Regression mechanism of cyanamide-induced inclusion bodies in the rat: a useful experimental pattern to study the beta-glycogen metabolization of hepatocytes.
Cyanamide, a drug used in alcohol aversion therapy, induces a distinctive liver cell lesion, both in human beings and rats. The lesion consists of cytoplasmic inclusion bodies which give a ground-glass appearance to the hepatocytes. In human beings the inclusion bodies do not persist but disappear some time after withdrawal of the drug. In order to confirm their disappearance and determine how they regress rats were treated with cyanamide (32 mg/kg) for 6 months before partial lobectomy. At this time, inclusion bodies were observed. After a period without further treatment (5-19 weeks) the animals were killed and a marked decrease in the number of inclusion bodies was observed, paralleling the period of time without treatment. Inclusion bodies regress as a result of glycogen removal by enzymatic activity of the smooth endoplasmic reticulum which then undergoes hyperplasia, plus a process of autophagocytosis and necrosis of inclusion-body-bearing hepatocytes which are then phagocytosed by macrophages.


Empyema thoracis: a 10-year comparative review of hospitalised children from south Asia.
To study the clinical and microbial profile of childhood empyema in South Asia and to identify the changes over the past three decades. A total of 265 children (aged 1 month to 12 years) with empyema admitted to the Advanced Pediatric Center, PGIMER, Chandigarh, India in 1989-98, were reviewed retrospectively. One third of children were under 5. Culture positivity had decreased significantly (48% v 75%) over the years. Staphylococcus aureus continues to be the commonest (77%) aetiological agent; clustering was seen during hot and humid months (46%). Culture positive Streptococcus pneumoniae cases also decreased (9% v 27%); all were seen during the winter and spring season. Gram negative rods grew in more patients (11% v 7%). Community acquired methicillin resistant S aureus (MRSA) was isolated in three patients. Most children (93%) were treated with parenteral cloxacillin and an aminoglycoside. Tube drainage (TD) was used in 92% of fibropurulent cases, and was successful in 79%. Of 48 patients with failed TD, 12 needed decortication; limited thoracotomy was sufficient in the remaining 36. Surgery was mainly required by children with persistent pleural sepsis after 10 days of TD. Delaying surgery until 14 days had a significantly higher potential of requiring decortication. Early change to oral antibiotics (after 1-2 weeks of parenteral therapy) reduced the hospital stay significantly (17+7 v 23+7 days) without compromising long term outcome. Twenty two patients presenting late in the chronic stage underwent decortication at admission.


High-contrast and low-power all-optical switch using Fano resonance based on a silicon nanobeam cavity.
We experimentally demonstrate an ultra-compact all-optical switch involving Fano resonance based on a side-coupled Fabry-Perot (F-P) resonator and a silicon photonic crystal (PhC) nanobeam cavity, with an area of only 11 μm2. By optimizing the structure of the nanobeam cavity to increase its intrinsic quality factor (Q), we achieve a sharp asymmetric transmission spectrum, with an extinction ratio (ER) as high as 40 dB and a peak loss as low as 0.6 dB. As far as we know, this is the highest measured ER in PhC-based Fano resonance. These excellent properties enable us to realize an all-optical switch with shorter switching recovery time, lower power consumption, and higher contrast, compared to that involving Lorentzian resonance. For example, under signal trains of 2.5 Gb/s, switching energy with a contrast of 3 dB for the Fano case is 113 fJ, which is 8 dB smaller than that for the Lorentzian case. Furthermore, by performing blue-detuned filtering on the 15-Gb/s output signal light, the switching contrast of the all-optical switch based on Fano resonance is significantly improved from 0.67 dB to 9.53 dB.


State of midwives in Nepal: HRH to improve maternal and neonatal health and survival.
Improving health and survival of mothers and newborns depends on the delivery of evidence-based cost effective interventions through a skilled care provider. Evidence suggests that midwives are compassionate skilled care providers to mothers, and ensuring these skilled human resources is a key to progress towards Millennium Development Goals 4 and 5. With this in mind, this article analyses the state of midwifery in Nepal and what strategies are needed to ensuretheir accessibility and availability. In Nepal, as a result of community mobilization through Female Community Health Volunteers for birth preparedness and complication readiness, there has been a demand for skilled care at birth. However the supply of skilled birth attendants has been inadequate both in terms of number as well as quality of care.


Cerebral sinovenous thrombosis in neonatal antiphospholipid syndrome: a new entity?
Neonatal antiphospholipid syndrome (neonatal APS) seems to be exceedingly rare, as the antiphospholipid antibodies (aPL) related thrombosis in the neonatal period. The pathogenesis of perinatal aPL related thrombosis may be explained both by the transplacental passage of the maternal antibodies and by the production of de novo antibodies by the neonate. However, few cases of neonatal APS are reported in the literature, especially regarding arterial thrombotic events. In particular, only two cases of neonatal aPL related isolated cerebral sinovenous thrombosis (CSVT) are described in the literature. Despite its frequency, CSVT results in significant mortality and morbidity, probably also due to the difficulty in early diagnosis and then in correct managing in the neonatal period. A diagnosis of neonatal APS should be considered in the evaluation of neonates with CSVT, as well as in any case of neonatal thrombosis, to correctly manage the affected neonates and counsel the mother for future pregnancies.


Specific volume and adiabatic compressibility measurements of native and aggregated recombinant human interleukin-1 receptor antagonist: density differences enable pressure-modulated refolding.
High hydrostatic pressures have been used to dissociate non-native protein aggregates and foster refolding to the native conformation. In this study, partial specific volume and adiabatic compressibility measurements were used to examine the volumetric contributions to pressure-modulated refolding. The thermodynamics of pressure-modulated refolding from non-native aggregates of recombinant human interleukin-1 receptor antagonist (IL-1ra) were determined by partial specific volume and adiabatic compressibility measurements. Aggregates of IL-1ra formed at elevated temperatures (55 degrees C) were found to be less dense than native IL-1ra and refolded at 31 degrees C under 1,500 bar pressure with a yield of 57%. Partial specific adiabatic compressibility measurements suggest that the formation of solvent-free cavities within the interior of IL-1ra aggregates cause the apparent increase in specific volume. Dense, pressure-stable aggregates could be formed at 2,000 bar which could not be refolded with additional high pressure treatment, demonstrating that aggregate formation conditions and structure dictate pressure-modulated refolding yields.


An update on iron physiology.
Iron is an essential micronutrient, as it is required for adequate erythropoietic function, oxidative metabolism and cellular immune responses. Although the absorption of dietary iron (1-2 mg/d) is regulated tightly, it is just balanced with losses. Therefore, internal turnover of iron is essential to meet the requirements for erythropoiesis (20-30 mg/d). Increased iron requirements, limited external supply, and increased blood loss may lead to iron deficiency (ID) and iron-deficiency anemia. Hepcidin, which is made primarily in hepatocytes in response to liver iron levels, inflammation, hypoxia and anemia, is the main iron regulatory hormone. Once secreted into the circulation, hepcidin binds ferroportin on enterocytes and macrophages, which triggers its internalization and lysosomal degradation. Thus, in chronic inflammation, the excess of hepcidin decreases iron absorption and prevents iron recycling, which results in hypoferremia and iron-restricted erythropoiesis, despite normal iron stores (functional ID), and anemia of chronic disease (ACD), which can evolve to ACD plus true ID (ACD + ID). In contrast, low hepcidin expression may lead to iron overload, and vice versa. Laboratory tests provide evidence of iron depletion in the body, or reflect iron-deficient red cell production. The appropriate combination of these laboratory tests help to establish a correct diagnosis of ID status and anemia.


Differentiation of tumor progression from pseudoprogression in patients with posttreatment glioblastoma using multiparametric histogram analysis.
The multiparametric imaging can show us different aspects of tumor behavior and may help differentiation of tumor recurrence from treatment related change. Our aim was to differentiate tumor progression from pseudoprogression in patients with glioblastoma by using multiparametric histogram analysis of 2 consecutive MR imaging studies with relative cerebral blood volume and ADC values. Thirty-five consecutive patients with glioblastoma with new or increased size of enhancing lesions after concomitant chemoradiation therapy following surgical resection were included. Combined histograms were made by using the relative cerebral blood volume and ADC values of enhancing areas for initial and follow-up MR imaging, and subtracted histograms were also prepared. The histogram parameters between groups were compared. The diagnostic accuracy of tumor progression based on the histogram parameters of initial and follow-up MR imaging and subtracted histograms was compared and correlated with overall survival. Twenty-four pseudoprogressions and 11 tumor progressions were determined. Diagnosis based on the subtracted histogram mode with a multiparametric approach was more accurate than the diagnosis based on the uniparametric approach (area under the receiver operating characteristic curve of 0.877 versus 0.801), with 81.8% sensitivity and 100% specificity. A high mode of relative cerebral blood volume on the subtracted histogram by using a multiparametric approach (relative cerebral blood volume ×ADC) was the best predictor of true tumor progression (P < .001) and worse survival (P = .003). Multiparametric histogram analysis of posttreatment glioblastoma was useful to predict true tumor progression and worse survival.


Online tobacco websites and online communities-who uses them and do users quit smoking? The quit-primo and national dental practice-based research network Hi-Quit studies.
Online tobacco cessation communities are beneficial but underused. Our study examined whether, among smokers participating in a web-assisted tobacco intervention (Decide2quit.org), specific characteristics were associated with navigating to BecomeAnEx.org, an online cessation community, and with subsequent quit rates. Among smokers (N = 759) registered with Decide2quit.org, we identified visitors to BecomeAnEx.org, examining associations between smoker characteristics and likelihood of visiting. We then tested for associations between visits and 6-month cessation (point prevalence). We also tested for an interaction between use of other online support-seeking (Decide2quit.org tobacco cessation coaches), visiting, and 6-month cessation. One quarter (26.0 %; n = 197) of the smokers visited BecomeAnEx.org; less than one tenth (7.5 %; n = 57) registered to participate in the online forum. Visitors were more likely to be female (73.0 vs. 62.6 % of non-visitors, P < 0.01) to have visited a cessation website before (33.0 vs. 17.4 %, P < 0.01) and to report quit attempts in the previous year (62.0 vs. 53.0 %, P = 0.03). In analyses of all participants, BecomeAnEx.org visiting was not associated with 6-month quit completion. Among participants who communicated with a coach, BecomeAnEx.org visiting also lacked a significant association with 6 month quit completion, although a non-significant trend toward quit completion in visitors was noted (OR 2.21, 95 % CI 0.81-3.1). Online cessation communities attract smokers with previous cessation website experience and recent quit attempts. Community visiting was not associated with quit rates in our study, but low use may have limited our power to detect differences. Further research should explore whether an additive effect can be achieved by offering community visitors support via online coaches.


