Accurate and agile digital control of optical phase, amplitude and frequency for coherent atomic manipulation of atomic systems.
We demonstrate a system for fast and agile digital control of laser phase, amplitude and frequency for applications in coherent atomic systems. The full versatility of a direct digital synthesis radiofrequency source is faithfully transferred to laser radiation via acousto-optic modulation. Optical beatnotes are used to measure phase steps up to 2π, which are accurately implemented with a resolution of ≤ 10 mrad. By linearizing the optical modulation process, amplitude-shaped pulses of durations ranging from 500 ns to 500 ms, in excellent agreement with the programmed functional form, are demonstrated. Pulse durations are limited only by the 30 ns rise time of the modulation process, and a measured extinction ratio of > 5 × 10(11) is achieved. The system presented here was developed specifically for controlling the quantum state of trapped ions with sequences of multiple laser pulses, including composite and bichromatic pulses. The demonstrated techniques are widely applicable to other atomic systems ranging across quantum information processing, frequency metrology, atom interferometry, and single-photon generation.


Phylogenetic relationships and pathogenicity variation of two Newcastle disease viruses isolated from domestic ducks in Southern China.
Newcastle disease (ND) is an OIE listed disease caused by virulent avian paramyxovirus type 1 (APMV-1) strains, which is enzootic and causes large economic losses in the poultry sector. Genotype VII and genotype IX NDV viruses were the predominant circulating genotype in China, which may possibly be responsible for disease outbreaks in chicken flocks in recent years. While ducks and geese usually have exhibited inapparent infections. In the present study, we investigate the complete genome sequence, the clinicopathological characterization and transmission of two virulent Newcastle disease viruses, SS-10 and NH-10, isolated from domestic ducks in Southern China in 2010. F, and the complete gene sequences based on phylogenetic analysis demonstrated that SS-10 (genotype VII) and NH-10 (genotype IX) belongs to class II. The deduced amino acid sequence was (112)R-R-Q-K/R-R-F(117) at the fusion protein cleavage site. Animal experiment results showed that the SS-10 virus isolated from ducks was highly pathogenic for chickens and geese, but low pathogenic for ducks. It could be detected from spleen, lung, kidney, trachea, small intestine, bursa of fabricius, thymus, pancreas and cecal tonsils, oropharyngeal and cloacal swabs, and could transmit to the naive contact birds. Moreover, it could transmit to chickens, ducks and geese by naive contact. However, the NH-10 virus isolated from ducks could infect some chickens, ducks and geese, but only caused chickens to die. Additionally, it could transmit to the naive contact chickens, ducks, and geese. The two NDV isolates exhibited different biological properties with respect to pathogenicity and transmission in chickens, ducks and geese. Therefore, no species-preference exists for chicken, duck or goose viruses and more attention should be paid to the trans-species transmission of VII NDVs between ducks, geese and chickens for the control and eradication of ND.


Beta-carotene and risk of coronary heart disease. A review of observational and intervention studies.
The production of free radicals may favour the processes of atherosclerosis, and antioxidant vitamins (including beta-carotene), which partly prevent such processes, might favorably influence cardiovascular disease (CVD); thus, their supplementation might be a useful tool in the prevention of coronary heart disease (CHD). The relationship between beta-carotene and CHD has been investigated in several observational studies, including ecological, cohort and case-control studies. Six cohort studies reported relative risks (RR) of CHD between 0.27 and 0.78 for high beta-carotene levels (plasma/serum levels and dietary intake), but four more recent ones reported RR around unity (range 0.84 to 1.19). The evidence from case-control studies supports a role of beta-carotene in the prevention of CHD (odds ratios, OR, between 0.37 and 0.71), with a possible stronger protection for current smokers. The four published randomized clinical trials of beta-carotene supplementation found RR close to unity (range 0.96 to 1.26) for the relation between beta-carotene and CHD. The apparent discrepancy between observational and intervention studies may depend on several factors. The benefit reported in some observational studies may be related to consumption of foods rich in beta-carotene rather than beta-carotene itself, as foods rich in beta-carotene are usually rich also in other antioxidant vitamins and micronutrients, or to time-related factors, i.e., longer supplementation in intervention studies. Thus, a reasonable recommendation for the prevention of CHD for the general population is to consume a balanced diet with emphasis on antioxidant rich fruit and vegetables and whole grains.


Diagnostic Testing for Migraine and Other Primary Headaches.
Most primary headaches can be diagnosed using the history and examination. Judicious use of neuroimaging and other testing, however, is indicated to distinguish primary headaches from the many secondary causes that may share similar features. This article evaluates the reasons for diagnostic testing and the use of neuroimaging, electroencephalography, lumbar puncture, and blood testing. The use of diagnostic testing in adults and children who have headaches and a normal neurologic examination, migraine, trigeminal autonomic cephalalgias, hemicrania continua, and new daily persistent headache are reviewed.


Evaluation of the clinical efficacy of pradofloxacin tablets for the treatment of canine pyoderma.
A third-generation fluoroquinolone, pradofloxacin (PRA), is currently being developed to treat bacterial infections in dogs. The purpose of this study was to assess the clinical efficacy in 20 dogs affected with superficial and deep pyoderma. An initial aerobic skin culture was performed in dogs with superficial pyoderma; aerobic/anaerobic tissue culture was performed in dogs with deep pyoderma; and skin cytology and biopsies were obtained from all dogs. Pradofloxacin (approximately 3 mg/kg per os [PO]) was administered daily to all dogs. Clinical efficacy was recorded at 4 weeks for dogs with superficial pyoderma and at 3 and 6 weeks for dogs with deep pyoderma. At a mean dosage of 3.7 mg/kg PO once daily, PRA treatment resulted in an excellent to good clinical response within 3 to 6 weeks for all 20 dogs with superficial and deep pyoderma.


Measurement of affectionate behaviors adolescent mothers display toward their infants in neonatal intensive care.
This paper describes two studies that had three purposes: (a) to modify a parent-child interaction tool used previously in a neonatal intensive care unit (NICU); (b) to demonstrate interrater reliability, Chronbach's Alpha reliability, and construct validity of the tool with adolescent mothers, and (c) to determine the ability of nurses engaged in usual work duties to observe maternal behaviors. The first study tested interrater reliability. Two NICU nurses were trained, observed adolescent mothers (n = 20) for the same 15 min, and then separately completed the measure. The second study tested internal consistency reliability and construct validity with 107 adolescent mothers with infants in a NICU. Nurses in the neonatal intensive care unit completed the measure, and data on maternal visits were gathered for construct validity. The intraclass correlation coefficient for the first study was r = .83. Results of the second study demonstrated a Chronbach's Alpha of .85 and a significant correlation between ratings of maternal behavior and visits. The instrument obtained acceptably reliable and valid estimates of adolescent mothers' affectionate behaviors toward their infants. In addition, the studies demonstrated that nurses can observe maternal behaviors while performing their usual duties.


Utility of the One-time HACOR Score as a Predictor of Weaning Failure from Mechanical Ventilation: A Prospective Observational Study.
To determine the utility of the HACOR score in predicting weaning failure in resource-limited settings. The primary objective was to determine a cut-off value of the HACOR score, sensitivity, and specificity to predict failed weaning. The secondary objective was to determine which out of five components of the score was significantly different between the successful weaning and the failed weaning groups. Most weaning indices are either inaccurate or are dependent on complex ventilatory parameters, which are difficult to measure in resource-limited settings. This study aimed to determine the utility of the HACOR score consisting of heart rate, acidosis, consciousness level, oxygenation, and respiratory rate as a predictor of weaning in the intensive care unit. It was a prospective observational study on 120 patients between 18 and 90 years. The HACOR score was evaluated at 30 minutes of spontaneous breathing trial (SBT). The total duration of SBT was 120 minutes. Out of 120 patients, 83 (69.2%) had successful weaning, whereas 37 (30.8%) had weaning failure. The median and interquartile range (IQR) of the HACOR score in the successful weaning group was 2 (0-3) and 6 (5-8) in the failed weaning group (p-value <0.001). There was a significant difference in each of the five components of the HACOR score between the successful and failed weaning groups (p <0.05). HACOR score ≥5 predicted failed weaning, sensitivity 83.8%, specificity 96.4%, area under the curve (AUC) 0.950, and 95% confidence interval (CI) [0.907-0.993], p <0.001. Multivariable logistic regression analysis showed that HACOR score ≥5 is an independent predictor of weaning failure [p <0.001, 95% CI (1.9-4.2), adjusted odds ratio 2.82]. A HACOR score ≥5 is an excellent predictor of weaning failure. This score may be useful as a weaning strategy in the intensive care unit. Chaudhuri S, Gupta N, Adhikari SD, Todur P, Maddani SS, Rao S. Utility of the One-time HACOR Score as a Predictor of Weaning Failure from Mechanical Ventilation: A Prospective Observational Study. Indian J Crit Care Med 2022;26(8):900-905. Prior to the commencement of the study, Institutional Ethics Committee permission was obtained (IEC: 197/2021) and Clinical Trial Registry of India (CTRI) registration was done before recruitment (CTRI/2021/07/035139). We obtained written informed consent from the legally authorized representative prior to recruiting patients for the study.


Plasmodium dihydroorotate dehydrogenase: a promising target for novel anti-malarial chemotherapy.
Malaria remains a globally prevalent infectious disease that leads to significant morbidity and mortality. While there are a number of drugs approved for its treatment, drug resistance has compromised most of them, making the development of new drugs for the treatment and prevention of malaria essential. The completion of the Plasmodium falciparum genome and a growing understanding of parasite biology are fueling the search for novel drug targets. Despite this, few targets have been chemically validated in vivo. The pyrimidine biosynthetic pathway illustrates one of the best examples of successful identification of anti-malarial drug targets. This review focuses on recent studies to exploit the fourth enzyme in the de novo pyrimidine biosynthetic pathway of P. falciparum, dihydroorotate dehydrogenase (PfDHODH), as a new target for drug discovery. Several chemical scaffolds have been identified by high throughput screening as potent inhibitors of PfDHODH and these show strong selectivity for the malarial enzyme over that from the human host. Potent activity against parasites in whole cell models with good correlation between activity on the enzyme and the parasite have also been observed for a number of the identified series. Lead optimization of a triazolopyrimidine-based series has identified an analog with prolonged plasma exposure, that is orally bioavailable, and which shows good efficacy against the in vivo mouse model of the disease. These data provide strong evidence that PfDHODH is a validated target for the identification of new antimalarial chemotherapy. The challenge remains to identify compounds with the necessary combination of potency and metabolic stability to allow identification of a clinical candidate.


