific Oatp1b2-mediated hepatocellular thyroid hormone entry, which then leads to reduced transcriptional activation of target genes of hepatic thyroid hormone receptor (TR), including Cyp7a1 and Pepck but also Dio1 and Glut2. Importantly, we assessed human relevance using a cohort of archived human livers in which OATP1B1 expression was noted to be highly associated with TR target genes, especially for glucose facilitating transporter 2 (GLUT2). Furthermore, GLUT2 expression was significantly decreased in livers harboring a common genetic polymorphism in SLCO1B1. Our findings reveal that OATP1B-mediated hepatic thyroid hormone entry is a key determinant of cholesterol and glucose homeostasis.


Cosmetic assessment of the human hair by confocal microscopy.
The optical sectioning property of the confocal microscope offers a breakthrough from the classic observation of the hair in a scanning electron microscope (SEM). Confocal microscopy requires minimal sampling preparation, and the hair can be observed in its natural environment with less damage than by other microscopic methods such as SEM. While used in the reflection mode, the true morphology of the cuticle and the various exogenous deposits at the surface can be identified and quantified. This relatively noninvasive, nondestructive technique is routinely used by us to monitor the efficiency of cleansing shampoos, to assess the homogeneity of layering polymers, and to evaluate the changes they induce in the optical properties of the hair surface in terms of opacity, transparency, and brilliancy. A second important field of investigation uses the fluorescence channel which reveals the internal structure of the hair. Fluorescent probes (rhodamine and its derivatives) demonstrate the routes of penetration and outline the geometry of cortical cells and of the medulla according to their lipophilic or hydrophilic properties. A volume rendering of a hair cylinder provides a better understanding of the interrelationships between cuticle cells, cortical cells, and the medullar channel. This recent technology is becoming an invaluable tool for the cosmetic assessment of the hair.


Prevention of coccidiosis in domestic dogs and captive coyotes (Canis latrans) with sulfadimethoxine-ormetoprim combination.
Sulfadimethoxine-ormetoprim combination was evaluated as a coccidiostat against experimentally induced coccidiosis in young dogs and coyotes (Canis latrans). The animals were experimentally inoculated with 50,000 or 100,000 sporulated oocysts of Isospora ohiohensis (98%) and Isospora canis (2%). In experiment 1, daily treatment for 13 to 23 days with a combination of 27.5 mg of sulfadimethoxine/kg of body weight (BW) and 5.5 mg of ormetoprim/kg of BW admixed to the feed resulted in no significant (P greater than 0.05) difference in fecal oocyst counts between treated and nontreated groups of dogs or coyotes. In experiment 2, treatment with a combination of 55 mg of sulfadimethoxine/kg of BW and 11 mg of ormetoprim/kg of BW for 23 days was 99.8% effective against Isospora spp infections in dogs. Significantly (P less than 0.05) fewer oocysts were present in feces of treated dogs than were present in feces of nontreated dogs from first passage of oocysts at day 4 to the end of the patent period at days 19 to 21. After the 2nd week of treatment, BW of treated dogs were significantly greater (P less than 0.05) than BW of nontreated dogs. Evidence of drug toxicity was not observed clinically or by serum chemical analyses.


All-optical 2-to-4 level encoder based on cross polarization modulation in a semiconductor optical amplifier utilized to develop an all-optical 2 input digital multiplexer.
An all-optical 2-to-4 level encoder based on cross polarization modulation in a semiconductor optical amplifier utilized to develop a 2 input digital multiplexer is presented. The most important feature of this device is the potential it has to improve the use of the available channel bandwidth on communications systems on an all-optical environment.


Evolutionary change within a bipotential switch shaped the sperm/oocyte decision in hermaphroditic nematodes.
A subset of transcription factors like Gli2 and Oct1 are bipotential--they can activate or repress the same target, in response to changing signals from upstream genes. Some previous studies implied that the sex-determination protein TRA-1 might also be bipotential; here we confirm this hypothesis by identifying a co-factor, and use it to explore how the structure of a bipotential switch changes during evolution. First, null mutants reveal that C. briggsae TRR-1 is required for spermatogenesis, RNA interference implies that it works as part of the Tip60 Histone Acetyl Transferase complex, and RT-PCR data show that it promotes the expression of Cbr-fog-3, a gene needed for spermatogenesis. Second, epistasis tests reveal that TRR-1 works through TRA-1, both to activate Cbr-fog-3 and to control the sperm/oocyte decision. Since previous studies showed that TRA-1 can repress fog-3 as well, these observations demonstrate that it is bipotential. Third, TRR-1 also regulates the development of the male tail. Since Cbr-tra-2 Cbr-trr-1 double mutants resemble Cbr-tra-1 null mutants, these two regulatory branches control all tra-1 activity. Fourth, striking differences in the relationship between these two branches of the switch have arisen during recent evolution. C. briggsae trr-1 null mutants prevent hermaphrodite spermatogenesis, but not Cbr-fem null mutants, which disrupt the other half of the switch. On the other hand, C. elegans fem null mutants prevent spermatogenesis, but not Cel-trr-1 mutants. However, synthetic interactions confirm that both halves of the switch exist in each species. Thus, the relationship between the two halves of a bipotential switch can shift rapidly during evolution, so that the same phenotype is produce by alternative, complementary mechanisms.


