Correlation of urinary furan with plasma gamma-glutamyltranspeptidase levels in healthy men and women.
Furan is a colorless, volatile compound that is found in heat-treated foods, such as canned and jarred foods, at levels up to 100 ppb. When animals ingest high doses, furan metabolites, such as cis-2-butene-1,4-dial, cause severe hepatotoxicity and carcinogenicity. However, the levels and effects of furan on humans are not known. Therefore, we measured urinary furan in 100 healthy individuals consumed normal diet (49 men, 51 women) using solid phase micro-extraction-gas chromatography-mass spectrometry (SPME-GCMS). Urinary furan was detected in 56 subjects (31 males, 25 females) and ranged up to 3.14 ppb. In individuals with detectable urinary furan, the level of gamma-glutamyltranspeptidase (gamma-GT), a marker for liver damage, was strongly correlated with the urinary furan concentration (r=0.56, p<0.0001). Linear regression analysis indicated that the urinary furan level was significantly associated with gamma-GT in both univariate (p<0.0001) and multiple (p=0.0001) models including age, sex, body weight, and blood pressure as covariates. To our knowledge, this is the first study to measure detectable levels of furan in human urine. These levels of urinary furan, which may be dietary origin, could be hepatotoxic in humans; therefore; the metabolic fates and potential toxicity of dietary furan in humans should be investigated further.


Recurrent locus-specific mutation resulting from a cryptic ectopic insertion in Neurospora.
New mutations are found among approximately 20% of progeny when one or both parents carry eas allele UCLA191 (eas(UCLA), easily wettable, hydrophobin-deficient, linkage group II). The mutations inactivate the wild-type allele of cya-8 (cytochrome aa3 deficient, linkage group VII), resulting in thin, "transparent" mycelial growth. Other eas alleles fail to produce cya-8 mutant progeny. The recurrent cya-8 mutations are attributed to repeat-induced point mutation (RIP) resulting from a duplicated copy of cya-8+ that was inserted ectopically at eas when the UCLA191 mutation occurred. As expected for RIP, eas(UCLA)-induced cya-8 mutations occur during nuclear proliferation prior to karyogamy. When only one parent is eas(UCLA), the new mutations arise exclusively in eas(UCLA) nuclei. Mutation of cya-8 is suppressed when a long unlinked duplication is present. Stable cya-8 mutations are effectively eliminated in crosses homozygous for rid, a recessive suppressor of RIP. The eas(UCLA) allele is associated with a long paracentric inversion. A discontinuity is present in eas(UCLA) DNA. The eas promoter is methylated in cya-8 progeny of eas(UCLA), presumably by the spreading of methylation beyond the adjoining RIP-inactivated duplication. These findings support a model in which an ectopic insertion that created a mutation at the target site acts as a locus-specific mutator via RIP.


Mechanism and specificity of a symmetrical benzimidazolephenylcarboxamide helicase inhibitor.
This study examines the effects of 1-N,4-N-bis[4-(1H-benzimidazol-2-yl)phenyl]benzene-1,4-dicarboxamide ((BIP)(2)B) on the NS3 helicase encoded by the hepatitis C virus (HCV). Molecular beacon-based helicase assays were used to show that (BIP)(2)B inhibits the ability of HCV helicase to separate a variety of RNA and DNA duplexes with half-maximal inhibitory concentrations ranging from 0.7 to 5 microM, depending on the nature of the substrate. In single turnover assays, (BIP)(2)B only inhibited unwinding reactions when it was preincubated with the helicase-nucleic acid complex. (BIP)(2)B quenched NS3 intrinsic protein fluorescence with an apparent dissociation constant of 5 microM, and in the presence of (BIP)(2)B, HCV helicase did not appear to interact with a fluorescent DNA oligonucleotide. In assays monitoring HCV helicase-catalyzed ATP hydrolysis, (BIP)(2)B only inhibited helicase-catalyzed ATP hydrolysis in the presence of intermediate concentrations of RNA, suggesting RNA and (BIP)(2)B compete for the same binding site. HCV helicases isolated from various HCV genotypes were similarly sensitive to (BIP)(2)B, with half-maximal inhibitory concentrations ranging from 0.7 to 2.4 microM. (BIP)(2)B also inhibited ATP hydrolysis catalyzed by related helicases from Dengue virus, Japanese encephalitis virus, and humans. (BIP)(2)B appeared to bind the HCV and human proteins with similar affinity (K(i) = 7 and 8 microM, respectively), but it bound the flavivirus proteins up to 270 times more tightly. Results are discussed in light of a molecular model of a (BIP)(2)B-HCV helicase complex, which is unable to bind nucleic acid, thus preventing the enzyme from separating double-stranded nucleic acid.


A global-scale expert assessment of drivers and risks associated with pollinator decline.
Pollinator decline has attracted global attention and substantial efforts are underway to respond through national pollinator strategies and action plans. These policy responses require clarity on what is driving pollinator decline and what risks it generates for society in different parts of the world. Using a formal expert elicitation process, we evaluated the relative regional and global importance of eight drivers of pollinator decline and ten consequent risks to human well-being. Our results indicate that global policy responses should focus on reducing pressure from changes in land cover and configuration, land management and pesticides, as these were considered very important drivers in most regions. We quantify how the importance of drivers and risks from pollinator decline, differ among regions. For example, losing access to managed pollinators was considered a serious risk only for people in North America, whereas yield instability in pollinator-dependent crops was classed as a serious or high risk in four regions but only a moderate risk in Europe and North America. Overall, perceived risks were substantially higher in the Global South. Despite extensive research on pollinator decline, our analysis reveals considerable scientific uncertainty about what this means for human society.


US graduate medical education, 1996-1997.
Workforce planners continue to be concerned that unlimited growth in graduate medical education (GME)-principally fueled by unrestrained federal support-will lead to a physician surplus. Because of this concern, in 1996 six major professional organizations called for a reduction in Medicare support of GME to bring residency training programs into more rational alignment with population needs. As of July 1, 1997, no final action had been taken by Congress to limit GME funding, although extensive discussions are under way. Even without governmental restrictions, the American Medical Association's annual survey of GME programs showed a reduction in the numbers of first-year residents in most major specialties and subspecialties. Minor reductions were initially noticed last year; now, the decreases are significant. Nearly all the specialties that had difficulty placing their graduates for 2 consecutive years also reported at least 10% fewer first-year residents than in 1994. More importantly, disciplines without employment difficulties also reported downsizing. The overall effect of these first-year reductions is easily masked by the addition of programs in new disciplines and some residents staying in the GME system longer. Entry-level reductions appear to be broader and more extensive than can be explained by market forces alone.


Ancylomarina longa sp. nov., isolated from southern Okinawa Trough sediment and emended description of the family Marinifilaceae.
A Gram-stain-negative, obligately anaerobic, non-motile, non-spore-forming, long-rod-shaped and non-flagellated bacterial strain, designated T3-2 S1-CT, was isolated from a sediment sample collected at the Okinawa Trough. Phylogenetic analyses of 16S rRNA gene sequences and the whole genome revealed that strain T3-2 S1-CT was a member of the family Marinifilaceae and exhibited less than 95.1 % sequence similarities to the closely related type strains of the family Marinifilaceae. Optimal growth occurred at pH 7.0, 28 °C and in the presence of 3 % (w/v) NaCl. The isoprenoid quinone of strain T3-2 S1-CT was identified as menaquinone-7 (MK-7) and the predominant fatty acids (>10 %) were iso-C15 : 0 (38.9 %) and anteiso-C15 : 0 (11.6 %). The major polar lipids were one phosphatidylethanolamine, one phosphatidylmonomethylethanolamine, one aminolipids, two unidentified lipids and two unidentified phospholipids. The DNA G+C content of strain T3-2 S1-CT was 35.7 mol%. On the basis of the results of polyphasic analyses, strain T3-2 S1-CT is considered to represent a novel species of the genus Ancylomarina, for which the name Ancylomarina longa sp. nov. is proposed. The type strain is T3-2 S1-CT (=KCTC 15505T=MCCC 1K01617T).


Cytochrome P450 and ischemic heart disease: current concepts and future directions.
The P450 enzymes (P450s) mediate the biotransformation of several drugs, steroid hormones, eicosanoids, cholesterol, vitamins, fatty acids and bile acids, many of which affect cardiovascular homeostasis. Experimental studies have demonstrated that several P450s modulate important steps in the pathogenesis of ischemic heart disease (IHD). This article discusses the current knowledge on i) the expression of P450s in cardiovascular and renal tissues; ii) the role of P450s in the pathophysiology of IHD, in particular the modulation of blood pressure and cardiac hypertrophy, coronary arterial tone, ischemia-reperfusion injury and the metabolism of cardiovascular drugs; iii) the available evidence from observational studies on the association between P450 gene polymorphisms and risk of myocardial infarction (MI); and iv) suggestions for further research in this area. P450s exert important modulatory effects in experimental models of IHD and MI. However, observational studies have provided conflicting results on the association between P450 genetic polymorphisms and MI. Further, adequately powered studies are required to ascertain the biological and clinical impact of P450s on clinical IHD end-points, that is, fatal and nonfatal MI, revascularization and long-term outcomes post MI. Pharmacogenetic substudies of recently completed cardiovascular clinical trials might represent an alternative strategy in this context.


A scoping review examining the availability of dialogue-based resources to support healthcare providers engagement with vaccine hesitant individuals.
There is growing attention around the need to improve the confidence and skills of healthcare providers to assist them in completing the complex task of communicating to vaccine hesitant parents and other individuals. While interventions have been developed and evaluated in a research setting, there is uncertainty regarding the public availability. This study aimed to examine the current landscape regarding the availability of online dialogue- based interventions which aim to support vaccination conversations. A scoping review was undertaken to identify and appraise the availability and accessibility of dialogue-based interventions. A dialogue-based intervention was defined as a strategy aiming to improve an individual's confidence and communication skills to engage with and respond to vaccine hesitant individuals. Two approaches were utilised to identify relevant interventions and resources. Firstly, the European Centre for Disease Prevention and Control Catalogue of Interventions was assessed to identify interventions that met the definition. Secondarily, a Google search (in English only) was conducted using key words, that reflected the strategy that healthcare providers may use to identify resources. We identified a total of 31 dialogue-based interventions, of which 29 were reviewed. The interventions were all text based and instructional in nature. Twenty-two were suitable for healthcare providers, as well as non-clinical immunisation spokespersons to use. Of issue, was that in many instances it was common to find the resource located on the fifth to tenth page of search entries, and usually disguised under seemingly non-descript and nonspecific titles. Lastly, not all resources were available for free and not all could be accessed directly from the site. Findings suggest that while there have been numerous interventions developed to support healthcare providers to communicate with vaccine hesitant parents/individuals, there are fundamental issues with accessing the materials in a timely and convenient way. Having a central repository or website (which links to the interventions) would not only assistant healthcare providers to have an improved comprehension of the different interventions available but also would theoretically increase the utilisation by providers.