Automatic physiological waveform processing for FMRI noise correction and analysis.
Functional MRI resting state and connectivity studies of brain focus on neural fluctuations at low frequencies which share power with physiological fluctuations originating from lung and heart. Due to the lack of automated software to process physiological signals collected at high magnetic fields, a gap exists in the processing pathway between the acquisition of physiological data and its use in fMRI software for both physiological noise correction and functional analyses of brain activation and connectivity. To fill this gap, we developed an open source, physiological signal processing program, called PhysioNoise, in the python language. We tested its automated processing algorithms and dynamic signal visualization on resting monkey cardiac and respiratory waveforms. PhysioNoise consistently identifies physiological fluctuations for fMRI noise correction and also generates covariates for subsequent analyses of brain activation and connectivity.


Pediatric bloodstream infections in Cambodia, 2007 to 2011.
Pediatric bacterial bloodstream infections (BSIs) are a major cause of morbidity and mortality worldwide. Epidemiological data from resource-limited settings in southeast Asia, such as Cambodia, are sparse but have important implications for treatment and public health strategies. We retrospectively investigated BSI in children at a pediatric hospital and its satellite clinic in Siem Reap, Cambodia, from January 1, 2007, to July 31, 2011. The range of bacterial pathogens and their antimicrobial susceptibility patterns were analyzed in conjunction with demographic, clinical and outcome data. Of 7682 blood cultures with results (99.9% of cultures taken), 606 (7.9%) episodes of BSI were identified in 588 children. The incidence of BSI increased from 14 to 50/1000 admissions (P < 0.001); this was associated with an increased sampling rate. Most BSI were community acquired (89.1%). Common pathogens included Salmonella Typhi (22.8% of all isolates), Staphylococcus aureus (12.2%), Streptococcus pneumoniae (10.0%), Klebsiella pneumoniae (6.4%) and Escherichia coli (6.3%). 21.5% of BSI were caused by a diverse group of uncommon organisms, the majority of which were environmental Gram-negative species. No Listeria monocytogenes or Group B streptococcal BSI were identified. Antimicrobial resistance, particularly among the Enterobacteriaceae, was common. Overall mortality was substantial (19.0%), higher in neonates (36.9%) and independently associated with meningitis/meningoencephalitis and K. pneumoniae infection. BSI is a common problem in Cambodian children attending hospital and associated with significant mortality. Further studies are needed to clarify the epidemiology of neonatal sepsis, the contribution of atypical organisms and the epidemiology of pneumococcal disease before the introduction of vaccine.


Protein mimicry of DNA from crystal structures of the uracil-DNA glycosylase inhibitor protein and its complex with Escherichia coli uracil-DNA glycosylase.
Uracil-DNA glycosylase (UDG), which is a critical enzyme in DNA base-excision repair that recognizes and removes uracil from DNA, is specifically and irreversably inhibited by the thermostable uracil-DNA glycosylase inhibitor protein (Ugi). A paradox for the highly specific Ugi inhibition of UDG is how Ugi can successfully mimic DNA backbone interactions for UDG without resulting in significant cross-reactivity with numerous other enzymes that possess DNA backbone binding affinity. High-resolution X-ray crystal structures of Ugi both free and in complex with wild-type and the functionally defective His187Asp mutant Escherichia coli UDGs reveal the detailed molecular basis for duplex DNA backbone mimicry by Ugi. The overall shape and charge distribution of Ugi most closely resembles a midpoint in a trajectory between B-form DNA and the kinked DNA observed in UDG:DNA product complexes. Thus, Ugi targets the mechanism of uracil flipping by UDG and appears to be a transition-state mimic for UDG-flipping of uracil nucleotides from DNA. Essentially all the exquisite shape, electrostatic and hydrophobic complementarity for the high-affinity UDG-Ugi interaction is pre-existing, except for a key flip of the Ugi Gln19 carbonyl group and Glu20 side-chain, which is triggered by the formation of the complex. Conformational changes between unbound Ugi and Ugi complexed with UDG involve the beta-zipper structural motif, which we have named for the reversible pairing observed between intramolecular beta-strands. A similar beta-zipper is observed in the conversion between the open and closed forms of UDG. The combination of extremely high levels of pre-existing structural complementarity to DNA binding features specific to UDG with key local conformational changes in Ugi resolves the UDG-Ugi paradox and suggests a potentially general structural solution to the formation of very high affinity DNA enzyme-inhibitor complexes that avoid cross- reactivity.


Hypoxia-Induced Fibroblast Growth Factor 11 Stimulates Osteoclast-Mediated Resorption of Bone.
Over-activation of osteoclasts is directly responsible for pathological bone loss in conditions such as rheumatoid arthritis and cancer metastasis to bone. Hypoxia is a common feature of these conditions, associated with poor prognosis, which also stimulates osteoclast-mediated bone resorption via induction of the hypoxia-inducible transcription factor HIF-1α. Here, we investigate the effects of fibroblast growth factor 11 (FGF11) on osteoclast function. FGF11 is an intracellular FGF that was induced both by hypoxia (2% O2, p < 0.01) and by inhibition of the HIF-regulating prolyl hydroxylase enzymes (CoCl2, p < 0.001) in osteoclasts. Isoform-specific siRNA demonstrated that the induction of Fgf11 mRNA expression by hypoxia is HIF-1α-dependent (p < 0.01). Hypoxic stimulation of bone resorption was inhibited in osteoclasts treated with siRNA targeting FGF11 (p < 0.05). This was at least partially due to reduced secretion of an unidentified pro-resorptive factor downstream of FGF11. FGF11 expression within hypoxic, resorbing osteoclasts co-localised with microtubule-associated alpha-tubulin. FGF11 was also abundantly expressed in osteoclasts within the rheumatoid synovium and in giant cell tumour of bone. This study suggests FGF11 as a novel factor driving pathological bone resorption in osteolytic disease and as a potential target for the development of new anti-resorptive therapeutic agents.


Terminal drought-tolerant pearl millet [Pennisetum glaucum (L.) R. Br.] have high leaf ABA and limit transpiration at high vapour pressure deficit.
It was previously shown that pearl millet genotypes carrying a terminal drought tolerance quantitative trait locus (QTL) had a lower transpiration rate (Tr; g cm(-2) d(-1)) under well-watered conditions than sensitive lines. Here experiments were carried out to test whether this relates to leaf abscisic acid (ABA) and Tr concentration at high vapour pressure deficit (VPD), and whether that leads to transpiration efficiency (TE) differences. These traits were measured in tolerant/sensitive pearl millet genotypes, including near-isogenic lines introgressed with a terminal drought tolerance QTL (NIL-QTLs). Most genotypic differences were found under well-watered conditions. ABA levels under well-watered conditions were higher in tolerant genotypes, including NIL-QTLs, than in sensitive genotypes, and ABA did not increase under water stress. Well-watered Tr was lower in tolerant than in sensitive genotypes at all VPD levels. Except for one line, Tr slowed down in tolerant lines above a breakpoint at 1.40-1.90 kPa, with the slope decreasing >50%, whereas sensitive lines showed no change in that Tr response across the whole VPD range. It is concluded that two water-saving (avoidance) mechanisms may operate under well-watered conditions in tolerant pearl millet: (i) a low Tr even at low VPD conditions, which may relate to leaf ABA; and (ii) a sensitivity to higher VPD that further restricts Tr, which suggests the involvement of hydraulic signals. Both traits, which did not lead to TE differences, could contribute to absolute water saving seen in part due to dry weight increase differences. This water saved would become critical for grain filling and deserves consideration in the breeding of terminal drought-tolerant lines.


MicroRNA-365 inhibits growth, invasion and metastasis of malignant melanoma by targeting NRP1 expression.
The role of miR-365 in cancer cells seemed controversial in previous studies. We thereby in this article aimed to define the role of miR-365 in malignant melanoma (MM) pathogenesis. We detected miR-365 expression in malignant melanoma cell lines and then investigated the effects of miR-365 on the metastasis and malignancy of melanoma cells. The correlation between miR-365 level and NRP1 (neuropilin1) was further investigated in clinical malignant melanoma specimens. MiR-365 was strongly down-regulated in malignant melanoma (MM) tissues and cell lines, and its expression levels were associated with lymph node metastasis and clinical stage, as well as overall survival and replase-free survival of MM. We also found that ectopic expression of miR-365 inhibited MM cell proliferation and MM metastasis in vitro and in vivo. We further identified a novel mechanism of miR-365 to suppress MM growth and metastasis. NRP1 was proved to be a direct target of miR-365, using luciferase assay and western blot. NRP1 over-expression in miR-365 expressing cells could rescue invasion and growth defects of miR-365. In addition, miR-365 expression inversely correlated with NRP1 protein levels in MM. Our data suggest that miR-365 functions as a tumor suppressor in MM development and progression, and holds promise as a prognostic biomarker and potential therapeutic target for MM.


Illness representations of restricting back pain: the older Person's perspective.
Back pain is the most common type of pain reported by older adults, leading to considerable morbidity and cost. Yet little is known about the segment of the population ≥80 years old that can be used to guide care in this age group. Illness representations provide a useful framework to understand older adults' beliefs and perceptions of their back pain. The objective of this study was to understand illness representations of back pain, severe enough to restrict activity (restricting back pain). Qualitative research using semi-structured interviews. Twenty-three community-living older adults ≥80 years old with restricting back pain. We used an interview guide to stimulate discussion about how older adults understand and perceive living with restricting back pain. Thematic codes were created to categorize the nuances of participants' restricting back pain experiences. Participants reported five important components of illness representation: 1) identity,the label and symptoms individuals assign to the illness; 2) timeline, the individual's perceived clinical course of the illness; 3) cause, the individual's perceived etiology of the illness; 4) consequences,the perceived impact of the illness; and 5) cure control,the perceived degree to which cure or management is possible/likely. Thematic analysis revealed that restricting back pain in older adults has variable and noteworthy physical, psychological and social consequences.There are several components of the illness representation of restricting back pain, specifically,the perceptions of consequences and control that may offer potential targets for clinical intervention.


