Honey and Radiation-Induced Stomatitis in Patients With Head and Neck Cancer.
Stomatitis is a common oral complication which affects 100% of patients undergoing head and neck radiotherapy. Acute stomatitis might cause failure and delay radiotherapy. Attention to mouth hygiene, particularly using mouthwash, has a fundamental importance for these patients. The current study came to addresses the effects of pure natural honey on radiation-induced stomatitis in patients with a variety of head and neck cancers. The present single-blinded nonrandomized controlled trial was conducted on 105 patients undergoing radiotherapy due to head and neck cancer at the radiation unit of Shafa hospital in Kerman, Iran, from October 2012 to March 2012. The research groups were selected by writing the names of the protocols (the mouthwashes of chamomile, honey and the common caring protocol at ward which uses water) on three cubes. The first extracted cube was related to the chamomile mouthwash (Matrica), the second to the honey mouthwash and the last cube to the water mouthwash. The first experimental group (n = 35) gurgled a solution containing 20 mL diluted honey, the second group gurgled a solution containing German chamomile, and the 35 patients in the control group were advised to gurgle 20 mL water (the ward routine). The results showed that severe stomatitis in groups of honey, chamomile and control was 0, 5.7%, and 17.6%, respectively. On the 14th day, it was 0, 0, and 17.6%, respectively. There were significant differences between the three groups regarding the severity of stomatitis in the 14th day (P < 0.001). The application of natural honey is effective in managing and preventing radiation-induced stomatitis in patients with head and neck cancers.


Familial steroid-sensitive idiopathic nephrotic syndrome: seven cases from three families in China.
Familial steroid-sensitive idiopathic nephrotic syndrome is rare, and only approximately 3% of patients have affected siblings. Herein, we report seven cases of patients with steroid-sensitive idiopathic nephrotic syndrome from three Chinese families. Mutational screening of the Nphs2 gene was performed in all the patients. All seven of the familial steroid-sensitive idiopathic nephrotic syndrome cases in our sample exhibited minimal change disease, and one case also presented with mesangial proliferative glomerulonephritis, according to the renal pathology. No significant was associations were found between Nphs2 gene mutations and the onset of proteinuria and nephrotic syndrome in these familial cases. The presence of minimal change disease is important, but it is not an unusual finding in patients with familial steroid-sensitive idiopathic nephrotic syndrome, which appears to be clinically benign and genetically distinct from other types of nephrosis.


Sequence diversity in the lasso peptide framework: discovery of functional microcin J25 variants with multiple amino acid substitutions.
Microcin J25 (MccJ25) is a ribosomally synthesized antimicrobial peptide that has an unusual threaded lasso structure in which the C-terminal "tail" of the peptide is fed through a macrocyclic "ring" formed by the N-terminal residues. Production of MccJ25 in Escherichia coli is dependent upon a four-gene cluster encoding the structural gene mcjA, two maturation enzymes mcjB and mcjC, and an immunity factor, mcjD, in the form of an MccJ25 export pump. Here we have developed a system for orthogonal control of the expression of mcjA and mcjD, thus permitting independent control of MccJ25 production and export/immunity in E. coli. We used this system to screen saturation mutagenesis libraries targeted to either the ring or tail portions of MccJ25 and discovered nearly 100 new MccJ25 variants that retain antimicrobial function. While multiple amino acid substitutions in the tail portion of the peptide are well-tolerated, mutagenesis of the ring portion of the peptide is detrimental to the antimicrobial function of MccJ25. We demonstrated that the decreased function of the ring variants is due to the inability of these variants to be transported to the cytoplasm of susceptible strains. Additionally, we found several MccJ25 variants from the tail library with improved efficacy toward the MccJ25-sensitive strains E. coli and Salmonella enterica serovar Newport with the best variants exhibiting a nearly 5-fold increase in potency. The results described here provide further evidence that diverse amino acid sequences can be tolerated by the rigid lasso peptide fold.


Avian influenza transmission risks: analysis of biosecurity measures and contact structure in Dutch poultry farming.
In the 2003 epidemic of highly pathogenic avian influenza in Dutch poultry, between-farm virus transmission continued for considerable time despite control measures. Gaining more insight into the mechanisms of this spread is necessary for the possible development of better control strategies. We carried out an in-depth interview study aiming to systematically explore all the poultry production activities to identify the activities that could potentially be related to virus introduction and transmission. One of the between-farm contact risks that were identified is the movement of birds between farms during thinning with violations of on-farm biosecurity protocols. In addition, several other risky management practices, risky visitor behaviours and biosecurity breaches were identified. They include human and fomite contacts that occurred without observing biosecurity protocols, poor waste management practices, presence of other animal species on poultry farms, and poor biosecurity against risks from farm neighbourhood activities. Among the detailed practices identified, taking cell phones and jewellery into poultry houses, not observing shower-in protocols and the exchange of unclean farm equipment were common. Also, sometimes certain protocols or biosecurity facilities were lacking. We also asked the interviewed farmers about their perception of transmission risks and found that they had divergent opinions about the visitor- and neighbourhood-associated risks. We performed a qualitative assessment of contact risks (as transmission pathways) based on contact type, corresponding biosecurity practices, and contact frequency. This assessment suggests that the most risky contact types are bird movements during thinning and restocking, most human movements accessing poultry houses and proximity to other poultry farms. The overall risk posed by persons and equipment accessing storage rooms and the premises-only contacts was considered to be medium. Most of the exposure risks are considered to be similar for layer and broiler farms. Our results, including those on farmer opinions, are relevant for the communication with farmers and poultry-related businesses about practices and risks. We conclude by providing recommendations for improvement of control strategies.


Global clinical response in Cushing's syndrome patients treated with mifepristone.
Mifepristone, a glucocorticoid receptor antagonist, improves clinical status in patients with Cushing's syndrome (CS). We examined the pattern, reliability and correlates of global clinical response (GCR) assessments during a 6-month clinical trial of mifepristone in CS. Post hoc analysis of secondary end-point data from a 24-week multicentre, open-label trial of mifepristone (300-1200 mg daily) in CS. Intraclass correlation coefficient (ICC) was used to examine rater concordance, and drivers of clinical improvement were determined by multivariate regression analysis. Forty-six adult patients with refractory CS along with diabetes mellitus type 2 or impaired glucose tolerance, and/or a diagnosis of hypertension. Global clinical assessment made by three independent reviewers using a three-point ordinal scale (+1 = improvement; 0 = no change; -1 = worsening) based on eight broad clinical categories including glucose control, lipids, blood pressure, body composition, clinical appearance, strength, psychiatric/cognitive symptoms and quality of life at Weeks 6, 10, 16, and 24. Positive GCR increased progressively over time with 88% of patients having improved at Week 24 (P < 0·001). The full concordance among reviewers occurred in 76·6% of evaluations resulting in an ICC of 0·652 (P < 0·001). Changes in body weight (P < 0·0001), diastolic blood pressure (P < 0·0001), two-hour postoral glucose challenge glucose concentration (P = 0·0003), and Cushingoid appearance (P = 0·022) were strong correlates of GCR. Mifepristone treatment for CS results in progressive clinical improvement. Overall agreement among clinical reviewers was substantial and determinants of positive GCR included change in weight, blood pressure, glucose levels and appearance.


Visualization of structural evolution and phase distribution of a lithium vanadium oxide (Li1.1V3O8) electrode via an operando and in situ energy dispersive X-ray diffraction technique.
Li1+nV3O8 (n = 0-0.2) has been extensively investigated as a cathode material for Li ion batteries because of its superior electrochemical properties including high specific energy and good rate capability. In this paper, a synchrotron based energy dispersive X-ray diffraction (EDXRD) technique was employed to profile the phase transitions and the spatial phase distribution of a Li1.1V3O8 electrode during electrochemical (de)lithiation in situ and operando. As annealing temperature during the preparation of the Li1.1V3O8 material has a strong influence on the morphology and crystallinity, and consequently influences the electrochemical outcomes of the material, Li1.1V3O8 materials prepared at two different temperatures, 500 and 300 °C (LVO500 and LVO300), were employed in this study. The EDXRD spectra of LVO500 and LVO300 cells pre-discharged at C/18, C/40 and C/150 were recorded in situ, and phase localization and relative intensity of the peaks were compared. For cells discharged at the C/18 rate, although α and β phases were distributed uniformly within the LVO500 electrode, they were localized on two sides of the LVO300 electrode. Discharging rates of C/40 and C/150 led to homogeneous β phase formation in both LVO500 and LVO300 electrodes. Furthermore, the phase distribution as a function of position and (de)lithiation extent was mapped operando as the LVO500 cell was (de)lithiated. The operando data indicate that (1) the lithiation reaction initiated from the side of the electrode facing the Li anode and proceeded towards the side facing the steel can, (2) during discharge the phase transformation from a Li-poor to a Li-rich α phase and the formation of a β phase can proceed simultaneously in the electrode after the first formation of a β phase, and (3) the structural evolution occurring during charging is not the reverse of that during discharge and takes place homogenously throughout the electrode.