Implementing Optimal Care Pathways for Aboriginal and Torres Strait Islander People With Cancer: A Survey of Rural Health Professionals' Self-Rated Learning Needs.
In 2018, the Optimal Care Pathway (OCP) for Aboriginal and Torres Strait Islander people with cancer was developed in Australia to improve the cancer care experiences and outcomes of Aboriginal and Torres Strait Islander people. Our study examined health professionals' learning needs to meet the clinical practice requirements of the new OCP. An electronic questionnaire was distributed to 120 health professionals providing oncology care in two rural areas in Victoria, Australia. Questions included demographics, practice, cancer OCPs and implementation recommendations. Descriptive, chi-square and thematic analyses were undertaken. Fifty-two health professionals from medicine (21%), nursing (37%) and allied health (37%) responded. All OCP sub-categories were selected, with a mean of 23 sub-categories identified as areas requiring additional learning. Aboriginal and Torres Strait Islander Perspectives, Treatment, and End of Life were the categories of higher interest. Care After Initial Treatment and Recovery was the category of lower interest. For respondents without cultural training, sub-categories involving practical tasks were of significant interest. Cultural education, connecting with Aboriginal and Torres Strait Islander services, putting learning into practice and respect emerged as themes. Strategies to address gaps included cultural safety training, person and family centred practice, and partnerships and connections with Aboriginal and Torres Strait Islander people and organisations across primary and tertiary sectors.


Presence of integrated DNA sequences of adeno-associated virus type 2 in four cell lines of human embryonic origin.
The human helper virus-dependent parvovirus adeno-associated virus (AAV) has been found in human female genital tissues including material from first trimester miscarriage. In the latter case, AAV type 2 (AAV-2) DNA and viral proteins were detected mainly in the trophoblast cell layer of placenta. In this report, we present evidence that AAV DNA is also present in established human trophoblast cell lines (JEG-3, JAr, BeWo) and in the human amnion cell line FL. In cells of these lines, AAV-2 DNA could be detected both by PCR and Southern blot analysis. Restriction enzyme analysis indicated that AAV DNA was integrated into the host cell genome. Although the cell lines supported AAV replication when infected with AAV-2 and adenovirus type 2 (Ad2) as a helper virus, superinfection with Ad2 alone did not induce replication of AAV DNA, i.e. it failed to rescue AAV from its integrated state. This is probably due to rearrangements within the integrated AAV genome. The presence of AAV DNA in cells derived from human embryonic tissue corroborates the suggestion that human embryonic tissue may be one of the targets of AAV infection.


High-pressure refolding of human vascular endothelial growth factor (VEGF) recombinantly expressed in bacterial inclusion bodies: refolding optimization, and feasibility assessment.
High-pressure has been established as an effective technique for refolding proteins at high concentrations. In this study, high hydrostatic pressure (1-3 kbar) was utilized to refold a homodimeric protein from inclusion bodies and the process was evaluated for large-scale manufacturing feasibility. This research focused on increasing protein concentration while maximizing yield and product quality. Refolding yields of 29-42% were achieved in the absence of urea at 2 kbar and at a protein concentration of 6 g/L. Optimization of the refolding buffer composition via multivariate design of experiments and other process parameters such as refolding pressure, gas sparging, and time under pressure are discussed. Although high-pressure refolding can be considered a viable technology for manufacturing if the gains are clearly identified, in this particular case, the benefits that the high-pressure technology offers do not compensate for the drawbacks of implementing new equipment in an existing facility, and unknown impact of scale-up for this molecule.


Rediscovery and New Morphological Data on Two Hassalstrongylus (Nematoda: Heligmonellidae) Coparasitic in the Marsh Rat Holochilus chacarius (Rodentia: Cricetidae) from Argentina.
Two species of Hassalstrongylus Durette-Desset, 1971, coparasitic in Holochilus chacarius Thomas (Rodentia, Cricetidae) and not recorded since their original description in 1937, were newly found in their type host and locality. Hassalstrongylus mazzai (Freitas, Lent and Almeida, 1937) and Hassalstrongylus argentinus (Freitas, Lent and Almeida, 1937) were obtained from Ho. chacarius from 2 different populations: one from Salta Province (northwest Argentina) and another from Chaco Province (northeast Argentina). The species described as Heligmonoides mazzai Freitas, Lent and Almeida, 1937 had been transferred to Hassalstrongylus even though its synlophe had never been studied. We provide the first descriptions and illustrations of the synlophe of males and females of Hassalstrongylus mazzai and the female of H. argentinus and account for morphological and metrical variability. We confirm, through the study of the synlophe, the placement of Hassalstrongylus mazzai in the genus Hassalstrongylus and designate neotypes for the species because the type material deposited by the authors could not be found. Females of both species were morphologically very similar, and a principal components analysis (PCA) performed on some morphometrical characters showed that the body length, uterus length, and an unexpected character as the number of eggs were useful characters in the discrimination of both species.


Advantages of real time three-dimensional echocardiography in the assessment of right ventricular volumes and function in patients with pulmonary hypertension compared with conventional two-dimensional echocardiography.
In recent years, right ventricular (RV) function has acquired greater relevance as a clinical and prognostic marker in many physiopathological conditions. The study aims to point out the value of real time three-dimensional echocardiography (RT3DE) and tissue Doppler imaging (TDI) in the evaluation of patients affected by pulmonary hypertension (PH), compared with conventional two-dimensional (2D) echocardiography. We enrolled 44 subjects affected by PH who underwent 2D and Doppler echocardiography, RT 3D Echocardiography and TDI evaluation of the RV, and a healthy control group. PH itself can induce severe functional and structural abnormalities of the RV, such as RV hypertrophy, RV dilation, and RV systolic and diastolic dysfunction. In this study, RV FAC, and TAPSE showed marked alterations in patients with PH compared to the control group (C): (RVFAC: [PH] 0.29 ± 0.07 vs. [C] 0.49 ± 0.05%, P < 0.0001; TAPSE: [PH] 15.3 ± 3.2 vs. [C] 21.1 ± 2.6 mm, P > 0.0001). The 3D RV end-diastolic volume was significantly higher in PH than in C (PH) (138.7 ± 25.3 vs. [C] 82.8 ± 12.5 mL, P < 0.0001] as well as 3D RV end-systolic volume (PH) (97.6 ± 21.5 vs. [C] 39.3 ± 9.5 mL, P < 0.0001). The 3D RV ejection fraction (EF) was significantly lower in the pulmonary hypertension group than in healthy subjects (31.8 ± 6.8 vs. [C] 52.5 ± 4.7%, P < 0.0001). In patients with PH, evaluation of the RV diastolic and systolic volume and EF by RT3DE has shown a higher discriminating power in comparison, respectively, with 2DRV diastolic area and the relative fractional area changes.


Mechanisms of mediator release from neutrophils.
The encounter of neutrophils with immune complexes and complement components - in the bulk phase or on a surface - leads to their secretion of lysosomal hydrolases, especially neutral proteases, which provoke tissue injury. Secretion of lysosomal enzymes and generation of reactive oxygen species (e.g., O2-. generation are stimulus-specific and can be dissected to establish cause and effect relationships by means of: a) kinetic analysis, b) variations in the stimulus, and c) use of impermeant reagents to block discrete responses. Neutrophils also generate products of 11-cyclooxygenase (e.g., PGE2, TxA2) and of the 5- and 15-lipoxygenases (mono-, di-, and tri-HETEs, LTB4, and their isomers). But the cyclooxygenase products (save TxA2) are not phlogistic by themselves: they inhibit the functions of neutrophils, platelets, macrophages, and mast cells. The most potent pro-inflammatory agent yet identified as a product of arachidonate is LTB4. LTB4 is a potent Ca ionophore, constricts airways, is a potent chemoattractant, and induces local inflammation.


Densely Connected U-Net with Criss-Cross Attention for Automatic Liver Tumor Segmentation in CT Images.
Automatic liver tumor segmentation plays a key role in radiation therapy of hepatocellular carcinoma. In this paper, we propose a novel densely connected U-Net model with criss-cross attention (CC-DenseUNet) to segment liver tumors in computed tomography (CT) images. The dense interconnections in CC-DenseUNet ensure the maximum information flow between encoder layers when extracting intra-slice features of liver tumors. Moreover, the criss-cross attention is used in CC-DenseUNet to efficiently capture only the necessary and meaningful non-local contextual information of CT images containing liver tumors. We evaluated the proposed CC-DenseUNet on the LiTS dataset and the 3DIRCADb dataset. Experimental results show that the proposed method reaches the state-of-the-art performance for liver tumor segmentation. We further experimentally demonstrate the robustness of the proposed method on a clinical dataset comprising 20 CT volumes.


[Deformability and aggregability of erythrocytes: significance in clinical biology].
In order to understand blood circulation, knowledge of the rheological properties of blood is required. However the characteristic parameters which must be considered differ according to the circulatory region investigated. A distinction must therefore be made between macrorheological parameters (viscosity, viscoelasticity) and the microrheological parameters (red blood cell deformability and aggregability). In this paper the main determinants of R.B.C. deformability and aggregability are discussed as well as the applications in clinical biology.