Synthesis, characterization, solubilization, cytotoxicity and antioxidant activity of aminomethylated dihydroquercetin.
A dihydroquercetin derivative (DHQA) was prepared through aminomethylation to overcome the low water solubility and bioavailability of dihydroquercetin (DHQ). DHQA was characterized through HPLC, nuclear magnetic resonance, scanning electron microscopy, X-ray diffraction, and thermogravimetric analyses. DHQA was converted into the amorphous form, but the major structure of DHQ remained unchanged. Solubilization and dissolution tests were also performed. Results showed that the solubility and dissolution rates of DHQA were approximately 16.28 and 6.31 times higher than those of DHQ, respectively. The MTT assay of DHQA showed a non-toxic effect against non-cancerous HEK-293T cells (EC50 = 820.00 μM), and potent inhibitory activity against cancerous Hela cells (EC50 = 138.17 μM). Finally, the antioxidant activity of DHQA was confirmed in vitro through DPPH and ABTS radical scavenging activity assays. DHQA displayed high antioxidant activities with low IC50 values (0.043 and 0.042 mM, respectively). Reducing Fe3+ power assay indicated that DHQA exhibited higher reducing power than DHQ and ascorbic acid.


A Laser-Locked Hollow Waveguide Gas Sensor for Simultaneous Measurements of CO2 Isotopologues with High Accuracy, Precision, and Sensitivity.
A laser frequency-locked hollow waveguide (HWG) gas sensor is demonstrated for simultaneous measurements of three isotopologues (12CO2, 13CO2, and 18OC16O) using wavelength modulation spectroscopy with a 2.73 μm distributed feedback laser. The first harmonic (1f) signal at the sampling point where the peak of the second harmonic (2f) signal was located was employed as the locking point to lock the laser frequency to the transition center of 13CO2, while the absorption lines of 12CO2 and 18OC16O were being scanned. Continuous measurements of the three isotopologues of 4.7% CO2 samples over 103 min under free running and frequency locking conditions were performed. The measurement accuracy and precision of the three isotopologues achieved under the frequency locking condition were at least 3 times and 1.3 times better than those obtained under the free running condition, respectively. The Allan variance plot of the developed laser-locked HWG gas sensor shows a detection limit of 0.72‰ for both δ13C and δ18O under the frequency locking condition with a long stability time of 766 s. This study demonstrated the high potential of a novel human breath diagnostic sensor for medical diagnostic with high accuracy, precision, and sensitivity and without frequently repeated calibration.


Cancer prevention, detection and survival--how hopeful is the outlook?
Recent overall appraisals of cancer occurrence, detection, treatment and survival have noted: rising incidences; relatively steady mortality rates; and disappointingly small improvements in survival time (the magnitudes of which are controversial). In this review attempts have been made to answer questions on countermeasures--principally, what could be done, and what is likely to be done. It is concluded, broadly, that in Western populations the only ameliorative changes likely are reductions in frequency and intensity of cigarette smoking, and improvements in early detection of certain cancers by screening procedures. Accordingly, the outlook is very unpromising. Claims of halving cancer mortality by the year 2000 would seem to be hyperbole. As to developing populations, frequencies of certain cancers (oesophageal, liver and cervix) are likely to fall, but they will be replaced by increases in cancers characteristic of Western populations. Yet rises in incidence of diet-related cancers (breast, colorectal, and possibly prostate) may be retarded by slow rises in socio-economic state.


Tattoo Image Search at Scale: Joint Detection and Compact Representation Learning.
The explosive growth of digital images in video surveillance and social media has led to the significant need for efficient search of persons of interest in law enforcement and forensic applications. Despite tremendous progress in primary biometric traits (e.g., face and fingerprint) based person identification, a single biometric trait alone can not meet the desired recognition accuracy in forensic scenarios. Tattoos, as one of the important soft biometric traits, have been found to be valuable for assisting in person identification. However, tattoo search in a large collection of unconstrained images remains a difficult problem, and existing tattoo search methods mainly focus on matching cropped tattoos, which is different from real application scenarios. To close the gap, we propose an efficient tattoo search approach that is able to learn tattoo detection and compact representation jointly in a single convolutional neural network (CNN) via multi-task learning. While the features in the backbone network are shared by both tattoo detection and compact representation learning, individual latent layers of each sub-network optimize the shared features toward the detection and feature learning tasks, respectively. We resolve the small batch size issue inside the joint tattoo detection and compact representation learning network via random image stitch and preceding feature buffering. We evaluate the proposed tattoo search system using multiple public-domain tattoo benchmarks, and a gallery set with about 300K distracter tattoo images compiled from these datasets and images from the Internet. In addition, we also introduce a tattoo sketch dataset containing 300 tattoos for sketch-based tattoo search. Experimental results show that the proposed approach has superior performance in tattoo detection and tattoo search at scale compared to several state-of-the-art tattoo retrieval algorithms.