Prenatal development of retinal ganglion cell axons: segregation into eye-specific layers within the cat's lateral geniculate nucleus.
The morphological changes in individual retinal ganglion cell axons associated with the formation of the eye-specific layers in the dorsal lateral geniculate nucleus (LGN) were studied during the prenatal development of the cat's visual system. Previous work has shown that the pattern of segregated eye inputs found in the adult arises from an immature state in which inputs from the two eyes are intermixed within the nucleus (Shatz, 1983). Here, this developmental process is examined at its fundamental unit of connectivity--the individual retinal ganglion cell axon. To do so, an in vitro method was used to label fetal cat optic tract axons with HRP at various times during development between embryonic day 38 (E38) and postnatal day 2 (P2) (gestation = 65 d). The results presented here are based on reconstructions of 172 axons. During the initial period of intermixing (E38-43), axons are relatively simple in morphology. Many axons studied at the earliest ages (E38) end in growth cones and have very few branches along the main axon trunk as they traverse the nucleus. By E43, the number of side branches given off along the main axon trunk has increased and most axons also have a simple terminal arbor. Over the next 2 weeks (E43-55), the majority of axons are studded with side branches and the terminal arbor is well defined. Then, between E55 and birth, axons lose their side branches and the eye-specific layers appear. By birth, nearly all axons have a smooth trunk and an elaborate terminal arbor restricted to the LGN layer appropriate to the eye of axon origin. When the number of side branches per axon was quantified, the time course of appearance and subsequent loss of side branches was found to parallel the time course of the initial intermixing of inputs and subsequent reduction in territory shared by the two eyes as determined from previous intraocular injection experiments. Our results also showed that the side branches along each axon were located primarily within LGN territory destined to be occupied by the other eye. Thus, the side branches are likely to represent a morphological substrate for the intermixing of inputs from the two eyes. These observations suggest that the segregation of eye input to the LGN involves two fundamental and simultaneous events. One event is the remodeling of the branching pattern along the length of the main axon trunk so that the side branches present early on are eliminated and the main axon trunk becomes smooth.(ABSTRACT TRUNCATED AT 400 WORDS)


HDL and atherothrombotic vascular disease.
High-density lipoproteins (HDLs) exert many beneficial effects which may help to protect against the development or progression of atherosclerosis or even facilitate lesion regression. These activities include promoting cellular cholesterol efflux, protecting low-density lipoproteins (LDLs) from modification, preserving endothelial function, as well as anti-inflammatory and antithrombotic effects. However, questions remain about the relative importance of these activities for atheroprotection. Furthermore, the many molecules (both lipids and proteins) associated with HDLs exert both distinct and overlapping activities, which may be compromised by inflammatory conditions, resulting in either loss of function or even gain of dysfunction. This complexity of HDL functionality has so far precluded elucidation of distinct structure-function relationships for HDL or its components. A better understanding of HDL metabolism and structure-function relationships is therefore crucial to exploit HDLs and its associated components and cellular pathways as potential targets for anti-atherosclerotic therapies and diagnostic markers.


Young advisors to the Ombudsman as co-operators of child psychiatry.
In Slovakia, Legislation regulates the rights of individuals with mental disorders. Observance of these regulations is monitored by a designated Ombudsman or Public Defender of Rights which was created with the adoption of the Constitutional Act No. 90/2001. The Public Defender of Rights pays special attention toward the young generation including mentally handicapped children which since 2002 serves as the basis for collaboration with Child Ombudsmen who also act in prevention of Child Abuse and Neglect Syndrome (CAN). Problematic children receive little attention not only in Slovakia. Such children can be found in many other countries and this is where the Child Ombudsman could act with beneficial effect. Since December 2008, Slovak school children have selected from their ranks a "Child Ombudsman" who is willing to defend the rights of every classmate, including those with mental problems. The Child Ombudsmen become assistants in Pedopsychiatry. An international network of Child Ombudspersons aimed at preventing development of mental and physical damage has been developed. Functioning in 22 European countries within The European Network of Ombudspersons for Children was implemented on a greater scale in April 2010. The Child Ombudspersons should be included in all public healthcare system.


Vesicle penicillinase of Bacillus licheniformis: existence of periplasmic-releasing factor(s).
In earlier studies of the membrane-bound penicillinase of Bacillus licheniformis 749/C, the enzyme present in the vesicles that were released during protoplast formation and the enzyme retained in the plasma membrane of protoplasts appeared to differ (i) in their behavior on gel permeation chromatography in the presence or absence of deoxycholate and (ii) in their tendency to convert to the hydrophilic exoenzyme (Sargent and Lampen, 1970). We have now shown that these vesicle preparations contain a soluble, heat-sensitive enzyme(s) that is released along with the vesicles during protoplast formation. The enzyme will convert the vesicle penicillinase to a form that resembles exopenicillinase, and this conversion can be inhibited by deoxycholate under certain circumstances. Sedimentation of such vesicle preparations at 100,000 X g produces vesicles which contain penicillinase that behaves as the plasma membrane enzyme obtained from protoplasts. Exopenicillinases released by growing cells at pH 6.5 and by washed cells or protoplasts at pH 9.0 have the same NH2-terminal residues (lysine and some glutamic acid); in addition, the various release systems show a parallel sensitivity to inhibition by deoxycholate, quinacrine, chloroquine, and o-phenanthroline. The formation of exopenicillinase (by cleavage of the membrane-bound enzyme) may well be dependent on the action of the releasing enzyme.


The GABA(B) receptor allosteric modulator CGP7930, like baclofen, reduces operant self-administration of ethanol in alcohol-preferring rats.
GABA systems have been implicated as targets for ethanol at the cellular, molecular and behavioural level. The present study was designed to further examine the potential of the GABA(B) receptor as a target for regulating operant alcohol responding. Given that the prototypic agonist, baclofen, reduces the self-administration of alcohol, we hypothesized that the GABA(B) receptor allosteric modulator, CGP7930, might have similar actions but a reduced side-effect profile. In this context, inbred alcohol-preferring (iP) rats were trained to respond for 10% v/v ethanol in a fixed ratio paradigm; all drug testing was performed under an FR3 schedule. Both baclofen and CGP7930 independently reduced voluntary responding for 10% ethanol in a dose-related manner. Neither drug impacted upon responding for water. A combination of subthreshold doses of baclofen and CGP7930 was also able to reduce operant responding for ethanol, suggesting that CGP7930 is indeed acting to facilitate GABA(B) receptor-mediated signalling in this paradigm. These data demonstrate the potential of positive allosteric modulators of metabotropic GABA(B) receptors to regulate alcohol responding.


Lipid profile but not highly sensitive C-reactive protein helps distinguish prehypertensives from normal subjects.
Early identification of the prehypertensive state can greatly improve the disease risk management. Although increased levels of highly sensitive C-reactive protein (hsCRP) and dyslipidemia is reported among patients with hypertension, the correlation of these parameters among prehypertensives in not known. Hence, the present study was designed to compare the levels of serum hsCRP and lipid profile among prehypertensives and normal subjects and correlate it with blood pressure (BP) levels. Anthropometric measurements and BP were recorded in 40 prehypertensive and 40 normal subjects. Subjects were assigned to a group based on their BP as per Joint National Committee 7 criteria. Serum hsCRP and lipid profile were measured and correlated with BP levels. Serum hsCRP showed no significant difference between the two groups. There was no significant correlation of BP with hsCRP in both the groups. Total cholesterol (TC) and low-density lipoprotein (LDL) were significantly increased in prehypertensives as compared to normal subjects. There was no significant association between BP and lipid parameters in prehypertensives. Significant increase of TC and LDL but not hsCRP was evident among prehypertensives as compared to normal subjects.


Accurate atom-mapping computation for biochemical reactions.
The complete atom mapping of a chemical reaction is a bijection of the reactant atoms to the product atoms that specifies the terminus of each reactant atom. Atom mapping of biochemical reactions is useful for many applications of systems biology, in particular for metabolic engineering where synthesizing new biochemical pathways has to take into account for the number of carbon atoms from a source compound that are conserved in the synthesis of a target compound. Rapid, accurate computation of the atom mapping(s) of a biochemical reaction remains elusive despite significant work on this topic. In particular, past researchers did not validate the accuracy of mapping algorithms. We introduce a new method for computing atom mappings called the minimum weighted edit-distance (MWED) metric. The metric is based on bond propensity to react and computes biochemically valid atom mappings for a large percentage of biochemical reactions. MWED models can be formulated efficiently as Mixed-Integer Linear Programs (MILPs). We have demonstrated this approach on 7501 reactions of the MetaCyc database for which 87% of the models could be solved in less than 10 s. For 2.1% of the reactions, we found multiple optimal atom mappings. We show that the error rate is 0.9% (22 reactions) by comparing these atom mappings to 2446 atom mappings of the manually curated Kyoto Encyclopedia of Genes and Genomes (KEGG) RPAIR database. To our knowledge, our computational atom-mapping approach is the most accurate and among the fastest published to date. The atom-mapping data will be available in the MetaCyc database later in 2012; the atom-mapping software will be available within the Pathway Tools software later in 2012.


Targeting of Evolutionarily Acquired Cancer Cell Phenotype by Exploiting pHi-Metabolic Vulnerabilities.
Evolutionary dynamics can be used to control cancers when a cure is not clinically considered to be achievable. Understanding Darwinian intratumoral interactions of microenvironmental selection forces can be used to steer tumor progression towards a less invasive trajectory. Here, we approach intratumoral heterogeneity and evolution as a dynamic interaction among subpopulations through the application of small, but selective biological forces such as intracellular pH (pHi) and/or extracellular pH (pHe) vulnerabilities. Increased glycolysis is a prominent phenotype of cancer cells under hypoxia or normoxia (Warburg effect). Glycolysis leads to an important aspect of cancer metabolism: reduced pHe and higher pHi. We recently showed that decreasing pHi and targeting pHi sensitive enzymes can reverse the Warburg effect (WE) phenotype and inhibit tumor progression. Herein, we used diclofenac (DIC) repurposed to control MCT activity, and Koningic acid (KA) that is a GAPDH partial inhibitor, and observed that we can control the subpopulation of cancer cells with WE phenotype within a tumor in favor of a less aggressive phenotype without a WE to control progression and metastasis. In a 3D spheroid co-cultures, we showed that our strategy can control the growth of more aggressive MDA-MB-231 cells, while sparing the less aggressive MCF7 cells. In an animal model, we show that our approach can reduce tumor growth and metastasis. We thus propose that evolutionary dynamics can be used to control tumor cells' clonal or sub-clonal populations in favor of slower growth and less damage to patients. We propose that this can result in cancer control for tumors where cure is not an option.


