Bugs as drugs, Part 1: Insects: the "new" alternative medicine for the 21st century?
Insects and insect-derived products have been widely used in folk healing in many parts of the world since ancient times. Promising treatments have at least preliminarily been studied experimentally. Maggots and honey have been used to heal chronic and post-surgical wounds and have been shown to be comparable to conventional dressings in numerous settings. Honey has also been applied to treat burns. Honey has been combined with beeswax in the care of several dermatologic disorders, including psoriasis, atopic dermatitis, tinea, pityriasis versicolor, and diaper dermatitis. Royal jelly has been used to treat postmenopausal symptoms. Bee and ant venom have reduced the number of swollen joints in patients with rheumatoid arthritis. Propolis, a hive sealant made by bees, has been utilized to cure aphthous stomatitis. Cantharidin, a derivative of the bodies of blister beetles, has been applied to treat warts and molluscum contagiosum. Combining insects with conventional treatments may provide further benefit.


Feedback suppression of meal-induced glucagon-like peptide-1 (GLP-1) secretion mediated through elevations in intact GLP-1 caused by dipeptidyl peptidase-4 inhibition: a randomized, prospective comparison of sitagliptin and vildagliptin treatment.
To compare directly the clinical effects of vildagliptin and sitagliptin in patients with type 2 diabetes, with a special emphasis on incretin hormones and L-cell feedback inhibition induced by dipeptidyl peptidase (DPP-4) inhibition. A total of 24 patients (12 on a diet/exercise regimen, 12 on metformin) were treated, in randomized order, for 7-9 days, with either vildagliptin (50 mg twice daily = 100 mg/d), sitagliptin (100 mg once daily in those on diet, 50 mg twice daily in those on metformin treatment = 100 mg/d) or placebo (twice daily). A mixed-meal test was performed. Intact glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide concentrations were doubled by both DPP-4 inhibitors. Meal-related total GLP-1 responses were reduced by vildagliptin and sitagliptin treatment alike in the majority of patients (vildagliptin: p = 0.0005; sitagliptin: p = 0.019), but with substantial inter-individual variation. L-cell feedback appeared to be more pronounced in those whose intact GLP-1 relative to total GLP-1 increased more, and who had greater reductions in fasting plasma glucose after DPP-4 inhibition. K-cell feedback inhibition overall was not significant. There were no differences in any of the clinical variables (glycaemia, insulin and glucagon secretory responses) between vildagliptin and sitagliptin treatment. Vildagliptin and sitagliptin affected incretin hormones, glucose concentrations, insulin and glucagon secretion in a similar manner. Inter-individual variations in L-cell feedback inhibition may indicate heterogeneity in the clinical response to DPP-4 inhibition.


Successful generation of structural information for fragment-based drug discovery.
Fragment-based drug discovery relies upon structural information for efficient compound progression, yet it is often challenging to generate structures with bound fragments. A summary of recent literature reveals that a wide repertoire of experimental procedures is employed to generate ligand-bound crystal structures successfully. We share in-house experience from setting up and executing fragment crystallography in a project that resulted in 55 complex structures. The ligands span five orders of magnitude in affinity and the resulting structures are made available to be of use, for example, for development of computational methods. Analysis of the results revealed that ligand properties such as potency, ligand efficiency (LE) and, to some degree, clogP influence the success of complex structure generation.


Structural Features of PbS Nanocube Monolayers upon Treatment with Mono- and Dicarboxylic Acids and Thiols at a Liquid-Air Interface.
This paper describes the ordering of PbS nanocubes (NCs) within free-standing monolayers (suspended on acetonitrile), upon exchanging the native oleate ligands for a series of thiolate and carboxylate ligands at the liquid-air interface. Treatment with either carboxylic acids or thiols effectively decreases the inter-NC separation of nearest-neighbor particles without etching the NC surface. Dicarboxylic acids and dithiols bridge neighboring NCs with an interparticle separation that is consistent with fully extended, bridging ligands. Monocarboxylic acids and monothiols separate NCs by an amount governed by their length, with long-chain ligands showing significant intercalation. (1)H NMR spectroscopy shows carboxylic acids are more effective at replacing the native oleate than are thiols, which we ascribe to the lower pKa values of carboxylic acids. The fast exchange that occurs upon treatment with monocarboxylic acids kinetically traps the clusters of particles in nonclosed packed geometries, so monolayers treated with monocarboxylic acids are, on average, less ordered than those treated with monothiols. Ex situ electron microscopy and grazing incidence small-angle X-ray scattering (GISAXS) analyses of deposited films on Si/SiO2 substrates show that NCs exchanged with nonbridging ligands pack more efficiently at long length scales than do NCs exchanged with bridging ligands, due primarily to the creation of defects within the NC lattice in response to the rigidity of the bridging ligand.


Understanding the essentials of drug interactions: a potential need for safe and effective use of drugs.
Drug interactions (DIs) represent an important and widely under recognized source of medication errors. An interaction is said to occur when the effects of one drug are changed by the presence of another drug(s), food, drink or an environmental chemical. When a therapeutic combination could lead to an unexpected change in the condition of the patient, this would be described as an interaction of potential clinical significance. DIs can arise in numerous ways; such as pharmacodynamic interaction, in which receptor effects of different agents interacts to produce synergy or antagonism of drug effects. In pharmacokinetic interaction, the blood levels of given agents may be raised or lowered based on the type of interaction. Special attention and thorough monitoring is needed for the patients who are predisposed to develop DIs and those on drugs with narrow therapeutic index. DIs can be a very important contributory factor for the occurrence of adverse drug reactions and adverse drug events. DIs monitoring programs should be initiated and strengthened in order to minimize their occurrence. Herbal drug interactions and DIs comprising over the counter medicines should also be considered seriously.


Approaching environmental health disparities and green spaces: an ecosystem services perspective.
Health disparities occur when adverse health conditions are unequal across populations due in part to gaps in wealth. These disparities continue to plague global health. Decades of research suggests that the natural environment can play a key role in sustaining the health of the public. However, the influence of the natural environment on health disparities is not well-articulated. Green spaces provide ecosystem services that are vital to public health. This paper discusses the link between green spaces and some of the nation's leading health issues such as obesity, cardiovascular health, heat-related illness, and psychological health. These associations are discussed in terms of key demographic variables—race, ethnicity, and income. The authors also identify research gaps and recommendations for future research.


Isolated fractures of the lesser trochanter in children.
In a retrospective study of 1126 children with fractures of the proximal third of the femur, three children were found to have isolated fractures of the lesser trochanter. This fracture occurred from a fall in one child and following sporting activities, without a history of injury, in the others. In the latter children, the clinical presentations were similar to those of children with transient synovitis of the hip or Perthes disease. In each child, plain radiographs showed an avulsion fracture of the bony portion of the lesser trochanter. Early and complete recovery followed symptomatic treatment even when there was marked proximal displacement of the avulsed segment of the lesser trochanter.


Experimental measurement of the photonic properties of icosahedral quasicrystals.
Quasicrystalline structures may have optical bandgap properties-frequency ranges in which the propagation of light is forbidden-that make them well-suited to the scientific and technological applications for which photonic crystals are normally considered. Such quasicrystals can be constructed from two or more types of dielectric material arranged in a quasiperiodic pattern whose rotational symmetry is forbidden for periodic crystals (such as five-fold symmetry in the plane and icosahedral symmetry in three dimensions). Because quasicrystals have higher point group symmetry than ordinary crystals, their gap centre frequencies are closer and the gaps widths are more uniform-optimal conditions for forming a complete bandgap that is more closely spherically symmetric. Although previous studies have focused on one-dimensional and two-dimensional quasicrystals, where exact (one-dimensional) or approximate (two-dimensional) band structures can be calculated numerically, analogous calculations for the three-dimensional case are computationally challenging and have not yet been performed. Here we circumvent the computational problem by doing an experiment. Using stereolithography, we construct a photonic quasicrystal with centimetre-scale cells and perform microwave transmission measurements. We show that three-dimensional icosahedral quasicrystals exhibit sizeable stop gaps and, despite their quasiperiodicity, yield uncomplicated spectra that allow us to experimentally determine the faces of their effective Brillouin zones. Our studies confirm that they are excellent candidates for photonic bandgap materials.


Regulation of 3-phosphoinositide-dependent protein kinase-1 (PDK1) by Src involves tyrosine phosphorylation of PDK1 and Src homology 2 domain binding.
3-Phosphoinositide-dependent protein kinase-1 (PDK1) appears to play a central regulatory role in many cell signalings between phosphoinositide-3 kinase and various intracellular serine/threonine kinases. In resting cells, PDK1 is known to be constitutively active and is further activated by tyrosine phosphorylation (Tyr(9) and Tyr(373/376)) following the treatment of the cell with insulin or pervanadate. However, little is known about the mechanisms for this additional activation of PDK1. Here, we report that the SH2 domain of Src, Crk, and GAP recognized tyrosine-phosphorylated PDK1 in vitro. Destabilization of PDK1 induced by geldanamycin (a Hsp90 inhibitor) was partially blocked in HEK 293 cells expressing PDK1-Y9F. Co-expression of Hsp90 enhanced PDK1-Src complex formation and led to further increased PDK1 activity toward PKB and SGK. Immunohistochemical analysis with anti-phospho-Tyr(9) antibodies showed that the level of Tyr(9) phosphorylation was markedly increased in tumor samples compared with normal. Taken together, these data suggest that phosphorylation of PDK1 on Tyr(9), distinct from Tyr(373/376), is important for PDK1/Src complex formation, leading to PDK1 activation. Furthermore, Tyr(9) phosphorylation is critical for the stabilization of both PDK1 and the PDK1/Src complex via Hsp90-mediated protection of PDK1 degradation.


