Equilibrium binding studies of non-claret disjunctional protein (Ncd) reveal cooperative interactions between the motor domains.
Non-claret disjunctional protein (Ncd) is a minus end-directed microtubule motor required for normal spindle assembly and integrity during Drosophila oogenesis. We have pursued equilibrium binding experiments to examine the affinity of Ncd for microtubules in the presence of the ATP nonhydrolyzable analog 5'-adenylyl-beta, gamma-imidodiphosphate (AMP-PNP), ADP, or ADP + Pi using both dimeric (MC1) and monomeric (MC6) Ncd constructs expressed in Escherichia coli. Both MC1 and MC6 sediment with microtubules in the absence of added nucleotide as well as in the presence of either ADP or AMP-PNP. Yet, in the presence of ADP + Pi, there is a decrease in the affinity of both MC1 and MC6 for microtubules. The data for dimeric MC1 show that release of the dimer to the supernatant is sigmoidal with the apparent Kd(Pi) for the two phosphate sites at 23.3 and 1.9 mM, respectively. The results indicate that binding at the first phosphate site enhances binding at the second site, thus cooperatively stimulating release. Stopped-flow kinetics indicate that MgATP promotes dissociation of the Mt.MC1 complex at 14 s-1, yet AMP-PNP has no effect on the Mt.MC1 complex. These results are consistent with a model for the ATPase cycle in which ATP hydrolysis occurs on the microtubule followed by detachment as the Ncd.ADP.Pi intermediate.


Allyl isothiocyanate is mutagenic in Salmonella typhimurium.
Allyl isothiocyanate, a naturally occurring compound, component of oil of mustard and human food plants such as cabbage, cauliflower and horseradish, has up to now been regarded as nonmutagenic in bacterial mutagenicity testing systems. Recently, however, it was found to cause transitional-cell papillomas in the urinary bladder of male F344 rats. Contrary to earlier reports, in this study allyl isothiocyanate showed clear mutagenicity for Salmonella typhimurium TA100 in the preincubation assay after longer, non-standard preincubation times (greater than 20 min). The mutagenicity is expressed only in the presence of a rat-liver homogenate metabolising system, i.e. it is indirect. However, high concentrations of rat-liver homogenate suppress the mutagenicity of allyl isothiocyanate. SKF525, inhibitor of microsomal oxygenase, reduces the mutagenic potential which on the other hand is increased in the presence of 1,1,1-trichloropropene-2-oxide, inhibitor of epoxide hydrolase. This indicates the occurrence of an epoxide intermediate in allyl isothiocyanate metabolism. Another metabolic pathway, namely hydrolysis to allyl alcohol and oxidation to acrolein, a known mutagen, also seems possible as cyanamide, inhibitor of aldehyde dehydrogenase, can slightly increase the mutagenic potential. The reason(s) for allyl isothiocyanate's requirement for long preincubation times to express mutagenicity still requires elucidation, and the question arises: is allyl isothiocyanate a single, exceptional case or not?


Towards improving dose administration aid supply: a quality improvement intervention aimed at reducing dispensing errors.
There is a risk that medicines can be dispensed into dose administration aids (DAAs), inaccurately or unsuitably. Quality improvement interventions (QIIs) may target this pharmacy medicine supply service and reduce the occurrence of these dispensing errors. In turn, medicine administration can improve in nursing homes (NHs) that use these devices. To develop, introduce and evaluate the potential of a QII to improve DAA medicine supply. Fourteen Victorian community pharmacies and 45 NHs. A QII was developed using findings from three focus groups with 13 participants involved with DAAs at community pharmacies and NHs. The intervention was introduced to community pharmacies and NHs via a pharmacist-facilitated education session; attendees completed an evaluation questionnaire. Potential usefulness and effectiveness of the QII at improving DAA supply and reducing dispensing errors. The QII was titled: 'Be alert and work together for medicine safety, DAA incident awareness toolkit'. Four-hundred and thirty-five questionnaires were returned (85.0 % response rate). Respondents believed the intervention had the potential to improve pharmacy medicine supply or NH medicine administration involving DAAs 'very' (47.3 % of responses) or 'extremely well' (23.4 %). The intervention had the potential to reduce the occurrence of DAA dispensing errors 'very' (49.6 %) or 'extremely well' (20.5 %). A stakeholder informed QII was perceived to have the potential to improve DAA medicine supply from community pharmacies to NHs and reduce the occurrence of dispensing errors found within them. Future quantitative evaluation of the intervention is required.


Syntheses and evaluation of anti-inflammatory, analgesic and ulcerogenic activities of 1,3,4-oxadiazole and 1,2,4-triazolo[3,4-b]-1,3,4-thiadiazole derivatives.
Several 2,5-disubstituted-1,3,4-oxadiazoles (4a-f) and 3,6-disubstituted-1,2,4-triazolo[3,4-b]-1,3,4-thiadiazoles (7a-f) were synthesized and characterized by elemental analyses and spectral data. These compounds were screened for their anti-inflammatory, analgesic, ulcerogenic and lipid peroxidation activities. Compound 7c showed excellent anti-inflammatory and remarkable analgesic activity with reduced ulcerogenic and lipid peroxidation activity when compared with ibuprofen.


Insights into phase transition kinetics from colloid science.
Colloids display intriguing transitions between gas, liquid, solid and liquid crystalline phases. Such phase transitions are ubiquitous in nature and have been studied for decades. However, the predictions of phase diagrams are not always realized; systems often become undercooled, supersaturated, or trapped in gel-like states. In many cases the end products strongly depend on the starting position in the phase diagram and discrepancies between predictions and actual observations are due to the intricacies of the dynamics of phase transitions. Colloid science aims to understand the underlying mechanisms of these transitions. Important advances have been made, for example, with new imaging techniques that allow direct observation of individual colloidal particles undergoing phase transitions, revealing some of the secrets of the complex pathways involved.


The genetics of malignant melanoma: lessons from mouse and man.
Therapeutic resistance and proclivity for metastasis are hallmarks of malignant melanoma. Genetic, epidemiological and genomic investigations are uncovering the spectrum of stereotypical mutations that are associated with melanoma and how these mutations relate to risk factors such as ultraviolet exposure. The ability to validate the pathogenetic relevance of these mutations in the mouse, coupled with advances in rational drug design, has generated optimism for the development of effective prevention programmes, diagnostic measures and targeted therapeutics in the near future.


The effect of cervical preflaring using different rotary nickel-titanium systems on the accuracy of apical file size determination.
An exact determination of the apical root canal diameter is crucial for correct cleaning and shaping of a root canal. The aim of this study was to investigate the discrepancies of the initial apical root canal diameter and the diameter that is measured by the initial apical file (IAF) after cervical flaring using current rotary nickel-titanium systems. Mesiobuccal canals of 40 extracted mandibular molars were randomly assigned to four groups. In the first group, root canals were not flared. Root canals of the other groups were preflared using FlexMaster (VDW, Munich, Germany), ProTaper (Dentsply, Konstanz, Germany), or RaCe (FKG Dentaire, Genf, Switzerland) instruments. The tooth length was determined by inserting an ISO 06 K-file to the apical foramen. The working length (WL) was set 1 mm short of the apical foramen. File sizes were increased after binding sensation was felt at the WL. Transversal sections of the WL regions were examined under stereomicroscope, and the diameter of the root canal and the IAF at WL were assessed. Canals preflared with RaCe instruments had the lowest discrepancy between the apical root canal diameter and the IAF diameter (15.7 ± 9.7 μm) followed by ProTaper (22.2 ± 11.0 μm) and FlexMaster (35.0 ± 17.2 μm). Preflaring of root canals prevents underestimation of the actual apical root canal diameter. The type of instruments used for preflaring show differences on the accuracy of IAF determination. Preflaring with larger tapered instruments leads to a more accurate apical sizing, and this information is crucial concerning the appropriate final diameter for complete apical shaping.


Efficacy of a combined contraceptive regimen consisting of condoms and emergency contraception pills.
To evaluate and compare the effectiveness of the combined regimen (consisting of condoms and emergency contraception pills (ECP)) and using condoms only for the purpose of preventing pregnancy. One-thousand-five-hundred-and-sixty-two (1,562) couples as volunteers enrolled at nine centers in Shanghai. Eight-hundred-and-twelve (812) were randomized to use male condoms and ECP (i.e., Levonorgestrel) as a back-up to condoms (the intervention group) and 750 to use male condoms only(the control group), according to their working unit. Participants were visited at admission and at the end of 1, 3, 6, 9, and 12 months. The cumulative life table rates were calculated for pregnancy and other reasons for discontinuation. The gross cumulative life table rates showed that the cumulative discontinuation rates for all reasons during the year of follow-up in the condoms plus emergency contraception group and the condoms only group were 7.76 ± 0.94 and 6.61 ± 0.91, respectively, per 100 women (χ2 = 0.41, p = 0.5227). The cumulative gross pregnancy rate of the condoms plus emergency contraception group and the condoms only group were 2.17 ± 0.52 and 1.25 ± 0.41, respectively, per 100 women (χ2 = 1.93, p = 0.1645). The Pearl Index in the condoms plus emergency contraception group and the condoms only group were 2.21% and 1.26%, respectively. Male condoms remain a highly effective contraceptive method for a period of one year while consistently and correctly used. In addition, the lowest pregnancy rate followed from perfect use condom.


Sonographic monitoring to guide the performance of postabortal uterine curettage.
This communication describes a technique of sonographically monitored uterine curettage. This method is of particular value in the management of postabortal endomyometritis associated with retained products of conception or in any situation in which anatomic variation (for instance, retroversion) makes curette insertion difficult.


Measuring reward with the conditioned place preference paradigm: a comprehensive review of drug effects, recent progress and new issues.
This review gives an overview of recent findings and developments in research on brain mechanisms of reward and reinforcement from studies using the place preference conditioning paradigm, with emphasis on those studies that have been published within the last decade. Methodological issues of the paradigm (such as design of the conditioning apparatus, biased vs unbiased conditioning, state dependency effects) are discussed. Results from studies using systemic and local (intracranial) drug administration, natural reinforcers, and non-drug treatments and from studies examining the effects of lesions are presented. Papers reporting on conditioned place aversion (CPA) experiments are also included. A special emphasis is put on the issue of tolerance and sensitization to the rewarding properties of drugs. Transmitter systems that have been investigated with respect to their involvement in brain reward mechanisms include dopamine, opioids, acetylcholine, GABA, serotonin, glutamate, substance P, and cholecystokinin, the motivational significance of which has been examined either directly, by using respective agonist or antagonist drugs, or indirectly, by studying the effects of these drugs on the reward induced by other drugs. For a number of these transmitters, detailed studies have been conducted to delineate the receptor subtype(s) responsible for the mediation of the observed drug effects, particularly in the case of dopamine, the opioids, serotonin and glutamate. Brain sites that have been implicated in the mediation of drug-induced place conditioning include the 'traditional' brain reward sites, ventral tegmental area and nucleus accumbens, but the medial prefrontal cortex, ventral pallidum, amygdala and the pedunculopontine tegmental nucleus have also been shown to play important roles in the mediation of place conditioning induced by drugs or natural reinforcers. Thus, although the paradigm has also been criticized because of some inherent methodological problems, it is clear that during the past decade place preference conditioning has become a valuable and firmly established and very widely used tool in behavioural pharmacology and addiction research.