The Profile of Non-Communicable Disease (NCD) research in the Middle East and North Africa (MENA) region: Analyzing the NCD burden, research outputs and international research collaboration.
Despite the rising risk factor exposure and non-communicable disease (NCD) mortality across the Middle East and the North African (MENA) region, public health policy responses have been slow and appear discordant with the social, economic and political circumstances in each country. Good health policy and outcomes are intimately linked to a research-active culture, particularly in NCD. In this study we present the results of a comprehensive analysis of NCD research with particular a focus on cancer, diabetes and cardiovascular disease in 10 key countries that represent a spectrum across MENA between 1991 and 2018. The study uses a well validated bibliometric approach to undertake a quantitative analysis of research output in the ten leading countries in biomedical research in the MENA region on the basis of articles and reviews in the Web of Science database. We used filters for each of the three NCDs and biomedical research to identify relevant papers in the WoS. The countries selected for the analyses were based on the volume of research outputs during the period of analysis and stability, included Egypt, Iran, Jordan, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, Turkey and the United Arab Emirates. A total of 495,108 biomedical papers were found in 12,341 journals for the ten MENA countries (here we consider Turkey in the context of MENA). For all three NCDs, Turkey's output is consistently the highest. Iran has had considerable growth in research output to occupy second place across all three NCDs. It appears that, relative to their wealth (measured by GDP), some MENA countries, particularly Oman, Qatar, Kuwait and the United Arab Emirates, are substantially under-investing in biomedical research. In terms of investment on particular NCDs, we note the relatively greater commitment on cancer research compared with diabetes or cardiovascular disease in most MENA countries, despite cardiovascular disease causing the greatest health-related burden. When considering the citation impact of research outputs, there have been marked rises in citation scores in Qatar, Lebanon, United Arab Emirates and Oman. However, Turkey, which has the largest biomedical research output in the Middle East has the lowest citation scores overall. The level of intra-regional collaboration in NCD research is highly variable. Saudi Arabia and Egypt are the dominant research collaborators across the MENA region. However, Turkey and Iran, which are amongst the leading research-active countries in the area, show little evidence of collaboration. With respect to international collaboration, the United States and United Kingdom are the dominant research partners across the region followed by Germany and France. The increase in research activity in NCDs across the MENA region countries during the time period of analysis may signal both an increasing focus on NCDs which reflects general global trends, and greater investment in research in some countries. However, there are several risks to the sustainability of these improvements that have been identified in particular countries within the region. For example, a lack of suitably trained researchers, low political commitment and poor financial support, and minimal international collaboration which is essential for wider global impact.


Variation in gene expression patterns as the insect pathogen Metarhizium anisopliae adapts to different host cuticles or nutrient deprivation in vitro.
Metarhizium anisopliae infects a broad range of insects by direct penetration of the host cuticle. To explore the molecular basis of this process, its gene expression responses to diverse insect cuticles were surveyed, using cDNA microarrays constructed from an expressed sequence tag (EST) clone collection of 837 genes. During growth in culture containing caterpillar cuticle (Manduca sexta), M. anisopliae upregulated 273 genes, representing a broad spectrum of biological functions, including cuticle-degradation (e.g. proteases), amino acid/peptide transport and transcription regulation. There were also many genes of unknown function. The 287 down-regulated genes were also distinctive, and included a large set of ribosomal protein genes. The response to nutrient deprivation partially overlapped with the response to Man. sexta cuticle, but unique expression patterns in response to cuticles from another caterpillar (Lymantria dispar), a cockroach (Blaberus giganteus) and a beetle (Popilla japonica) indicate that the pathogen can respond in a precise and specialized way to specific conditions. The subtilisins provided an example of a large gene family in which differences in regulation could potentially allow virulence determinants to target different hosts and stages of infection. Comparisons between M. anisopliae and published data on Trichoderma reesei and Saccharomyces cerevisiae identified differences in the regulation of glycolysis-related genes and citric acid cycle/oxidative phosphorylation functions. In particular, M. anisopliae has multiple forms of several catabolic enzymes that are differentially regulated in response to sugar levels. These may increase the flexibility of M. anisopliae as it responds to nutritional changes in its environment.


Non-coding RNAs profiling in head and neck cancers.
The majority of studies on human cancers published to date focus on coding genes. More recently, however, non-coding RNAs (ncRNAs) are gaining growing recognition as important regulatory components. Here we characterise the ncRNA landscape in 442 head and neck squamous cell carcinomas (HNSCs) from the cancer genome atlas (TCGA). HNSCs represent an intriguing case to study the potential role of ncRNA as a function of viral presence, especially as HPV is potentially oncogenic. Thus, we identify HPV16-positive (HPV16+) and HPV-negative (HPV-) tumours and study the expression of ncRNAs on both groups. Overall, the ncRNAs comprise 36% of all differentially expressed genes, with antisense RNAs being the most represented ncRNA type (12.6%). Protein-coding genes appear to be more frequently downregulated in tumours compared with controls, whereas ncRNAs show significant upregulation in tumours, especially in HPV16+ tumours. Overall, expression of pseudogenes, antisense and short RNAs is elevated in HPV16+ tumours, while the remaining long non-coding RNA types are more active in all HNSC tumours independent of HPV status. In addition, we identify putative regulatory targets of differentially expressed ncRNAs. Among these 'targets' we find several well-established oncogenes, tumour suppressors, cytokines, growth factors and cell differentiation genes, which indicates the potential involvement of ncRNA in the control of these key regulators as a direct consequence of HPV oncogenic activity. In conclusion, our findings establish the ncRNAs as crucial transcriptional components in HNSCs. Our results display the great potential for the study of ncRNAs and the role they have in human cancers.


Large particulate allergens can elicit mast cell-mediated anaphylaxis without exit from blood vessels as efficiently as do small soluble allergens.
Anaphylaxis is a rapid-onset, life-threatening allergic reaction in that IgE, mast cells and histamine are commonly involved. It can be experimentally induced in IgE-sensitized animals by intravenous injection of corresponding allergens, and the sign of anaphylactic reaction can be detected within minutes after allergen challenge. However, it remains puzzling why the anaphylactic reaction can be initiated in vivo so quickly, considering that allergens are delivered into the blood circulation while mast cells reside within peripheral tissues but not in the blood circulation. To address this issue, we compared two different forms of the same allergen, small soluble and large particulate ones, in their ability to induce anaphylaxis in IgE-sensitized mice. In contrast to our expectation, particulate allergens could induce anaphylaxis as quickly and efficiently as did soluble allergens, even though they remained inside of blood vessels. In vivo imaging analysis suggested the direct interaction of intravascular particulate allergens and perivascular mast cells across the capillary wall. Taken together with previous report that perivascular mast cells can capture IgE in the blood circulation by extending cell processes across the vessel wall, our findings imply that blood-circulating allergens, regardless of their size, can stimulate mast cells without exit from blood vessels, by means of cross-linking IgE on mast cell processes inserted into the vessel lumen, and hence initiate anaphylactic reaction so quickly.


Evidence of favorable sleep-EEG patterns in adolescent male vigorous football players compared to controls.
Sleep is crucial for psychological functioning and daily performance. Both lay and scientific opinion hold that physical activity encourages restorative sleep. However, research on this in adolescence is limited. The aim of the present study was to compare sleep-EEG patterns of vigorous exercisers and controls. Twelve adolescent male football players (14 h of vigorous exercise per week) and 12 controls (1.5 h of vigorous exercise per week) matched for gender, age (about 16 years), and educational level, took part in the study. Sleep-EEG registration was performed following a day without exercise. Sleep-EEG analyses revealed that, compared to controls, the football players showed greater sleep efficiency, shortened sleep onset latency, less awakenings after sleep onset, more stage 4, and less REM sleep. Importantly, this pattern of results emerged following a day without exercise. Moreover, vigorous football players reported better daily performance and displayed less weeknight (Sunday to Thursday) to weekend night (Friday and Saturday nights) variation. Findings suggest that for the football players, vigorous exercise seemed to lead to longer-lasting electrophysiological change in brain activity irrespective of acute bouts of exercise.


Endothelial nitric oxide synthase mediates cutaneous vasodilation during local heating and is attenuated in middle-aged human skin.
Local skin heating is used to assess microvascular function in clinical populations because NO is required for full expression of the response; however, controversy exists as to the precise NO synthase (NOS) isoform producing NO. Human aging is associated with attenuated cutaneous vasodilation but little is known about the middle aged, an age cohort used for comparison with clinical populations. We hypothesized that endothelial NOS (eNOS) is the primary isoform mediating NO production during local heating, and eNOS-dependent vasodilation would be reduced in middle-aged skin. Vasodilation was induced by local heating (42°C) and during acetylcholine dose-response (ACh-DR: 0.01, 0.1, 1.0, 5.0, 10.0, 50.0, 100.0 mmol/l) protocols. Four microdialysis fibers were placed in the skin of 24 men and women; age cohorts were 12 middle-aged (53 ± 1 yr) and 12 young (23 ± 1 yr). Sites served as control, nonselective NOS inhibited [N(G)-nitro-l-arginine methyl ester (l-NAME)], inducible NOS (iNOS) inhibited (1400W), and neuronal NOS (nNOS) inhibited (N(ω)-propyl-l-arginine). After full expression of the local heating response, l-NAME was perfused at all sites. Cutaneous vascular conductance was measured and normalized to maximum (%CVC(max): Nitropress). l-NAME reduced %CVCmax at baseline, all phases of the local heating response, and at all ACh concentrations compared with all other sites. iNOS inhibition reduced the initial peak (53 ± 2 vs. 60 ± 2%CVC(max); P < 0.001); however, there were no other differences between control, nNOS-, and iNOS-inhibited sites during the phases of local heating or ACh-DR. When age cohorts were compared, NO-dependent vasodilation during local heating (52 ± 6 vs. 68 ± 4%CVC(max); P = 0.013) and ACh perfusion (50 mmol/l: 83 ± 3 vs. 93 ± 2%CVC(max); 100 mmol/l: 83 ± 4 vs. 92 ± 3%CVC(max); both P = 0.03) were reduced in middle-aged skin. There were no differences in NOS isoform expression obtained from skin biopsy samples between groups (all P > 0.05). These data suggest that eNOS mediates the production of NO during local heating and that cutaneous vasodilation is attenuated in middle-aged skin.


A Novel Zebrafish ret Heterozygous Model of Hirschsprung Disease Identifies a Functional Role for mapk10 as a Modifier of Enteric Nervous System Phenotype Severity.
Hirschsprung disease (HSCR) is characterized by absence of enteric neurons from the distal colon and severe intestinal dysmotility. To understand the pathophysiology and genetics of HSCR we developed a unique zebrafish model that allows combined genetic, developmental and in vivo physiological studies. We show that ret mutant zebrafish exhibit cellular, physiological and genetic features of HSCR, including absence of intestinal neurons, reduced peristalsis, and varying phenotype expressivity in the heterozygous state. We perform live imaging experiments using a UAS-GAL4 binary genetic system to drive fluorescent protein expression in ENS progenitors. We demonstrate that ENS progenitors migrate at reduced speed in ret heterozygous embryos, without changes in proliferation or survival, establishing this as a principal pathogenic mechanism for distal aganglionosis. We show, using live imaging of actual intestinal movements, that intestinal motility is severely compromised in ret mutants, and partially impaired in ret heterozygous larvae, and establish a clear correlation between neuron position and organised intestinal motility. We exploited the partially penetrant ret heterozygous phenotype as a sensitised background to test the influence of a candidate modifier gene. We generated mapk10 loss-of-function mutants, which show reduced numbers of enteric neurons. Significantly, we show that introduction of mapk10 mutations into ret heterozygotes enhanced the ENS deficit, supporting MAPK10 as a HSCR susceptibility locus. Our studies demonstrate that ret heterozygous zebrafish is a sensitized model, with many significant advantages over existing murine models, to explore the pathophysiology and complex genetics of HSCR.