Systemic administration of 17beta-estradiol reduces apoptotic cell death and improves functional recovery following traumatic spinal cord injury in rats.
Recent evidence indicates that estrogen exerts neuroprotective effects in both brain injury and neurodegenerative diseases. We examined the protective effect of estrogen on functional recovery after spinal cord injury (SCI) in rats. 17beta-estradiol (3, 100, or 300 microg/kg) was administered intravenously 1-2 h prior to injury (pre-treatment), and animals were then subjected to a mild, weight-drop spinal cord contusion injury. Estradiol treatment significantly improved hind limb motor function as determined by the Basso-Beattie-Bresnahan (BBB) locomotor open field behavioral rating test. Fifteen to 30 days after SCI, BBB scores were significantly higher in estradiol-treated (100 microg/kg) rats when compared to vehicle-treated rats. Morphological analysis showed that lesion sizes increased progressively in either vehicle-treated or 17beta-estradiol-treated spinal cords. However, in response to treatment with 17beta-estradiol, the lesion size was significantly reduced 18-28 days after SCI when compared to vehicle-treated controls. Terminal deoxynucleotidyl transferase-mediated UTP nickend labeling (TUNEL) staining and DNA gel electrophoresis revealed that apoptotic cell death peaked 24-48 h after injury. Also, SCI induced a marked increase in activated caspase-3 in the spinal cord, evident by 4 h after injury. However, administration of 17beta-estradiol significantly reduced the SCI-induced increase in apoptotic cell death and caspase-3 activity after SCI. Furthermore, 17beta-estradiol significantly increased expression of the anti-apoptotic genes, bcl-2 and bcl-x, after SCI while expression of the pro-apoptotic genes, bad and bax, was not affected by drug treatment. Finally, intravenous administration of 17beta-estradiol (100 microg/kg) immediately after injury (post-treatment) also significantly improved hind limb motor function 19-30 days after SCI compared to vehicle-treated controls. These data suggest that after SCI, 17 beta-estradiol treatment improved functional recovery in the injured rat, in part, by reducing apoptotic cell death.


Capturing Public Opinion on Public Health Topics: A Comparison of Experiences from a Systematic Review, Focus Group Study, and Analysis of Online, User-Generated Content.
Capturing public opinion toward public health topics is important to ensure that services, policy, and research are aligned with the beliefs and priorities of the general public. A number of approaches can be used to capture public opinion. We are conducting a program of work on the effectiveness and acceptability of health promoting financial incentive interventions. We have captured public opinion on financial incentive interventions using three methods: a systematic review, focus group study, and analysis of online user-generated comments to news media reports. In this short editorial-style piece, we compare and contrast our experiences with these three methods. Each of these methods had their advantages and disadvantages. Advantages include tailoring of the research question for systematic reviews, probing of answers during focus groups, and the ability to aggregate a large data set using online user-generated content. However, disadvantages include needing to update systematic reviews, participants conforming to a dominant perspective in focus groups, and being unable to collect respondent characteristics during analysis of user-generated online content. That said, analysis of user-generated online content offers additional time and resource advantages, and we found it elicited similar findings to those obtained via more traditional methods, such as systematic reviews and focus groups. A number of methods for capturing public opinions on public health topics are available. Public health researchers, policy makers, and practitioners should choose methods appropriate to their aims. Analysis of user-generated online content, especially in the context of news media reports, may be a quicker and cheaper alternative to more traditional methods, without compromising on the breadth of opinions captured.


Effect of genetic variants in two chemokine decoy receptor genes, DARC and CCBP2, on metastatic potential of breast cancer.
The inhibitory effect of two chemokine decoy receptors (CDRs), DARC and D6, on breast cancer metastasis is mainly due to their ability to sequester pro-malignant chemokines. We hypothesized that genetic variants in the DARC and CCBP2 (encoding D6) genes may be associated with breast cancer progression. In the present study, we evaluated the genetic contributions of DARC and CCBP2 to metastatic potential, indicated by lymph node metastasis (LNM). Ten single-nucleotide polymorphisms (SNPs) (potentially functional SNPs and block-based tagging SNPs) in DARC and CCBP2 were genotyped in 785 breast cancer patients who had negative lymph nodes and 678 patients with positive lymph nodes. Two non-synonymous SNPs, rs12075 (G42D) in DARC and rs2228468 (S373Y) in CCBP2, were observed to be associated with LNM in univariate analysis and remained significant after adjustment for conventional clinical risk factors, with odds ratios (ORs) of 0.54 (95% confidence interval [CI], 0.37 to 0.79) and 0.78 (95% CI, 0.62 to 0.98), respectively. Additional functional experiments revealed that both of these significant SNPs could affect metastasis of breast cancer in xenograft models by differentially altering the chemokine sequestration ability of their corresponding proteins. Furthermore, heterozygous GD genotype of G42D on human erythrocytes had a significantly stronger chemokine sequestration ability than homozygous GG of G42D ex vivo. Our data suggest that the genetic variants in the CDR genes are probably associated with the varied metastatic potential of breast cancer. The underlying mechanism, though it needs to be further investigated, may be that CDR variants could affect the chemokine sequestration ability of CDR proteins.


The action potential of Dionaea muscipula Ellis.
The intention of this investigation was to acquire more concise information about the nature of the action potential of Dionaea muscipula Ellis and the different types of cells generating and conducting it. It is shown by microelectrode measurements that, besides the sensory cells, all the major tissues of the trap lobes are excitable, firing action potentials with pronounced after-hyperpolarizations. The action potentials are strictly dependent on Ca(2+). Their peak depolarizations are shifted 25-27 mV in a positive direction after a tenfold increase in external Ca(2+) concentration. Perfusions with 1 mM ethylene glycol-bis(β-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) or 1 mM LaCl3 completely inhibit excitability. Magnesium ions only slightly affect the peak depolarizations but considerably prolong action potentials. Sodium azide and 2,4-dinitrophenol also abolish excitation, probably by reducing the intracellular ATP concentration. Furthermore, it is tested whether the sensory cells can be distinguished from the other cells of the trap by their electrical behaviour. The resting potentials of sensory cells (-161±7 mV) and mesophyll cells (-155±8 mV) are of the same magnitude. Changes in external ion concentrations affect resting and action potentials in both cell types in a similar way. Additional freeze-fracture studies of both cell types reveal similar numbers and distributions of intramembrane particles on the fracture faces of the plasma membrane, which is most likely the mechanosensor. These findings stress the view that the high mechanosensitivity of the sensory hair results from its anatomy and not from a specialized perception mechanism. It is proposed that trap closure is triggered by a rise in the cytoplasmic concentration of Ca(2+) or a Ca(2+)-activated regulatory complex, which must exceed a threshold concentration. Since the Ca(2+) influx during a single action potential does not suffice to reach this threshold, at least two stimulations of the trap are necessary to elicit movement.


Long-term dynamics of production in western Mediterranean seagrass meadows: Trade-offs and legacies of past disturbances.
Seagrasses are marine angiosperms that can form highly productive, and valuable underwater meadows, which are currently in regression. A reliable assessment of their status and future evolution requires studies encompassing long-term temporal scales. With the aim of understanding seagrass ecosystem dynamics over the last centuries and millennia, twelve sediment cores were studied from seagrass meadows located along the Andalusian coast and at the Cabrera Island (western Mediterranean). This study is pioneer in using Fourier Transform Infrared (FTIR) spectroscopy as a tool to study environmental change in seagrass sediments. FTIR is a form of vibrational spectroscopy that provides information about the sediment chemical composition. Principal Component Analysis (PCA) was used to summarise spatio-temporal data of the FTIR vibratory peaks in combination with climate and geochemical proxy data. Several PCA signals were identified: (1) one likely related to the relative changes of the main primary producers and the sedimentary environment (carbonate or siliciclastic sediments, with aromatic or aliphatic organic matter); (2) the marine community production (polysaccharides, total organic matter content and biogenic silica); and (3) the seagrass production (aromatics, carbohydrates, phenols, proteins and lipids). A decrease of seagrass production along the mainland coast was evident since AD ~1850, which may be due to combined negative impacts of seawater warming, local anthropogenic impacts, and extreme setting conditions. The legacy of these combined stressors might have influenced the current poor state of seagrass meadows in the Alboran Sea. Our results also revealed a significant long-term trade-off between the level of seagrass production and its temporal stability (calculated as the inverse of the coefficient of variation). This study provides a reliable baseline data, helping to assess the magnitude of seagrass regression and its drivers. This paleoecological information can help design more targeted management plans and identify meadows where local management could be more efficient.


[Analysis of parent-child sleeping and living habits related to later bedtimes in children].
To find the relationship between parents' sleeping and living behaviors and their children's sleeping habits, and to investigate factors specifically related to children staying up late in recent Japan. During regular health check-ups of children at three local health centers in the city A, we recruited the parents of one-and-half-year-old and three-year-old children to participate in the Child Sleep Cohort Project (ChiSCoP). Parents of 184 children who consented to participation were mailed three questionnaires by placement method. These are "sleeping diary for 10 days," "sleeping and lifetime rhythm survey," and "emotional behavior assessment scale (CBCL : Child Behavior Checklist 2rd/3rd edition)," of which valid data on 178 children were collected over two years and analyzed. Participants' demographic data, perceived and actual sleeping and living habits, and bedtime patterns were compared among the groups classified by bedtime of children. Bedtimes were classified as early (before 21 : 00), normal (21 : 00 to 21 : 59), and late (after 22 : 00). Using one-way analysis of variance with two (early vs. late) and three bedtime categories, significant differences were found among the three bedtime categories about childcare environmental factors (meal, daytime activity, TV, nap, and bath). So we performed logistic regression analysis with "late bedtime" as the dependent variable and scores of environmental factors (upper or lower than median values) as independent variables in a stepwise manner to eliminate collinear variables and to obtain adjusted odds ratios. 1) Among the 178 children, 96 and 82 were recruited during the physical check-up for one-and-half-year-old and three-years-old, respectively. There were 49, 72, and 57 children in the early, normal, and late bedtime groups, respectively, and no significant difference in attribute factors was found. 2) In children of the early bedtime group, proportions of those with "efforts to establish good life rhythm" (P < 0.0001), "efforts to cultivate sleeping habits" (P < 0.0001), and "keeping a regular bedtime" (P < 0.05) were significantly higher, as well as for children who had more than 105 minutes of "daytime nap" compared to children who had less (P < 0.05). 3) Children's bedtimes were significantly correlated with "mother's wake-up time on weekdays" (r = 0.33) and "mother's bedtime on weekdays" (r = 0.33). Children's wake-up times were also correlated with "mother's wake-up time on weekdays and weekends" (r = 0.49) and "mother's bedtime on weekdays" (r = 0.34), which indicates that children's wake-up times had relationship with mother's sleeping and life habits. 4) Later "wake-up time on weekends" (odds ratio = 4.9) and "regular bedtime hour" (odds ratio = 3.53) were found to be the determinant of late bedtimes of children. To encourage earlier bedtimes in children, it is important to take he mother's sleeping and living habits into account and to maintain a regular wake-up and bedtime schedule across weekdays and weekends.