Human papillomavirus type 16 E6-induced degradation of E6TP1 correlates with its ability to immortalize human mammary epithelial cells.
Recent analyses have identified a number of binding partners for E6, including E6AP, ERC55, paxillin, hDlg, p300, interferon regulatory factor 3, hMCM7, Bak, and E6TP1. Notably, association with E6 targets p53, E6TP1, myc, hMCM7, and Bak for degradation. However, the relative importance of the various E6 targets in cellular transformation remains unclear. E6 alone can dominantly immortalize normal human mammary epithelial cells (MECs), permitting an assessment of the importance of various E6 targets in cellular transformation. Studies in this system indicate that E6-induced degradation of p53 and E6 binding to ERC55 or hDlg do not correlate with efficient immortalization. Here, we have examined the role of E6TP1, a Rap GTPase-activating protein, in E6-induced immortalization of MECs. We tested a large set of human papillomavirus type 16 E6 mutants for their ability to bind and target E6TP1 for degradation in vitro and in vivo. We observed a strict correlation between the ability of E6 protein to target E6TP1 for degradation and its ability to immortalize MECs. Recent studies have identified telomerase as a target of E6 protein. Previous analyses of E6 mutants have revealed this trait to closely correlate with MEC immortalization. We examined our entire panel of E6 mutants for rapid induction of telomerase activity and found in general a strong correlation with immortalizing ability. The tight correlation between E6TP1 degradation and MEC immortalization strongly supports a critical role of functional inactivation of E6TP1 in E6-induced cellular immortalization.


Protective effects of natsumikan (Citrus natsudaidai) extract on acetaminophen-induced lethal hepatotoxicity in mice.
Like other citrus fruits, natsumikan (Citrus natsudaidai) contains several antioxidative nutrients which occur in higher concentrations in the peel than in the pulp. A high dose of acetaminophen (APAP) generates highly reactive intermediates and causes fatal liver injury. In this study, we examined whether an extract from immature natsumikan peel prevents lethal hepatotoxicity induced by a lethal dose of APAP in mice. Male ICR mice were treated orally with natsumikan extract (300 and 1,000 mg/kg) 2, 26, and 50 h before single oral APAP (300 mg/kg) administration. Mice were fasted for 18 h before APAP treatment, but given tap water ad libitum. Survival was assessed for 24 h after APAP treatment. Following administration of 300 mg/kg APAP, all mice died within 6 h. However, pretreatment with natsumikan extract (300 and 1,000 mg/kg) or silymarin (300 and 1,000 mg/kg) increased the survival rate to 16.7%, 33.3%, 16.7%, and 50%, respectively, at 24 h. The results suggest that natsumikan has a protective effect on APAP-induced lethal hepatotoxicity.


Nonenhancing motor eloquent gliomas: navigated transcranial magnetic stimulation oncobiological signature.
Preoperative grading of nonenhancing motor eloquent gliomas is hampered by a lack of specific imaging surrogates. Tumor grading is crucial for the informed consent discussion before tumor resection. In this paper, the authors hypothesized that navigated transcranial magnetic stimulation (nTMS)-derived metrics could provide significant information to distinguish between high- and low-grade motor eloquent gliomas that present as nonenhancing tumors and therefore contribute to improving patient counseling, timing of treatment, preoperative planning, and intraoperative strategies. The authors conducted a retrospective single-center cohort study of patients admitted for tumor surgery between January 2018 and April 2022 with a nonenhancing motor eloquent glioma and preoperative bilateral nTMS mapping. nTMS data including resting motor threshold (RMT), interhemispheric RMT ratio (iRMTr), Cortical Excitability Score (CES), area and volume of cortical activation, and motor evoked potential (MEP) characteristics were obtained and integrated with demographic and clinical data. Thirty patients met the inclusion criteria, and 10 healthy participants were recruited for comparison. Seizures were the most common presenting symptom (25 patients) and WHO grade 3 the most common tumor grade (21 patients). The area and volume of functional cortical activation of both the abductor pollicis brevis and first dorsal interosseous muscles were decreased in healthy participants compared with patients with WHO grade 3 glioma (p < 0.05). An abnormal iRMTr for the lower limbs (16.7% [1/6] WHO grade 2, 76.2% [16/21] WHO grade 3, 100% [3/3] WHO grade 4; p = 0.015) and a higher CES (maximal abnormal CES: 0% [0/6] WHO grade 2, 38% [8/21] WHO grade 3, 66.7% [2/3] WHO grade 4; p = 0.010) were associated with the prediction of high-grade lesions. A total of 7280 MEPs were analyzed. A significant increase in the amplitude and a significant decrease in latency in the MEPs for the first dorsal interosseous and abductor digiti minimi muscles (p < 0.0001) were identified in healthy participants compared with WHO grade 3 glioma patients. Nonenhancing motor eloquent gliomas have a different impact on both anatomical and functional reorganization of motor areas according to their WHO grading.


Efficient method for site-specific 18F-labeling of biomolecules using the rapid condensation reaction between 2-cyanobenzothiazole and cysteine.
An efficient method based on a rapid condensation reaction between 2-cyanobenzothiazole (CBT) and cysteine has been developed for (18)F-labeling of N-terminal cysteine-bearing peptides and proteins. An (18)F-labeled dimeric cRGD ([(18)F]CBTRGD(2)) has been synthesized with an excellent radiochemical yield (92% based on radio-HPLC conversion, 80% decay-corrected, and isolated yield) and radiochemical purity (>99%) under mild conditions using (18)F-CBT, and shown good in vivo tumor targeting efficiency for PET imaging. The labeling strategy was also applied to the site-specific (18)F-labeling of a protein, Renilla lucifierase (RLuc8) with a cysteine residue at its N-terminus. The protein labeling was achieved with 12% of decay-corrected radiochemical yield and more than 99% radiochemical purity. This strategy should provide a general approach for efficient and site-specific (18)F-labeling of various peptides and proteins for in vivo molecular imaging applications.


[Nutritional importance of selenium].
Selenium is an important trace element that was considered toxic for humans and animals for a long time. The best known biochemical role of selenium is, as a selenocysteine residue, to be a part of the active site of the enzyme glutathione peroxidase (GSH-Px). The highest values of selenium have been found in protein foods (meat and fish); although selenium from vegetables sources are more available than from the other foods. Nowadays are not known exactly the recommended dietary allowances for humans, mainly for children. The selenium intake in Spain is 221 micrograms/person/day and the plasmatic values of Spanish people (87 +/- 14 micrograms/L) are within the European average (85 micrograms/L).


Coming to grips with reality: Real grasps, but not pantomimed grasps, resist a simultaneous tilt illusion.
Investigations of grasping real, 3D objects subjected to illusory effects from a pictorial background often choose in-flight grasp aperture as the primary variable to test the hypothesis that the visuomotor system resists the illusion. Here we test an equally important feature of grasps that has received less attention: in-flight grasp orientation. The current study tested a variant of the simultaneous tilt illusion using a mirror-apparatus to manipulate the availability of haptic feedback. Participants performed grasps with haptic feedback (real grasps) and without it (pantomime grasps), reaching for the reflection of a real, 3D bar atop a background grating that induced a 1.1° bias in the perceived orientation of the bar in a separate sample of participants. Analysis of the hand's in-flight grasp orientation at early, late, and end stages of the reach showed that at no point were the real grasps biased by the illusion. In contrast, pantomimed grasps were affected by the illusion at the late and end stages of the reach. At each stage, the effect on the real grasps was significantly weaker than the effect of the illusion as measured by the mean point of subjective equality (PSE) in a two-alternative forced-choice task. In contrast, the effect on the pantomime grasps was statistically indistinguishable from the mean PSE at all three stages of the reach. These findings reinforce the idea that in-flight grasp orientation, like grasp aperture to pictorial illusions of target size, is refractory to pictorial backgrounds that bias perceived orientation.


Gender and deprivation and rates of referral and thereby admission to a national neurorehabilitation service.
To investigate the association between gender and deprivation and rates of admission to a national neurorehabilitation facility following subarachnoid haemorrhage or traumatic brain injury. Retrospective analysis of hospital activity data. Lothian Health Board hospital activity; national neurorehabilitation centre. Patients with subarachnoid haemorrhage or traumatic brain injury. We obtained data for hospital discharge for subarachnoid haemorrhage and traumatic brain injury for patients living in the Lothian Health Board area for the five years 1995 to 1999 by age (15 and over), sex and deprivation category of home residence from nationally held data sets. Similar data were extracted for discharges from the national neurorehabilitation unit. Rates of neurorehabilitation admission per 1000 hospital admissions. Chi-squared testing was used to assess statistical significance. Data for 13338 hospital admissions and 329 neurorehabilitation admissions were available. We observed higher than expected rates of rehabilitation admission for men with subarachnoid haemorrhage and for patients from more affluent postcode sectors with traumatic brain injury. Higher rehabilitation rates are seen among men following subarachnoid haemorrhage and may indicate a focus on return-to-work in the referral or assessment of those suitable for or requiring neurorehabilitation. Higher rehabilitation rates in head injury in those from Carstairs Deprivation Category (DepCat) 2 postcode sectors may represent a bias favouring those from affluent areas in the interaction between the individual and the health service in this group.


Validation of the German revised Addenbrooke's cognitive examination for detecting mild cognitive impairment, mild dementia in alzheimer's disease and frontotemporal lobar degeneration.
The diagnostic accuracy of the German version of the revised Addenbrooke's Cognitive Examination (ACE-R) in identifying mild cognitive impairment (MCI), mild dementia in Alzheimer's disease (AD) and mild dementia in frontotemporal lobar degeneration (FTLD) in comparison with the conventional Mini Mental State Examination (MMSE) was assessed. The study encompasses 76 cognitively healthy elderly individuals, 75 patients with MCI, 56 with AD and 22 with FTLD. ACE-R and MMSE were validated against an expert diagnosis based on a comprehensive diagnostic procedure. Statistical analysis was performed using the receiver operating characteristic method and regression analyses. The optimal cut-off score for the ACE-R for detecting MCI, AD, and FTLD was 86/87, 82/83 and 83/84, respectively. ACE-R was superior to MMSE only in the detection of patients with FTLD [area under the curve (AUC): 0.97 vs. 0.92], whilst the accuracy of the two instruments did not differ in identifying MCI and AD. The ratio of the scores of the memory ACE-R subtest to verbal fluency subtest contributed significantly to the discrimination between AD and FTLD (optimal cut-off score: 2.30/2.31, AUC: 0.77), whereas the MMSE and ACE-R total scores did not. The German ACE-R is superior to the most commonly employed MMSE in detecting mild dementia in FTLD and in the differential diagnosis between AD and FTLD. Thus it might serve as a valuable instrument as part of a comprehensive diagnostic workup in specialist centres/clinics contributing to the diagnosis and differential diagnosis of the cause of dementia.