Expression of wnt and frizzled genes during early sea star development.
The Wnt signaling pathway is highly conserved across metazoa and has pleiotropic functions in the development of many animals. Binding of a secreted Wnt ligand to its Frizzled (Fz) receptor activates Dishevelled, which then drives one of three major signaling cascades, canonical (β-catenin), calcium, or planar cell polarity signaling. These pathways have distinct developmental effects and function in different processes in different organisms. Here we report the expression of six wnt and three fz genes during embryogenesis of the sea star, Patiria miniata, as a first step in uncovering the roles of Wnt signaling in the development of this organism. wnt3, wnt4, wnt8, and wnt16 are expressed in nested domains in the endoderm and lateral ectoderm from blastula through late gastrula stages; wnt2 and wnt5 are expressed in the mesoderm and anterior endoderm. Expression of different fz paralogs is detected in the mesoderm; posterior endoderm and ectoderm; and anterior ectoderm. Taken together, this suggests that Wnt signaling can occur throughout most of the embryo and may therefore play multiple roles during sea star development.


Serum Leptin, Resistin, and Adiponectin Concentrations in Psoriasis: A Meta-Analysis of Observational Studies.
Psoriasis is an immune-mediated, inflammatory disease. Adipokines contribute to the regulation of immune-mediated processes and inflammation. The aim of our study was to systematically review the literature for studies that have evaluated the circulating concentrations of adipokines in patients with psoriasis and controls and to meta-analyze the best evidence available. Eligible were studies that have assessed leptin, resistin, or adiponectin concentrations in psoriatic patients and a reference group. The study was conducted in adherence with the PRISMA standards. Psoriatic patients had higher leptin concentrations compared to controls (random effects model, mean difference, MD = 5.64 ng/mL, 95% CI: 3.00-8.29, p < 0.0001). Heterogeneity among studies was high (I2 = 95.9%). Psoriatic patients had higher resistin concentrations compared to controls (MD = 4.66 ng/mL, 95% CI: 2.62-6.69, p < 0.0001). Heterogeneity was high (I2 = 99.2%). Finally, psoriatic patients had lower adiponectin concentrations compared to controls (MD = -1.87 μg/mL, 95% CI: -2.76 to -0.98, p < 0.0001). Heterogeneity was high (I2 = 95.9%). The study supported the hypothesis that leptin and resistin concentrations are higher and adiponectin concentrations are lower in patients with psoriasis compared to controls. Hereby, the suggested pathogenic link between psoriasis and metabolic syndrome/obesity is reinforced and the role of comorbidities in psoriasis is highlighted.


Can I leave the theatre? A key to more reliable workplace-based assessment.
The value of workplace-based assessments such as the mini-clinical evaluation exercise (mini-CEX), and clinicians' confidence and engagement in the process, has been constrained by low reliability and limited capacity to identify underperforming trainees. We proposed that changing the way supervisors make judgements about trainees would improve score reliability and identification of underperformers. Anaesthetists regularly make decisions about the level of trainee independence with a case, based on how closely they need to supervise them. We therefore used this as the basis for a new scoring system. We analysed 338 mini-CEXs where supervisors scored trainees using the conventional system, and also scored trainee independence, based on the need for direct, or more distant, supervision. As supervisory requirements depend on case difficulty, we then compared the actual trainee independence score and the expected trainee independence score obtained externally. Compared with the conventional scoring system used in previous studies, reliability was very substantially improved using a system based on a trainee's level of independence with a case. Reliability improved further when this score was corrected for case difficulty. Furthermore, the new scoring system overcame the previously identified problem of assessor leniency and identified a number of trainees performing below expectations. Supervisors' judgements on trainee independence with a case, based on the need for direct or more distant supervision, can generate reliable scores of trainee ability without the need for an onerous number of assessments, identify trainees performing below expectations, and track trainee progress towards independent specialist practice.


Stable isotopes and elasmobranchs: tissue types, methods, applications and assumptions.
Stable-isotope analysis (SIA) can act as a powerful ecological tracer with which to examine diet, trophic position and movement, as well as more complex questions pertaining to community dynamics and feeding strategies or behaviour among aquatic organisms. With major advances in the understanding of the methodological approaches and assumptions of SIA through dedicated experimental work in the broader literature coupled with the inherent difficulty of studying typically large, highly mobile marine predators, SIA is increasingly being used to investigate the ecology of elasmobranchs (sharks, skates and rays). Here, the current state of SIA in elasmobranchs is reviewed, focusing on available tissues for analysis, methodological issues relating to the effects of lipid extraction and urea, the experimental dynamics of isotopic incorporation, diet-tissue discrimination factors, estimating trophic position, diet and mixing models and individual specialization and niche-width analyses. These areas are discussed in terms of assumptions made when applying SIA to the study of elasmobranch ecology and the requirement that investigators standardize analytical approaches. Recommendations are made for future SIA experimental work that would improve understanding of stable-isotope dynamics and advance their application in the study of sharks, skates and rays.


Population differentiation determined from putative neutral and divergent adaptive genetic markers in Eulachon (Thaleichthys pacificus, Osmeridae), an anadromous Pacific smelt.
Twelve eulachon (Thaleichthys pacificus, Osmeridae) populations ranging from Cook Inlet, Alaska and along the west coast of North America to the Columbia River were examined by restriction-site-associated DNA (RAD) sequencing to elucidate patterns of neutral and adaptive variation in this high geneflow species. A total of 4104 single-nucleotide polymorphisms (SNPs) were discovered across the genome, with 193 putatively adaptive SNPs as determined by F(ST) outlier tests. Estimates of population structure in eulachon with the putatively adaptive SNPs were similar, but provided greater resolution of stocks compared with a putatively neutral panel of 3911 SNPs or previous estimates with 14 microsatellites. A cline of increasing measures of genetic diversity from south to north was found in the adaptive panel, but not in the neutral markers (SNPs or microsatellites). This may indicate divergent selective pressures in differing freshwater and marine environments between regional eulachon populations and that these adaptive diversity patterns not seen with neutral markers could be a consideration when determining genetic boundaries for conservation purposes. Estimates of effective population size (N(e)) were similar with the neutral SNP panel and microsatellites and may be utilized to monitor population status for eulachon where census sizes are difficult to obtain. Greater differentiation with the panel of putatively adaptive SNPs provided higher individual assignment accuracy compared to the neutral panel or microsatellites for stock identification purposes. This study presents the first SNPs that have been developed for eulachon, and analyses with these markers highlighted the importance of integrating genome-wide neutral and adaptive genetic variation for the applications of conservation and management.


Optimized quinoline amino alcohols as disruptors and dispersal agents of Vibrio cholerae biofilms.
The biofilm state is an integral part of the lifecycle of many bacterial pathogens. Identifying inhibitors as molecular probes against bacterial biofilms has numerous potential biomedical applications. Here we report quinoline amino alcohol as a highly potent disruptor of V. cholerae biofilms. Additionally, was able to disperse preformed biofilms, an activity exhibited by few compounds with biofilm inhibiting activity.


Alterations in the mechanical properties of the human chondrocyte pericellular matrix with osteoarthritis.
In articular cartilage, chondrocytes are surrounded by a pericellular matrix (PCM), which together with the chondrocyte have been termed the "chondron." While the precise function of the PCM is not know there has been considerable speculation that it plays a role in regulating the biomechanical environment of the chondrocyte. In this study, we measured the Young's modulus of the PCM from normal and osteoarthritic cartilage using the micropipette aspiration technique, coupled with a newly developed axisymmetric elastic layered half-space model of the experimental configuration. Viable, intact chondrons were extracted from human articular cartilage using a new microaspiration-based isolation technique. In normal cartilage, the Young's modulus of the PCM was similar in chondrons isolated from the surface zone (68.9 +/- 18.9 kPa) as compared to the middle and deep layers (62.0 +/- 30.5 kPa). However, the mean Young's modulus of the PCM (pooled for the two zones) was significantly decreased in osteoarthritic cartilage (66.5 +/- 23.3 kPa versus 41.3 +/- 21.1 kPa, p < 0.001). In combination with previous theoretical models of cell-matrix interactions in cartilage, these findings suggest that the PCM has an important influence on the stress-strain environment of the chondrocyte that potentially varies with depth from the cartilage surface. Furthermore, the significant loss of PCM stiffness that was observed in osteoarthritic cartilage may affect the magnitude and distribution of biomechanical signals perceived by the chondrocytes.


Hospitalization of individuals with systemic lupus erythematosus: characteristics and predictors of outcome.
We performed a retrospective study of patients with systemic lupus erythematosus (SLE) admitted to hospital during a one-year period to describe characteristics associated with a poor outcome. There were 348 episodes of hospitalization of 223 individuals. The cause of admission was clinical flare of SLE (58%), infection (37%) and thromboembolic disease (8%). Readmission occurred in 35.8% and was associated with: active nephritis (HR 2.53, P < 0.01), flare of lupus (HR 2.0, P < 0.01) and more ACR criteria (HR 1.34 per extra criteria, P < 0.01). Individuals with multiple reasons for admission had a longer duration of stay [one = four days (2, 6), two = five days (3, 7) and three = 9.5 days (6.5, 14.5), P < 0.01]. There were 11 deaths (3.2% of admissions). The deaths were due to infection in nine cases (four with concurrent active SLE). In multivariate modelling, the main predictors of death were: previous multiple admissions (OR 12.4, P < 0.01), the presence of infection (OR 7.3, P < 0.01) and younger age (OR 0.93 per increase of one year, P = 0.03). The presence of active lupus nephritis and multisystem disease makes readmission more likely and individuals with multiple problems at the time of admission have longer hospital stays. Young patients with frequent readmissions and coexistent infections are most likely to die.