Hypertension in primary hyperparathyroidism in relation to histopathology.
Hypertension in primary hyperparathyroidism (HPT) was previously attributed to hypercalcemia per se or to impaired kidney function. Of 441 consecutive patients operated on for HPT over 24 years, 57% were hypertensive. Preoperative blood pressure remained fairly constant during the study period, despite otherwise markedly changing clinical picture with, latterly, more asymptomatic patients. The preoperative systolic blood pressure (SBP) was significantly correlated to both serum calcium (p less than 0.001) and serum creatinine (p less than 0.05), but not when the influence of age was taken into account in a multiple regression analysis. Other pathogenetic factors in hypertension were therefore probable. When the statistical analysis was adjusted for differences in age and serum calcium, blood pressure was lower in the HPT patients with parathyroid hyperplasia than in those with adenoma (153 +/- 31/90 +/- 14 vs. 163 +/- 29/91 +/- 14 mmHg, p less than 0.01 for SBP). The concept that parathyroid hyperplasia represents a mild (early) form of HPT that may precede adenoma formation is corroborated by our observations, which also indicate that there is no simple cause-and-effect relationship accounting for hypertension in primary HPT.


Single dose testosterone administration increases men's facial femininity preference in a Chinese population.
Sex hormones are thought to influence human mate preferences. Previous studies have reported mixed results regarding the association between men's testosterone levels and their mate preferences. The present study investigated the effect of testosterone administration on men's facial femininity preference. Heterosexual Chinese male participants (n = 140) received a single dose of 150 mg testosterone or placebo gel in a double-blind, placebo-controlled, between-participant design. Results showed that Chinese men demonstrated general preferences for feminized women's faces, consistent with previous results from the Western population. More importantly, men showed stronger attraction to femininity in women's faces three hours after testosterone administration than at the beginning of the session. In the placebo group, no significant change in facial femininity preferences was found between time points. These results indicate that exogenous testosterone increases men's facial femininity preferences in a Chinese population.


Predictors of parental quality of life after child open heart surgery: a 6-month prospective study.
To prospectively assess parental health-related quality of life (HRQoL) and its predictors after child open heart surgery. Mothers (n = 135) and fathers (n = 97) of 138 children were assessed at discharge from hospital and 6 months after open heart surgery of their child. Parental HRQoL was compared with population norms. Medical, demographic, and psychosocial predictors of HRQoL were examined. In both parents, several domains of HRQoL were decreased at their child's hospital discharge with mothers showing lower HRQoL than fathers. Mental domains were more affected than physical domains. At 6 months, parental HRQoL was within or above population norms. At discharge, symptoms of post-traumatic stress and at 6 months a high impact of the child's disease on family life were associated with low mental HRQoL in both parents. In mothers, lower socioeconomic status and foreign nationality were also associated with a higher risk for low mental HRQoL at discharge. Parents' mental HRQoL is low in the immediate period after their child's open heart surgery but normalizes after 6 months. However, parents in whom the child's disease has a high impact on their family life are at increased risk for persistent low mental HRQoL.


Modelling the effect of subcellular mutations on the migration of cells in the colorectal crypt.
Many cancers arise from mutations in cells within epithelial tissues. Mutations manifesting at the subcellular level influence the structure and function of the tissue resulting in cancer. Previous work has proposed how cell level properties can lead to mutant cell invasion, but has not incorporated detailed subcellular modelling RESULTS: We present a framework that allows the straightforward integration and simulation of SBML representations of subcellular dynamics within multiscale models of epithelial tissues. This allows us to investigate the effect of mutations in subcellular pathways on the migration of cells within the colorectal crypt. Using multiple models we find that mutations in APC, a key component in the Wnt signalling pathway, can bias neutral drift and can also cause downward invasion of mutant cells in the crypt. Our framework allows us to investigate how subcellular mutations, i.e. knockouts and knockdowns, affect cell-level properties and the resultant migration of cells within epithelial tissues. In the context of the colorectal crypt, we see that mutations in APC can lead directly to mutant cell invasion.