Radiographic abnormalities and exposure to asbestos-contaminated vermiculite in the community of Libby, Montana, USA.
Mining, handling, processing, and personal or commercial use of asbestos-contaminated vermiculite have led to widespread contamination of the Libby, Montana, area. We initiated a medical testing program in response to reports of respiratory illness in the community. The purpose of this analysis was to identify and quantify asbestos-related radiographic abnormalities among persons exposed to vermiculite in Libby and to examine associations between these outcomes and participants' self-reported exposures. A cross-sectional interview and medical testing were conducted in Libby from July through November 2000 and from July through September 2001. A total of 7,307 persons who had lived, worked, or played in Libby for at least 6 months before 31 December 1990 completed the interview. Of those, 6,668 participants > or = 18 years of age received chest radiographs to assess the prevalence of pleural and interstitial abnormalities. We observed pleural abnormalities in 17.8% of participants and interstitial abnormalities in < 1% of participants undergoing chest radiography. We examined 29 occupational, recreational, household, and other exposure pathways in the analysis. The prevalence of pleural abnormalities increased with increasing number of exposure pathways, ranging from 6.7% for those who reported no apparent exposures to 34.6% for those who reported > or = 12 pathways. The factors most strongly associated with pleural abnormalities were being a former W.R. Grace worker, being older, having been a household contact of a W.R. Grace worker, and being a male. In addition to being a former W.R. Grace worker, environmental exposures and other nonoccupational risk factors were also important predictors of asbestos-related radiographic abnormalities.


[Sanitary costs of osteoarthritis]
Muscoloskeletal disorders are the first cause of disability and the second cause of permanent disablement in Italy. Osteoarthritis is the most frequent rheumatic disease and affects about 4 million Italians. In spite of that, data concerning social costs are lacking. On account of this lack we measured sanitary costs of 314 patients suffering from osteoarthritis. A retrospective, prevalence-based multicentric study was performed using a bottom-up approach. The study period was 12 months and referred to 1999. Eight percent of patients didn't take any drug for the treatment of osteoarthritis; NSAIDs were prescribed to 86.9% of patients, analgesics to 29.9%, chondroprotective drugs to 7.6%, and gastroprotective drugs to 36.9%. Total sanitary costs came to 455 euro / patient / year: 122 euro were spent on diagnostics, 293 euro on therapy and 40 euro on management of drug-related gastropathy. Since the costs of anti-inflammatory drugs came to 30 euro we calculated iatrogenic cost factor of 2.3. Moreover, the study supplied interesting informations about prescriptive habits, which differ in Italy from international guidelines for the medical treatment of OA, about patient management, because of hospitalization, which by itself absorbs 1/3 of resources, and about physiotherapy, which costs twice as much as pharmacological therapy. At last, data analysis gave the cue for suggestions on changing patients' management.


Clinical utility of traditional and new tests in the diagnosis of biceps tendon injuries and superior labrum anterior and posterior lesions in the shoulder.
Clinical tests are a key element in diagnosing shoulder lesions. This study examined the clinical utility of traditional and new examination tests, the upper cut for biceps injuries, and the modified dynamic labral shear for superior glenoid labral lesions. Cohort study (Diagnosis); Level of evidence, 2. A total of 325 consecutive patients who were seen for shoulder pain underwent a standardized clinical testing battery. Six clinical tests that have been previously reported in the literature (Yergason's, Speed's, bear hug, belly press, O'Brien's, and anterior slide) and 2 new examination tests (upper cut and modified dynamic labral shear) were performed. Clinical examination findings were correlated with findings in those who came to surgery (101 patients). Sensitivity, specificity, accuracy, positive/negative predictive value, and positive/negative likelihood ratio were calculated for each test. A binary logistic regression analysis was used to determine which tests produced the most significant findings. For biceps disease, the bear hug and upper cut were most sensitive (0.79 and 0.73, respectively), whereas the belly press and Speed's test were most specific (0.85 and 0.81, respectively). The upper cut was most accurate (0.77) and produced the highest positive likelihood ratio (3.38). For labral injury, the modified dynamic labral shear demonstrated sensitivity of 0.72, specificity of 0.98, accuracy of 0.84, and a positive likelihood ratio of 31.57. A binary logistic regression analysis revealed that the combination of the upper cut and Speed's tests were significantly better at detecting biceps lesions (P = .021, R(2) = .400) than other tests, whereas labral lesions were best identified by combination of the modified dynamic labral shear and O'Brien's maneuvers (P = .045, R(2) = .641). The new tests are helpful additions to the clinical examination for shoulder injury. The modified dynamic labral shear test demonstrates high scores for clinical utility and exhibits a high likelihood ratio, indicating a significant probability of affecting the clinical decision, which should moderately or significantly improve the diagnostic conclusion and allow the clinician to be more efficient in making an accurate diagnosis.


Pediatric traumatic brain injury is inconsistently regionalized in the United States.
Traumatic brain injury is a leading cause of death in children. On the basis of evidence of better outcomes, the American College of Surgery Committee on Trauma recommends that children with severe traumatic brain injury receive care at high-level trauma centers. We assessed rates of adherence to these recommendations and factors associated with adherence. We studied population and hospital discharge data from 2001 from all of the health care referral regions (n = 68) in 6 US states (Florida, Massachusetts, New Jersey, New York, Texas, and Virginia). We identified children with severe traumatic brain injury by using International Classification of Diseases, Ninth Revision, Clinical Modification, codes and American College of Surgery Committee on Trauma criteria. We defined "high-level centers" as either level I or pediatric trauma centers. We considered an area to be well regionalized if >or=90% of severe traumatic brain injury hospitalizations were in high-level centers. We also explored how use of level II trauma centers affected rates of care at high-level centers. Of 2117 admissions for severe pediatric traumatic brain injury, 67.3% were in high-level centers, and 87.3% were in either high-level or level II centers. Among states, 56.4% to 93.6% of severe traumatic brain injury admissions were in high-level centers. Only 2 states, Massachusetts and Virginia, were well regionalized. Across health care referral regions, 0% to 100% of severe traumatic brain injury admissions were in high-level centers, and only 19.1% of health care referral regions were well regionalized. Only a weak relationship existed between the distance to the nearest high-level center and regionalization. The age of statewide trauma systems had no relationship to the extent of regionalization. Despite evidence for improved outcomes of severely injured children admitted to high-level trauma centers, we found that almost one third of the children with severe traumatic brain injury failed to receive care in such centers. Only 2 of 6 states and less than one fifth of 68 health care referral regions were well regionalized. This study highlights problems with current pediatric trauma care that can serve as a basis for additional research and health care policy.


Markers of sexually transmitted diseases in seminal fluid of male clients of female sex workers.
To screen for certain STD markers in a group of male clients of female sex workers. Condoms with seminal fluid were collected at 10 "massage parlours" in Copenhagen. The seminal fluid samples were examined for HIV antibodies, markers of hepatitis B virus (HBV), Chlamydia trachomatis, and Mycoplasma genitalium. All samples (n = 332) were negative for HIV antibodies. Out of 327 samples examined for HBV markers 32 (9.8%) were positive for HBV core antibodies, one of which was also positive for HBV antigen. C trachomatis could be demonstrated in six out of 122 (4.9%) samples and M genitalium in one out of 122 samples. The finding of a C trachomatis prevalence of 4.9% is considerable higher than expected in men with a presumed age of 35-55 years. The demonstration of a prevalence of HBV markers of 9.8% indicates that these clients have an increased risk of HBV infection, a finding that further consolidates the recommendation of HBV vaccination of sex workers. As shown in this study, STD transmission in commercial sex may also have the client as the source.


[Copy number variation of trinucleotide repeat in dynamic mutation sites of autosomal dominant cerebellar ataxias related genes].
To standardize the experimental procedure of the gene test for autosomal dominant cerebellar ataxias (ADCA), and provide the basis for quantitative criteria of the dynamic mutation of spinocerebellar ataxia (SCA) genes in Chinese population. Genotyping of the dynamic mutation loci of the SCA1, SCA2, SCA3, SCA6 and SCA7 genes was performed, using florescence PCR-capillary electrophoresis followed by DNA sequencing, to investigate the variation range of copy number of CAG tandem repeat of the genes in 263 probands of ADCA pedigrees and 261 non-related normal controls. Based on the sequencing result, the bias of the CAG copy number estimation using capillary electrophoresis with different DNA controls was compared to analyze the technical detailes of the electrophresis method in testing the dynamic mutation sites. PCR products containing dynamic mutation loci of the SCA genes showed significantly higher mobility than that of molecular weigh marker with relatively balanced GC content. This was particularly obvious in the SCA2, SCA 6 and SCA7 genes whereas the deviation of copy number could be corrected to +/-1 when known CAG copy number fragments were used as controls. The mobility of PCR products was primarily related to the copy number of CAG repeat when the fragments contained normal CAG repeat. In the 263 ADCA pedigrees, 6 (2.28%) carried SCA1 gene mutation, 8 (3.04%) had SCA2 mutation and 81 (30.80%) harbored SCA3 mutation. The gene mutation of SCA6 and SCA7 was not found. The normal variation range of the CAG repeat was 17-36 copies in SCA1 gene, 13-30 copies in SCA2, 14-39 copies in SCA3, 6-16 copies in SCA6 and 6-13 copies in SCA7. The heterozygosity was 76.1%, 17.7%, 74.4%, 72.1% and 41.3%, respectively. The mutation range of the CAG repeat was 49-56 copies in SCA1 gene, 36-41 copies in SCA2, 59-81 copies in SCA3. Neither homozygous mutation of an SCA gene nor double heterozygous mutation of the SCA genes was observed in the study. The copy number of the CAG repeat in SCA genes could be calculated accurately based on the result of florescence PCR-capillary electrophoresis when limited amount of known repeat copy number controls were used. Our result supported that the notion that SCA3 gene mutation was the most common cause for ADCA, and the obtained data would be helpful for establishing quantitative criteria of the dynamic mutation of the SCA genes in Chinese.


Effect of gypsum application on enzymatic browning activity in lettuce.
A comprehensive study to evaluate calcium, in terms of gypsum (CaSO4.2H2O) by soil dressing application, on enzymatic browning activity of Polyphenol oxidase (PPO) and internal qualities was tested on lettuce var. Grand Rapids under field conditions. A factorial in completely randomized design was arranged with four replications. The results showed that plants-treated with 50 mg kg(-1) gypsum applied at 40 DAP had the maximal fresh weight of 25.83 g plant(-1). The internal qualities of the lettuce at harvest showed that plants treated with 50 mg kg(-1) gypsum had the maximal chlorophyll content (26.80 mg m(-2)), while all gypsum concentrations applied in this study, had less content of ascorbic acid than the control plants. Plants-treated with 100 mg kg(-1) gypsum affected to the lowest level of PPO activity at week 3 after transplanting. Furthermore, gypsum application had no effect to biomass, leaf colour, the contents of phenolic and quinone in lettuce at harvesting stage.