Denoising performance of modified dual-tree complex wavelet transform for processing quadrature embolic Doppler signals.
Quadrature signals are dual-channel signals obtained from the systems employing quadrature demodulation. Embolic Doppler ultrasound signals obtained from stroke-prone patients by using Doppler ultrasound systems are quadrature signals caused by emboli, which are particles bigger than red blood cells within circulatory system. Detection of emboli is an important step in diagnosing stroke. Most widely used parameter in detection of emboli is embolic signal-to-background signal ratio. Therefore, in order to increase this ratio, denoising techniques are employed in detection systems. Discrete wavelet transform has been used for denoising of embolic signals, but it lacks shift invariance property. Instead, dual-tree complex wavelet transform having near-shift invariance property can be used. However, it is computationally expensive as two wavelet trees are required. Recently proposed modified dual-tree complex wavelet transform, which reduces the computational complexity, can also be used. In this study, the denoising performance of this method is extensively evaluated and compared with the others by using simulated and real quadrature signals. The quantitative results demonstrated that the modified dual-tree-complex-wavelet-transform-based denoising outperforms the conventional discrete wavelet transform with the same level of computational complexity and exhibits almost equal performance to the dual-tree complex wavelet transform with almost half computational cost.


Optimum deposition conditions of ultrasmooth silver nanolayers.
Reduction of surface plasmon-polariton losses due to their scattering on metal surface roughness still remains a challenge in the fabrication of plasmonic devices for nanooptics. To achieve smooth silver films, we study the dependence of surface roughness on the evaporation temperature in a physical vapor deposition process. At the deposition temperature range 90 to 500 K, the mismatch of thermal expansion coefficients of Ag, Ge wetting layer, and sapphire substrate does not deteriorate the metal surface. To avoid ice crystal formation on substrates, the working temperature of the whole physical vapor deposition process should exceed that of the sublimation at the evaporation pressure range. At optimum room temperature, the root-mean-square (RMS) surface roughness was successfully reduced to 0.2 nm for a 10-nm Ag layer on sapphire substrate with a 1-nm germanium wetting interlayer. Silver layers of 10- and 30-nm thickness were examined using an atomic force microscope (AFM), X-ray reflectometry (XRR), and two-dimensional X-ray diffraction (XRD2). 63.22.Np Layered systems; 68. Surfaces and interfaces; thin films and nanosystems (structure and nonelectronic properties); 81.07.-b Nanoscale materials and structures: fabrication and characterization.


Catenuloplanes crispus (Petrolini et al. 1993) comb. nov.: incorporation of the genus Planopolyspora Petrolini 1993 into the genus Catenuloplanes Yokota et al. 1993 with an amended description of the genus Catenuloplanes.
The taxonomic position of the genus Planopolyspora comprising a single species, Planopolyspora crispa, was reviewed. This genus was originally characterized by formation of long, curly and sometimes branching sporangia containing numerous zoospores arranged in a single row and by the presence of meso-diaminopimelic acid and madurose (3-O-methyl-D-galactose) in whole-cell hydrolysates. However, our chemotaxonomic analyses of the type strain of P. crispa did not agree with the original description. The peptidoglycan contained L-lysine but not meso-diaminopimelic acid, and the whole-cell hydrolysate contained xylose as the characteristic sugar but not madurose. These characteristics and other chemotaxonomic profiles (e.g. menaquinone, phospholipid and cellular fatty acid compositions) of the genus Planopolyspora coincided with those of the genus Catenuloplanes. These two genera also had very similar morphological characteristics, but in the original description of the genus Catenuloplanes the presence of sporangia was not referred to. This difference is considered to originate from a divergence of views owing to the ambiguity of the definition of the term 'sporangium' in actinomycete morphology. Phylogenetic analysis based on 16S rDNA sequences also supported the proposal that the genera Planopolyspora and Catenuloplanes should be combined into one genus. Levels of DNA relatedness among the type strains of P. crispa and six Catenuloplanes species and their cultural, physiological and biochemical characteristics indicated that P. crispa should be classified as an independent species of the genus Catenuloplanes, which has priority over the genus Planopolyspora. Therefore, it is proposed that Planopolyspora crispa be transferred to the genus Catenuloplanes as Catenuloplanes crispus comb. nov.


Usefulness of a commercial equine IgG test and serum protein concentration as indicators of failure of transfer of passive immunity in hospitalized foals.
Detection of failure of transfer of passive immunity (FTPI) is important in reducing morbidity and mortality in neonatal foals. We investigated the performance of a commercial equine IgG test (SNAP Foal IgG Test Kit) to diagnose FTPI in hospitalized foals. Furthermore, we evaluated the usefulness of serum total protein (STP) and serum globulin (SG) concentrations as indicators of FTPI. Serum IgG concentration was measured by means of the SNAP test and single radial immunodiffusion, and SG and STP concentrations were determined by means of a clinical chemistry analyzer. Subjects were 67 hospitalized foals <19 days old. The SNAP test was repeated on 37 samples from 29 foals, with identical results for 24 samples (kappa statistic, 0.64; 95% confidence interval [CI], 0.46-0.82). The sensitivity of the SNAP test to detect serum IgG concentration [IgG] < or =400 and < or =800 mg/dl was 90% (95% CI, 71-98%) and 95% (85-99%), respectively, and the specificity was 79% (71-82%) and 52% (39-57%), respectively. Sensitivity for detection of [IgG] < or =400 mg/dl was not affected (P > .05) by plasma fibrinogen concentration, sepsis score, or bacteremia. Specificity for detection of [IgG] < or = 800 mg/dl was lower (P < .05) in foals with sepsis score < or =11 (50% [31-60%] versus 100% [8-100%]) and bacteremia (25% [5-56%] versus 62% [45-62%]). Sensitivity and specificity of [STP] < or = 5.0 g/dl for [IgG] < or =800 mg/dl was 94% (83-99%) and 47% (30-56%), respectively. Performance of the SNAP test in hospitalized foals is impaired because of low specificity, but can have usefulness provided that the properties of the test and characteristics of the foal being examined are considered when interpreting the results. The STP and SG concentrations are poor sole indicators of FTPI in hospitalized foals, but may be useful adjunctive tests.


Molecular diversity of Mycobacterium tuberculosis isolates from patients with pulmonary tuberculosis in Sri Lanka.
The strain diversity of 100 Mycobacterium tuberculosis isolates collected over a period of 18 months from tuberculosis (TB) cases in Sri Lanka was studied by spoligotyping. When compared to the international spoligotyping database, 43 spoligotype patterns were identified, of which 20 were previously described. The majority of isolates (72.45%) were clustered into major genetic group 1, and the most common spoligotype pattern belonged to the Beijing (ST1) strain family. All the Beijing strain isolates belonged to more recently evolved sublineages of M. tuberculosis. The characterization of Sri Lankan M. tuberculosis isolates by spoligotyping shows a heterogeneous pattern. The physical separation from the main Indian peninsula may be responsible for the different patterns observed between the two countries. An in-depth field study is needed to understand the spread and the true epidemiology of this infection.


First-line antihypertensive treatment in patients with pre-diabetes: rationale, design and baseline results of the ADaPT investigation.
Recent clinical trials reported conflicting results on the reduction of new-onset diabetes using RAS blocking agents. Therefore the role of these agents in preventing diabetes is still not well defined. Ramipril is an ACE inhibitor (ACEi), that has been shown to reduce cardiovascular events in high risk patients and post-hoc analyses of the HOPE trial have provided evidence for its beneficial action in the prevention of diabetes. The ADaPT investigation ("ACE inhibitor-based versus diuretic-based antihypertensive primary treatment in patients with pre-diabetes") is a 4-year open, prospective, parallel group phase IV study. It compares an antihypertensive treatment regimen based on ramipril versus a treatment based on diuretics or betablockers. The primary evaluation criterion is the first manifestation of type 2 diabetes. The study is conducted in primary care to allow the broadest possible application of its results. The present article provides an outline of the rationale, the design and baseline characteristics of AdaPT and compares these to previous studies including ASCOT-BLPA, VALUE and DREAM. Until March 2006 a total of 2,015 patients in 150 general practices (general physicians and internists) throughout Germany were enrolled. The average age of patients enrolled was 67.1 +/- 10.3 years, with 47% being male and a BMI of 29.9 +/- 5.0 kg/m2. Dyslipidemia was present in 56.5%. 37.8% reported a family history of diabetes, 57.8% were previously diagnosed with hypertension (usually long standing). The HbA1c value at baseline was 5.6 %. Compared to the DREAM study patients were older, had more frequently hypertension and patients with cardiovascular disease were not excluded. Comparing the ADaPT design and baseline data to previous randomized controlled trial it can be acknowledged that AdaPT included patients with a high risk for diabetes development. Results are expected to be available in 2010. Data will be highly valuable for clinical practice due to the observational study design.


Glycogen metabolism has a key role in the cancer microenvironment and provides new targets for cancer therapy.
Metabolic reprogramming is a hallmark of cancer cells and contributes to their adaption within the tumour microenvironment and resistance to anticancer therapies. Recently, glycogen metabolism has become a recognised feature of cancer cells since it is upregulated in many tumour types, suggesting that it is an important aspect of cancer cell pathophysiology. Here, we provide an overview of glycogen metabolism and its regulation, with a focus on its role in metabolic reprogramming of cancer cells under stress conditions such as hypoxia, glucose deprivation and anticancer treatment. The various methods to detect glycogen in tumours in vivo as well as pharmacological modulators of glycogen metabolism are also reviewed. Finally, we discuss the therapeutic value of targeting glycogen metabolism as a strategy for combinational approaches in cancer treatment.


Aspirin in prevention of sporadic colorectal cancer: current clinical evidence and overall balance of risks and benefits.
In addition to longstanding evidence from observational studies, evidence from randomised trials of the effectiveness of aspirin for chemoprevention of colorectal cancer has increased substantially in recent years. Trials have shown that daily aspirin reduces the risk of any recurrent colorectal adenoma by 17 % and advanced adenoma by 28 %, and that daily aspirin for about 5 years reduces incidence and mortality due to colorectal cancer by 30-40 % after 20 years of follow-up, and reduces the 20-year risk of all-cause cancer mortality by about 20 %. Recent evidence also shows that the risk of major bleeding on aspirin diminishes with prolonged use, suggesting that the balance of risk and benefit favours the use of daily aspirin in primary prevention of colorectal and other cancers. Updated clinical guidelines are currently awaited.