Supervised exercise therapy versus home-based exercise therapy versus walking advice for intermittent claudication.
Although supervised exercise therapy (SET) provides significant symptomatic benefit for patients with intermittent claudication (IC), it remains an underutilized tool. Widespread implementation of SET is restricted by lack of facilities and funding. Structured home-based exercise therapy (HBET) with an observation component (e.g., exercise logbooks, pedometers) and just walking advice (WA) are alternatives to SET. This is the second update of a review first published in 2006. The primary objective was to provide an accurate overview of studies evaluating effects of SET programs, HBET programs, and WA on maximal treadmill walking distance or time (MWD/T) for patients with IC. Secondary objectives were to evaluate effects of SET, HBET, and WA on pain-free treadmill walking distance or time (PFWD/T), quality of life, and self-reported functional impairment. The Cochrane Vascular Information Specialist searched the Cochrane Vascular Specialised Register (December 16, 2016) and the Cochrane Central Register of Controlled Trials (2016, Issue 11). We searched the reference lists of relevant studies identified through searches for other potential trials. We applied no restriction on language of publication. We included parallel-group randomized controlled trials comparing SET programs with HBET programs and WA in participants with IC. We excluded studies in which control groups did not receive exercise or walking advice (maintained normal physical activity). We also excluded studies comparing exercise with percutaneous transluminal angioplasty, bypass surgery, or drug therapy. Three review authors (DH, HF, and LG) independently selected trials, extracted data, and assessed trials for risk of bias. Two other review authors (MvdH and JT) confirmed the suitability and methodological quality of trials. For all continuous outcomes, we extracted the number of participants, mean outcome, and standard deviation for each treatment group through the follow-up period, if available. We extracted Medical Outcomes Study Short Form 36 outcomes to assess quality of life, and Walking Impairment Questionnaire outcomes to assess self-reported functional impairment. As investigators used different scales to present results of walking distance and time, we standardized reported data to effect sizes to enable calculation of an overall standardized mean difference (SMD). We obtained summary estimates for all outcome measures using a random-effects model. We assessed the quality of evidence using the GRADE approach. For this update, we included seven additional studies, making a total of 21 included studies, which involved a total of 1400 participants: 635 received SET, 320 received HBET, and 445 received WA. In general, SET and HBET programs consisted of three exercise sessions per week. Follow-up ranged from six weeks to two years. Most trials used a treadmill walking test to investigate effects of exercise therapy on walking capacity. However, two trials assessed only quality of life, functional impairment, and/or walking behavior (i.e., daily steps measured by pedometer). The overall methodological quality of included trials was moderate to good. However, some trials were small with respect to numbers of participants, ranging from 20 to 304.SET groups showed clear improvement in MWD/T compared with HBET and WA groups, with overall SMDs at three months of 0.37 (95% confidence interval [CI] 0.12 to 0.62; P = 0.004; moderate-quality evidence) and 0.80 (95% CI 0.53 to 1.07; P < 0.00001; high-quality evidence), respectively. This translates to differences in increased MWD of approximately 120 and 210 meters in favor of SET groups. Data show improvements for up to six and 12 months, respectively. The HBET group did not show improvement in MWD/T compared with the WA group (SMD 0.30, 95% CI -0.45 to 1.05; P = 0.43; moderate-quality evidence).Compared with HBET, SET was more beneficial for PFWD/T but had no effect on quality of life parameters nor on self-reported functional impairment. Compared with WA, SET was more beneficial for PFWD/T and self-reported functional impairment, as well as for some quality of life parameters (e.g., physical functioning, pain, and physical component summary after 12 months), and HBET had no effect.Data show no obvious effects on mortality rates. Thirteen of the 1400 participants died, but no deaths were related to exercise therapy. Overall, adherence to SET was approximately 80%, which was similar to that reported with HBET. Only limited adherence data were available for WA groups. Evidence of moderate and high quality shows that SET provides an important benefit for treadmill-measured walking distance (MWD and PFWD) compared with HBET and WA, respectively. Although its clinical relevance has not been definitively demonstrated, this benefit translates to increased MWD of 120 and 210 meters after three months in SET groups. These increased walking distances are likely to have a positive impact on the lives of patients with IC. Data provide no clear evidence of a difference between HBET and WA. Trials show no clear differences in quality of life parameters nor in self-reported functional impairment between SET and HBET. However, evidence is of low and very low quality, respectively. Investigators detected some improvements in quality of life favoring SET over WA, but analyses were limited by small numbers of studies and participants. Future studies should focus on disease-specific quality of life and other functional outcomes, such as walking behavior and physical activity, as well as on long-term follow-up.


Familiarity affects the assessment of female facial signals of fertility by free-ranging male rhesus macaques.
Animals signal their reproductive status in a range of sensory modalities. Highly social animals, such as primates, have access not only to such signals, but also to prior experience of other group members. Whether this experience affects how animals interpret reproductive signals is unknown. Here, we explore whether familiarity with a specific female affects a male's ability to assess that female's reproductive signals. We used a preferential looking procedure to assess signal discrimination in free-ranging rhesus macaques, a species in which female facial luminance covaries with reproductive status. We collected images of female faces throughout the reproductive cycle, and using faecal hormone analysis to determine ovulation, categorized images as coming from a female's pre-fertile, ovulating, or post-fertile period. We printed colour-calibrated stimuli of these faces, reproducing stimuli perceptually the same in colour and luminance to the original appearance of females. These images were presented to males who were either unfamiliar or familiar with stimuli females. Overall, males distinguished ovulatory from pre-ovulatory faces. However, a significant proportion of males did so only among males familiar with stimuli females. These experiments demonstrate that familiarity may increase a receiver's ability to use a social partner's signals to discern their reproductive status.


Membrane Diffusion Occurs by Continuous-Time Random Walk Sustained by Vesicular Trafficking.
Diffusion in cellular membranes is regulated by processes that occur over a range of spatial and temporal scales. These processes include membrane fluidity, interprotein and interlipid interactions, interactions with membrane microdomains, interactions with the underlying cytoskeleton, and cellular processes that result in net membrane movement. The complex, non-Brownian diffusion that results from these processes has been difficult to characterize, and moreover, the impact of factors such as membrane recycling on membrane diffusion remains largely unexplored. We have used a careful statistical analysis of single-particle tracking data of the single-pass plasma membrane protein CD93 to show that the diffusion of this protein is well described by a continuous-time random walk in parallel with an aging process mediated by membrane corrals. The overall result is an evolution in the diffusion of CD93: proteins initially diffuse freely on the cell surface but over time become increasingly trapped within diffusion-limiting membrane corrals. Stable populations of freely diffusing and corralled CD93 are maintained by an endocytic/exocytic process in which corralled CD93 is selectively endocytosed, whereas freely diffusing CD93 is replenished by exocytosis of newly synthesized and recycled CD93. This trafficking not only maintained CD93 diffusivity but also maintained the heterogeneous distribution of CD93 in the plasma membrane. These results provide insight into the nature of the biological and biophysical processes that can lead to significantly non-Brownian diffusion of membrane proteins and demonstrate that ongoing membrane recycling is critical to maintaining steady-state diffusion and distribution of proteins in the plasma membrane.


Predictors of condom-use among young never-married males in Nigeria.
This study examined the factors that influence condom-use among young never-married males in Nigeria. Such information can help improve the design of a prevention programme for young never-married, especially, males to reduce their vulnerability to sexually transmitted infections (STIs) and HIV/AIDS transmission. Data were derived from the 2003 Nigeria Demographic and Health Survey (NDHS). Analysis of data was restricted to 827 males aged 15-24 years, who had never married or lived together with a woman. Both descriptive and analytical methods were used for assessing the net effects of socioeconomic factors on condom-use. The analysis used logistic regression models for determining the predictors of sexual behaviour and condom-use among young never-married males in Nigeria. About 43% of the study population was sexually experienced, and the use of a condom remained low. One in five reported the use of a condom at sexual debut. Level of education, place of residence in childhood, urban/rural region, religious affiliation, economic status index, and exposure to mass media were associated with sexual experience and use of protective measures. Economic status index and mass-media exposure were associated with the use of a condom by the respondents during their last sex encounter. About two-fifths (43%) of the young unmarried Nigerian men were sexually experienced but the condom-use remained low, thus making this sub-group of Nigerian population highly vulnerable to STIs, including HIV/AIDS.


Relative risks of radiation-associated cancer: comparison of second cancer in therapeutically irradiated populations with the Japanese atomic bomb survivors.
In this paper the radiation-associated relative risks of second primary cancer incidence in groups treated for first primary cancer by radiotherapy are compared with radiation-associated relative risk estimates in the Japanese atomic bomb survivor cancer incidence data. For four cancer sites, namely lung cancer, bone cancer, ovarian cancer and leukaemia, the relative risks in the comparable (age at exposure, time since exposure, sex matched) subsets of the Japanese data are significantly greater than those in the majority of second cancer studies. Even when the differences between the relative risks in the Japanese atomic bomb survivors and the medical series do not approach conventional levels of statistical significance, relative risks tend to be higher in the Japanese data than in the second cancer studies. At least for leukaemia, the discrepancy between the Japanese and second cancer risks can be largely explained by cell-sterilisation effects. There are few indications of modification of radiation-associated second cancer relative risk among those treated with adjuvant chemotherapy, nor are there strong indications of modification of radiation-associated relative risk by heritable genetic factors. If anything, there is evidence that second cancer relative excess risks are lower among those patients with cancer-prone disorders than among non-susceptible patients. However, the higher underlying cancer risk in some of these medically exposed populations should also be considered, in particular for those with cancer-prone conditions, so that the absolute excess risk is sometimes higher than in the Japanese data.


Care managers can be useful for patients with depression but their role must be clear: a qualitative study of GPs' experiences.
Objective: Explore general practitioners' (GPs') views on and experiences of working with care managers for patients treated for depression in primary care settings. Care managers are specially trained health care professionals, often specialist nurses, who coordinate care for patients with chronic diseases. Design: Qualitative content analysis of five focus-group discussions. Setting: Primary health care centers in the Region of Västra Götaland and Dalarna County, Sweden. Subjects: 29 GPs. Main outcome measures: GPs' views and experiences of care managers for patients with depression. Results: GPs expressed a broad variety of views and experiences. Care managers could ensure care quality while freeing GPs from case management by providing support for patients and security and relief for GPs and by coordinating patient care. GPs could also express concern about role overlap; specifically, that GPs are already care managers, that too many caregivers disrupt patient contact, and that the roles of care managers and psychotherapists seem to compete. GPs thought care managers should be assigned to patients who need them the most (e.g. patients with life difficulties or severe mental health problems). They also found that transition to a chronic care model required change, including alterations in the way GPs worked and changes that made depression treatment more like treatment for other chronic diseases. Conclusion: GPs have varied experiences of care managers. As a complementary part of the primary health care team, care managers can be useful for patients with depression, but team members' roles must be clear. KEY POINTS A growing number of primary health care centers are introducing care managers for patients with depression, but knowledge about GPs' experiences of this kind of collaborative care is limited. GPs find that care managers provide support for patients and security and relief for GPs. GPs are concerned about potential role overlap and desire greater latitude in deciding which patients can be assigned a care manager. GPs think depression can be treated using a chronic care model that includes care managers but that adjusting to the new way of working will take time.