Podoplanin and E-cadherin expression in preoperative incisional biopsies of oral squamous cell carcinoma is related to lymph node metastases.
Metastases to cervical lymph nodes (LNs) are an important independent adverse indicator in the prognosis of oral squamous cell carcinoma (OSCC). An accurate evaluation of molecular patterns favoring the metastatic process can be helpful in predicting cases of OSCC with elevated probability of early or late metastases and, moreover, in planning the proper therapeutic procedures before surgery. To this end, immunohistochemical expressions of both E-cadherin and podoplanin were evaluated on preoperative incisional biopsies of OSCC from 102 patients. The probability to have or develop metastases was very low when high E-cadherin expression was found in a preoperative sample or when a low podoplanin expression was found. Therefore, because of the strong association with LN metastases, high E-cadherin/low podoplanin immunohistochemical expression should also be assessed on preoperative incisional biopsies as a useful tool for evaluating the probability of early or late LN metastases of OSCCs.


Meconium aspiration syndrome: do we know?
Meconium is a common finding in amniotic fluid and placental specimens, particularly in the term or post-term pregnancy. The most important consequence of meconium-stained amniotic fluid (MSAF) is meconium aspiration syndrome (MAS), and at least 5% of infants born through MSAF develop MAS. MAS continues to be a threat to many newborns throughout the world, with a case fatality rate of 5% (as much as 40%), in addition to short- and long-term pulmonary and neurodevelopmental sequelae. The exact pathophysiology of meconium passage into the amniotic fluid and consequences of meconium aspiration are unknown. There are three prevailing and possibly compatible theories for mechanisms of meconium release. Firstly, meconium passage is probably related with the maturation of the gastrointestinal tract, because meconium passage in the preterm third trimester fetus has been reported to be a rare event, as typically it occurs near or post-term. Secondly, an alternate hypothesis for in utero meconium passage is that pathologic processes, such as stress via hypoxia or infection, can trigger meconium passage. However, the predictive values of MSAF for fetal distress and acidosis at birth are poor and controversial. Thirdly, an alternative route for the presence of MSAF in the presence of fetal hypoxia is reduced clearance of defecated meconium due to impaired fetal swallowing or unidentified placental dysfunction in addition to or instead of an increase in its passage. The pathophysiology of MAS is multifactorial and extremely complex. Meconium causes mechanical obstruction and pulmonary air leak, induces surfactant inactivation, causes pulmonary inflammation, and induces apoptosis. Preventing prolonged pregnancy by labor induction might reduce the risk of MSAF. Labor induction with prostaglandins appears to be associated with the occurrence of MSAF. Amnioinfusion for suspected umbilical cord compression has no clear effect on the occurrence of MSAF. Intrapartum suctioning of the naso- and oropharynx before delivery of the shoulders as well as postnatal endotracheal suctioning of vigorous infants with MSAF are no longer recommended. Currently, endotracheal suction is recommended only in neonates born through MSAF who are not vigorous at birth. Indications for mechanical ventilation in infants with MAS are arbitrary. Surfactant administration may reduce the severity of MAS. Bronchoalveolar lavage with surfactant in infants with MAS is risky and it cannot be recommended for routine use. At present, there is insufficient evidence to propose routine steroid therapy in the management of MAS. Although prophylactic antibiotics in infants with MAS are not justified, most of these patients receive antibiotics during the first days of life, before the diagnosis of pneumonia can be completely ruled out. Children surviving severe MAS are in fact reported to have higher prevalence of asthmatic symptoms and bronchiolar hyperreactivity than children in the general population. It remains undetermined how often and at what intensity systemic inflammation occurs in association with MAS and what its significance is for the outcome of infants with severe MAS.


Laser-induced-breakdown-spectroscopy-based detection of metal particles released into the air during combustion of solid propellants.
Numerous metals and metal compounds are often added to propellants and explosives to tailor their properties such as heat release rate and specific impulse. When these materials combust, these metals can be released into the air, causing adverse health effects such as pulmonary and cardiovascular disease, particulate-matter-induced allergies, and cancer. Hence, robust, field-deployable methods are needed to detect and quantify these suspended metallic particles in air, identify their sources, and develop mitigation strategies. Laser-induced breakdown spectroscopy (LIBS) is a technique for elemental detection, commonly used on solids and liquids. In this study, we explored nanosecond-duration LIBS for detecting airborne metals during reactions of solid propellant strands, resulting from additives of aluminum (Al), copper, lead, lead stearate, and mercury chloride. Using the second harmonic of a 10-ns-duration 10-Hz, Nd:YAG laser, plasma was generated in the gas-phase exhaust plume of burning propellant strands containing the target metals. Under the current experimental conditions, the ns-LIBS scheme was capable of detecting Al at concentrations of 5%, 10%, and 16% by weight in the propellant strand. As the weight percentage increased, the LIBS signal was detected by more laser shots, up to a point where the system transition from being nonhomogeneous to a more-uniform distribution of particles. Further measurements and increased understanding of the reacting flow field are necessary to quantify the effects of other metal additives besides Al.


The safety profile and angioarchitectural changes after acute targeted embolization of ruptured arteriovenous malformations.
The aim of this study was to 1) compare the safety and efficacy of acute targeted embolization of angiographic weak points in ruptured brain arteriovenous malformations (bAVMs) versus delayed treatment, and 2) explore the angioarchitectural changes that follow this intervention. The authors conducted a retrospective analysis of a prospectively acquired database of ruptured bAVMs. Three hundred sixteen patients with ruptured bAVMs who presented to the hospital within 48 hours of ictus were included in the analysis. The first analysis compared clinical and functional outcomes of acutely embolized patients to those with delayed management paradigms. The second analysis compared these outcomes of patients with acute embolization to those with angiographic targets who did not undergo acute embolization. Finally, a subset of 20 patients with immediate postembolization angiograms and follow-up angiograms within 6 weeks of treatment were studied to determine the angioarchitectural changes after acute targeted embolization. Kaplan-Meier curves for survival between the groups were devised. Multivariate logistical regression analysis was conducted. There were three deaths (0.9%) and an overall rerupture rate of 4.8% per year. There was no statistical difference in demographic variables, mortality, and rerupture rate between patients with acute embolization and those with delayed management. Patients with acute embolization were more likely to present functionally worse (46.9% vs 69.8%, modified Rankin Scale score 0-2, p = 0.018) and to require an adjuvant therapy (71.9% vs 26.4%, p < 0.001). When comparing acutely embolized patients to those nonacutely embolized angiographic targets, there was a significant protective effect of acute targeted therapy on rerupture rate (annual risk 1.2% vs 4.3%, p = 0.025) and no difference in treatment complications. Differences in the survival curves for rerupture were statistically significant. Multivariate analyses significantly predicted lower rerupture in acute targeted treatment and higher rerupture in those with associated aneurysms, deep venous anatomy, and higher Spetzler-Martin grade. All patients with acute embolization experienced complete obliteration of the angiographic weak point with various degrees of resolution of the nidus; however, some had spontaneous recurrence of their bAVM, while others had spontaneous resolution over time. No patients developed new angiographic weak points. This study demonstrates that acute targeted embolization of angiographic weak points, particularly aneurysms, is technically safe and protective in the early phase of recovery from ruptured bAVMs. Serial follow-up imaging is necessary to monitor the evolution of the nidus after targeted and definitive treatments. Larger prospective studies are needed to validate these findings.


Absence of calretinin protein expression in malignant mesotheliomas from asbestos-exposed NF2+/- mice and mouse mesothelioma cell lines from various mouse strains.
Calretinin is the most widespread positive marker for the immunohistochemical identification of malignant mesothelioma (MM) and was proposed to serve as a blood-based biomarker. Functionally, evidence has accumulated that calretinin might be implicated in MM tumorigenesis. We aimed to identify calretinin (CR; Calb2) in murine MM and reactive mesothelial cells in granuloma from asbestos-exposed NF2+/- mice, a line heterozygous for the tumor suppressor merlin (NF2), used as a mouse MM model. Additionally, we sought to ascertain the presence of calretinin in MM cell lines from other mouse strains. We also intended to investigate the role of calretinin in mesotheliomagenesis by comparing the survival of asbestos-exposed NF2+/- and NF2+/-CR-/- mice. NF2+/- and NF2+/-CR-/- mice, both lines on a C57Bl/6J background, were exposed to asbestos following an established protocol. Tumor histology and asbestos-induced mortality were assessed. MM and granuloma from NF2+/- mice were analyzed with immunohistochemical methods for calretinin expression. Levels of Calb2 mRNA and calretinin expression in tumors and MM cell lines of various mouse strains were determined by RT-qPCR and Western blot analysis, respectively. No expression of calretinin at the protein level was detected, neither in MM from NF2+/- mice, NF2+/- MM-derived cell lines nor immortalized mesothelial cells of mouse origin. At the mRNA level we detected Calb2 expression in MM cell lines from different mouse strains. Survival of NF2+/- and NF2+/-CR-/- mice exposed to asbestos showed no significant difference in a log-rank (Kaplan-Meier) comparison. The concomitant determination of calretinin and mesothelin blood levels has been proposed for early detection of human MM. Mouse MM models based on asbestos exposure are assumed to yield helpful information on the time course of appearance of mesothelin and calretinin in the blood of asbestos-treated mice determining the earliest time point for interventions. However, the observed absence of calretinin in MM from NF2+/- mice and derived cell lines, as well as from MM cells from Balb/c and C3H mice likely precludes the use of calretinin as a biomarker for mouse MM. The results also indicate possible species differences with respect to an involvement of calretinin in the formation of MM.


The Assessment Unit of the Epilepsy Centre, Quarriers Homes.
The work of the Assessment Unit in the Epilepsy Centre, Quarriers Homes, Scotland is described. One hundred and thirty patients with severe epilepsy were admitted over a three year period for investigation of seizures and rationalisation of therapy. The degree of psychomotor impairment due to epilepsy itself, or to anti-epileptic drugs was estimated. Cognitive functioning and levels of ability with interpersonal relationships were measured and plans were drawn up for rehabilitation. A plea is made for NHS funding to support the provision of this service for people with epilepsy.