Pain and wound healing in surgical patients.
Human and animal laboratory studies have shown that stress delays healing of standardized punch biopsy wounds. This 5-week prospective study of 17 women who underwent elective gastric bypass surgery addressed the association between postsurgical pain intensity and subsequent healing of a standard 2.0-mm punch biopsy wound. Participants were assessed 1 week before surgery, within 3 hr before surgery, 1 to 3 days postsurgery, and at weekly intervals for 4 weeks following surgery. Patient ratings of greater acute postsurgical pain, averaged over Days 1 and 2 postsurgery, and greater persistent postsurgical pain, averaged over 4 weekly postsurgery pain ratings, were significantly associated with subsequent delayed healing of the punch biopsy wound. Presence of depressive symptoms on the day of surgery, pre-existing persistent pain, and medical complications following initial discharge from the hospital were not related to wound healing. Depressive symptoms on the day of surgery and pre-existing persistent pain did predict persistent postsurgical pain intensity. These findings extend the previous laboratory models of wound healing to a surgical population, providing the first evidence that pain plays an important role in postsurgery wound healing, a key variable in postsurgical recovery.


Functional and molecular characterization of hyposensitive underactive bladder tissue and urine in streptozotocin-induced diabetic rat.
The functional and molecular alterations of nerve growth factor (NGF) and Prostaglandin E2 (PGE2) and its receptors were studied in bladder and urine in streptozotocin (STZ)-induced diabetic rats. Diabetes mellitus was induced with a single dose of 45 mg/kg STZ Intraperitoneally (i.p) in female Sprague-Dawley rats. Continuous cystometrogram were performed on control rats and STZ treated rats at week 4 or 12 under urethane anesthesia. Bladder was then harvested for histology, expression of EP receptors and NGF by western blotting, PGE2 levels by ELISA, and detection of apoptosis by TUNEL staining. In addition, 4-hr urine was collected from all groups for urine levels of PGE2, and NGF assay. DM induced progressive increase of bladder weight, urine production, intercontraction interval (ICI) and residual urine in a time dependent fashion. Upregulation of Prostaglandin E receptor (EP)1 and EP3 receptors and downregulation of NGF expression, increase in urine NGF and decrease levels of urine PGE2 at week 12 was observed. The decrease in ICI by intravesical instillation of PGE2 was by 51% in control rats and 31.4% in DM group at week 12. DM induced hyposensitive underactive bladder which is characterized by increased inflammatory reaction, apoptosis, urine NGF levels, upregulation of EP1 and EP3 receptors and decreased bladder NGF and urine PGE2. The data suggest that EP3 receptor are potential targets in the treatment of diabetes induced underactive bladder.


Olive oil and cardiovascular health.
The Mediterranean diet, in which olive oil is the primary source of fat, is associated with a low mortality for cardiovascular disease. Data concerning olive oil consumption and primary end points for cardiovascular disease are scarce. However, a large body of knowledge exists providing evidence of the benefits of olive oil consumption on secondary end points for the disease. Besides the classical benefits on the lipid profile provided by olive oil consumption compared with that of saturated fat, a broad spectrum of benefits on cardiovascular risk factors is now emerging associated with olive oil consumption. We review the state of the art concerning the knowledge of the most important biological and clinical effects related to olive oil and its minor components. The recent advances in human nutrigenomics associated with olive oil consumption will also be assessed. The wide range of benefits associated with olive oil consumption could contribute to explaining the low rate of cardiovascular mortality found in southern European-Mediterranean countries, in comparison with other westernized countries, despite a high prevalence of coronary heart disease risk factors.


Anti-replicative recombinant 5S rRNA molecules can modulate the mtDNA heteroplasmy in a glucose-dependent manner.
Mutations in mitochondrial DNA are an important source of severe and incurable human diseases. The vast majority of these mutations are heteroplasmic, meaning that mutant and wild-type genomes are present simultaneously in the same cell. Only a very high proportion of mutant mitochondrial DNA (heteroplasmy level) leads to pathological consequences. We previously demonstrated that mitochondrial targeting of small RNAs designed to anneal with mutant mtDNA can decrease the heteroplasmy level by specific inhibition of mutant mtDNA replication, thus representing a potential therapy. We have also shown that 5S ribosomal RNA, partially imported into human mitochondria, can be used as a vector to deliver anti-replicative oligoribonucleotides into human mitochondria. So far, the efficiency of cellular expression of recombinant 5S rRNA molecules bearing therapeutic insertions remained very low. In the present study, we designed new versions of anti-replicative recombinant 5S rRNA targeting a large deletion in mitochondrial DNA which causes the KSS syndrome, analyzed their specific annealing to KSS mitochondrial DNA and demonstrated their import into mitochondria of cultured human cells. To obtain an increased level of the recombinant 5S rRNA stable expression, we created transmitochondrial cybrid cell line bearing a site for Flp-recombinase and used this system for the recombinase-mediated integration of genes coding for the anti-replicative recombinant 5S rRNAs into nuclear genome. We demonstrated that stable expression of anti-replicative 5S rRNA versions in human transmitochondrial cybrid cells can induce a shift in heteroplasmy level of KSS mutation in mtDNA. This shift was directly dependent on the level of the recombinant 5S rRNA expression and the sequence of the anti-replicative insertion. Quantification of mtDNA copy number in transfected cells revealed the absence of a non-specific effect on wild type mtDNA replication, indicating that the decreased proportion between mutant and wild type mtDNA molecules is not a consequence of a random repopulation of depleted pool of mtDNA genomes. The heteroplasmy change could be also modulated by cell growth conditions, namely increased by cells culturing in a carbohydrate-free medium, thus forcing them to use oxidative phosphorylation and providing a selective advantage for cells with improved respiration capacities. We discuss the advantages and limitations of this approach and propose further development of the anti-replicative strategy based on the RNA import into human mitochondria.


Platelet accumulation in regions of low blood flow during the postischemic period.
Various studies indicate that after a latent interval, a progressive focal deterioration of microvascular perfusion can develop in zones of acute damage to the central nervous system (CNS). In order to obtain reliable information concerning the possibility of platelet participation in this phenomenon, platelet deposition was investigated by means of 111Indium-labeled platelets, and compared with local cerebral blood flow (CBF) and cortical sensory evoked response (CSER). Studies were performed with a model of focal ischemia in which small volumes of air were injected selectively into one internal carotid artery of dogs anesthetized with alpha chloralose throughout the experiment. The ischemic period was followed by a 10-min, 60-min or 4-hr recovery period. The main result was a prominent and diffuse accumulation of platelets in zones of low CBF in dogs subjected to 4 hr recovery.


Second-harmonic generation in lithium niobate nanowires for local fluorescence excitation.
We study the nonlinear optical properties of lithium niobate (LiNbO(3)) nanowires (NWs) fabricated by a top-down ion beam enhanced etching method. First, we demonstrate generation and propagation of the second-harmonic (SH) light in LiNbO(3) NWs of typical rectangular cross-sections of 400 x 600 nm(2) and length from 10 to 50 μm. Then, we show local fluorescent excitation of 4',6-diamidino-2-phenylindole (DAPI) dye with the propagated SH signal in standard concentrations as for biological applications. By measuring the detected average power of the propagated fundamental harmonic (FH) and the SH signal at the output of the NWs, we directly prove the dominating role of the SH signal over possible two-photon excitation processes with the FH in the DAPI dye. We estimate that 63 ± 6 pW of the propagated SH average power is required for detectable dye excitation. Finally, we model the waveguiding of the SH light to determine the smallest NW cross-section (around 40x60 nm(2)) which is potentially able to excite fluorescence with a FH intensity below the cell damage threshold.


Concurrent evolution of cancer cachexia and heart failure: bilateral effects exist.
Cancer cachexia is defined as a multifactorial syndrome of involuntary weight loss characterized by an ongoing loss of skeletal muscle mass and progressive functional impairment. It is postulated that cardiac dysfunction/atrophy parallels skeletal muscle atrophy in cancer cachexia. Cardiotoxic chemotherapy may additionally result in cardiac dysfunction and heart failure in some cancer patients. Heart failure thus may be a consequence of either ongoing cachexia or chemotherapy-induced cardiotoxicity; at the same time, heart failure can result in cachexia, especially muscle wasting. Therefore, the subsequent heart failure and cardiac cachexia can exacerbate the existing cancer-induced cachexia. We discuss these bilateral effects between cancer cachexia and heart failure in cancer patients. Since cachectic patients are more susceptible to chemotherapy-induced toxicity overall, this may also include increased cardiotoxicity of antineoplastic agents. Patients with cachexia could thus be doubly unfortunate, with cachexia-related cardiac dysfunction/heart failure and increased susceptibility to cardiotoxicity during treatment. Cardiovascular risk factors as well as pre-existing heart failure seem to exacerbate cardiac susceptibility against cachexia and increase the rate of cardiac cachexia. Hence, chemotherapy-induced cardiotoxicity, cardiovascular risk factors, and pre-existing heart failure may accelerate the vicious cycle of cachexia-heart failure. The impact of cancer cachexia on cardiac dysfunction/heart failure in cancer patients has not been thoroughly studied. A combination of serial echocardiography for detection of cachexia-induced cardiac remodeling and computed tomography image analysis for detection of skeletal muscle wasting would appear a practical and non-invasive approach to develop an understanding of cardiac structural/functional alterations that are directly related to cachexia.


Scientific rationale for study design of community-based simplified antibiotic therapy trials in newborns and young infants with clinically diagnosed severe infections or fast breathing in South Asia and sub-Saharan Africa.
Newborns and young infants suffer high rates of infections in South Asia and sub-Saharan Africa. Timely access to appropriate antibiotic therapy is essential for reducing mortality. In an effort to develop community case management guidelines for young infants, 0-59 days old, with clinically diagnosed severe infections, or with fast breathing, 4 trials of simplified antibiotic therapy delivered in primary care clinics (Pakistan, Democratic Republic of Congo, Kenya and Nigeria) or at home (Bangladesh and Nigeria) are being conducted. This article describes the scientific rationale for these trials, which share major elements of trial design. All the trials are in settings of high neonatal mortality, where hospitalization is not feasible or frequently refused. All use procaine penicillin and gentamicin intramuscular injections for 7 days as reference therapy and compare this to various experimental arms utilizing comparatively simpler combination regimens with fewer injections and oral amoxicillin. The results of these trials will inform World Health Organization policy regarding community case management of young infants with clinical severe infections or with fast breathing.