Temporal and spatial cooperation of Snail1 and Twist1 during epithelial-mesenchymal transition predicts for human breast cancer recurrence.
Epithelial-mesenchymal transition (EMT) is a normal developmental program that is considered to also play an important role in cancer metastasis. Ultimate inducers of EMT are transcriptional repressors that individually can induce experimental EMT, yet in many cells, particularly cancer cells, multiple inducers are expressed simultaneously. Why, and if, and how they interact to regulate EMT is unanswered. Using RNA interference technology to affect protein knockdown and avoid potential overexpression artifact coupled with transient TGFβ treatment to better mimic in vivo conditions we show, in both nontumorigenic and tumorigenic epithelial cancer cells, that Snail1 is uniquely required for EMT initiation, whereas Twist1 is required to maintain late EMT. Twist1, present in resting epithelial cells, is dispensable for EMT initiation. Mechanistically, in response to transient TGFβ treatment, transient Snail1 expression represses Twist1 transcription directly, which is subsequently upregulated, as Snail1 levels decrease, to sustain E-cadherin downregulation and growth arrest of EMT. Persistent Twist1 expression is associated with a p38 and extracellular signal-regulated kinase signal feedback loop that sustains growth-inhibitory signals characteristic of quiescent micrometastatic tumors. This Snail1-Twist1 temporal and spatial cooperation was also observed in vivo during human breast cancer progression to metastasis. Twist1 level, but not Snail1 level, and Twist1:Snail1 ratio in disseminated micrometastatic bone marrow tumor cells was found to correlate with survival and treatment resistance and is highly predictive of metastatic or recurrent disease.


Empirical values of the ground state energies for methane transitions between 5500 and 6150 cm(-1).
The strengths of more than 1600 lines of CH(4) have been measured in the spectral interval between 5500 and 6150 cm(-1) at room temperature and reduced temperatures. The variation of the measured strengths allows the energy of the lower state of the transition to be determined empirically using the temperature dependence of the methane partition function and the Boltzmann factor for the energy level populations. An error analysis, based on assumed errors in the strength and temperature measurements, is included. The average measured uncertainty in J is 0.2.


The influence of the number of follicles on pregnancy rates in intrauterine insemination with ovarian stimulation: a meta-analysis.
The influence of multifollicular growth on pregnancy rates in subfertile couples undergoing intrauterine insemination (IUI) with controlled ovarian hyperstimulation (COH) remained unclear. Relevant papers were identified by searching MEDLINE, EMBASE and the Cochrane Library. A meta-analysis was performed and Mantel-Haenszel pooled odd ratios (ORs) and risk differences with 99% confidence intervals (CIs) were calculated to express the relation between the number of follicles and pregnancy rates. We included 14 studies reporting on 11 599 cycles. The absolute pregnancy rate was 8.4% for monofollicular and 15% for multifollicular growth. The pooled OR for pregnancy after two follicles as compared with monofollicular growth was 1.6 (99% CI 1.3-2.0), whereas for three and four follicles, this was 2.0 and 2.0, respectively. Compared with monofollicular growth, pregnancy rates increased by 5, 8 and 8% when stimulating two, three and four follicles. The pooled OR for multiple pregnancies after two follicles was 1.7 (99% CI 0.8-3.6), whereas for three and four follicles this was 2.8 and 2.3, respectively. The risk of multiple pregnancies after two, three and four follicles increased by 6, 14 and 10%. The absolute rate of multiple pregnancies was 0.3% after monofollicular and 2.8% after multifollicular growth. Multifollicular growth is associated with increased pregnancy rates in IUI with COH. Since in cycles with three or four follicles the multiple pregnancy rate increased without substantial gain in overall pregnancy rate, IUI with COH should not aim for more than two follicles. One stimulated follicle should be the goal if safety is the primary concern, whereas two follicles may be accepted after careful patient counselling.


Endogenous formation and repair of oxidatively induced G[8-5 m]T intrastrand cross-link lesion.
Exposure to reactive oxygen species (ROS) can give rise to the formation of various DNA damage products. Among them, d(G[8-5 m]T) can be induced in isolated DNA treated with Fenton reagents and in cultured human cells exposed to γ-rays, d(G[8-5m]T) can be recognized and incised by purified Escherichia coli UvrABC nuclease. However, it remains unexplored whether d(G[8-5 m]T) accumulates in mammalian tissues and whether it is a substrate for nucleotide excision repair (NER) in vivo. Here, we found that d(G[8-5 m]T) could be detected in DNA isolated from tissues of healthy humans and animals, and elevated endogenous ROS generation enhanced the accumulation of this lesion in tissues of a rat model of Wilson's disease. Additionally, XPA-deficient human brain and mouse liver as well as various types of tissues of ERCC1-deficient mice contained higher levels of d(G[8-5 m]T) but not ROS-induced single-nucleobase lesions than the corresponding normal controls. Together, our studies established that d(G[8-5 m]T) can be induced endogenously in mammalian tissues and constitutes a substrate for NER in vivo.


Further characterization of the second oestrogen-binding species of the rat granulosa cell.
Rat granulosa cell cytosol contains a second oestrogen-binding species (SOB) distinguished from the classical oestrogen receptor by its lower dissociation constant (approx. 45 nmol/l) and the ability to bind oestrogens, antioestrogens, androgens and progesterone but not diethylstilboestrol. The SOB and the oestrogen receptor can be further distinguished by their differential adsorption to spheroidal hydroxylapatite and Concanavalin A-Sepharose. Addition of chaotropic salts or molybdate to granulosa cell cytosol did not alter the concentration of SOB or oestrogen receptor measured, indicating that there are no 'masked' binding sites in the two species caused by aggregation phenomena. The association rate of oestradiol with SOB at 4 degrees C (1.72 +/- 0.27(S.E.M.) X 10(8) mol/h) and 25 degrees C (4.50 +/- 0.36 X 10(8) mol/h) was faster than with the oestrogen receptor (7.20 +/- 0.15 X 10(7) mol/h and 1.23 +/- 0.15 X 10(8) mol/h respectively). The biphasic dissociation kinetics of [3H]oestradiol from the oestrogen receptor at 25 degrees C (rate constants k-1 = 0.30 +/- 0.07/min and k-2 = 3.73 +/- 0.57 X 10(-3)/min) were similar to those reported in other target tissues but the dissociation of [3H]oestradiol from SOB appeared to be much more rapid and could not be measured by the Sephadex LH-20 separation method employed for determining receptor kinetics. Using sucrose density-gradient (SDG) analysis and Sephacryl S-200 gel chromatography the oestrogen receptor fractionated in an aggregated form (10.3S, Stokes radius greater than 5.2 nm) in low ionic strength buffers and as a small species (4.4S, Stokes radius 3.5 nm) in buffers containing 0.4 M-KCl. However, the SOB fractionated as 2-3S, Stokes radius 3.7-4.0 nm at low ionic strength and as 5.8S, Stokes radius 3.5 nm in 0.4 M-KCl. In contrast to the receptor from other target tissues the granulosa cell oestrogen receptor did not bind to the artificial acceptor matrix oligo(dT)-cellulose and heat activation did not promote a 4S to 5S conversion when analysed on SDG. The salt-extracted form of nuclear receptor sedimented at 4.6S, mol. wt 69-72000 on SDG.


Differential expression of cytokine genes among sickle-cell-trait (HbAS) and normal (HbAA) children infected with Plasmodium falciparum.
The human immune response to Plasmodium falciparum infection involves the release of cytokines that may contribute to the control of the parasites' replication. These cytokines are also involved in the pathogenesis of the malaria caused by the infection, leading to the appearance of symptoms of varying severity. In a cross-sectional study, the expression of the genes that code for pro-inflammatory cytokines (tumour necrosis factor, interferon-gamma, interleukin-6 and interleukin-12) and anti-inflammatory cytokines (interleukin-10 and interleukin-4) among 80 children infected with P. falciparum (from a malaria-endemic area of Sudan) and five healthy controls (from a non-endemic area) was explored. The infected children were either non-sicklers, with severe malaria (18 children), mild malaria (30) or no symptoms of malaria (18), or asymptomatic sicklers (14). Interleukin-12 was found to be weakly expressed by all the groups of children. In general, compared with the other groups, the asymptomatic non-sicklers had lower expression of all the cytokines studied. The asymptomatic sicklers had significantly lower expression of tumour necrosis factor than the non-sicklers with severe malaria, but these two groups showed similar expression of interferon-gamma, interleukin-4 and interleukin-6. Gene expression of the regulatory cytokine, interleukin-10, by the asymptomatic sicklers was significantly lower than that by the non-sicklers with severe malaria but higher than that recorded in the non-sicklers with mild malaria. Their regulation of cytokine release appears to protect sicklers from clinical malaria.


How Has Educational Expansion Shaped Social Mobility Trends in the United States?
This contribution provides a long-term assessment of intergenerational social mobility trends in the United States across the 20th and early 21st century and assesses the determinants of those trends. In particular, we study how educational expansion has contributed to the observed changes in mobility opportunities for men across cohorts. Drawing on recently developed decomposition methods, we empirically identify the contribution of each of the multiple channels through which changing rates of educational participation shape mobility trends. We find that a modest but gradual increase in social class mobility can nearly exclusively be ascribed to an interaction known as the compositional effect, according to which the direct influence of social class backgrounds on social class destinations is lower among the growing number of individuals attaining higher levels of education. This dominant role of the compositional effect is also due to the fact that, despite pronounced changes in the distribution of education, class inequality in education has remained stable while class returns to education have shown no consistent trend. Our analyses also provide a cautionary tale about mistaking increasing levels of social class mobility for a general trend towards more fluidity in the United States. The impact of parental education on son's educational and class attainment has grown or remained stable, respectively. Here, the compositional effect pertaining to the direct association between parental education and son's class attainment counteracts a long-term trend of increasing inequality in educational attainment tied to parents' education.