Establishment of a sentinel surveillance network for sexually transmissible infections and blood borne viruses in Aboriginal primary care services across Australia: the ATLAS project.
Sexually transmissible infection (STI) and blood-borne virus (BBV) diagnoses data are a core component of the Australian National Notifiable Diseases Surveillance System (NNDSS). However, the NNDSS data alone is not enough to understand STI and BBV burden among priority population groups, like Aboriginal and Torres Strait Islander people, because it lacks testing, treatment and management data. Here, we describe the processes involved in establishing a STI and BBV sentinel surveillance network representative of Aboriginal Community-Controlled Health Services (ACCHS)-known as the ATLAS network-to augment the NNDSS and to help us understand the burden of disease due to STI and BBV among Aboriginal and Torres Strait Islander peoples. Researchers invited participation from ACCHS in urban, regional and remote areas clustered in five clinical hubs across four Australian jurisdictions. Participation agreements were developed for each clinical hub and individual ACCHS. Deidentified electronic medical record (EMR) data relating to STI and BBV testing, treatment and management are collected passively from each ACCHS via the GRHANITEtm data extraction tool. These data are analysed centrally to inform 12 performance measures which are included in regular surveillance reports generated for each ACCHS and clinical hub. The ATLAS network currently includes 29 ACCHS. Regular reports are provided to ACCHS to assess clinical practice and drive continuous quality improvement initiatives internally. Data is also aggregated at the hub, jurisdictional and national level and will be used to inform clinical guidelines and to guide future research questions. The ATLAS infrastructure can be expanded to include other health services and potentially linked to other data sources using GRHANITE. The ATLAS network is an established national surveillance network specific to Aboriginal and Torres Strait Islander peoples. The data collected through the ATLAS network augments the NNDSS and will contribute to improved STI and BBV clinical care, guidelines and policy program-planning.


Pharmacokinetics of a F(ab')2 scorpion antivenom in healthy human volunteers.
This paper presents the first study of F(ab')2 scorpion antivenom pharmacokinetics in humans. We have studied the pharmacokinetics of an antiscorpion venom preparation (Alacramyn) in eight human healthy volunteers. The fabotherapic was administered as a 47.5 mg i.v. bolus. Blood samples were drawn at 0, 5, 15, 30, 45, 60, 90, 120, 180 and 360 min after antivenom administration. Subsequently, the volunteers made seven visits to the hospital. Four of them at 24 h intervals, one at day 10, and one at day 21. We measured antivenom plasmatic concentrations using a specific high sensitivity ELISA method for F(ab')2. The time course of F(ab')2 in serum of seven subjects was well described by a lineal combination of three exponential components; a four exponential component model was necessary to fit the eighth subject. The most significant antivenom pharmacokinetic parameters determined were: AUC(infinity)=596.9 (369.3, 891.2) mg h l(-1); V(c) = 3.1 (2.3, 4.3)l; V(ss) = 15.4 (12.8, 39.9)l; MRT = 250.0 (218.8, 310.2) h; CL = 96.6 (58.0, 139.2) ml h(-1); t(1/2,tau1) (also called t(1/2,alpha)) = 0.25 (0.13, 0.37) h; t(1/2,tau(z)) (corresponding to the slowest component) = 161.3 (141.0, 212.0) h.


Laboratory evolution of Pyrococcus furiosus alcohol dehydrogenase to improve the production of (2S,5S)-hexanediol at moderate temperatures.
There is considerable interest in the use of enantioselective alcohol dehydrogenases for the production of enantio- and diastereomerically pure diols, which are important building blocks for pharmaceuticals, agrochemicals and fine chemicals. Due to the need for a stable alcohol dehydrogenase with activity at low-temperature process conditions (30 degrees C) for the production of (2S,5S)-hexanediol, we have improved an alcohol dehydrogenase from the hyperthermophilic archaeon Pyrococcus furiosus (AdhA). A stable S-selective alcohol dehydrogenase with increased activity at 30 degrees C on the substrate 2,5-hexanedione was generated by laboratory evolution on the thermostable alcohol dehydrogenase AdhA. One round of error-prone PCR and screening of approximately 1,500 mutants was performed. The maximum specific activity of the best performing mutant with 2,5-hexanedione at 30 degrees C was tenfold higher compared to the activity of the wild-type enzyme. A 3D-model of AdhA revealed that this mutant has one mutation in the well-conserved NADP(H)-binding site (R11L), and a second mutation (A180V) near the catalytic and highly conserved threonine at position 183.


The burden in chronic prurigo: patients with chronic prurigo suffer more than patients with chronic pruritus on non-lesional skin: A comparative, retrospective, explorative statistical analysis of 4,484 patients in a real-world cohort.
Chronic prurigo (CPG) is known as a high burdensome disease characterized by severe pruritus and multiple pruriginous lesions. Interestingly, the disease-specific burden is not well established and there are no data which compare the impact of CPG with chronic pruritus (CP) on non-lesional skin (CP-NL). To address this issue, we analysed datasets from 4484 patients with either CPG or CP-NL. Demographic medical data and additional information collected by validated patient reported outcome tools were analysed. The visual analogue scale and numerical rating scale (NRS) were used for assessing the pruritus intensity, the ItchyQoL for patients' quality of life, the Hospital Anxiety and Depression Scale and the Patient Needs Questionnaire' as a part of Patient Benefit Index for Pruritus for measuring the importance of 27 patient needs in terms of treatment goals. The Neuroderm questionnaire was used to assess the history of pruritus characteristics and the impact on sleep. Patients with CPG suffered longer and with a higher intensity from pruritus [NRS worst the last 24 h, CPG 6.0 (4.0;8.0) vs. CP-NL 3.0 (5.0;7.0), P < 0.001]. In them, pruritus occurred more often and the whole day and night which led to more loss in sleeping hours [CPG 3.0 h (2.0;4.0) vs. CP-NL 2.0 h (1.0;4.0), P < 0.001]. Patients with CPG showed higher scores for depression [HADS-D, CPG 6.0 (3.0;10.0) vs. CP-NL 5.0 (2.0;8.0), P < 0.001], more impaired quality of life [ItchyQol; CPG: 72.6 (61.6;83.6) vs. CP-NL 59.4 (48.4;70.4), P < 0.001] and higher weighted needs in the predefined treatment goals. Not only the presence of severe pruritus and pruriginous lesions but also sleep disorders and other mental symptoms may contribute to a higher burden in patients with CPG when compared with patients with CP-NL.


Age-related reduction in the differential pathways involved in internal and external movement generation.
Age-related differences in regional brain activation during two different movement generation modes were examined. Old and young volunteers were scanned while performing cyclical hand-foot flexion-extension movements in the presence and the absence of augmented visual feedback, referring to external and internal movements generation, respectively. Performing the coordination task under both conditions resulted in the activation of two distinct neural networks in the young adults, i.e., the hMT/V5+, and parietal and premotor cortices were typically involved during the visually guided mode, whereas the supplementary motor area (SMA), cingulate motor area (CMA), frontal operculum (FO) and secondary somatosensory area (S2) were typically involved during internally guided movements. Remarkably, much less differentiation between both feedback dependent networks was observed in the seniors, i.e., they exhibited high activity in the SMA, CMA, FO and S2 during both modes, suggesting that the typical network differentiation was largely diminished. This is hypothesized to reflect a general increase in processing resources within areas contributing to motor control and associated sensory processing, supporting motor performance in the elderly.


Regulation of renal urate excretion: a critical review.
Uric acid metabolism is reviewed as it relates mainly to kidney and electrolyte disorders, with emphasis on the difficulties in understanding urate transport because of its bidirectional transport and the species differences in which animal data may not have relevance to the human condition. A critical review of the effects of pyrazinamide and extracellular volume expansion on urate transport raises questions about the current popular teachings that pyrazinamide exclusively blocks tubule urate secretion and extracellular volume expansion has a major role in controlling urate excretion. There appears to be a renal salt-wasting syndrome with overlapping clinical features that make it indistinguishable from the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), except possibly for extracellular volume depletion. Hypouricemia and the elevation in the fractional excretion of urate (%E/Furate) are extensively reviewed with a proposal to use the persistence of hypouricemia and elevated %E/Furate after the correction of hyponatremia to differentiate these patients from those with SIADH. An algorithm is proposed to differentiate one group from the other. A plasma natriuretic factor has been shown in some with probable renal salt wasting, which includes patients with AIDS, cancer, and pulmonary and intracranial diseases. The natriuretic factor may have etiologic implications and diagnostic and therapeutic applications.


Modified asymmetric T-tube model to infer arterial wave reflection at the aortic root.
A modified version of the T-tube model was constructed to represent the systemic arterial loading system as "seen" by the left ventricle (LV). This model consisted of two uniform tubes connected in parallel. It differs from the original T-tube model in that the transmission paths have no frictional losses and are terminated with complex impedances, rather than simple resistors. To estimate model parameters (load and tube compliances, tube inertances, characteristic impedances, and peripheral resistances) we measured ascending aortic pressure and flow in a group of five open-chest, anesthetized dogs. Parameter estimates were obtained by fitting experimental pressure to the pressure predicted by the model from experimental flow. To check the reliability of the model, an additional experiment was performed where flow in the upper descending thoracic aorta was measured in addition to ascending aorta pressure and flow. The fit between the experiment and model predicted ascending aortic pressure was satisfactory in all six dogs. This pressure was always characterized by the presence of a prominent diastolic oscillation. Our model showed that this oscillation is due to reflections from the lower body, the effective reflection site being most probably located at the level of middle to low abdominal aorta. The effective reflection site located in the upper body is closer to the heart. The related reflected wave affects pressure in late systole.


Combined effects of the vessel type and bottle closure during Chilean Sauvignon Blanc wine storage over its volatile profile.
A Sauvignon Blanc wine was subjected to a maturation period of six months by using four different types of vessels in triplicate: cylindrical stainless steel tanks, oval-shaped polyethylene tanks, cubic-shaped polyethylene tanks, and clay jars. After maturation in the different vessels, wines were bottled using three different closures (natural cork, synthetic cork, and screwcaps). The volatile compound profiles of the wine samples were recorded by SPME-GC-MS throughout vessel maturation as well as after the bottle storage period. In general terms, wines stored in stainless steel tanks showed the highest contents of volatile compounds when compared with the other tested vessels. Moreover, wines from bottles capped with screwcaps showed the highest contents of most of the volatile compounds when compared with the other closures. Moreover, an interaction between the vessel and the closure was observed: when screwcaps were used during bottle aging, the resulting wines were very similar to those matured in stainless steel vessels. These results suggest that the use of screwcaps hides the differences originating from wine composition during maturation in vessels other than stainless steel.