Intense, carrier frequency and bandwidth tunable quasi single-cycle pulses from an organic emitter covering the Terahertz frequency gap.
In Terahertz (THz) science, one of the long-standing challenges has been the formation of spectrally dense, single-cycle pulses with tunable duration and spectrum across the frequency range of 0.1-15 THz (THz gap). This frequency band, lying between the electronically and optically accessible spectra hosts important molecular fingerprints and collective modes which cannot be fully controlled by present strong-field THz sources. We present a method that provides powerful single-cycle THz pulses in the THz gap with a stable absolute phase whose duration can be continuously selected between 68 fs and 1100 fs. The loss-free and chirp-free technique is based on optical rectification of a wavelength-tunable pump pulse in the organic emitter HMQ-TMS that allows for tuning of the spectral bandwidth from 1 to more than 7 octaves over the entire THz gap. The presented source tunability of the temporal carrier frequency and spectrum expands the scope of spectrally dense THz sources to time-resolved nonlinear THz spectroscopy in the entire THz gap. This opens new opportunities towards ultrafast coherent control over matter and light.


Inhibition of nuclear translocation of apoptosis-inducing factor is an essential mechanism of the neuroprotective activity of pigment epithelium-derived factor in a rat model of retinal degeneration.
Photoreceptor apoptosis is a critical process of retinal degeneration in retinitis pigmentosa (RP), a group of retinal degenerative diseases that result from rod and cone photoreceptor cell death and represent a major cause of adult blindness. We previously demonstrated the efficient prevention of photoreceptor apoptosis by intraocular gene transfer of pigment epithelium-derived factor (PEDF) in animal models of RP; however, the underlying mechanism of the neuroprotective activity of PEDF remains elusive. In this study, we show that an apoptosis-inducing factor (AIF)-related pathway is an essential target of PEDF-mediated neuroprotection. PEDF rescued serum starvation-induced apoptosis, which is mediated by AIF but not by caspases, of R28 cells derived from the rat retina by preventing translocation of AIF into the nucleus. Nuclear translocation of AIF was also observed in the apoptotic photoreceptors of Royal College of Surgeons rats, a well-known animal model of RP that carries a mutation of the Mertk gene. Lentivirus-mediated retinal gene transfer of PEDF prevented the nuclear translocation of AIF in vivo, resulting in the inhibition of the apoptotic loss of their photoreceptors in association with up-regulated Bcl-2 expression, which mediates the mitochondrial release of AIF. These findings clearly demonstrate that AIF is an essential executioner of photoreceptor apoptosis in inherited retinal degeneration and provide a therapeutic rationale for PEDF-mediated neuroprotective gene therapy for individuals with RP.


POU domain factor Brn-3a controls the differentiation and survival of trigeminal neurons by regulating Trk receptor expression.
Mice lacking the POU domain-containing transcription factor Brn-3a have several neuronal deficits. In the present paper, we show that Brn-3a plays two distinct roles during development of the trigeminal ganglion. In this ganglion, neurons expressing the neurotrophin receptors, TrkB and TrkC, are born between E9.5 and E11.5. In the absence of Brn-3a, very few neurons ever express TrkC, but TrkB-expressing neurons are present at E12.5 in elevated numbers, suggesting that Brn-3a may be a constituent of a regulatory circuit determining which Trk receptor is expressed by these early-born neurons. Most neurons expressing the neurotrophin receptor TrkA are generated between E11.5 and E13.5 in this ganglion and their initial generation is not prevented by absence of Brn-3a. However, after E12. 5, absence of Brn-3a results in a progressive loss in neuronal TrkA and TrkB expression, which leads to a massive wave of apoptosis that peaks at E15.5. Despite complete absence of the Trk receptors at E17. 5 and P0, approximately 30% of the normal complement of neurons survive to birth in Brn-3a mutants. Approximately 70% of these express the GDNF receptor subunit, c-ret; many can be sustained by GDNF, but not by NGF in culture. Thus, the vast majority of surviving neurons are probably sustained in vivo by trophic factor(s) whose receptors are not regulated by Brn-3a. In conclusion, our data indicate the specific functions of Brn-3a in controlling the survival and differentiation of trigeminal neurons by regulating expression of each of the three Trk receptors.


News on ABA transport, protein degradation, and ABFs/WRKYs in ABA signaling.
The recent identification of abscisic acid (ABA) transporters provides an important insight into the delivery of ABA from the vascular system and its uptake by target cells. A putative connection with PYR/PYL receptors is envisaged, linking ABA uptake and intracellular perception by a fast and efficient mechanism. Downstream signaling of the core pathway involves regulation of ABA-responsive element binding factors (ABFs/AREBs) through phosphorylation, ubiquitination, and sumoylation in the case of ABI5. Several E3 ligases appear to regulate ABA signaling either positively or negatively, although relatively few targets are known yet. ABFs/AREBs are themselves subjected to transcriptional regulation, and some transcription factors (TFs) harboring the WRKY domain (WRKYs) appear to regulate their expression through W-box sequences present in the promoters of ABFs/AREBs.


Transverse velocity dependence of the proton-antiproton ratio as a signature of the QCD critical point.
The presence of a critical point in the QCD phase diagram can deform the trajectories describing the evolution of the expanding fireball in the mu_B-T phase diagram. If the average emission time of hadrons is a function of transverse velocity, as microscopic simulations of the hadronic freeze-out dynamics suggest, the deformation of the hydrodynamic trajectories will change the transverse velocity (beta_T) dependence of the proton-antiproton ratio when the fireball passes in the vicinity of the critical point. An unusual beta_T dependence of the [over]p/p ratio in a narrow beam energy window would thus signal the presence of the critical point.


Convergence and stability of quantized Hopfield networks operating in a fully parallel mode.
Hopfield neural networks (HNNs) have proven useful in solving optimization problems that require fast response times. However, the original analog model has an extremely high implementation complexity, making discrete implementations more suitable. Previous work has studied the convergence of discrete-time and quantized-neuron models but has limited the analysis to either two-state neurons or serial operation mode. Nevertheless, two-state neurons have poor performance, and serial operation modes lose fast convergence, which is characteristic of analog HNNs. This letter is the first in the field analyzing the convergence and stability of quantized Hopfield networks (QHNs)-with more than two states-operating in fully parallel mode. Moreover, this letter presents some further analysis on the energy minimization of this type of network. The main conclusion drawn is that QHNs operating in fully parallel mode always converge to a stable state or a cycle of length two and any stable state is a local minimum of the energy.


Membrane drug transporters and chemoresistance in human pancreatic carcinoma.
Pancreatic cancer ranks among the tumors most resistant to chemotherapy. Such chemoresistance of tumors can be mediated by various cellular mechanisms including dysregulated apoptosis or ineffective drug concentration at the intracellular target sites. In this review, we highlight recent advances in experimental chemotherapy underlining the role of cellular transporters in drug resistance. Such contribution to the chemoresistant phenotype of tumor cells or tissues can be conferred both by uptake and export transporters, as demonstrated by in vivo and in vitro data. Our studies used human pancreatic carcinoma cells, cells stably transfected with human transporter cDNAs, or cells in which a specific transporter was knocked down by RNA interference. We have previously shown that 5-fluorouracil treatment affects the expression profile of relevant cellular transporters including multidrug resistance proteins (MRPs), and that MRP5 (ABCC5) influences chemoresistance of these tumor cells. Similarly, cell treatment with the nucleoside drug gemcitabine or a combination of chemotherapeutic drugs can variably influence the expression pattern and relative amount of uptake and export transporters in pancreatic carcinoma cells or select for pre-existing subpopulations. In addition, cytotoxicity studies with MRP5-overexpressing or MRP5-silenced cells demonstrate a contribution of MRP5 also to gemcitabine resistance. These data may lead to improved strategies of future chemotherapy regimens using gemcitabine and/or 5-fluorouracil.


Three-dimensional distribution of the electric field induced in the brain by transcranial magnetic stimulation using figure-8 and deep H-coils.
The H-coils are a novel development in transcranial magnetic stimulation (TMS), designed to achieve effective stimulation of deep neuronal regions without inducing unbearable fields cortically, thus broadly expanding the potential feasibility of TMS for research and for treating various neurologic disorders. This study compared the field distribution of two H-coil versions, termed H1 and H2, and of a standard figure-of-eight coil. Three-dimensional electrical field distributions of the H1 and H2-coils, designed for effective stimulation of prefrontal regions, and of a standard figure-8 coil, were measured in a head model filled with physiologic saline solution. With stimulator output at 120% of the hand motor threshold, suprathreshold field is induced by the H1-coil at lateral and medial frontal regions at depths of up to 4 to 5 cm, and by the H2-coil at medial prefrontal regions up to 2 to 3 cm, and at lateral frontal regions up to 5 to 6 cm. The figure-8 coil induced suprathreshold field focally under the coil's central segment, at depths of up to 1.5 cm. The ability of the H-coils to stimulate effectively deeper neuronal structures is obtained at the cost of a wider electrical field distribution in the brain. However, the H-coils enable simultaneous stimulation of several brain regions, whereas the depth penetration in each region can be controlled either by adjusting the stimulator output, and/or by varying the distance between various coil elements and the skull.


Epigenetic Determinism in Science and Society.
The epigenetic "revolution" in science cuts across many disciplines, and it is now one of the fastest growing research areas in biology. Increasingly, claims are made that epigenetics research represents a move away from the genetic determinism that has been prominent both in biological research and in understandings of the impact of biology on society. We discuss to what extent an epigenetic framework actually supports these claims. We show that, in contrast to the received view, epigenetics research is often couched in language as deterministic as genetics research in both science and the popular press. We engage the rapidly emerging conversation about the impact of epigenetics on public discourse and scientific practice, and we contend that the notion of epigenetic determinism - or the belief that epigenetic mechanisms determine the expression of human traits and behaviors - matters for understandings of the influence of biology and society on population health.