Spectrophotometric determination of the total phenolic content, spectral and fluorescence study of the herbal Unani drug Gul-e-Zoofa (Nepeta bracteata Benth).
This study quantitatively determined the total phenolic contents in ethanolic and aqueous extracts of Gul-e-Zoofa (flowers of Nepeta bracteata Benth) using a spectrophotometric method. We also performed a spectral study (UV and IR) of the ethanolic extract and a fluorescence study of the powdered drug and successive extracts to identify and characterize the genuine herbal drug, which has not been previously performed. The total phenolic content was determined quantitatively using the Folin Ciocalteu reagent, with Gallic acid as the standard. The fluorescence characteristics of the powdered drug and successive extracts with and without chemical treatment during the day and under a UV light were recorded. The UV and IR spectra of the alcoholic extract of Gul-e-Zoofa were recorded using a spectrometer. The total phenolic contents of the alcoholic and aqueous extracts were found to be 326.28 and 319.14 mg/g of the Gallic acid equivalent (GAE), respectively. The wavelength of the maximum absorption in the UV spectrum was 320 nm, and the characteristic frequencies in the IR spectrum were 3465.31, 3220.07, 2927.3, 2856.1, 1709.07, 1610.19, 1404.5, 1250.2, 1056.42, 823.04, 775.58, 577.81, and 463.10 cm-1. The fluorescence characteristics of the powdered drug were also observed. This spectral and fluorescence study of the drug will be helpful for confirming the identity and purity of the genuine drug. The total phenolic content will be helpful for developing new drugs and standardizing the drug. The presence of a high total phenolic content shows that the flowers of N. bracteata Benth may possess antioxidant properties, which could lead to a new field of research in the future.


Incidence and dynamics of Epstein-Barr virus reactivation after alemtuzumab-based conditioning for allogeneic hematopoietic stem-cell transplantation.
Reactivation of Epstein-Barr virus (EBV) infection and posttransplant lymphoproliferative disorder (PTLD) pose a significant risk after T-cell-depleted (TCD) allogeneic hematopoietic stem-cell transplantation (HSCT). The pattern of EBV reactivation in patients receiving allogeneic HSCT, incorporating in vivo or in vitro alemtuzumab as the method of TCD, is not known. Monitoring for EBV DNA was performed by quantitative polymerase chain reaction on whole blood in 111 consecutive adults undergoing HSCT using alemtuzumab-based TCD. Patients with more than 40,000 copies/mL were screened for PTLD, followed by the withdrawal of immunosuppression and a single infusion of rituximab. The 2-year cumulative incidence of EBV DNAemia was 40.3%. In vivo alemtuzumab was associated with earlier EBV reactivation than in vitro alemtuzumab (100-day incidence 22.7% vs. 2.8%, P=0.006). Eighteen patients (16%) had EBV DNAemia of more than 40,000 copies/mL. In evaluable patients, the initial rate of increase in EBV DNA levels was significantly faster in those who went on to treatment with rituximab than in patients who were left untreated (mean doubling time 3.5 days vs. 4.2 days, P=0.003). Rituximab treatment induced rapid declines in EBV DNA with an average half-life of 1.2+/-0.7 days. Only one patient (0.9%) had histologic confirmation of PTLD and subsequently attained a complete remission with rituximab that persists at 18 months. Alemtuzumab-based TCD is associated with a high frequency of EBV reactivation but a low (<1%) risk of PTLD using a strategy of preemptive rituximab therapy.


Insights into the genetic history of French cattle from dense SNP data on 47 worldwide breeds.
Modern cattle originate from populations of the wild extinct aurochs through a few domestication events which occurred about 8,000 years ago. Newly domesticated populations subsequently spread worldwide following breeder migration routes. The resulting complex historical origins associated with both natural and artificial selection have led to the differentiation of numerous different cattle breeds displaying a broad phenotypic variety over a short period of time. This study gives a detailed assessment of cattle genetic diversity based on 1,121 individuals sampled in 47 populations from different parts of the world (with a special focus on French cattle) genotyped for 44,706 autosomal SNPs. The analyzed data set consisted of new genotypes for 296 individuals representing 14 French cattle breeds which were combined to those available from three previously published studies. After characterizing SNP polymorphism in the different populations, we performed a detailed analysis of genetic structure at both the individual and population levels. We further searched for spatial patterns of genetic diversity among 23 European populations, most of them being of French origin, under the recently developed spatial Principal Component analysis framework. Overall, such high throughput genotyping data confirmed a clear partitioning of the cattle genetic diversity into distinct breeds. In addition, patterns of differentiation among the three main groups of populations--the African taurine, the European taurine and zebus--may provide some additional support for three distinct domestication centres. Finally, among the European cattle breeds investigated, spatial patterns of genetic diversity were found in good agreement with the two main migration routes towards France, initially postulated based on archeological evidence.


Enamel wear caused by monolithic zirconia crowns after 6 months of clinical use.
The purpose of this study was to evaluate enamel wear caused by monolithic zirconia crowns and to compare this with enamel wear caused by contralateral natural antagonists. Twenty monolithic zirconia crowns were placed in 20 patients requiring full molar crowns. For measurement of wear, impressions of both jaws were made at baseline after crown cementation and at 6-month follow-up. Mean and maximum wear of the occlusal contact areas of the crowns, of their natural antagonists and of the two contralateral natural antagonists were measured by the use of plaster replicas and 3D laser scanning methods. Wear differences were investigated by the use of two-sided paired Student's t-tests and by linear regression analysis. Mean vertical loss (maximum vertical loss in parentheses) was 10 (43) μm for the zirconia crowns, 33 (112) μm for the opposing enamel, 10 (58) μm for the contralateral teeth and 10 (46) μm for the contralateral antagonists. Both mean and maximum enamel wear were significantly different between the antagonists of the zirconia crowns and the contralateral antagonists. Gender and activity of the masseter muscle at night (bruxism) were identified as possible confounders which significantly affected wear. Under clinical conditions, monolithic zirconia crowns seem to be associated with more wear of opposed enamel than are natural teeth. With regard to wear behaviour, clinical application of monolithic zirconia crowns is justifiable because the amount of antagonistic enamel wear after 6 months is comparable with, or even lower than, that caused by other ceramic materials in previous studies.


Solar 8B and hep neutrino measurements from 1258 days of Super-Kamiokande data.
Solar neutrino measurements from 1258 days of data from the Super-Kamiokande detector are presented. The measurements are based on recoil electrons in the energy range 5.0-20.0 MeV. The measured solar neutrino flux is 2.32+/-0.03(stat)+0.08-0.07(syst)x10(6) cm(-2) x s(-1), which is 45.1+/-0.5(stat)+1.6-1.4(syst)% of that predicted by the BP2000 SSM. The day vs night flux asymmetry (Phi(n)-Phi(d))/Phi(average) is 0.033+/-0.022(stat)+0.013-0.012(syst). The recoil electron energy spectrum is consistent with no spectral distortion. For the hep neutrino flux, we set a 90% C.L. upper limit of 40x10(3) cm(-2) x s(-1), which is 4.3 times the BP2000 SSM prediction.


Management of atypical cranial meningiomas, part 2: predictors of progression and the role of adjuvant radiation after subtotal resection.
The efficacies of adjuvant stereotactic radiosurgery (SRS) and external beam radiation therapy (EBRT) for atypical meningiomas (AMs) after subtotal resection (STR) remain unclear. To analyze the clinical, histopathological, and radiographic features associated with progression in AM patients after STR. Fifty-nine primary AMs after STR were examined for predictors of progression, including the impact of SRS and EBRT, in a retrospective cohort study. Twenty-seven patients (46%) progressed after STR (median, 30 months). On univariate analysis, spontaneous necrosis positively (hazard ratio = 5.2; P = .006) and adjuvant radiation negatively (hazard ratio = 0.3; P = .009) correlated with progression; on multivariate analysis, only adjuvant radiation remained independently significant (hazard ratio = 0.3; P = .006). SRS and EBRT were associated with greater local control (LC; P = .02) and progression-free survival (P = .007). The 2-, 5-, and 10-year actuarial LC rates after STR vs STR/EBRT were 60%, 34%, and 34% vs 96%, 65%, and 45%. The 2-, 5-, and 10-year actuarial progression-free survival rates after STR vs STR/EBRT were 60%, 30%, and 26% vs 96%, 65%, and 45%. Compared with STR alone, adjuvant radiation therapy significantly improved LC in AMs that lack spontaneous necrosis (P = .003) but did not improve LC in AMs with spontaneous necrosis (P = .6). Adjuvant SRS or EBRT improved LC of AMs after STR but only for tumors without spontaneous necrosis. Spontaneous necrosis may aid in decisions to administer adjuvant SRS or EBRT after STR of AMs.


Orthonasal and retronasal detection thresholds of 26 aroma compounds in a model alcohol-free beer: Effect of threshold calculation method.
Detection thresholds are used routinely to determine the odour-active compounds in foods. The composition of a food matrix, such as hydrophobicity or solids content, has an impact on the release of flavour compounds, and thus on thresholds. In the case of beer, thresholds determined in alcoholic beer may not be the same for alcohol-free beer (AFB). Therefore, the aim of this study was to determine detection thresholds for aroma compounds typically found in beer, within a model AFB. The model was designed to match the sugar concentration and pH of an AFB brewed by a cold contact process. Thresholds were measured using a 3-AFC procedure and calculated using either Best Estimate Threshold (BET) method or by logistic regression. Moreover, an algorithm for the removal of false positives was applied to adjust the assessors' raw responses. Retronasal thresholds were generally lower than orthonasal. Those calculated by BET were significantly higher (p < 0.05) than those from logistic regression, and removal of false positives also produced significantly higher thresholds than those from raw data. The use of logistic regression has the advantage of providing the mathematical model describing the behaviour of the group. The results from this study can be used to better understand the role of flavour compounds in AFB and the effect of the calculation method to prevent under- or overestimated results.