The Role of the Type III Secretion System in the Intracellular Lifestyle of Enteric Pathogens.
Several pathogens have evolved to infect host cells from within, which requires subversion of many host intracellular processes. In the case of Gram-negative pathogenic bacteria, adaptation to an intracellular life cycle relies largely on the activity of type III secretion systems (T3SSs), an apparatus used to deliver effector proteins into the host cell, from where these effectors regulate important cellular functions such as vesicular trafficking, cytoskeleton reorganization, and the innate immune response. Each bacterium is equipped with a unique suite of these T3SS effectors, which aid in the development of an individual intracellular lifestyle for their respective pathogens. Some bacteria adapt to reside and propagate within a customized vacuole, while others establish a replicative niche in the host cytosol. In this article, we review the mechanisms by which T3SS effectors contribute to these different lifestyles. To illustrate the formation of a vacuolar and a cytosolic lifestyle, we discuss the intracellular habitats of the enteric pathogens Salmonella enterica serovar Typhimurium and Shigella flexneri, respectively. These represent well-characterized systems that function as informative models to contribute to our understanding of T3SS-dependent subversion of intracellular processes. Additionally, we present Vibrio parahaemolyticus, another enteric Gram-negative pathogen, as an emerging model for future studies of the cytosolic lifestyle.


Wind turbine noise, annoyance and self-reported health and well-being in different living environments.
To evaluate the prevalence of perception and annoyance due to wind turbine noise among people living near the turbines, and to study relations between noise and perception/annoyance, with focus on differences between living environments. A cross-sectional study was carried out in seven areas in Sweden across dissimilar terrain and different degrees of urbanisation. A postal questionnaire regarding living conditions including response to wind turbine noise was completed by 754 subjects. Outdoor A-weighted sound pressure levels (SPLs) were calculated for each respondent. Perception and annoyance due to wind turbine noise in relation to SPLs was analysed with regard to dissimilarities between the areas. The odds of perceiving wind turbine noise increased with increasing SPL (OR 1.3; 95% CI 1.25 to 1.40). The odds of being annoyed by wind turbine noise also increased with increasing SPLs (OR 1.1; 95% CI 1.01 to 1.25). Perception and annoyance were associated with terrain and urbanisation: (1) a rural area increased the risk of perception and annoyance in comparison with a suburban area; and (2) in a rural setting, complex ground (hilly or rocky terrain) increased the risk compared with flat ground. Annoyance was associated with both objective and subjective factors of wind turbine visibility, and was further associated with lowered sleep quality and negative emotions. There is a need to take the unique environment into account when planning a new wind farm so that adverse health effects are avoided. The influence of area-related factors should also be considered in future community noise research.


Acrylic AB and ABA block copolymers based on poly(2-ethylhexyl acrylate) (PEHA) and poly(methyl methacrylate) (PMMA) via ATRP.
Acrylic block copolymers have several advantages over conventional styrenic block copolymers, because of the presence of a saturated backbone and polar pendant groups. This investigation reports the preparation and characterization of di- and triblock copolymers (AB and ABA types) of 2-ethylhexyl acrylate (EHA) and methyl methacrylate (MMA) via atom transfer radical polymerization (ATRP). A series of block copolymers, PEHA-block-PMMA(AB diblock) and PMMA-block-PEHA-block-PMMA(ABA triblock) were prepared via ATRP at 90 °C using CuBr as catalyst in combination with N,N,N',N″,N″-pentamethyl diethylenetriamine (PMDETA) as ligand and acetone as additive. The chemical structure of the macroinitiators and molar composition of block copolymers were characterized by (1)H NMR analysis, and molecular weights of the polymers were analyzed by GPC analysis. DSC analysis showed two glass transition temperatures (T(g)), indicating formation of two domains, which was corroborated by AFM analysis. Small-angle X-ray scattering (SAXS) analysis of AB and ABA block copolymers showed scattering behavior inside the measuring limits indicating nanophase separation. However, SAXS pattern of AB diblock copolymers indicated general phase separation only, whereas for ABA triblock copolymer an ordered or mixed morphology could be deduced, which is assumed to be the reason for the better mechanical properties achieved with ABA block copolymers than with the AB analogues.


The Rational Design, Synthesis, and Antimicrobial Properties of Thiophene Derivatives That Inhibit Bacterial Histidine Kinases.
The emergence of multidrug-resistant bacteria emphasizes the urgent need for novel antibacterial compounds targeting unique cellular processes. Two-component signal transduction systems (TCSs) are commonly used by bacteria to couple environmental stimuli to adaptive responses, are absent in mammals, and are embedded in various pathogenic pathways. To attenuate these signaling pathways, we aimed to target the TCS signal transducer histidine kinase (HK) by focusing on their highly conserved adenosine triphosphate-binding domain. We used a structure-based drug design strategy that begins from an inhibitor-bound crystal structure and includes a significant number of structurally simplifiying "intuitive" modifications to arrive at the simple achiral, biaryl target structures. Thus, ligands were designed, leading to a series of thiophene derivatives. These compounds were synthesized and evaluated in vitro against bacterial HKs. We identified eight compounds with significant inhibitory activities against these proteins, two of which exhibited broad-spectrum antimicrobial activity. The compounds were also evaluated as adjuvants for the treatment of resistant bacteria. One compound was found to restore the sensivity of these bacteria to the respective antibiotics.


Late-life anxiety is coming of age.
Anxiety is an adaptive human experience that may occur at all ages and serves to help draw attention to, avoid or cope with immanent threat and danger. Given its evolutionary importance, it has strong genetic and biological underpinnings, and when it serves that adaptive function for the organism, anxiety may be viewed as useful. However, complex adaptive systems, such as our adaptation to threat or stress, by definition provide many and often interrelated points of breakdown or dysregulation, which, if sustained, may lead to psychopathology. Anxiety has been described as a common currency for psychopathology, indicating that it is a first line and universal way for us to respond to stress and threat. It is more or less prominent in patients diagnosed with practically all psychiatric or neurodegenerative disorders. This has lead to the inclusion of anxiety as a cross-cutting symptom measure in the development of DSM-5 (APA, 2013). Given that they are rooted in a complex adaptive system that has many potential points of impact to develop pathology, it is not surprising that anxiety disorders are extremely heterogeneous. This heterogeneity of anxiety disorders pertains to symptomatology, etiology and outcomes, and poses great challenges to both research and clinical practice.


Psychosocial Support Issues Affecting Older Patients: A Cross-sectional Paramedic Perspective.
This research aimed to gain an understanding of the psychosocial support needs of older patients in the out-of-hospital setting from the perspective of paramedics. Specifically, we investigate if and how paramedics are able to meet the needs of older adults, and the barriers preventing them from achieving this. This study was a cross-sectional study utilizing a sequential design with both quantitative and qualitative methodologies. All participants agreed or strongly agreed that older patients have needs beyond the physical and that they would like to do more for older patients. Paramedics discussed that psychosocial support issues are rarely in isolation and straightforward but were often coupled with broader, longer term physical health and social support issues. They would like to be able to do more for patients but feel hamstrung by lack of time, resources, and know-how.


A highly efficacious pediculicide based on dimeticone: randomized observer blinded comparative trial.
Infestation with the human head louse (Pediculus humanus capitis) occurs worldwide. Existing treatment options are limited, and reports of resistance to commonly used pediculicides have been increasing. In this trial we assessed the efficacy of a product containing a high (92%) concentration of the silicone oil dimeticone (identical in composition to NYDA(R)), as compared to a 1% permethrin lotion. Randomized, controlled, observer blinded clinical trial. Participants were recruited from a poor urban neighbourhood in Brazil where pediculosis capitis was highly prevalent. To minimize reinfestation during the trial, participants (145 children aged 5-15 years with head lice infestations) were transferred to a holiday resort outside the endemic area for a period of 9 days. Two applications of dimeticone or 1% permethrin were done, seven days apart. Outcome measures were defined as cure (absence of vital head lice) after first application and before and after second applications, degree of itching, cosmetic acceptability, and clinical pathology. Overall cure rates were: day 2 - dimeticone 94.5% (95% CI: 86.6% - 98.5%) and permethrin 66.7% (95% CI: 54.6% - 77.3%; p < 0.0001); day 7 - dimeticone 64.4% (95% CI: 53.3% - 75.3%) and permethrin 59.7% (95% CI: 47.5% - 71.1%; p = 0.5); day 9 - dimeticone 97.2% (95% CI: 90.3% - 99.7%) and permethrin 67.6% (95% CI: 55.4%-78.2%); p < 0.0001). Itching was reduced similarly in both groups. Cosmetic acceptability was significantly better in the dimeticone group as compared to the permethrin group (p = 0.01). Two mild product-related incidents occurred in the dimeticone group. The dimeticone product is a safe and highly efficacious pediculicide. Due to its physical mode of action (interruption of the lice's oxygen supply of the central nervous system), development of resistance is unlikely. Current Controlled Trials ISRCTN15117709.


The impact of methodology on the reproducibility and rigor of DNA methylation data.
Epigenetic modifications are crucial for normal development and implicated in disease pathogenesis. While epigenetics continues to be a burgeoning research area in neuroscience, unaddressed issues related to data reproducibility across laboratories remain. Separating meaningful experimental changes from background variability is a challenge in epigenomic studies. Here we show that seemingly minor experimental variations, even under normal baseline conditions, can have a significant impact on epigenome outcome measures and data interpretation. We examined genome-wide DNA methylation and gene expression profiles of hippocampal tissues from wild-type rats housed in three independent laboratories using nearly identical conditions. Reduced-representation bisulfite sequencing and RNA-seq respectively identified 3852 differentially methylated and 1075 differentially expressed genes between laboratories, even in the absence of experimental intervention. Difficult-to-match factors such as animal vendors and a subset of husbandry and tissue extraction procedures produced quantifiable variations between wild-type animals across the three laboratories. Our study demonstrates that seemingly minor experimental variations, even under normal baseline conditions, can have a significant impact on epigenome outcome measures and data interpretation. This is particularly meaningful for neurological studies in animal models, in which baseline parameters between experimental groups are difficult to control. To enhance scientific rigor, we conclude that strict adherence to protocols is necessary for the execution and interpretation of epigenetic studies and that protocol-sensitive epigenetic changes, amongst naive animals, may confound experimental results.