Assessing the association of the HNF1A G319S variant with C-reactive protein in Aboriginal Canadians: a population-based epidemiological study.
C-reactive protein (CRP), a biomarker of inflammation, has been associated with increased risk of developing cardiovascular disease. Common variants of the hepatocyte nuclear factor 1A (HNF1A) gene encoding HNF-1alpha have been associated with plasma CRP in predominantly European Caucasian samples. HNF1A might therefore have an impact on vascular disease and diabetes risk that is mediated by CRP. In an Aboriginal Canadian population, a private polymorphism, HNF1A G319S, was associated with increased prevalence of type 2 diabetes. However, it has not been investigated whether this association is mediated by CRP. We aimed to investigate whether CRP was mediating the association between HNF1A G319S and type 2 diabetes in an Aboriginal Canadian population with a high prevalence of diabetes. A total of 718 individuals who participated in a diabetes prevalence and risk factor survey were included in the current analysis. Participants were genotyped for HNF1A G319S. Fasting plasma samples were analyzed for CRP. Fasting plasma glucose and a 75-g oral glucose tolerance test were obtained to determine type 2 diabetes. The prevalence rate of type 2 diabetes was 17.4% (125/718) using the 1999 World Health Organization definition and was higher among S319 allele carriers compared to G/G homozygotes (p < 0.0001). Among participants without type 2 diabetes, CRP levels were higher among G/G homozygotes (1.64 [95% confidence interval 1.35-2.00] mg/l) than in S319 carriers (1.26 [1.04-1.54] mg/l) (p = 0.009) after adjustment for age, sex, 2-h post-load glucose, waist circumference, and serum amyloid A. CRP levels were elevated among those with diabetes after similar adjustment (4.39 [95% confidence interval 3.09-6.23] and 4.44 [3.13-6.30] mg/L, respectively), and no significant difference in CRP was observed between S319 carriers and non-carriers (p = 0.95). CRP levels were lower in S319 allele carriers of the HNF1A gene compared to non-carriers among individuals without diabetes, but this difference was not present among those with diabetes, who uniformly had elevated CRP levels. Therefore, while HNF1A appears to influence CRP concentrations in the non-diabetic state, chronic elevation of CRP is unlikely mediating the association between the HNF1A polymorphism and the high prevalence of type 2 diabetes in this Aboriginal population.


Genetic analysis of male reproductive contributions in Chamaelirium luteum (L.) gray (Liliaceae).
Genealogical analysis is a powerful tool for analysis of reproductive performance in both natural and captive populations, but assignment of paternity has always been a stumbling block for this sort of work. Statistical methods for determining paternity have undergone several phases of development, ranging from straightforward genetic exclusion to assignment of paternity based on genetic likelihood criteria. In the present study, we present a genetic likelihood-based iterative procedure for fractional allocation of paternity within a progeny pool and apply this method to a population of Chamaelirium luteum, a dioecious member of the Liliaceae. Results from this analysis clearly demonstrate that different males make unequal contributions to the overall progeny pool, with many males contributing essentially nothing to the next generation. Furthermore, the distribution of paternal success among males shows a highly significant departure from (Poisson) randomness. The results from the present analysis were compared with earlier results obtained from the same data set, using likelihood-based categorical paternity assignments. The general biological pattern revealed by the two analyses is the same, but the estimates of reproductive success are only modestly (though significantly) correlated. The iterative procedure makes more complete use of the data and generates a more sharply resolved distribution of male reproductive success.


Hierarchical Approach to Classify Food Scenes in Egocentric Photo-Streams.
Recent studies have shown that the environment where people eat can affect their nutritional behavior [1]. In this paper, we provide automatic tools for personalized analysis of a person's health habits by the examination of daily recorded egocentric photo-streams. Specifically, we propose a new automatic approach for the classification of food-related environments, that is able to classify up to 15 such scenes. In this way, people can monitor the context around their food intake in order to get an objective insight into their daily eating routine. We propose a model that classifies food-related scenes organized in a semantic hierarchy. Additionally, we present and make available a new egocentric dataset composed of more than 33 000 images recorded by a wearable camera, over which our proposed model has been tested. Our approach obtains an accuracy and F-score of 56% and 65%, respectively, clearly outperforming the baseline methods.


Contribution of urinary tract infection to the burden of febrile illnesses in young children in rural Kenya.
The clinical features of UTI in young children may not localize to the urinary tract and closely resemble other febrile illnesses. In malaria endemic areas, a child presenting with fever is often treated presumptively for malaria without investigation for UTI. Delayed or inadequate treatment of UTI increases the risk of bacteremia and renal scarring in young children and subsequently complications as hypertension and end stage renal disease in adulthood. A cross-sectional study was carried out in a hospital in western Kenya. Inpatients and outpatients 2 months to five years with axillary temperature ≥37.5°C and no antibiotic use in the previous week were enrolled between September 2012 and April 2013. Urine dipstick tests, microscopy, and cultures were done and susceptibility patterns to commonly prescribed antibiotics established. UTI was defined as presence of pyuria (a positive urine dipstick or microscopy test) plus a positive urine culture. A total of 260 subjects were recruited; 45.8% were female and the median age was 25months (IQR: 13, 43.5). The overall prevalence of UTI was 11.9%. Inpatients had a higher prevalence compared to outpatients (17.9% v 7.8%, p = 0.027). UTI co-existed with malaria but the association was not significant (OR 0.80, p = 0.570). The most common organisms isolated were Escherichia coli (64.5%) and Staphylococcus aureus (12.9%) and were sensitive to ciproflaxin, cefuroxime, ceftriaxone, gentamycin and nitrofurantoin but largely resistant to more commonly used antibiotics such as ampicillin (0%), amoxicillin (16.7%), cotrimoxazole (16.7%) and amoxicillin-clavulinate (25%). Our study demonstrates UTI contributes significantly to the burden of febrile illness in young children and often co-exists with other infections. Multi-drug resistant organisms are common therefore choice of antimicrobial therapy should be based on local sensitivity pattern.


Renal cell carcinoma risk associated with lower intake of micronutrients.
Kidney cancer incidence in African Americans (AA) is higher than among European Americans (EA); reasons for this disparity are not fully known. Dietary micronutrients may have a protective effect on renal cell carcinoma (RCC) development by inhibiting oxidative DNA damage and tumor growth. We evaluated whether any micronutrient associations differed by race in the US Kidney Cancer Study. 1142 EA and AA RCC cases and 1154 frequency-matched controls were enrolled in a population-based case-control study between 2002 and 2007. Dietary micronutrient intake was derived from an interviewer-administered diet history questionnaire. RCC risk associated with micronutrient intake was estimated using adjusted odds ratios from logistic regression comparing lower to highest quartiles of intake and sample weighting. Inverse associations with RCC risk were observed for α-carotene, β-carotene, lutein zeaxanthin, lycopene, vitamin A, folate, thiamin, vitamin C, α-tocopherol, β-tocopherol, γ-tocopherol, and selenium. A trend for β-cryptoxanthin was suggested among EA but not AA or the total sample (P-interaction = .04). Otherwise, findings did not differ by race, gender, age, or smoking status. The increase in RCC risk associated with lower micronutrient intake is similar within AA and EA populations. A diet rich in sources of micronutrients found in fruits, vegetables, and nuts may help to reduce the overall risk of RCC.


Three decades of neoliberalism in Mexico: the destruction of society.
Neoliberalism has been implemented in Latin America for about three decades. This article reviews Mexico's neoliberal trajectory to illustrate the political, economic, and social alterations that have resulted from this process. It finds that representative democracy has been perverted through fear, putting central political decisions in the hands of power groups with special interests. The border between the state of law and the state of exception is blurred. Economic structural adjustment with liberalization and privatization has provoked recurrent crisis, but has been maintained, leading to the destruction of the national productive structure in favor of supranational corporations, particularly financial capital. The association between criminal economy and economic criminality is also discussed. The privatization of social benefits and services requires state subsidies and allows the privatization of profits and the socialization of losses. The social impact of this process has been devastating, with a polarized income distribution, falling wages, increased precarious jobs, rising inequality, and extreme violence. Health conditions have also deteriorated and disorders associated with violence, chronic stress, and a changing nutritional culture have become dominating. However, in Latin America, massive, organized political and social mobilization has broken the vicious neoliberal circle and elected progressive governments that are struggling to reverse social and economic devastation.


Assessing resolution in super-resolution imaging.
Resolution is a central concept in all imaging fields, and particularly in optical microscopy, but it can be easily misinterpreted. The mathematical definition of optical resolution was codified by Abbe, and practically defined by the Rayleigh Criterion in the late 19th century. The limit of conventional resolution was also achieved in this period, and it was thought that fundamental constraints of physics prevented further increases in resolution. With the recent development of a range of super-resolution techniques, it is necessary to revisit the concept of optical resolution. Fundamental differences in super-resolution modalities mean that resolution is not a directly transferrable metric between techniques. This article considers the issues in resolution raised by these new technologies, and presents approaches for comparing resolution between different super-resolution methods.


Endovascular coiling versus neurosurgical clipping in patients with unruptured intracranial aneurysm: a systematic review.
To compare the effects of endovascular coiling and neurosurgical clipping in patients with unruptured intracranial aneurysm. Sixteen electronic databases were searched for articles published between 1950 and July 2010 to compare clinical outcomes of clipping and coiling. Researchers reviewed all searched articles and extracted data independently. The quality of studies and evidence were evaluated using MINORS and GRADEprofiler, respectively. The odds ratio (OR) was calculated using the inverse variance meta-analysis method for each study outcome. To assess heterogeneity of ORs across cohorts, Cochran's Q statistic and I² were used. Of 4160 studies, 24 were identified (n = 31865). Clipping resulted in significantly higher disability using the Glasgow Outcome Scale (OR, 2.38; 95% CI, 1.33-4.26) and Modified Rankin Scale (OR, 2.83; 95% CI, 1.42-5.63) when compared with coiling. ORs for complications were also higher with clipping (ORs for neurological and cardiac complications were 1.94 with a 95% confidence interval [CI] of 1.09-3.47 and 2.51 with a 95% CI of 1.15-5.50). Clipping resulted in significantly greater disability in the short term (≤6 m)(OR on the Glasgow Outcome Scale, 2.72; 95% CI, 1.16-6.34), but not in the long term (>6 m)(OR for Glasgow Outcome Scale, 2.12; 95% CI, 0.93-4.84). Coiling was a better procedure for treatment of unruptured intracranial aneurysm in terms of disability, complications, especially in the short term. Because of the limitations of the reviewed studies, further studies are required to support the present results.