Risperidone for psychosis-induced aggression or agitation (rapid tranquillisation).
Aggressive, agitated or violent behaviour due to psychosis constitutes an emergency psychiatric treatment where fast-acting interventions are required. Risperidone is a widely accessible antipsychotic that can be used to manage psychosis-induced aggression or agitation. To examine whether oral risperidone alone is an effective treatment for psychosis-induced aggression or agitation. We searched the Cochrane Schizophrenia Group's Study-Based Register of Trials (up to April 2017); this register is compiled by systematic searches of major resources (including AMED, BIOSIS CINAHL, Embase, MEDLINE, PsycINFO, PubMed, and registries of clinical trials) and their monthly updates, handsearches, grey literature, and conference proceedings. There are no language, date, document type, or publication status limitations for inclusion of records into the register. Randomised controlled trials (RCTs) comparing rapid use of risperidone and other drugs, combinations of drugs or placebo for people exhibiting aggression or agitation (or both) thought to be due to psychosis. We independently inspected all citations from searches, identified relevant abstracts, and independently extracted data from all included studies. For binary data we calculated risk ratio (RR) and for continuous data we calculated mean difference (MD), all with 95% confidence intervals (CI) and used a fixed-effect model. We assessed risk of bias for the included studies and used the GRADE approach to produce a 'Summary of findings' tables. The review now contains data from nine trials (total n = 582) reporting on five comparisons. Due to risk of bias, small size of trials, indirectness of outcome measures and a paucity of investigated and reported 'pragmatic' outcomes, evidence was graded as very-low quality. None of the included studies provided useable data on our primary outcome 'tranquillisation or asleep' by 30 minutes, repeated need for tranquillisation or any economic outcomes. Data were available for our other main outcomes of agitation or aggression, needing restraint, and incidence of adverse effects.Risperidone versus haloperidol (up to 24 hours follow-up)For the outcome, specific behaviour - agitation, no clear difference was found between risperidone and haloperidol in terms of efficacy, measured as at least 50% reduction in the Positive and Negative Syndrome Scale - Psychotic Agitation Sub-score (PANSS-PAS) (RR 1.04, 95% CI 0.86 to 1.26; participants = 124; studies = 1; very low-quality evidence) and no effect was observed for need to use restraints (RR 2.00, 95% CI 0.43 to 9.21; participants = 28; studies = 1; very low-quality evidence). Incidence of adverse effects was similar between treatment groups (RR 0.94, 95% CI 0.54 to 1.66; participants = 124; studies = 1; very low-quality evidence).Risperidone versus olanzapineOne small trial (n = 29) reported useable data for the comparison risperidone versus olanzapine. No effect was observed for agitation measured as PANSS-PAS endpoint score at two hours (MD 2.50, 95% CI -2.46 to 7.46; very low-quality evidence); need to use restraints at four days (RR 1.43, 95% CI 0.39 to 5.28; very-low quality evidence); specific movement disorders measured as Behavioural Activity Rating Scale (BARS) endpoint score at four days (MD 0.20, 95% CI -0.43 to 0.83; very low-quality evidence).Risperidone versus quetiapineOne trial reported (n = 40) useable data for the comparison risperidone versus quetiapine. Aggression was measured using the Modified Overt Aggression Scale (MOAS) endpoint score at two weeks. A clear difference, favouring quetiapine was observed (MD 1.80, 95% CI 0.20 to 3.40; very-low quality evidence). No evidence of a difference between treatment groups could be observed for incidence of akathisia after 24 hours (RR 1.67, 95% CI 0.46 to 6.06; very low-quality evidence). Two participants allocated to risperidone and one allocated to quetiapine experienced myocardial ischaemia during the trial.Risperidone versus risperidone + oxcarbazepineOne trial (n = 68) measured agitation using the Positive and Negative Syndrome Scale - Excited Component.(PANSS-EC) endpoint score and found a clear difference, favouring the combination treatment at one week (MD 2.70, 95% CI 0.42 to 4.98; very low-quality evidence), but no effect was observed for global state using Clinical Global Impression - Improvement (CGI-I) endpoint score at one week (MD -0.20, 95% CI -0.61 to 0.21; very-low quality evidence). Incidence of extrapyramidal symptoms after 24 hours was similar between treatment groups (RR 1.59, 95% CI 0.49 to 5.14; very-low quality evidence).Risperidone versus risperidone + valproic acidTwo trials compared risperidone with a combination of risperidone plus valproic acid. No clear differences between the treatment groups were observed for aggression (MOAS endpoint score at three days: MD 1.07, 95% CI -0.20 to 2.34; participants = 54; studies = 1; very low-quality evidence) or incidence of akathisia after 24 hours: RR 0.75, 95% CI 0.28 to 2.03; participants = 122; studies = 2; very low-quality evidence). Overall, results for the main outcomes show no real effect for risperidone. The only data available for use in this review are from nine under-sampled trials and the evidence available is of very low quality. This casts uncertainty on the role of risperidone in rapid tranquillisation for people with psychosis-induced aggression. High-quality pragmatic RCTs are feasible and are needed before clear recommendations can be drawn on the use of risperidone for psychosis-induced aggression or agitation.


Effects of hospital closures and hospital characteristics on emergency department ambulance diversion, Los Angeles County, 1998 to 2004.
We assess the effects of nearby hospital closures and other hospital characteristics on emergency department (ED) ambulance diversion. The study design was a retrospective, multiple interrupted time series with control group. We studied all ambulance-receiving hospitals with EDs in Los Angeles County from 1998 to 2004. The main outcome measure was monthly ambulance diversion hours because of ED saturation. Our sample included 80 hospitals, of which 9 closed during the study period. There were increasing monthly diversion hours over time, from an average of 57 hours (95% confidence interval [CI] 51 to 63 hours) in 1998 to 190 hours (95% CI 180 to 200 hours) in 2004. In multivariate modeling, hospital closure increased ambulance monthly diversion hours by an average of 56 hours (95% CI 28 to 84 hours) for 4 months at the nearest ED. County-operated hospitals had 150 hours (95% CI 90 to 200 hours) and trauma centers had 48 hours (95% CI 9 to 87 hours) more diversion than other hospitals. Diversion hours for a given facility were positively correlated with diversion hours of the nearest ED (0.3; 95% CI 0.28 to 0.32). There was a significant and positive interaction between diversion hours of the nearest ED and time, suggesting that the effects of an adjacent facility's diversion hours increased during the study period. Hospital closure was associated with a significant but transient increase in ambulance diversion for the nearest ED. The temporal trend toward more diversion hours, as well as increasing effects of the nearest facility's diversion hours over time, implies that the capacity to absorb future hospital closures is declining.


Complications of inappropriate use of spironolactone in heart failure: when an old medicine spirals out of new guidelines.
This study was designed to investigate the appropriateness and complications of the use of spironolactone for heart failure (HF) in clinical practice. Spironolactone was reported by one prospective randomized trial to decrease morbidity and mortality in patients with New York Heart Association (NYHA) class III and IV HF. With this report (Randomized Spironolactone Evaluation Study [RALES] trial), we noted a marked increase in widespread use of spironolactone in patients with HF. Long-term outcome data with respect to safety and utilization of this medication in HF are not available. To investigate the use of spironolactone for HF in a clinical setting, we analyzed the application of the RALES trial protocol to the care of 104 patients, whom we identified as being started on spironolactone for HF after prerelease of the RALES trial. We found broader use, less intensive follow-up, and increased complications with spironolactone treatment compared with the RALES trial. Cardiologists provided more appropriate care than did primary care providers. These data suggest that spironolactone is being used widely in HF without consideration of the NYHA class and ejection fraction, and without optimization of background treatment with angiotensin-converting enzyme inhibitors and beta-blockers. Clinical follow-up does not adhere to the RALES trial guidelines, resulting in higher complications. We conclude that long-term studies with further safety and efficacy data are needed.


Vertebrate herbivores influence soil nematodes by modifying plant communities.
Abiotic soil properties, plant community composition, and herbivory all have been reported as important factors influencing the composition of soil communities. However, most studies thus far have considered these factors in isolation, whereas they strongly interact in the field. Here, we study how grazing by vertebrate herbivores influences the soil nematode community composition of a floodplain grassland while we account for effects of grazing on plant community composition and abiotic soil properties. Nematodes are the most ubiquitous invertebrates in the soil. They include a variety of feeding types, ranging from microbial feeders to herbivores and carnivores, and they perform key functions in soil food webs. Our hypothesis was that grazing affects nematode community structure and composition through altering plant community structure and composition. Alternatively, we tested whether the effects of grazing may, directly or indirectly, run via changes in soil abiotic properties. We used a long-term field experiment containing plots with and without vertebrate grazers (cattle and rabbits). We compared plant and nematode community structure and composition, as well as a number of key soil abiotic properties, and we applied structural equation modeling to investigate four possible pathways by which grazing may change nematode community composition. Aboveground grazing increased plant species richness and reduced both plant and nematode community heterogeneity. There was a positive relationship between plant and nematode diversity indices. Grazing decreased the number of bacterial-feeding nematodes, indicating that in these grasslands, top-down control of plant production by grazing leads to bottom-up control in the basal part of the bacterial channel of the soil food web. According to the structural equation model, grazing had a strong effect on soil abiotic properties and plant community composition, whereas plant community composition was the main determinant of nematode community composition. Other pathways, which assumed that grazing influenced nematode community composition by inducing changes in soil abiotic properties, did not significantly explain variation in nematode community composition. We conclude that grazing-induced changes in nematode community composition mainly operated via changes in plant community composition. Influences of vertebrate grazers on soil nematodes through modification of abiotic soil properties were of less importance.


Locomotion in young rats with induced brain cellular edema - effects of recombinant human erythropoietin.
Effect of recombinant human erythropoietin (rhEPO) on spontaneous motor activity was tested in young rats after intraperitoneal (i.p.) administration of rhEPO, followed by induction of cellular brain edema (CE). Induced changes in the spontaneous horizontal locomotor activity was studied by open field test (OFT). CE was induced by water intoxication (WI) using standard method of fractional hyperhydration accompanied with desmopressin administration. Using the accepted method of OFT average time spent in locomotion (s) was determined. 48 young rats at the age of 25, and 35 days were divided into three groups - controls, rats after WI (OFT followed after 44 hours), and rats administered with rhEPO prior to application WI (OFT after 48 hours). In 35-day-old rats rhEPO administration increased the spontaneous locomotor activity, previously decreased by cellular edema. In 25-day-old rats, rhEPO administration prior to the induced CE, decreased spontaneous locomotor activity. Presented results demonstrate the neuroprotective capacity of rhEPO, manifested by elimination of the suppressive influence of CE on the locomotion in 35-day-old rats. In 25-day-old rats the neuroprotective effect was not present. These results confirmed that the 10 day interval in the development may represent a different stage of brain maturation in the relation to the neuroprotective effect of rhEPO.