Drought and heat stress mediated activation of lipid signaling in plants: a critical review.
Lipids are a principal component of plasma membrane, acting as a protective barrier between the cell and its surroundings. Abiotic stresses such as drought and temperature induce various lipid-dependent signaling responses, and the membrane lipids respond differently to environmental challenges. Recent studies have revealed that lipids serve as signal mediators forreducing stress responses in plant cells and activating defense systems. Signaling lipids, such as phosphatidic acid, phosphoinositides, sphingolipids, lysophospholipids, oxylipins, and N-acylethanolamines, are generated in response to stress. Membrane lipids are essential for maintaining the lamellar stack of chloroplasts and stabilizing chloroplast membranes under stress. However, the effects of lipid signaling targets in plants are not fully understood. This review focuses on the synthesis of various signaling lipids and their roles in abiotic stress tolerance responses, providing an essential perspective for further investigation into the interactions between plant lipids and abiotic stress.


Synthesis, proton-affinity and anti-cancer properties of the prodigiosin-group natural products.
The prodigiosin-group natural products are a family of tripyrrole red-pigments that are produced by microorganisms such as Streptomyces and Serratia and contain a common 4-methoxy-2,2'-bipyrrole ring system. They were first isolated in 1929 and studied as antibiotic and cytotoxic agents in the 1960s, but were not developed clinically due to their high systemic toxicity. However, during the past decade some prodigiosins have shown potentially useful immunosuppressive activity when administered at doses that are not toxic. They have also been found to exhibit selective cytotoxicity against melanoma and liver cancer cells. These results have fueled various studies on the biological mechanisms of the prodigiosins and it has now been established that they inhibit phosphorylation and activation of JAK-3, a cytoplasmic tyrosine kinase associated with the cell surface receptor component called common gamma-chain. They also uncouple lysosomal vacuolar-type ATPases through promotion of H(+)/Cl(-) symport and facilitate oxidative double-strand DNA cleavage in the presence of copper. A simple and elegant synthesis of the prodigiosins has also been developed, which has allowed a number of the natural prodigiosins and synthetic analogues to be prepared. These studies have served to renew interest in the prodigiosin-group natural products. In this review the recent advances on the synthesis, proton-affinity and biological activities of the prodigiosins are discussed. With regard to their anti-cancer properties, particular attention is given to their ability to facilitate oxidative DNA damage, which provides a rationale for the cytotoxic properties of the prodigiosin-group natural products.


Stellarex Drug-Coated Balloon for Treatment of Femoropopliteal Disease: Twelve-Month Outcomes From the Randomized ILLUMENATE Pivotal and Pharmacokinetic Studies.
Drug-coated balloons (DCBs) are a predominant revascularization therapy for symptomatic femoropopliteal artery disease. Because of the differences in excipients, paclitaxel dose, and coating morphologies, varying clinical outcomes have been observed with different DCBs. We report the results of 2 studies investigating the pharmacokinetic and clinical outcomes of a new DCB to treat femoropopliteal disease. In the ILLUMENATE Pivotal Study (Prospective, Randomized, Single-Blind, U.S. Multi-Center Study to Evaluate Treatment of Obstructive Superficial Femoral Artery or Popliteal Lesions With A Novel Paclitaxel-Coated Percutaneous Angioplasty Balloon), 300 symptomatic patients (Rutherford class 2-4) were randomly assigned to DCB (n=200) or standard angioplasty (percutaneous transluminal angioplasty [PTA]) (n=100). The primary safety end point was freedom from device- and procedure-related death through 30 days, and freedom from target limb major amputation and clinically driven target lesion revascularization through 12 months. The primary effectiveness end point was primary patency through 12 months. In the ILLUMENATE PK study (Pharmacokinetic Study of the Stellarex Drug-Coated Angioplasty Balloon), paclitaxel plasma concentrations were measured after last DCB deployment and at prespecified times (at 1, 4, 24 hours and at 7 and 14 days postprocedure) until no longer detectable. In the ILLUMENATE Pivotal Study, baseline characteristics were similar between groups: 50% had diabetes mellitus, 41% were women, mean lesion length was 8.3 cm, and 44% were severely calcified. The primary safety end point was met (92.1% for DCB versus 83.2% for PTA, P=0.025 for superiority) and the primary patency rate was significantly higher with DCB (76.3% for DCB versus 57.6% for PTA, P=0.003). Primary patency per Kaplan-Meier estimates at day 365 was 82.3% for DCB versus 70.9% for PTA (P=0.002). The rate of clinically driven target lesion revascularization was significantly lower in the DCB cohort (7.9% versus 16.8%, P=0.023). Improvements in ankle-brachial index, Rutherford class, and quality of life were comparable, but the PTA cohort required twice as many revascularizations. Pharmacokinetic outcomes showed that all patients had detectable paclitaxel levels after DCB deployment that declined within the first hour (54.4±116.9 ng/mL to 1.4±1.0 ng/mL). The data demonstrate superior safety and effectiveness of the Stellarex DCB in comparison with PTA, and plasma levels of paclitaxel fall to low levels within 1 hour. URL: http://clinicaltrials.gov. Unique identifiers: NCT01858428 and NCT01912937.


Small dense low-density lipoprotein and its role as an independent predictor of cardiovascular disease.
This review discusses whether the relationship of small dense low-density lipoprotein to cardiovascular risk is direct, due to the atherogenic properties of the particle, or a reflection of concomitant abnormalities in high-density lipoprotein and plasma triglyceride. Recent studies have examined whether low-density lipoprotein size distribution or concentration of small low-density lipoprotein is related more strongly to risk. It appears that the latter is a better predictor in major surveys, although in smaller cohort studies particle size shows a strong association with atherosclerosis burden. While the main causes of the formation of small dense low-density lipoprotein are relatively well understood, novel metabolic factors may also play a role, and pharmacologic interventions such as glitazones may have a direct regulatory impact. Evidence links abnormalities in low-density lipoprotein structure to cardiovascular risk. The plasma concentration of small dense low-density lipoprotein is likely to be more informative than relative low-density lipoprotein particle size, and although methods are available for quantitation of this subfraction, there is considerable room for improvement. It is not yet clear how knowledge of the small dense low-density lipoprotein concentration may add to risk prediction.


Continuous monitoring of intracellular volumes in isolated rat hearts during normothermic perfusion and ischemia.
The present study describes an experimental setup that enables continuous measurement of cellular volumes in isolated organs. The procedure is a modification of a recently reported method that uses multinuclear NMR measured by 59Co NMR of cobalticyanide and 1H NMR of water in isolated rat hearts at normothermia. The new apparatus contains a background flow which is shown to improve the rate of exchange of the marker between the interstitium and the external solution and allows detection of cellular shrinkage during no-flow ischemia. A series of experiments of marker loading and wash-out were performed to validate the method. In the Langendorff preparation, intracellular volumes (in units of milliliters per gram dry weight) of hearts perfused with Krebs-Henseleit solution oscillated around a mean value of 2.50 +/- 0.06 ml/gdw. During 30 min of ischemia the cells swelled to 2.88 +/- 0.08 ml/gdw and residual edema was observed after 30 min of reperfusion (2.62 +/- 0.08 ml/gdw). A hypoosmotic shock was used to assess changes in membrane permeability at different time points of ischemia and reperfusion. Water influx induced by the hypoosmotic shock at the end of ischemia was similar to that elicited in perfused hearts. After 15 and 30 min of reperfusion, the magnitude of the response to hypoosmolarity decreased by 9 and 37%, respectively, indicating a gradual permeabilization of the membranes, presumably to ions. The experimental setup was also used to monitor intracellular volumes as a function of time in anisoosmotic conditions. Cellular swelling/shrinkage were delayed for periods of 5 and 8 min at osmolarities of +/-50 and +/-100 mosmol/liter, suggesting a limited capability of the heart to absorb an anisoosmotic shock. The variation in cellular volumes was proportional to the deviation of the conditions from isoosmolarity, and activation of volume-regulatory mechanisms was demonstrated. The noninvasive technique presented in this study is capable of providing quantitative evidence of changes in cellular volumes in isolated hearts at a temporal resolution of 1 min and a spatial resolution of 4% (of cellular volume). As demonstrated in the cases of global ischemia and anisoosmolar conditions, the technique is expected to provide new insights into the mechanism of cellular-volume regulation.


[Experience in penetrating keratoplasty in children: graft survival, functional results and risk factors].
Penetrating keratoplasty in children is related with a labor-consuming process of follow-up and care as well as with a high risk of graft rejection and a moderate vision improvement. Nonetheless, keratoplasty has been and still remains a surgery of choice due to a lack of an alternative procedure; its technique and results have been gradually promoted in practice. The authors analyzed 112 keratoplasties in childhood-age corneal opacifications of different types. The graft survival amounted to 71%, 61% and to around 55% after 1, 2 and 5 postoperative years, respectively. Neovascularization, glaucoma, repeated keratoplasty, an original vitreous pathology, an expanded surgical scope (reconstructions) etc. were attributed to risk factors. The visual acuity improved by more than 0.02 in 54% of cases; it remained unchanged or worsened in 22% of cases and it could not be assessed in 24% of cases. The best results were achieved in a group of patients with acquired corneal opacifications of the nontraumatic nature; the worst results were observed in congenital anomalies of the anterior eye segment. Finally, the success of penetrating keratoplasty in children was ensured through a careful selection of patients, an accurate surgical technique and through a fast treatment of postoperative complications.


Expression and intracellular distribution of the G protein-coupled receptor 30 in rat hippocampal formation.
Although the expression and distribution of nuclear estrogen receptors in the hippocampus has been described, it has been proposed that the nuclear receptors may not explain all aspects of estrogen function in the hippocampus. Recently, a G protein-coupled receptor for estrogen, GPR30, was identified as a membrane-localized estrogen receptor in several cancer cell lines. In this study, we examined the expression and intracellular distribution of GPR30 in the rat hippocampal formation. We found expression of GPR30 in pyramidal cells of CA1-3 and granule cells of the dentate gyrus at both mRNA and protein levels. Specific markers for intracellular organelles and immunoelectron microscopy revealed that GPR30 was mainly localized to the Golgi apparatus and partially in the endoplasmic reticulum of the neuron but could not detect the protein at the cell surface. Expression levels were not different among male, female in proestrus and female in estrus at the adult stage, but were higher in newborn male than newborn female.