Cytokeratin 14 is expressed in immature cells in rat taste buds.
We analyzed the differentiation of taste bud cells, by precisely describing expression profiles of cytokeratins (CKs) 8 and 14 in relation to those of marker molecules including label of 5-bromo-2'-deoxy uridine (BrdU) injected. In rat circumvallate papillae, cell division was observed at the basal layer of the epithelium expressing CK14 and located outside taste buds. The progenitor cells began to migrate toward the apical surface and maintained CK14 expression at 1 day after BrdU injection (day 1). On the other hand, a minor population of newly divided cells was infrequently incorporated into taste buds and also maintained CK14 expression at day 1. In taste buds, the conversion of CK subtypes occurred from CK14 to cytokeratin 8 (CK8) at day 2-3, showing the differentiation from immature cells expressing CK14 into mature or maturing cells expressing CK8. Functionally matured cells such as taste receptor cells expressing inositol triphospate receptor type 3 (IP(3)R3) never expressed CK14, suggesting that CK14 would be expressed only in immature cells. On the other hand, a small but distinct population of BrdU-positive cells still showed CK14 immunoreactivity in taste buds even at day 12, which might correspond to the cells that remain undifferentiated for a long period within taste buds.


Modeling visual aesthetic perception: bridges between computed texture features and perceived beauty qualities in semantic experiments.
The exploration of the potential relationship between computable low-level texture, such as features extracted from color and texture, and the perceived high-level aesthetic properties, such as warm or cold, soft or hard, has been a hot research topic of neuroaesthetics. First, the selection and clustering of aesthetic antonyms used to represent the aesthetic properties of visual texture are completed through two semantic differential experiments. Subsequently, 151 visual textures are rated according to the selected aesthetic antonyms by participants in a third semantic differential experiment. Third, 106 textural features are extracted using four different image analysis algorithms to describe the low-level characteristics of visual textures. Finally, the construction and evaluation of the visual aesthetic perception model based on multiple linear and nonlinear regression algorithms are discussed. We analyzed the frequency of each aesthetic antonym selected from 20 pairs of semantic antonyms, and the most frequently mentioned 8 pairs of semantic antonyms were selected as the core set for model building. The extracted low-level features are highly correlative. Of the correlation coefficients based on absolute values, 3383 are less than 0.75, accounting for 14.84% of the total. The correlation coefficients were larger than 0.5 accounts for 27.29% of the total. Through neighborhood component analysis, the top 10 low-level features are selected with lower correlation. The gap between low-level calculated features and high-level perceived aesthetic emotions can be bridged by a brain-inspired model of visual aesthetic perception.


Imaging and implications of tumor thrombus in abdominal malignancies: reviewing the basics.
Extension of tumor tissue within a vein is a recognized prognostic factor in abdominal malignancy because of its influence on tumor staging and selection of therapeutic management. With the advent of newer surgical techniques, and variable treatment strategies, imaging plays a crucial role in categorizing patients according to the tumor resectability and vascular reconstruction techniques during surgery. Understanding the clinical impact of tumor thrombus increases the awareness of the radiologist about the key findings in tumor staging and decision-making of surgical approach. Ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) can be used individually and in combination to accurately assess the tumor thrombus. In our pictorial review, we will discuss the imaging findings and clinical consequences of tumor thrombosis in abdominal malignancies, including hepatocellular carcinoma, pancreatic neuroendocrine tumor, renal cancer, and adrenal cortical carcinoma.


The pharmacological management of hypertension in pregnancy.
The management of pregnancy-induced hypertension (PIH) and preeclampsia using antihypertensive drug therapy remains contentious. Conflicts arise due to differences in diagnostic criteria and varying attitudes regarding the value of treating hypertension, which is only one aspect of this systemic disorder. The following review assesses the role of individual agents and their effects upon both maternal and foetal/neonatal wellbeing. Human clinical trials of each of the main antihypertensive drugs used in the management of PIH/preeclampsia are reviewed. The value of randomized, placebo-controlled trials and long-term paediatric follow up is stressed. A number of agents have a favourable benefit-risk profile for use in women with PIH/preeclampsia; these include alpha-methyldopa, beta-blockers, hydralazine, prazosin, calcium channel antagonists and ketanserin. Diazoxide and sodium nitroprusside may also be used for acute severe hypertension. Angiotensin converting enzyme inhibitors are contra-indicated. Low-dose aspirin is presently being investigated in multicentre trials and may play a major role in the prevention of preeclampsia. Decisions regarding the need for antihypertensive treatment during pregnancy and the selection of a specific antihypertensive agent should be based upon an assessment of the relative benefits and risks for the individual patient. In future studies, the effects of antihypertensive agents upon the underlying pathophysiological processes involved in PIH/preeclampsia may guide therapeutic decision making.


[Preliminary study on anti-periodontitis immunization with DNA vaccine].
To observe the protection against periodontal bone loss in the Sprague-Dawley (SD) rats periodontitis model, with the recombined plasmid pcDNA3.1+/kgpcd as DNA gene vaccine. PcDNA3.1+/kgpcd was delivered into rats by submandibular gland-targeted injection. The anti-KGPcd sIgA in saliva was measured by indirect ELISA method. Immunohistochemistry staining was used to assess the protection in the animal model. The level of specific anti-KGPcd sIgA in saliva of the experimental group was significantly higher than that of control group. HE staining showed that immunization with recombined plasmid pcDNA3.1+/kgpcd could protect or minimize tissue destruction caused by subsequent P. gingivalis challenge in the rat model. The results indicate that pcDNA3.1+/kgpcd was a good candidate for anti-periodontitis gene vaccine and could provide protection against Porphyromonas gingivalis-caused periodontitis in rat lesion model.


Separations of flavonoids and alkaloids in medicinal herbs by high-speed counter-current chromatography.
Counter-current chromatography is a new liquid-liquid partition chromatography without using solid support. Recently, the technique has been remarkably improved in both partition efficiency and separation time. In this paper the capability of this high-speed counter-current chromatography was demonstrated on separation of two sets of samples obtained from medicinal herbs: a synthetic mixture of 3'-hydroxygenkwanin, luteolin and apigenin was separated on a two-phase solvent system composed of chloroform-methanol-water (4:3:2, v/v/v) and a crude ethanol extract from Anisodus tangulicus (Maxin) Pasch on chloroform-0.07 M sodium phosphate (pH 6.4) (1:1, v/v). In the light of chromatograms obtained from these samples, advantages of high-speed counter-current chromatography over other chromatographic methods were discussed in terms of partition efficiency, peak resolution, separation time, sample loading capacity, etc.


Antipsychotic polypharmacy: a Japanese survey of prescribers' attitudes and rationales.
While combining antipsychotics is common in schizophrenia treatment, the literature on the reasons for antipsychotic polypharmacy (APP) is limited. We aimed to identify prescriber attitudes and rationales for APP in Japan where high APP utilization is reported. Two-hundred and seventeen psychiatrists participated in the survey, which assessed APP attitudes and behaviors. Prescribing APP to 47.7±24.7% (mean±S.D.) of their patients, psychiatrists reported that they were "moderately" concerned about APP. The most APP-justifiable factors were (1="not at all" to 5="extreme") cross titration (4.50±0.67), randomized controlled evidence (3.67±0.83), and treatment of comorbid conditions (3.31±0.83). Conversely, APP-discouraging factors were chronic side effects (4.14±0.64), difficulty determining cause and effect (4.07±0.74), and acute side effects (3.99±0.81). Comparing high to low APP prescribers (>50% vs. ≤50% of patients), no differences emerged regarding APP justification and concerns. In multivariate analyses, high APP use was associated with practice at a psychiatric hospital (OR: 2.70, 95% CI: 1.29-5.67, p=0.009), concern about potential drug-drug interactions (OR: 1.56, 95% CI: 1.04-2.35, p=0.031), and less reliance on case reports of APP showing efficacy (OR: 0.64, 95% CI: 0.44-0.92, p=0.017) (r(2)=0.111, p=0.001). High and low APP prescribers shared a comparable degree of justifications and concerns. Future research should examine the impact of cultural determinants on APP.


Safety, Tolerability and Pharmacokinetics of Bencycloquidium Bromide, a Novel Inhaled Anticholinergic Bronchodilator, in Healthy Subjects: Results from Phase I Studies.
Bencycloquidium bromide (BCQB) is a novel inhaled anticholinergic bronchodilator with high selectivity for muscarinic M3 receptor. BCQB's potential utility of for therapy in Chronic obstructive pulmonary disease (COPD) has been indicated in pre-clinical studies. To investigate the initial safety, tolerability and pharmacokinetics of BCQB delivered via pressurised Metered Dose Inhaler (pMDI) in healthy subjects. This study consisted of single-ascending-dose (SAD), multiple-ascending-dose (MAD) tolerability study periods, and single- plus multiple-dose pharmacokinetic study periods. Randomized, double-blind, placebo-controlled, dose-escalating tolerability and pharmacokinetic studies were conducted. Seventy-two healthy subjects were assigned 3:1 (BCQB: placebo) to 7 single-dose cohorts (125, 250, 500, 750, 1125, 1500 and 2000 μg) and 2 multiple-dose cohorts (1500 μg/d and 2000 μg/d). In the pharmacokinetic periods, 12 subjects were allocated three-way crossover to receive single dose of 250, 750 or 2000 μg BCQB, respectively. Subsequently, the same 12 subjects received multiple dose of 750 μg/d and 1000 μg/d for 7 days. Pharmacokinetic, safety and tolerability assessments were performed. BCQB administered by inhalation was well tolerated, especially with favorable cardiovascular safety profile. BCQB was rapidly absorbed into plasma after inhalation through pMDI, with peak concentrations achieved within 5 to 10 minutes. Repeated inhalation caused certain degree of accumulation with the accumulation ratio RCmax 2.50, RAUC 3.49 for 3 times-a-day and RCmax 2.23, RAUC 3.44 for 4 times-a-day, respectively. Twice-a-day or even once-a-day dosage could be suggested in phase II study. Sex didn't affect the pharmacokinetics of BCQB and dose adjustments based on sex is not anticipated in clinical use. Approximately 4% of the BCQB dose excreted unchanged in urine and liver metabolism is the main biotransformation route of BCQB in human. The results of our study provided the initial safety, tolerability and pharmacokinetic profiles of BCQB inhalation, and could enable further clinical development in COPD patients.