Engineering simulations for cancer systems biology.
Computer simulation can be used to inform in vivo and in vitro experimentation, enabling rapid, low-cost hypothesis generation and directing experimental design in order to test those hypotheses. In this way, in silico models become a scientific instrument for investigation, and so should be developed to high standards, be carefully calibrated and their findings presented in such that they may be reproduced. Here, we outline a framework that supports developing simulations as scientific instruments, and we select cancer systems biology as an exemplar domain, with a particular focus on cellular signalling models. We consider the challenges of lack of data, incomplete knowledge and modelling in the context of a rapidly changing knowledge base. Our framework comprises a process to clearly separate scientific and engineering concerns in model and simulation development, and an argumentation approach to documenting models for rigorous way of recording assumptions and knowledge gaps. We propose interactive, dynamic visualisation tools to enable the biological community to interact with cellular signalling models directly for experimental design. There is a mismatch in scale between these cellular models and tissue structures that are affected by tumours, and bridging this gap requires substantial computational resource. We present concurrent programming as a technology to link scales without losing important details through model simplification. We discuss the value of combining this technology, interactive visualisation, argumentation and model separation to support development of multi-scale models that represent biologically plausible cells arranged in biologically plausible structures that model cell behaviour, interactions and response to therapeutic interventions.


Barrier characteristics of epithelial cultures modelling the airway and intestinal mucosa: a comparison.
The barrier characteristics of polarized layers of Calu-3 and Caco-2 cell lines, as commonly used in vitro models of intestinal and airway mucosa, respectively, were investigated by assessing the translocation of model macromolecules and nanoparticles. The barrier capacity of the cell layers towards the movement of macromolecules and nanoparticulates differed considerably between the cell lines. Permeability studies revealed the existence of a notably larger solute molecular weight limit for paracellular diffusion in Caco-2 monolayers compared to Calu-3 cells. Removal of mucus in Calu-3 cells resulted in cell layers exhibiting a larger macromolecular permeability, in addition to improved nanoparticle translocation. Microscopic examination of the tight junctions, as cellular features that play a major role in preventing transepithelial movement of macromolecules, revealed that the appearance of cell-cell boundaries was notably different in the two cell lines, which could explain the differences in macromolecular permeability. The data overall showed that epithelial layers of airway Calu-3 and intestinal Caco-2 cell cultures in vitro exhibit a different level of restrictiveness and this is due to the cell morphology and the presence of mucus.


Kinetics of electrogenic transport by the ADP/ATP carrier.
The electrogenic transport of ATP and ADP by the mitochondrial ADP/ATP carrier (AAC) was investigated by recording transient currents with two different techniques for performing concentration jump experiments: 1) the fast fluid injection method: AAC-containing proteoliposomes were adsorbed to a solid supported membrane (SSM), and the carrier was activated via ATP or ADP concentration jumps. 2) BLM (black lipid membrane) technique: proteoliposomes were adsorbed to a planar lipid bilayer, while the carrier was activated via the photolysis of caged ATP or caged ADP with a UV laser pulse. Two transport modes of the AAC were investigated, ATP(ex)-0(in) and ADP(ex)-0(in). Liposomes not loaded with nucleotides allowed half-cycles of the ADP/ATP exchange to be studied. Under these conditions the AAC transports ADP and ATP electrogenically. Mg(2+) inhibits the nucleotide transport, and the specific inhibitors carboxyatractylate (CAT) and bongkrekate (BKA) prevent the binding of the substrate. The evaluation of the transient currents yielded rate constants of 160 s(-1) for ATP and >/=400 s(-1) for ADP translocation. The function of the carrier is approximately symmetrical, i.e., the kinetic properties are similar in the inside-out and right-side-out orientations. The assumption from previous investigations, that the deprotonated nucleotides are exclusively transported by the AAC, is supported by further experimental evidence. In addition, caged ATP and caged ADP bind to the carrier with similar affinities as the free nucleotides. An inhibitory effect of anions (200-300 mM) was observed, which can be explained as a competitive effect at the binding site. The results are summarized in a transport model.


Assessing criminal justice involvement as an indicator of human immunodeficiency virus risk among women in methadone treatment.
This study examines the relationship between criminal justice involvement and high-risk sexual partnerships among a random sample of 416 women in methadone treatment in New York City. Logistic regression models were used to estimate the associations between recent criminal justice involvement (arrest or incarceration in the past 6 months) and recent high-risk partnerships (multiple sex partners, sex trading, or sex with a risky partner in the past 6 months) when adjusting for sociodemographic factors and recent regular drug use. Women with recent criminal justice involvement demonstrated higher odds of engaging in high-risk sex partnerships. Although regular drug use was a significant confounder of several of these relationships, recent arrest or incarceration remained significantly associated with multiple sex partnerships, sex with a risky partner, and engaging in unprotected sex and a high-risk partnership even after controlling for regular drug use and other social stressors. This study highlights the vulnerability of drug-involved women offenders to human immunodeficiency virus (HIV) risk and points to the need for investigation into the role of arrest and incarceration as factors that may contribute to HIV infection.


[Analysis of the Cochrane Review: Anti-vascular Endothelial Growth Factor for Prevention of Postoperative Vitreous Cavity Hemorrhage after Vitrectomy for Proliferative Diabetic Retinopathy. Cochrane Database Syst Rev. 2015;8:CD008214.]
Postoperative vitreous hemorrhage is a complication following vitrectomy for proliferative diabetic retinopathy, delaying visual recovery and making fundus examination and disease follow-up more difficult. Anti-vascular endothelial growth factor drugs such as bevacizumab, when injected in the vitreous cavity, reduce vascular proliferation and their use has been proposed to reduce the incidence of postoperative vitreous hemorrhage. The authors of this Cochrane systematic review evaluated all randomized controlled trials on the pre- or intraoperative use of anti-vascular endothelial growth factor to reduce postoperative vitreous hemorrhage occurrence after vitrectomy in patients with proliferative diabetic retinopathy. The results suggested that the use of intravitreal bevacizumab was effective in reducing early postoperative vitreous hemorrhage (i.e. at four weeks) occurrence, with a good safety profile. This work aims to summarize and discuss the findings and clinical implications of this Cochrane systematic review.


Structural and functional analysis of the transcriptional regulator Rv3066 of Mycobacterium tuberculosis.
The Mmr multidrug efflux pump recognizes and actively extrudes a broad range of antimicrobial agents, and promotes the intrinsic resistance to these antimicrobials in Mycobacterium tuberculosis. The expression of Mmr is controlled by the TetR-like transcriptional regulator Rv3066, whose open reading frame is located downstream of the mmr operon. To understand the structural basis of Rv3066 regulation, we have determined the crystal structures of Rv3066, both in the absence and presence of bound ethidium, revealing an asymmetric homodimeric two-domain molecule with an entirely helical architecture. The structures underscore the flexibility and plasticity of the regulator essential for multidrug recognition. Comparison of the apo-Rv3066 and Rv3066-ethidium crystal structures suggests that the conformational changes leading to drug-mediated derepression is primarily due to a rigid body rotational motion within the dimer interface of the regulator. The Rv3066 regulator creates a multidrug-binding pocket, which contains five aromatic residues. The bound ethidium is found buried within the multidrug-binding site, where extensive aromatic stacking interactions seemingly govern the binding. In vitro studies reveal that the dimeric Rv3066 regulator binds to a 14-bp palindromic inverted repeat sequence in the nanomolar range. These findings provide new insight into the mechanisms of ligand binding and Rv3066 regulation.


The Screening of Genes Sensitive to Long-Term, Low-Level Microwave Exposure and Bioinformatic Analysis of Potential Correlations to Learning and Memory.
To gain a better understanding of gene expression changes in the brain following microwave exposure in mice. This study hopes to reveal mechanisms contributing to microwave-induced learning and memory dysfunction. Mice were exposed to whole body 2100 MHz microwaves with specific absorption rates (SARs) of 0.45 W/kg, 1.8 W/kg, and 3.6 W/kg for 1 hour daily for 8 weeks. Differentially expressing genes in the brains were screened using high-density oligonucleotide arrays, with genes showing more significant differences further confirmed by RT-PCR. The gene chip results demonstrated that 41 genes (0.45 W/kg group), 29 genes (1.8 W/kg group), and 219 genes (3.6 W/kg group) were differentially expressed. GO analysis revealed that these differentially expressed genes were primarily involved in metabolic processes, cellular metabolic processes, regulation of biological processes, macromolecular metabolic processes, biosynthetic processes, cellular protein metabolic processes, transport, developmental processes, cellular component organization, etc. KEGG pathway analysis showed that these genes are mainly involved in pathways related to ribosome, Alzheimer's disease, Parkinson's disease, long-term potentiation, Huntington's disease, and Neurotrophin signaling. Construction of a protein interaction network identified several important regulatory genes including synbindin (sbdn), Crystallin (CryaB), PPP1CA, Ywhaq, Psap, Psmb1, Pcbp2, etc., which play important roles in the processes of learning and memorye. Long-term, low-level microwave exposure may inhibit learning and memory by affecting protein and energy metabolic processes and signaling pathways relating to neurological functions or diseases.


Creating Value through Incremental Innovation: Managing Culture, Structure, and Process.
While the looming threat of large-scale disruptive innovation consumes disproportionate attention, incremental innovation remains an important tool for preserving and growing radiology practices within a dynamic marketplace. Incremental innovation, defined as the process of making improvements or additions to an organization while maintaining the organization's core product or service model, is accessible to practices of all sizes and must not be overlooked if practices are to maintain their competitive advantage. This article explores cultural, structural, and process enablers for incremental innovation. Successful innovation cultures foster the ability to import and exploit external knowledge (adaptive capacity), encourage creative thought from all levels of the organization, display sensitivity toward the competency-destroying potential of certain changes, cultivate a positive perceptual bias toward organizational threats, and build tolerance for risk and uncertainty when prototyping new ideas. Structural elements promoting incremental innovation include dedicated resources for innovation planning, flexible and organic team structures, strong centralized governance models, robust communication systems, and organizational incentives encouraging exploration of new concepts. Processes important to innovation include periodic environmental scanning, strategic and scenario planning, use of an objectively gated system for testing and filtering new ideas, and use of an approach to implementation that emphasizes empowerment of project managers, removal of barriers, and proactive communication around change.