Learning From the Crowd in Terminology Mapping: The LOINC Experience.
National policies in the United States require the use of standard terminology for data exchange between clinical information systems. However, most electronic health record systems continue to use local and idiosyncratic ways of representing clinical observations. To improve mappings between local terms and standard vocabularies, we sought to make existing mappings (wisdom) from healt care organizations (the Crowd) available to individuals engaged in mapping processes. We developed new functionality to display counts of local terms and organizations that had previously mapped to a given Logical Observation Identifiers Names and Codes (LOINC) code. Further, we enabled users to view the details of those mappings, including local term names and the organizations that create the mappings. Users also would have the capacity to contribute their local mappings to a shared mapping repository. In this article, we describe the new functionality and its availability to implementers who desire resources to make mapping more efficient and effective.


Intensification of milk somatic cell response to intramammary device.
Treatments consisting of copper-impregnated polyethylene intramammary device (PIMD-Cu), PIMD-Cu which had been abraded to ensure exposure of surface copper (APIMD-Cu), PIMD which had been abraded in an identical manner (APIMD), and an untreated control were established in mammary quarters of 2 cows. Quarters selected were bacteria free and had milk somatic cell counts (MSCC) in strippings of less than 240 X 10(3) ml. Milk somatic cell counts were determined from strippings immediately after milking and 6 hours later. Cows were monitored for 4 weeks after devices were inserted. Milk samples (250 ml) were collected and analyzed for free fatty acids, a measure of hydrolytic rancidity, at 14 days. The devices were removed from mammary quarters after 4 weeks and examined with a scanning electron microscope. Surfaces of the devices were assessed for plaque buildup and presence of leukocytes. Immediately after and 6 hours later, geometric mean MSCC for APIMD, APIMD-Cu, PIMD-Cu, and control quarters average 946/1,556, 1,479/2,882, 512/1,148, and 161/190 X 10(3) ml, respectively. There was no difference in free fatty acid values of samples from treated and control quarters. Plaque formation was observed over the entire surface of APIMD. Numerous leukocytes were found associated with plaque and appeared to initiate development of plaque. Smaller amounts of plaque were found on APIMD-Cu, and minimal amounts were found on PIMD-Cu. Results indicate that modification of PIMD by abrading or addition of copper will increase MSCC to concentrations (greater than 900 X 10(3) ml) that should be protective against establishment of infection by mastitis pathogens.


(17α,20E)-17,20-[(1-methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11) is a partial agonist of the androgen receptor.
A novel steroid compound, (17α,20E)-17,20-[(1-methoxyethylidene)bis(oxy)]-3-oxo-19-norpregna-4,20-diene-21-carboxylic acid methyl ester (YK11), was found to be a partial agonist of the androgen receptor (AR) in an androgen responsive element (ARE)-luciferase reporter assay. YK11 accelerates nuclear translocation of AR. Furthermore, YK11 does not induce amino/carboxyl-terminal (N/C) interaction and prevents 5-α-dihydrotestosterone (DHT)-mediated N/C interaction. Thus, YK11 activates AR without causing N/C interaction, which may in turn be responsible for the partially agonistic nature of YK11 observed in the ARE-luciferase reporter system. YK11 acts as a gene-selective agonist of AR in MDA-MB 453 cells. The effect of YK11 on gene expression relative to that of androgen agonist varies depending on the gene context. YK11 activated the reporter gene by inducing the translocation of the AR into the nuclear compartment, where its amino-terminal domain (NTD) functions as a constitutive activator of AR target genes. Our results suggest that YK11 might act as selective androgen receptor modulator (SARM).


Overexpression of the DEC1 protein induces senescence in vitro and is related to better survival in esophageal squamous cell carcinoma.
Esophageal squamous cell carcinoma (ESCC) is a leading cause of cancer-related death in China and has limited effective therapeutic options except for early surgery, since the underlying molecular mechanism driving its precursor lesions towards invasive ESCC is not fully understood. Cellular senescence is the state of the permanent growth arrest of a cell, and is considered as the initial barrier of tumor development. Human differentiated embryo chondrocyte expressed gene 1 (Dec1) is an important transcription factor that related to senescence. In this study, DEC1 immunohistochemical analysis was performed on tissue microarray blocks constructed from ESCC combined with adjacent precursor tissues of 241 patients. Compared with normal epithelia, DEC1 expression was significantly increased in intraepithelial neoplasia and DEC1 expression was significantly decreased in ESCC in comparison with intraepithelial neoplasia. In vitro, DEC1 overexpression induced cellular senescence, and it inhibited cell growth and colony formation in ESCC cell line EC9706. Fresh esophagectomy tissue sections from five ESCC patients were detected by immunohistochemistry of DEC1 and senescence-associated β-galactosidase (SA-β-Gal) activity, and strongly positive expression of DEC1 was correlated to more senescent cells in these fresh tissue sections. Kaplan-Meier method analysis of the 241 patients revealed that DEC1 expression levels were significantly correlated with the survival of ESCC patients after surgery. The expression levels of DEC1 were also correlated with age, tumor embolus, depth of invasion of ESCC, lymph metastasis status and pTNMs. These results suggest that DEC1 overexpression in precursor lesions of ESCC is a protective mechanism by inducing cellular senescence in ESCC initiation, and DEC1 may be a potential prognostic marker of ESCC.