Anatomic features of the eye disclosed with nuclear magnetic resonance imaging.
Nuclear magnetic resonance (NMR) imaging of the eye and paraorbital areas was performed in 35 volunteers and in four patients with ocular pathology. Two- and three-dimensional images were performed with saturation recovery (SR), inversion recovery (IR), and spin echo (SE) pulse sequences. Fat was brighter than surrounding tissue on images obtained with all pulse sequences, while muscle and optic nerve were of decreased intensity. The optic chiasm and vitreous were of decreased intensity compared with orbital fat on SR. The lens had even less signal intensity than the vitreous on SR and IR images and blended into the surroundings on SE images. A melanoma of the ciliary body and a lymphoma of the lacrimal gland were identified. In conclusion, NMR images can be used to identify normal and pathologic orbital and eyeball anatomy. Image contrast is provided by high intensity fat, which is interspersed throughout other orbital structures.


Exploring the over-time, multifaceted impacts of three COVID-19 lockdowns on aspects of capability, wellbeing and mental health across vulnerabilities in Austria.
The Austrian government imposed multiple major lockdowns during the COVID-19 pandemic, but the relevant measures and their perceptions varied over time. The aim of this study was to compare the over-time impacts of the three COVID-19 lockdowns between March 2020 and December 2021 for (capability) wellbeing and mental health in Austria. Adult Austrian residents (n = 87) completed an online survey about their experiences during three COVID-19 lockdowns, including capabilities (OxCAP-MH), depression and anxiety (HADS), and general wellbeing (WHO-5). Differences across the baseline and follow-up scores of these instruments were summarised by demographic/socioeconomic characteristics. Longitudinal comparisons of the impacts of the lockdowns were conducted using random effect models on panel data for overall instrument scores and individual capability items. The levels of (capability) wellbeing and mental health decreased for most respondents across the three lockdowns: average 2.4% reduction in OxCAP-MH scores, 18.8% and 9% increases in HADS depression and anxiety subscale scores respectively, and 19.7% reduction in WHO-5 score between the first and third lockdowns. Mental health treatment prior to the pandemic, social support and satisfaction with government measures were the most influential characteristics that determine the association with impacts of the chain of lockdowns. Our study is the first to assess the differential capability limiting aspects of lockdowns over time alongside their impacts on mental health and general wellbeing and calls for special attention for mental health patients, isolation and satisfaction with government measures.


Molecular-based approaches to characterize coastal microbial community and their potential relation to the trophic state of Red Sea.
Molecular-based approaches were used to characterize the coastal microbiota and to elucidate the trophic state of Red Sea. Nutrient content and enterococci numbers were monitored, and used to correlate with the abundance of microbial markers. Microbial source tracking revealed the presence of >1 human-associated Bacteroides spp. at some of the near-shore sampling sites and at a heavily frequented beach. Water samples collected from the beaches had occasional exceedances in enterococci numbers, higher total organic carbon (TOC, 1.48-2.18 mg/L) and nitrogen (TN, 0.15-0.27 mg/L) than that detected in the near-shore waters. Enterococci abundances obtained from next-generation sequencing did not correlate well with the cultured enterococci numbers. The abundance of certain genera, for example Arcobacter, Pseudomonas and unclassified Campylobacterales, was observed to exhibit slight correlation with TOC and TN. Low abundance of functional genes accounting for up to 41 copies/L of each Pseudomonas aeruginosa and Campylobacter coli were detected. Arcobacter butzleri was also detected in abundance ranging from 111 to 238 copies/L. Operational taxonomic units (OTUs) associated with cyanobacteria, Prochlorococcus, Ostreococcus spp. and Gramella were more prevalent in waters that were likely impacted by urban runoffs and recreational activities. These OTUs could potentially serve as quantifiable markers indicative of the water quality.


Molecular studies in Finnish patients with familial juvenile nephronophthisis exclude a founder effect and support a common mutation causing mechanism.
Familial juvenile nephronophthisis (NPH) is an autosomal recessive tubulointerstitial kidney disease associated with formation of medullary and corticomedullary cysts. It progresses to end stage renal failure and its biochemical defect is unknown. An NPH locus has been assigned to a 2 cM interval on chromosome 2q13 by linkage studies. Homozygous deletions of approximately 250 kb have been detected in 80% of familial cases and 65% of sporadic cases and a common mutation mechanism has been suggested. We examined 14 Finnish families for the presence or absence of a deletion. After detecting a deletion in 12 patients belonging to nine families, we studied a possible founder effect by haplotype analysis using markers D2S340, D2S1889, and D2S1893. No common ancestral disease associated haplotype was found suggesting no founder effect. Results of pairwise linkage analyses were suggestive of linkage in the nine families with a deletion (lod scores of 1.39-3.89 at a recombination fraction of 0). Negative lod scores were obtained in the five families without a deletion suggesting that the disease locus in these families lies elsewhere. The end stage renal disease occurred at a more advanced age in patients without a deletion compared to patients with a deletion, indicating a phenotypic difference between these two groups.


Evidence for human norovirus infection of dogs in the United kingdom.
Human noroviruses (HuNoVs) are a major cause of viral gastroenteritis, with an estimated 3 million cases per year in the United Kingdom. HuNoVs have recently been isolated from pet dogs in Europe (M. Summa, C.-H. von Bonsdorff, and L. Maunula, J Clin Virol 53:244-247, 2012, http://dx.doi.org/10.1016/j.jcv.2011.12.014), raising concerns about potential zoonotic infections. With 31% of United Kingdom households owning a dog, this could prove to be an important transmission route. To examine this risk, canine tissues were studied for their ability to bind to HuNoV in vitro. In addition, canine stool samples were analyzed for the presence of viral nucleic acid, and canine serum samples were tested for the presence of anti-HuNoV antibodies. The results showed that seven different genotypes of HuNoV virus-like particles (VLPs) can bind to canine gastrointestinal tissue, suggesting that infection is at least theoretically possible. Although HuNoV RNA was not identified in stool samples from 248 dogs, serological evidence of previous exposure to HuNoV was obtained in 43/325 canine serum samples. Remarkably, canine seroprevalence for different HuNoV genotypes mirrored the seroprevalence in the human population. Though entry and replication within cells have not been demonstrated, the canine serological data indicate that dogs produce an immune response to HuNoV, implying productive infection. In conclusion, this study reveals zoonotic implications for HuNoV, and to elucidate the significance of this finding, further epidemiological and molecular investigations will be essential.


Giving feedback in medical education: verification of recommended techniques.
We investigated naturally occurring feedback incidents to substantiate literature-based recommended techniques for giving feedback effectively. A faculty development course for improving the teaching of the medical interview, with opportunities for participants to receive feedback. Seventy-four course participants (clinician-educators from a wide range of medical disciplines, and several behavioral scientists). We used qualitative and quantitative approaches. Participants provided narratives of helpful and unhelpful incidents experienced during the course and then rated their own narratives using a semantic-differential survey. We found strong agreement between the two approaches, and congruence between our data and the recommended literature. Giving feedback effectively includes: establishing an appropriate interpersonal climate; using an appropriate location; establishing mutually agreed upon goals; eliciting the learner's thoughts and feelings; reflecting on observed behaviors; being nonjudgmental; relating feedback to specific behaviors; offering the right amount of feedback; and offering suggestions for improvement. Feedback techniques experienced by respondents substantiate the literature-based recommendations, and corrective feedback is regarded as helpful when delivered appropriately. A model for providing feedback is offered.


Global report on preterm birth and stillbirth (2 of 7): discovery science.
Normal and abnormal processes of pregnancy and childbirth are poorly understood. This second article in a global report explains what is known about the etiologies of preterm births and stillbirths and identifies critical gaps in knowledge. Two important concepts emerge: the continuum of pregnancy, beginning at implantation and ending with uterine involution following birth; and the multifactorial etiologies of preterm birth and stillbirth. Improved tools and data will enable discovery scientists to identify causal pathways and cost-effective interventions. PREGNANCY AND PARTURITION CONTINUUM: The biological process of pregnancy and childbirth begins with implantation and, after birth, ends with the return of the uterus to its previous state. The majority of pregnancy is characterized by rapid uterine and fetal growth without contractions. Yet most research has addressed only uterine stimulation (labor) that accounts for <0.5% of pregnancy. ETIOLOGIES: The etiologies of preterm birth and stillbirth differ by gestational age, genetics, and environmental factors. Approximately 30% of all preterm births are indicated for either maternal or fetal complications, such as maternal illness or fetal growth restriction. Commonly recognized pathways leading to preterm birth occur most often during the gestational ages indicated: (1) inflammation caused by infection (22-32 weeks); (2) decidual hemorrhage caused by uteroplacental thrombosis (early or late preterm birth); (3) stress (32-36 weeks); and (4) uterine overdistention, often caused by multiple fetuses (32-36 weeks). Other contributors include cervical insufficiency, smoking, and systemic infections. Many stillbirths have similar causes and mechanisms. About two-thirds of late fetal deaths occur during the antepartum period; the other third occur during childbirth. Intrapartum asphyxia is a leading cause of stillbirths in low- and middle-income countries. Utilizing new systems biology tools, opportunities now exist for researchers to investigate various pathways important to normal and abnormal pregnancies. Improved access to quality data and biological specimens are critical to advancing discovery science. Phenotypes, standardized definitions, and uniform criteria for assessing preterm birth and stillbirth outcomes are other immediate research needs. Preterm birth and stillbirth have multifactorial etiologies. More resources must be directed toward accelerating our understanding of these complex processes, and identifying upstream and cost-effective solutions that will improve these pregnancy outcomes.