Opinion on the ethical aspects of health care of patients at the end of life.
Demographic evolution and scientific progress in the treatment of fatal diseases have brought about a large number of disabled old persons and of greatly dependent persons. Nowadays, the dying process of people in such conditions is slower, though irreversible, and it has created a new form of medical care known as palliative medicine. Seven situations of this kind are discussed, with the corresponding ethical appraisal of the possible medical decisions in each case. The opinion on this matter by the Portuguese National Council of Ethics for the Life Sciences, based on the initial report, is then reproduced. It is against euthanasia strictu sensu being legalised and no longer a criminal offence, recommending however the development of all forms of palliative medicine.


Construction and application of a protein interaction map for white spot syndrome virus (WSSV).
White spot syndrome virus (WSSV) is currently the most serious global threat for cultured shrimp production. Although its large, double-stranded DNA genome has been completely characterized, most putative protein functions remain obscure. To provide more informative knowledge about this virus, a proteomic-scale network of WSSV-WSSV protein interactions was carried out using a comprehensive yeast two-hybrid analysis. An array of yeast transformants containing each WSSV open reading frame fused with GAL4 DNA binding domain and GAL4 activation domain was constructed yielding 187 bait and 182 prey constructs, respectively. On screening of ∼28,000 pairwise combinations, 710 interactions were obtained from 143 baits. An independent coimmunoprecipitation assay (co-IP) was performed to validate the selected protein interaction pairs identified from the yeast two-hybrid approach. The program Cytoscape was employed to create a WSSV protein-protein interaction (PPI) network. The topology of the WSSV PPI network was based on the Barabási-Albert model and consisted of a scale-free network that resembled other established viral protein interaction networks. Using the RNA interference approach, knocking down either of two candidate hub proteins gave shrimp more protection against WSSV than knocking down a nonhub gene. The WSSV protein interaction map established in this study provides novel guidance for further studies on shrimp viral pathogenesis, host-viral protein interaction and potential targets for therapeutic and preventative antiviral strategies in shrimp aquaculture.


Health-related quality of life in systemic lupus erythematosus and its association with disease and work disability.
To determine the health-related quality of life (HRQOL) and its relationship to disease variables, vertebral fractures, and employment status in female patients with systemic lupus erythematosus (SLE). HRQOL was assessed with the Swedish version of the Medical Outcomes Study (MOS) 36-Item Short Form Survey (SF-36) in female patients (n=163) and in age- and sex-matched controls (n=1045). Associations between the SF-36 score and demographics, disease variables, prevalent vertebral fractures, and employment status were analysed. The SLE patients, aged 20 to 82 years, scored significantly lower than the controls on all SF-36 subscales. Patients with vertebral fractures were older, had greater disease damage, and lower physical functioning (PF) than patients without fractures. Of the SLE patients of working age (n=142), 54% worked full or part time. These patients scored their HRQOL significantly higher (better) than patients not working. Being able to work was significantly associated with low age and high scores in PF and role physical (RP): the area under the receiver operating characteristic (ROC) curve for these variables was 0.82, confidence interval 0.75-0.89. HRQOL is substantially lower in SLE than in the general population but working ability indicates better health. We encourage further research regarding the effects on HRQOL by preventive actions taken against work disability in SLE.


Regulation of blood flow by aspirin following muscle ischemia.
The vascular endothelium secretes a balance of dilator and constrictor substances which regulate vascular tone. During ischemic stress, this balance changes. After a short period of ischemia, a protective mechanism known as reactive hyperemia (RH) contributes to a post-ischemic increase in blood flow. The agents regulating this phenomenon remain controversial. The purpose of this study was to examine whether aspirin regulates vascular endothelial function following ischemia. Sixteen healthy volunteers presented for two visits, each serving as their own control, and randomized to receive 500 mg aspirin or placebo. Forearm blood flow (FBF) was measured at baseline and during reactive hyperemia (RH) which was induced by five minutes of arterial occlusion. Blood samples were analyzed for vWF and lipids. After ischemia, RH was attenuated when subjects were pre-medicated with 500 mg aspirin compared to placebo: AUC[aspirin] = 1450 +/- 201 mL/100 mL tissue/min vs. AUC[pIacebo] = 2207 +/- 294 mL/100 mL tissue/min; (p < 0.05). Separation of the subjects with high HDL or low HDL levels resulted in a similar peak FBF response with placebo, but in the high-HDL group only, aspirin ingestion attenuated peak FBF after ischemia compared to the placebo condition (22.6 +/- 1.7 m/100 mL tissue/min vs. 33.5 +/- 3.2 mL/100 mL tissue/min, respectively) (p < 0.05). Aspirin partially regulates the RH response following ischemia compared to placebo, and this effect appears to be more profound when adjusting for plasma HDL concentration in healthy individuals. This suggests that the post-ischemic RH response may be partially mediated by arachidonic acid-derived mediators such as the prostaglandins.


Neuroglobin and cytoglobin expression in the human brain.
Neuroglobin and cytoglobin are new members of the heme-globin family. Both globins are primarily expressed in neurons of the brain and retina. Neuroglobin and cytoglobin have been suggested as novel therapeutic targets in various neurodegenerative diseases based on their oxygen binding and cell protecting properties. However, findings in Neuroglobin-deficient mice question the endogenous neuroprotective properties. The expression pattern of neuroglobin and cytoglobin in the rodent brain is also in contradiction to a major role of neuronal protection. In a recent study, neuroglobin was ubiquitously expressed and up-regulated following stroke in the human brain. The present study aimed at confirming our previous observations in rodents using two post-mortem human brains. The anatomical localization of neuroglobin and cytoglobin in the human brain is much like what has been described for the rodent brain. Neuroglobin is highly expressed in the hypothalamus, amygdale and in the pontine tegmental nuclei, but not in the hippocampus. Cytoglobin is highly expressed in the habenula, hypothalamus, thalamus, hippocampus and the pontine tegmental nuclei. We only detected a low expression of neuroglobin and cytoglobin in the cerebral cortex, while no expression in the cerebellar cortex was detectable. We provide a neuroanatomical indication for a different role of neuroglobin and cytoglobin in the human brain.


SIV Infection of Lung Macrophages.
HIV-1 depletes CD4+ T cells in the blood, lymphatic tissues, gut and lungs. Here we investigated the relationship between depletion and infection of CD4+ T cells in the lung parenchyma. The lungs of 38 Indian rhesus macaques in early to later stages of SIVmac251 infection were examined, and the numbers of CD4+ T cells and macrophages plus the frequency of SIV RNA+ cells were quantified. We showed that SIV infected macrophages in the lung parenchyma, but only in small numbers except in the setting of interstitial inflammation where large numbers of SIV RNA+ macrophages were detected. However, even in this setting, the number of macrophages was not decreased. By contrast, there were few infected CD4+ T cells in lung parenchyma, but CD4+ T cells were nonetheless depleted by unknown mechanisms. The CD4+ T cells in lung parenchyma were depleted even though they were not productively infected, whereas SIV can infect large numbers of macrophages in the setting of interstitial inflammation without depleting them. These observations point to the need for future investigations into mechanisms of CD4+ T cell depletion at this mucosal site, and into mechanisms by which macrophage populations are maintained despite high levels of infection. The large numbers of SIV RNA+ macrophages in lungs in the setting of interstitial inflammation indicates that lung macrophages can be an important source for SIV persistent infection.


Intermediate Progenitors Facilitate Intracortical Progression of Thalamocortical Axons and Interneurons through CXCL12 Chemokine Signaling.
Glutamatergic principal neurons, GABAergic interneurons and thalamocortical axons (TCAs) are essential elements of the cerebrocortical network. Principal neurons originate locally from radial glia and intermediate progenitors (IPCs), whereas interneurons and TCAs are of extrinsic origin. Little is known how the assembly of these elements is coordinated. C-X-C motif chemokine 12 (CXCL12), which is known to guide axons outside the neural tube and interneurons in the cortex, is expressed in the meninges and IPCs. Using mouse genetics, we dissected the influence of IPC-derived CXCL12 on TCAs and interneurons by showing that Cxcl12 ablation in IPCs, leaving meningeal Cxcl12 intact, attenuates intracortical TCA growth and disrupts tangential interneuron migration in the subventricular zone. In accordance with strong CXCR4 expression in the forming thalamus and TCAs, we identified a CXCR4-dependent growth-promoting effect of CXCL12 on TCAs in thalamus explants. Together, our findings indicate a cell-autonomous role of CXCR4 in promoting TCA growth. We propose that CXCL12 signals from IPCs link cortical neurogenesis to the progression of TCAs and interneurons spatially and temporally. Significance statement: The cerebral cortex exerts higher brain functions including perceptual and emotional processing. Evolutionary expansion of the mammalian cortex is mediated by intermediate progenitors, transient amplifying cells generating cortical excitatory neurons. During the peak period of cortical neurogenesis, migrating precursors of inhibitory interneurons originating in subcortical areas and thalamic axons invade the cortex. Although defects in the assembly of cortical network elements cause neurological and mental disorders, little is known how neurogenesis, interneuron recruitment, and axonal ingrowth are coordinated. We demonstrate that intermediate progenitors release the chemotactic cytokine CXCL12 to promote intracortical interneuron migration and growth of thalamic axons via the cognate receptor CXCR4. This paracrine signal may ensure thalamocortical connectivity and dispersion of inhibitory neurons in the rapidly growing cortex.


Junctions between lens fiber cells are labeled with a monoclonal antibody shown to be specific for MP26.
A monoclonal antibody (mcAb) that recognizes an intracellular domain of the major lens membrane protein in both chicken and bovine lenses is described. Mice were immunized with chicken lens fiber cell membranes that had been washed with 7 M urea. Hybridomas were screened by means of enzyme-linked immunosorbent assays and the molecular specificities of the mcAbs were determined using electrophoretic transfer procedures, "Westerns." One of these mcAbs, an IgG designated B2, reacted with a single band of 28,000 Mr from the chicken embryo lens (MP28) and the analogous 26,000 Mr protein in the bovine lens (MP26). Monoclonal B2 was shown to be specific for these proteins, since (a) heating in SDS caused MP26 to aggregate and reduced B2 binding to the protein band at an Mr of 26,000 in Western transfer analysis; (b) apparent dimers were bound by B2 in Western transfers; (c) soluble protein fractions from the lens contained no detectable B2 antigens; and (d) a cyanogen bromide fragment of MP26 was bound by B2. Studies with several proteases indicated that the antigenic site for B2 resides on a 2-kd, protease-sensitive region at the C-terminal end of MP26 and MP28. Evidence for B2 binding on the cytoplasmic side of the membrane comes from labeling studies done at the ultrastructural level. These studies, utilizing indirect methods with peroxidase and colloidal gold markers, clearly demonstrated that B2 labels two types of junctional profiles. In our calf lens membrane preparations after tannic acid staining, the predominant type (80%) measured 16-18 nn thick, with the second type measuring only 12-14 nm. Chick embryo lens cells that had differentiated in vitro and formed groups of lens fiber-like cells (termed lentoids), fluoresced brightly only when they had been permeabilized before labeling with B2 and a fluorochrome-conjugated antibody. This binding was concentrated at the plasma membranes of cells within the lentoids, even outside areas of cell-cell contact. Surrounding epithelioid cells were not stained. Solubilized lens cultures, examined by Westerns, displayed a single immunoreactive band, which co-migrated with MP28.