Progressive MS trials: Lessons learned.
Up to very recently, no treatments had proved effective in progressive multiple sclerosis (MS). In 2016, four drugs, two tested in phase 3 and two in phase 2 trials, showed a beneficial effect in primary or secondary progressive MS. Although this could indicate a turning point in progressive MS treatment, most of these successes have been modest and mainly restricted to patients with active inflammation, in the context of trials with powerful anti-inflammatory agents. This paper summarises these reasons, particularly focusing on the main lessons learned for the design of future trials. First, a drug's mechanism of action should tackle the specific pathogenic mechanisms that characterise progressive MS. Second, trial populations where new drugs are to be tested should be carefully chosen, possibly including younger patients with shorter disease durations, which have greater chances of showing active deterioration during the trial, therefore increasing the power to detect treatment effects. Third, outcome measures used in future phase 2 and phase 3 trials should be highly sensitive and be accompanied by smart trial designs.


The radiologic progression of ameloblastomas.
In developing countries, many diagnosed cases of ameloblastoma (AB) have a significant delay in receiving treatment because of patient factors and healthcare facility constraints. The radiologic progression of ABs with delayed treatment was analysed using panoramic radiographs and cone-beam computed tomography imaging. Histopathologically confirmed cases of AB with follow-up radiographs indicating no treatment were retrospectively reviewed over a study period of 10 years. Fifty-seven cases with 57 initial and 107 follow-up radiographs were included. Each follow-up radiograph was analysed for changes in borders, locularity, effects on surrounding structures and lesion size. There was a general increase in poorly-demarcated lesions, with seven cases transforming from an initial unilocular to a multilocular appearance. At follow-up, there was an increase in cortical thinning and cortical destruction. Ameloblastomas presented with a three-fold increase in average size from the initial to follow-up visits. Regression analysis showed a statistically significant relationship between lesion duration and length (p = 0.001). A statistically significant relationship existed between duration and overall lesion dimensions when only the first and last observations per patient were used (p = 0.044). Considering the aggressive nature and unlimited growth potential, ABs with delayed treatment may show extensive growth, complicating their eventual management. This study aimed to raise awareness of the importance of the timeous management of patients with AB by highlighting the detrimental effects of delayed treatment.


Usefulness of extracorporeal membrane oxygenation using double roller pumps in a low body weight newborn: A novel strategy for mechanical circulatory support in an infant.
Extracorporeal membrane oxygenation (ECMO) with a centrifugal pump requires a certain flow rate; therefore, its application for low body weight infants is frequently accompanied by oxygenator membrane malfunction and/or inadequate perfusion. To prevent low-flow associated complications, we report a case in which a novel system of dual roller pumps was used. A baby girl with a body mass index 0.25 m(2), who experienced difficulty weaning from cardiopulmonary bypass after a Norwood-like operation, required an ECMO. Concerns for the tube lifespan reduction due to roller pump friction led to the use of a double roller pump circulation. The termination of ECMO during tube exchange is not needed, because circulation is maintained by another roller pump. The novel strategy of ECMO with double roller pumps will allow low perfusion rate to provide adequate circulatory support for low body weight patients.


Nonrandom chromosome arrangements in germ line nuclei of Sciara coprophila males: the basis for nonrandom chromosome segregation on the meiosis I spindle.
Meiosis I in males of the Dipteran Sciara coprophila results in the nonrandom distribution of maternally and paternally derived chromosome sets to the two division products. Based on an earlier study (Kubai, D.F. 1982. J. Cell Biol. 93:655-669), I suggested that the meiosis I spindle does not play a direct role in the nonrandom sorting of chromosomes but that, instead, haploid sets are already separated in prophase nuclei well before the onset of spindle formation. Here I report more direct evidence that this hypothesis is true; this evidence was gained from ultrastructural reconstruction analyses of the arrangement of chromosomes in germ line nuclei (prophase nuclei in spermatogonia and spermatocytes) of males heterozygous for an X-autosome chromosome translocation. Because of this translocation, the maternal and paternal chromosome sets are distinguishable, so it is possible to demonstrate that (a) the two haploid chromosome sets occupy distinct maternal and paternal nuclear compartments and that (b) nuclei are oriented so that the two haploid chromosome sets have consistent relationships to a well-defined cellular axis. The consequences of such nonrandom aspects of nuclear structure for chromosome behavior on premeiotic and meiotic spindles are discussed.