Colorectal cancer screening barriers and facilitators in older persons.
This systematic review identifies factors that are most consistently mentioned as either barriers to or facilitators of colorectal cancer (CRC) screening in older persons. A systematic literature search (1995-2008) was conducted to identify studies that reported barriers to or facilitators of CRC screening uptake, compliance or adherence specifically for older persons (> or = 65 years). Information on study characteristics and barriers and facilitators related to subjects; healthcare providers; policies; and screening tests were then abstracted and analyzed. Eighty-three studies met the eligibility criteria. Low level of education, African American race, Hispanic ethnicity, and female gender were the most frequently reported barriers, whereas being married or living with a partner was the most frequently reported facilitator. The most cited barrier related to healthcare providers was lack of screening recommendation by a physician; having a usual source of care was a commonly reported facilitator. Lack of health insurance, and dual coverage with Medicare and Medicaid were the most frequently reported barriers, whereas Medicare's coverage of screening colonoscopy was consistently reported as a facilitator. Barriers to, and facilitators of, CRC screening among older persons are reported. Particular attention should be paid to modifiable factors that could become the focus of interventions aimed at increasing CRC screening participation in older persons.


A vibrational sum frequency spectroscopy study of the liquid-gas interface of acetic acid-water mixtures: 1. Surface speciation.
Aqueous acetic acid solutions have been studied by vibrational sum frequency spectroscopy (VSFS) in order to acquire molecular information about the liquid-gas interface. The concentration range 0-100% acetic acid has been studied in the CH/OH and the C-O/C=O regions, and in order to clarify peak assignments, experiments with deuterated acetic acid and water have also been performed. Throughout the whole concentration range, the acetic acid is proven to be protonated. It is explicitly shown that the structure of a water surface becomes disrupted even at small additions of acetic acid. Furthermore, the spectral evolution upon increasing the concentration of acetic acid is explained in terms of the different complexes of acetic acid molecules, such as the hydrated monomer, linear dimer, and cyclic dimer. In the C=O region, the hydrated monomer is concluded to give rise to the sum frequency (SF) signal, and in the CH region, the cyclic dimer contributes to the signal as well. The combination of results from the CH/OH and the C-O/C=O regions allows a thorough characterization of the behavior of the acetic acid molecules at the interface to be obtained.


Reconstructing the equilibrium Boltzmann distribution from well-tempered metadynamics.
Metadynamics is a widely used and successful method for reconstructing the free-energy surface of complex systems as a function of a small number of suitably chosen collective variables. This is achieved by biasing the dynamics of the system. The bias acting on the collective variables distorts the probability distribution of the other variables. Here we present a simple reweighting algorithm for recovering the unbiased probability distribution of any variable from a well-tempered metadynamics simulation. We show the efficiency of the reweighting procedure by reconstructing the distribution of the four backbone dihedral angles of alanine dipeptide from two and even one dimensional metadynamics simulation.


Chemokines and TRANCE as genetic adjuvants for a DNA vaccine to rabies virus.
An adaptive immune response is initiated by mature dendritic cells presenting processed antigen to nai;ve T cells. Assuming that the magnitude of the immune response is influenced by the number and type of antigen-presenting dendritic cells and by the duration of antigen presentation, we tested if chemokines that bind to receptors expressed on immature dendritic cells or TRANCE, a survival factor for mature dendritic cells, can serve as adjuvants. None of the immunomodulaters given as genetic adjuvants with a DNA vaccine encoding the full-length rabies virus glycoprotein augmented the transgene product-specific response. However, RANTES, MCP-1, MIP 1-beta, and TRANCE given together with a DNA vaccine expressing a truncated and thus secreted version of the rabies virus glycoprotein enhanced the response suggesting that the tested genetic adjuvants promoted preferentially presentation of reprocessed antigen originating from transduced tissue cells.


The S-cone contribution to luminance depends on the M- and L-cone adaptation levels: silent surrounds?
Under dim background conditions, the S-cones make little or no contribution to luminance (A. Eisner & D. I. MacLeod, 1980; W. Verdon & A. J. Adams, 1987), yet under conditions of intense long-wavelength adaptation, a small but robust contribution to luminance--as defined by heterochromatic flicker photometry (A. Stockman, D. I. MacLeod, & D. D. DePriest, 1987, 1991) or motion (J. Lee & C. F. Stromeyer, 1989)--can be found. Here, by using selective adaptation and/or tritanopic metamers to isolate the S-cone response, we investigate the dependence of the S-cone luminance input on changes in background wavelength and radiance. Interestingly, the S-cone luminance input disappears completely when no adapting background is present, even though the same S-cone stimulus makes a clear contribution to luminance when a background is present. The dependence of the S-cone luminance input on the wavelength and radiance of the adapting background is surprising. We find that the S-cone signal can be measured on fields of 491 nm and longer wavelengths that exceed a criterion background radiance. These criterion radiances roughly follow an L + M spectral sensitivity, which suggests that the S-cone luminance input is silent unless the L- and M-cones are excited above a certain level. We hypothesize that the L + M cone signals produced by the steady adapting backgrounds somehow "gate" the S-cone luminance signals, perhaps by being modulated by them.


Seasonal variations of organic-carbon and nutrient transport through a tropical estuary (Tsengwen) in southwestern Taiwan.
This paper reports the fluvial fluxes and estuarine transport of organic carbon and nutrients from a tropical river (Tsengwen River), southwestern Taiwan. Riverine fluxes of organic carbon and nutrients were highly variable temporally, due primarily to temporal variations in river discharge and suspended load. The sediment yield of the drainage basin during the study period (1995-1996, 616 tonne km(-2) year(-1)) was ca. 15 times lower than that of the long-term (1960-1998) average (9379 tonne km2 year(-1)), resulting mainly from the damming effect and historically low record of river water discharge (5.02 m3 s(-1)) in 1995. The flushing time of river water in the estuary varied from 5 months in the dry season to >4.5 days in the wet season and about 1 day in the flood period. Consequently, distributions of nutrients, dissolved organic carbon (DOC) and particulate organic carbon (POC) were of highly seasonal variability in the estuary. Nutrients and POC behaved nonconservatively but DOC behaved conservatively in the estuary. DOC fluxes were generally greater than POC fluxes with the exception that POC fluxes considerably exceeded DOC fluxes during the flood period. Degradation of DOC and POC within the span of flushing time was insignificant and may contribute little amount of CO2 to the estuary during the wet season and flood period. Net estuarine fluxes of nutrients were determined by riverine fluxes and estuarine removals (or additions) of nutrients. The magnitude of estuarine removal or addition for a nutrient was also seasonally variable, and these processes must be considered for net flux estimates from the river to the sea. As a result, nonconservative fluxes of dissolved inorganic phosphorus (deltaDIP) from the estuary are -0.002, -0.09 and -0.59 mmol m(-2) day(-1), respectively, for dry season, wet season and flood period, indicating internal sinks of DIP during all seasons. Due to high turbidity and short flushing time of estuarine water, deltaDIP in the flood period may be derived largely from geochemical processes rather than biological removal, and this deltaDIP should not be included in an annual estimate of carbon budget. The internal sink of phosphorus corresponds to a net organic carbon production (photosynthesis-respiration, p-r) during dry (0.21 mmol m(-2) day(-1)) and wet (9.5 mmol m(-2) day(-1)) seasons. The magnitude of net production (p-r) is 1.5 mol m(-2) year(-1), indicating that the estuary is autotrophic in 1995. However, there is a net nitrogen loss (nitrogen fixation-denitrification < 0) in 1995, but the magnitude is small (-0.17 mol m(-2) year(-1)).


Experimental Traumatic Brain Injury Induces Chronic Glutamatergic Dysfunction in Amygdala Circuitry Known to Regulate Anxiety-Like Behavior.
Up to 50% of traumatic brain injury (TBI) survivors demonstrate persisting and late-onset anxiety disorders indicative of limbic system dysregulation, yet the pathophysiology underlying the symptoms is unclear. We hypothesize that the development of TBI-induced anxiety-like behavior in an experimental model of TBI is mediated by changes in glutamate neurotransmission within the amygdala. Adult, male Sprague-Dawley rats underwent midline fluid percussion injury or sham surgery. Anxiety-like behavior was assessed at 7 and 28 days post-injury (DPI) followed by assessment of real-time glutamate neurotransmission in the basolateral amygdala (BLA) and central nucleus of the amygdala (CeA) using glutamate-selective microelectrode arrays. The expression of anxiety-like behavior at 28 DPI coincided with decreased evoked glutamate release and slower glutamate clearance in the CeA, not BLA. Numerous factors contribute to the changes in glutamate neurotransmission over time. In two additional animal cohorts, protein levels of glutamatergic transporters (Glt-1 and GLAST) and presynaptic modulators of glutamate release (mGluR2, TrkB, BDNF, and glucocorticoid receptors) were quantified using automated capillary western techniques at 28 DPI. Astrocytosis and microglial activation have been shown to drive maladaptive glutamate signaling and were histologically assessed over 28 DPI. Alterations in glutamate neurotransmission could not be explained by changes in protein levels for glutamate transporters, mGluR2 receptors, astrocytosis, and microglial activation. Presynaptic modulators, BDNF and TrkB, were significantly decreased at 28 DPI in the amygdala. Dysfunction in presynaptic regulation of glutamate neurotransmission may contribute to anxiety-related behavior and serve as a therapeutic target to improve circuit function.


Connectivity of Caribbean coral populations: complementary insights from empirical and modelled gene flow.
Understanding patterns of connectivity among populations of marine organisms is essential for the development of realistic, spatially explicit models of population dynamics. Two approaches, empirical genetic patterns and oceanographic dispersal modelling, have been used to estimate levels of evolutionary connectivity among marine populations but rarely have their potentially complementary insights been combined. Here, a spatially realistic Lagrangian model of larval dispersal and a theoretical genetic model are integrated with the most extensive study of gene flow in a Caribbean marine organism. The 871 genets collected from 26 sites spread over the wider Caribbean subsampled 45.8% of the 1900 potential unique genets in the model. At a coarse scale, significant consensus between modelled estimates of genetic structure and empirical genetic data for populations of the reef-building coral Montastraea annularis is observed. However, modelled and empirical data differ in their estimates of connectivity among northern Mesoamerican reefs indicating that processes other than dispersal may dominate here. Further, the geographic location and porosity of the previously described east-west barrier to gene flow in the Caribbean is refined. A multi-prong approach, integrating genetic data and spatially realistic models of larval dispersal and genetic projection, provides complementary insights into the processes underpinning population connectivity in marine invertebrates on evolutionary timescales.