Unique selectivity trends of highly permeable PAP[5] water channel membranes.
Artificial water channels are a practical alternative to biological water channels for achieving exceptional water permeability and selectivity in a stable and scalable architecture. However, channel-based membrane fabrication faces critical barriers such as: (1) increasing pore density to achieve measurable gains in permeability while maintaining selectivity, and (2) scale-up to practical membrane sizes for applications. Recently, we proposed a technique to prepare channel-based membranes using peptide-appended pillar[5]arene (PAP[5]) artificial water channels, addressing the above challenges. These multi-layered PAP[5] membranes (ML-PAP[5]) showed significantly improved water permeability compared to commercial membranes with similar molecular weight cut-offs. However, due to the distinctive pore structure of water channels and the layer-by-layer architecture of the membrane, the separation behavior is unique and was still not fully understood. In this paper, two unique selectivity trends of ML-PAP[5] membranes are discussed from the perspectives of channel geometry, ion exclusion, and linear molecule transport.


Governing the Access to COVID-19 Tools Accelerator: towards greater participation, transparency, and accountability.
The Access to COVID-19 Tools Accelerator (ACT-A) is a multistakeholder initiative quickly constructed in the early months of the COVID-19 pandemic to respond to a catastrophic breakdown in global cooperation. ACT-A is now the largest international effort to achieve equitable access to COVID-19 health technologies, and its governance is a matter of broad public importance. We traced the evolution of ACT-A's governance through publicly available documents and analysed it against three principles embedded in the founding mission statement of ACT-A: participation, transparency, and accountability. We found three challenges to realising these principles. First, the roles of the various organisations in ACT-A decision making are unclear, obscuring who might be accountable to whom and for what. Second, the absence of a clearly defined decision making body; ACT-A instead has multiple centres of legally binding decision making and uneven arrangements for information transparency, inhibiting meaningful participation. Third, the nearly indiscernible role of governments in ACT-A, raising key questions about political legitimacy and channels for public accountability. With global public health and billions in public funding at stake, short-term improvements to governance arrangements can and should now be made. Efforts to strengthen pandemic preparedness for the future require attention to ethical, legitimate arrangements for governance.


A prospective study of serum 25-hydroxyvitamin d levels and mortality among African Americans and non-African Americans.
The beneficial biologic effects attributed to vitamin D suggest a potential to influence overall mortality. Evidence addressing this hypothesis is limited, especially for African Americans who have a high prevalence of vitamin D insufficiency. The authors conducted a nested case-control study within the prospective Southern Community Cohort Study to relate baseline serum levels of 25-hydroxyvitamin D (25(OH)D) with subsequent mortality. Cases were 1,852 participants who enrolled from 2002 to 2009 and died >12 months postenrollment. Controls (n = 1,852) were matched on race, sex, age, enrollment site, and blood collection date. The odds ratios for quartile 1 (<10.18 ng/mL) versus quartile 4 (>21.64 ng/mL) levels of 25(OH)D were 1.60 (95% confidence interval (CI): 1.20, 2.14) for African Americans and 2.11 (95% CI: 1.39, 3.21) for non-African Americans. The effects were strongest for circulatory disease death, where quartile 1 versus quartile 4 odds ratios were 2.53 (95% CI: 1.44, 4.46) and 3.25 (95% CI: 1.33, 7.93) for African Americans and non-African Americans, respectively. The estimated odds of total mortality were minimized in the 25(OH)D range of 35-40 ng/mL. These findings provide support for the hypothesis that vitamin D status may have an important influence on mortality for both African Americans and non-African Americans.


[Experience in diagnostics and treatment of patients with odontogenous maxillary sinusitis].
210 sick dontogenous maxillary sinusitis were studied. To 150 patients surgical treatment with use of a method of a osteo-plastic sinusotomy of a genyantrum is lead. Patients have been taken on a dispensary observation. According to the lead postoperative computer tomography of additional sinuses of a nose in two projections, and also ortopantomography, rentgenographies of sinuses in semiaxial projection, the pneumatization of the operated genyantrums has not been disturbed, the osteal forward wall has been kept on all extent, was absent retraction soft tissues of infraorbital area, that as a whole speaks about efficiency and not so traumaticaly the lead surgical treatment. The offered way of surgical treatment promotes to the greatest degree to conservation of anatomic structures of maxillofacial area, possessing the least traumatism in comparison with other ways. This technique is simple, effective and does not demand application of the expensive equipment.


Development of a simplified method of human semen storage for the testing of sperm DNA fragmentation using the Halosperm G2 test kit.
To develop a simple, convenient, and stable storage method for semen before DNA fragmentation testing. Experimental cross-sectional study. Fertility clinic. 164 male partners of infertile couples. Comparison of sperm DNA fragmentation levels (DFLs) using fresh, snap-frozen and air-dried semen, with air-dried samples stored at different temperatures and time periods to assess DNA stability. DFL determined by Halosperm G2 kit. Results are expressed as mean ± standard error of the mean. The DFLs from fresh and air-dried semen gave comparable results (1.08% ± 0.65%), and from snap-frozen and fresh samples a statistically significant difference (5.5% ± 1.09%). Air-dried semen stored at room temperature for 7 days had a statistically significantly higher DFL compared with semen stored overnight (46.29% ± 9.12%). Samples stored at 4°C for 7 days or 1 day showed no statistically significant difference (0.83% ± 0.82%). DFLs from samples stored for either 1 or 30 days at 4°C showed a statistically significant difference (19.59% ± 5.72%); those stored at -22°C showed no statistically significant difference (0.68% ± 0.53%). Air-drying semen is a simple and stable storage method for up to 1 month at -22°C before DNA fragmentation testing.


A 3D co-culture microtissue model of the human placenta for nanotoxicity assessment.
There is increasing evidence that certain nanoparticles (NPs) can overcome the placental barrier, raising concerns on potential adverse effects on the growing fetus. But even in the absence of placental transfer, NPs may pose a risk to proper fetal development if they interfere with the viability and functionality of the placental tissue. The effects of NPs on the human placenta are not well studied or understood, and predictive in vitro placenta models to achieve mechanistic insights on NP-placenta interactions are essentially lacking. Using the scaffold-free hanging drop technology, we developed a well-organized and highly reproducible 3D co-culture microtissue (MT) model consisting of a core of placental fibroblasts surrounded by a trophoblast cell layer, which resembles the structure of the in vivo placental tissue. We could show that secretion levels of human chorionic gonadotropin (hCG) were significantly higher in 3D than in 2D cell cultures, which indicates an enhanced differentiation of trophoblasts grown on 3D MTs. NP toxicity assessment revealed that cadmium telluride (CdTe) and copper oxide (CuO) NPs but not titanium dioxide (TiO2) NPs decreased MT viability and reduced the release of hCG. NP acute toxicity was significantly reduced in 3D co-culture MTs compared to 2D monocultures. Taken together, 3D placental MTs provide a new and promising model for the fast generation of tissue-relevant acute NP toxicity data, which are indispensable for the safe development of NPs for industrial, commercial and medical applications.


Image reconstruction using a gradient impulse response model for trajectory prediction.
Gradient imperfections remain a challenge in MRI, especially for sequences relying on long imaging readouts. This work aims to explore image reconstruction based on k-space trajectories predicted by an impulse response model of the gradient system. Gradient characterization was performed twice with 3 years interval on a commercial 3 Tesla (T) system. The measured gradient impulse response functions were used to predict actual k-space trajectories for single-shot echo-planar imaging (EPI), spiral and variable-speed EPI sequences. Image reconstruction based on the predicted trajectories was performed for phantom and in vivo data. Resulting images were compared with reconstructions based on concurrent field monitoring, separate trajectory measurements, and nominal trajectories. Image reconstruction using model-based trajectories yielded high-quality images, comparable to using separate trajectory measurements. Compared with using nominal trajectories, it strongly reduced ghosting, blurring, and geometric distortion. Equivalent image quality was obtained with the recent characterization and that performed 3 years prior. Model-based trajectory prediction enables high-quality image reconstruction for technically challenging sequences such as single-shot EPI and spiral imaging. It thus holds great promise for fast structural imaging and advanced neuroimaging techniques, including functional MRI, diffusion tensor imaging, and arterial spin labeling. The method can be based on a one-time system characterization as demonstrated by successful use of 3-year-old calibration data. Magn Reson Med 76:45-58, 2016. © 2015 Wiley Periodicals, Inc.


Genotype of metabolic enzymes and the benefit of tamoxifen in postmenopausal breast cancer patients.
Tamoxifen is widely used as endocrine therapy for oestrogen-receptor-positive breast cancer. However, many of these patients experience recurrence despite tamoxifen therapy by incompletely understood mechanisms. In the present report we propose that tamoxifen resistance may be due to differences in activity of metabolic enzymes as a result of genetic polymorphism. Cytochrome P450 2D6 (CYP2D6) and sulfotransferase 1A1 (SULT1A1) are polymorphic and are involved in the metabolism of tamoxifen. The CYP2D6*4 and SULT1A1*2 genotypes result in decreased enzyme activity. We therefore investigated the genotypes of CYP2D6 and SULT1A1 in 226 breast cancer patients participating in a trial of adjuvant tamoxifen treatment in order to validate the benefit from the therapy. The patients were genotyped using PCR followed by cleavage with restriction enzymes. Carriers of the CYP2D6*4 allele demonstrated a decreased risk of recurrence when treated with tamoxifen (relative risk = 0.28, 95% confidence interval = 0.11-0.74, P = 0.0089). A similar pattern was seen among the SULT1A1*1 homozygotes (relative risk = 0.48, 95% confidence interval = 0.21-1.12, P = 0.074). The combination of CYP2D6*4 and/or SULT1A1*1/*1 genotypes comprised 60% of the patients and showed a 62% decreased risk of distant recurrence with tamoxifen (relative risk = 0.38, 95% confidence interval = 0.19-0.74, P = 0.0041). The present study suggests that genotype of metabolic enzymes might be useful as a guide for adjuvant endocrine treatment of postmenopausal breast cancer patients. However, results are in contradiction to prior hypotheses and the present sample size is relatively small. Findings therefore need to be confirmed in a larger cohort.