Cone Beam Computed Tomography Analysis of Root and Root Canal Morphology of First Permanent Lower Molars in a Middle East Subpopulation.
The aim of this study was to investigate variations in the number of roots and root canals in first permanent lower molars (FPLMs) using cone beam computed tomography (CBCT). A total of 640 CBCT images were analyzed using SIDEXIS XG software version 2.62 (Sirona Dental Systems, Bensheim, Germany). The entire root anatomy of FPLMs was investigated in three dimensions and the number of roots, root canals, and the number of canals per root were recorded. Statistical analysis was performed using the Statistical Package for the Social Sciences (SPSS) software, version 24, (IBM Corporation, USA) to determine the relationship between root anatomy and gender, age, or tooth location (right or left side). The majority of FPLMs had two roots (96%), whereas the remaining 32 FPLMs (4%) had three roots. Almost two-thirds of the sample (62.7%) had three root canals, whereas only three cases (0.4%) of the FPLMs had six canals. When comparing bilateral differences in the distribution of root canals, it was determined that a quarter of FPLMs (24.1%) had an unequal number of canals. Moreover, there were differences in the number of additional canals between the mesial and distal roots with 17.5% of the former having three canals as compared with only 0.5% of the distal root. Interestingly, not more than one canal was observed in all additional root cases. No significant differences were observed in the number of canals between males and females or between right and left sides of the examined FPLMs (P > 0.05). Dental clinicians should be aware of the presence of an additional root in 4% of FPLMs, and about a quarter of the cases (27%) had an extra middle mesial canal in the mesial root, which was found to be more prevalent in middle age groups.


Perforations of right heart chambers associated with electrophysiology catheters and temporary transvenous pacing leads.
Perforation of heart chambers is one of the rare complications observed during electrophysiological studies and placement of pacemaker leads. In this study, we performed a retrospective evaluation of patients with catheter-related right heart perforation, aiming to determine its incidence and clinical course. We reviewed cases with catheter-related cardiac perforations observed at our institution from June 2002 to November 2007. During the study period, a total of 2,385 procedures were performed (1,287 electrophysiologic studies, 1,098 temporary nonballoon-floating pacing lead placements). Eight cardiac perforations were diagnosed, with the overall procedure-based and catheter-based incidences of 0.34% (8/2,385) and 0.14% (8/5,603), respectively. Three of these perforations were related to diagnostic electrophysiology catheters, and five were related to temporary (1 permanent) transvenous pacemaker leads. Seven perforations involved the right ventricle and one involved the right atrium. Three patients in whom right ventricular perforation was detected at a late stage died suddenly after pacemaker lead implantation. One patient underwent surgical exploration because of right atrial perforation. Two patients underwent coronary bypass operation and, in one of these patients, perforation was detected during surgery. Two patients were managed conservatively. Although right ventricular perforations detected early have a relatively benign course, those detected late and right atrial perforations require emergent surgical exploration and may have catastrophic consequences.


Gene therapy and tissue engineering.
Gene therapy, the science of altering cellular function or structure at a molecular level, is currently one of the most exciting fields of research across medical specialties. By replacing lost or defective genes or adding genes known to produce proteins with beneficial effects, investigators hope to treat and possibly cure everything from inborn errors of metabolism to acquired diseases, such as emphysema and atherosclerosis. Genetic modification of engineered tissue, the offspring of these two fields, offers the promise of not simply replacing tissue, but improving on the restoration. The studies presented in this article demonstrate many of the principles that form the basis of gene therapy and provide insight into the potential of this emerging technology.


[Clinicopathological and molecular genetic characteristics of ELOC mutated renal cell carcinoma].
Objective: To investigate the clinicopathological features, molecular genetic features, differential diagnosis and prognosis of ELOC mutated renal cell carcinoma. Methods: From January 2015 to June 2022, 11 cases of renal cell carcinoma with clear-cell morphology, expression of CAⅨ and CK7 and no 3p deletion were collected. Two cases of ELOC mutant renal cell carcinoma were diagnosed using whole exome sequencing (WES). The clinical features, morphology, immunophenotype, FISH and WES results were analyzed. The relevant literature was reviewed. Results: The two patients were both male, aged 29 and 51 years, respectively. They were both found to have a renal mass by physical examination. The maximum diameters of the tumors were 3.5 cm and 2.0 cm, respectively. At the low magnification, the tumors were well-defined. The tumor cells showed a pushing border and were separated by thick fibrous bands, forming nodules. The tumor cells were arranged in a variety of patterns, including tubular, papillary, solid nest or alveolar. At high magnification, the tumor cells were large, with well-defined cell borders and clear cytoplasm or fine eosinophilic granules. CAⅨ was diffusely box-like positive in both cases. Case 1 was partially and moderately positive for CK7, strongly positive for CD10, diffusely and moderately positive for P504S, and weakly positive for 34βE12. In case 2, CK7 and CD10 were both partially, moderately positive and P504s were diffusely positive, but 34βE12 was negative. FISH results showed that both cases had no 3p deletion. ELOC c.235T>A (p.Y79N) mutation was identified using WES in case 1, while ELOC c.236_237inv (p.Y79C) mutation was identified in case 2. Conclusions: As a new clinical entity, ELOC mutated renal cell carcinoma may be underdiagnosed due to its overlap with clear cell renal cell carcinoma in morphology and immunophenotype. The diagnosis of renal cell carcinoma with ELOC mutation should be confirmed by morphology, immunohistochemistry, FISH and gene mutation detection. However, more additional cases are needed to explain its biological behavior and prognosis.