Antitumor vascular strategy for controlling experimental metastatic spread of human small-cell lung cancer cells with ZD6474 in natural killer cell-depleted severe combined immunodeficient mice.
Small-cell lung cancer is often characterized by rapid growth and metastatic spread. Because tumor growth and metastasis are angiogenesis dependent, there is great interest in therapeutic strategies that aim to inhibit tumor angiogenesis. The effect of ZD6474, an orally available inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and epidermal growth factor tyrosine kinases, was studied in experimental multiple-organ metastasis models with human small-cell lung cancer cell lines (SBC-3 or SBC-5) in natural killer cell-depleted severe combined immunodeficient mice. Intravenously inoculated SBC-5 cells produced experimental metastases in the liver, lung, and bone whereas SBC-3 cells produced the metastases in the liver, systemic lymph nodes, and kidneys. Daily oral treatment with ZD6474 (50 mg/kg), started on day 14 (after the establishment of micrometastases), significantly reduced the frequency of large (>3 mm) metastatic colonies (in the liver and lymph nodes) and osteolytic bone lesions. ZD6474 treatment did not significantly reduce the frequency of small (<2-3 mm) metastatic lesions found in the lung (SBC-5) or kidney (SBC-3), consistent with an antiangiogenic mechanism of action. Immunohistochemical analysis of SBC-5 metastatic deposits in the liver showed that ZD6474 treatment inhibited VEGFR-2 activation and induced apoptosis of tumor-associated endothelial cells, resulting in decreasing tumor microvessel density. ZD6474 treatment was also associated with a decrease in tumor cell proliferation and an increase in tumor cell apoptosis. The antitumor effects of ZD6474 were considered likely to be due to inhibition of VEGFR-2 tyrosine kinase because gefitinib, a small-molecule inhibitor of epidermal growth factor receptor tyrosine kinase, was inactive in these models. These results suggest that ZD6474 may be of potential therapeutic value in inhibiting the growth of metastatic small-cell lung cancer in humans. Phase II trials with ZD6474 are currently ongoing in a range of solid tumors.


Two-year evaluation of Borrelia burgdorferi culture and supplemental tests for definitive diagnosis of Lyme disease.
Lyme disease is usually diagnosed and treated based on clinical manifestations. However, laboratory testing is useful for patients with confusing presentations and for validation of disease in clinical studies. Although cultivation of Borrelia burgdorferi is definitive, prior investigations have shown that no single test is optimal for Lyme disease diagnosis. We applied high-volume blood culture, skin biopsy culture, PCR, and serodiagnosis to a cohort of patients with suspected Lyme disease acquired in Maryland and southern Pennsylvania. The study was performed to confirm the relative utility of culture and to identify laboratory testing algorithms that will supplement clinical diagnosis. Overall, 30 of 86 patients (35%) were culture positive, whereas an additional 15 of 84 (18%) were seropositive only (51% total sero- and culture positive), and PCR on skin biopsy identified 4 additional patients who were neither culture nor seropositive. Among 49 laboratory test-positive patients, the highest sensitivity (100%) for diagnosis was obtained when culture, skin PCR, and serologic tests were used, although serologic testing with skin PCR was almost as sensitive (92%). Plasma PCR was infrequently positive and provided no additional diagnostic value. Although culture is definitive and has a relatively high sensitivity, the results required a mean of 3.5 weeks to recovery. The combination of acute-phase serology and skin PCR was 75% sensitive, offering a practical and relatively rapid alternative for confirming clinical impression. The full battery of tests could be useful for patients with confusing clinical signs or for providing strong laboratory support for clinical studies of Lyme disease.


Pandemic H1N1 influenza vaccine induces a recall response in humans that favors broadly cross-reactive memory B cells.
We have previously shown that broadly neutralizing antibodies reactive to the conserved stem region of the influenza virus hemagglutinin (HA) were generated in people infected with the 2009 pandemic H1N1 strain. Such antibodies are rarely seen in humans following infection or vaccination with seasonal influenza virus strains. However, the important question remained whether the inactivated 2009 pandemic H1N1 vaccine, like the infection, could also induce these broadly neutralizing antibodies. To address this question, we analyzed B-cell responses in 24 healthy adults immunized with the pandemic vaccine in 2009. In all cases, we found a rapid, predominantly IgG-producing vaccine-specific plasmablast response. Strikingly, the majority (25 of 28) of HA-specific monoclonal antibodies generated from the vaccine-specific plasmablasts neutralized more than one influenza strain and exhibited high levels of somatic hypermutation, suggesting they were derived from recall of B-cell memory. Indeed, memory B cells that recognized the 2009 pandemic H1N1 HA were detectable before vaccination not only in this cohort but also in samples obtained before the emergence of the pandemic strain. Three antibodies demonstrated extremely broad cross-reactivity and were found to bind the HA stem. Furthermore, one stem-reactive antibody recognized not only H1 and H5, but also H3 influenza viruses. This exceptional cross-reactivity indicates that antibodies capable of neutralizing most influenza subtypes might indeed be elicited by vaccination. The challenge now is to improve upon this result and design influenza vaccines that can elicit these broadly cross-reactive antibodies at sufficiently high levels to provide heterosubtypic protection.


In vitro comparative bond strength of contemporary self-adhesive resin cements to zirconium oxide ceramic with and without air-particle abrasion.
This study compared shear bond strengths of six self-adhesive resin cements to zirconium oxide ceramic with and without air-particle abrasion. One hundred twenty zirconia samples were air-abraded (group SB; n = 60) or left untreated (group NO). Composite cylinders were bonded to the zirconia samples with either BisCem (BC), Maxcem (MC), G-Cem (GC), RelyX Unicem Clicker (RUC), RelyX Unicem Applicator (RUA), or Clearfil SA Cement (CSA). Shear bond strength was tested after thermocycling, and data were analyzed with analysis of variance and Holm-Sidak pairwise comparisons. Without abrasion, RUA (8.0 MPa), GC (7.9 MPa), and CSA (7.6 MPa) revealed significantly higher bond strengths than the other cements. Air-particle abrasion increased bond strengths for all test cements (p < 0.001). GC (22.4 MPa) and CSA (18.4 MPa) revealed the highest bond strengths in group SB. Bond strengths of self-adhesive resin cements to zirconia were increased by air-particle abrasion. Cements containing adhesive monomers (MDP/4-META) were superior to other compositions.


Treatment of unfavourable results of flexor tendon surgery: Skin deficiencies.
We recently reported a small study at the Federation of European Societies for Surgery of the hand, which was entitled 'What is secondary flexor tendon surgery'? This study concluded that 'secondary flexor tendon surgery' was a generic name encompassing a multitude of pathologies. Between 10% and 15% of cases exhibited pathology of the skin and subcutaneous fat and required flap reconstruction of these tissues. Skin replacement may be used prophylactically at primary surgery or become necessary at secondary surgery after release of scar contractures, to achieve cover of vital structures. The long-term problem of skin deficiency relating to flexor tendon function is one of loss of extension from longitudinal scar shortening of the integument, even if the flexor tendons are primarily concerned with bending the digits, not straightening them. This loss of extension can only be tolerated in a hand to a certain degree without significant loss of function. This paper is largely an analysis of the flaps available and suitable for different degrees of skin deficiency and at different places along the course of the flexor system. It attempts to dispel the idea that 'any flap will do' provided the flexors are adequately covered.


Complex structural variants in Mendelian disorders: identification and breakpoint resolution using short- and long-read genome sequencing.
Studies have shown that complex structural variants (cxSVs) contribute to human genomic variation and can cause Mendelian disease. We aimed to identify cxSVs relevant to Mendelian disease using short-read whole-genome sequencing (WGS), resolve the precise variant configuration and investigate possible mechanisms of cxSV formation. We performed short-read WGS and analysis of breakpoint junctions to identify cxSVs in a cohort of 1324 undiagnosed rare disease patients. Long-read WGS and gene expression analysis were used to resolve one case. We identified three pathogenic cxSVs: a de novo duplication-inversion-inversion-deletion affecting ARID1B, a de novo deletion-inversion-duplication affecting HNRNPU and a homozygous deletion-inversion-deletion affecting CEP78. Additionally, a de novo duplication-inversion-duplication overlapping CDKL5 was resolved by long-read WGS demonstrating the presence of both a disrupted and an intact copy of CDKL5 on the same allele, and gene expression analysis showed both parental alleles of CDKL5 were expressed. Breakpoint analysis in all the cxSVs revealed both microhomology and longer repetitive elements. Our results corroborate that cxSVs cause Mendelian disease, and we recommend their consideration during clinical investigations. We show that resolution of breakpoints can be critical to interpret pathogenicity and present evidence of replication-based mechanisms in cxSV formation.


Skin sensitizers differentially regulate signaling pathways in MUTZ-3 cells in relation to their individual potency.
Due to the recent European legislations posing a ban of animal tests for safety assessment within the cosmetic industry, development of in vitro alternatives for assessment of skin sensitization is highly prioritized. To date, proposed in vitro assays are mainly based on single biomarkers, which so far have not been able to classify and stratify chemicals into subgroups, related to risk or potency. Recently, we presented the Genomic Allergen Rapid Detection (GARD) assay for assessment of chemical sensitizers. In this paper, we show how the genome wide readout of GARD can be expanded and used to identify differentially regulated pathways relating to individual chemical sensitizers. In this study, we investigated the mechanisms of action of a range of skin sensitizers through pathway identification, pathway classification and transcription factor analysis and related this to the reactive mechanisms and potency of the sensitizing agents. By transcriptional profiling of chemically stimulated MUTZ-3 cells, 33 canonical pathways intimately involved in sensitization to chemical substances were identified. The results showed that metabolic processes, cell cycling and oxidative stress responses are the key events activated during skin sensitization, and that these functions are engaged differently depending on the reactivity mechanisms of the sensitizing agent. Furthermore, the results indicate that the chemical reactivity groups seem to gradually engage more pathways and more molecules in each pathway with increasing sensitizing potency of the chemical used for stimulation. Also, a switch in gene regulation from up to down regulation, with increasing potency, was seen both in genes involved in metabolic functions and cell cycling. These observed pathway patterns were clearly reflected in the regulatory elements identified to drive these processes, where 33 regulatory elements have been proposed for further analysis. This study demonstrates that functional analysis of biomarkers identified from our genomics study of human MUTZ-3 cells can be used to assess sensitizing potency of chemicals in vitro, by the identification of key cellular events, such as metabolic and cell cycling pathways.