Substance P levels in various regions of the rat central nervous system after acute and chronic morphine treatment.
Substance P levels were measured in various CNS regions from rats treated acutely and chronically with morphine. There was no observable effect in the group treated with an acute dose of morphine (10 mg/kg) and sacrificed after 2 h. After 35 days chronic treatment with increasing doses of the drug, the rats were divided into three groups and sacrificed 2 h, 24 h and 7 days after the last injection. The substance P level was increased in the corpus striatum 2 h and 24 h and in the medulla oblongata and dorsal part of the spinal cord 2 h after withdrawal. Seven days after the last injection the levels had returned to normal in these areas. No effects were observed in the cerebral cortex, the hypothalamus or the ventral spinal cord at any time of measurement. Earlier studies have demonstrated that morphine inhibits release of substance P. The observed increase in tissue levels after long-term treatment is therefore interpreted as an accumulation of substance P in the neurons.


Play-based procedural preparation and support intervention for cranial radiation.
The primary objective of this study was to examine the relationship between play-based procedural preparation and support intervention and use of sedation in children with central nervous system (CNS) tumors during radiation therapy. The secondary objective was to analyze the cost-effectiveness of the intervention compared to costs associated with daily sedation. A retrospective chart review was conducted, and 116 children aged 5-12 years met criteria for inclusion. Outcome measures included the total number of radiation treatments received, the number of treatments received with and without sedation, and the type and duration of interventions, which consisted of developmentally appropriate play, education, preparation, and distraction provided by a certified child life specialist. The results of univariate analyses showed that age, tumor location, and total number and duration of interventions were significantly associated with sedation use during radiation therapy. Multivariate analyses showed that, after adjustment for age, tumor location, and craniospinal radiation, a significant relationship was found between the total number and duration of the interventions and sedation use. The implementation of a play-based procedural preparation and support intervention provided by a certified child life specialist significantly reduced health-care costs by decreasing the necessity of daily sedation. Support interventions provided by child life specialists significantly decreased both sedation use and the cost associated with daily sedation during cranial radiation therapy in children with CNS tumors. This study supports the value of the child life professional as a play-based developmental specialist and a crucial component of cost-effective healthcare.


Lower breast cancer survival in mothers of children with a malignancy: a national study.
As it is unclear if hereditary factors affect breast cancer survival, this was compared using fertility and cancer registry data, among all women so diagnosed during 1961-1999 in Sweden, having a child with childhood cancer (<or=20 years of age; n=254) and with that of other women (n=74,781). Those having a child with a childhood malignancy had a significantly worse survival than other women, relative risk (RR)=1.25, 95% CI 1.02-1.55, P<0.04, adjusted for age at diagnosis, year of diagnosis, parity and time since last pregnancy. Childhood sarcomas or acute myeloid leukaemia seemed to be most associated with a worse survival in the mother (RR=1.38 and 1.69, respectively). The lower survival of the mother was present for breast cancer diagnosed both before and after 50 years of age. The Li-Fraumeni syndrome and possibly other genetic disorders may lower breast cancer survival.


Induction of autophagy via the PI3K/Akt/mTOR signaling pathway by Pueraria flavonoids improves non-alcoholic fatty liver disease in obese mice.
Non-alcoholic fatty liver disease (NAFLD) is the most common among lipid metabolism disorders. Autophagy plays an important role in lipid metabolism in NAFLD. Pueraria flavonoids, the main active ingredients of Pueraria lobata, exert antioxidant and anti-inflammatory effects. Herein, we report the potential lipid-lowering and anti-inflammatory effects of Pueraria flavonoids on NAFLD induced by a high-fat diet. In vivo and in vitro experiments showed that Pueraria flavonoids reduced intracellular lipid deposition by inhibiting lipid synthesis and the release of pro-inflammatory cytokines. We analyzed the autophagy flux by mRFP-GFP-LC3 plasmid transfection to assess the role of autophagy in intracellular scavenging. After treating mice fed on high fat and HepG2 cells with Pueraria flavonoids, the number of autophagosomes increased significantly, along with the level of autophagy. The autophagy loss after siRNA transfection aggravated lipid deposition and the release of inflammatory cytokines. Mechanistically, Pueraria flavonoids trigger autophagy through PI3K/Akt/mTOR signaling pathway to reduce lipid deposition and inflammation. In summary, our results showed that Pueraria flavonoids stimulated autophagy by inhibiting the PI3K/Akt/mTOR signaling pathway, thereby reducing intracellular lipid accumulation and inflammation levels and alleviating NAFLD.


Isolation of an R- M+ mutant of Yersinia enterocolitica serotype O:8 and its application in construction of rough mutants utilizing mini-Tn5 derivatives and lipopolysaccharide-specific phage.
A generally applicable procedure was used to isolate a spontaneous restriction-deficient mutant of Yersinia enterocolitica serotype O:8. Transposition frequency in the mutant strain 8081-res was approximately 6.7 x 10(-6) per recipient, while it was practically zero in the wild-type strain 8081-c. Mobilization frequency into 8081-res was 10(5) times higher than that into the wild-type strain. The mutant had lost the ability to express the YenI restriction endonuclease activity present in serotype O:8 strains. This allowed the construction of a transposon library in 8081-res. Insertion mutants with transposons in the genes of the rfa region were selected from this library.


Are child eating patterns being transformed globally?
To examine the extent to which child dietary patterns and trends are changing globally. Diets of children 2 to 19 years of age were studied with nationally representative data from Russia and the United States, nationwide data from China, and regional data from metropolitan Cebu, Philippines. Twenty-four-hour dietary recalls were examined at several points in time to examine trends in calories consumed away from home, snacking behavior, and soft drink and modern fast food consumption. Urban-rural trends were compared. U.S. and Cebu youth consume more than one-third of their daily calories and a higher proportion of snack calories from foods prepared away from home. In contrast, away from home food consumption is minimal in Chinese and Russian children. U.S. and Cebu youth consume about one-fifth of their total daily energy from snacks, but snacks provide a much lower proportion of energy in Russia ( approximately 16%) and China (where snacks provide only approximately 1% of energy). Fast food plays a much more dominant role in the American diet ( approximately 20% of energy vs. 2% to 7% in the other countries), but as yet does not contribute substantially to children's diets in the other countries. Urban-rural differences were found to be important, but narrowing over time, for China and Cebu, whereas they are widening for Russia. This research suggests that globalization of the fast food and other modern food sectors is beginning to affect child eating patterns in several countries undergoing nutrition transition. However, the contribution of fast food and soft drinks to the diet of children remains relatively small in China, Russia, and Cebu, Philippines, relative to the United States.


Improved selenium, carnitine and taurine status in an enterally fed population.
Ten adult, male, nonambulant and gastrostomy-fed individuals had received commercially available enteral feedings containing negligible amounts of selenium, carnitine, and taurine for an average of 59 months. Blood levels of these three nutrients were below published normal ranges as were the urinary excretions of carnitine and taurine. After 9 weeks on a product that was fortified with 23 micrograms of selenium, 39 mg of carnitine, and 38 mg of taurine per 8 ounces, blood levels were significantly increased with the levels of selenium and carnitine being normalized.


Involvement of cyclic nucleotides in prejunctional modulation of noradrenaline release in mouse atria.
1 In mouse isolated atria previously incubated with [3H]-noradrenaline, 8-bromo-cyclic AMP (3-270 microM) produced a concentration-dependent increase in the fractional stimulation-induced outflow of radioactivity. 8-Bromo-cyclic GMP induced a lesser increase in the stimulation-induced outflow. 2 The phosphodiesterase inhibitors: M&B 22948 (90 microM); ICI 63197 (30 and 90 microM) and 3-isobutyl-1-methylxanthine (90 microM) increased the fractional stimulation-induced outflow. Together these results indicate that cyclic AMP may have a modulatory effect on noradrenaline release. 3 The inhibition of the stimulation-induced outflow produced by clonidine (0.03 microM) and its facilitation produced by phentolamine (1 microM) were unaltered in the presence of 8-bromo-cyclic AMP (90 microM). However, in the presence of 8-bromo-cyclic AMP (270 microM), the facilitatory effect of phentolamine was enhanced, but the inhibitory effect of clonidine (0.03 microM) was unaltered. In the presence of ICI 63197 (30 microM) the inhibitory effect of clonidine (0.03 microM) was unaltered, but the facilitatory effect of phentolamine (1 microM) was slightly enhanced. 4 Isoprenaline (0.003-0.1 microM) enhanced the fractional stimulation-induced outflow, an effect blocked by propranolol (0.1 microM). In the presence of 8-bromo-cyclic AMP (90 microM), the facilitatory effect of isoprenaline (0.01 microM) was blocked. In the presence of ICI 63197 (30 microM) the facilitatory effect of isoprenaline (0.003 microM) was potentiated. 5 These results suggest that whereas beta-adrenoceptor-mediated enhancement of noradrenaline release is linked to the stimulation of adenylate cyclase and enhanced formation of cyclic AMP, alpha-adrenoceptor-mediated inhibition of noradrenaline release is not linked to inhibition of adenylate cyclase activity.


Gene-trap mutagenesis using Mol/MSM-1 embryonic stem cells from MSM/Ms mice.
The MSM/Ms strain is derived from the Japanese wild mouse Mus musculus molossinus and displays characteristics not observed in common laboratory strains. Functional genomic analyses using genetically engineered MSM/Ms mice will reveal novel phenotypes and gene functions/interactions. We previously reported the establishment of a germline-competent embryonic stem (ES) cell line, Mol/MSM-1, from the MSM/Ms strain. To analyze its usefulness for insertional mutagenesis, we performed gene-trapping using these cells. In the present study, we compared the gene-trap events between Mol/MSM-1 and a conventional ES cell line, KTPU8, derived from the F1 progeny of a C57BL/6 × CBA cross. We introduced a promoter-trap vector carrying the promoterless β-galactosidase/neomycin-resistance fusion gene into Mol/MSM-1 and KTPU8 cells, isolated clones, and identified the trapped genes by rapid amplification of cDNA 5'-ends (5'-RACE), inverse PCR, or plasmid rescue. Unexpectedly, the success rate of 5'-RACE in Mol/MSM trap clones was 47 %, lower than the 87 % observed in KTPU8 clones. Genomic analysis of the 5'-RACE-failed clones revealed that most had trapped ribosomal RNA gene regions. The percentage of ribosomal RNA region trap clones was 41 % in Mol/MSM-1 cells, but less than 10 % in KTPU8 cells. However, within the Mol/MSM-1 5'-RACE-successful clones, the trapping frequency of annotated genes, the chromosomal distribution of vector insertions, the frequency of integration into an intron around the start codon-containing exon, and the functional spectrum of trapped genes were comparable to those in KTPU8 cells. By selecting 5'-RACE-successful clones, it is possible to perform gene-trapping efficiently using Mol/MSM-1 ES cells and promoter-trap vectors.