Periodontal treatment needs in Central and Eastern Europe.
The aim of the present review is to evaluate the periodontal conditions and treatment needs in Central and Eastern Europe and to compare these data to the epidemiological data from the industrialised and developing countries. The recent prevalence and severity data provided by national surveys based on the CPITN methods are summarised. The periodontal conditions in the age groups 15-19 and 35-44 are discussed in detail. The CPITN data show no major differences in the extent and severity of destructive periodontal disease in different countries. In the age group 15-19 just a few European surveys reported 'score 4 sextant' and the prevalence of 'score 3' sextants was also below 10% in each survey. However calculus formation and bleeding on probing were very frequent findings both in Western and Eastern Europe. In the age group 35-44 the average prevalence of 'score 4 sextant' in Western and Eastern Europe were comparable while the proportion of periodontally absolutely healthy individuals was lower in Eastern Europe than in the Western part of the Continent. Five to 20% of the populations are affected by destructive periodontitis at the age of 40. This indicates the magnitude of the disease as a public health problem both in the industrialised West and the Eastern European countries. The same 10-15% prevalence rate of destructive periodontitis imposes a great challenge to the health authorities of these post-communist countries amid social and economic transition, because the nationwide preventive and basic periodontal therapeutic measures should be managed and financed from a substantially lower GDP than in the industrialised West.


Therapeutic significance of estrogen receptor β agonists in gliomas.
Gliomas are the most common and devastating central nervous system neoplasms. A gender bias exists in their development: females are at lower risk than males, implicating estrogen-mediated protective effects. Estrogen functions are mediated by two estrogen receptor (ER) subtypes: ERα, which functions as tumor promoter, and ERβ, which functions as tumor suppressor. We examined the potential use of ERβ agonists as a novel therapeutic to curb the growth of gliomas. Western analysis of six glioma model cells showed detectable expression of ERβ with little or no ERα. Treatment of glioma cells with ERβ agonists resulted in significant decrease in proliferation. Immunohistochemical analysis of tumor tissues revealed that ERβ expression is downregulated in high-grade gliomas. We found that ERβ agonists promote both expression and tumor-suppressive functions of ERβ in glioma cells. Liquiritigenin, a plant-derived ERβ agonist significantly reduced in vivo tumor growth in a xenograft model. Compared with control mice, animals treated with liquiritigenin had greater than 50% reduction in tumor volume and size. Immunohistochemical analysis of tumors revealed a significant increase in the nuclear ERβ expression with a concomitant decrease in cell proliferation in the liquiritigenin-treated group. Our results suggest that ERβ signaling has a tumor-suppressive function in gliomas. Because ERβ agonists are currently in clinical trials and are well tolerated with fewer side effects, identification of an ERβ agonist as a therapeutic agent can be readily extended to clinical use with current chemotherapies, providing an additional tool for enhancing survival in glioma patients.


Consequences of hoxb1 duplication in teleost fish.
Vertebrate evolution is characterized by gene and genome duplication events. There is strong evidence that a whole-genome duplication occurred in the lineage leading to the teleost fishes. We have focused on the teleost hoxb1 duplicate genes as a paradigm to investigate the consequences of gene duplication. Previous analysis of the duplicated zebrafish hoxb1 genes suggested they have subfunctionalized. The combined expression pattern of the two zebrafish hoxb1 genes recapitulates the expression pattern of the single Hoxb1 gene of tetrapods, possibly due to degenerative changes in complementary cis-regulatory elements of the duplicates. Here we have tested the hypothesis that all teleost duplicates had a similar fate post duplication, by examining hoxb1 genes in medaka and striped bass. Consistent with this theory, we found that the ancestral Hoxb1 expression pattern is subdivided between duplicate genes in a largely similar fashion in zebrafish, medaka, and striped bass. Further, our analysis of hoxb1 genes reveals that sequence changes in cis-regulatory regions may underlie subfunctionalization in all teleosts, although the specific changes vary between species. It was previously shown that zebrafish hoxb1 duplicates have also evolved different functional capacities. We used misexpression to compare the functions of hoxb1 duplicates from zebrafish, medaka and striped bass. Unexpectedly, we found that some biochemical properties, which were paralog specific in zebrafish, are conserved in both duplicates of other species. This work suggests that the fate of duplicate genes varies across the teleost group.