Lack of behavioral effects in the rhesus monkey: high peak microwave pulses at 1.3 GHz.
The current safety standards for radiofrequency and microwave exposure do not limit the peak power of microwave pulses for general or occupational exposures. While some biological effects, primarily the auditory effect, depend on pulsed microwaves, hazards associated with very high peak-power microwave pulses in the absence of whole-body heating are unknown. Five rhesus monkeys, Macaca mulatta, were exposed to peak-power densities of 131.8 W/cm2 (RMS) while performing a time-related behavioral task. The task was composed of a multiple schedule of reinforcement consisting of three distinct behavioral components: inter-response time, time discrimination, and fixed interval. Trained monkeys performed the multiple schedule during exposure to 1.3-GHz pulses at low pulse-repetition rates (2-32 Hz). No significant change was observed in any behavior during irradiation as compared to sham-irradiation sessions. Generalization of these findings to experimental results with higher peak-power densities, other pulse rates, different carrier frequencies, or other behaviors is limited.


Trends in the discovery of new marine natural products from invertebrates over the last two decades--where and what are we bioprospecting?
It is acknowledged that marine invertebrates produce bioactive natural products that may be useful for developing new drugs. By exploring untapped geographical sources and/or novel groups of organisms one can maximize the search for new marine drugs to treat human diseases. The goal of this paper is to analyse the trends associated with the discovery of new marine natural products from invertebrates (NMNPI) over the last two decades. The analysis considers different taxonomical levels and geographical approaches of bioprospected species. Additionally, this research is also directed to provide new insights into less bioprospected taxa and world regions. In order to gather the information available on NMNPI, the yearly-published reviews of Marine Natural Products covering 1990-2009 were surveyed. Information on source organisms, specifically taxonomical information and collection sites, was assembled together with additional geographical information collected from the articles originally describing the new natural product. Almost 10000 NMNPI were discovered since 1990, with a pronounced increase between decades. Porifera and Cnidaria were the two dominant sources of NMNPI worldwide. The exception was polar regions where Echinodermata dominated. The majority of species that yielded the new natural products belong to only one class of each Porifera and Cnidaria phyla (Demospongiae and Anthozoa, respectively). Increased bioprospecting efforts were observed in the Pacific Ocean, particularly in Asian countries that are associated with the Japan Biodiversity Hotspot and the Kuroshio Current. Although results show comparably less NMNPI from polar regions, the number of new natural products per species is similar to that recorded for other regions. The present study provides information to future bioprospecting efforts addressing previously unexplored taxonomic groups and/or regions. We also highlight how marine invertebrates, which in some cases have no commercial value, may become highly valuable in the ongoing search for new drugs from the sea.


Prenatal exposure to polychlorinated biphenyls: a neuropsychologic analysis.
A large body of literature documents the effects of prenatal exposure to polychlorinated biphenyls (PCBs) on cognitive development of children. Despite this fact, no integrative synthesis has been published yet to identify the cognitive functions that are particularly affected. Our aim is to review this literature in an attempt to identify the cognitive profile associated with prenatal PCB exposure. Studies were identified by searching the PubMed database for articles published before June 2008. We reviewed data from nine prospective longitudinal birth cohorts for different aspects of cognition. Associations between indicators of prenatal PCB exposure and performance on cognitive tasks reported in the selected studies are summarized and classified as general cognitive abilities, verbal or visual-spatial skills, memory, attention, and executive functions. The most consistent effects observed across studies are impaired executive functioning related to increased prenatal PCB exposure. Negative effects on processing speed, verbal abilities, and visual recognition memory are also reported by most studies. Converging results from different cohort studies in which exposure arises from different sources make it unlikely that co-exposure with another associated contaminant is responsible for the observed effects. Prenatal PCB exposure appears to be related to a relatively specific cognitive profile of impairments. Failure to assess functions that are specifically impaired may explain the absence of effects found in some studies. Our findings have implications in the selection of cognitive assessment methods in future studies.


Integrin α7 Is a Functional Marker and Potential Therapeutic Target in Glioblastoma.
Functionally relevant markers of glioblastoma stem-like cells (GSCs) have potential for therapeutic targeting to treat this aggressive disease. Here we used generation and screening of thousands of monoclonal antibodies to search for receptors and signaling pathways preferentially enriched in GSCs. We identified integrin α7 (ITGA7) as a major laminin receptor in GSCs and in primary high-grade glioma specimens. Analyses of mRNA profiles in comprehensive datasets revealed that high ITGA7 expression negatively correlated with survival of patients with both low- and high-grade glioma. In vitro and in vivo analyses showed that ITGA7 plays a key functional role in growth and invasiveness of GSCs. We also found that targeting of ITGA7 by RNAi or blocking mAbs impaired laminin-induced signaling, and it led to a significant delay in tumor engraftment plus a strong reduction in tumor size and invasion. Our data, therefore, highlight ITGA7 as a glioblastoma biomarker and candidate therapeutic target.


Comparison of three cholesterol-lowering diets in normolipidemic men.
Saturated fatty acids and cholesterol in the diet raise the plasma cholesterol concentration, and a reduction in these constituents is recommended widely. However, there is not general agreement as to which nutrients should replace saturated fatty acids. Several different substitute nutrients are possible. In this study, three cholesterol-lowering diets were compared in nine men living in a domiciliary. On a typical American diet at baseline, cholesterol levels were in the normal range. One replacement diet was high in polyunsaturated fatty acids (High Poly); another had 30% fat and corresponded to the American Heart Association's (AHA) recommended diet for the general public (AHA phase I); the third diet had 20% fat, equivalent to the AHA phase III diet for treatment of hypercholesterolemia. Compared with baseline levels, all diets caused similar reductions in total cholesterol and low-density lipoprotein cholesterol levels, but the High Poly and AHA phase III diets lowered the high-density lipoprotein cholesterol level more than the AHA phase I diet. Thus, for the limited number of patients in this study, the diet recommended for the general public appeared as effective for lowering of cholesterol levels as diets containing more polyunsaturates or more carbohydrates.


Hidden Parameter Markov Decision Processes: A Semiparametric Regression Approach for Discovering Latent Task Parametrizations.
Control applications often feature tasks with similar, but not identical, dynamics. We introduce the Hidden Parameter Markov Decision Process (HiP-MDP), a framework that parametrizes a family of related dynamical systems with a low-dimensional set of latent factors, and introduce a semiparametric regression approach for learning its structure from data. We show that a learned HiP-MDP rapidly identifies the dynamics of new task instances in several settings, flexibly adapting to task variation.


Association of POAG risk factors and the Thr377Met MYOC mutation in an isolated Greek population.
To characterize the MYOC genotype correlation with phenotypes in an isolated Greek population with a high incidence of glaucoma. Five hundred thirty-one villagers were enrolled in the study. Participants underwent a comprehensive ophthalmic examination. All three exons of myocilin were bidirectionally sequenced. Power calculations and measured genotype analysis was conducted using the genetic variance analysis program, SOLAR version 4.2, to account for the relatedness between individuals. The participants, 376 of whom were linked in a single 11-generation pedigree, ranged in age from 10 to 95 years with a mean age of 49. Sixty-five individuals had POAG, and 27 of those carried the Thr377Met MYOC mutation. Both peak intraocular pressure and vertical cup-to dis- ratio were significantly associated with the MYOC Thr377Met variant (P = 9 x 10(-14) and P = 9 x 10(-8), respectively), whereas central corneal thickness showed no significant association (P < 0.7). This village had a high frequency of glaucoma, with 12% of the participants aged 10 to 95 years having the disease. In this cohort, the Thr377Met MYOC mutation was significantly associated with both high intraocular pressures and high vertical cup-to-disc ratios. No association was found with central corneal thickness.