Canadian Society of Nephrology Commentary on the 2012 KDIGO clinical practice guideline for glomerulonephritis: management of glomerulonephritis in adults.
The KDIGO (Kidney Disease: Improving Global Outcomes) clinical practice guideline for management of glomerulonephritis was recently released. The Canadian Society of Nephrology convened a working group to review the recommendations and comment on their relevancy and applicability to the Canadian context. A subgroup of adult nephrologists reviewed the guideline statements for management of glomerular disease in adults and agreed with most of the guideline statements developed by KDIGO. This commentary highlights areas for which there is lack of evidence and areas in need of translation of evidence into clinical practice. Areas of controversy or uncertainty, including the choice of second-line agents, are discussed in more detail. Existing practice variation also is addressed. The relevance of treatment recommendations to the Canadian practitioner is discussed.


Comparison of the effects of morphine-lidocaine-ketamine and fentanyl-lidocaine-ketamine combinations administered as constant rate infusions on postprocedure rectal temperature in dogs.
To compare the effects of morphine-lidocaine-ketamine (MLK) and fentanyl-lidocaine-ketamine (FLK) combinations administered as constant rate infusions (CRIs) during and after veterinary procedures on postprocedure rectal temperature in dogs. 32 clinically normal client-owned dogs undergoing nonemergent procedures. Dogs were randomly assigned to receive an MLK or FLK combination (16 dogs/group). During the procedure, each dog received 2% lidocaine hydrochloride (1 mg/kg/h; both groups), ketamine hydrochloride (0.6 mg/kg/h; both groups), and morphine (0.36 mg/kg/h; MLK group) or fentanyl (4 μg/kg/h; FLK group) via CRI for analgesia; esophageal temperature was maintained at 37° to 39°C. At extubation, each drug dose in each assigned combination was halved and administered (via CRI) for 12 additional hours for postprocedure analgesia. Rectal temperature and other data were recorded at baseline (prior to administration of premedicants), extubation (0 hours), and 0.5, 1.5, 3, 6, and 12 hours thereafter. Mean postprocedure rectal temperature was significantly lower at each postextubation time point for the MLK group, compared with corresponding values for the FLK group. Compared with the baseline value, mean postprocedure rectal temperature was significantly lower at 0, 0.5, 1.5, and 3 hours for the FLK group and at all postprocedure time points for the MLK group. Hypothermia (rectal temperature < 37°C) was detected at ≥ 1 postprocedure time point more often in dogs in the MLK group (9/16) than in the FLK group (1/16). Dogs that received an MLK combination for analgesia during and after a veterinary procedure developed hypothermia more commonly than did dogs that received an FLK combination under similar conditions.


IPr# - highly hindered, broadly applicable N-heterocyclic carbenes.
IPr (IPr = 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene) represents the most important NHC (NHC = N-heterocyclic carbene) ligand throughout the field of homogeneous catalysis. Herein, we report the synthesis, catalytic activity, and full structural and electronic characterization of novel, sterically-bulky, easily-accessible NHC ligands based on the hash peralkylation concept, including IPr#, Np# and BIAN-IPr#. The new ligands have been commercialized in collaboration with Millipore Sigma: IPr#HCl, 915653; Np#HCl; 915912; BIAN-IPr#HCl, 916420, enabling broad access of the academic and industrial researchers to new ligands for reaction optimization and screening. In particular, the synthesis of IPr# hinges upon cost-effective, modular alkylation of aniline, an industrial chemical that is available in bulk. The generality of this approach in ligand design is demonstrated through facile synthesis of BIAN-IPr# and Np#, two ligands that differ in steric properties and N-wingtip arrangement. The broad activity in various cross-coupling reactions in an array of N-C, O-C, C-Cl, C-Br, C-S and C-H bond cross-couplings is demonstrated. The evaluation of steric, electron-donating and π-accepting properties as well as coordination chemistry to Au(i), Rh(i) and Pd(ii) is presented. Given the tremendous importance of NHC ligands in homogenous catalysis, we expect that this new class of NHCs will find rapid and widespread application.


Leaf litter traits of invasive species slow down decomposition compared to Spanish natives: a broad phylogenetic comparison.
Leaf traits related to the performance of invasive alien species can influence nutrient cycling through litter decomposition. However, there is no consensus yet about whether there are consistent differences in functional leaf traits between invasive and native species that also manifest themselves through their "after life" effects on litter decomposition. When addressing this question it is important to avoid confounding effects of other plant traits related to early phylogenetic divergences and to understand the mechanism underlying the observed results to predict which invasive species will exert larger effects on nutrient cycling. We compared initial leaf litter traits, and their effect on decomposability as tested in standardized incubations, in 19 invasive-native pairs of co-familial species from Spain. They included 12 woody and seven herbaceous alien species representative of the Spanish invasive flora. The predictive power of leaf litter decomposition rates followed the order: growth form > family > status (invasive vs. native) > leaf type. Within species pairs litter decomposition tended to be slower and more dependent on N and P in invaders than in natives. This difference was likely driven by the higher lignin content of invader leaves. Although our study has the limitation of not representing the natural conditions from each invaded community, it suggests a potential slowing down of the nutrient cycle at ecosystem scale upon invasion.


APC/C(Fzr/Cdh1)-dependent regulation of cell adhesion controls glial migration in the Drosophila PNS.
Interactions between neurons and glia are a key feature during the assembly of the nervous system. During development, glial cells often follow extending axons, implying that axonal outgrowth and glial migration are precisely coordinated. We found that the anaphase-promoting complex/cyclosome (APC/C) co-activator fizzy-related/Cdh1 (Fzr/Cdh1) is involved in the non-autonomous control of peripheral glial migration in postmitotic Drosophila neurons. APC/C(Fzr/Cdh1) is a cell-cycle regulator that targets proteins that are required for G1 arrest for ubiquitination and subsequent degradation. We found that Fzr/Cdh1 function is mediated by the immunoglobulin superfamily cell adhesion molecule Fasciclin2 (Fas2). In motor neurons Fzr/Cdh1 is crucial for the establishment of a graded axonal distribution of Fas2. Axonal Fas2 interacts homophilically with a glial isoform of Fas2. Glial migration is initiated along axonal segments that have low levels of Fas2 but stalls in axonal domains with high levels of Fas2 on their surfaces. This represents a simple mechanism by which a subcellular gradient of adhesiveness can coordinate glial migration with axonal growth.


Nutrition economics - food as an ally of public health.
Non-communicable diseases (NCD) are a major and increasing contributor to morbidity and mortality in developed and developing countries. Much of the chronic disease burden is preventable through modification of lifestyle behaviours, and increased attention is being focused on identifying and implementing effective preventative health strategies. Nutrition has been identified as a major modifiable determinant of NCD. The recent merging of health economics and nutritional sciences to form the nascent discipline of nutrition economics aims to assess the impact of diet on health and disease prevention, and to evaluate options for changing dietary choices, while incorporating an understanding of the immediate impacts and downstream consequences. In short, nutrition economics allows for generation of policy-relevant evidence, and as such the discipline is a crucial partner in achieving better population nutritional status and improvements in public health and wellness. The objective of the present paper is to summarise presentations made at a satellite symposium held during the 11th European Nutrition Conference, 28 October 2011, where the role of nutrition and its potential to reduce the public health burden through alleviating undernutrition and nutrition deficiencies, promoting better-quality diets and incorporating a role for functional foods were discussed.


Diphosphonates and phosphate homoeostasis in man.
1. The effects of three intravenous diphosphonates (etidronate, clodronate and aminohexane diphosphonate) on phosphate homoeostasis were studied in 30 patients with Paget's disease of bone and in three patients with hypoparathyroidism. 2. In Paget's disease, all three diphosphonates induced significant increases in serum phosphate and renal tubular reabsorption of phosphate. This effect was most marked and persistent after etidronate, whereas in the clodronate- and aminohexane diphosphonate-treated patients the increases were less, of shorter duration and followed thereafter by significant decreases in serum phosphate and renal tubular reabsorption of phosphate. Unlike etidronate, both clodronate and aminohexane diphosphonate caused a significant reduction in serum and urinary calcium, with appropriate homoeostatic increases in immunoassayable parathyroid hormone. 3. Phosphaturic responses to infused parathyroid hormone were observed in two patients with etidronate-induced hyperphosphataemia. 4. In three hypoparathyroid patients, clodronate induced a more marked increase in serum phosphate and renal tubular reabsorption of phosphate than in Paget's disease, which was of comparable degree but of shorter duration than that after etidronate in Paget's disease. 5. These findings suggest that all three diphosphonates increase renal tubular reabsorption of phosphate, but that this effect is attenuated with those diphosphonates which induce secondary hyperparathyroidism.


Antidepressant pharmaceuticals in two U.S. effluent-impacted streams: occurrence and fate in water and sediment, and selective uptake in fish neural tissue.
Antidepressant pharmaceuticals are widely prescribed in the United States; release of municipal wastewater effluent is a primary route introducing them to aquatic environments, where little is known about their distribution and fate. Water, bed sediment, and brain tissue from native white suckers (Catostomus commersoni) were collected upstream and at points progressively downstream from outfalls discharging to two effluent-impacted streams, Boulder Creek (Colorado) and Fourmile Creek (Iowa). A liquid chromatography/tandem mass spectrometry method was used to quantify antidepressants, including fluoxetine, norfluoxetine (degradate), sertraline, norsertraline (degradate), paroxetine, citalopram, fluvoxamine, duloxetine, venlafaxine, and bupropion in all three sample matrices. Antidepressants were not present above the limit of quantitation in water samples upstream from the effluent outfalls but were present at points downstream at ng/L concentrations, even at the farthest downstream sampling site 8.4 km downstream from the outfall. The antidepressants with the highest measured concentrations in both streams were venlafaxine, bupropion, and citalopram and typically were observed at concentrations of at least an order of magnitude greater than the more commonly investigated antidepressants fluoxetine and sertraline. Concentrations of antidepressants in bed sediment were measured at ng/g levels; venlafaxine and fluoxetine were the predominant chemicals observed. Fluoxetine, sertraline, and their degradates were the principal antidepressants observed in fish brain tissue, typically at low ng/g concentrations. A qualitatively different antidepressant profile was observed in brain tissue compared to streamwater samples. This study documents that wastewater effluent can be a point source of antidepressants to stream ecosystems and that the qualitative composition of antidepressants in brain tissue from exposed fish differs substantially from the compositions observed in streamwater and sediment, suggesting selective uptake.