[Physician's role in health promotion: healthy lifestyle counseling in the clinical encounter].
Health promotion is the foundation to prevent disease-related risk factors. It is a multi-discipLinary activity including several professions. Within this complex, the physician has an important role in prevention and counseling on heaLthy lifestyLe in order to reduce morbidity and mortality. Nevertheless, there are many factors impeding the physician's involvement in health promotion counseling. This review aims to investigate the physician's role in health promotion during the clinical encounter. The authors focus on a healthy lifestyle, especially on diet, smoking cessation and physical activity. The article presents the evidence related to physicians' ability and self efficacy in health promotion, the type of counseling to be provided, time allocated, efficiency of counseling, model employed during the clinical encounter and factors impeding or promoting the counseling. The understanding of attitudes, strength of the evidence available regarding the efficacy of counseling and the factors promoting or impeding physicians in providing health promotion advice will help to remove existing barriers and to develop training programs to encourage physicians to be involved in primary and secondary prevention during the clinicaL encounter.


American College Of Radiology/Society of Breast Imaging curriculum for resident and fellow education in breast imaging.
The ACR and the Society of Breast Imaging have revised the curriculum for resident and fellow education in breast imaging on the basis of substantial changes in breast imaging practice since the initial curriculum was published in 2000. This curriculum provides guidance to academic chairs, residency program directors, and academic section chiefs in assessing and improving their residency and fellowship training programs and indicates to residents and breast imaging fellows the topics they need to learn and the experience they should try to acquire during their training. Radiologists already in practice also may find the curriculum useful in outlining the material they need to know to remain up to date in the practice of breast imaging.


Population attributable risks of patient, child and organizational risk factors for perinatal mortality in hospital births.
The main objective of this study was to estimate the contributing role of maternal, child, and organizational risk factors in perinatal mortality by calculating their population attributable risks (PAR). The primary dataset comprised 1,020,749 singleton hospital births from ≥22 weeks' gestation (The Netherlands Perinatal Registry 2000-2008). PARs for single and grouped risk factors were estimated in four stages: (1) creating a duplicate dataset for each PAR analysis in which risk factors of interest were set to the most favorable value (e.g., all women assigned 'Western' for PAR calculation of ethnicity); (2) in the primary dataset an elaborate multilevel logistic regression model was fitted from which (3) the obtained coefficients were used to predict perinatal mortality in each duplicate dataset; (4) PARs were then estimated as the proportional change of predicted- compared to observed perinatal mortality. Additionally, PARs for grouped risk factors were estimated by using sequential values in two orders: after PAR estimation of grouped maternal risk factors, the resulting PARs for grouped child, and grouped organizational factors were estimated, and vice versa. The combined PAR of maternal, child and organizational factors is 94.4 %, i.e., when all factors are set to the most favorable value perinatal mortality is expected to be reduced with 94.4 %. Depending on the order of analysis, the PAR of maternal risk factors varies from 1.4 to 13.1 %, and for child- and organizational factors 58.7-74.0 and 7.3-34.3 %, respectively. In conclusion, the PAR of maternal-, child- and organizational factors combined is 94.4 %. Optimization of organizational factors may achieve a 34.3 % decrease in perinatal mortality.


Momelotinib versus danazol in symptomatic patients with anaemia and myelofibrosis (MOMENTUM): results from an international, double-blind, randomised, controlled, phase 3 study.
Janus kinase (JAK) inhibitors approved for myelofibrosis provide spleen and symptom improvements but do not meaningfully improve anaemia. Momelotinib, a first-in-class inhibitor of activin A receptor type 1 as well as JAK1 and JAK2, has shown symptom, spleen, and anaemia benefits in myelofibrosis. We aimed to confirm the differentiated clinical benefits of momelotinib versus the active comparator danazol in JAK-inhibitor-exposed, symptomatic patients with anaemia and intermediate-risk or high-risk myelofibrosis. MOMENTUM is an international, double-blind, randomised, controlled, phase 3 study that enrolled patients at 107 sites across 21 countries worldwide. Eligible patients were 18 years or older with a confirmed diagnosis of primary myelofibrosis or post-polycythaemia vera or post-essential thrombocythaemia myelofibrosis. Patients were randomly assigned (2:1) to receive momelotinib (200 mg orally once per day) plus danazol placebo (ie, the momelotinib group) or danazol (300 mg orally twice per day) plus momelotinib placebo (ie, the danazol group), stratified by total symptom score (TSS; <22 vs ≥22), spleen size (<12 cm vs ≥12 cm), red blood cell or whole blood units transfused in the 8 weeks before randomisation (0 units vs 1-4 units vs ≥5 units), and study site. The primary endpoint was the Myelofibrosis Symptom Assessment Form (MFSAF) TSS response rate at week 24 (defined as ≥50% reduction in mean MFSAF TSS over the 28 days immediately before the end of week 24 compared with baseline). MOMENTUM is registered with ClinicalTrials.gov, number NCT04173494, and is active but not recruiting. 195 patients were randomly assigned to either the momelotinib group (130 [67%]) or danazol group (65 [33%]) and received study treatment in the 24-week randomised treatment period between April 24, 2020, and Dec 3, 2021. A significantly greater proportion of patients in the momelotinib group reported a 50% or more reduction in TSS than in the danazol group (32 [25%] of 130 vs six [9%] of 65; proportion difference 16% [95% CI 6-26], p=0·0095). The most frequent grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were haematological abnormalities by laboratory values: anaemia (79 [61%] of 130 vs 49 [75%] of 65) and thrombocytopenia (36 [28%] vs 17 [26%]). The most frequent non-haematological grade 3 or higher treatment-emergent adverse events with momelotinib and danazol were acute kidney injury (four [3%] of 130 vs six [9%] of 65) and pneumonia (three [2%] vs six [9%]). Treatment with momelotinib, compared with danazol, resulted in clinically significant improvements in myelofibrosis-associated symptoms, anaemia measures, and spleen response, with favourable safety. These findings support the future use of momelotinib as an effective treatment in patients with myelofibrosis, especially in those with anaemia. Sierra Oncology.


Association between family history of cancer and mutagen sensitivity in upper aerodigestive tract cancer patients.
This study evaluated the relationship between family history of cancer and bleomycin-induced mutagen sensitivity. The study included 108 patients who registered at The University of Texas M.D. Anderson Cancer Center from June 1987 to June 1991 with histologically confirmed and previously untreated squamous cell carcinoma of the upper aerodigestive tract. All patients underwent the mutagen sensitivity assay and completed a self-administered risk evaluation questionnaire, including a detailed family history. The patients reported having 650 first-degree relatives, including 54 cases with cancers. The patients were classified as mutagen sensitive (> or = 1 chromosome break/cell) or not mutagen sensitive (< or = 0.99 chromosome breaks/cell). Odds ratios (ORs) were calculated to test for significant associations between mutagen sensitivity and family history of cancer. We found a significant OR (OR = 2.63; 95% confidence interval = 1.06-6.53) for patients who were mutagen sensitive and had one first-degree relative affected with cancer. For mutagen-sensitive patients with two or more first-degree relatives affected with cancer, the OR increased to 6.59 (95% confidence interval = 1.69-25.72). Although 88% of the patients were ever smokers, cigarette smoking was not found to be related to mutagen sensitivity. The study findings suggest that patients who have defective DNA repair capability as evidenced by the mutagen sensitivity assay are significantly more likely to report a family history of cancer than patients who are not mutagen sensitive. Further studies are needed to confirm that mutagen-sensitive individuals have inherited an increased risk of cancer.


Identification of two functionally distinct endosomal recycling pathways for dopamine D₂ receptor.
Dopamine D₂ receptor (DRD2) is important for normal function of the brain reward circuit. Lower DRD2 function in the brain increases the risk for substance abuse, obesity, attention deficit/hyperactivity disorder, and depression. Moreover, DRD2 is the target of most antipsychotics currently in use. It is well known that dopamine-induced DRD2 endocytosis is important for its desensitization. However, it remains controversial whether DRD2 is recycled back to the plasma membrane or targeted for degradation following dopamine stimulation. Here, we used total internal reflection fluorescent microscopy (TIRFM) to image DRD2 with a superecliptic pHluorin tagged to its N terminus. With these technical advances, we were able to directly visualize vesicular insertion events of DRD2 in cultured mouse striatal medium spiny neurons. We showed that insertion of DRD2 occurs on neuronal somatic and dendritic surfaces. Lateral diffusion of DRD2 was observed following its insertion. Most importantly, using our new approach, we uncovered two functionally distinct recycling pathways for DRD2: a constitutive recycling pathway and a dopamine activity-dependent recycling pathway. We further demonstrated that Rab4 plays an important role in constitutive DRD2 recycling, while Rab11 is required for dopamine activity-dependent DRD2 recycling. Finally, we demonstrated that the two DRD2 recycling pathways play distinct roles in determining DRD2 function: the Rab4-sensitive constitutive DRD2 recycling pathway determines steady-state surface expression levels of DRD2, whereas the Rab11-sensitive dopamine activity-dependent DRD2 recycling pathway is important for functional resensitization of DRD2. Our findings underscore the significance of endosomal recycling in regulation of DRD2 function.


Genetic medicine and incidental findings: it is more complicated than deciding whether to disclose or not.
The aim of this study was to explore the clinical management of incidental findings. Advances in the speed and sensitivity of genetic technologies have not only improved the diagnostic rate but also result in an increase in unanticipated diagnoses. Recent debate on such "incidental findings" has considered whether or not to actively search for and, then, disclose incidental findings. In our experience, many incidental findings need to be investigated in family members before their clinical significance can be assessed. This adds complexity to the debate about disclosure. Using anonymized clinical examples, we illustrate the downstream implications when a result reveals an incidental abnormality of potential clinical significance that is not related to the reasons for doing the test. Our examples illustrate that the determination of clinical significance may require participation of family members in both testing and surveillance. The need to investigate multiple relatives in order to decide whether or not a finding is clinically significant has implications for consent and disclosure practices. Communication with, and care for, relatives who have no reason to suspect particular diagnoses is a challenge for any health-care service. These costs also need to be taken into account as genetic testing enters mainstream medicine.