Efficacy and tolerability of oxymorphone immediate release for acute postoperative pain after abdominal surgery: a randomized, double-blind, active- and placebo-controlled, parallel-group trial.
Patients are typically switched from parenteral opioids to oral opioids during the 24 to 48 hours after surgery. In June 2006, an oral immediate-release (IR) tablet formulation of oxymorphone was approved for the treatment of acute moderate to severe pain. Single doses of oxymorphone IR have been reported to provide significant pain relief after orthopedic surgery. This study assessed the efficacy and tolerability of multiple fixed doses of oxymorphone IR in the treatment of acute postoperative pain after abdominal surgery. This was a multicenter, randomized, double-blind, active- and placebo-controlled, parallel-group study in men and women aged >or=18 years undergoing abdominal surgery that required a >or=3-cm incision. Patients who discontinued short-acting parenteral opioids and developed moderate or severe pain (4-point categorical scale [none, mild, moderate, or severe] and pain intensity >or=50 mm on a 100-mm visual analog scale [from 0 = no pain to 100 = worst pain imaginable]) within 30 hours after abdominal surgery were randomized to receive oxymorphone IR 10 or 20 mg, oxycodone IR 15 mg, or placebo every 4 to 6 hours after the previous dose. The study included 2 efficacy assessments: a single-dose evaluation for up to 6 hours after the dose, and a multipledose evaluation for up to 48 hours after the first dose. Pain was assessed at 15-minute intervals during the hour after the first dose, hourly thereafter for the next 5 hours, and before each subsequent dose. The primary efficacy end point was the median time to study discontinuation for all causes. Assessment of tolerability was based on the proportion of study discontinuations due to treatment-emergent adverse events (AEs). Three hundred thirty-one patients were included in the study. Demographic characteristics were similar across all groups: 98.8% (327) of patients were women, and 80.1% (265) of the abdominal surgeries were hysterectomies. The mean (SD) age of the study population was 42.6 (9.3) years. The median time to study discontinuation for all causes was significantly longer for all active treatments compared with placebo (oxymorphone IR 10 mg, 17.9 hours; oxymorphone IR 20 mg, 20.3 hours; oxycodone IR 15 mg, 24.1 hours; placebo, 4.8 hours; P < 0.006). Oxymorphone IR 20 mg was significantly more effective than placebo over the 6-hour single-dose evaluation (P < 0.05). With multiple dosing, all active-treatment groups had significantly lower least squares mean current and average pain intensities compared with placebo (P < 0.004 and P < 0.005, respectively). The least squares means of the average pain intensity were significantly lower among patients treated with oxymorphone IR 10 mg, oxymorphone IR 20 mg, or oxycodone IR 15 mg compared with those who received placebo (39.7, 35.2, 39.8, and 50.1, respectively; P < 0.005). Discontinuations due to treatment-emergent AEs did not differ significantly between groups: 8.5% (7/82), 17.3% (14/81), 13.3% (11/83), and 12.9% (11/85) in the oxymorphone IR 10-mg, oxymorphone IR 20-mg, oxycodone IR 15-mg, and placebo groups, respectively. The proportions of patients reporting at least 1 treatment-emergent AE were 46.3% (38/82), 51.9% (42/81), and 54.2% (45/83) in the oxymorphone IR 10-mg, oxymorphone IR 20-mg, and oxycodone IR 15-mg groups, respectively, compared with 34.1% (29/85) in the placebo group (P = NS). The fixed-dose design was a study limitation, as it did not allow titration to effect and thus did not mirror clinical practice. In this predominantly female population undergoing abdominal surgery, oxymorphone IR given every 4 to 6 hours for up to 48 hours provided efficacious and tolerable analgesia for moderate to severe pain.


Knowledge, Attitude, Behavior, and Practices Regarding HIV, Viral Hepatitis, and Sexually Transmitted Infections Among Migrants From Sub-Saharan Africa Living in Germany: A Multicenter Survey Protocol.
Migration has an impact on the epidemiology of viral hepatitis B and C (HEP) and HIV in Germany; migrants from sub-Saharan Africa (MisSA) in Germany are disproportionally affected by HIV. In the last 10 years, a total of 10%-15% of all newly diagnosed HIV cases were among MisSA; 20%-30% of them acquired HIV in Germany. Prevalence of HEP among MisSA in Germany is unknown, but Western Africa, from where most MisSA in Germany originate, reports the highest prevalence of hepatitis B worldwide. There is limited information on knowledge, attitudes, behaviors, and practices (KABP) regarding HIV, HEP, and sexually transmitted infections (STIs), as MisSA are not reached with surveys targeting the general population. Our objective was to determine the HIV, HEP, and STI information and prevention needs of MisSA in Germany. We conducted a multicenter, cross-sectional, KABP survey regarding HIV, HEP, and STIs among MisSA living in Germany using convenience sampling. The study design was developed as a community-based participatory health research (CBPHR) project; HIV/STI-prevention specialists, key persons from MisSA communities, and HIV/STI researchers were involved in all steps of the research process. Trained peer researchers recruited participants in six study cities. Potential modes of survey administration were interview or self-completion, and the questionnaire was available in English, French, and German. Questions on knowledge about HIV, HEP, and STIs were presented as true statements; participants were asked if they had known the information before. Focus groups with MisSA were conducted to interpret results. Data collection took place from October 2014 to November 2016. Recruitment by peer researchers concluded with 3040 eligible participants. Data collection was completed in November 2016. We are currently analyzing the quantitative data and qualitative data from focus groups. We are conducting working group meetings to discuss the results in the respective study cities and to evaluate the application of participatory health research in epidemiological studies. First results are expected by the end of 2017. Working with peer researchers to collect data allowed accessibility to a diverse sample of MisSA and, particularly, allowed us to reach vulnerable subgroups, such as MisSA without legal status. The ability to access hard-to-reach groups is one of the big advantages of CBPHR. The active inclusion of the persons under study in the design of the study resulted in higher acceptance and ownership of the research project in the target community; this ultimately lead to better quality of collected data. Furthermore, the participation of MisSA in the development of study design and data collection assures a better understanding of the interests, needs, and living conditions of this group.


Clinical features of neuromyelitis optica in children: US Network of Pediatric MS Centers report.
To compare clinical features of pediatric neuromyelitis optica (NMO) to other pediatric demyelinating diseases. Review of a prospective multicenter database on children with demyelinating diseases. Case summaries documenting clinical and laboratory features were reviewed by an adjudication panel. Diagnoses were assigned in the following categories: multiple sclerosis (MS), acute disseminated encephalomyelitis, NMO, and recurrent demyelinating disease not otherwise specified. Thirty-eight cases of NMO were identified by review panel, 97% of which met the revised International Panel on NMO Diagnosis NMO-SD 2014 criteria, but only 49% met 2006 Wingerchuk criteria. Serum or CSF NMO immunoglobulin G (IgG) was positive in 65% of NMO cases that were tested; however, some patients became seropositive more than 3 years after onset despite serial testing. No patient had positive CSF NMO IgG and negative serum NMO IgG in contemporaneous samples. Other than race (p = 0.02) and borderline findings for sex (p = 0.07), NMO IgG seropositive patients did not differ in demographic, clinical, or laboratory features from seronegatives. Visual, motor, and constitutional symptoms (including vomiting, fever, and seizures) were the most common presenting features of NMO. Initiation of disease-modifying treatment was delayed in NMO vs MS. Two years after onset, patients with NMO had higher attack rates, greater disability accrual measured by overall Expanded Disability Status Scale score, and visual scores than did patients with MS. The new criteria for NMO spectrum disorders apply well to the pediatric setting, and given significant delay in treatment of NMO compared to pediatric MS and worse short-term outcomes, it is imperative to apply these to improve access to treatment.


Vitamin K-dependent proteins GAS6 and Protein S and TAM receptors in patients of systemic lupus erythematosus: correlation with common genetic variants and disease activity.
Growth arrest-specific gene 6 protein (GAS6) and protein S (ProS) are vitamin K-dependent proteins present in plasma with important regulatory functions in systems of response and repair to damage. They interact with receptor tyrosine kinases of the Tyro3, Axl and MerTK receptor tyrosine kinase (TAM) family, involved in apoptotic cell clearance (efferocytosis) and regulation of the innate immunity. TAM-deficient mice show spontaneous lupus-like symptoms. Here we tested the genetic profile and plasma levels of components of the system in patients with systemic lupus erythematosus (SLE), and compare them with a control healthy population. Fifty SLE patients and 50 healthy controls with matched age, gender and from the same geographic area were compared. Genetic analysis was performed in GAS6 and the TAM receptor genes on SNPs previously identified. The concentrations of GAS6, total and free ProS, and the soluble forms of the three TAM receptors (sAxl, sMerTK and sTyro3) were measured in plasma from these samples. Plasma concentrations of GAS6 were higher and, total and free ProS were lower in the SLE patients compared to controls, even when patients on oral anticoagulant treatment were discarded. Those parameters correlated with SLE disease activity index (SLEDAI) score, GAS6 being higher in the most severe cases, while free and total ProS were lower. All 3 soluble receptors increased its concentration in plasma of lupus patients. The present study highlights that the GAS6/ProS-TAM system correlates in several ways with disease activity in SLE. We show here that this correlation is affected by common polymorphisms in the genes of the system. These findings underscore the importance of mechanism of regulatory control of innate immunity in the pathology of SLE.


Life with oxygen.
The survival of all metazoan organisms is dependent on the regulation of O2 delivery and utilization to maintain a balance between the generation of energy and production of potentially toxic oxidants. Hypoxia-inducible factor 1 (HIF-1) is a transcription factor that functions as a master regulator of oxygen homeostasis and has essential roles in metazoan development, physiology, and disease pathogenesis. Remarkable progress has been made in delineating the molecular mechanisms whereby changes in cellular oxygenation are transduced to the nucleus as changes in gene transcription through the activity of HIF-1. Pharmacologic agents that activate or inhibit the hypoxia signal transduction pathway may be useful therapies for ischemic and neoplastic disorders, respectively, which are the major causes of mortality in industrialized societies.


Group-based Cognitive Behavioural Therapy for Anxiety Disorder in Children with Autism Spectrum Disorder: a feasibility study.
Purpose: Autism spectrum disorder (ASD) includes core symptoms that affect general and social development. High risk of developing comorbid disorders such as anxiety is prominent. Up to 60% of children with ASD suffer from anxiety disorders which can negatively influence educational, social and general development together with quality of life. This study is the first to investigate the feasibility of the manualised cognitive behavioural therapy (CBT) group programme 'Cool Kids ASD' for anxiety adapted for children with ASD in a general hospital setting. Methods: Nine children, aged 9-13 years, with ASD and anxiety recruited from a public child psychiatric health clinic were enrolled in the study. Outcome measures were collected from both child and parent pre- and post-treatment and at 3-month follow-up and included scores from a semi-structured anxiety interview, together with questionnaires on anxiety symptoms, life interference, children's automatic thoughts and satisfaction with the programme. Results: Eight out of nine families found the programme useful and would recommend it to other families in a similar situation. Six families attended all 12 sessions in the programme, two missed one session and one family only managed to attend eight sessions. At follow-up, five children were free of all anxiety diagnoses and a further two out of the nine children no longer met the criteria for their primary anxiety diagnosis. Conclusions: This study suggests that the transition of the group programme 'Cool Kids ASD' from University Clinics to standard child psychiatric clinical settings is feasible. Further randomised studies are needed to confirm the efficacy of the programme in a larger sample.