Survivin as a biological biomarker for diagnosis and therapy.
Introduction: Survivin (SVN) is a member of the inhibitor of apoptosis (IAP) protein family that promotes cellular proliferation and inhibits apoptosis. Overexpression of SVN is associated with autoimmune disease, hyperplasia, and tumors and can be used as a biomarker in these diseases. SVN is widely recognized as a tumor-associated antigen (TAA) and has become an important target for cancer diagnosis and treatment.Areas covered: We reviewed SVN research progress from the PubMed and clinical trials focused on SVN from https://clinicaltrials.gov since 2000 and anticipate future developments in the field. The trials reviewed cover various modalities including diagnostics for early detection and disease progression, small molecule inhibitors of the SVN pathway and immunotherapy targeting SVN epitopes.Expert opinion: The most promising developments involve anti-SVN immunotherapy, with several therapeutic SVN vaccines under evaluation in phase I/II trials. SVN is an important new immune-oncology target that expands the repertoire of individualized combination treatments for cancer.


A Novel Method for Estimating Low-Density Lipoprotein (LDL) Levels: Total Cholesterol and Non-High-Density Lipoprotein (HDL) Can Be Used to Predict Abnormal LDL Level in an Apparently Healthy Population.
BACKGROUND We aimed to predict the abnormal LDL level by using TG, TC, HDL, and non-HDL in this study. MATERIAL AND METHODS Triglyceride (TG), total cholesterol (TC), high-density lipoprotein (HDL), and low-density lipoprotein (LDL) data were obtained from the Laboratory Information System (LIS) for 4 years (Oct 1, 2013 to Sept 30, 2017) from among 34 270 healthy Chinese patients at Shuyang People's Hospital. TG, TC, HDL, and LDL (direct clearance method) were measured using a TBA2000FR biochemical analyzer. The non-HDL was calculated as TC minus HDL. Correlations between TG, TC, non-HDL, and LDL were analyzed using Spearman's rank correlation. Receiver operating characteristics (ROC) curve analysis was used to evaluate the predictive utility of TG, TC, and non-HDL for the abnormal LDL level (<130 mg/dL). RESULTS Both TC (r=0.870) and non-HDL (r=0.893) were significantly positively correlated with LDL. The area under curve of TC and non-HDL can be used to predict abnormal LDL levels. Optimal thresholds were 182.5 mg/Dl (4.72 mmol/L) for TC and 135.3 mg/Dl (3.50 mmol/L) for non-HDL. Based on these optimal thresholds, less than 0.5% and 0.4% of tests with elevated LDL were missed using TC and non-HDL, respectively, but the value of these missed LDL levels was not very high (<147.3 mg/dL). CONCLUSIONS If the value of non-HDL is less than 135.3 mg/Dl (3.50 mmol/L) and/or TC is less than 182.5 mg/Dl (4.72 mmol/L) for the apparently healthy populations, the LDL level will be less than 130 mg/Dl (3.36 mmol/L). TC and non-HDL can be used to predict the abnormal LDL level in apparently healthy populations.


Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts.
Defects in the availability of haem substrates or the catalytic activity of the terminal enzyme in haem biosynthesis, ferrochelatase (Fech), impair haem synthesis and thus cause human congenital anaemias. The interdependent functions of regulators of mitochondrial homeostasis and enzymes responsible for haem synthesis are largely unknown. To investigate this we used zebrafish genetic screens and cloned mitochondrial ATPase inhibitory factor 1 (atpif1) from a zebrafish mutant with profound anaemia, pinotage (pnt (tq209)). Here we describe a direct mechanism establishing that Atpif1 regulates the catalytic efficiency of vertebrate Fech to synthesize haem. The loss of Atpif1 impairs haemoglobin synthesis in zebrafish, mouse and human haematopoietic models as a consequence of diminished Fech activity and elevated mitochondrial pH. To understand the relationship between mitochondrial pH, redox potential, [2Fe-2S] clusters and Fech activity, we used genetic complementation studies of Fech constructs with or without [2Fe-2S] clusters in pnt, as well as pharmacological agents modulating mitochondrial pH and redox potential. The presence of [2Fe-2S] cluster renders vertebrate Fech vulnerable to perturbations in Atpif1-regulated mitochondrial pH and redox potential. Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Fech to synthesize haem, resulting in anaemia. The identification of mitochondrial Atpif1 as a regulator of haem synthesis advances our understanding of the mechanisms regulating mitochondrial haem homeostasis and red blood cell development. An ATPIF1 deficiency may contribute to important human diseases, such as congenital sideroblastic anaemias and mitochondriopathies.


Performance of re-used pacemakers and implantable cardioverter defibrillators compared with new devices at Groote Schuur Hospital in Cape Town, South Africa.
Little is known about the performance of re-used pacemakers and implantable cardioverter defibrillators (ICDs) in Africa. We sought to compare the risk of infection and the rate of malfunction of re-used pacemakers and ICDs with new devices implanted at Groote Schuur Hospital in Cape Town, South Africa. This was a retrospective case comparison study of the performance of re-used pacemakers and ICDs in comparison with new devices implanted at Groote Schuur Hospital over a 10-year period. The outcomes were incidence of device infection, device malfunction, early battery depletion, and device removal due to infection, malfunction, or early battery depletion. Data for 126 devices implanted in 126 patients between 2003 and 2013 were analysed, of which 102 (81%) were pacemakers (51 re-used and 51 new) and 24 (19%) were ICDs (12 re-used and 12 new). There was no device infection, malfunction, early battery depletion or device removal in either the re-used or new pacemaker groups over the median follow up of 15.1 months [interquartile range (IQR), 1.3-36.24 months] for the re-used pacemakers, and 55.8 months (IQR, 20.3-77.8 months) for the new pacemakers. In the ICD group, no device infection occurred over a median follow up of 35.9 months (IQR, 17.0-70.9 months) for the re-used ICDs and 45.7 months (IQR, 37.6-53.7 months) for the new ICDs. One device delivered inappropriate shocks, which resolved without intervention and with no harm to the patient. This re-used ICD subsequently needed generator replacement 14 months later. In both the pacemaker and ICD groups, there were no procedure-non-related infections documented for the respective follow-up periods. No significant differences were found in performance between re-used and new pacemakers and ICDs with regard to infection rates, device malfunction, battery life and device removal for complications. Pacemaker and ICD re-use is feasible and safe and is a viable option for patients with bradyarrhythmias and tachyarrthythmias.


The family approach at each moment.
In this paper I have demonstrated some of the skills involved in an approach to the entire family at each moment. I have focused on a family approach in well child care, episodic care for children, and adolescent pregnancy and have demonstrated how such an approach is essentially preventive. The traditional relationship of the family physician with individuals, usually women and mothers, creates an implicit alliance with the symptom bearer which may work contrary to the goals of treatment. Avoidance of hidden alliances and open communication with all members of the family permit the doctor to engage with families in a relationship which is both preventive and therapeutic.


Plasticity in gene transcription explains the differential performance of two invasive fish species.
Phenotypic plasticity buffers organisms from environmental change and is hypothesized to aid the initial establishment of nonindigenous species in novel environments and postestablishment range expansion. The genetic mechanisms that underpin phenotypically plastic traits are generally poorly characterized; however, there is strong evidence that modulation of gene transcription is an important component of these responses. Here, we use RNA sequencing to examine the transcriptional basis of temperature tolerance for round and tubenose goby, two nonindigenous fish species that differ dramatically in the extent of their Great Lakes invasions despite similar invasion dates. We used generalized linear models of read count data to compare gene transcription responses of organisms exposed to increased and decreased water temperature from those at ambient conditions. We identify greater response in the magnitude of transcriptional changes for the more successful round goby compared with the less successful tubenose goby. Round goby transcriptional responses reflect alteration of biological function consistent with adaptive responses to maintain or regain homeostatic function in other species. In contrast, tubenose goby transcription patterns indicate a response to stressful conditions, but the pattern of change in biological functions does not match those expected for a return to homeostatic status. Transcriptional plasticity plays an important role in the acute thermal tolerance for these species; however, the impaired response to stress we demonstrate in the tubenose goby may contribute to their limited invasion success relative to the round goby. Transcriptional profiling allows the simultaneous assessment of the magnitude of transcriptional response as well as the biological functions involved in the response to environmental stress and is thus a valuable approach for evaluating invasion potential.


Method of making mosaic gratings by using a two-color heterodyne interferometer containing a reference grating.
We propose and demonstrate a two-color heterodyne interferometric method for making a perfect mosaic of two planar gratings that can substitute for a single and larger grating without introducing wavefront aberration at any wavelength. The lateral and longitudinal phase errors are separated and eliminated by use of two wavelengths in the interferometry. The accuracy of the phase difference measurement is improved by this heterodyne scheme. The method ensures that the lateral gap between the two subaperture gratings is an integer multiple of the grating period. For a pair of 0.72 microm period gratings we experimentally achieved a lateral alignment error of less than 1% of the grating period.


Variation in species-level plant functional traits over wetland indicator status categories.
Wetland indicator status (WIS) describes the habitat affinity of plant species and is used in wetland delineations and resource inventories. Understanding how species-level functional traits vary across WIS categories may improve designations, elucidate mechanisms of adaptation, and explain habitat optima and niche. We investigated differences in species-level traits of riparian flora across WIS categories, extending their application to indicate hydrologic habitat. We measured or compiled data on specific leaf area (SLA), stem specific gravity (SSG), seed mass, and mature height of 110 plant species that occur along the Colorado River in Grand Canyon, Arizona. Additionally, we measured leaf δ13C, δ15N, % carbon, % nitrogen, and C/N ratio of 56 species with C3 photosynthesis. We asked the following: (i) How do species-level traits vary over WIS categories? (ii) Does the pattern differ between herbaceous and woody species? (iii) How well do multivariate traits define WIS categories? (iv) Which traits are correlated? The largest trait differences among WIS categories for herbaceous species occurred for SSG, seed mass, % leaf carbon and height, and for woody species occurred for height, SSG, and δ13C. SSG increased and height decreased with habitat aridity for both woody and herbaceous species. The δ13C and hence water use efficiency of woody species increased with habitat aridity. Water use efficiency of herbaceous species increased with habitat aridity via greater occurrence of C4 grasses. Multivariate trait assemblages differed among WIS categories. Over all species, SLA was correlated with height, δ13C, % leaf N, and C/N; height was correlated with SSG and % leaf C; SSG was correlated with % leaf C. Adaptations of both herbaceous and woody riparian species to wet, frequently inundated habitats include low-density stem tissue. Adaptations to drier habitats in the riparian zone include short, high-density cavitation-resistant stem tissue, and high water use efficiency. The results enhance understanding about using traits to describe plant habitat in riparian systems.