Spiral coronary angiography using a blood pool agent.
To experimentally investigate the optimum dose of an iron-oxide-based blood pool agent for spiral coronary MR angiography (MRA), and the difference between single and multiple spiral excitations in each cardiac cycle. Images using single and triple spiral excitations in each cardiac cycle were obtained in late diastole of the left main coronary artery in eight pigs following an inversion prepulse. Measurements were obtained before and after injection of increasing doses of an iron oxide blood pool agent (Clariscan) corresponding to concentrations of 0.8, 2.2, and 3.9 mg Fe/kg BW. The signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were measured. For 0.8 mg Fe/kg BW relative to precontrast values, a significant increase was observed for both one (SNR: 2.3, CNR: 3.8) and three (SNR: 1.4, CNR: 2.2) excitations (P < 0.01). When the dose was increased from 0.8 mg Fe/kg BW to 2.2 mg Fe/kg BW, only the SNR (P < 0.01) increased further. Significantly higher CNR (1.6-1.8) and SNR (1.4-1.6) values were seen for one excitation relative to three excitations at all concentrations (P < 0.05). At low concentrations, an iron oxide blood pool agent can increase SNR and CNR significantly with both single excitation and triple excitations using an inversion-prepared spiral acquisition scheme. At higher concentrations, T2* effects reduce image quality.


Echoes of Global Silence: Is there protection and safety for Venezuelan children and adolescents?
As the crisis in Venezuela deepens, an increasing number of children urgently needs shelter, protection, and access to basic services, including food, medicine, clean water, and sanitation. Children and young people in transit are particularly at risk of criminal activity or being separated from their families. The consequences of the humanitarian crisis for children could be devastating for the country's future. The child labor problem was fueled by a mass migration of more than five million Venezuelans that turned many children into livelihoods for their families. The pandemic has aggravated risk factors for child labor. The work ranges from working in dumps to agricultural fields, adding that children in rural areas are more likely to depend on public assistance and are at greater risk of being recruited by gangs. Some Venezuelan women and girls are traveling for hours or days to cross the Colombian border and earn money as sex workers. The complex and multifaceted reality of international migration reveals enormous challenges that directly affect the lives of children and adolescents, especially the most vulnerable, and demand urgent responses from the constituted powers and civil society in the face of countless human rights violations those people experience.


Metabolic energy requirements during teleost melanophore adaptations.
Inhibition of oxidative phosphorylation by 2,4-dinitrophenol or sodium cyanide promotes complete melanosome aggregation in teleost melanophores. This aggregation is not promoted via the alpha-sympathetic receptor sites because it occurs in the presence of tolazoline hydrochloride, an alpha-receptor blocking agent. Interpretation of these results suggests metabolic energy release is required in the centrifugal direction only.


Association of hyperinsulinemia with chlorpropamide toxicity.
Clinical and metabolic features of chlorpropamide toxicity are described in two patients with diabetes mellitus and accidental chlorpropamide overdosage. Elevated serum insulin levels were found during hypoglycemia in both patients. The world's literature was reviewed for other cases of chlorpropamide toxicity in which insulin levels have been measured during hypoglycemia. A consistent feature of chlorpropamide toxicity is hyperinsulinemia. It is concluded that stimulation of the pancreatic beta cells during chlorpropamide toxicity leads to hyperinsulinemia and hypoglycemia.


Quantitative analysis of choroidal vasculature in central serous chorioretinopathy using ultra-widefield swept-source optical coherence tomography angiography.
We aimed to quantitatively compare the choroid blood flow and choroid thickness at the periphery among eyes with central serous chorioretinopathy (CSC), fellow eyes and healthy eyes using ultra-widefield swept-source optical coherence tomography angiography (UWF SS-OCTA). Retrospective analysis of 49 patients with CSC (98 eyes, including unaffected fellow eyes) and 49 age and sex matched controls were included. We obtained 3-dimensional data of vertical 20 mm × horizontal 24 mm × scan depth 6 mm, comprising 9 subfields (superotemporal, upper, superonasal, temporal, central, nasal, inferotemporal, lower, inferonasal regions). CSC eyes presented with greater density of large-vessel choroidal layer in all the 9 subfields compared with controls. Compared with normal eyes, CSC eyes had greater choroidal thickness (superotemporal, upper, superonasal, temporal, central, nasal, inferotemporal, and inferonasal subfields) and choroidal volume (superotemporal, upper, superonasal, temporal, central, and nasal subfields). Compared with control eyes, the choriocapillaris density in the superotemporal, inferotemporal and inferonasal subfields was greater in patients with CSC. Our study may provide further evidence for the congestion of vortex vein in the pathogenesis of CSC. UWF SS-OCTA can be used to evaluate the abnormalities of the choroidal structures even at the periphery in eyes with CSC.


Follicular lymphoma manifests as multiple erosive and proliferative lesions of the oral mucosa: case report and brief literature review.
Erosion is one of the most common and basic lesions of oral mucosal diseases. Long-term refractory oral erosions, induced by autoimmune blistering diseases, infectious diseases, malignant diseases, and some rare conditions, may substantially reduce the quality of life of patients or even constitute a life-threatening condition, resulting in a clinical dilemma regarding the accurate diagnosis and precise management of these diseases. As a special type of malignant lymphoma, most lesions of follicular lymphoma (FL) in the oral mucosa present as masses or swelling of the oral mucosa, while emerging novel presentations lead to intractable diagnoses. Hence, diagnostic algorithms for such diseases are clinically required. CASE PRESENTATION: A 55-year-old female patient presented to the clinic with long-lasting oral mucosal erosions and proliferative lesions. Blood tests, pathological examinations of oral lesions including haematoxylin-eosin (HE) staining, and direct immunofluorescence precluded all of the potential diagnoses described previously. Unexpectedly, positron emission tomography/computed tomography (PET/CT) and abdominal CT of the patient revealed a dense mass in the retroperitoneal area, and the final diagnosis of the retroperitoneal mass was FL. After three courses of chemotherapy conducted by the haematologist, the erosion and proliferative lesions in the patient's oral mucosa had significantly improved. HE and immunohistochemical staining results of intraoral lesions also confirmed it as oral FL. The successful diagnosis of FL in this case is of great clinical significance, as the oral and abdominal FL were treated in a timely manner to avoid unfavourable outcomes. To the best of our knowledge, this is the first case of FL that exhibited widespread erosions interspersed with proliferative lesions. Clinicians should be aware of oral FL or seek systemic factors in the presence of similar refractory oral erosions when treatment is non-responsive and the diagnosis is intractable.


Murine strain differences and the effects of zinc on cadmium concentrations in tissues after acute cadmium exposure.
The role of strain differences in cadmium tissue distribution was studied using sensitive (129/J) and resistant (A/J) mice. These murine strains have previously been shown to differ in their susceptibility to cadmium-induced testicular toxicity. Cadmium concentration was measured in testis, epididymis, seminal vesicle, liver, and kidney at 24 h after cadmium chloride exposure (4, 10, and 20 micromol/kg CdCl2). The 129/J mice exhibited a significant increase in cadmium concentration in testis, epididymis, and seminal vesicle at all cadmium doses used, compared to A/J mice. However, cadmium concentrations in liver and kidney were not different between the strains, at any dose, indicating that cadmium uptake is similar in these organs at 24 h. These murine strains demonstrate similar hepatic and renal cadmium uptake but significantly different cadmium accumulation in the reproductive organs at 24 h. The mechanism of the protective effect of zinc on cadmium toxicity was studied by assessing the impact of zinc acetate (ZnAc) treatment on cadmium concentrations in 129/J mice after 24 h. Zinc pretreatment (250 micromol/kg ZnAc), given 24 h prior to 20 micromol/kg CdCl2 administration, significantly decreased the amount of cadmium in the testis, epididymis, and seminal vesicle of 129/J mice, and significantly increased the cadmium content of the liver after 24 h. Cadmium levels in the kidney were unaffected at this time. Zinc pretreatment also prevented the cadmium-induced decrease in testicular sperm concentration and epididymal sperm motility seen in 129/J mice. These findings suggest that the differences in the two murine strains may be attributed partly to the differential accumulation of cadmium in murine gonads. This may be caused by strain differences in the specificity of cadmium transport mechanisms. The protective role of zinc in cadmium-induced testicular toxicity in the sensitive strain may be due to an interference in the cadmium uptake by susceptible reproductive organs.


Differences of four catechins in cell cycle arrest and induction of apoptosis in LoVo cells.
(-)-Epigallocatechin-3-gallate (EGCG), (-)-epigallocatechin (EGC), (-)-epicatechin-3-gallate (ECG), and (-)-epicatechin (EC) were found to have different cytotoxicities to human colon carcinoma LoVo cells. EGCG and EGC suppressed the growth of LoVo cells in dose-dependent manner; ECG and EC, however, had no obvious effects. At lower concentrations, EC did seem to promote slight proliferation. Similarly, EGCG and EGC, rather than ECG and EC, were found to induce apoptosis in LoVo cells. Moreover, EGCG, EGC, and ECG arrested G(1) phase in the cell cycle progression, whereas EC resulted in S phase arrest. We suggest that there are differences in the cytotoxicities of the four catechins to LoVo cells. They exert the effects by inducing apoptosis and regulating the cell cycle.


Oncostatin M attenuates tumor necrosis factor-α-induced synthesis of macrophage-colony stimulating factor via suppression of Akt in osteoblasts.
Oncostatin M produced by osteal macrophages, a cytokine that belongs to the interleukin-6 family, is implicated in bone fracture healing. Macrophage colony-stimulating factor (M-CSF) secreted from osteoblasts plays an important role in osteoclastogenesis. We have previously reported that tumor necrosis factor-α (TNF-α), a potent bone resorptive agent, stimulates the activation of p44/p42 mitogen-activated protein (MAP) kinase, Akt, and p70 S6 kinase in osteoblast-like MC3T3-E1 cells, and induces the synthesis of M-CSF at least in part via Akt. In the present study, we investigated whether oncostatin M affects the TNF-α-induced M-CSF synthesis in MC3T3-E1 cells and the underlying mechanisms. Clonal osteoblast-like MC3T3-E1 cells were treated with oncostatin M or rapamycin and then stimulated with TNF-α. M-CSF release was assessed by ELISA. M-CSF mRNA expression level was assessed by real-time RT-PCR. Phosphorylation of Akt, p44/p42 MAP kinase, and p70 S6 kinase was detected by Western blot analysis. Oncostatin M dose-dependently reduced the TNF-α-stimulated M-CSF release. The expression of M-CSF mRNA induced by TNF-α was significantly suppressed by oncostatin M. Rapamycin, an inhibitor of mTOR/p70 S6 kinase, had little effect on the M-CSF release by TNF-α. Oncostatin M significantly reduced the TNF-α-induced phosphorylation of Akt and p44/p42 MAP kinase. However, the p70 S6 kinase phosphorylation by TNF-α was not affected by oncostatin M. These results strongly suggest that oncostatin M attenuates TNF-α-stimulated synthesis of M-CSF in osteoblasts, and the inhibitory effect is exerted at a point upstream of Akt and p44/p42 MAP kinase but not p70 S6 kinase.