The RNA World: molecular cooperation at the origins of life.
The RNA World concept posits that there was a period of time in primitive Earth's history - about 4 billion years ago - when the primary living substance was RNA or something chemically similar. In the past 50 years, this idea has gone from speculation to a prevailing idea. In this Review, we summarize the key logic behind the RNA World and describe some of the most important recent advances that have been made to support and expand this logic. We also discuss the ways in which molecular cooperation involving RNAs would facilitate the emergence and early evolution of life. The immediate future of RNA World research should be a very dynamic one.


Defect-targeted self-healing of multiscale damage in polymers.
Self-healing materials capable of restoring functionality in response to damage are expected to gain prolonged service lifespan. Yet the ability to repair damage of diverse length scales which is demanded for the survival of highly capricious and uncontrolled damage modes has not been demonstrated with current self-healing approaches. Herein the repeatable self-healing of multiscale damage ranging from nanometer to millimeter is achieved in thermoplastic polymers through defect-targeted heating and welding. The key to the ability to deal with multiscale damage is the automatic and targeted transport and assembly of superparamagnetic nanoparticles toward the defect site. This allows the concentrated nanoparticles to deliver a high heating power under an oscillating magnetic field and locally fuse the matrix, whereas the overall dimensional integrity of the material is well preserved. Moreover, as the polymer melt drives progressively into the open volume of the crack, the nanoparticles keep migrating with the edge of the crack until the fractured portions are united. The cracking-healing cycle can be repeated 100 times with a constantly high healing efficiency above 95%. This work sheds light on the new design of self-healing materials where the ability to deal with complex damage modes represents a key merit to prompt real-world applications.


Associations of Obstructive Sleep Apnea With Atrial Fibrillation and Continuous Positive Airway Pressure Treatment: A Review.
Obstructive sleep apnea (OSA) is the most common clinically significant breathing abnormality during sleep. It is highly prevalent among patients with atrial fibrillation (AF), and it promotes arrhythmogenesis and impairs treatment efficacy. The prevalence of OSA ranges from 3% to 49% in population-based studies and from 21% to 74% in patients with AF. Diagnosis and treatment of OSA in patients with AF requires a close interdisciplinary collaboration between electrophysiologists, cardiologists, and sleep specialists. Because the prevalence of OSA is high in patients with AF and most do not report daytime sleepiness, sleep-study evaluation may be reasonable for patients being considered for rhythm control strategy. Acute, transient apnea-associated atrial electrophysiological changes and increased occurrence of AF triggers associated with short episodes of intermittent deoxygenation and reoxygenation, intrathoracic pressure changes during obstructed breathing efforts, and sympathovagal activation combine to create a stimulus for AF triggers and a complex and dynamic substrate for AF during sleep. Repeated episodes of long-term OSA are eventually associated with structural remodeling and changes in electrical conduction in the atrium. Observational data suggest OSA reduces the efficacy of catheter-based and pharmacological antiarrhythmic therapy. Nonrandomized studies have shown that treatment of OSA by continuous positive airway pressure can help to maintain a sinus rhythm after electrical cardioversion and catheter ablation in patients with AF. However, it remains unclear which sleep apnea metric should be used to determine severity and guide such treatment in patients with AF. Data from nonrandomized studies of patients with AF suggest that treatment of OSA by continuous positive airway pressure may help to maintain sinus rhythm after electrical cardioversion and improve catheter ablation success rates. Randomized clinical trials are needed to confirm the association between OSA and AF the benefits of treatment of OSA and the need for and cost-effectiveness of routine OSA screening and treatment.


Fibroblast growth factor 23: associations with antiretroviral therapy in patients co-infected with HIV and hepatitis C.
Fibroblast growth factor 23 (FGF23) has been associated with cardiovascular mortality. We estimate associations between the level of plasma FGF23 and exposure to abacavir (ABC) and to other components of antiretroviral therapy in patients co-infected with HIV and hepatitis C. Both intact and c-terminal FGF23 were measured in plasma using commercial assays for a sub-cohort of 295 patients selected at random from the 1150 patients enrolled in the Canadian Co-infection Cohort. The multiplicative effects of antiretroviral drug exposures and covariates on median FGF23 were then estimated using a hierarchical Bayesian model. The median level of intact FGF23 was independent of either past or recent exposure to abacavir, with multiplicative ratios of 1.00 and 1.07, 95% credible intervals 0.90-1.12 and 0.94-1.23, respectively. Median intact FGF23 tended to increase with past use of both nonnucleoside reverse-transcriptase inhibitors and protease inhibitors, but tended to decrease with recent use of either tenofovir, efavirenz or lopinavir. There were no obvious associations between the median level of c-terminal FGF23 and individual drugs or drug classes. Age, female gender, smoking and the aspartate aminotransferase to platelet ratio index were all associated with a higher median c-terminal FGF23 but not with a higher median intact FGF23. The level of FGF23 in plasma was independent of exposure to ABC. Lower levels of intact FGF23 with recent use of tenofovir, efavirenz or lopinavir may reflect their adverse effects on bone and vitamin D metabolism relative to other drugs in their respective drug classes.


Fish-like three-dimensional swimming with an autonomous, multi-fin, and biomimetic robot.
Fish migrate across considerable distances and exhibit remarkable agility to avoid predators and feed. Fish swimming performance and maneuverability remain unparalleled when compared to robotic systems, partly because previous work has focused on robots and flapping foil systems that are either big and complex, or tethered to external actuators and power sources. By contrast, we present a robot-the Finbot-that combines high degrees of autonomy, maneuverability, and biomimicry with miniature size (160 cm3). Thus, it is well-suited for controlled three-dimensional experiments on fish swimming in confined laboratory test beds. Finbot uses four independently controllable fins and sensory feedback for precise closed-loop underwater locomotion. Different caudal fins can be attached magnetically to reconfigure Finbot for swimming at top speed (122 mm s-1≡ 1 BL s-1) or minimal cost of transport (CoT = 8.2) at Strouhal numbers as low as 0.53. We conducted more than 150 experiments with 12 different caudal fins to measure three key characteristics of swimming fish: (i) linear speed-frequency relationships, (ii) U-shaped CoT, and (iii) reverse Kármán wakes (visualized with particle image velocimetry). More fish-like wakes appeared where the CoT was low. By replicating autonomous multi-fin fish-like swimming, Finbot narrows the gap between fish and fish-like robots and can address open questions in aquatic locomotion, such as optimized propulsion for new fish robots, or the hydrodynamic principles governing the energy savings in fish schools.


Carbohydrate-active enzymes involved in the secondary cell wall biogenesis in hybrid aspen.
Wood formation is a fundamental biological process with significant economic interest. While lignin biosynthesis is currently relatively well understood, the pathways leading to the synthesis of the key structural carbohydrates in wood fibers remain obscure. We have used a functional genomics approach to identify enzymes involved in carbohydrate biosynthesis and remodeling during xylem development in the hybrid aspen Populus tremula x tremuloides. Microarrays containing cDNA clones from different tissue-specific libraries were hybridized with probes obtained from narrow tissue sections prepared by cryosectioning of the developing xylem. Bioinformatic analyses using the sensitive tools developed for carbohydrate-active enzymes allowed the identification of 25 xylem-specific glycosyltransferases belonging to the Carbohydrate-Active EnZYme families GT2, GT8, GT14, GT31, GT43, GT47, and GT61 and nine glycosidases (or transglycosidases) belonging to the Carbohydrate-Active EnZYme families GH9, GH10, GH16, GH17, GH19, GH28, GH35, and GH51. While no genes encoding either polysaccharide lyases or carbohydrate esterases were found among the secondary wall-specific genes, one putative O-acetyltransferase was identified. These wood-specific enzyme genes constitute a valuable resource for future development of engineered fibers with improved performance in different applications.


Effects of supplements of folic acid, vitamin B12, and rumen-protected methionine on whole body metabolism of methionine and glucose in lactating dairy cows.
The present experiment was undertaken to determine the effects of dietary supplements of rumen-protected methionine and intramuscular injections of folic acid and vitamin B(12), given 3 wk before to 16 wk after calving, on glucose and methionine metabolism of lactating dairy cows. Twenty-four multiparous Holstein cows were assigned to 6 blocks of 4 cows each according to their previous milk production. Within each block, 2 cows were fed a diet estimated to supply methionine as 1.83% metabolizable protein, equivalent to 76% of methionine requirement, whereas the 2 other cows were fed the same diet supplemented daily with 18 g of rumen-protected methionine. Within each diet, the cows were administrated either no vitamin supplement or weekly intramuscular injections of 160 mg of folic acid plus 10 mg of vitamin B(12.) To investigate metabolic changes at 12 wk of lactation, glucose and methionine kinetics were measured by isotope dilution using infusions of 3[U-(13)C]glucose, [(13)C]NaHCO(3) and 3[1-(13)C,(2)H(3)] methionine. Milk and plasma concentrations of folic acid and vitamin B(12) increased with vitamin injections. Supplementary B-vitamins increased milk production from 34.7 to 38.9 +/- 1.0 kg/d and increased milk lactose, protein, and total solids yields. Whole-body glucose flux tended to increase with vitamin supplementation with a similar quantitative magnitude as the milk lactose yield increase. Vitamin supplementation increased methionine utilization for protein synthesis through increased protein turnover when methionine was deficient and through decreased methionine oxidation when rumen-protected methionine was fed. Vitamin supplementation decreased plasma concentrations of homocysteine independently of rumen-protected methionine feeding, although no effect of vitamin supplementation was measured on methionine remethylation, but this could be due to the limitation of the technique used. Therefore, the effects of these B-vitamins on lactation performance were not mainly explained by methionine economy because of a more efficient methylneogenesis but were rather related to increased glucose availability and changes in methionine metabolism.


Airborne viable particles and total number of airborne particles: comparative studies of active air sampling.
This paper presents results from a comparative study of different impaction air samplers under simulated operational conditions in a controlled environment. Furthermore measurements have been performed in a body-box during evaluation of clean-room clothing and in a day care center. Microbial monitoring of controlled environments can be performed in several ways, and with the aid of different sampling instruments. Knowing the limitations of the chosen system is of vital importance for the correct evaluation and interpretation of the results. The number of Colony Forming Units (CFU) detected by one method cannot be directly compared with results from another method. The obtained results seem to indicate that in a controlled environment the exposure situation with a human contamination source gives an approximate relationship between the total number of airborne particles and the number of aerobic airborne viable particles detectable with standard methods.