Effects of high salinity, high temperature and pH on capsid structure of white spot syndrome virus.
The structural stability of white spot syndrome virus (WSSV) capsids at high salinity, high temperature and various pH values was studied. To obtain the viral capsids, the nucleocapsids were treated with high salinity. The results showed that high salinity treatment can cause the dissociation of VP15 and most of VP95 from the nucleocapsid, but there were no noticeable alterations in morphology and ultrastructure of the nucleocapsid and capsid. The capsids retained morphological integrity at temperatures <45°C but became aberrant at >60°C. In addition, the capsids were relatively resistant to strong acid conditions and were tolerant to a broad pH range of 1 to 10. However, morphological change occurred at pH 10.5. The capsids broke up into small pieces at pH 11 and completely degraded in 0.1 and 1.0 M NaOH. These results indicated that the WSSV capsid is acid-stable and alkali-labile.


HCFA and the states: politics and intergovernmental leverage.
In this article, we seek to explain variations in the Health Care Financing Administration's (HCFA) relationship to state governments. After reviewing several alternative models of the policy-making process, we argue that the utility of each model depends on certain issue characteristics, especially salience and conflict. We further argue that HCFA's choice of intergovernmental tools, rooted in a political setting, depends on the same issue characteristics. We illustrate our arguments by examining HCFA's behavior during the Clinton administration and by focusing on four cases: HMO performance measurement, nursing home regulation, lead screening for children, and the Children's Health Insurance Program (CHIP).


Formation and remodeling of epithelial polarity.
Polarity is a fundamental property of all eukaryotic cells that underlies many developmental processes. A recent EMBO workshop (March 27-31) organized by Thomas Lecuit, Norbert Perrimon, and Keith Mostov brought cell and developmental biologists together on the Mediterranean coast near Marseille, France, to share views on how epithelium polarity is established and remodeled during development and disease. Participants witnessed and celebrated the emerging convergence of intellectual and experimental approaches to address how individual cells acquire polarity and form polarized tissues in the context of developing embryos.


Pneumothorax after transthoracic needle biopsy of lung lesions under CT guidance.
Transthoracic needle biopsy (TTNB) is done with imaging guidance and most frequently by a radiologist, for the aim is to diagnose a defined mass. It is integral in the diagnosis and treatment of many thoracic diseases, and is an important alternative to more invasive surgical procedures. FNAC is a method of aspiration cytopathology, which with transthoracic biopsy ("core biopsy") is a group of percutaneous minimally invasive diagnostic procedures for exploration of lung lesions. Needle choice depends mostly upon lesion characteristics and location. A recent innovation in biopsy needles has been the introduction of automatic core biopsy needle devices that yield large specimens and improve the diagnostic accuracy of needle biopsy. Both computed tomography and ultrasound may be used as imaging guidance for TTNB, with CT being more commonly utilized. Common complications of TTNB include pneumothorax and hemoptysis. The incidence of pneumothorax in patients undergoing TTNB has been reported to be from 9-54%, according to reports published in the past ten years, with an average of around 20%. Which factors statistically correlate with the frequency of pneumothorax remain controversial, but most reports have suggested that lesion size, depth and the presence of emphysema are the main factors influencing the incidence of pneumothorax after CT-guided needle biopsy. On the contrary, gender, age, and the number of pleural passes have not been shown to correlate with the incidence of pneumothorax. The problem most responsible for complicating outpatient management, after needle biopsy was performed, is not the presence of the pneumothorax per se, but an increase in the size of the pneumothorax that requires chest tube placement and patient hospitalization. Although it is a widely accepted procedure with relatively few complications, precise planning and detailed knowledge of various aspects of the biopsy procedure is mandatory to avert complications.


The fusion kinase ITK-SYK mimics a T cell receptor signal and drives oncogenesis in conditional mouse models of peripheral T cell lymphoma.
Peripheral T cell lymphomas (PTCLs) are highly aggressive malignancies with poor prognosis. Their molecular pathogenesis is not well understood and small animal models for the disease are lacking. Recently, the chromosomal translocation t(5;9)(q33;q22) generating the interleukin-2 (IL-2)-inducible T cell kinase (ITK)-spleen tyrosine kinase (SYK) fusion tyrosine kinase was identified as a recurrent event in PTCL. We show that ITK-SYK associates constitutively with lipid rafts in T cells and triggers antigen-independent phosphorylation of T cell receptor (TCR)-proximal proteins. These events lead to activation of downstream pathways and acute cellular outcomes that correspond to regular TCR ligation, including up-regulation of CD69 or production of IL-2 in vitro or deletion of thymocytes and activation of peripheral T cells in vivo. Ultimately, conditional expression of patient-derived ITK-SYK in mice induces highly malignant PTCLs with 100% penetrance that resemble the human disease. Our work demonstrates that constitutively enforced antigen receptor signaling can, in principle, act as a powerful oncogenic driver. Moreover, we establish a robust clinically relevant and genetically tractable model of human PTCL.


Reducing obesity prejudice in medical education.
Healthcare worker attitudes toward obese individuals facilitate discrimination and contribute to poor health outcomes. Previous studies have demonstrated medical student bias toward obese individuals, but few have examined effects of the educational environment on these prejudicial beliefs. We sought to determine whether an innovative educational intervention (reading a play about obesity) could diminish obesity prejudice relative to a standard medical lecture. We conducted a randomized, controlled trial enrolling medical students (n = 129) from three universities. Students were assigned to play-reading or a standard lecture. Explicit attitudes and implicit bias toward obese individuals were assessed prior to intervention and after four months. At baseline, students demonstrated moderate explicit and implicit bias toward obese people despite high scores on empathy. Students randomized to the play-reading group had significantly decreased explicit fat bias (P = 0.01) at follow-up, while students in the lecture group showed increased endorsement of a prescriptive model of care at the expense of a patient-centered approach (P = 0.03). There was a significant increase in empathy for those in both the theater (P = 0.007) and lecture group (P = 0.02). The intervention had no significant effect on implicit bias or regard for obesity as a civil rights issue. Dramatic reading may be superior to traditional medical lectures for showcasing patient rights and preferences. The present study demonstrates for the first time that play-reading diminishes conscious obesity bias. Further research should determine whether nontraditional methods of instruction promote improved understanding of and care for obese patients.


Genotype and phenotype of 101 dutch patients with congenital stationary night blindness.
To investigate the relative frequency of the genetic causes of the Schubert-Bornschein type of congenital stationary night blindness (CSNB) and to determine the genotype-phenotype correlations in CSNB1 and CSNB2. Clinic-based, longitudinal, multicenter study. A total of 39 patients with CSNB1 from 29 families and 62 patients with CSNB2 from 43 families. Patients underwent full ophthalmologic and electrophysiologic examinations. On the basis of standard electroretinograms (ERGs), patients were diagnosed with CSNB1 or CSNB2. Molecular analysis was performed by direct Sanger sequencing of the entire coding regions in NYX, TRPM1, GRM6, and GPR179 in patients with CSNB1 and CACNA1F and CABP4 in patients with CSNB2. Data included genetic cause of CSNB, refractive error, visual acuity, nystagmus, strabismus, night blindness, photophobia, color vision, dark adaptation (DA) curve, and standard ERGs. A diagnosis of CSNB1 or CSNB2 was based on standard ERGs. The photopic ERG was the most specific criterion to distinguish between CSNB1 and CSNB2 because it showed a "square-wave" appearance in CSNB1 and a decreased b-wave in CSNB2. Mutations causing CSNB1 were found in NYX (20 patients, 13 families), TRPM1 (10 patients, 9 families), GRM6 (4 patients, 3 families), and GPR179 (2 patients, 1 family). Congenital stationary night blindness 2 was primarily caused by mutations in CACNA1F (55 patients, 37 families). Only 3 patients had causative mutations in CABP4 (2 families). Patients with CSNB1 mainly had rod-related problems, and patients with CSNB2 had rod- and cone-related problems. The visual acuity on average was better in CSNB1 (0.30 logarithm of the minimum angle of resolution [logMAR]) than in CSNB2 (0.52 logMAR). All patients with CSNB1 and only 54% of the patients with CSNB2 reported night blindness. The dark-adapted threshold was on average more elevated in CSNB1 (3.0 log) than in CSNB2 (1.8 log). The 3 patients with CABP4 had a relative low visual acuity, were hyperopic, had severe nonspecific color vision defects, and had only 1.0 log elevated DA threshold. Congenital stationary night blindness 1, despite different causative mutations, shows 1 unique CSNB1 phenotype. Congenital stationary night blindness 2 caused by mutations in CABP4 merely shows cone-related problems and therefore appears to be distinct from CSNB2 caused by mutations in CACNA1F. The author(s) have no proprietary or commercial interest in any materials discussed in this article.


Temperature dependence of normal mode reconstructions of protein dynamics.
Normal mode (NM) analysis is a widely used technique for reconstructing conformational changes of proteins from the knowledge of native structures. In this Letter, we investigate to what extent NMs capture the salient features of the dynamics over a range of temperatures from close to T=0 to above unfolding. We show that the use of normal modes at room temperature is justified provided proteins are cooperative, that is, globular and highly structured. On the other hand, it is imperative to consider several modes in order to eliminate the unpredictable temperature dependence of single-mode contributions to the protein fluctuations.