SIDS is associated with prenatal drug use: a meta-analysis and systematic review of 4 238 685 infants.
To conduct a meta-analysis to determine the association between prenatal drug exposure and risk of sudden infant death syndrome (SIDS). Studies were searched using PubMed, Medline and Embase and restricted to English, with no publication date limit. Selected studies included published cohort, population or case studies comparing the incidence of SIDS among drug-exposed with drug-free controls. This study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses and Meta-Analysis of Observational Studies in Epidemiology guidelines. Data were pooled using a random-effects model to evaluate risk ratios (RR). High-income countries. Children with a history of prenatal drug exposure. None. RR of SIDS between drug-exposed and control infants. Sixteen studies (36 730 infants with any prenatal drug exposure, 21 661 exposed to opioids, 21 571 exposed to cocaine, 5031 exposed to methadone compared with 4 201 955 with no exposure). Any prenatal drug exposure was associated with an increased crude risk of SIDS (RR 7.84, 95% CI 5.21 to 11.81). Prenatal opioid exposure had the highest associative crude risk of SIDS (RR 9.76, 95% CI 5.28 to 18.05), followed by methadone (RR 9.52, 95% CI 4.60 to 19.70) and cocaine (RR 4.40, 95% CI 2.52 to 7.67). Increased crude risk persisted after adjusting for socioeconomic factors (RR 4.24, 95% CI 1.39 to 12.88). The incidence of SIDS for this cohort decreased between 1972 and 2020 but remained significantly higher than controls. Exposure to any drug of dependency during pregnancy is associated with an increased risk of SIDS after controlling for socioeconomic factors. Further study to evaluate mechanisms and contribution of other confounders (eg, smoking) is warranted.


The complete chloroplast genome of Korean bred apple 'Kamhong' (Malus domestica Borkh.).
Apple (Malus domestica (Suckow) Borkh., 1803) is economically important horticultural fruit crop in the world. In this study, the complete chloroplast genome of Korean apple cultivar 'Kamhong' was characterized through the de novo assembly of Illumina sequencing data. The chloroplast genome is a circular molecule of 161,069 bp length with 36.55% GC content and has a total of 112 genes including 78 protein-coding genes, 30 transfer RNA genes, and 4 ribosomal RNA genes. Phylogenetic analysis with protein-coding sequences of chloroplast genome revealed that 'Kamhong' was closely grouped with M. domestica cultivars reported in China. The genomic data generated in this study can extend a molecular basis for phylogenetic relationships of Korean cultivar 'Kamhong' with other M. domestica cultivars bred in other countries.


Effect of exposure to fluoride, nitrogen compounds and SO2 on the numbers of spruce shoot aphids on Norway spruce seedlings.
Development of spruce shoot aphid (Cinara pilicornis Hartig) populations was monitored in natural and artificial infestations of Norway spruce (Picea abies Karst.) seedlings, exposed to air pollutants in an experimental field. The pollutants, applied both singly and in mixtures, were gaseous sulphur dioxide, NaF (30 mg l-1 F) and Ca(NO3)2 or (NH4)2SO4 in aqueous solutions (200 mg l-1 N). Aphid numbers on 10 seedlings in each treatment and two control plots were counted at 2-week intervals. At the beginning of the experiment aphid numbers did not differ between treatments. Aphid populations peaked in late June and early July. All the pollutants and their combinations significantly increased the numbers of aphids per seedling. Four apterous females were transferred to spruce seedlings which were growing in containers in the same plots. After 4-5 weeks aphid numbers were significantly higher in the fluoride treatment and in the combined treatment of fluoride, nitrogen and SO2. The pollution treatments did not have a significant effect on shoot growth. Concentrations of F and S in needles were higher in treatments involving these pollutants. There were no significant differences in the concentrations of free amino acids in shoot stems between control and fluoride treatment. However, the relatively low concentration of arginine in the F treatment at the end of the growing season might indicate disturbances in the nitrogen metabolism of spruce seedlings.


Histological evaluation of Curcuma longa-ghee formulation and hyaluronic acid on gingival healing in dog.
The experimental finding of Asian traditional medicine revealed the pharmacological effect of the local application of ghee which was taken from cow butterfat and the rhizomes of Curcuma longa. These materials significantly improved the healing process of the wound. In addition, ancient physicians of Middle East discovered that the powdered rhizomes of Curcuma longa (common turmeric) also had impressive medicinal qualities. Over the centuries, this spice has been used as a pain relieving, anti-inflammatory agent to relieve pain and inflammation in the skin and muscles. We decided to mix ghee which was taken from sheep butterfat with the powdered rhizomes of Curcuma longa to formulate a novel cost-benefit material and then, evaluate its potential therapeutic effect on acceleration of surgical wound healing; moreover, this present study was performed to compare the effects of Curcuma longa-ghee formulation and hyaluronic acid on gingival wound healing following surgery. Five healthy 3-year-old male beagle dogs were used in this study. They had intact teeth and the clinical and radiographic examination revealed no periodontal disease. Ghee was obtained from the refined sheep butterfat heated to 70 degrees C mixed with the powdered rhizomes of Curcuma longa and was applied with two different ratios including materials A and B. Randomly, these three materials including hyaluronic acid, materials A and B were applied topically in test regions and then covered with periodontal pack. Histological changes were monitored in days 4 and 7 after operation to evaluate the inflammatory and repair stage of healing process. We observed significant difference in the inflammatory and repair parameters of the healing process between cases treated with this new formulation and cases of hyaluronic acid application. The results suggested a positive potential therapeutic effect on surgical wound healing particularly improvement of periodontal treatment consequences after surgery.


Is there a carcinoma in situ of gastric mucosa?
Carcinoma in situ, a precancerous lesion in the strict sense, was first recognized in stratified squamous epithelia. It is characterized by markedly atypical cells replacing the autochthonous epithelial cells without stromal invasion, the basement membrane being well preserved. Notwithstanding gradual transitions between carcinoma in situ on the one hand and dysplasias and invasive cancer on the other hand, its histological separation from the latter is feasible in the uterine portio. Its recognition has decisive therapeutic and prognostic implications, particularly in view of the frequently observed latent period between purely superficial spread and early invasive growth. In contrast difficulties are encountered in applying the concept of Carcinoma in situ to mucosal lesions of the stomach, though an analogous replacement stage has to be postulated, because the gastric and cervical mucous membranes differ fundamentally in their structural characteristics. The epithelial cells of the surface, pits and tubular glands do exhibit progressive atypia during cancerization. However, the single-layered epithelium offers far less distinctive criteria than the stratified squamous epithelium. Newly formed glandular complexes cannot be accepted as evidence for in situ growth. The latent period between purely superficial replacement by atypical cells and invasion appears to be considerably shorter in the stomach than in the portio, probably because the mechanical resistance of the loosely textured gastric lamina propria is small. In addition, stromal invasion may originate from any one epithelial cell in the gastric mucosa, whilst it is just the basal layer from which invasively growing cells may emanate in the uterine portio. The occurrence of dysplasia in the mucosa of the stomach does not justify a gastrectomy, according to our current experience, there being no intervention in gastric surgery equivalent to that of conization.


Discrimination by SZL49 between contractions evoked by noradrenaline in longitudinal and circular muscle of human vas deferens.
The effects of irreversible alpha1-adrenoceptor antagonists, SZL-49 (an alkylating analogue of prazosin), dibenamine and benextramine on contractions to noradrenaline (NA) in longitudinal and circular muscle of human epididymal vas deferens were investigated. Competitive alpha1-adrenoceptor antagonists were also used to further characterize the alpha1-adrenoceptor subtype stimulated by NA in longitudinal and circular muscle. NA evoked concentration-dependent contractions of both muscle types (pD2; 5.4 and 5.2 respectively). The contraction of circular muscle was comparatively more sensitive than that of longitudinal muscle to pretreatment with SZL-49. In contrast, dibenamine or benextramine produced comparable effects in both muscle types. The relationship between receptor occupancy and contraction in either longitudinal or circular muscle was nonlinear, with half-maximal response requiring similar receptor occupancy (longitudinal muscle 14%, circular muscle 16%). Maximal response in both muscle types occurred with little or no receptor reserve (<10%). The competitive alpha1-adrenoceptor antagonists produced dextral shifts of the dose-response curves to NA in longitudinal and circular muscle. The inhibitory potencies, estimated from the apparent pKB values were significantly different in longitudinal and circular muscle respectively for either WB 4101 (pKB, 8.6 and 9.5) or RS-17053 (pKB, 7.1 and 9.0) but not for Rec 15/2739 (pKB, 9.2 and 9.8) or HV 723 (pKB, 8.3 and 8.4). In conclusion, the potency profile of the competitive alpha1-adrenoceptor antagonists and the lack of different receptor reserves for NA in the muscle types suggest that the discriminatory effects of SZL-49 is primarily due to a predominance of the alpha1L-adrenoceptor subtype in longitudinal muscle and alpha1A-subtype in circular muscle.


A phase II randomised controlled trial of adjuvant tumour-infiltrating lymphocytes for pretreatment Epstein-Barr virus DNA-selected high-risk nasopharyngeal carcinoma patients.
The safety and objective clinical responses were observed in the phase I study using adjuvant autologous tumour-infiltrating lymphocytes (TILs) following concurrent chemoradiotherapy (CCRT) in nasopharyngeal carcinoma (NPC) patients. One hundred fifty-six patients with stage III-IVb and pretreatment Epstein-Barr virus DNA levels of ≥4000 copies/ml were randomly assigned to receive CCRT combined with TIL infusion (n = 78) or CCRT alone (n = 78). All patients received CCRT and patients assigned to the TIL group received TIL infusion within 1 week after CCRT. The primary endpoint was investigator-assessed progression-free survival (PFS) at 3 years. After a median follow-up of 62.3 months, no significant difference was observed in the 3-year PFS rate between the CCRT plus TIL infusion group and CCRT alone group (75.6% versus 74.4%, hazard ratios, 1.08; 95% confidence intervals, 0.62-1.89). TIL infusion was safe without grade 3 or 4 adverse events and all the high-grade adverse effects were associated with myelosuppression caused by CCRT. Exploratory analysis showed that a potential survival benefit was observed with TILs in patients with lower levels of circulating CD8+TIM3+ cells, serum IL-8 or PD-L1. The infused TIL products in patients with favourable outcomes were associated with increased transcription of interferon-γ and a series of inflammatory related genes and a lower exhausted score. The primary objective of prolonging PFS with CCRT plus TILs in high-risk NPC patients was not met. These findings may provide evidence for the design of future trials investigating the combination of TILs plus immune checkpoint inhibitors based on CCRT in high-risk NPC patients. NCT02421640.