Multi-Locus Next-Generation Sequence Typing of DNA Extracted From Pooled Colonies Detects Multiple Unrelated Candida albicans Strains in a Significant Proportion of Patient Samples.
The yeast Candida albicans is an important opportunistic human pathogen. For C. albicans strain typing or drug susceptibility testing, a single colony recovered from a patient sample is normally used. This is insufficient when multiple strains are present at the site sampled. How often this is the case is unclear. Previous studies, confined to oral, vaginal and vulvar samples, have yielded conflicting results and have assessed too small a number of colonies per sample to reliably detect the presence of multiple strains. We developed a next-generation sequencing (NGS) modification of the highly discriminatory C. albicans MLST (multilocus sequence typing) method, 100+1 NGS-MLST, for detection and typing of multiple strains in clinical samples. In 100+1 NGS-MLST, DNA is extracted from a pool of colonies from a patient sample and also from one of the colonies. MLST amplicons from both DNA preparations are analyzed by high-throughput sequencing. Using base call frequencies, our bespoke DALMATIONS software determines the MLST type of the single colony. If base call frequency differences between pool and single colony indicate the presence of an additional strain, the differences are used to computationally infer the second MLST type without the need for MLST of additional individual colonies. In mixes of previously typed pairs of strains, 100+1 NGS-MLST reliably detected a second strain. Inferred MLST types of second strains were always more similar to their real MLST types than to those of any of 59 other isolates (22 of 31 inferred types were identical to the real type). Using 100+1 NGS-MLST we found that 7/60 human samples, including three superficial candidiasis samples, contained two unrelated strains. In addition, at least one sample contained two highly similar variants of the same strain. The probability of samples containing unrelated strains appears to differ considerably between body sites. Our findings indicate the need for wider surveys to determine if, for some types of samples, routine testing for the presence of multiple strains is warranted. 100+1 NGS-MLST is effective for this purpose.


Using global budgets in the United States.
This article discusses the range of possibilities regarding how global budgets for health care spending might be used in the U.S. and the global budget designs that provide the most and least cost control. The article is a condensation of one chapter of the author's recently published special report, Getting Ready for Global Budgets.


Antisense oligonucleotide therapy for KCNT1 encephalopathy.
Developmental and epileptic encephalopathies (DEEs) are characterized by pharmaco-resistant seizures with concomitant intellectual disability. Epilepsy of infancy with migrating focal seizures (EIMFS) is one of the most severe of these syndromes. De novo variants in ion channels, including gain-of-function variants in KCNT1, which encodes for sodium activated potassium channel protein KNa1.1, have been found to play a major role in the etiology of EIMFS. Here, we test a potential precision therapeutic approach in KCNT1-associated DEE using a gene-silencing antisense oligonucleotide (ASO) approach. We generated a mouse model carrying the KCNT1 p.P924L pathogenic variant; only the homozygous animals presented with the frequent, debilitating seizures and developmental compromise that are seen in patients. After a single intracerebroventricular bolus injection of a Kcnt1 gapmer ASO in symptomatic mice at postnatal day 40, seizure frequency was significantly reduced, behavioral abnormalities improved, and overall survival was extended compared with mice treated with a control ASO (nonhybridizing sequence). ASO administration at neonatal age was also well tolerated and effective in controlling seizures and extending the life span of treated animals. The data presented here provide proof of concept for ASO-based gene silencing as a promising therapeutic approach in KCNT1-associated epilepsies.


Lower limb lymphedema in gynecological cancer survivors--effect on daily life functioning.
Lower limb lymphedema (LLL) is a common condition after pelvic cancer treatment but few studies have evaluated its effect on the quality of life and its consequences on daily life activities among gynecological cancer survivors. We identified a cohort of 789 eligible women, treated with pelvic radiotherapy alone or as part of combined treatment of gynecological cancer, from 1991 to 2003 at two departments of gynecological oncology in Sweden. As a preparatory study, we conducted in-depth interviews with gynecological cancer survivors and constructed a study-specific questionnaire which we validated face-to-face. The questionnaire covered physical symptoms originating in the pelvis, demographic, psychological, and quality of life factors. In relation to the lymph system, 19 questions were asked. Six hundred sixteen (78 %) gynecological cancer survivors answered the questionnaire and participated in the study. Thirty-six percent (218/606) of the cancer survivors reported LLL. Overall quality of life was significantly lower among cancer survivors with LLL. They were also less satisfied with their sleep, more worried about recurrence of cancer, and more likely to interpret symptoms from the body as recurrence. Cancer survivors reported that LLL kept them from physical activity (45 %) and house work (29 %) and affected their ability to partake in social activities (27 %) or to meet friends (20 %). Lower limb lymphedema has a negative impact on quality of life among gynecological cancer survivors, affecting sleep and daily life activities, yet only a few seek professional help.


Shoulder abduction-induced reductions in reaching work area following hemiparetic stroke: neuroscientific implications.
A stroke-related loss of corticospinal and corticobulbar pathways is postulated to result in an increased use of remaining neural substrates such as bulbospinal pathways as individuals with stroke are required to generate greater volitional shoulder abduction torques. The effect of shoulder abduction on upper extremity reaching range of motion (work area) was measured in 18 individuals with stroke using the Arm Coordination Training 3-D (ACT(3D)) device. This robotic system is capable of quantifying movement kinematics when a subject attempts to reach while simultaneously generating various levels of active shoulder abduction torque. We have provided data demonstrating an incremental increase of abnormal coupling of elbow flexion for greater levels of shoulder abduction in the paretic limb that results in a reduction in available work area as a function of active limb support. The progressive increase in the expression of abnormal shoulder/elbow coupling can be explained by a progressive reliance on the indirect cortico-bulbospinal connections that remain in individuals following a stroke-induced brain injury.


Geospatial Mapping of Early Cases in Multistate Foodborne Disease Outbreaks: A Strategy To Expedite Identification of Contaminated Imported Produce, United States, 2006 to 2013.
From 1998 to 2008, produce-related illness outbreaks accounted for roughly one-half of reported foodborne outbreaks in the United States. In 2013, Mexico accounted for approximately 50 and 30% of the monetary value of all vegetables and fruits, respectively, imported into the United States. We used historical import data to examine the correlation between the port of entry for five implicated produce vehicles from five multistate outbreaks and the geospatial and temporal distribution of illnesses in the corresponding outbreaks in the United States. For comparison, we analyzed the geospatial and temporal distribution of cases from two U.S. multistate outbreaks associated with domestically grown produce. The geospatial distribution of illnesses in the two outbreaks linked to domestic produce differed from that of the import-related produce outbreaks. The results of our pilot study suggest that geospatial distribution of early-onset cases may be used to identify ports of entry for produce likely to be responsible for causing multistate outbreaks in the United States and that targeted sampling of produce items from these ports of entry may expedite identification of an outbreak vehicle.


Why are IPTp coverage targets so elusive in sub-Saharan Africa? A systematic review of health system barriers.
Use of intermittent preventive treatment (IPTp) is a proven cost-effective intervention for preventing malaria in pregnancy. However, despite the roll-out of IPTp policies across Africa more than ten years ago, utilization levels remain low. This review sought to consolidate scattered evidence as to the health system barriers for IPTp coverage in the continent. Relevant literature from Africa was systematically searched, reviewed and synthesized. Only studies containing primary data were considered. Studies reveal that: (i) poor leadership and governance contribute to slow decentralization of programme management, lack of harmonized guidelines, poor accountability mechanisms, such as robust monitoring and evaluation systems; (ii) low budgetary allocation towards policy implementation slows scale-up, while out-of-pocket expenditure deters women from seeking antenatal services that include IPTp; (iii) there are rampant human resource challenges including low staff motivation levels attributed to such factors as incorrect knowledge of IPTp recommendations and inadequate staffing; (iv) implementation of IPTp policies is hampered by prevailing service delivery barriers, such as long waiting time, long distances to health facilities and poor service provider/client relations; and (v) drug stock-outs and poor management of information and supply chains impair sustained availability of drugs for IPTp. For successful IPTp policy implementation, it is imperative that malaria control programmes target health system barriers that result in low coverage and hence programme ineffectiveness.


Elimination of flare light in hologram recording of diffuse objects.
We have demonstrated that the intermodulation light, normally found in off-axis holograms of real (diffuse) objects, can be suppressed to any desired degree by a scanned illumination recording technique. This is accomplished by illuminating the object only over a very small region (spot) at a given time. An improvement in speed and reconstruction efficiency over the spot-scan recording is obtained by a line-scan technique. For three-dimensional objects, an additional problem arises due to the finite aperture of the hologram, and a double-scan technique is described to obviate this difficulty. Experimental results are presented for all three methods.


HALP Score as a New Prognostic Factor for Patients with Metastatic Bladder Cancer.
To investigate the effect of the haemoglobin, albumin, lymphocyte, and platelet (HALP) score (Haemoglobin, Albumin, Lymphocyte, Platelet count) on survival as a new prognostic factor in metastatic bladder cancer. Descriptive study. Place and Duration of the Study: Department of Medical Oncology, Celal Bayar University, Manisa, Turkey, and Adnan Menderes University, Aydin, Turkey, from 2010 to 2020. The medical charts of patients with metastatic bladder cancer were reviewed retrospectively. Prognostic value of the HALP score as a marker of overall survival was examined through a receiver operating characteristic (ROC) curve analysis. The cut-off value for the HALP score in the ROC curve analysis was 29. The median overall survival (OS) was 19 months when the HALP score was less than 29, and the median OS was 40 months when the HALP score was 29 or greater, and this finding was statistically significant (p = 0.003). The HALP score is closely related to prognosis in metastatic bladder cancer. A high HALP score is associated with better survival outcomes. HALP score, Metastatic bladder cancer, Overall survival.


Low serum testosterone as an indicator of metastatic bronchial carcinoma.
Serum testosterone concentrations were measured preoperatively in 39 men undergoing thoracotomy for histologically proved bronchial carcinoma, in 10 patients with pulmonary opacities that transpired to be non-malignant (benign group) and in 23 men were undergoing minor elective surgical procedures (control group). Thirteen of the 39 patients with known bronchial carcinoma were considered to have had curative surgery and 26 a palliative procedure when operative and pathological findings were taken into consideration. Low serum testosterone concentrations (less than 12 nmol/l) were detected in four patients in the curative group, in 22 in the palliative group (chi 2 test: p less than 0.001), three in the benign group, and in two patients in the control group. A low serum testosterone concentration in patients with bronchial carcinoma may be an indicator of metastatic disease and sequential serum testosterone estimations may prove useful in the follow up of patients thought to have undergone curative surgery.