Universal gestational age effects on cognitive and basic mathematic processing: 2 cohorts in 2 countries.
To determine whether general cognitive ability, basic mathematic processing, and mathematic attainment are universally affected by gestation at birth, as well as whether mathematic attainment is more strongly associated with cohort-specific factors such as schooling than basic cognitive and mathematical abilities. The Bavarian Longitudinal Study (BLS, 1289 children, 27-41 weeks gestational age [GA]) was used to estimate effects of GA on IQ, basic mathematic processing, and mathematic attainment. These estimations were used to predict IQ, mathematic processing, and mathematic attainment in the EPICure Study (171 children <26 weeks GA). For children born <34 weeks GA, each lower week decreased IQ and mathematic attainment scores by 2.34 (95% CI: -2.99, -1.70) and 2.76 (95% CI: -3.40, -2.11) points, respectively. There were no differences among children born 34-41 weeks GA. Similarly, for children born <36 weeks GA, mathematic processing scores decreased by 1.77 (95% CI: -2.20, -1.34) points with each lower GA week. The prediction function generated using BLS data accurately predicted the effect of GA on IQ and mathematic processing among EPICure children. However, these children had better attainment than predicted by BLS. Prematurity has adverse effects on basic mathematic processing following birth at all gestations <36 weeks and on IQ and mathematic attainment <34 weeks GA. The ability to predict IQ and mathematic processing scores from one cohort to another among children cared for in different eras and countries suggests that universal neurodevelopmental factors may explain the effects of gestation at birth. In contrast, mathematic attainment may be improved by schooling.


Cardiovascular disease and type 2 diabetes in evolutionary perspective: a critical role for helminths?
Heart disease and type 2 diabetes are commonly believed to be rare among contemporary subsistence-level human populations, and by extension prehistoric populations. Although some caveats remain, evidence shows these diseases to be unusual among well-studied hunter-gatherers and other subsistence populations with minimal access to healthcare. Here we expand on a relatively new proposal for why these and other populations may not show major signs of these diseases. Chronic infections, especially helminths, may offer protection against heart disease and diabetes through direct and indirect pathways. As part of a strategy to insure their own survival and reproduction, helminths exert multiple cardio-protective effects on their host through their effects on immune function and blood lipid metabolism. Helminths consume blood lipids and glucose, alter lipid metabolism, and modulate immune function towards Th-2 polarization - which combined can lower blood cholesterol, reduce obesity, increase insulin sensitivity, decrease atheroma progression, and reduce likelihood of atherosclerotic plaque rupture. Traditional cardiometabolic risk factors, coupled with the mismatch between our evolved immune systems and modern, hygienic environments may interact in complex ways. In this review, we survey existing studies in the non-human animal and human literature, highlight unresolved questions and suggest future directions to explore the role of helminths in the etiology of cardio-metabolic disease.


Assessment of impacts produced by anthropogenic sources in a little city near an important industrial area (Modugno, Southern Italy).
An annual monitoring campaign of VOCs, consisting of twelve sampling periods, was carried out from June 2008 to June 2009 in Modugno, a city located in the Apulia region (Southern Italy), in order to assess the urban air quality, identify the main emission sources, and quantify the cancer and no-cancer risk attributable to inhalation exposures. Monitoring, carried out by using the Radiello diffusive samplers, was conducted in eleven sampling sites throughout the city taking into account the traffic density and the architecture of the city. From the study of the data, it was found that, among all considered VOCs, benzene, toluene, ethylbenzene, and xylenes (BTEX) are the pollutants at higher concentration. The analysis of VOC concentrations, the study of the topography of the city, and the use of different diagnostic ratios between the BTEX species showed that the vehicular traffic emissions were the predominant source of VOCs in the urban area of Modugno. Despite that the annual concentration of benzene is lower than the regulatory limit, the estimation of cancer risk showed that the global lifetime cancer risk attributed to the investigated VOC exposure was not negligible and therefore should be taken into account in future regulatory approaches.


Successful conviction of intoxicated drivers at a level I trauma center.
Conviction rates for drivers driving under the influence (DUI) and in motor vehicle collisions (MVC) presenting to trauma centers are based primarily on data from the 1990s. Our goal was to identify DUI conviction rates of intoxicated drivers in MVCs presenting to a trauma center and to identify factors associated with the failure to obtain a DUI conviction. Retrospective study of adults (>18 years) presenting to a trauma center emergency department (ED) in 2007. Eligible subjects were drivers involved in a MVC with an ED blood alcohol level (BAL) ≥ 80mg/dL. Subjects were matched to their Department of Motor Vehicle (DMV) records to identify DUI convictions from the collision, the legal blood alcohol concentration (BAC), and arresting officer's impression of the driver's sobriety. We entered potential variables predictive of failure to obtain a DUI conviction into a regression model. The 241 included subjects had a mean age of 34.1 ± 12.8 years, and 185 (77%) were male. Successful DUI convictions occurred in 142/241 (58.9%, 95% CI 52.4, 65.2%) subjects. In a regression model, Injury Severity Score > 15 (odds ratio = 2.70 (95% CI 1.06, 6.85)) and a lower ED BAL from 80 to 200mg/dL (odds ratio = 5.03 (95% CI 1.69, 14.9) were independently associated with a failure to obtain a DUI conviction. Slightly more than half of drivers who present to an ED after a MVC receive a DUI conviction. The most severely injured subjects and those with lower BALs are least likely to be convicted of a DUI.


Resolution of components of non-photochemical chlorophyll fluorescence quenching in barley leaves.
Non-photochemical chlorophyll fluorescence quenching (qN) in barley leaves has been analysed by monitoring its relaxation in the dark, by applying saturating pulses of light. At least three kinetically distinct phases to qN recovery are observed, which have previously been identified (Quick and Stitt 1989) as being due to high-energy state quenching ('fast'), excitation energy redistribution due to a state transition ('medium') and photoinhibition ('slow'). However, measurements of chlorophyll fluorescence at 77 K from leaf extracts show that state transitions only occur in low light conditions, whereas the 'medium' component of qN is very large in high light. The source of that part of the 'medium' component not accounted for by a state transition is discussed.


HIV-1 Nef impairs MHC class II antigen presentation and surface expression.
HIV-1-infected cells can avoid cytotoxic T lymphocyte killing by Nef-mediated down-regulation of surface MHC I. Here, we show that HIV-1 Nef inhibits MHC II restricted peptide presentation to specific T cells and thus may affect the induction of antiviral immune responses. Nef mediates this effect by reducing the surface level of mature (i.e., peptide-loaded) MHC II while increasing levels of immature MHC II, which are functionally incompetent because of their association with the invariant chain. Nef was the only HIV-1 gene product to possess this capacity, which was also observed in the context of the whole HIV-1 genome. Other proteins of the endocytic pathway were not affected by Nef expression, suggesting that Nef effects on MHC II did not result from a general alteration of the endocytic pathway. Response patterns to previously characterized mutations of Nef differed for Nef-induced modulation of mature and immature MHC II. Furthermore, the doses of Nef required to observe each of the two effects were clearly different, suggesting that Nef could affect MHC II peptide presentation through distinct mechanisms. Cooperation between those mechanisms may enable Nef to efficiently inhibit MHC II function.


Should in-line filters be used in peripheral intravenous catheters to prevent infusion-related phlebitis? A systematic review of randomized controlled trials.
In this systematic review, we assessed the effect of in-line filters on infusion-related phlebitis associated with peripheral IV catheters. The study was designed as a systematic review and meta-analysis of randomized controlled trials. We used MEDLINE and the Cochrane Controlled Trial Register up to August 10, 2009. Two reviewers independently assessed trial quality and extracted data. Data on phlebitis were combined when appropriate, using a random-effects model. The impact of the risk of phlebitis in the control group (baseline risk) on the effect of in-line filters was studied by using meta-regression based on the bivariate meta-analysis model. The quality of the evidence was determined by using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) method. Eleven trials (1633 peripheral catheters) were included in this review to compare the effect of in-line filters on the incidence of phlebitis in hospitalized patients. Baseline risks across trials ranged from 23% to 96%. Meta-analysis of all trials showed that in-line filters reduced the risk of infusion-related phlebitis (relative risk, 0.66; 95% confidence interval, 0.43-1.00). This benefit, however, is very uncertain, because the trials had serious methodological shortcomings and meta-analysis revealed marked unexplained statistical heterogeneity (P < 0.0000, I(2) = 90.4%). The estimated benefit did not depend on baseline risk. In-line filters in peripheral IV catheters cannot be recommended routinely, because evidence of their benefit is uncertain.


The simultaneous detection of trivalent & hexavalent chromium in exhaled breath condensate: A feasibility study comparing workers and controls.
The analytical method outlined in this feasibility study has been used to show that trivalent chromium (Cr(III)) and hexavalent chromium (Cr(VI)) can be detected and measured in exhaled breath condensate (EBC) samples. EBC samples and urine samples were collected from a cohort of 58 workers occupationally exposed to hexavalent chromium compounds and 22 unexposed volunteers (control group). Levels of Cr(III) and Cr(VI) were determined in EBC samples and total chromium levels were determined in urine samples. Pre and post working week samples for both EBC and urine were collected in tandem. Total chromium in urine samples was analysed by inductively coupled plasma mass spectrometry (ICP-MS). Analysis of Cr(III) and Cr(VI) in EBC samples used a hyphenated micro liquid chromatography (μLC) system coupled to an ICP-MS. Separation was achieved using an anion exchange micro-sized column. The results showed that the occupationally exposed workers had significantly higher levels of Cr(III) and Cr(VI) in their EBC samples than the control group, as well as higher levels of total chromium in their urine samples. However, for the exposed workers no significant difference was found between pre and post working week EBC samples for either Cr(III) or Cr(VI). This study has established that Cr(III) and Cr(VI) can simultaneously be detected and measured in 'real' EBC samples and will help in understanding inhalation exposure.


Epigenetic control of intestinal barrier function and inflammation in zebrafish.
The intestinal epithelium forms a barrier protecting the organism from microbes and other proinflammatory stimuli. The integrity of this barrier and the proper response to infection requires precise regulation of powerful immune homing signals such as tumor necrosis factor (TNF). Dysregulation of TNF leads to inflammatory bowel diseases (IBD), but the mechanism controlling the expression of this potent cytokine and the events that trigger the onset of chronic inflammation are unknown. Here, we show that loss of function of the epigenetic regulator ubiquitin-like protein containing PHD and RING finger domains 1 (uhrf1) in zebrafish leads to a reduction in tnfa promoter methylation and the induction of tnfa expression in intestinal epithelial cells (IECs). The increase in IEC tnfa levels is microbe-dependent and results in IEC shedding and apoptosis, immune cell recruitment, and barrier dysfunction, consistent with chronic inflammation. Importantly, tnfa knockdown in uhrf1 mutants restores IEC morphology, reduces cell shedding, and improves barrier function. We propose that loss of epigenetic repression and TNF induction in the intestinal epithelium can lead to IBD onset.