Prematurity may negatively impact means-end problem solving across the first two years of life.
Preterm infants are at risk for delays in motor, perceptual, and cognitive development. While research has shown preterm infants may exhibit learning delays in the first months of life, these delays are commonly under-diagnosed. The purpose of this study was to longitudinally evaluate behavioral performance and learning in two means-end problem-solving tasks for 30 infants born preterm (PT) and 23 born full-term (FT). Infants were assessed at 6, 9, 12, 18, and 24 months-old in tasks that required towel pulling or turntable rotation to obtain a distant object. PT infants performed more non-goal-directed and less goal-directed behavior than FT infants throughout the study, resulting in a lower success rate among PT infants. PT infants showed delayed emergence of intentionality (prevalence of goal-directed behaviors) compared to FT infants in both tasks. Amount and variability of behavioral performance significantly correlated with task success differentially across age. The learning differences documented between PT and FT infants suggest means-end problem-solving tasks may be useful for the early detection of learning delays. The identification of behaviors associated with learning and success across age may be used to guide interventions aimed at advancing early learning for infants at risk.


Referred Sensation Areas in Bilateral Upper Limb Amputee.
Phantom limb pain (PLP) following amputation considerably reduces the quality of life, given a difficult to treat pain of highly variate profile. The loss of sensory input induces a complex pattern of neuroplastic changes of the sensory neural pathways and their central projections. Referred sensation areas (RSAs) may occur on the stump as a consequence of amputation, providing a direct path towards the altered central sensory projections. Modulated electrical stimulation of RSAs was investigated in a long-term experiment in the case of a 62 years-old participant with bilateral upper limb amputation due to traumatic injury. RSAs were investigated using mechanical (vibration and pressure) and electrical stimuli over five sessions within a five weeks period. Further test of sensations induced by steady state and modulated electrical stimuli was performed during additional 4 sessions. Location and features of RSAs were highly dependent on the type of stimulus and time of delivery between sessions.Clinical Relevance- The case study presents a variety of types and locations of the sensation induced by electrical and mechanical stimuli that may eventually be used as artificially generated sensory input as individualized alternative form of therapy for PLP alleviation. Furthermore, possible multichannel stimulus delivery on RSAs on both arms and the cross-over effect of the bilateral amputation in perception of the induced sensation in the opposite phantom hand may be considered in dedicated design of an experimental setup that may possibly help investigation of mechanisms for PLP.


Technology assessment and transfer in district health systems.
Initially reviewing the concepts of a district health system and technologies, the article develops into a discussion on health technologies and the process of their transnational diffusion, as well as their impact on district health systems in developing countries. Finally, the paper points to the need for assessment and quality assurance in a managed transfer of technologies.


Optimisation of a Novel Bio-Substrate as a Treatment for Atrophic Age-Related Macular Degeneration.
Atrophic age-related macular degeneration (AMD) is the most common form of AMD accounting for 90% of patients. During atrophic AMD the waste/exchange pathway between the blood supply (choroid) and the retinal pigment epithelium (RPE) is compromised. This results in atrophy and death of the RPE cells and subsequently the photoreceptors leading to central blindness. Although the mechanisms behind AMD are unknown, the growth of fatty deposits known as drusen, have been shown to play a role in the disease. There is currently no treatment or cure for atrophic AMD. Much research focuses on developing a synthetic substrate in order to transplant healthy cells to the native Bruch's membrane (BM), however, the diseased native BM and related structures still leave potential for transplanted cells to succumb to disease. In this proof-of-concept work we electrospun poly(ethylene terephthalate) (PET) to fabricate a nanofibrous cytocompatible synthetic BM. The apical surface of the membrane was cultured with ARPE-19 cells and the underside was decorated with poly(lactic acid-co-glycolic acid) (PLGA) or poly(glycolic acid) (PGA) degradable nanoparticles by electrospraying. The membrane exhibited hydrophilicity, high tensile strength and structurally resembled the native BM. ARPE-19 cells were able to form a monolayer on the surface of the membrane and no cell invasion into the membrane was seen. The presence of both PLGA and PGA nanoparticles increased ARPE-19 cell metabolism but had no effect on cell viability. There was a decrease in pH of ARPE-19 cell culture media 7 days following culturing with the PLGA nanoparticles but this change was eliminated by 2 weeks; PGA nanoparticles had no effect on cell culture media pH. The fluorescent dye FITC was encapsulated into nanoparticles and showed sustained release from PLGA nanoparticles for 2 weeks and PGA nanoparticles for 1 day. Future work will focus on encapsulating biologically active moieties to target drusen. This could allow this novel bioactive substrate to be a potential treatment for atrophic AMD that would function two-fold: deliver the required monolayer of healthy RPE cells to the macula on a synthetic BM and remove diseased structures within the retina, restoring the waste/exchange pathway and preventing vision loss.