Boosting photocatalytic degradation of antibiotic wastewater by synergy effect of heterojunction and phosphorus doping.
Phosphorus-doped g-C3N4/ZnIn2S4 (PCN/ZIS) heterojunction photocatalysts were constructed by solvothermal method. The physical and chemical properties were investigated with X-ray diffraction (XRD), transmission electron microscopy (TEM), X-ray photoelectron spectroscopy (XPS), UV-vis diffuse reflectance spectroscopy (DRS), etc. The degradation of antibiotic wastewater was used to investigate the photocatalytic activities of composites under visible-light irradiation. The 10% PCN/ZIS had the best photocatalytic degradation performance for tetracycline with a photodegradation rate of 0.0874 min-1, which is respectively about 2.9 and 52.0 times than that of pure ZIS and PCN. Meanwhile, it was concluded that the holes and ⋅O2- (superoxide radicals) play dominant roles in the photocatalytic reactions through radicals trapping experiments, while ⋅OH (hydroxyl radicals) has a negative effect. In addition, 10%PCN/ZIS, with excellent stability and recyclability, also exhibited high photocatalytic activity for terramycin, chlortetracycline and ofloxacin. Overall, with the enhanced photocatalytic performance, PCN/ZIS could be potentially applied for photocatalytic degradation of antibiotic wastewater.


Anti-MAG IgM antibodies in patients with neuropathy and IgM M proteins: detection by ELISA.
In some patients with plasma cell dyscrasia and neuropathy, there are IgM M proteins that react with the myelin-associated glycoprotein (MAG). We used an enzyme-linked immunosorbent assay (ELISA) system to detect anti-MAG IgM antibodies. Reactivity with human MAG by ELISA correlated with demonstration of anti-MAG IgM antibodies by the "immunoblot" technique. Human MAG was more effective than bovine MAG as antigen, and there was no significant reactivity with mouse MAG. The ELISA system is a simple and convenient method for detecting anti-MAG IgM antibodies.


Poor outcomes in patients with sepsis undergoing emergency laparotomy and laparoscopy are attenuated by faster time to care measures.
Emergency laparotomy and laparoscopy (EmLap) are amongst the commonest surgical procedures, with high prevalence of sepsis and hence poorer outcomes. However, whether time taken to receive care influences outcomes in patients requiring antibiotics for suspected infection remains largely unexplored. The aim of this work was to determine whether (1) time to care contributes to outcome differences between patients with and without suspected infection and (2) its impact on outcomes only amongst those with suspected infection. Clinical information was retrospectively obtained from the 2017-2018 Emergency Laparotomy and Laparoscopic Scottish Audit (ELLSA). Time to care referred to six temporal variables describing radiological investigation, anaesthetic triage and surgical management. Outcome measures [mortality, readmission, hospital death, postoperative destination and length of stay (LoS)] were compared using adjusted and unadjusted regression analyses to determine whether the outcome differences could be explained by faster or slower time to care. Amongst 2243 EmLap patients [median age 65 years (interquartile range 51-75 years), 51.1% female], 892 (39.77%) received antibiotics for suspected infection. Although patients with suspected infection had faster time to care (all p ≤ 0.001) and worse outcomes compared with those who did not, outcome differences were not statistically significant when accounted for time (all p > 0.050). Amongst those who received antibiotics, faster time to care was also associated with decreased risk of postoperative intensive care unit (ICU) stay and shorter LoS (all p < 0.050). Worse outcomes associated with infection in EmLap patients were attenuated by faster time to care, which additionally reduced the LoS and ICU stay risk amongst those with suspected infection.


Embryonal carcinoma cells adhere preferentially to fibronectin and laminin but their endodermal differentiation leads to a reduced adherence to laminin.
F9 and PC13 embryonal carcinoma (EC) cells adhered rapidly to growth substrata coated with fibronectin or laminin. When F9 cells were induced to differentiate into visceral or parietal endoderm-like cells, their ability to adhere to laminin diminished, but their adherence to fibronectin remained unchanged. Correspondingly, permanently differentiated teratocarcinoma-derived endoderm cells (PYS-2 and PSA-5e) adhered markedly less efficiently to laminin than to fibronectin. F9 cells adhered to proteolytic fibronectin fragments containing the cell-binding site but not to fragments containing gelatin- or heparin-binding sites. They also adhered slowly to gelatin, but this adhesion was completely blocked by cycloheximide. The results show that the teratocarcinoma stem cells may have specific mechanisms mediating adhesion to fibronectin and laminin and that endodermal differentiation leads to a reduction in their capacity to adhere to laminin but not to fibronectin.


Isolation and distribution of rabbit keratocyte precursors.
To isolate multipotent precursors from the rabbit corneal stroma and to compare the distribution and proliferative capacity of keratocyte precursors obtained from the central and peripheral regions of the corneal stroma. The rabbit corneal stroma was divided into a peripheral region (6.0-10.0 mm in diameter) and a central region (6.0 mm in diameter). A sphere-forming assay was then performed to isolate precursors from the stroma of each region. To promote differentiation, isolated sphere colonies were plated in wells with a medium containing fetal bovine serum. Expression of various markers by the sphere colonies and their progeny was examined using immunocytochemistry and/or reverse-transcription polymerase chain reaction (RT-PCR). The rate of primary sphere formation by cells from the peripheral stroma (51.4+/-10.1/10,000 cells) was significantly higher than by cells from the central stroma (35.9+/-3.0/10,000 cells; p=0.00021). Secondary sphere formation rate was significantly higher in the peripheral stroma (45.6+/-6.4/10,000 cells) than in the central stroma (33.4+/-2.1/10,000 cells; p=0.00002). Cells from the spheres were positive for CD34 and nestin. Their progeny showed a keratocyte-like spindle shape and expressed vimentin, alpha-smooth muscle actin, and two neural differentiation markers (microtubule-associated protein-2 and neuron-specific enolase). Expression of nestin and vimentin was confirmed by RT-PCR. Our findings demonstrate that both the peripheral and central regions of the corneal stroma contain a significant number of precursors, but the peripheral stroma has more precursors with a stronger proliferative capacity than that of cells from the central stroma.


Lumen Expansion Facilitates Epiblast-Primitive Endoderm Fate Specification during Mouse Blastocyst Formation.
Epithelial tissues typically form lumina. In mammalian blastocysts, in which the first embryonic lumen forms, many studies have investigated how the cell lineages are specified through genetics and signaling, whereas potential roles of the fluid lumen have yet to be investigated. We discover that in mouse pre-implantation embryos at the onset of lumen formation, cytoplasmic vesicles are secreted into intercellular space. The segregation of epiblast and primitive endoderm directly follows lumen coalescence. Notably, pharmacological and biophysical perturbation of lumen expansion impairs the specification and spatial segregation of primitive endoderm cells within the blastocyst. Luminal deposition of FGF4 expedites fate specification and partially rescues the reduced specification in blastocysts with smaller cavities. Combined, our results suggest that blastocyst lumen expansion plays a critical role in guiding cell fate specification and positioning, possibly mediated by luminally deposited FGF4. Lumen expansion may provide a general mechanism for tissue pattern formation.


The epidemiology of haemochromatosis: a population-based study.
The discovery of the HFE genotype has revolutionized the diagnosis of haemochromatosis, changing the associated mortality and morbidity. To investigate the clinical significance of a diagnosis of haemochromatosis. In a cohort study, we identified 501 people with haemochromatosis and 4950 age- and gender-matched controls from the UK General Practice Research Database between 1987 and 2002. The incidence of a diagnosis of haemochromatosis increased approximately 2-fold over the study period and was associated with a 2.2-fold increase in mortality [hazard ratio, 95% confidence interval (95% CI), 1.6-3.0]. There was no increase in extra hepatic malignancy, but an absolute risk excess of liver cancer of 0.89% per year. Diabetes, impotence, osteoarthritis and crystal arthritis were associated with haemochromatosis with odds ratios of 5.4 (95% CI, 4.1-7.0), 2.7(95% CI, 1.8-4.0), 1.9(95% CI, 1.5-2.4) and 2.1(95% CI, 1.4-3.1) respectively. Increasing numbers of people are being diagnosed with haemochromatosis, and the mortality associated with this disease remains high. However, people are living with considerably lower levels of morbidity than previously reported. This encouragingly suggests earlier diagnoses are being made, prior to the development of complications.


How DRACMA changes clinical decision for the individual patient in CMA therapy.
To describe the impact of the diagnosis and rationale for action against cow's milk allergy (DRACMA) guidelines on the decision process in the therapy of cow's milk allergy (CMA). We report here the experience of a 2-year application of DRACMA worldwide. Variations in the socioeconomic profile of CMA sufferers and their context can modify the application of DRACMA recommendations. As an example, we use the country-by-country modifications of the social structure and the modifications of the prices for special formula in Italy. The DRACMA guidelines were issued to inform formula choice for CMA treatment by integrating patients' underlying values, preferences and remarks into grading of recommendations assessment, development and evaluation (GRADE) recommendations, which serve to facilitate their interpretation. This method allows every pediatrician/allergist to follow the changing variables of formulas (cost, palatability, nutritional value) and tailor their prescription for individual patients accordingly. The art of CMA treatment has always relied on physicians' interpretation and the goal of the DRACMA guidelines is to provide a rationale-based and evidence-based indication for choosing an appropriate formula.


In-depth characterization of the salivary adenoid cystic carcinoma transcriptome with emphasis on dominant cell type.
Adenoid cystic carcinoma (ACC), 1 of the most common salivary gland malignancies, arises from the intercalated ducts, which are composed of inner ductal epithelial cells and outer myoepithelial cells. The objective of this study was to determine the genomic subtypes of ACC with emphasis on dominant cell type to identify potential specific biomarkers for each subtype and to improve the understanding of this disease. A whole-genome expression study was performed based on 42 primary salivary ACCs and 5 normal salivary glands. RNA from these specimens was subjected to expression profiling with RNA sequencing, and results were analyzed to identify transcripts in epithelial-dominant ACC (E-ACC), myoepithelial-dominant ACC (M-ACC), and all ACC that were expressed differentially compared with the transcripts in normal salivary tissue. In total, the authors identified 430 differentially expressed transcripts that were unique to E-ACC, 392 that were unique to M-ACC, and 424 that were common to both M-ACC and E-ACC. The sets of E-ACC-specific and M-ACC-specific transcripts were sufficiently large to define and differentiate E-ACC from M-ACC. Ingenuity pathway analysis identified known cancer-related genes for 60% of the E-ACC transcripts, 69% of the M-ACC transcripts, and 68% of the transcripts that were common in both E-ACC and M-ACC. Three sets of highly expressed candidate genes-distal-less homeobox 6 (DLX6) for E-ACC; protein keratin 16 (KRT16), SRY box 11 (SOX11), and v-myb avian myeloblastosis viral oncogene homolog (MYB) for M-ACC; and engrailed 1 (EN1) and statherin (STATH), which are common to both E-ACC and M-ACC)-were further validated at the protein level. The current results enabled the authors to identify novel potential therapeutic targets and biomarkers in E-ACC and M-ACC individually, with the implication that EN1, DLX6, and OTX1 (orthodenticle homeobox 1) are potential drivers of these cancers. Cancer 2016;122:1513-22. © 2016 American Cancer Society.