Global differences in vitamin D status and dietary intake: a review of the data.
Internationally, concern has been repeatedly raised about the little notable progress in the collection, analysis and use of population micronutrient status and deficiency data globally. The need for representative status and intake data for vitamin D has been highlighted as a research priority for well over a decade. A narrative review which aims to provide a summary and assessment of vitamin D nutritional status data globally. This review divides the world into the Food and Agriculture Organisation's (FAO) major regions: the Americas, Europe, Oceania, Africa and Asia. Emphasis was placed on published data on the prevalence of serum 25-hydroxyvitamin D (25(OH)D) < 25/30 and <50 nmol/L (reflecting vitamin D deficiency and inadequacy, respectively) as well as vitamin D intake, where possible from nationally representative surveys. Collating data from the limited number of available representative surveys from individual countries might suggest a relatively low overall prevalence of vitamin D deficiency in South America, Oceania and North America, whereas there is more moderate prevalence in Europe and Asia, and possibly Africa. Overall, the prevalence of serum 25(OH)D < 25/30 and <50 nmol/L ranges from ~5 to 18% and 24 to 49%, respectively, depending on FAO world region. Usual intakes of vitamin D can also vary by FAO world region, but in general, with a few exceptions, there are very high levels of inadequacy of vitamin D intake. While the burden of vitamin D deficiency and inadequacy varies by world regions and not just by UVB availability, the global burden overall translates into enormous numbers of individuals at risk.


Hydroxysafflor yellow A inhibits IL-1β-induced release of IL-6, IL-8, and MMP-1 via suppression of ERK, NF-κB and AP-1 signaling in SW982 human synovial cells.
Hydroxysafflor yellow A (HSYA), the main active ingredient in medical and edible dual purpose plant safflower, is reported to have multiple bioactivities. In the present study, the anti-inflammatory effects of HSYA and the underlying mechanisms were investigated in interleukin (IL)-1β-induced SW982 human synovial cells. The cells were pretreated with HSYA at various concentrations (2.5, 10 and 40 μM) followed by IL-1β (10 ng mL-1) stimulation. HSYA significantly inhibited the expression of IL-6, IL-8 and matrix metalloproteinase (MMP)-1 in IL-1β-stimulated SW982 cells. HSYA also inhibited the phosphorylation of extracellular signal-regulated kinase (ERK), p65 and c-Jun. It also suppressed the degradation of IκBα and blocked p65 translocation into the nucleus. These results indicate that the inhibitory effects of HSYA on IL-1β-induced IL-6, IL-8 and MMP-1 release might be mediated via suppression of ERK, nuclear factor-κB (NF-κB) and activator protein-1 (AP-1) signaling pathways. The present data support the potential role of HSYA as an effective therapeutic agent in osteoarthritis.


Fanconi anaemia, BRCA2 mutations and childhood cancer: a developmental perspective from clinical and epidemiological observations with implications for genetic counselling.
Fanconi anaemia (FA) is an inherited condition characterised by congenital and developmental abnormalities and a strong cancer predisposition. In around 3-5% of cases FA is caused by biallelic mutations in the BRCA2 gene. Individuals heterozygous for BRCA2 mutations have an increased risk of inherited breast and ovarian cancer. We reviewed the mutation spectrum in BRCA2-associated FA, and the spectrum and frequency of BRCA2 mutations in distinct populations. The rarity of FA due to biallelic BRCA2 mutations supports a fundamental role of BRCA2 for prevention of malignant transformation during development. The spectrum of malignancies seen associated with FA support the concept of a tissue selectivity of BRCA2 mutations for development of FA-associated cancers. This specificity is illustrated by the distinct FA-associated BRCA2 mutations that appear to predispose to specific brain or haematological malignancies. For some populations, the number of FA-patients with biallelic BRCA2 disruption is smaller than that expected from the carrier frequency, and this implies that some pregnancies with biallelic BRCA2 mutations do not go to term. The apparent discrepancy between expected and observed incidence of BRCA2 mutation-associated FA in high-frequency carrier populations has important implications for the genetic counselling of couples with recurrent miscarriages from high-risk populations.


The non-vital discolored central incisor dilemma.
The restoration of anterior teeth is frequently a demanding mission. Patients generally have high expectations for the anterior region, which makes the emotional side of treatment especially important. When this involves discolored endodontically treated teeth, consensus can hardly ever be found as to the chosen approach. Bleaching with direct composites is undoubtedly the most conservative choice for these cases. However, this may require more maintenance (touch-up bleaching and repairs) in the long term, which is an important issue for adult patients. On the other hand, bonded porcelain veneers represent a more 'high-end' option, as they recover the original biomechanics of the intact tooth, allow an optimal masking of the substrate, remain stable, and have a reasonable biological cost when compared to full-coverage crowns. This strategy is explained in this article and documented with a clinical case. We describe treatment planning based on the biomimetic concept, taking into consideration what is possible with current materials and techniques when combined with the patient's particular needs, including the introduction of an innovative step during dentin sealing--the microsuction. The laboratory work was totally accomplished by 'teledentistry', with no direct contact between the dental technologist and the patient.


Cardioembolic stroke in primary oxalosis with cardiac involvement.
Primary oxalosis is a rare disorder of oxalate metabolism, characterized by nephrocalcinosis, nephrolithiasis, and extrarenal deposition of calcium oxalate in several tissues, including the heart. We report the case of a 34-year-old man with sudden right hemiparesis and aphasia from the occlusion of the left middle cerebral artery. Clinical features and the results of laboratory investigations led to the diagnosis of primary oxalosis. Two-dimensional echocardiography disclosed the presence of massive intracardiac calcifications compatible with deposition of calcium oxalate. The absence of other causes of stroke strengthened a cause-and-effect relation between cardiac oxalosis and cerebral infarction. Consequently, cardiac oxalosis should be considered among possible occult cardiac sources of cerebral embolism.


The antimalarial potential of 4-quinolinecarbinolamines may be limited due to neurotoxicity and cross-resistance in mefloquine-resistant Plasmodium falciparum strains.
The clinical potential of mefloquine has been compromised by reports of adverse neurological effects. A series of 4-quinolinecarbinolamines were compared in terms of neurotoxicity and antimalarial activity in an attempt to identify replacement drugs. Neurotoxicity (MTT [thiazolyl blue reduction] assay) was assessed by exposure of cultured embryonic rat neurons to graded concentrations of the drugs for 20 min. The 50% inhibitory concentration (IC(50)) of mefloquine was 25 microM, while those of the analogs were 19 to 200 microM. The relative (to mefloquine) therapeutic indices of the analogs were determined after using the tritiated hypoxanthine assay for assessment of the antimalarial activity of the analogs against mefloquine-sensitive (W2) and -resistant (D6 and TM91C235) Plasmodium falciparum strains. Five analogs, WR157801, WR073892, WR007930, WR007333, and WR226253, were less neurotoxic than mefloquine and exhibited higher relative therapeutic indices (RTIs) against TM91C235 (2.9 to 12.2). Conventional quinoline antimalarials were generally less neurotoxic (IC(50)s of 400, 600, and 900 for amodiaquine, chloroquine, and quinine) or had higher RTIs (e.g., 30 for halofantrine against TM91C235). The neurotoxicity data for the 4-quinolinecarbinolamines were used to develop a three-dimensional (3D), function-based pharmacophore. The crucial molecular features correlated with neurotoxicity were a hydrogen bond acceptor (lipid) function, an aliphatic hydrophobic function, and a ring aromatic function specifically distributed in the 3D surface of the molecule. Mapping of the 3D structures of a series of structurally diverse quinolines to the pharmacophore allowed accurate qualitative predictions of neurotoxicity (or not) to be made. Extension of this in silico screening approach may aid in the identification of less-neurotoxic quinoline analogs.


Refined crystal structures of native human angiogenin and two active site variants: implications for the unique functional properties of an enzyme involved in neovascularisation during tumour growth.
Human angiogenin (Ang), an unusual member of the pancreatic RNase superfamily, is a potent inducer of angiogenesis in vivo. Its ribonucleolytic activity is weak (10(4) to 10(6)-fold lower than that of bovine RNase A), but nonetheless seems to be essential for biological function. Ang has been implicated in the establishment of a wide range of human tumours and has therefore emerged as an important target for the design of new anti-cancer compounds. We report high-resolution crystal structures for native Ang in two different forms (Pyr1 at 1.8 A and Met-1 at 2.0 A resolution) and for two active-site variants, K40Q and H13A, at 2.0 A resolution. The native structures, together with earlier mutational and biochemical data, provide a basis for understanding the unique functional properties of this molecule. The major structural features that underlie the weakness of angiogenin's RNase activity include: (i) the obstruction of the pyrimidine-binding site by Gln117; (ii) the existence of a hydrogen bond between Thr44 and Thr80 that further suppresses the effectiveness of the pyrimidine site; (iii) the absence of a counterpart for the His119-Asp121 hydrogen bond that potentiates catalysis in RNase A (the corresponding aspartate in Ang, Asp116, has been recruited to stabilise the blockage of the pyrimidine site); and (iv) the absence of any precise structural counterparts for two important purine-binding residues of RNase A. Analysis of the native structures has revealed details of the cell-binding region and nuclear localisation signal of Ang that are critical for angiogenicity. The cell-binding site differs dramatically from the corresponding regions of RNase A and two other homologues, eosinophil-derived neurotoxin and onconase, all of which lack angiogenic activity. Determination of the structures of the catalytically inactive variants K40Q and H13A has now allowed a rigorous assessment of the relationship between the ribonucleolytic and biological activities of Ang. No significant change outside the enzymatic active site was observed in K40Q, establishing that the loss of angiogenic activity for this derivative is directly attributable to disruption of the catalytic apparatus. The H13A structure shows some changes beyond the ribonucleolytic site, but sites involved in cell-binding and nuclear translocation are essentially unaffected by the amino acid replacement.


Different methods for ethical analysis in health technology assessment: an empirical study.
Ethical analysis can highlight important ethical issues related to implementing a technology, values inherent in the technology itself, and value-decisions underlying the health technology assessment (HTA) process. Ethical analysis is a well-acknowledged part of HTA, yet seldom included in practice. One reason for this is lack of knowledge about the properties and differences between the methods available. This study compares different methods for ethical analysis within HTA. Ethical issues related to bariatric (obesity) surgery were independently evaluated using axiological, casuist, principlist, and EUnetHTA models for ethical analysis within HTA. The methods and results are presented and compared. Despite varying theoretical underpinnings and practical approaches, the four methods identified similar themes: personal responsibility, self-infliction, discrimination, justice, public funding, and stakeholder involvement. The axiological and EUnetHTA models identified a wider range of arguments, whereas casuistry and principlism concentrated more on analyzing a narrower set of arguments deemed more important. Different methods can be successfully used for conducting ethical analysis within HTA. Although our study does not show that different methods in ethics always produce similar results, it supports the view that different methods of ethics can yield relevantly similar results. This suggests that the key conclusions of ethical analyses within HTA can be transferable between methods and countries. The systematic and transparent use of some method of ethics appears more important than the choice of the exact method.