Basis of narrow-spectrum activity of fidaxomicin on Clostridioides difficile.
Fidaxomicin (Fdx) is widely used to treat Clostridioides difficile (Cdiff) infections, but the molecular basis of its narrow-spectrum activity in the human gut microbiome remains unknown. Cdiff infections are a leading cause of nosocomial deaths1. Fidaxomicin, which inhibits RNA polymerase, targets Cdiff with minimal effects on gut commensals, reducing recurrence of Cdiff infection2,3. Here we present the cryo-electron microscopy structure of Cdiff RNA polymerase in complex with fidaxomicin and identify a crucial fidaxomicin-binding determinant of Cdiff RNA polymerase that is absent in most gut microbiota such as Proteobacteria and Bacteroidetes. By combining structural, biochemical, genetic and bioinformatic analyses, we establish that a single residue in Cdiff RNA polymerase is a sensitizing element for fidaxomicin narrow-spectrum activity. Our results provide a blueprint for targeted drug design against an important human pathogen.


Expression of thurincin H, ChiA74 and Cry proteins at the sporulation phase in Bacillus thuringiensis HD1.
The objective of this study was to produce thurincin H, ChiA74 and Cry proteins together using Bacillus thuringiensis subsp. kurstaki HD1 as a heterologous host. pSTAB-ThurH and pSTAB-ChiA74 constructs were designed to produce thurincin H and chitinase, respectively, at the sporulation phase. They were transformed into Bt HD1 generating the recombinant strains HD1/pSTAB-ThurH and HD1/pSTAB-ThurH/pSTAB-ChiA74. Antimicrobial and chitinolytic activity tests were performed with recombinant strains. Both strains were able to produce thurincin H up to 72 h with antibacterial activity of ~4000 U mg-1 . The HD1/pSTAB-ThurH/pSTAB-ChiA74 strain also showed chitinolytic activity of ~23 mU mg-1 at 72 h. All B. thuringiensis strains exhibited crystal formation at 72, and 96 h. In addition, the application of thurincin H in corn seeds increased the germination percentage and root length by 7% and 10%, respectively. We showed that is possible to produce three proteins of biotechnological interest at the sporulation stage in B. thuringiensis, which two of them (thurincin H, and ChiA74) are naturally expressed in the vegetative stage. These results form the basis for developing of a biocontrol and biostimulator product that can be used as an alternative for chemical application.


Ischemic Stroke and Six Genetic Variants in CRP, EPHX2, FGA, and NOTCH3 Genes: A Meta-Analysis.
Ischemic stroke (IS) is a leading cause of death and disability worldwide. As genetic heritability for IS is estimated at about 35%-40%, the identification of genetic variants associated with IS risk is of great importance. The main objective of this study was to carry out a meta-analysis for polymorphisms in CRP, EPHX2, FGA, and NOTCH3 genes and the risk for IS. Literature search for 6 candidate polymorphisms and IS was conducted using HuGE Navigator, PubMed, and Google Scholar databases. Meta-Analyst program was used to calculate pooled odds ratios (ORs) with a random effects model. Twenty-five published studies for 6 candidate polymorphisms were included: CRP-rs1800947 (5 studies), CRP-rs1205 (3 studies), EPHX2-rs751141 (5 studies), FGA-rs6050 (6 studies), NOTCH3-rs3815188 (3 studies), and NOTCH3-rs1043994 (3 studies), for a total number of 7,825 IS cases and 56,532 control subjects. We did not find significant pooled ORs (P values > .05) for any of the genetic variants evaluated in this work. Our meta-analysis results did not show significant associations between these 6 polymorphisms in 4 candidate genes and IS, despite the functional role of some of these single nucleotide polymorphisms (e.g., rs6050 in FGA gene). Future studies are needed to identify additional main genetic risk factors for IS in different populations.


The regulation of PTEN: Novel insights into functions as cancer biomarkers and therapeutic targets.
This review summarizes the implications of the primary tumor suppressor protein phosphatase and tensin homolog (PTEN) in aggressive cancer development. PTEN interacts with other cellular proteins or factors suggesting the existence of an intricate molecular network that regulates their oncogenic function. Accumulating evidence has shown that PTEN exists and plays a role in the cytoplasmic organelles and in the nucleus. PTEN blocks phosphoinositide 3-kinases (PI3K)-protein kinase B-mammalian target of rapamycin signaling pathway by dephosphorylating phosphatidylinositol (PI)-3,4,5-triphosphate to PI-4,5-bisphosphate thus counteracting PI3K function. Studies have shown that PTEN expression is tightly regulated at transcriptional, posttranscriptional, and posttranslational levels (including protein-protein interactions and posttranslational modifications). Despite recent advances in PTEN research, the regulation and function of the PTEN gene remain largely unknown. How mutation or loss of specific exons in the PTEN gene occurs and involves in cancer development is not clear. This review illustrates the regulatory mechanisms of PTEN expression and discusses how PTEN participates in tumor development and/or suppression. Future prospects for the clinical applications are also highlighted.


The impact of a community mental health initiative on outcomes for offenders with a serious mental disorder.
The Community Mental Health Initiative (CMHI) is mandated to assist offenders with serious mental disorders in their transition from institutions to the community, but this incorporates different styles of service. An important unanswered question is whether these are equivalent. Our aim was to compare outcomes for different intervention styles within the CMHI, a programme for serious offenders in prison who also have at least one major mental disorder. Our specific research questions were as follows: do outcomes differ according to whether offenders with mental health difficulties receive (1) clinical discharge planning only; (2) community mental health services only; (3) the combined services or (4) none, although meeting criteria for any CMHI service? Survival analyses, controlling for variables with a significant effect on recidivism or return to prison, were used to test for differences in recidivism or return to prison rates between the intervention and no-intervention groups during a fixed follow-up period. Men receiving only community mental health services had a significantly lower risk of returning to custody and of recidivism than men receiving discharge planning alone or no community mental health service at all, even after controlling for potential confounders including age, number of previous imprisonments and number of previous community failures. The advantages were apparent within 3-6 months and sustained for up to 4 years. Provision of specialised community mental health services for higher-risk male offenders with a mental disorder may reduce recidivism in the short and longer term - within 3 months and up to 4 years respectively. Statistical modelling also pointed to the need to include treatment for substance abuse and assistance in identifying stable accommodation and brokerage of community services among the interventions and services. Copyright © 2016 John Wiley & Sons, Ltd.


Imaging of posterior chamber phakic intraocular lens by optical coherence tomography.
We demonstrate the applicability of optical coherence tomography to visualize the distance between the intraocular lens (IOL) and the lens capsule (lens vault) after implantation of the Staar Collamer posterior phakic IOL, also known as the implantable contact lens (ICL). Maintaining a substantial lens vault may be important to avoid cataract formation, but the lens vault was found to change over time; changes in accommodation and pupil size have also been noted. Optical coherence tomography allows precise assessment of the anatomic relationship between the ICL and the crystalline lens in a noncontact, noninvasive manner, permitting dynamic monitoring of changes in accommodation and pupil size.


EUS-guided FNA combined with flow cytometry in the diagnoses of suspected or recurrent intrathoracic or retroperitoneal lymphoma.
Limited data exist on the combined use of EUS-guided FNA (EUS-FNA) and flow cytometry (FC) in the diagnosis of lymphoma. The aim of this study was to evaluate the accuracy of EUS-FNA combined with FC in the diagnosis of primary or recurrent lymphoma. This study was a retrospective analysis of a prospective collection of data over a 3-year period. Over 3 years, 29 patients with lesions (n=31) suspicious for lymphoma underwent EUS-FNA and FC. Of the 29 patients, 10 patients had lymphoma and 17 patients had nonlymphoma lesions; for two patients, final diagnosis was indeterminate because of insufficient material for FC. The lymphoma cases included non-Hodgkin's lymphoma (n=6, including 3 recurrences), mucosa-associated lymphoid tissue (MALT) lymphoma (n=2), a non-GI lymphoma with mediastinal lymphadenopathy (n=1), and an uncharacterized lymphoma (n=1). Of the 31 lesions, 8 were true positive, 18 were true negative, and 3 were false negative; for two lesions, we could not determine the final diagnosis. No false-positive results were encountered. The sensitivity, the specificity, and the accuracy of EUS-FNA combined with FC for diagnosing lymphoma were 72.7%: 95% CI [43.3%, 90.3%], 100%: 95% CI [82.4%, 100.0%], and 89.7%: 95% CI [73.6%, 96.4%], respectively. Limitations to this study include a short duration of follow-up and a lack of a surgical criterion standard. EUS-FNA in combination with FC allows the diagnosis of primary suspected or recurrent lymphoma. It also is an adjunct in staging MALT lymphoma and could direct clinicians toward further investigative procedures.


Blood pressure and metabolic effects of 18-oxo-cortisol in sheep.
18-Oxo-cortisol (18-oxo-F) has been isolated from the urine of subjects with primary aldosteronism. This study examines the pressor, mineralocorticoid and glucocorticoid effects of 18-oxo-F in conscious sheep--a well studied species for the assessment of the pressor effect of steroid hormones. 18-oxo-F (24 mg/day i.v. for 5 days, n = 3) increased mean arterial pressure MAP (64 +/- 2 mmHg control and 75 +/- 6 mmHg on day 5 P less than 0.001). There was no change in heart rate. Plasma [K+] decreased from a control of 4.3 +/- 0.1 mmol/l control to 2.9 +/- 0.3 mmol/l on day 5 (P less than 0.001). Urinary Na+ excretion decreased on the first infusion day (233 +/- 18 mmol/day control and 124 +/- 20 mmol/day on infusion day 1 P less than 0.001). Urinary K+ excretion was reduced on days 1, 4 and 5 of the infusion. Thus in sheep, 18-oxo-F increased blood pressure associated with in vivo evidence of mineralocorticoid activity.


Correction: Development and validation of a novel risk score for the detection of insignificant prostate cancer in unscreened patient cohorts.
Since the publication of this paper, the authors noticed that Amar Ahmad was not credited as contributing equally to the paper. He should be considered as a joint first author with Lorenzo Dutto. In addition, the author Ashwin Sridhar was incorrectly listed as Ashwin Shridhar, and the author Gregory L. Shaw was incorrectly listed as Gregory Shaw. The correct names are listed above.